Fetal Medicine Insights For Clinicians

Fetal
Medicine
Insights for Clinicians
Chinmayee Ratha
Ashok Khurana
123
Fetal Medicine
Chinmayee Ratha • Ashok Khurana
Fetal Medicine
Insights for Clinicians
Chinmayee Ratha Ashok Khurana
Resolution Fetal Medicine Centre and The Ultrasound Lab
Research Institute New Delhi, India
Hyderabad, India
ISBN 978-981-19-6098-7 ISBN 978-981-19-6099-4 (eBook)

https://doi.org/10.1007/978-981-19-6099-4
© Springer Nature Singapore Pte Ltd. 2022

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Preface
Fetal medicine is the branch of clinical medicine dedicated to the health con-
ditions of the fetus in utero. This is a relatively new clinical specialty where
the focus of health care shifts toward the unborn fetus in a given pregnancy
and hence poses a unique challenge to Obstetricians who have been used to
considering only the pregnant lady, or “mother,” as their primary patient. Yet,
the final outcome of a pregnancy is deemed successful when both mother and
the baby/babies are safe and healthy. The importance of fetal health care has
now become evident with better understanding of the cause and effect of fetal
conditions. Many of these events remained obscure in the yesteryears when
there was neither the technology to visualize the fetus at different stages of
life nor the understanding of pathogenetic mechanisms of its problems. Today
it has become imperative to consider fetal outcomes as a parameter of perina-
tal health with such clarity that the fetus itself is treated as a separate patient
in a pregnancy. It has now been understood that every pregnancy merits
screening and managing fetal issues like risk of chromosomal aneuploidies,
structural abnormalities, and fetal growth problems. The complexity in the
Obstetric paradigm has also increased with a rise in the average maternal age,
environmental teratogens, ability of women with medical conditions to con-
ceive, and of course assisted reproduction in general. This creates a bigger
scope to investigate and detect fetal problems which need special attention. In
such times, clinicians need a thorough understanding of the remit of fetal
medicine. This book intends to provide such an understanding to every clini-
cian who will deal with fetal problems either directly or indirectly.
The fact that even preconceptional health of the parents can affect the
well-being of the fetus opens the scope of fetal medicine into almost every
clinical specialty. The authors hope that this book will help create a bridge of
understanding of fetal medicine which will empower clinicians to address yet
another patient who may be yet to be born or even conceived.
The style of this book is descriptive and clinically oriented to give readers
a ready perspective for practical, clinical application. References for further
reading have been provided for readers looking for in-depth theoretical infor-
mation. This book will serve as a foundation of understanding the concepts of
fetal medicine for students of obstetrics and gynecology, pediatrics, radiol-
ogy, and even internal medicine as this subspecialty is going to be an integral
part of their day-to-day practice. Other branches of clinical medicine will also
benefit from the simple language of description of fetal conditions because
v
vi Preface
every clinician today needs to be aware of potential fetal effects of the condi-
tions they are managing as well as the management modalities they are using.
There was a need for one comprehensive book which can form the base of
understanding of fetal medicine. This can be used as a textbook for founda-
tion years as well as a handbook for clinical practitioners. We wish the read-
ers a happy journey in the path of understanding fetal medicine.
Hyderabad, India Chinmayee Ratha

New Delhi, India Ashok Khurana
Contents
1 Introduction to Fetal Medicine �� 1

2
History Taking in the Fetal Medicine Clinic�� 5
2.1 At the First Antenatal Visit�� 5
3
Timeline of Fetal Evaluation in Normal Pregnancy �� 7
3.1 4–6 Weeks of Gestation�� 7
3.10 Beyond 40 Weeks of Gestation �� 10
4
Principles and Methods of Screening for Fetal Aneuploidies�� 13
4.1 What Is Screening? �� 13
4.2 The Concept of “Intermediate Risk”�� 15
4.3 Which Pregnant Woman Should Be Offered
Screening for Fetal Aneuploidies?�� 16
4.4 Which Are the Tests Available for Screening for Fetal
Aneuploidies? �� 16
4.5 First Trimester Combined Screening Test�� 17
4.6 Second Trimester Maternal Serum Biochemistry
(Quadruple Test) �� 19
4.7 Cell-Free Fetal DNA Test �� 20
4.8 The Midtrimester Genetic Sonogram�� 20
Suggested Reading�� 21
5
Basics of Imaging for Fetal Evaluation�� 23
5.1 Fetal MRI�� 26
5.2 Safety of Ultrasound �� 28
5.3 Some Good Practice Points�� 28
5.4 Ethical Considerations�� 28
vii
viii Contents
6 Evaluation
of Fetal Biometry�� 31
6.1 Ultrasound Biometry in Early Pregnancy �� 31
6.2 Significance of Early Pregnancy Biometry�� 34
6.3 “Dating Is a New Beginning!!”�� 34
6.4 Fetal Biometry in Second and Third Trimester�� 35
6.5 Biparietal Diameter�� 35
6.6 Head Circumference �� 36
6.7 Abdominal Circumference�� 38
6.8 Measurement of Fetal Femur Length�� 39
6.9 Calculation of Estimated Fetal Weight on Ultrasound�� 39
6.10 Supplementary Biometry: The Transcerebellar Diameter�� 40
7 Midtrimester Fetal Anomaly Scan�� 43
7.1 Prerequisites to Performing a Fetal Anomaly Scan�� 43
7.2 Fetal Number and Viability�� 45
7.3 Orientation of the Fetus (Assessment of Situs)�� 46
7.4 Fetal Anatomy Assessment �� 47
7.4.1 Fetal Skull �� 47
7.4.2 Fetal Brain�� 48
7.4.3 Fetal Face�� 49
7.4.4 Fetal Neck �� 49
7.4.5 Fetal Thorax�� 51
7.4.6 Fetal Heart�� 51
7.4.7 Fetal Abdomen�� 53
7.4.8 Fetal Spine�� 54
7.4.9 Fetal Limbs �� 55
7.4.10 Genitalia�� 56
7.4.11 Other Parameters Assessed at the MTAS�� 56
7.5 Scope of the Midtrimester Anomaly Scan�� 57
7.6 Planning Further Care After Detecting Fetal Anomaly�� 58
8 Basics
of Doppler Imaging and Application in Fetal Medicine�� 59
8.1 Fetal Circulation�� 62
8.2 Umbilical Artery Doppler �� 64
8.3 Fetal Middle Cerebral Artery Doppler�� 64
8.4 Fetal Ductus Venosus Doppler�� 65
8.5 Uterine Artery Doppler �� 67
8.6 Safety Issues with Fetal Doppler�� 68
9 Fetal Growth Disorders �� 71
9.1 Fetal Growth Restriction�� 72
9.1.1 Etiology and Classification of Fetal
Growth Restriction�� 73
9.1.2 Diagnosis and Evaluation of Fetal
Growth Restriction�� 74
9.1.3 Management of Fetal Growth Restriction�� 77
9.2 Fetal Overgrowth Conditions�� 78
Contents ix
10
The “First Trimester (11–14 Weeks) Scan” �� 81
10.1 Reconfirmation of Fetal Viability and Dating�� 82
10.2 Detailed Fetal Structural Assessment
at the 11–14 Weeks’ Scan �� 85
10.3 Screening for Spina Bifida by IT
(Intracranial Translucency) �� 95
10.4 Markers for Fetal Aneuploidy Screening
in the 11–14 Weeks’ Scan �� 96
10.4.1 Fetal NT�� 96
10.4.2 Fetal Nasal Bone �� 96
10.4.3 Tricuspid Blood Flow �� 98
10.4.4 Ductus Venosus Blood Flow �� 98
10.5 Basic Workup of Multifetal Pregnancy
at the 11–14-Week Scan�� 100
10.6 Evaluation of Uterine Artery Doppler
in First Trimester Scan�� 102
10.7 Evaluation of Maternal Cervix
in First Trimester Scan�� 103
11
Multiple Pregnancy Evaluation in Fetal Medicine Clinic�� 105
11.1 Establishing the Diagnosis and Chorionicity
of Multifetal Pregnancy�� 105
11.2 Dating of a Multifetal Pregnancy�� 107
11.3 Systematic Labeling of Fetuses in Multifetal Gestation �� 108
11.4 Aneuploidy Screening in Multifetal Pregnancy�� 109
11.5 Screening for Fetal Anomalies in Multifetal Pregnancy�� 111
11.6 Planning a Rational Follow-up for Serial
Monitoring of Multiple Pregnancy �� 112
11.6.1 DICHORIONIC DIAMNIOTIC Twins�� 112
11.6.2 MONOCHORIONIC DIAMNIOTIC Twins�� 114
11.7 Twin Reversed Arterial Perfusion (TRAP) Sequence�� 117
11.8 Monochorionic Monoamniotic (MCMA) Twins�� 120
11.8.1 Conjoined Twins �� 120
11.9 Higher-Order Multiples (Triplets, Quadruplets,
and So on) �� 121
12
Placenta, Cord, Amniotic Fluid, and Cervix �� 123
12.1 Evaluation of the Placenta in Pregnancy�� 124
12.2 Placenta in Second Trimester�� 125
12.3 Location and Edges�� 125
12.4 Size�� 128
12.5 Morphology of the Placenta�� 129
12.6 Umbilical Cord Insertion�� 132
12.7 Assessment of Umbilical Cord Morphology�� 132
12.8 Single Umbilical Artery�� 134
12.9 Persistent Right Umbilical Vein�� 134
12.10 Amniotic Fluid�� 137
12.11 Assessment of Cervix �� 139
x Contents
13 Basics
of Genetics in Fetal Medicine�� 143
13.1 Fluorescence in Situ Hybridization (FISH)�� 147
13.2 Quantitative Fluorescent PCR (QfPCR) �� 149
13.3 Multiplex Ligation-Dependent Probe
Amplification (MLPA)�� 151
13.4 Clinical Exome Sequencing (CEX)�� 152
13.5 Targeted Mutation Analysis�� 153
14 Recurrent Fetal Problems: Looking for Solutions�� 155
15 Invasive
Prenatal Diagnostic and Therapeutic Procedures�� 161
15.1 Indication�� 161
15.2 Pretest Counseling�� 162
15.3 Rhesus Status Check �� 162
15.4 Maternal HIV and Hepatitis B Screening �� 162
15.5 Consent �� 162
15.6 Amniocentesis�� 163
15.7 Chorionic Villus Sampling (CVS)�� 164
15.8 Fetal Blood Sampling �� 165
15.9 Invasive Prenatal Threapeutic Procedures�� 166
16 Rhesus
Isoimmunization and Fetal Infections�� 167
16.1 Rhesus Isoimmunization�� 167
16.2 Fetal Infections�� 170
17 Potential
for Assessing Maternal Morbidity
in Fetal Medicine Clinics �� 175
17.1 Uterine Artery Doppler Studies Predict
Risk of Preeclampsia�� 175
17.2 Hyperglycemia in Pregnancy�� 178
17.3 Maternal Autoimmune Diseases �� 178
18 Essentials
of Counseling in Fetal Medicine�� 181
18.1 Pretest Counseling�� 181
18.2 Pretest Counseling for Fetal Scans �� 181
18.3 Posttest Counseling for Fetal Scans�� 182
18.4 Pretest Counseling for Fetal Screening Tests�� 182
About the Authors
Chinmayee Ratha, MS (ObGyn), FRCOG, FIMSA, FICOG is the

Director and Lead Consultant—fetal medicine at the Resolution Fetal
Medicine Centre and Research Institute, Hyderabad. She runs a fetal medi-
cine practice catering to the needs of patients and clinicians from all over
Telangana and even adjoining states. She is a passionate teacher and an FMF
(UK) approved trainer for fetal medicine scans. She runs a clinical fellowship
program for subspecialty trainees in fetal medicine in India, including the
ICOG-certified fetal medicine course, since 2018. She has spent the last two
decades increasing the awareness of fetal problems and available solutions
not only among clinicians but also among the public through various infor-
mation dissemination platforms. She is a popular orator and is known for the
simplicity and clarity of her thoughts during her presentations. She has pub-
lished papers in peer-reviewed, indexed journals and has received several
awards and prizes for presentations of her research projects and audits at vari-
ous state, national, and international seminars. She is a member of several
prestigious professional bodies like FOGSI, SFM, FMF, RCOG, and ISUOG,
in addition to local bodies and has served in official positions in many of
these organizations. She is currently the Chairperson of the FOGSI
Perinatology Committee (2021–2024) and the President of SFM Telangana
Chapter (2022–2024).
Ashok Khurana commenced his medical studies at All India Institute of

Medical Sciences, New Delhi, India. Apart from running a private medical
facility with the vision of providing world-class ultrasound services, Dr
Ashok Khurana has to his credit several academic and technological firsts in
the city, including transrectal scans, transvaginal scans, color Doppler, 3D
and 4D ultrasound, and ultrasound-guided surgical procedures.He has
authored two medical textbooks, one on 3D and 4D ultrasound and the other
on breast ultrasound. He has contributed several articles on ultrasound in
prestigious medical journals. This includes pioneering work in cancer of the
uterus. Dr Khurana is currently the Secretary of the Society of Fetal Medicine.
He is a member of several academic societies where he has lectured exten-
sively, conducted training workshops, and chaired several scientific sessions.
These include the International Society for Ultrasound in Obstetrics and
Gynecology, Indian Radiological and Imaging Association, Indian Medical
Association, Federation of Obstetric and Gynecological Societies of India,
Indian Academy of Human Reproduction, and the Indian Federation of
xi
xii About the Authors
Ultrasound in Medicine and Biology. He is also a member of the FOGSI

Genetic and Fetal Medicine Committee for which he conducts several aca-
demic exercises. His ultrasound facility is accredited by FOGSI for training
programs. Dr Khurana is also the former Clinical Director of the Test-Tube
Baby facility of the Institute for Fertility Fulfilment, former President of the
Indian Federation of Ultrasound in Medicine and Biology, Delhi Chapter, and
former Secretary, Indian Radiological and Imaging Association, Delhi
branch.
Introduction to Fetal Medicine
1
Fetal medicine is a branch of medicine dealing

with screening, diagnosing, and treating health
issues of the fetus—the unborn patient. What
started as a refinement of fetal imaging has now
transformed into a complete speciality dealing
Fetal Imaging Maternal care
with all aspects of fetal health. As the mother
and the fetus are always together, fetal medi- Screening for Reduce morbidity
cine is closely entwined to maternal medicine. fetal conditions and
risk of preterm birth
As a natural consequence, majority of the pres-
ent-day fetal medicine specialists are basically
obstetricians who have concentrated their train- Diagnosis
ing and practice into health issues of the fetus.
The practice of fetal medicine thus requires a Therapy
thorough insight into the concepts of fetal imag-
ing and fetal physiology, explaining the variety of
findings on imaging along with maternal well- Fig. 1.1 Concept of fetal medicine
being, and planning delivery under optimal cir-
cumstances to help the “fetus” in utero smoothly
progress into a “newborn” that is received satis- with. Just as the role of “antenatal” care became
factorily by the neonatologist in the best possible as important as “intrapartum” care in the present-
circumstances (Fig. 1.1). Also, several fetal con- day obstetrics—the role of “fetal medicine” has
ditions need specialized newborn care, or some emerged as the major “discovery” in the last
maternal conditions can dictate the need for quarter of a century when every practitioner
delivering a preterm fetus or even otherwise, the effectively realized few important facts as listed
neonatologist becomes the natural caretaker of below:
the fetus after birth such that there is an emer-
gence of the concept of “perinatology” which is a 1. The final outcome of pregnancy is both a
cusp of fetal-maternal medicine, obstetrics, and healthy mother and a healthy baby.
neonatology. 2. The complexity of pregnancy care is increas-
For centuries, pregnancy care had been ing with maternal morbidity being better
focused on the mother and even “obstetrics” was handled and these morbidities can affect the
more of a parturition related science to begin fetus.
© Springer Nature Singapore Pte Ltd. 2022 1

C. Ratha, A. Khurana, Fetal Medicine, https://doi.org/10.1007/978-981-19-6099-4_1
2 1 Introduction to Fetal Medicine
3. The concept of “fetal origin of adult dis- specialists as the case may be. Therefore, it is a
ease” became more acceptable in the face of fact that fetal medicine is a multidisciplinary sci-
unequivocal evidence that optimizing pre- ence with multiple stakeholders with the primary
natal health could help reduce the burden of aim of delivering a healthy baby of a healthy
adult disease. mother.
4. “Screening” for fetal aneuploidies and The most important aspect of fetal medicine is
anomalies became a logical part of antenatal the acknowledgment that the fetus in utero
care spectrum. deserves full medical attention and that too not
5. Advances in genetics and ultrasound enabled only while it is physically formed but well in
safe and effective “prenatal diagnosis” of advance in cases where maternal morbidity indi-
fetal aneuploidies and genetic problems. cates the possibility of fetal problems in future
6. Mutifetal pregnancies are increasing in inci- pregnancies or where previous pregnancy issues
dence and are posing fetus-specific chal- indicate a risk of recurrence. It is now imperative
lenges to management. for all subspecialists to be aware that their
7. Neonatology is evolving so that limits of via- patients are not merely taking medicines to cure
bility have been pushed to earlier gestation or manage their ailments, but also these people
and “intact survival” requires precise fetal are part of a reproductive process that may get
surveillance and optimizing time of delivery. affected due to the primary condition and its
8. Awareness and management of structural treatment. For example, a girl with SLE will
anomalies has improved, and again proper achieve a pregnancy if she is under a good rheu-
fetal workup seems to be the vital measure in matologist but unless her medications are “fetus
optimizing outcome. safe” in pregnancy or the anti-Ro/anti-LA anti-
9. “Fetal therapy” has evolved with bet- body levels have been optimized—we may deal
ter understanding of fetal physiology and with fetal complications that could have been
improvisation in instruments and anesthesia. potentially avoidable! So it would be useful for
10. Finally, a risk of liability has emerged if fetal
rheumatologists treating women of reproductive
problems have been missed and the overall age to have appropriate “preconception” counsel-
perinatal outcome is compromised for any ing and workup with maternal-fetal medicine
reason. specialists. The same holds true for women with
cardiac diseases who are on warfarin or women
Every pregnancy is now understood as a on antiepileptic medications—success of medi-
“maternal-fetal” situation. All obstetricians have cal therapy and obstetrics till the last few decades
redefined pregnancy care and allocated an equal was measured in terms of ability to carry on a
measure of attention and resources to the fetus. pregnancy in this case; medical care in this cen-
Fetal evaluation starts in early pregnancy and at tury is not just about “survival” but rather about
every stage some vital information about the “intact survival” and hence the focus has shifted
fetus is obtained through tests. on fetal medicine.
Present-day clinicians have accepted the While screening and diagnosing remained the
emergence of “fetal medicine” as a separate mainstay of fetal care for many decades, it is
branch of obstetrics. The major speciality that remarkable that advances in technology espe-
justifies fetal medicine as a subspecialty seems to cially endoscopy and better understanding of
be obstetrics as the primary patient is the mother fetal physiology along with great contributions
who houses the fetus within her. There is, how- from pediatric surgery colleagues, the scope of
ever, a significant role of an imaging specialist fetal “therapy” has enhanced a lot. From needle-
and neonatologist in all cases along with a case- based procedures to insertion of shunts to
based role of subspecialists like pediatric neurol- fetoscopy-guided surgery and finally open fetal
ogists, pediatric surgeons, pediatric cardiologists surgery is all part of realistic fetal care although
in specific situations, and maternal medicine sub- the permeation is patchy at the global level.
1 Introduction to Fetal Medicine 3
Nevertheless, hope for successful therapy for obstetric physiology and epidemiology of fetal
fetal problems which was dismal earlier is look- problems to be able to contribute meaningfully to
ing brighter day by day. fetal care. It is heartening to see the emergence of
Many doctors equate obstetric scanning with interest and avenues of such interdisciplinary
fetal medicine, and it is important to understand training and collaboration at all levels such that
that while scanning is extremely important in the beneficiary is primarily the fetus in utero, and
examining a fetus, imaging is only one part of the finally the society at large.
entire fetal health evaluation. Obstetricians who In epitome, fetal medicine (Fig. 1.2) is a con-
plan to practice fetal medicine have to learn the glomeration of all aspects of medicine and tech-
basics of ultrasound scans and their application nology that can help to screen, examine, evaluate,
in fetal imaging. Similarly, radiologists who wish and treat the fetus in utero to ensure that it
to concentrate on fetal health have to understand receives the best healthcare that present-day tech-
the background embryological development and nology and clinical evidence can provide.
Fig. 1.2
Multidisciplinary setup Fetal Medicine specialist
for FM
cian st
tetri etici
Obs Gen
st
ciali
spe
ing
I mag
eon
surg
tric
Pedia
c
iatri ts
Ped pecialis
b s Neonatologist
su
History Taking in the Fetal
Medicine Clinic 2
The aim of antenatal care is to ensure the birth of A thorough history for potential fetal prob-
a healthy baby at term while maintaining mater- lems is a MUST at the first antenatal visit for
nal well-being throughout pregnancy and puerpe- every pregnant woman. It is surprising that in
rium. This aim, if well achieved, has far-reaching many cases that actually come to fetal medicine
consequences in ensuring the overall health of clinics, there is a lot of basic information yet
the society, and it is so important that both mater- unexplored in the patient’s history. The points to
nal and infant morbidity and mortality indicators be definitely covered are the following:
have become the benchmark parameters of a
good healthcare system. Anticipating complica- 1. Age of the mother—Although most women
tions is the first step toward planning better nowadays are very sure of their age, in some
management. societies, women do not know there exact
All obstetricians are mentally alert and techni- date of birth and provide a number which may
cally equipped to address maternal issues and do not be accurate! Based on clinical situations if
an extensive antenatal care plan layout usually the doctor is not convinced, spending a few
during the first antenatal visit. However, the ulti- extra minutes in obtaining this information is
mate success of any pregnancy management plan very useful—reconfirm dates by any reliable
is when both the mother and her fetus(es) make it documents if available or even correlate her
safely through pregnancy and remain healthy lifetime events to some well-known dates like
after the delivery. It is imperative therefore to a political event, sports event, or contempo-
make a specific care plan for the fetus in each rary life events of another person in the family
pregnancy. A timeline for fetal evaluation would with a confirmed date of birth! This may
be one of the preliminary steps for the same. sound hilarious to some readers who are for-
tunate to have a more enlightened patient
population, but in many parts of the develop-
2.1 At the First Antenatal Visit ing countries, such ignorance is still common
and needs to be addressed.
It is natural for every obstetrician to take a 2. The mother’s blood group and rhesus sta-
detailed clinical history at the time of the first tus—Testing the mother’s blood group and
antenatal visit of the expectant mother. At this rhesus type provides a very basic medical
opportunity, specific issues that may necessitate information and is of unquestionable impor-
modification of the care plan for further fetal tance in obstetric population; thus, it is imper-
evaluation and assessment may be made. ative that a pregnant woman MUST have a

6 2 History Taking in the Fetal Medicine Clinic
documented report of her blood group and genetic disorder and the scope and feasibility
rhesus status. One would be surprised how of prenatal diagnosis can be explored.
many pregnant women present at the tertiary Similarly, history of consanguinity is impor-
care fetal medicine centers for evaluation and tant to look for clues regarding presence of
do not have this basic report. Worse still, some any genetic conditions in the family which
women just quote an answer without actually may be inherited in the “autosomal recessive”
knowing the importance, so one must insist manner. Such problems can affect fetuses of
that a documented blood group report is avail- apparently healthy parents and may not
able in her obstetric notes at all times. always present as structural abnormalities but
3. Mode of conception—This is important in may have very severe adverse effect on qual-
fetal medicine for many reasons: induced ity of life of babies like severe neurodevelop-
ovulation results in changes in biochemical mental delays or in some cases even death in
parameters used for aneuploidy screening; in the newborn period due to metabolic abnor-
ART procedures if “donor gametes” are used, malities which remains elusive and often clas-
then age correction for aneuploidy screening sified as “unexplained” neonatal deaths
has to be done accordingly; and similarly the 7. General medical/surgical history—
risk of inheritance of genetic problems will Preexisting maternal medical conditions like
vary in such cases, so the need for prenatal hypothyroidism, diabetes mellitus, epilepsy,
testing has to be reviewed accordingly. or cardiac disease can all have impact on the
4. Menstrual regularity and last period pregnancy as well as the fetus. Some condi-
date—This is important in evaluating the tions require medications which are poten-
accuracy of dating a pregnancy. If a woman tially teratogenic (e.g., anti-epileptics), while
has longer menstrual cycles, say 35-day peri- in many conditions, the disease itself may
ods, then we expect that the ovulation will be cause fetal problems like hyperglycemia in
5–7 days later in her case than the usually peripartum period thereby increasing chances
expected 28-day cycles—this in turn will of structural defects in the fetus or when anti-
affect the expected date of conception and Ro/anti-LA antibodies can cause congenital
hence the expected gestational age of the fetus heart blocks in the fetus.
has to be readjusted accordingly.
5. Obstetric history—Previous births: mode, The abovementioned checklist may not be
gestational age, and birth weights, any preg- “complete” in all cases as there will be specific
nancy complications, any special issues with issues that may have significance in individual
the children like congenital anomalies cases, but it is a comprehensive list of “never to
detected before or after birth, and develop- miss” points during history taking in a fetal medi-
mental history of the children in particular are cine clinic. Unless a proper history has been taken,
important as they can have a bearing on the the context of fetal imaging remains obscure and
fetus in the present pregnancy. In cases of the final goal of solving that patient’s specific con-
fetal or neonatal losses, detailed recollection cerns will not be fulfilled. A memory aid for the
of facts and, if possible, review of notes are points in history taking is shown in Fig. 2.1 as a
also important. It is sad that many families do simple alphabetical mnemonic of ABCDEFG.
not preserve medical records of fetal and neo-
natal losses due to sentimental and supersti-
tious reasons, but we must start sensitizing A- Age
our patients toward the importance of keeping B- Blood group /Rh
C- Conception type
a detailed record of every detail in the cases D- Dates
that have adverse outcomes so that future E- Each past pregnancy
workup is facilitated. F- Family history
G- General Medical/Surgical history
6. Family history—Any specific medical condi-
tion affecting several members of a family is Fig. 2.1 Memory aid for basic history taking in the FM
very important as it may indicate a heritable clinic
Timeline of Fetal Evaluation
in Normal Pregnancy 3
A normal pregnancy is a journey of a zygote 3.1 4–6 Weeks of Gestation

through 37–40 weeks while it develops into a
complete human being from a single totipotent This is the period when most women discover
cell! Most women would suspect that they are their pregnancy and are very excited about it. In
pregnant when they miss a normal menstrual most cases, it would be prudent to plan the first
period and then confirm their pregnancy by the fetal evaluation only after 2 weeks of a confirmed
urine pregnancy tests. pregnancy test so that at least a definite gesta-
They usually then visit the doctor either tional sac could be seen. Very often, women get a
immediately or after a couple of weeks to seek scan done as soon as they have a pregnancy test
antenatal care. At every stage of pregnancy, a positive and then get very anxious if the preg-
definite evaluation of the fetus is part of the nancy viability remains doubtful, even if the rea-
“total” antenatal care scheme. Depending on son may be totally physiological!
what period of gestation the woman presents at In some cases where there is a worrying symp-
the antenatal clinic, specific tests can be offered tom like lower abdominal pain or bleeding per
to check the well-being of the fetus growing vaginam or where there is a history of ectopic
within her womb. pregnancy or factors predisposing to such an
A “timeline” for fetal evaluation is expressed occurrence, an early pregnancy assessment at
in Fig. 3.1 and further elaborated in this chapter. 4–6 weeks of gestation may be done, best by
4-6 6-10 11-14 wks 16-18 18-20 20-28 wks 28 - 32 wks 32 - 40 weeks
Fig. 3.1 Timeline for fetal evaluation in a normal pregnancy

8 3 Timeline of Fetal Evaluation in Normal Pregnancy
transvaginal ultrasound, with the primary aim of become widely recognized and accepted as the
detecting an intrauterine pregnancy and ruling “first fetal anomaly scan” or an “early TIFFA”
out an extrauterine gestation. in common practice. A “head-to toe” evaluation
The primary aim is to establish the presence of for major developmental milestones in fetal
a pregnancy sac, and if viability is doubtful, it is anatomy is possible and is imperative to be
better to reassess the woman after 1 week rather done by anyone who scans a fetus at this stage.
than declaring a pregnancy failure. A detailed description of all that can be per-
formed at this stage is given in the Chap. 10. All
obstetricians should try and check these details
3.2 6–11 Weeks of Gestation on the first trimester scan report to ensure that
an optimal fetal assessment has been done. In
At 6–11 weeks, fetal evaluation is usually done to fact, the checklist given in the first trimester
ensure the presence, viability, size, and even mul- scan protocol is designed to help the obstetri-
tiplicity of the pregnancy. By 6 weeks, a definite cian plan her pregnancy care better and start
fetal pole MUST be seen, and if the crown-rump necessary interventions to avoid problems later.
length of the fetus is 7 mm or more, a definite For example, detection of a major anomaly like
cardiac activity MUST be seen in a viable anencephaly which warrants termination can be
pregnancy. addressed right away as the process of first tri-
Early pregnancy evaluation should include a mester termination is always safer and less
documentation of the CRL as this is also an accu- traumatic both physically and emotionally than
rate method of dating the pregnancy. In case of later.
multiple pregnancies, documentation of more The fetal nuchal translucency has been firmly
than one fetal poles and an early assessment of established as a marker for risk of fetal chromo-
number of sacs and placenta can be done although somal abnormalities, and along with other mark-
in some cases, the findings may not be very clear ers, the “NT scan” has become a very effective
till about 9–10 weeks and thus a repeat evaluation screening tool for fetal aneuploidies. The details
around this gestation may be planned to clarify of the NT assessment and its implications are
such doubts. given later in the book in the chapter on “screen-
Assessment of the uterine contour to rule out ing or fetal aneuploidies.”
any uterine anomalies and examination of the Any findings that are suspicious of fetal prob-
adnexa to rule out extrauterine gestation of other lems can help to triage the fetuses for further test-
adnexal masses is an important aspect of the ing at the right time to ensure a good perinatal
early pregnancy ultrasound scan. outcome.
This period of gestation has been now identi-
fied as the base of the “inverted pyramid of ante-
3.3 11–14 Weeks of Gestation natal care” such that efforts to screen for maternal
problems like preeclampsia are also possible.
This is the time frame for the first comprehensive
fetal evaluation. The ultrasound scan done in the
11–14 weeks of gestation (fetal CRL between 45 3.4 14–16 Weeks of Gestation
and 84 mm) has become one such investigation
which has enhanced its scope to predict many If all the above said investigations and workup
pregnancy complications—both maternal and have been done correctly, this period of preg-
fetal. nancy does not warrant any specific testing for
A detailed fetal anatomy assessment is pos- the fetus. In fact, there is very little that can be
sible at the first trimester scan such that it has offered based on current evidence at this gesta-
3.7 20–28 Weeks of Gestation 9
tion. Ideally, we would expect women to have 3.6 18–20 Weeks of Gestation
booked for antenatal care earlier and had the
workup as delineated above, but just in case that This is usually a scheduled appointment for a
has not happened, then for women who present fetal anomaly scan—popularly also known as the
for the first time at this gestation or for those who TIFFA (Targeted Imaging for Fetal Anomalies).
for some reason did not have the tests earlier, a This period of gestation is an optimal window for
fetal evaluation scan can be done at this stage the detailed midtrimester anomaly scan espe-
with the purpose of identifying the viability, cially in countries where the law is strict about
number, and basic anatomy of the fetus and rul- not allowing termination of pregnancy for fetal
ing out any obvious adnexal pathology to the indications beyond 20 weeks. A normal anomaly
extent possible now. scan is very reassuring, whereas any markers/
In terms of screening for aneuploidies, there anomalies detected on the scan allow some time
are no obvious scan-based parameters validated for workup and results prior to the legal deadline
in this window, but the option of cell-free DNA for decisions regarding continuation of
testing is available in appropriately counseled pregnancy.
cases. If parents want conventional screening, The protocol for the anomaly scan involves a
then the option is available after 16 weeks. systemic evaluation of fetal viability, structure,
biometry, and general evaluation of activity and
other intrauterine factors. These issues have been
3.5 16–18 Weeks of Gestation explained in relevant chapters that follow in this
book. Some standard formats for reporting an
Again, this evaluation is not routinely scheduled anomaly scan have also been given in later
for a fetus if appropriate first trimester workup chapters.
has been done, but if the woman books for ante- Some conditions warrant a detailed fetal echo-
natal care at this gestation or has missed her ear- cardiography and that can be performed well at
lier workup, then the fetal evaluation starts from this gestation, but if views are limited, it is accept-
now on. A basic fetal anatomy evaluation along able to review the fetus for a fetal echo at around
with confirmation of viability, number, and biom- 24 weeks.
etry can be done to check dating of the pregnancy.
However, if a proper first trimester scan has been
done and documented, then the dating estab- 3.7 20–28 Weeks of Gestation
lished in early scans should not be changed based
on the biometry now. If there is a discrepancy, If all the previously mentioned fetal evaluation
then the cause should be evaluated rather than sessions have been accomplished successfully,
conveniently changing dates. there is usually no routine indication for a fetal
Sometimes, a 16–18-week evaluation may be checkup in this window in a normal pregnancy.
scheduled for an early anomaly scan in case However, some specific indications may necessi-
there is very high risk for structural defects in tate a fetal checkup.
the fetus, e.g., pregestational diabetes or intake As mentioned earlier, some women may be
of teratogens in the first trimester. Another indi- recalled for a fetal echocardiography due to spe-
cation for a scheduled fetal evaluation at this cific indications. In some units, there is a recall at
gestation could be for the second trimester bio- 22 weeks for uterine artery Doppler evaluation
chemical screening (quadruple test) for assess- for screening for preeclampsia, but with recent
ing the risk for fetal aneuploidies or a genetic emerging evidence of the preponement of pre-
sonogram based on ultrasound markers for eclampsia screening to first trimester, and initiat-
aneuploidies. ing prophylactic medications earlier, there is
10 3 Timeline of Fetal Evaluation in Normal Pregnancy
little use of this extra visit at the fetal medicine Another important aspect of late term fetal
clinic. evaluation is confirmation of fetal lie and placen-
In case there is a high risk for preeclampsia tal position—both these parameters at this time
and fetal growth restriction, the first “growth period are closely related to final obstetric deci-
scan” is recommended at 26 weeks. Similarly, sions regarding mode of delivery.
some fetuses with special needs like those having
correctable anomalies may be reviewed in this
window with individualized protocols specific to 3.10 Beyond 40 Weeks
their situation. of Gestation
Although fetal monitoring at this stage is largely

3.8 28–32 Weeks of Gestation by CTG and clinical methods, there may be spe-
cific indications to scan for amniotic fluid levels
This is the time frame for the first “routine” or the fetal biophysical profile to take crucial
growth scan in a normal pregnancy. Even if all is decisions regarding continuation of pregnancy
apparently going well with the mother, there is versus induction of labor or decision to deliver.
evidence to support at least one growth assess- As is evident, the bulk of the activity in terms
ment for the fetus in the third trimester so that of fetal evaluation is actually concentrated in the
any deviation from the normal growth patterns first part of pregnancy (Fig. 3.2), and thus the tra-
can be detected early and followed up optimally. ditional thinking of obstetricians needs a radical
Till many years back, this one growth scan modification such that women are referred to
being normal would suffice for the remainder of fetal medicine clinics earlier than later if any
the pregnancy, but with emerging evidence about meaningful fetal workup is expected. Although a
“late-onset fetal growth restriction,” it is now third trimester scan yields a lot of information,
imperative to suggest a “late growth scan” closer fetal growth evaluation may be meaningless
to term. without a first trimester confirmation of dates.
Similarly, if the crucial first trimester risk assess-
ment for aneuploidies is missed, a golden oppor-
3.9 32–40 Weeks of Gestation tunity is lost, and since all the markers may be
gestation specific, they may disappear and there
A late growth scan has now become an accept- may be no other reason to be alerted to the pos-
able practice in most setups since the identifica- sibility of a fetal aneuploidy. Even evaluation of
tion of the concept of the “late-onset fetal growth fetal structure is extremely difficult in the third
restriction.” Fetal biometry is ideally represented trimester, and thus the anomaly scan must be
in “centiles for gestation” and plotted on charts offered in the midtrimester. In settings where the
such that trends of fetal growth can be assessed onus is on the woman and her family to accept or
and significant fall or rise in centiles will alert the decline tests, the correct action on the part of the
clinician to growth disorders. While the late clinician is to suggest the right test at the right
growth scan is an important landmark opportu- time. This suggestion must be backed up with rel-
nity to detect fetal growth restriction, it is also the evant information and support material. Fetal
ideal time to detect “macrosomia” that is a com- medicine has expanded its scope tremendously
mon occurrence due to suboptimal glycemic con- over the decades, but nothing can be achieved
trol in late pregnancy and may help in optimizing successfully unless the patient, i.e., the “fetus,”
perinatal care to avoid fetal injury due to peripar- actually gets to meet the fetal medicine care team
tum complications of maternal hyperglycemia. at the right time!!
3.10 Beyond 40 Weeks of Gestation 11
Viability
Dating Detailed anatomy screen Early growth and
Number of sacs PIH/FGR/PTB screen Doppler in screen
Aneuploidy screen positive cases
Upto
11-14wks 16-22 wks 22-26 wks 26-30 wks 30-40 weeks
11wks
Routine or follow up third

NT scan Secondary anatomy
trimester growth and
Anatomy screen check –
Doppler
Aneuploidy screen echo/neurosonogram/
Biophysical profile SOS
PIH /FGR/ PTB screen skeletal follow up
Placental relocalisation SOS
Chorionicity in multiple gestation
Fig. 3.2 Possibility of fetal evaluation in the first, second, and third trimester
Principles and Methods
of Screening for Fetal 4
Aneuploidies
Screening for fetal problems is a vital aspect of ploidy. This “risk” or “probability” appears to
fetal care as our knowledge in background litera- increase with increasing maternal age, but really,
ture and even each clinician’s individual experi- there is no age at which a woman “cannot” have
ence tells us that most problems actually happen an aneuploidic gamete so over the years, it has
in pregnancies which were traditionally thought been clearly understood that every pregnancy has
of as the “low-risk” group. Every obstetrician a risk of fetal aneuploidy.
now feels uncomfortable in declaring a “low-
risk” pregnancy because essentially this is a ret-
rospective diagnosis! It is therefore imperative 4.1 What Is Screening?
that we spend optimum time and resources in
“screening” for problems in pregnancy, stratify • Screening is a process applied on apparently
risk categories based on the screening tests and healthy individuals to detect the risk of any
then institute appropriate care modification to the particular problem. It is offered to a general
high-risk group such that the final perinatal out- population, and the results of screening will
come is improved. Pregnancy care is essentially determine whether the individual is at “high
preventive care aimed at optimizing maternal and risk” or “low risk” for a given condition
fetal outcome. Screening for potential problems (Fig. 4.1). So the results of a screening test are
in the mother and the fetus during pregnancy is “screen positive,” i.e., “high risk” for a condi-
therefore an important issue as it helps to pick up tion, or “screen negative,” i.e., “low risk”
a “high-risk” group who can then be offered spe- which indicates low probability of having that
cial care to help reduce the incidence, morbidity, condition.
and complications of the particular condition for • SCREENING IS NOT THE SAME AS
which they have screened “positive.” DIAGNOSIS. Hence, the results of screening
Fetal aneuploidies are conditions where there tests can only guide us to the need for con-
is an “abnormal number” of chromosomes in the ducting diagnostic tests. Screening tests do not
fetus. This abnormality happens most commonly confirm or rule out the condition completely.
due to “nondisjunction” during meiosis which is They only allocate the “risk” or “probability”
the “reduction” division of cells leading to for- for a certain condition. Someone who is “high
mation of gametes. This process occurs every risk” may not have the condition (false posi-
time a gamete is released, and technically, it is tive). Similarly, a “low risk” also may have the
acceptable to say that every pregnancy has a condition (false negative). Hence, “screening”
potential “risk” or “probability” for fetal aneu- is NOT a “diagnosis.”

14 4 Principles and Methods of Screening for Fetal Aneuploidies
Apparently normal population
SCREENING TEST
High risk for a condition
Low risk for a condition
High risk for a condition
DIAGNOSTIC TEST
NORMAL/Not affected
ABNORMAL/Affected
Fig. 4.1 Screening concept
When we talk about screening for fetal chro- ner, seeing a limited number of cases, one may
mosomal abnormalities, we need to first under- not encounter these problems much in daily prac-
stand that every pregnant woman carries a risk of tice and may remain oblivious to their potential
having a fetus with chromosomal abnormali- presence. Then one fine day when there is a birth
ties—this risk is called the “background risk” or of a baby with aneuploidy in their patient group,
a priori risk and depends on maternal age and they suddenly get disturbed by the aftermath of
some factors in her medical history. This risk can this case. In some cases, clinicians are so hassled
be reassessed based on screening tests to “high” with the explanation of the results of screening
or “low” risk. tests that the discussion that ensues often scares
Clinicians often find the whole concept of the patients so much that they may even discon-
screening as “confusing” and as an added “bur- tinue a pregnancy based on a “high-risk” result
den” to their clinical schedules. So it is a well- on screening alone! Since quantitative assess-
known fact that many clinicians do not offer ment of human behavior or attitude will remain
screening for fetal aneuploidies as part of their controversial, we may never be able to generate
regular antenatal care. As the incidence of these “evidence” for the fact that it is the “understand-
problems is rather low, as an individual practitio- ing and attitude” of the clinician which is a pri-
4.2 The Concept of “Intermediate Risk” 15
mary determinant in the success of a screening chromosomal abnormality in the fetus is high
program. A very common, real-life example of a based on the results of the screening test.
“screening” test is the “baggage screening” that Therefore, a screening test helps in optimizing
happens in airports when we travel through them. the need for invasive testing while increasing
Every piece of baggage is screened, which the pickup rate for fetal chromosomal problems
implies “screening is universal”—or in other (aneuploidies).
words, only universal screening can help achieve
the purpose of screening at all!! The purpose of
this screening is to detect and prevent any possi- 4.2 The Concept
ble unsafe material being carried on board. of “Intermediate Risk”
“Cutoffs” are fixed based on either “size,”
“weight,” “metal detection,” or “sharpness,” etc., The post-screening test classification yields a
and only articles that are within these “cutoffs” quantitative “risk” for every woman and this
are screened as “low risk” and allowed through number may be “high risk” or “low risk” depend-
the screening center. In any case of the baggage ing on the “cutoff” set for that population. It is a
being “suspicious,” it is taken to another place challenge to set this “cutoff” as at every level, an
and “opened” or checked with different “inva- optimum trade-off between “detection rate” and
sive” methods. The first-level screening is sim- “false positives” has to be set. The detection rate
pler, caters to a large quantity of article, and is will improve if the test is refined, but increased
“noninvasive.” Those who are “screen negative” complexity of a test is a limiting factor for
are allowed to continue along their normal routes. population-based implementation. Therefore, the
Those who are “screen positive” are subjected to idea of having an “intermediate-risk” group
“invasive” testing like opening the bags or dis- (Fig. 4.2) helps increasing the final “detection
mantling an equipment—and if found safe (“false rate” while reducing the need of very refined tests
positives”), they too are allowed to continue to only for a limited subgroup.
boarding but if found truly dangerous (“true posi- The “cutoffs” for these risk levels can be fixed
tives”) are removed from the boarding process an as per local protocols. Some units may use fixed
dealt with through a different channel numerical cutoffs for the whole population, for
individually. example, “low-risk” group is less than 1 in 1000,
The design of a “screening test” is such that “high-risk” group is more than 1 in 50, and the
it will pick up any case with a possibility of the group with risks between 1 in 50 and 1 in 1000 is
problem as “high risk,” and hence this group the intermediate-risk group. Similarly, some
will contain not only the cases which really have units follow another protocol like using a fixed
the condition (true positives) but also some cutoff for the “high-risk group,” e.g., 1 in 300,
cases which actually are normal but have been while the intermediate-risk group is related to the
picked up in the high-risk category (false posi- maternal age risk. Say a woman age-related risk
tives) due to the “high sensitivity” of a screen- for trisomy 21 is 1 in 1200 and her risk after pri-
ing test which determines its ability not to miss mary screening is 1 in 700, she falls in the
“true positives.” The natural fallout in this pro- intermediate- risk group, but if her age-related
cess is that there will be a certain number of risk is 1 in 400 and final risk is 1 in 700, then she
“false positives” in every screening test. Since a falls in the low-risk group.
good screening test is unlikely to miss “true Screening protocols have evolved over the
positives,” women with “low risk” can be reas- years with better understanding of what is accept-
sured, while those with “high risk” can be able and implementable in populations along
offered confirmatory tests to check fetal chro- with better technology in the tests available. It
mosomes. The tests to confirm fetal chromo- will be correct to say that the exact protocols as
somes are generally “invasive tests” which carry we have them today are likely to change in future,
a risk of miscarriage, and hence they are justifi- but the “concept” of screening for fetal aneuploi-
ably undertaken only if the risk of finding a dies will remain the same.
No further tests
needed: reassure
Low Risk
Primary Intermediate Secondary

screening Risk screening
test test
High Risk Diagnostic

test
Fig. 4.2 Concept of intermediate risk
4.3 Which Pregnant Woman 5. If she accepts screening tests, then the optimal
Should Be Offered Screening test should be offered and the results should
for Fetal Aneuploidies? be explained to her in a session dedicated to
“posttest counseling.”
Every woman has a risk of having a fetus with 6. In cases of artificial reproduction if “frozen
aneuploidy—this risk varies with her age and his- self-eggs” or “donor ova” are used for fertil-
tory of previous aneuploidic pregnancies, but ization, then the age of the mother at the time
there is no age at which there is a “zero risk” of of egg retrieval or the age of the “donor” at the
fetal chromosomal abnormality. Therefore, every time of egg retrieval must be used as baseline
pregnant woman should be offered a screening “age risk” for fetal aneuploidies.
test for fetal aneuploidies. It is important here to
remember few points about screening tests:
4.4 Which Are the Tests
1. As a concept, screening for fetal aneuploidies Available for Screening
should be offered to all pregnant women. for Fetal Aneuploidies?
2. Adequate pretest counseling must be done
(details of counseling are dealt with in the There are several tests available for screening for
Chap. 18 later in this book). fetal aneuploidies in pregnancy. The components
3. Accepting or declining the test is a woman’s of these tests vary, and it is important for clini-
prerogative as long as she makes an informed cians to understand each of these tests well so
choice. that they apply it logically and appropriately to
4. If she declines such tests, this fact must be their patients and get the desired results. The fol-
duly documented in her notes. lowing tests can be offered to any pregnant
4.5 First Trimester Combined Screening Test 17
woman who opts for “fetal aneuploidy “central tendency,” it is easier to understand and
screening”: remember that the “normal” value would be close
to 1 MoM. Any deviations from this value is
1. First trimester combined screening test expressed as increased (e.g., 3.5 MoMs is 3.5
2. Second trimester quadruple test times higher than expected) or decreased MoMs
3. Cell-free fetal DNA test (e.g., 0.2 MoMs is almost a fifth of what is
4. Second trimester genetic sonogram expected at that gestation).
PAPP-A is a protein produced first by the
outer layer of the developing trophoblast and
4.5 First Trimester Combined then by the growing placenta. During a normal
Screening Test pregnancy, PAPP-A levels increase in the moth-
er’s blood until delivery. Fetuses with aneuploidy
This test involves the nuchal translucency scan tend to be associated with low levels of PAPP-A
(11–14 weeks) and a blood test with biomarkers production in placenta, and thus this is used as a
that help in assessing the risk for aneuploidies. parameter for risk assessment for the same.
Traditionally, two biomarkers were part of the The “double marker” test can be offered any-
combined test—free beta-hCG (human chorionic time from 9 to 14 weeks of gestation, but the “NT
gonadotropin) and PAPP-A (pregnancy-scan” for risk assessment of aneuploidies can be
associated plasma protein-A). Nuchal translu- done only in the time frame when the fetal CRL
cency is defined as the sonographic appearance is between 45 and 84 mm. This is usually between
of the subcutaneous collection of fluid behind the 11 and 14 weeks of gestation. The sensitivity of
fetal neck in the first trimester in pregnancy. the “combined test” is much better than the indi-
Increased nuchal translucency has been associ- vidual performance of first trimester biochemis-
ated with increased risk of fetal aneuploidies. try or the NT scan alone in screening for
The details about the NT scan are available in the aneuploidies. As there are two tests involved and
chapter on “first trimester scan.” The biomarkers logistically it may not be possible for all fetal
are chemicals produced in the “fetoplacental” medicine clinics to provide both results on the
unit, and their relative levels vary in aneuploidic same day, different protocols could be used based
pregnancies in a statistically significant manner on a unit’s infrastructure and facilities. Variations
such that these values can be used to generate a in arranging logistics and patient acceptability
quantitative risk allocation for aneuploidies in a have necessitated different protocols (Table 4.1)
given pregnancy. for conducting the first trimester combined test.
Human chorionic gonadotropin (hCG) is a The sensitivity of the “combined test” is about
hormone produced by the developing fetus and 90–95% for a false-positive rate of 5% with this
then large quantities by the placenta. The free performance yield limited to “FMF-accredited”
beta subunit of hCG is used in first trimester sonographers and labs. Unless the criteria which
screening. Concentrations of serum hCG usually were used in evaluation and validation of these
rise rapidly in the mother’s circulation for the methods are followed, this efficacy cannot be
first 8–10 weeks and then decrease and stabilize expected.
at a lower level for the rest of the pregnancy. The The first trimester combined test can be used
values of free beta hCG are found to be almost even for twin pregnancies as long as the “chori-
twice the normal values in the first trimester in onicity” is confirmed. Further screening issues
fetuses with trisomy 21 as compared to euploid with multiple pregnancies are dealt with in the
fetuses. In fetuses with trisomy 13 or 18, the free chapter on “multiple pregnancy assessment”
beta hCG levels are very low as compared to later.
euploid fetuses. The absolute value of these bio- As the scope of the first trimester screening is
markers is expressed in “multiples of median” increasing and the spectrum of care provided at
(MoM) for that gestation, and for the ease of the first trimester clinic widens, there is a drive
comparison and as “median” is a measure of toward achieving more goals from tests at this
Table 4.1 Different protocols for performing the combined first trimester screening
Protocol Advantages Limitations
Module 1 Patient visits once between 11 and 1. Single visit for patient 1. Needs intensive
14 weeks (fetal CRL is between 45 in-house-accredited lab
and 84 mm); blood test is taken— support
“One-stop patient waits in the clinic and both 2. Ability to offer results 2. May increase the cost of
clinic” results are combined to give her the and counseling in one the test
“combined test” result on the same visit—better acceptability 3. Although “convenient”
day for both components of for the patient, she gets
the “combined test” lesser time to think about
the test and may not
understand everything well
Module 2 Patient attends twice for the 1. Can be provided even 1. Two visits required—
screening test. In the first visit, she in centers that do not have chances of noncompliance
gives the biochemistry test sample in-house-accredited labs increase
and schedules the NT scan
appointment after a few days. On the
day of the scan, the “combined”
result is communicated to her.
Two visits— It is important to remember that “risk 2. Pretest counseling can 2. In few cases where there
biochemistry calculation” is done ONLY after be done at first visit and will be a fetal miscarriage,
first/early BOTH scan and biochemistry results she gets enough time to patient dissatisfaction over
biochemistry are available—not individually understand the concept a seemingly “unnecessary”
and ask questions about test creates some problems
the process—better in counseling for the care
overall patient satisfaction provider
Module 3 Patient attends twice for the 1. Can be provided even 1. Two visits required—
screening test. In the first visit, she in centers that do not have chances of noncompliance
has the NT scan and then counseled in-house-accredited labs increase
about the biochemistry to help
improve the sensitivity of the
screening test. She then gives the
sample for the blood test and returns
for posttest counseling in a few days
when results are ready.
Two visits— It is important to remember that “risk 2. Pretest counseling can 2. Even after a “normal”
scan first calculation” is done ONLY after be done at first visit and scan, there is a possibility
followed by BOTH scan and biochemistry results she gets enough time to of high-risk result on the
biochemistry are available—not individually understand the concept combined test, and it
and ask questions about sometimes makes the
the process—better patient anxious and may
overall patient satisfaction warrant extensive
3. In few cases where counseling
there are gross
abnormalities on the scan,
the final care plan may
have to be modified
irrespective of the
biochemistry results so it
allows to avoid that test in
these specific cases. Such
issues are important in
settings where patients
pay for their tests and
would like to save on
unnecessary tests
4.6 Second Trimester Maternal Serum Biochemistry (Quadruple Test) 19
stage of pregnancy. Addition of certain placental Table 4.2 Analytes assessed in quadruple test and varia-
tions expected in trisomy 21
biomarkers to the first trimester biochemistry
protocol is opening up opportunities for screen- Expected variation in trisomy 21
pregnancies as compared to
ing for maternal preeclampsia too, and these Analyte pregnancies with euploid fetuses
issues are dealt with in the chapter on “screening HCG Increased
for maternal disorders in the fetal medicine Inhibin A Increased
clinic” later on in this book. AFP Decreased
Unconjugated Decreased
estriol
4.6 Second Trimester Maternal
Serum Biochemistry
(Quadruple Test) nancy dating methods remain the most accurate
method of dating. For all practical purposes, the
The composition of certain “fetoplacental” EDD established during early pregnancy assess-
chemicals can be tested in the maternal serum ment can be used for dating throughout preg-
between 15 and 22 weeks to establish the risk for nancy to avoid confusions. Many labs use the
fetal aneuploidies. The relative proportion of second trimester BPD and reallocate dates even
these chemicals change in pregnancies associated in cases of confirmed first trimester dating, and
with chromosomal abnormalities, and this is the that is not desirable as gestational age allocation
rationale of evaluating the quantity of these sub- should be done once in early pregnancy and
stances and comparing them in terms of “multi- should not be changed repeatedly. In case there is
ples of median (MoM)” for that stage of no first trimester fetal assessment and the mother
gestation. has booked late or her dates are unreliable, then
Traditionally, the triple serum test was per- the most reasonable option remains to use the
formed which elevated maternal serum alfa- second trimester biometry—especially the BPD
fetoprotein, hCG, and unconjugated estriol to for dating although it comes with the caveats of
assess the risk for Down syndrome. Triple test discrepancy due to early IUGR or fetal anoma-
had a sensitivity of 60–70% for a false-positive lies. In case the BPD is used for dating, the labs
rate of 10–15%. With the addition of one more generally use a range of 30–50 mm for the qua-
analyte—inhibin A—to the triple test, the quadruple test, and similarly if the EDD is used, a
druple marker test has been designed, and this is window of 15–22 weeks is acceptable although
known to have a better sensitivity (80–85%) with 16–18 weeks of gestation is optimal.
a lower false-positive rate (10%), and hence this Another important point with risk allocation
has become the preferred modality of second tri- in the second trimester screening is to consider
mester maternal serum biochemistry. The ana- the first trimester screening results in case they
lytes involved in quadruple test and their expected are available. Ideally, if the first trimester com-
changes in trisomy 21 are expressed in Table 4.2. bined screen is “low risk,” there is no need to
The composite algorithm for calculating risks conduct a second trimester biochemistry as this
based on these analytes is done by approved soft- test has a lower sensitivity than the FTS.
ware, and the crucial points remain baseline The quadruple test is also a “screening test”
maternal age and correct estimation of gesta- and the results generally indicated a “low risk” or
tional age. This quadruple test can therefore be “high risk” for fetal aneuploidies. The “low-risk”
offered to women who have missed the first tri- patients can be reassured, and the “high-risk”
mester screening for any reason and want a good patients are explained that they need to be further
risk reassessment in the second trimester. Dating evaluated to establish the need for definitive diag-
the pregnancy is important and hence early preg- nostic tests to confirm fetal karyotype.
4.7 Cell-Free Fetal DNA Test 4.8 The Midtrimester Genetic

Sonogram
This is a SCREENING test for major fetal aneu-
ploidies with very high sensitivity (99%). It is This is a systematic ultrasound evaluation of the
based on analysis of “cell”-free fetal DNA which fetus to look for any obvious “markers” for fetal
is circulating in the mother’s blood due to pas- aneuploidy in midtrimester (16–24 weeks). There
sage of DNA fragments into maternal circulation are “major markers” or “minor markers” that can
through the fetoplacental vessels after apoptosis be seen at the time of the scan. The major mark-
of fetal cells in the placental bed. ers are major structural anomalies which defini-
It is based on a maternal blood test which can tively increase the risk for associated
be done after 10 weeks of gestation. The “fetal chromosomal abnormalities and hence justify the
fraction” of DNA is analyzed and if that fraction need for invasive testing to confirm fetal karyo-
is more than 4%, then the results are valid for type. The “minor markers” are subtle features
fetal screening. Assuming that the mother is which can be detected by trained sonographers,
euploid and there is no other source of “nonma- and although they may not cause any functional
ternal” DNA in the maternal blood stream, the implications to the fetus as such, their presence
results are likely to indicate fetal DNA-based or absence alters the risk for fetal aneuploidies.
results and are hence highly sensitive with more There are many “minor” or soft markers associ-
than 99% sensitivity reported for chromosome 21 ated with risk of fetal aneuploidies when detected
trisomy assessment. The results are again like in the midtrimester scan, e.g., absent/hypoplastic
“high risk” or “low risk” for aneuploidies and nasal bone, ventriculomegaly, aberrant right sub-
high-risk results warrant invasive test. The “low- clavian artery, intracardiac echogenic foci, echo-
risk” cases can be reassured as the negative pre- genic bowel, fetal renal pyelectasis, short femur
dictive value (with good fetal fraction) of this test or humerus, etc. Individual markers and their
is very good, but in cases of “high-risk” results, importance have been mentioned in the chapter
confirmation of fetal chromosomal status with of system-wise midtrimester scan evaluation.
amniocentesis is indicated. There are some This alteration occurs based on the “likelihood
causes that can contribute to false-positive results ratio” of that particular minor marker with rela-
like confined placental mosaicism, maternal tion to fetal aneuploidy. This ratio (LR) is calcu-
chromosomal mosaicism, maternal neoplasia- lated by the “likelihood” of finding this marker in
related karyotypic aberrations, etc. Hence, this is an aneuploid fetus versus the “likelihood” of
NOT a diagnostic test and “high-risk” results on finding this marker in normal euploid fetuses.
cell-free fetal DNA test must be followed up with Thus, a marker which is present commonly in
a diagnostic test. euploid fetuses and is also seen in aneuploid
The greater sensitivity of this test is definitely fetuses will have a lower likelihood ratio than a
“tempting” to the clinician who is hassled often marker which is seldom seen in normal fetuses.
with the extensive counseling for “false posi- An important concept here to understand is
tives” and lower detection rates of standard that just like the presence of a particular marker
screening tests. However, the cell-free fetal DNA that increases the risk of trisomy 21 based on its
does not prove to be very useful or cost-effective isolated positive likelihood ratio, the absence of
as a “primary screening test.” The added benefits other markers also reduces the risk of trisomy 21
of the first trimester scan for issues well beyond based on their collective negative likelihood
aneuploidy screening still place it as a better tool ratios. Thus, any report which mentions presence
for primary screening as the “combined test” in of one soft marker must also mention presence/
first trimester. absence of other soft markers. The final risk of
trisomy 21 will depend on the composite calcula-
tion of positive and negative likelihood ratios.
From time to time, the individual markers vary in
importance as more and more data accumulates
Further Reading 21
based on the prevalence of these markers in nor-

mal population as compared to aneuploid fetuses. 2. The options of tests available and their
It is thus imperative for all fetal medicine practi- efficacy and limitations must be dis-
tioners to keep themselves updated on the latest cussed in a PRETEST counseling.
protocols for such screening. 3. Screening is voluntary and those who
In summary, there are a range of tests avail- opt out of the process have a right to do
able for screening and each has its own merits so—the decision should be well
and limitations. All tests are not meant to be informed and documented.
offered to all patients as it will lead to tremen- 4. Screening protocols should be up to
dous confusion and defeat the purpose of the date considering constant advancement
tests!! Each unit has to adopt a screening protocol of science, technology, and contempo-
that fits best to their local practices, but it must be rary guidelines.
backed up by methods that carry evidence-based 5. Screening test results should be
sanction for use. Literature is plenty about “com- explained to women in a POSTTEST
bined” screening, “sequential” screening, “con- counseling session to help alleviate
tingent” screening, or “integrated” screening. doubts and concerns.
Each model can be applied in a unit depending on 6. A rational approach to screening strate-
the overall availability of resources, efficiency, gies can help provide a very satisfying
and patient satisfaction. In many cases, one has to experience to women and is a good
have a plan for “opportunistic” screening models adjunct to pregnancy healthcare.
as healthcare seekers may not present uniformly
at a certain gestation or may come with several
past confusing reports—that is the reality in
many sectors where practices are yet to be stan-
Suggested Reading
dardized. While the drive to uniform and
evidence-based care should be a continuous for- Agathokleous M, et al. Meta-analysis of second-trimester
ward movement, clinicians have to understand markers for trisomy 21. Ultrasound Obstet Gynecol.
and adapt practices befitting their local popula- 2013;41:247–61.
tion so as to at least sensitize the population Benn P, et al. Position statement from the chromosome
abnormality screening committee on behalf of the
toward fetal screening in the first place. The final board of the international society for prenatal diagno-
goal would be to provide an ideal screening solu- sis. Prenat Diagn. 2015;35(8):725–34.
tion to every pregnant woman. Cuckle HS, Wald NJ. Principles of screening. In: Wald N,
Leck I, editors. Antenatal & neonatal screening. 2nd
ed. Oxford: Oxford University Press; 2000. p. 3–22.
Nicolaides KH. A model for a new pyramid of prenatal
care based on the 11 to 13 weeks’ assessment. Prenat
Key Learning Points in Screening for Fetal Diagn. 2011;31:3–6.
Aneuploidies Nicolaides KH, et al. First-trimester contingent screening
for trisomies 21, 18 and 13 by biomarkers and mater-
1. Screening for aneuploidies should be nal blood cell-free DNA testing. Fetal Diagn Ther.
offered UNIVERSALLY to all pregnant 2013;35:185.
women.
Basics of Imaging for Fetal
Evaluation 5
Imaging of the fetus is one of the most important ing!!). Obstetric ultrasound employs frequencies
aspects of evaluating the fetus who is the “patient” of 2–15 megahertz (MHz). The higher the fre-
in the science of fetal medicine. Just like the pro- quency of the ultrasound wave, the better is the
tocol of any clinical examinations that starts with resolution, but penetration depth is lesser than a
“inspection,” even in fetal medicine, “inspecting” lower-frequency wave. Thus, in fetal imaging, an
the fetus starts the actual examination. Now optimal compromise has to be made between
unlike other specialities, our patient in fetal med- resolution and penetration to get the best possible
icine comes to us hidden from our view, posi- information required for fetal evaluation.
tioned inside the mother! Therefore, in order to An ultrasound machine has a transducer or
visualize the fetus, we have to use techniques to “probe” which is used to transmit and receive sig-
overcome the barrier of maternal tissues, and the nals from the area of investigation, a processor in
“ultrasound” has become our “magic eye” which the machine which processes this information
helps us see the fetus through the mother’s abdo- into images that is relayed on the “screen” which
men rather “noninvasively.” we view as “images,” and a “control panel” that
Doctors generally get intimidated by the con- helps in coordinating commands in the entire
cepts of physics that are the basis of this ultra- process (Fig. 5.1).
sound technology, and we think it is impossible The probe or transducer has several “piezo-
for us to understand this heavy theoretical phys- electric” crystals mounted together. These crys-
ics stuff!! However, it is important not only to tals can produce a mechanical wave when electric
understand the basics but also to be aware of the pulse is applied to them, and inversely, when
potential and limitations of this brilliant technol- pressure is applied to the surface of certain crys-
ogy because it is a revolutionary tool and its tals, an electric current is produced. This “piezo-
applications are increasing day by day. electric effect” and its inversion lead to formation
Sound waves are mechanical waves that have of images on the scanning machine which we are
the property of getting reflected when they able to decipher to understand fetal anatomy and
encounter an obstacle. Ultrasound is conducted physiology.
as “waves” and the “frequency” is defined as the The ultrasound waves pass into the tissues in
number of vibrations (cycles) per second. The their path and get reflected back from tissue inter-
unit of frequency is Hertz (Hz). Ultrasound waves faces. Reflection takes place at the interfaces of
have a frequency of greater than 20,000 Hz and media with different acoustic densities and is
cannot be heard by the human ear (20–20,000 Hz proportionate to the acoustic density differences
approximately is the range of the human hear- in the sampled area. If the acoustic density differ-

24 5 Basics of Imaging for Fetal Evaluation
Fig. 5.1 Ultrasound probe, machine electricity source
Fig. 5.2 Hyperechoic “Hyperechoic” –

and hypoechoic appears white
“Anechoic” –
appears black
“Hypo echoic” –
appears in varying
shades of grey
ences are low, low level echoes result. If the the computer monitor (screen). The velocity of
acoustic densities are all identical as in sound waves is constant at 1540 m/s and is deter-
homogeneous fluids like blood, amniotic fluid, mined by the wavelength and frequency. The
and urine, the entire wave is transmitted and none higher the frequency, the shorter the wavelength.
is reflected resulting in a “hypoechoic” image. Higher-frequency transducers have a better spa-
When the acoustic densities are markedly differ- tial resolution. This means that they can better
ent such as when dense tissue like bone is encoun- differentiate two closely located side-by-side
tered, the image is “hyperechoic” (Fig. 5.2). spots in the region of interest. The penetration of
The information contained in the returning high-frequency waves is, however, limited.
waves is converted back into electrical impulses Therefore, high-frequency probes are used to
and fed into the computer for processing into an look at near structures and lower-frequency
ultrasound image. The processor computes the probes are used to study tissues at depth.
location (depth) of the signal based on time dif- Abdominal transducers use a frequency of
ferences between transmitting and receiving. 2–6.5 MHz and transvaginal transducers use fre-
Echoes reflected back from tissues close to the quencies of 5–15 MHz.
transducer come in earlier than those from tissues The most common form of ultrasound scan
deeper in the field. The ultrasound picture as used for fetal studies today is a real-time gray-
computed by the processor is then displayed on scale “B-mode” study. B-mode studies indicate
5 Basics of Imaging for Fetal Evaluation 25
reflections arranged along two axes in the region ter is achieved at the cost of some “fuzziness” in
of interest. They use a grayscale which reflects bony margins.
the intensity of the signal and imparts texture to The other attribute of B-mode studies is
the image. real-time. When ultrasound was first used, the
In fetal evaluation, the image on the screen has image was static. It has now for many decades
to be interpreted by the operator in terms of the moved into the real-time mode where the
fetal parts being represented, and thus it is impor- image moves in the same manner as the region
tant to keep in mind the “orientation” of the part of interest moves in real life, similar to the dif-
being scanned. Many times operators do not use ference between a photograph and a video. To
the entire display screen and struggle to see struc- this can be added the concept of depth or the
tures on the screen without magnifying the third dimension. This is made possible by a
image. Most machines have the ability to “zoom” special transducer and computer software
the image, and it is imperative to magnify the arrangement and is referred to as 3D ultra-
area of interest to use the screen optimally and sound. This has further advanced to real-time
visualize better. 3D ultrasound which is known as 4D ultra-
The “gain” on the machine can be adjusted sound. 3D/4D imaging has taken the potential
to alter the brightness and contrast features of of fetal imaging another step forward such that
the image. As a rule, when highly echogenic apart from mere imaging planes, “volume”
structures like bone are visualized, the “gain” analysis is possible and better delineation of
is usually reduced so that the margins become fetal anatomy, placental planes, etc. can be
sharply defined. However, when better soft tis- achieved. Figure 5.4 shows a comparative dis-
sue delineation is expected, the gain has to be play of 2D and 3D pictures—the fourth dimen-
increased. sion in “4D” ultrasound is actually “time” such
The picture (Fig. 5.3) here demonstrates the that real-time imaging in 3D is actually called
effects of gain alteration in obtaining pictures of 4D imaging.
the fetal head. When the gain is low, the skull The term M-mode refers to a motion mode in
margins are sharply delineated but the intracra- B-mode studies. This is currently employed in
nial structures are not clearly seen. When the gain obstetrics to assess fetal cardiac motion to assess
is increased, better visualization of the brain mat- heart rate and rhythm as well as for studying the
Fig. 5.3 Gain settings: high and low

Fig. 5.4 2D/3D pictures
Fig. 5.5 M-mode
excursions of the valves and the myocardium.

Figure 5.5 shows an M-mode study of the fetal 5.1 Fetal MRI
heart rate. The cursor runs across a section of
tissues and any motion is detected by pulses on In very limited indications, fetal MRI can be used
the image corresponding to the region of the to augment findings of the ultrasound and help in
moving object. refining the diagnosis. Over the years, MRI has
5.1 Fetal MRI 27
corroborated findings of ultrasound, and espe- the findings of ultrasound and better documenta-
cially in fetal CNS malformations, the role of tion and demonstration for sharing a medicolegal
MRI has been accepted in view of better delinea- responsibility in case the ultrasound findings are
tion of soft tissue arrangements. There were some questioned. Thus, an MRI is not a replacement
initial studies which suggested a definite advan- for ultrasound in fetal imaging but has some
tage of MRI over ultrasound, but considering the adjunctive role which can be justified in select
improvement both in ultrasound technology and cases with rational indications.
in the expertise of fetal ultrasound, the practical In a nutshell, plan 2D ultrasound remains the
utility of fetal MRI remains rather limited. Fetal most important method of fetal imaging which is
movement is a hindrance to good image acquisi- easily complemented by Doppler techniques.
tion on MRI, and sometimes the efforts to achieve Additional multiplanar imaging (3D/4D) is done
fetal quiescence can increase the time taken for for surface rendering, better storage of imaging
MRI, hence increasing the cost and time inputs data, and post-storage processing options which
further (Fig. 5.6). help in learning and teaching. Fetal MRI has a
MRI can provide useful information about limited role as an adjunct modality for corrobora-
fetal CNS malformations in the third trimester, tion of ultrasound findings when in doubt espe-
but by then the obstetric plans cannot change cially in CNS malformations where soft tissue
much. Safety of 1.5 T MRI without contrast has delineation is vital.
been accepted in all trimesters of pregnancy. A pictorial representation of all imaging
Sometimes getting an MRI helps in reconfirming modalities in fetal medicine is given in Fig. 5.7.
Fig. 5.6 Fetal MRI

supply should be connected to prevent potentially

dangerous voltage fluctuations. The probes must
be handled carefully to prevent any mechanical
2D Ultrasound damage. After the scan is over, the surface of the
in all cases with probe should be wiped clean using a soft tissue or
Doppler studies
3D/4D cloth to remove any remnants of the coupling gel.
as needed multiplanar
imaging in
MRI It is important to “freeze” the probe when it is not
in select
some cases indications being used to prevent unnecessary heating of its
piezoelectric crystals. Most machines are
Imaging in Fetal Medicine mounted on wheels that can be locked and
unlocked to facilitate movement of the unit.
Training the scan room assistant staff members in
Fig. 5.7 Imaging in fetal medicine
the correct handling of the machine and probes
will go a long way in increasing the longevity of
5.2 Safety of Ultrasound the scan machine by minimizing the avoidable
wear and tear problems.
Ultrasound remains one of the safest methods of
fetal evaluation, and despite its use through
decades, there are no confirmed biologic effects 5.4 Ethical Considerations
on patients and their fetuses from the use of diag-
nostic ultrasound evaluation. The benefits to It is important to remember that the woman
patients exposed to the prudent use of this modal- undergoing an ultrasound examination is a human
ity outweigh the risks if any. Most research and being and not a laboratory specimen. She may
monitoring bodies have corroborated this fact already be well informed and have undergone
and have laid down safety guidelines to further several examinations in the past but is equally
minimize any potential damage that can be fore- likely to be a first-timer with the attendant anxi-
seen. It is wise, therefore, as for any medical test, ety, ignorance, and apprehension. She should be
to perform the examination only when clearly reassured about the “painlessness” and safety,
indicated. The operator performing the examina- particularly in the context of the fetus. A brief
tion should exercise due care to use appropriate overview of the information wanting to be
energies and keep a track of the duration of the obtained by the clinician should be conveyed. An
study in order to comply with the ALARA prin- appropriate review of clinical features should be
ciple. This principle simply states that the use of carried out, and appropriate clinical information
technicalities should be optimized to obtain qual- and consent forms should be completed as per
ity images with frequencies, power, and duration institutional and legal norms. Since the procedure
as low as reasonably achievable. involves an invasion of privacy, however legal,
care should be taken to restrict the flow of medi-
cal personnel into and out of the examining suite.
5.3 Some Good Practice Points Where possible, an attempt should be made to
keep those parts of the anatomy covered that do
While ultrasound itself is a safe method of fetal not need to come in contact with the transducer.
evaluation, the ultrasound machine needs to be Since ultrasound gel and bleeding can be messy,
kept in optimum condition to get the best results it is considerate to offer the patient a gown to
of fetal imaging. The machine should be placed change into.
in a room with a temperature regulation facility Fasting is not required for fetal scans and
to maintain a stable room temperature as there must be stated prior to wall women waiting for
can be significant heat generated while the scan- their scans. The transabdominal scan is done in
ner is functioning. A stable, uninterrupted power a supine position. In advanced pregnancy, this
5.4 Ethical Considerations 29
might compromise venous return to the heart gel is rather cool and can be uncomfortable
from the lower limbs. The patient could feel sometimes so it should be warmed in winter
faint or vaguely uncomfortable and should be months. When using this gel for assisting in
put into a lateral position for a few minutes ultrasound-guided procedures, it is useful to
before resuming the scan. Transvaginal scans do sterilize it to prevent infections.
not require a lithotomy position or suspension After the completion of the fetal scan, the
of the feet in stirrups. A foldaway table is useful finalization of the report and conveying the same
to help angulate the vaginal transducer. If the to the parents should be done with utmost sensi-
luxury of this is not available, a cushion under tivity and confidentiality. When the results are
the pelvis is useful. A condom could be used to normal, a fetal scan should be a very satisfying
cover the transducer if special probe covers are experience for the parents. In situations where a
unavailable. Operators must use gloves for a fetal anomaly is detected, measures should be
transvaginal procedure and disposable probe taken in confirming the facts and preparing a
covers are mandatory. Air-drying of transducers multidisciplinary care plan so that the parents
is adequate for destroying the human immuno- have understood the problem and have clarity
deficiency virus but inadequate for several other toward the next step.
microbes. Some centers additionally use trans- Imaging in fetal medicine is therefore a very
ducer dipping in microbicidal solutions. vital part of fetal evaluation but is only one aspect
Manufacturers’ recommendations need to be of the entire concept of fetal care. The purpose of
followed for this, and there are specialized this chapter was to introduce the reader to the
probe decontamination instruments available basics of instruments and technology used for
too. Ultrasound gel should be used as necessary fetal imaging which will help produce the images
to permit smooth transducer movements. This as explained in the following chapters.
Evaluation of Fetal Biometry
6
Bios stands for life, and metros for measure- nique of measuring fetal parts that are used to
ment—so “biometry” is a term used for an activ- derive the assessment of fetal size at every stage
ity where we are “measuring” living things. In of pregnancy.
fetal medicine, biometry is the activity of mea- At different stages of fetal development, the
suring certain parts of the fetus such that an biometry parameters are different and have been
assessment of growth can be made and with some validated for correlation with gestational age
combination of measurements, fetal weight can such that growth assessment can be done.
be estimated.
Measurements are taken on images magnified
on the screen of the ultrasound machine, and 6.1 Ultrasound Biometry in Early
these “absolute” values are then expressed as Pregnancy
“centiles” for that stage of gestation based on
data amalgamated through large population stud- The most important aspect of early pregnancy
ies—both cross-sectional and longitudinal. These ultrasound is to establish an intrauterine preg-
measurements or “biometry” is an integral part of nancy and its viability followed by biometry. The
any fetal evaluation because the status of fetal “gestational sac” first becomes visible on TVS
growth—whether appropriate or aberrant—is during the fifth week appearing as a small sono-
one of the basic parameters of establishing nor- lucent area surrounded by an echogenic ring of
malcy of the fetus. Even in the absence of any chorionic villi. The yolk sac appears during sixth
detectable anomaly, a fetus whose growth is lag- week and is seen as a hypoechoic ring with echo-
ging behind its expected gestational age parame- genic margin. By the end of sixth week, the fetal
ters (small for dates—SGA) or one which shows pole is visible on TVS as a 2–8 mm pole with
an accelerated pace of growth (large for dates— embryonic cardiac activity.
LGA) has a worse prognosis than an appropri- On TAS these landmarks are visible 1 week
ately grown fetus. What is the “normal parameter” later than on TVS. With ultrasound equipment
is defined based on reference charts and standard improving in quality of resolution and penetra-
graphs derived from population-based studies, tion, every year these limits are bound to get
and the concept of “fetal growth” will be dealt redefined (Fig. 6.1).
with in detail in a separate chapter in this book. The biometric parameters in early pregnancy
The present chapter concentrates on the tech- ultrasound are mentioned in Table 6.1.

32 6 Evaluation of Fetal Biometry
Yolk sac
Fetal pole
Intrauterine gestational sac
Fig. 6.1 Early pregnancy scan
Table 6.1 Biometric parameters in early pregnancy ultrasound

What and how to measure Picture
Fetal pole Length: The fetal pole is measured as
the longest measurement along its
longitudinal axis excluding the yolk
sac and extremities and expressed as
crown-rump length (CRL) in
millimeters (mm) or centimeters (cm)
Yolk sac Diameter: The longest diameter of the

yolk sac is measured as a straight line
6.1 Ultrasound Biometry in Early Pregnancy 33
Table 6.1 (continued)

What and how to measure Picture
Gestational Mean sac diameter (MSD): The
sac longitudinal diameter of the GS is
measured in three orthogonal planes
and then divided by 3
Fetal heart Beats per minute: Measured using

rate calipers on an M-mode tracing of the
fetal cardiac activity
Any adnexal Dimensions: Linear measurements at

structure (e.g., least in two perpendicular planes
maternal
ovaries or any
other mass
like cysts,
etc.)
6.2 Significance of Early 6.3 “Dating Is a New

Pregnancy Biometry Beginning!!”
CRL is measured as the largest dimension of This “dating” is of utmost importance in the
embryo in its longitudinal axis, and it is used as overall management of pregnancy as major
a primary measure of gestational age between 6 obstetric and perinatal decisions are led by the
and 14 weeks (or up to a CRL of 84 mm). This estimation of gestational age. The phrase “dating
concept of dating a pregnancy based on the is a new beginning” has been coined with the idea
crown-rump length of the fetal pole was sug- of establishing how “dating” the pregnancy helps
gested by Hugh Robinson in a seminal paper in in properly planning further care—it is as good as
1975, and it is indeed one of those “time tested” a new beginning to the whole gamut of mater-
facts that even today continues to be accepted, nofetal evaluation in pregnancy. Table 6.2 enu-
quoted, and referenced even in the most recent merates some important issues which are based
publications on dating of human pregnancies. on proper dating of the pregnancy.
Since it is widely acknowledged that maternal This leads us to the fact that by the end of the
recall of last menstrual period dates may be first trimester, there should be an unequivocal
inaccurate for the purpose of dating in almost clarity about the dating of the pregnancy. As we
40% cases due to a number of reasons, have understood that the LMP is not the most
ultrasound-based dating is the most accurate accurate method and hence after checking both
estimation of gestational age in early pregnancy. LMP and the CRL of the first trimester scan, an
Studies have accepted that as long as the ultra- expected date of delivery or “EDD” should be
sound dating and LMP-based dating are concor- allocated to the pregnancy. Thereafter, in that
dant within a week’s time, it is acceptable to use pregnancy, the patient must be explained to quote
either method, but if the disparity is more than a her EDD every time she comes for an obstetric
week, it is better to redate based on the USG in evaluation as women are traditionally accus-
early pregnancy. tomed to quote their LMP and this leads to sig-
In multifetal gestations, where there are nificant confusion in maternofetal evaluation.
more than one fetuses, the CRL of the larger EDD once allocated in first trimester should not
fetus is taken into account to date the preg- be changed subsequently in the same pregnancy.
nancy. The rationale behind this is that while
there are known causes of early fetal growth Table 6.2 Importance of “dating” a pregnancy
restriction, it is highly unlikely for macroso- 1. Assessment of appropriateness of fetal growth
mia to set this so early and hence the larger 2. Timing of fetal aneuploidy and anomaly screening
scans
fetus probably represents the normal growth
3. Timing and interpretation of serum biochemistry-
pattern. In multiple pregnancies, especially based aneuploidy/PIH screening
with ART and delayed embryo transfers, these 4. Planning invasive prenatal diagnostic tests
concepts are getting further refined. This aspect 5. Decisions to deliver in cases of PPROM/IUGR/
will be dealt with in detail in the chapter on complications of fetal anomalies/multiple
“multiple pregnancy.” gestations, etc.
6.5 Biparietal Diameter 35
All obstetricians and fetal medicine practitio- The rationale of using one method over the
ners should remember to “date” a pregnancy other is based on the fact that in the age of the
BEFORE starting to evaluate the fetus. This will earlier scan machines, it was easier to define the
automatically dispel most confusions regarding inner margin of the distal parietal bone—this is
growth problems. A detailed discussion on hardly an issue with the excellent resolution abil-
growth evaluation will be done in Chap. 9 (“Fetal ities of the present-day machines.
Growth Disorders”). The proponents of the “outer-to-outer” mea-
surement claim that this is clinically better justi-
fied because when the head circumference is
6.4 Fetal Biometry in Second measured after birth, it is always along the outer
and Third Trimester margin of the skull, so logically the same
approach should be followed antenatally.
The standard fetal biometric measurements Table 6.3 enumerates the important points to be
reported on second and third trimester ultrasound considered while measuring the fetal BPD.
are:
• Biparietal diameter (BPD)

• Head circumference (HC)
• Abdominal circumference (AC)
• Femur length (FL)
These measurements when calculated together

based on formulas give the estimated fetal weight.
Most modern ultrasound machines have these
formulae included in their basic calculation soft-
ware such that one need not memorize these, but
it is important to understand their derivation.
6.5 Biparietal Diameter Fig. 6.2 BPD
This is the length between the two parietal emi-

nences in the fetal skull measured in an axial Table 6.3 Measurement of fetal biparietal diameter
plane—either a transventricular plane or a transt- (BPD)
halamic plane. Axial view of the skull along transventricular/
This is measured perpendicular to falx cerebri at transthalamic plane
the broadest part of the skull, either from the outer Low gain settings to get sharper margins of the bone
CSP should be well visualized interrupting the falx
margin of proximal parietal bone to either the inner
cerebri. Cerebellum should NOT be seen in this view
margin of distal parietal bone or the outer margin of Largest diameter between the parietal eminences is
the same (Fig. 6.2). The academic debate between measured perpendicular to the falx
which method should be used remains unanswered One may measure either O-O or O-I but it is important
as in reality there is not much a difference in the that the same protocol be used in all serial
measurements of a particular fetus
actual measurement either ways.
6.6 Head Circumference Similarly at times, the head shape is some-

what squarish with a smaller OFD compensated
It is measured at the outer edges of calvarium. by a larger BPD leading to brachycephaly
The anatomical slice required to measure the HC (Fig. 6.4b). This may be a normal variant but is
is the same as that for the BPD. The HC may be associated with some fetal anomalies and tri-
directly measured with an ellipse (see Fig. 6.3a, somy 21.
b) or can be derived from the BPD and the The ratio between the biparietal diameter and
occipital-frontal diameter (OFD). the occipitofrontal diameter is known as the
The BPD is measured as explained above, and “cephalic index,” and it is calculated using the
the OFD is obtained by placing the calipers in the formula: CI = BPD/OFD × 100.
middle of the bone echo at both the frontal and In normal cases, it ranges between 75% and
occipital skull bones. 78% in the second and third trimesters with a
After taking two mutually perpendicular mea- gradually increasing trend in pregnancy such that
surements, the head’s circumference is computed fetuses at term and in cephalic presentation have
using the formula: HC = (BPD + OFD) × 1.62. higher CI than preterm fetuses or those in breech
In some cases, the OFD is longer than usual presentation.
which is compensated by a smaller BPD and the The advantage of the ellipse method is its ease
cross section of the fetal head looks somewhat of application, but it may not work very well in
oval as shown in Fig. 6.4a, a condition called cases where there is significant distortion of the
dolichocephaly. This may be a normal variant in perimeter either due to inherent anomalies or a
many cases especially when the fetus is in breech deeply engaged head when it is difficult to get a
presentation in utero but rarely may be part of a complete view of the fetal head. Independent
dysmorphology sequence and hence needs a measurements of two perpendicular axes are
detailed evaluation. helpful in such situations.
a b Two methods of measuring HC
Ellipse method
BPD
OFD
Fig. 6.3 (a) HC. (b) Methods to measure HC

6.6 Head Circumference 37
a OFD>>>BPD : Dolicocephaly
Biparietal diameter
Occipitofrontal diameter
b BPD = OFD : Branchycephaly
Biparietal diameter
Occipitofrontal diameter
Fig. 6.4 (a) Dolichocephaly. (b) Brachycephaly

Both these methods are acceptable in clinical

a
practice and most users have a personal prefer-
ence of one or the other. What is important is to
maintain similar measurement protocols to avoid
confusion in comparison in serial evaluations.
Accurate measurement of fetal head circum-
ference is important as it is acceptable as a
method of dating in the second trimester for those
where first trimester dating is unavailable. For
every stage of gestation, biometry charts are
available which can convert numerical measure-
ments into “centiles,” and a measurement
between 5th and 95th centile is considered appro- b
priate for dates. In case the HC measurements are
below the 5th centile (microcephaly) or above
95th centile (macrocephaly), one is alerted to the
possibility of a fetal anomaly, and it warrants
detailed evaluation and follow-up. Ellipse method
S
Biometry can be represented in centiles, or as p

i
UV
n
±2.5 SD from mean or as Z-score deviations e
depending on which method adheres to local pro- stomach

tocol and the comfort level of the users. The use
of Z-scores in recent publications depicts that
there is a distinct advantage especially for com-
APAD-TAD method
parison, but as most conventional users are well
versed with the concept of “centiles,” it is still the Fig. 6.5 (a) AC. (b) Different methods of AC
most prevalent method of clinical explanation of measurement
fetal biometry.
in Fig. 6.5b. The APAD is the linear distance
between the skin over the anterior abdominal
6.7 Abdominal Circumference wall to the back of the spine, while the transverse
diameter is the widest distance perpendicular to
This is measured on the transverse section of the the APAD in the same section.
abdomen as the outer margin of the plane where The AC is then calculated using the formula:
the stomach bubble is seen and the entry of AC = π(APAD + TAD)/2 = 1.57(APAD + TAD).
umbilical vein to DV is seen as a J shape curving The important considerations while taking AC
toward right with a single rib on each side. Again, measurements are given in Table 6.4.
like the HC, AC can be measured as an ellipse The fetal abdominal circumference is one of
along the outer margins of the plane described the first parameters that is altered in growth dis-
above or as a composite measurement of the orders like IUGR or macrosomia. This is related
transverse and anteroposterior diameters at the to the fact that most of the fetal abdominal cir-
same level as shown in Fig. 6.5a, b. cumference is due to the size of the fetal liver
The AC is measured along the external skin which is the storehouse of fetal energy. A growth-
line, either with the “ellipse” method or using restricted fetus will have a smaller abdomen
two perpendicular linear measurements—the much before restriction of size of the fetal head
anteroposterior abdominal diameter (APAD) and or long bones start and thus changes in fetal AC
transverse abdominal diameter (TAD) as shown are sensitive indicators of fetal growth.
6.9 Calculation of Estimated Fetal Weight on Ultrasound 39
Table 6.4 Important points while measuring the fetal AC

Axial view of the fetal abdomen is obtained with the
abdominal segment of the umbilical vein seen at the
level of the portal sinus
Medium gain settings to get soft tissue shadows in
addition to the bony rib margins
Normally, the stomach bubble should be seen in this
view but NOT the fetal kidneys
AC can be measured as an ellipse along the outer
margin of this view
Alternatively, TAD and APAD can be measured
separately as described in the text
It is better to measure the AC in a view such that the
spine is laterally placed—at 3 o’clock or 9 o’clock
position rather than directly anterior or posterior
Fig. 6.6 Femur length
Excessive pressure on the maternal abdomen can
distort the AC and lead to erroneous measurement.
skeletal dysplasia and that required detailed

testing and workup. The femur closer to the
6.8 Measurement of Fetal Femur probe is measured to avoid artifacts and
Length inaccuracy.
In routine biometry, it is not necessary to mea-
In second and third trimesters, fetal femur length sure all long bones individually, and a general
is taken as an important component of the for- visualization of the presence and symmetry of
mula that helps in estimating the fetal weight the limbs is sufficient. However, whenever the
through ultrasonographic measurements. All femur length is discrepant for gestational age, it
long bones are examined in low gain settings to is imperative to measure all long bines and tho-
get a sharper definition of the edges and are mea- racic circumference to check whether the prob-
sured end to end, excluding the epiphysis. The lem is isolated or generalized.
femur is thus measured along its long diameter,
while the image is optimally magnified and the
bone is placed at an angle of insonation of 6.9 Calculation of Estimated
45–90°. Care is taken to exclude the distal femo- Fetal Weight on Ultrasound
ral epiphyses and only the ossified diaphysis is
measured. The angle of insonation should be Using the biometric parameters described above,
optimal lest it may foreshorten or lengthen the the fetal weight can be estimated by several for-
bone shadow leading to inaccurate measurements mulae. There are more than 30 such formulae
(Fig. 6.6). suggested in literature claiming various degrees
The bone length is plotted on the reference of accuracy, but in common usage, the Hadlock
chart and the centiles are followed on serial formulae are used and in these the composite
growth estimation. Bone length is a familial trait (AC-FL-HC-BPD):
and sometimes in families with low average
adult height, the fetal long bones may appear to • Hadlock 1: Log 10 (weight) = 1.304 + 0.052
be along the lower centiles. As long as the shape 81*Ac + 0.1938*FL − 0.004*AC*FL
and echogenicity are normal and there is defi- • Hadlock 2: Log 10 (weight) = 1.335 − 0.003
nite positive interval linear growth in 2–3-week 4*AC*FL + 0.0316*BPD + 0.0457*AC + 0.
intervals, it is expected to be a normal pattern. 1623*FL
However, if the femur length is well below the • Hadlock 3: Log 10 (weight) = 1.326 − 0.003
5th centile in addition to abnormal shape or cur- 26*AC*FL + 0.0107*HC + 0.0438*AC + 0.
vature of the shaft, then there is a likelihood of 158*FL
• Hadlock 4: Log 10 (weight) = 1.3596 − 0.00

386*AC*FL + 0.0064*HC + 0.00061*BPD*
AC + 0.0424*AC + 0.174*FL
The estimation of fetal weight is accurately up

to 90% and errors creep in at larger sizes and
larger gestational ages. The estimated fetal
weight is a marker for fetal “size,” but fetal
growth can only be determined by a temporal
assessment of progressive increase in this size.
Hence, growth is commented upon only after
serial measurements of size over at least 2–3-
week intervals. Fetal growth and its related con-
Fig. 6.7 Tanscerebellar diameter
cepts will be dealt with separately in Chap. 9.
The cerebellum is located in the posterior cra-

6.10 Supplementary Biometry: nial fossa surrounded by the dense petrous ridges
The Transcerebellar and the occipital bone making it withstand the
Diameter deformation caused by extrinsic pressure, and
this makes it possible for assessing GA even in
While all the abovementioned parameters are third trimester by this measurement. Thus, it is a
routinely used to assess fetal size and dates, the good practice to include TCD measurements as
transcerebellar diameter is also measured in the part of the regular biometry protocol for fetal
second and third trimester as a corroborative evi- evaluation.
dence of fetal dating. TCD is measured in a plane The above biometry parameters are used com-
identified by obtaining an oblique view through monly to assign size of a fetus. Several other
posterior fossa that included visualization of parameters can be assessed and measured in the
midline thalamus, cerebellar hemispheres, and fetus. Such parameters may be relevant in spe-
cisterna magna. The longest diameter across the cific circumstances and need not be included in
cerebellar peduncles is measured and the values each and every fetal assessment. A common
are compared to the nomograms for that gesta- example is the measurement of all fetal long
tion. Fetal cerebellum can be visualized as early bones whenever the femur length appears shorter
as 10–11 weeks by USG. From second trimester than expected or measuring the interorbital dis-
onward, it grows with a linear correlation with tance when the facial evaluation suggests dys-
gestational age. In cases of IUGR, the cerebellum morphism or asymmetry. In these situations,
is the least affected parameter maintaining its objective measurements help in quantifying the
size in case of fetal growth restriction; hence, problem or ruling out one as may be the case. The
accurate GA can be predicted with TCD purpose of this chapter is to provide a basic over-
(Fig. 6.7). view of fetal biometry for the “generalist” who
Further Reading 41
wants a clearer understanding of the basics. We

have not included such extended biometry in this 3. Once an EDD is allocated in early preg-
chapter to avoid confusion. nancy, it should not be changed.
Having understood basic fetal biometry, it is 4. BPD, HC, AC, and FL are used for cal-
equally important to realize that biometry only culation of EFW.
assigns the “size” of a fetus and does not neces- 5. TCD may be measured to help corrobo-
sarily correspond to “growth.” To comment on rate dates ad growth in difficult cases.
growth, at least one baseline confirmation of 6. Measurements should be compared
dates is needed and even better to have serial fetal with standard nomograms based on
biometry readings which can help in commenting centiles/SD or Z-scores.
on the pattern of growth. We will deal with fetal 7. Biometry is the measurement of the
growth issues in detail in a separate chapter. “size” of a fetus—“growth” assessment
requires serial biometry.
Key Learning Points in Fetal Biometry

1. Ideally, a pregnancy should be “dated” Suggested Reading
in early gestation—maximum by the
Hadlock FP, et al. Estimation of fetal weight with the use
end of the first trimester, a confirmed of head, body, and femur measurements--a prospective
EDD should be allocated. study. Am J Obstet Gynecol. 1985;151(3):333–7.
2. Up to 14-week CRL can be used for dat- ISUOG. Practice Guidelines: ultrasound assessment
of fetal biometry and growth. Ultrasound Obstet
ing pregnancies (i.e., up to a CRL of Gynecol. 2019;53:715–23.
84 mm); thereafter, HC should be used Robinson HP, Fleming JEE. A critical evaluation of
for dating if needed. sonar “crown-rump length” measurements. BJOG.
1975;82(9):702–10.
Midtrimester Fetal Anomaly Scan
7
A systematic evaluation of fetal anatomy is of care, sensible, reproducible, and practical proto-
paramount importance in planning fetal health- cols for conducting the scan have also emerged.
care. The most commonly performed scan for Such protocols help in standardizing the conduct
fetal evaluation is usually the midtrimester anom- of the scan and moderating the expected results
aly scan. Although the science of fetal medicine thereof. The midtrimester fetal anomaly evalua-
is advancing, the first trimester evaluation of tion is by far the most “potential” opportunity to
anatomy is gaining importance; the midtrimester detect most of the fetal congenital anomalies and
anomaly scan cannot be dispensed with because that too at a time when meaningful decisions
many anatomical parameters just cannot be regarding the course of the pregnancy can be
assessed in the first trimester based on their phys- made.
iological nondevelopment at that stage. The While confirming normal fetal anatomy is
details of first trimester fetal evaluation are given extremely reassuring for the parents and doctors,
in Chap. 10. This chapter will concentrate on the the diagnosis of any fetal anomaly warrants an
second trimester fetal anatomy evaluation. intensive workup to establish prognosis and insti-
This “targeted” anomaly scan is done for rou- tute modifications in antenatal, perinatal, and
tine screening of fetal anatomy in the second tri- postnatal care of the fetus based on the specific
mester and must be offered to all pregnant issues surrounding the fetal anomaly. A detailed
women. This evaluation can reassure most par- description of all anomalies is beyond the scope
ents about normal anatomy of the fetus and just of this book, but this chapter will outline the
in case any fetal structural abnormality is remit of systematic evaluation of the fetal anat-
detected, appropriate modification of care can be omy as expected in standard settings and will
planned. also provide a brief preview into common anom-
It is a known fact that fetal structural anoma- alies and their expected workup plans.
lies can occur in about 2–3% of pregnancies even
in an apparently “low-risk” population. The
potential to detect these abnormalities has 7.1 Prerequisites to Performing
increased manifold over the decades with better a Fetal Anomaly Scan
resolution of ultrasound machines and better
understanding of the fetal anatomy and physiol- The fetal anomaly scan is a highly specialized
ogy. Over the years, with more and more clinical method of screening fetal anatomy with the aim
units including this evaluation as part of routine of detecting fetal structural anomalies. It requires

44 7 Midtrimester Fetal Anomaly Scan
specialized training to develop the skill of fetal ment, often significantly. It is unreasonable to
imaging and interpretation to get the expected expect state-of-the-art equipment in every obstet-
results of fetal evaluation. A good resolution ric scanning unit all over the world. Therefore,
ultrasound machine is also a necessary some basic cutoff is needed to set a bar uniformly
prerequisite to performing a fetal anomaly scan at which level it is acceptable to perform a fetal
along with some technical capacity to acquire anomaly scan. The International Society of ultra-
and store images for documentation. There are sound in Obstetrics and Gynecology (ISUOG)
several types of ultrasound machines available in has prescribed some important features to be
the market and many new fancy features keep present in any machine used for satisfactory fetal
getting added to the usual basic software almost anatomy evaluation. Table 7.1 enumerates these
every year due to tremendous progress in science features.
and technology. While new features always add As is evident from the above list, the require-
more clarity in acquisition and demonstration of ments are very basic and expected to be present
images, they also add to the cost of the equip- in most standard machines which are affordable
to average obstetric scan units. The next most
Table 7.1 Machine requirements to perform a fetal important requirement is a skilled operator who
anomaly scan can make accurate diagnosis of fetal anomalies.
• Real-time, grayscale imaging This skill can be acquired by structured training
• Transabdominal transducer 3–5 MHz and certification and honed further by constant
• Adjustable acoustic power output controls with practice.
output display standards
After fulfilling the prerequisites, the plan for
• Freeze frame capabilities
the midtrimester anomaly scan (Fig. 7.1)
• Electronic calipers
• Capacity to pin/store images
includes a general survey of the fetus in utero to
• Regular maintenance and servicing for optimum assess fetal number, viability, biometry, and
performance anatomy along with the placenta, cord, and
cervix.
Fig. 7.1 Remit of the

midtrimester fetal The midtrimester fetal anomaly scan
anomaly scan
Who should be offered? What can be seen?
• Every pregnant woman

should be offered the scan for • Fetal number
checking for fetal anomalies • Fetal cardiac activity
• Fetal biometry
• Basic fetal anatomy
• Umbilical cord
• Placental apperance
When should it be done? and location
• Cervical length
• Timing may be adjusted
between 18-22 weeks
depending on the local rules
7.2 Fetal Number and Viability 45
This chapter will deal specifically with the 7.2 Fetal Number and Viability
assessment of fetal anatomy as the other
aspects have been addressed in other chapters A general survey of the gravid uterus will reveal
of this book. The checklist for fetal anatomy the number of fetuses and one must be always
would include the structures enumerated in alert to the possibility of multifetal gestation
Table 7.2. especially with the rising numbers of the same. In
most cases nowadays, women would have had
first trimester scans and the diagnosis of multife-
Table 7.2 Checklist for fetal ultrasound evaluation at the tal pregnancy would have been established early,
MTAS but in case this is her first fetal ultrasound evalu-
• Start scan by checking fetal number, ation in pregnancy, it would not be unreasonable
viability, and situs assessment before to assume an undetected multiple gestation.
a detailed anatomy check
In case of multifetal pregnancy, the number of
Fetal anatomy: Others:
• Skull • Placenta
fetuses and chronicity/amnionicity assessment
• Brain • Umbilical must be performed followed by detailed anatomi-
cord cal assessment of each fetus.
• Face • Amniotic Majority of pregnancies are singleton and this
fluid should be established and documented in the
• Neck • Cervical report of a fetal anomaly scan.
length
Fetal viability is determined by an actively
• Thorax • Uterine
artery beating fetal heart. This can be seen in real-time
Doppler ultrasound as movements of heart valves and
• Heart chamber muscles rhythmically. It is however a
• Abdomen good idea to document the same by taking one
• Spine measurement of the fetal heart rate. In the second
• Limbs
trimester, this is usually done by using spectral
• Genitalia (local legal limits apply)
wave gate across any of the heart valves (Fig. 7.2),
Fig. 7.2 Rhythmic beating of the fetal heart

and the expected normal heart rate is anything default, then one may miss major abnormalities
between 120 and 160 bpm. like dextrocardia or dextrogastria where the
arrangements are reversed. It is therefore impor-
tant first to understand which side is left and
7.3 Orientation of the Fetus which side is right while performing ultrasound
(Assessment of Situs) scan on a fetus and then checking that organs
expected to be on that side are situated in their
Fetal situs determines how the visceral organs are correct position.
arranged inside the fetal body. Before embarking A popular method used as an aid to determine
upon a detailed anatomy scan, it is useful to fetal situs is the “right-hand thumb” rule
assess fetal situs and ensure that the organs are described by Bronstein et al. for assessing fetal
arranged as expected in “normal” anatomical situs during transabdominal scans. In this method,
arrangement. Just like before starting a long jour- the palm of the right hand represents the face of
ney, one must review the navigation parameters the fetus, and the fetal heart and stomach are on
and orient oneself to the expected route, and the same side of the examiner’s thumb. The oper-
establishing fetal situs before doing the anatomy ator can thus place his right hand in supine posi-
scan is of utmost importance. Sometimes, the tion for dorsoposterior orientation and prone for
stomach and the heart may be situated in opposite dorsoanterior orientation.
sides of the fetus (Fig. 7.3), and then it is impor- Many machines have inbuilt guides for orien-
tant to find out which one is on the left and which tation of the operator with the fetal lie which is
one on the right. useful for beginners. It may also be a practically
We know that the fetal heart points toward useful exercise to keep a doll in the scan room
the left and that the fetal stomach is also nor- and place it in the fetal position in case one is
mally found in the left upper abdomen, but if we confused with other methods of determining
assume left laterality of the heart or stomach by situs.
Fig. 7.3 Stomach and heart on opposite sides—situs anomaly

7.4 Fetal Anatomy Assessment 47
Many methods have been suggested to check in the general functioning of the individual. The
fetal situs and each has its own merit. By far the normal appearance of these skull bones with the
most reliable method is to imagine yourself in expected “gaps” at the anatomical suture lines is
the fetal position once you see the fetus on the highly reassuring. The measurement of fetal head
screen. The left and the right of the screen show circumference and biparietal diameter is done as
different landmarks of the fetus, and if one notes explained in the Chap. 6. The normal shape of the
the position of the fetal head and spine, it is sim- fetal skull in axial view is oval with possible vari-
ple to imagine yourself lying in that position and ations due to familial, genetic, or ethnic charac-
establish right-left laterality. This can be applied teristics like brachycephaly, dolichocephaly, etc.
to the fetus in that position and the position of However, major abnormalities in shape may be
the fetal stomach and heart apex can be then indicative of underlying structural malforma-
noted to confirm that they are on the left side as tions, e.g., “lemon-shaped” skull in spina bifida
expected; this is the simplest method of deter- or “cloverleaf” skull in craniosynostosis, etc.
mining situs and works well in whichever posi- As the fetal skull houses the fetal brain, it is of
tion the fetus is, whether the operator is utmost significance that it provides a strong case
left-handed or right-handed. along with adequate space and capacity for the
brain to grow in time. Abnormal protrusions from
the fetal skull are seen in cases of encephaloceles,
7.4 Fetal Anatomy Assessment and poor mineralization of skull bones (e.g., in
osteogenesis imperfecta) indicates association of
7.4.1 Fetal Skull genetic defects. Some common anomalies seen
associated with the fetal skull are absence of the
The presence of the fetal skull along with its nor- skull vault or acrania and premature fusion of the
mal shape and contours is noted (Fig. 7.4). The sutures (craniosynostosis) leading to abnormal
skull bones are assessed for size, shape, integrity, shape of the skull. Figure 7.5 shows images of
and bone density. The skull bones are arranged in some of these conditions.
a manner to form an appropriate “casing” for the Absence of fetal skull or acrania is uni-
brain and cranial nerves which are so important formly lethal in postnatal life and there is no
Fetal Skull checklist at anomaly scan
• Presence of the skull
• Normal contour of the skull usually checked in

axial section
• Normal mineralisation of
skull bones and presence of
the “suture gaps”
Fig. 7.4 Normal fetal skull

Abnormalities of the fetal skull
Absent cranial vault - acrania Clover leaf skull - craniosynostosis
Frontal scalloping – lemon shaped skull Defect in Occipital bone with encephalocele
Fig. 7.5 Abnormalities of the fetal skull
reasonable treatment available for the same. 2. Transventricular view

This often warrants termination of pregnancy 3. Transcerebellar view
and fortunately this diagnosis can be achieved
in the first trimester scan, and thus obstetric A checklist approach helps in establishing
decisions can be taken at a time safer for the normal anatomical parameters for a given gesta-
woman. tion, and in the midtrimester scan, it is recom-
mended to check the following structures during
fetal brain examination:
7.4.2 Fetal Brain
• Lateral ventricles
The fetal brain is evaluated in the midtrimes- • Bilateral choroid plexi
ter scan based on the recommendations of the • Cavum septi pellucidi
current practice guidelines by standard orga- • The midline falx cerebri
nizations. According to the ISUOG and the • Thalami
FMF guidelines, the expected standards of a • Cerebellum
routine anomaly scan should include evalua- • Cisterna magna
tion of the fetal brain in three axial views
(Fig. 7.6): In case any abnormalities (Fig. 7.7) are detected
during this basic brain evaluation, the fetus should
1. Transthalamic view be referred for a detailed “neurosonogram.”
Trans thalamic Trans ventricular Transcerebellar
Fig. 7.6 Standard axial views of fetal brain
Ventriculomegaly “Tear drop” ventricle
“Banana” Cerebellum
Posterior fossa cyst
Fig. 7.7 Common fetal brain anomalies
It is also important to remember that the fetal show the nostrils too. Another view to check fetal
brain is a developing structure, and even if all facial features is the axial view through the orbits
parameters appear normal at a certain gestation, and just below it, the fetal hard palate can be
it must be conveyed to the parents that some seen.
abnormalities may “evolve” over time and mani- Common abnormalities of the fetal face are
fest during future scans. shown in Fig. 7.9 including cleft lip and palate,
retro- or micrognathia, anophthalmia, hypo- or
hypertelorism, or abnormal facial profile.
7.4.3 Fetal Face
Fetal face is examined in the median sagittal 7.4.4 Fetal Neck

plane and coronal views. The sagittal section
helps to demonstrate the facial profile (Fig. 7.8) The normal fetal neck is (Fig. 7.10) seen as a
with the nasal protuberance, nasal bones, and cylindrical structure connecting the head and the
upper and lower jaws. The frontal coronal view body composed of the cervical vertebrae in the
represents the intact upper lip and slight tilt can dorsal aspect and soft tissue anteriorly.
Profile Lips/Nose Orbits Hard palate
Fig. 7.8 Standard views of normal fetal face
Flat Profile Cleft lip Anophthalmia Cleft palate
Fig. 7.9 Common abnormalities of the fetal face
Fig. 7.10 Fetal neck in longitudinal section and axial view for nuchal fold assessment
Fig. 7.11 Abnormal swelling in the dorsal aspect of fetal neck
No abnormal protrusions, masses, or cysts Common neck masses include cystic hygro-
are expected in this area, and if any of these are mas, thyroid masses, hemangiomas, etc. The
seen, then it is deemed as an abnormality nuchal fold thickness is also measured in the
(Fig. 7.11). fetus, and increased nuchal fold thickness is con-
sidered a marker for fetal aneuploidies and struc- has significant impact on fetal physiology as both
tural malformations. heart and lungs are important organs.
7.4.5 Fetal Thorax 7.4.6 Fetal Heart
Evaluation of fetal thorax is done mostly on the Presence of fetal cardiac activity is one of the first
axial views although the operator also evaluates a steps in fetal assessment, but evaluating the fetal
longitudinal view to assess the diaphragm, gen- heart in the anomaly scan extends to a more
eral appearance of the rib cage, and a smooth structured evaluation of the cardiac chambers and
merging of the thoracic boundaries with the outflow tracts. The basic cardiac examination
abdomen. In the axial section, the normal fetal (Fig. 7.14) includes demonstration of the normal
thorax appears to have normal-shaped ribs outlin- four-chamber view with a normally placed heart
ing the cross section with the heart occupying the defined by an orientation of the cardiac axis at
middle one third and flanked by two equal sized, 45 ± 20° from the midline toward the left and
similar appearing lungs on either side (Fig. 7.12). beating rhythmically at a rate between 120 and
In cases of abnormal contents or arrangement 160 bpm.
of thoracic organs (Fig. 7.13), there may be pres- An extended basic cardiac examination
sure effects on thoracic contents, and this usually (Fig. 7.15) includes the evaluation of right and
Thorax : Axial Thorax : Longitudinal
Fig. 7.12 Axial and longitudinal view of fetal thorax
CPAM mixed CDH

CPAM microcystic bilateral CPAM microcystic unilateral
Fig. 7.13 Thoracic malformations

Fig. 7.14 Basic fetal cardiac views—normal
3 vessel view Multiple views of fetal cardia
Cavocaval view Aortic arch view
Fig. 7.15 Extended basic fetal cardiac views—normal
left ventricular outflow tracts which help exclud- disciplined evaluation protocol helps in detecting
ing major cardiac anomalies like the conotruncal these problems. In case any deviation from nor-
anomalies and transposition of great vessels. mal is observed in the basic examination
Addition of the “three-vessel view” is considered (Fig. 7.16), the fetus should be referred for a
optional during a routine fetal anatomy scan as detailed “echocardiography.”
per guidelines. This view enhances the pickup of Fetal echocardiography refers to a detailed
cardiac malformations’ manifold as discrepancy evaluation of fetal cardiac anatomy and flow pat-
of sizes and orientation of outflow tracts is easily terns. This includes a 2D evaluation of the con-
picked up. Similarly, in some units, the extended figuration and connections, a color flow mapping
protocol includes evaluation of the cavocaval of flow in the chambers and outflow tracts, and a
views and the aortic arch views. Doppler spectral analysis of flow across the
Considering that cardiovascular abnormalities valves and in the outflow tracts. This can be sup-
are some of the commonest congenital malfor- plemented by 3D and 4D studies. With the
mations, a sturdy cardiac examination plan is a present-day machines and technology, it is pos-
very useful part of the fetal anatomy assessment. sible to delineate structural anomalies and assess
It may be noted that most congenital cardiac mal- chamber capacity, contractility, and even pres-
formations occur in the so-called “low-risk” sure gradients so that optimum information can
pregnant women. A high index of suspicion and a be provided to the cardiologist helping them
AVSD VSD Complex defects
Fig. 7.16 Common congenital cardiac defects
Fetal
bladder
Cord insertion site

Fetal stomach
Fig. 7.17 Normal views of fetal stomach, abdominal wall, and urinary bladder
prognosticate the cardiac malformations while the stomach like a “hockey stick.” The fetal
planning treatment. “abdominal circumference” is measured at this
level which is part of the routine biometry
protocol.
7.4.7 Fetal Abdomen Fetal bowel is seen filling the lower abdomen
and the echogenicity of the bowel and liver is
The fetal abdomen is assessed in the axial and more or less similar although bowel shows
longitudinal views (Fig. 7.17) to examine the intermittent peristalsis and is thus distinguish-
presence and position of the visceral organs along able. The lower abdomen shows a hypoechoic
with evaluation of the abdominal wall and urinary bladder and the fetal kidneys are either
abdominothoracic diaphragm. Once fetal situs is in a transverse section of the lower abdomen or
established, presence of a normal-sized stomach in coronal view from the back of the spine
“bubble” in the left hypochondrium is reassuring (Fig. 7.18).
as it indicates patency of the upper GI tract and The abdominal wall cord insertion can be doc-
ability of the fetus to swallow amniotic fluid umented either in a transverse section or in longi-
which fills in the stomach and makes it appear tudinal view, and a normal insertion excludes any
like an hypoechoic bubble. In case the stomach anterior abdominal wall defects. The differential
bubble is absent, it is important to wait for at least diagnosis for any cystic structure seen around the
40 min and recheck so that normal emptying and umbilical cord and its insertion include pseudo-
filling cycle of the fetal stomach is established. cyst, omphalomesenteric duct cyst, hemangioma,
Absent stomach bubble is an important marker and omphalocele or anterior abdominal wall
for fetal GI anomalies or neuromuscular defects.
conditions. There is usually no free fluid seen in fetal
The fetal liver occupies the right hypochon- abdomen and the bowel lumen also generally
drium, and in a transverse section, the umbilical appears unremarkable. Unusual fluid collections
vein is seen curving toward the liver, away from like fetal ascites or abnormal bowel dilatation or
Kidneys :axial Kidneys :coronal Bilateral renal arteries
Fig. 7.18 Normal fetal kidneys
Duodenal atresia Dilated bowel loops Ascites
Omphalocele Gastroschisis
Umb cord cyst with Omphalocele
Fig. 7.19 Fetal GI anomalies
abdominal cysts should be noted and documented a position even if it demands an additional sitting
(Fig. 7.19). for the scan.
It may be noted that many spinal defects
(Fig. 7.21) can have intracranial manifestations,
7.4.8 Fetal Spine and hence any cranial abnormality like ventricu-
lomegaly must warrant a detailed evaluation of
Fetal spine is evaluated in the longitudinal, coro- the fetal spine.
nal, and axial views (Fig. 7.20). The best views Routine evaluation of the spine can be done on
are obtained when the fetus is dorsoanterior. It is 2D grayscale imaging with remarkable clarity,
imperative to visualize not only the normal and use of multiplanar imaging is not necessary
skeletal elements of the vertebrae but also the as per standard guidelines of the fetal anomaly
intact skin above them so as to exclude possibil- scan.
ity of any open spina bifida. Small meningoceles In cases where abnormalities are detected, mul-
can be easily missed if the spine is not visualized tidimensional, multiplanar imaging (Fig. 7.22)
in its entirety and with evidence of intact skin helps in demonstrating the defect clearly and can
covering it. It is therefore useful to wait for such be employed for better documentation.
Coronal spine Axial spine

Sagittal spine
Fig. 7.20 Standard views of fetal spine
Spina bifida Diastematomyelia Hemivertebra
Fig. 7.21 Common fetal spine malformations
Normal spine Kyphoscoliosis
Fig. 7.22 3D rendering of fetal spine
7.4.9 Fetal Limbs ing unhindered movements of the limbs through-

out the course of the scan (Fig. 7.23). While it is
Evaluation of fetal limbs includes assessing all important to measure the femur length as part of
segments of both upper limbs and lower limbs. In the biometry protocol, all other long bones may
each segment, the long bones are checked and the be assessed as per unit protocol. Some units mea-
intersegmental joint mobility is assessed by not- sure all long bones while others only follow a
Lower limbs Open hand Upper limbs
Fig. 7.23 Standard views of fetal limbs
Fig. 7.24 Limb abnormalities
rule of “eyeballing” the long bones and limb such examination only in situations allowed in
movements. Each approach has its relevance the PCPNDT Act (Pre-Conception and Pre-Natal
depending on local requirements. Diagnostic Techniques Act).
In case any abnormality is suspected or
detected in any limb (Fig. 7.24), it is imperative
to document the length of all long bones to make 7.4.11 Other Parameters Assessed at
an objective assessment of limb anatomy. The the MTAS
hands and the feet must be checked to assess their
presence and normal orientation along the wrist Other important parameters assessed along-
and ankle joints bilaterally. side fetal anatomy (Fig. 7.25) in the midtri-
However, counting of fingers and toes has not mester anomaly scan include the evaluation of
been specifically recommended in routine fetal the placenta, umbilical cord, amniotic fluid,
anatomy assessment. This may need to be done in cervical length, and uterine artery Dopplers
cases where specific anomalies are suspected or depending on the protocol of the unit in which
found. the scan is being performed. Umbilical cord
vessels may be counted as an optional compo-
nent of the routine fetal anatomical survey.
7.4.10 Genitalia The technique to assess these parameters and
their clinical relevance is discussed in specific
The fetal genitalia “can” be assessed on the chapters in this book. These parameters may
midtrimester anomaly scan as the basic external not be directly listed under fetal anatomy eval-
genitalia are distinctively formed by this time. uation, but they can affect the overall outcome
However, whether they “should” be assessed and/ of pregnancy and hence a midtrimester fetal
or reported depends on the local legal guidelines. evaluation will remain essentially incomplete
In some countries like India, the law prohibits unless such relevant information is also
routine evaluation of the genitalia but permits included in the report.
7.5 Scope of the Midtrimester Anomaly Scan 57
Placenta Cord Cervix Uterine artery Doppler
Fig. 7.25 Other parameters assessed at MTAS
7.5 Scope of the Midtrimester It is important to explain the limitations of the

Anomaly Scan scan to the parents. It may be useful to provide a
“pretest” information leaflet to them so that they
Despite the fact that the second trimester are well informed about the scope and limitations
anomaly scan is an important checkpoint for of the scan.
almost 90–95% of major structural anomalies, Every operator must make an attempt of
the fact remains that “all” fetal anomalies can- obtaining the standard views and completing the
not be determined by ultrasound scan. We are checklist for fetal anatomy survey. If the standard
used to inserting this sentence in our disclaim- views are unattainable despite correct position
ers, but more importantly, this information and machine settings, an anomaly is suspected.
must be conveyed sensitively so as to allow Based on the operator’s knowledge of fetal anat-
them to have realistic expectations from the omy, the anomaly is identified and defined.
scan. Some fetal anomalies cannot be seen on Presence of one anomaly must alert the operator
ultrasound and some structural issues like late to look for any other issue as isolated abnormali-
onset microcephaly, intestinal obstructive ties and multisystem anomalies are different in
pathologies, nonlethal skeletal dysplasias, terms of their cause, effect, and recurrence risk.
cerebral ventriculomegaly, congenital heart In case a fetal anomaly is detected on the sec-
blocks, etc. may become apparent only later in ond trimester anomaly scan, a detailed evaluation
pregnancy. of the fetus must be done using advanced meth-
Detection of problems in the third trimester ods of evaluation available in contemporary med-
after an apparently normal second trimester eval- icine to firmly establish the anomaly and its
uation causes of a lot of anguish to both parents severity. Fetal anomalies detected may be “lethal”
and doctors. It is imperative, therefore, to include or “nonlethal” but associated with significant
parents in an appropriate “pretest” counseling postnatal morbidity and long-term disability.
explaining to them that although a detailed anat- Some fetal conditions can be offered potential
omy check is undertaken, detection of structural intrauterine therapy to prevent morbidity and
anomalies will never be 100%. Detection rates mortality, while others will require postnatal
will be different depending on the type of anom- investigation or treatment and lead to a reason-
aly, the gestational age at scanning, the skill of ably good outcome. Thus, timely diagnosis of
the operator, the quality of the equipment used, fetal anomalies allows for institution of a relevant
and the time allocated for the scan. It is therefore multidisciplinary care team for counseling the
also suggestive that all these parameters need to parents, allowing them to clarify all their doubts
be optimized to obtain the best results from an and apprehensions summarily and planning fur-
anomaly scan. ther care.
7.6 Planning Further Care After genetic tests are given in future chapters of this
Detecting Fetal Anomaly book.
Some anomalies may be lethal postnatally or
Once a fetal anomaly is detected, the pathway of may be such that the effect on the quality of life
antenatal care changes direction in a manner to postnatally would be severely jeopardized and the
address the consequences of the specific anom- parents may wish to discontinue the pregnancy.
aly that has been detected. After confirming the Within the legal limits applicable, such decisions
diagnosis and sensitively informing the parents may be duly supported by the medical staff as per
about the anomaly, a decision for further testing the unit protocol. In case the etiology of the
and management is made. In case of correctable anomaly could involve chromosomal/genetic
fetal anomalies, after ensuring that the given problems, an attempt to test for the same on the
anomaly is isolated, its natural history and effect fetal sample should be made either by prenatal
on antenatal fetal development need to be testing or on the postnatal sample. A discussion
reviewed and a multidisciplinary team (MDT) is about the possibility of perinatal pathology exam-
formed to provide further guidance. The MDT ination may be made here so that parents are given
consists of the primary obstetrician, the fetal the option of an autopsy of the fetus after termina-
medicine specialist, a clinical geneticist, the tion. These issues may be difficult to discuss in
neonatologist, and relevant pediatric subspecial- cases where the parents are extremely distressed,
ist (e.g., the pediatric surgeon, neurosurgeon, or but the onus lies on the fetal medicine specialist
neurologist, pediatric cardiac surgeon or cardi- and obstetrician to help the parents understand the
ologist, etc.). relevance of this workup which can help
Some anomalies may warrant specific prena- immensely in planning for future pregnancies.
tal intervention to mitigate the antenatal deterio- Very often, given the delicate nature of the
ration and help in postnatal repair. Few anomalies situation emotionally and even due to financial
are amenable to primary antenatal repair in the constraints, such discussions are ignored and
appropriate settings, while most fetal anomalies valuable data is lost. Clinicians must understand
are managed by postnatal correction. Details of the fact that if a pregnancy outcome is adverse, it
some of these fetal “therapeutic” and “palliative” is not the need of the story but the beginning of a
procedures are given in a separate chapter in this puzzle that will need to be solved in the future.
book. Vital clues can be obtained by effective perinatal
Depending on the nature of the anomaly, a workup, documentation, and counseling.
consultation with the relevant pediatric subspe-
cialist and neonatologist can be arranged for the
parents to get a better idea of the expected post- Suggested Reading
natal course. After the multidisciplinary consul-
tation, the parents can now understand the Bronshtein M, Gover A, Zimmer EZ. Sonographic
definition of the fetal situs. Obstet Gynecol.
anomaly better and have a clear perception of 2002;99(6):1129–30.
modifications in antenatal and postnatal course. Fetal Medicine. Fetal anomaly scan – FMF guidelines.
They can make their personal arrangements London: Fetal Medicine. www.fetalmedicine.org.
accordingly to tackle the events that will follow. Ratha C, Optimising Multidisciplinary Perinatal Care in
Correctable Foetal Anomalies. In: Current Progress in
In many anomalies, the complete workup Obstetrics & Gynaecology Volume-6. Studd J, Tan SL,
involves getting chromosomal/genetic tests done Chervenak FA (eds). 2021.
to exclude such associations. Prenatal testing like Salomon LJ, Alfirevic Z, Berghella V, et al. Performance
amniocentesis can be performed and the relevant of the routine mid-trimester fetal ultrasound scan.
Ultrasound Obstet Gynecol. 2011;37(1):116–26.
genetic tests done. Details of prenatal testing and
Basics of Doppler Imaging
and Application in Fetal Medicine 8
The use of Doppler technology has revolution- In fetal evaluation, blood flow patterns are
ized fetal evaluation in a very dynamic way not studied using Doppler. The source and receptor
just literally because it deals with moving objects, of the signals are the ultrasound probe, and the
but because this has enabled a real-time under- moving target is a blood cell in the blood vessels
standing of fetal hemodynamics opening up an in the region of interest. The returning signal is
opportunistic window for prediction, diagnosis, mapped in two ways—color or spectral. A map of
and prognostication of conditions affecting fetal the vessels can be obtained as “colors” which can
health. The term “Doppler” in ultrasound is used be superimposed on the grayscale image. This is
to indicate information regarding blood flow in known as color flow mapping (Fig. 8.2). This
blood vessels. Technically, Doppler studies are indicates direction and velocity of flow.
based on the “Doppler effect” which enables The other method of mapping is known as the
echo-based delineation of moving objects. In a Doppler spectrum which consists of a graph
broader and simpler sense, “Doppler” imaging is showing flow characteristics as a waveform—
based on interaction of the ultrasound beam to a spectral Doppler (Fig. 8.3). These can then be
“moving” target as opposed to a static one. It is quantified as velocities, ratios, and indices. As
based on the “Doppler” effect (Fig. 8.1) wherein shown in the figure, the “waveforms” are created
the returning frequency of waves is altered by the by the phases of the cardiac cycle. The vessel
relative movement of a source and a target. The shows a crest in blood flow during cardiac systole
classical example of the train siren appearing and a trough during diastole. If the vessel is com-
louder to the passenger standing on a platform as pliant and the “resistance” of its walls is not very
the train approaches and similarly appearing seri- high, there is a smooth transition from systole to
ally more feeble as the train departs indicates the diastole, and there is some positive end-diastolic
“apparent change” in frequency of a sound due to flow also through the lumen of the vessel being
the “relative motion” between the source and the studied. If the peripheral resistance of the vessel
receptor of the signal. The train blows the siren at wall is high, the transition from systole to dias-
a fixed frequency, but observers at two points per- tole may be marked by a “notch,” and sometimes
ceive it differently depending on whether the the flows may be absent or reversed in diastole.
train (source of sound) is moving toward them or Visualizing the wave pattern gives a qualita-
away from them. tive assessment of the blood flow but objectivity

60 8 Basics of Doppler Imaging and Application in Fetal Medicine
This observer perceives a louder siren This observer perceives a feeble siren
Source moving towards the observer Source moving away from the observer
Doppler effect Larger Wavelength

Smaller Wavelength Lower Frequency
Higher Frequency “More feeble”
“Louder”
Fig. 8.1 Depiction of the “Doppler effect” when the source of sound is moving
Fig. 8.2 Color flow mapping

8 Basics of Doppler Imaging and Application in Fetal Medicine 61
Red:
Velocity of blood flow

Flow towards the probe
0cm/s
Blue :
Flow away from the probe
Fig. 8.3 Spectral flow
is best achieved by quantification. Hence, the the color vary with the velocity of the blood flow
need for measurable ratios and indices arises. in the area of investigation (Fig. 8.2). When there
The peak systolic velocity (S), the end-diastolic is no movement, there is obviously no signal and
velocity (D), and the average velocity over one hence the color on the screen is “black.” As
cycle (A) are determined. movement starts, the colors become either red or
blue depending on the direction of flow. A
Pulsatility index = (S − D)/A smooth, homogenous red or blue signal indicates
Resistive index = (S − D)/D smooth, laminar flow in the lumen. However, as
the velocities increase, the color changes and red
It may be noted that while both are measures tends toward orange, while blue tends toward
of vascular resistance, the pulsatility index func- light blue as seen in the picture here. When there
tions better for statistical calculations as it will is “turbulence” in flow, then this smooth pattern
have a finite value even in absent diastolic flows. turns into a riot of colors which is known in tech-
In fetal medicine, PI is the commonly used nical terms as “aliasing” (Fig. 8.4).
Doppler index. In assessing for fetal anemia, the Power Doppler (Fig. 8.5) is another form of
peak systolic velocity (PSV) is used. flow imaging. It uses amplitude of scatter rather
Color flow mapping gives information of than a frequency shift to make a map of tissue
blood flow over a large area of investigation, but flow. It is by its inherent nature far more sensitive
the information is rather generic—presence or to slow flow and therefore proving to be useful in
absence of flow and direction of flow. The colors placental angiogenesis studies and in the vascular
are coded usually as red and blue with the code evaluation of some fetal malformations.
demonstrated on the screen such that one color Based on real-time echoes from moving blood
denotes the movement of the target toward the cells within the lumen of blood vessels, Dopplers
probe and the other color denotes the same move- help in establishing details of hemodynamics like
ment away from the probe. On closer evaluation velocity of blood flow during specific stages of
of this “code,” it is obvious that the shades within the cardiac cycle. Fetal Doppler studies have
Fig. 8.4 Smooth and

turbulent flows
Fig. 8.5 Power Doppler
become crucial in planning management of 8.1 Fetal Circulation

growth-restricted fetuses in order to optimize
perinatal outcome. With the emergence of more Circulation of blood in the fetus is a dynamic cir-
and more sophisticated ultrasound machines, we cuit between the placenta and the fetal body. The
are able to define fetal hemodynamics really fetus itself is not capable of respiratory function
well, but the actual clinical significance of these and thus relies on the maternal circulation to
studies depends on the extent of our comprehen- carry out gas, nutrient, and waste exchange. The
sion of the fetal circulation. Understanding the fetal and maternal blood never mix; instead, they
pathways of fetal blood flow and the expected interface at the placenta which allows the
pattern of flow velocities and vessel resistance exchange of gases and metabolites to help oxy-
helps in defining the biophysical condition of the genate, cleanse, and nourish the fetus.
fetus. Color Doppler allows clear visualization of Consequently, the fetal lungs are nonfunctional,
blood flow in the fetal circulation. and a series of shunts exist in the fetal vascular
8.1 Fetal Circulation 63
Placenta
Umbilical Vein
Ductus Portal Vein

Venosus Liver
VenaCava
Foramen
Ovale
Left Atrium Lungs Right Atrium
Head Ductus
and Aorta
Arteriosus
Heart
Tissues
Umbilical Arteries
Fig. 8.6 Fetal circulation
pathways so that these organs are almost com- returning from the nonfunctional lungs via the
pletely bypassed. Figure 8.6 is a systematic rep- pulmonary veins.
resentation of the fetal circulation. The blood then goes to the left ventricle and
Oxygenated blood enters the fetus through the gets pumped into the aorta and into the systemic
umbilical vein and through the ductus venosus in circulation. The blood from the right ventricle is
the liver, most of it bypassing the liver to enter pumped to the pulmonary trunk where, due to the
the inferior vena cava. The ductus venosus links high resistance in the collapsed fetal lungs, a
the umbilical vein to the caudal vena cava, and larger volume passes through the ductus arterio-
the flow of blood is controlled by a sphincter, sus to the caudal aorta. The ductus arteriosus con-
enabling the proportion traveling to the heart via nects the pulmonary artery to the aorta and allows
the liver to be altered. equivalent ventricular function in the fetus. The
In the fetal heart, oxygenated blood enters into ductus arteriosus empties blood into the aorta
the right atrium and the foramen ovale, which is after the artery to the head has branched off, thus
an opening between the two atrial shunts’ highly ensuring that the brain receives well-oxygenated
oxygenated blood from the right atrium to the left blood.
atrium enabling blood to be channeled directly Most of the blood in the aorta is then returned
into the systemic circulation, thereby bypassing to the placenta for oxygenation through the
the lungs. The septum secundum directs the umbilical arteries. Once we have understood the
majority of the blood entering the right atrium basic fetal circulation, it is easy to understand the
through the foramen ovale into the left atrium. significance of the fetal vessels investigated to
Here it mixes with a small volume of blood establish fetal well-being.
8.2 Umbilical Artery Doppler 8.3 Fetal Middle Cerebral Artery

Doppler
The umbilical arteries are representative of the
fetal peripheral circulation, and during normal The other important blood vessel investigated
fetal functioning, the umbilical artery Dopplers during fetal evaluation is the fetal middle cere-
show a pattern with a good systolic and diastolic bral artery (MCA). The MCA arises from the
forward flow (Fig. 8.7). The umbilical Doppler is internal carotid and supplies blood to many
performed usually on a free loop of the umbilical parts of the lateral cerebral cortex, the anterior
artery using color Doppler to identify the vessel temporal lobes, and the insular cortices. This
and then placing the pulse wave Doppler with a vessel carries about 80% of the flow volume
gate of 2–3 mm right in the middle of the vessel received by the cerebral hemisphere. This ves-
with the angle of the gate preferably aligned sel is interrogated at the junction of the proxi-
along the long axis of the vessel. There is a peak mal one-third and the distal two-thirds of its
in cardiac systole and a trough in diastole with length. The Doppler gate is 2–3 mm and the
significant positive end diastolic flow seen in all angle of insonation should be as close to zero
cycles. as possible such that the velocity measure-
When the fetus is under stress, the umbilical ments are reliable. The normal flow pattern in
artery resistance to flow increased which is the fetal MCA is one with tall peaks in systole
reflected in increase in the height of the peaks (Fig. 8.8). During fetal hypoxemia, there is
and progressive diminution of diastolic flow cerebral vasodilatation and the blood flow pat-
leading to “absent end-diastolic flow” (AEDF) as tern in MCA changes so that the diastolic flow
the first sign of a physiological decompensation increases and the phenomenon is called the
mechanism. When fetal distress persists, there is “brain sparing” effect. This is a sign of physi-
a hemodynamic reversal with “reversed end- ological compensation in the fetal circulation
diastolic flow” (REDF) in the umbilical arteries to maintain perfusion to the vital organ—the
as shown in the figure below. fetal brain.
…..
Fig. 8.7 Umbilical artery flow patterns (normal, absent EDF, reversed EDF)
Fig. 8.8 MCA flows

8.4 Fetal Ductus Venosus Doppler 65
The fetal middle cerebral artery blood flow 8.4 Fetal Ductus Venosus
pattern helps in diagnosing another important Doppler
condition which affects fetal hemodynamics—
fetal anemia. When the fetus becomes anemic, The fetal ductus venosus is a conduit between the
the peak systolic velocity of the fetal MCA umbilical vein and the inferior vena cava. The
rises above 1.5 times the multiple of median umbilical vein brings in oxygenated blood from
for that stage of gestation. The charts of nomo- the placenta to the fetus, and hence the DV carries
grams for MCA-PSV at different stages of this oxygenated blood into the IVC into which
gestation are available, and it is useful to plot shunts in order for this to reach the fetal cardiac
the MCA-PSV on a serial nomogram while right atrium. The flow pattern in the ductus veno-
monitoring fetuses at suspicion for developing sus reflects the portocaval pressure gradient and
anemia. As a ballpark figure, the 1.5 MoM at the pressure on the right side of the heart (Fig. 8.9).
any gestation is roughly twice the gestational Normal flow in the fetal ductus venosus repre-
age in weeks, e.g., at 32 weeks of gestation, a sents blood flow velocities during ventricular and
PSV in the fetal MCA greater than 64 cm/s atrial contraction phases. Abnormal venous
would be likely suggestive of fetal anemia. It waveforms are characterized by a decrease of
is recommended however that standard charts diastolic peak forward and increase of peak
be followed and the graphs plotted reverse velocities with atrial contraction in the
accordingly. inferior vena cava and right hepatic vein. The DV
The sensitivity of fetal MCA-PSV in detect- is one of the last vessels to be compromised in
ing fetal anemia is so accurate (>99%) that in fetal growth restriction due to fetal compensatory
a setting of clinical suspicion, raised MCA- mechanisms as it is critical to the supply of oxy-
PSV is enough to diagnose anemia, and there genated blood to the fetus. Abnormal DV Doppler
are methods of quantifying it to warrant a fetal is the single most important indicator of risk of
blood transfusion. The details of this evalua- fetal demise as it indicates a breakdown of fetal
tion and management are given in the Chap. hemodynamic compensatory mechanisms in the
16. face of hypoxia.
Fig. 8.9 DV flow

Another Doppler studied in the fetus is that of assessing the aortic isthmus flow and the interob-
the aortic isthmus. The aortic isthmus is the server variability and lack of robust data has lim-
region in the fetal aorta between the origin of the ited its wide application in clinical practice as of
left subclavian artery and the junction of the duc- now (Fig. 8.10).
tus arteriosus. This isthmus represents an inter- In the cascade of events leading to fetal com-
face between highly oxygenated blood that flows promise in fetal growth restriction, the umbilical
toward the upper part of the body and the partly artery changes occur first. The early changes like
deoxygenated blood going toward the lower parts increased resistance with positive diastolic flow
of the body in the fetal circulatory outflow. Under are followed by late changes like absent or
normal circulatory patterns, there is forward flow reversed end-diastolic flow. The late changes are
in the ductus arteriosus in all stages of the cardiac representative of fetal decompensatory mecha-
cycle. The isthmus is a narrow zone and shows a nisms, and unless the gestational age is the limit-
sharp peak flow in systole with a forward flow in ing factor, the fetus may be delivered to avoid
diastole that follows a narrow incisura post sys- further intrauterine compromise. Progressive
tole. However, reversal of diastolic flow in the fetal compromise is associated with changes in
aortic isthmus is considered abnormal and indi- middle cerebral artery, aortic isthmus, and then
cates reduced oxygen supply to the fetal brain. the venous flow changes which are indicative of
These changes in aortic isthmus occur almost a severe fetal decompensation. The challenge in
week before the changes in ductus venosus flow, managing these fetuses in distress is to strike the
so it has become a potential marker for prognos- right balance between in utero maturation at the
ticating “intact survival” rather than only “sur- cost of further compromise and ex utero survival
vival.” However, the technical difficulty in at the cost of prematurity. The interpretation of
Fig. 8.10 Aortic isthmus Doppler

8.5 Uterine Artery Doppler 67
these Doppler changes is thus of paramount duction of bradykinin, which causes smooth
importance in understanding the level of fetal muscle contraction which closes the shunt. This
stress and optimizing the timing of delivery. This physiological closure causes blood to be directed
is the most important decision in a case of fetal from the pulmonary arteries to the lungs which
growth restriction, but many factors are taken now have expanded and are functioning. Although
into account prior to finalizing this decision— functional closure occurs first, the actual anatom-
fetal evaluation, maternal comorbid conditions, ical closure takes about 2 months and occurs by
neonatology facilities available, and also parental infolding of the endothelium and proliferation of
wishes. the subintimal connective tissue layer resulting in
The significance of interpreting the fetal a residual ligament called the ligamentum arteri-
Dopplers is getting a clarity about the fetal circu- osum. The closure of these unique shunt mecha-
lation along with its unique shunt mechanisms, nisms marks the transition of fetal circulation to
namely, the ductus venosus, foramen ovale, and postnatal circulatory adaptations, and the fetal
ductus arteriosus. dependence on placenta for oxygen shifts to the
The fetal circulation maintains fetal physio- neonatal dependence on its lungs.
logical functions through exchange of oxygen,
nutrients, and metabolites through the placenta
throughout pregnancy. At birth, with the discon- 8.5 Uterine Artery Doppler
nection of the placental pathway, there are sig-
nificant circulatory changes that occur in the The uterine artery is a maternal blood vessel that
newborn baby due to the replacement of the pla- is studied for predicting the risk of maternal pre-
centa by the lungs as the organ of respiratory eclampsia and fetal growth restriction in preg-
exchange. When a newborn baby takes its first nancy. Uterine artery arises from the anterior
breath, the lungs and pulmonary vessels expand, division of the internal iliac artery and can be
thereby significantly lowering the resistance to evaluated close to the cervix in the first trimester
blood flow. This subsequently lowers the pres- and at the crossover across the external iliac ves-
sure in the pulmonary artery and the right side of sels in the second trimester. Both uterine arteries
the heart. On the other hand, the removal of the are evaluated and the mean PI is determined. This
placenta causes an increase in the resistance of can be used for risk assessment of abovemen-
the systemic circulation and hence an increase in tioned issues in an extended screening protocol
the pressure of the left side of the heart—these which is discussed in detail in the Chap. 11.
changes cause the closure of the foramen ovale In addition to assessing stages of fetal hypoxia
which was patent throughout pregnancy. and its associated compensatory events, specific
The birth of the baby also triggers the closure Doppler findings can be used to correlate risk fac-
of the other fetal circulatory shunts. The ductus tors for fetal aneuploidies, to diagnose and prognos-
venosus is weakly responsive to prostaglandin E2 ticate fetal anomalies, and to define unique problems
(PGE2) and prostacyclin (PGI2) which behave as of multiple pregnancies. The individual conditions
vasodilators. With improved pulmonary clear- will be dealt with in detail in their respective chap-
ance resulting from the absence of an umbilical ters in the book, but here is a comprehensive table
blood supply, these prostaglandin effects are (Table 8.1) summarizing the application of fetal
diminished. This loss of blood supply also causes Doppler in various clinical situations.
the sphincter in the ductus venosus to constrict, Clearly, the technology of Dopplers has revo-
thereby diverting blood to the liver. Closure of lutionized the assessment of the anatomy and
the ductus venosus becomes permanent after physiology of the fetus and can be implemented
2–3 weeks of birth, and the remnant of the ductus in diagnosing, prognosticating, and even treating
venosus forms the ligamentum venosum. problems in fetal health. It is therefore imperative
The ductus arteriosus is a muscular artery and that every obstetrician acquires a reasonable
immediately after birth, increased oxygen con- understanding of the basics of the use of Dopplers
tent of the blood passing through it and the pro- in obstetrics.
Table 8.1 Application of fetal Doppler in specific clinical conditions

Doppler examination Clinical condition Interpretation
1. Spectral Doppler across To assess fetal heart rate The fetal heart rate and rhythm can be
cardiac valves assessed to establish viability, normal
patterns, or abnormalities like
arrhythmias or heart blocks
2. First trimester fetal ductus Risk assessment for fetal Raised resistance to DV flows is
venosus aneuploidies correlated with high risk of fetal
aneuploidies
3. First trimester fetal tricuspid Risk assessment for fetal Tricuspid regurgitation raises the risk
regurgitation aneuploidies and cardiac of fetal aneuploidies and cardiac
anomalies anomalies
4. Midtrimester perivesical Color flow is used to ascertain two Normal cord vasculature can be
umbilical vessels patent umbilical arteries demonstrated and anomalies like
two-vessel cord can be detected
5. Midtrimester cardiac Color flow is used to check Abnormal flow patterns can reveal
chambers and outflow tracts chamber patency and flow patterns septal defects, valvular dysfunctions,
or abnormal connections
6. Assessment of fetal Color flow is used to identify Presence of renal arteries rules out
anomalies several conditions, e.g., vascular renal agenesis, abnormal course of
malformations and presence of superior mesenteric artery helps in
certain blood vessels or altered identifying bowel herniation through
course of the same can be checked fetal diaphragm, etc.
to prognosticate anomalies
7. Assessment of problems in Color flow assessment for blood Abnormal Doppler flows help in
multiple pregnancies flow discordance in monochorionic classifying TTTS, TAPS, and TRAP
twin complications in MC twins
8. Assessment of fetal Spectral flows across critical High PSV in MCA is indicative of
hemodynamic compensation vessels help in diagnosing fetal fetal anemia. High resistance flows in
in physiological disturbances anemia and prognosticating fetal umbilical arteries, DV, and aortic
growth restriction isthmus indicate worsening
compensatory efforts on fetal growth
restriction just as low resistance flow
in MCA is a marker for fetal hypoxia
8.6 Safety Issues with Fetal

Doppler Key Learning Points in Doppler Imaging
1. Doppler technology provides a very
Doppler involves exposure of the fetus to high- useful method to assess feto-maternal
frequency signals and thus there are safety con- hemodynamics.
cerns, so the principle of ALARA (as low as 2. Appropriate use of Doppler studies pro-
reasonably achievable) must be adhered to while vides very important information
using this technology. The safety issues are dis- regarding physiological and pathologi-
cussed in the chapter on “basics of fetal imag- cal processes in the feto-maternal-
ing” too. As with any technology, the best results placental unit.
of using Dopplers in fetal medicine can be 3. A thorough understanding of fetal cir-
obtained only by optimal use, proper case selec- culation is of paramount importance in
tion, and adherence to the correct protocols of interpreting fetal Doppler results.
practice.
Further Reading 69
Suggested Reading
4. Blood vessels have definite flow pat-
terns which can be studied quantita- ISUOG. Practice guidelines: use of Doppler ultraso-
nography in obstetrics. Ultrasound Obstet Gynecol.
tively by Doppler indices and used for 2013;41(2):233–9.
correlating clinical outcomes.
5. Use of fetal Doppler can help provide a
very reliable method to prognosticate
fetal outcome in conditions like fetal
growth restriction, anemia, MC twin
complications, and other fetal anoma-
lies such that rational decisions to
deliver can be made.
6. Doppler studies have emerged as the
technology providing the basis to sup-
port most crucial clinical decisions in
current perinatal practice.
Fetal Growth Disorders
9
Fetal “growth” is a continuous process that starts reporting software which enable the user to plot
at conception and continues till birth in a regu- the fetal biometry at each evaluation date and
lated manner depending on its inherent genetic obtain trends of fetal growth.
potential. “Growth” is considered to be a basic A normal growth process involves attaining
characteristic of human life and is defined as an these parameters in a certain time frame. A devia-
increase in physical size. Here it is important to tion from the expected growth trajectory is classi-
recall that “size” and “growth,” although closely fied as a growth disorder—growth may either be
related, have a basic difference. Size can be less or more than expected. The figure below
defined by current biometric parameters and this (Fig. 9.1) shows an example of a growth chart
may or may not be within normal ranges, but and the expected trend of fetal growth alongside
“growth” is a serial process—so even if “size” the actual observed trend thus showing the
may be within normal limits, growth may be sub- difference.
optimal, while even if size is small, interval In Fig. 9.1, it is seen that the observed growth
growth may be normally maintained. parameters were below the expected levels and
We have explained in the Chap. 6 that fetal hence this is an example of “slowing” of growth
parts can be measured, and these composite mea- velocity. The three reference curves indicate the
surements provide a statement of fetal “size.” At 10th, 50th, and 90th centiles of fetal growth
every stage of gestation, there are specific fetal which is represented by the fetal weight in grams
growth parameters that can be measured and along the vertical axis (Y-axis on the graph) for
expressed as a percentile for that stage of gesta- that stage of gestation in weeks (X-axis on the
tion. Whenever we want to quantify fetal growth graph). Fetal biometry is considered appropriate
and label it in comparison to expected parameters for gestational age if individual measurements
at that gestational age, it is a good practice to plot are falling within the 10th to 90th centile for that
the actual growth into charts representing the 5th, stage of gestation. Fetal growth disorders are
50th, and 95th centiles of that parameter as diagnosed when there is significant deviation
expected in that period of gestation. Most ultra- from the expected growth pattern. The accepted
sound machines used today for obstetric scans definition of “crossing centiles” is a slowing by
have these charts inbuilt in their reporting format. more than 2 quartiles as compared to an earlier
There are also specific obstetric ultrasound growth estimate. “Normal fetal growth” is

72 9 Fetal Growth Disorders
Fetal growth chart
Expected trend Observed trend
Fig. 9.1 Observed and expected fetal growth pattern plotted on a growth chart
expected to follow a “growth curve” maintaining 7 days. If the disparity exceeds 7 days, then it is
a trajectory of similar centiles upon serial biom- better to redate the pregnancy based on the early
etry, as gestation advances. pregnancy CRL. Once the dates are confirmed,
In any case, where fetal biometry parameters each pregnancy can be allocated an “EDD”
are not “appropriate for gestational age,” we have (expected date of delivery) which corresponds to
to consider the possibilities of: 40 weeks of gestation. Henceforth, in this preg-
1. Mistaken dates nancy, the EDD should be used for dating to
2. Fetal growth disorders—small or large for avoid any confusion whatsoever.
dates Despite correction of dates if the fetal growth
Once again, this brings us to the revision of curve varies from the expected trend, then we
the concept of dating a pregnancy which has been diagnose fetal growth disorders. The more com-
discussed in earlier chapters. No fetal evaluation mon growth disorder encountered in clinical fetal
should be started without first confirming the medicine is fetal growth restriction and we shall
actual dates of the pregnancy. An early pregnancy discuss this first.
ultrasound with an appropriately measured CRL
is by far the most appropriate method of dating a
pregnancy. The criteria of correct measurement 9.1 Fetal Growth Restriction
of CRL are given in the earlier chapter on “fetal
biometry.” Inability of a fetus to achieve its genetically
Once an early pregnancy ultrasound is per- determined potential for growth is called fetal
formed, the dates allocated by the CRL at that growth restriction. This is a very important
stage should correspond to the dates based on the clinical condition and has tremendous impact
woman’s recollection of her last menstrual on perinatal health; hence, it is imperative that
period, with an allowance of disparity within all doctors involved in fetal and neonatal care
9.1 Fetal Growth Restriction 73
understand this concept very clearly. Over the ric” the fetal head biometry was less affected than
decades, we have witnessed massive amount of fetal abdominal biometry parameters. This clas-
research in this area, and although macroscopi- sification aimed to distinguish the etiology of
cally, it seems that concepts are changing in FGR with the presumption that symmetric FGR
reality, it is just that we are understanding the could result from problems like inherently poor
core issues better and redefining the “cause- genetic potential to grow. On the other hand,
effect” relationship of various biophysical, asymmetric FGR represented a “restriction” to
biochemical, and ultrasound parameters. We growth due to extraneous factors like placental
are now able to correlate the clinical events in insufficiency which would start after some degree
utero to their logical sequelae ex utero by prog- of “normal growth” that would have happened
nosticating the disease in a stage- based earlier on in pregnancy. As a natural adaptive
manner. mechanism, there would be a “redistribution” of
The time tested Barker’s hypothesis of “fetal resources to try and preserve fetal brain growth
origin of adult disease” finds numerous examples while compromising on the peripheral organs.
in the pathophysiology of fetal growth restriction Thus, fetal head biometry (BPD or HC) may still
where the in utero stress on various organs and be within normal limits, while the fetal abdomi-
systems has the capacity to present as organic nal circumference (AC) is at lower centiles–the
malfunctions in later life. With further under- ratio of BPD/AC and HC/AC therefore gets
standing of the origin of these stressors and better altered in asymmetric FGR. There is also lesser
ability to monitor these fetuses along with refine- blood flow to kidneys leading to less amniotic
ment of neonatal care, today meaningful manage- fluid and with serial progression classical Doppler
ment of fetal growth restriction involves greatest changes ensue.
emphasis on ensuring not just ex utero survival Symmetrical FGR is usually due to inherent
but also “intact survival” for the neonate and fetal problems like aneuploidies and genetic syn-
future adult. dromes where the potential to grow is lesser than
normal, but instead of “constitutional,” it is clas-
sified as “growth restriction” because there is
9.1.1 Etiology and Classification serial fall in growth velocity indicating a worsen-
of Fetal Growth Restriction ing growth potential due to “restriction” related
to the pathology.
Fetal growth is affected by the inherent genetic The more recent classification of fetal growth
growth potential of the fetus along with external restriction has been into “early” and “late” FGR
factors which could be maternal conditions, pla- depending on the time of onset of growth restric-
cental support issues, and finally inherent fetal tion in pregnancy. An arbitrary cutoff has been
problems like malformations. Figure 9.2 high- set at 32 weeks of gestation such that if FGR is
lights the major factors that could be causing identified before 32 weeks, then it is called early
fetal growth restriction. FGR, while typically late FGR is expected to set
As is evident from the figure (Fig. 9.2), many in only after 32 weeks. Here it is important to
of these factors are interdependent, and hence realize that just because a case of FGR is diag-
fetal growth is a result of a complex interplay of nosed at 35 weeks, it cannot automatically be
forces which finely balance themselves to facili- labeled as “late onset” unless there is evidence
tate the process of fetal growth and development. to show that till 32 weeks the growth was fol-
If any of the adverse forces become predominant, lowing normal centiles. Serial monitoring of
then fetal growth is “restricted.” fetal growth will help reduce this confusion as
Fetal growth restriction was classified earlier “late onset FGR” and late identification of
as “symmetric” or “asymmetric”. In symmetric “early onset IUGR” will have different progno-
FGR, all fetal parts lagged behind in biometry ses as they represent different pathophysiologi-
proportionally to each other, while in “asymmet- cal processes.
Factors causing Fetal Growth Restriction
MATERNAL FACTORS
Maternal systemic illness

PLACENTAL FACTORS (Chronic or Acute)
Pre eclampsia
Smoking/ Subtance
Poorly formed placenta
abuse
(Inadequate trophoblastic activity, Severe malnutrition
inadequate formation of villi)
Wrongly placed placenta
(placenta previa,
Abnormal cord insertion)
Partially separated placenta
(Large subchoronic bleeds leading FETAL FACTORS
to persistent retro chorial clots)
Placental pathology Structural malformations
Genetic syndromes
(mesenchymal dysplasia, Chromosomal abnormalities
inadequate maturation of villi) Intrauterine infections
Fig. 9.2 Factors causing fetal growth restriction
This classification of “early” and “late” FGR 9.1.2 Diagnosis and Evaluation
involves looking at the placenta playing a pivotal of Fetal Growth Restriction
role in facilitating fetal growth. If the placenta
malfunctions, then one or the other type of growth The fact that “growth restriction” and “small-
restriction ensues depending on the timing of pla- ness” are not always synonymous has been clari-
cental dysfunction. In early FGR, it has been fied in the preceding sections. Therefore, the
shown that the placentae generally are smaller diagnosis of fetal growth restriction involves
and have a smaller number of villi per unit s urface methods beyond simple biometry. Appropriate
area. This results in poor exchange of nutrients as dating and serial biometry remain the most
well as a high vascular “resistance” in the placen- important clues for suspecting fetal growth
tal bed. This resistance may be reflected by high restriction, but fetal Doppler studies help in
resistance flows in the umbilical arteries of the establishing the diagnosis and segregating the
fetus and uterine arteries of the mother. The group of “constitutionally” small fetuses.
details of fetal circulation and Doppler flows are Figure 9.3 depicts an algorithm to establish the
given in the chapter on “fetal Dopplers.” diagnosis of fetal growth restriction.
Fig. 9.3 Algorithm to

diagnose fetal growth Diagnosis of FGR
restriction
Fetal Biometry based on correct dating of pregnancy
Small Umbilical artery and MCA

Normal
Doppler studies
Growth velocity Normal
Slowing by more
Normal Abnormal CPR
than 2 quartiles
Normal growth
Normal
Fetal Growth restriction Constitutionally small
Umbilical artery Doppler changes are evi- The Doppler changes are rather subtle in late
dent once at least 30% of the placental function FGR such that there may be reduction in the
is compromised. In “early onset FGR,” the pla- MCA PI with little change in the umbilical flows.
cental villi are deficient and hence the placental In this situation, sometimes the ratio of MCA PI
function is suboptimal, so it will be expected and umbilical artery PI—the cerebroplacental
that umbilical artery Doppler changes start ratio or CPR—shows perceptible changes even
early. The cascade of umbilical artery Doppler when the individual parameters may not be sig-
deterioration starts with increased resistance nificantly altered. Therefore, in late FGR, the
followed by absent end-diastolic flow and finally MCA Doppler and CPR are good indicators of
reversed end-diastolic flow. This aggravated fetal compromise unlike early FGR where umbil-
placental resistance then exerts stress on the ical artery changes precede the others and are far
entire fetal hemodynamic system which then more obvious in severity. Table 9.1 summarizes
responds by “redistributing” the fetal circula- the various differences between early onset and
tion in a manner to favor vital organs while late onset FGR.
reducing the perfusion of peripheral structures Once the diagnosis of fetal growth restriction
like the intestines, kidneys, and limbs. This is established, fetal Dopplers play an important
redistribution is a compensatory mechanism and role in evaluation and have a very important
as it gets severe, it has adverse effects on fetal prognostic role. Most management decisions will
organs. be guided by the Doppler abnormalities as these
In “late onset FGR,” the placental villi lack closely correlate with the severity of the fetal
maturity and start to dysfunction later in preg- physiological changes due to FGR. Figure 9.4
nancy such that the manifestations are usually shows the clinical significance of Doppler abnor-
seen as suboptimal fetal growth after 32 weeks. malities in fetal growth restriction.
Table 9.1 Differences between early and late onset FGR

Early onset FGR Late onset FGR
Gestation at “onset” Less than 32 weeks Onset after 32 weeks GA
Prevalence Approx. 1% 3–5%
Fetal biometry The EFW is usually below the 10th or The EFW may or may not be below 10th
even 5th centile centile always but growth restriction is noticed
due to significant drop in centiles from
preceding trend
Doppler changes Umbilical Doppler is altered first The MCA alteration is more apparent, while
followed by MCA and DV changes umbilical changes may be subtle and DV may
remain normal. CPR changes are obvious
Placental pathology The placenta is expected to have less The placental villi are not reduced in number
number of villi with significantly lower but have inadequate maturation
villous vascular area
Clinical challenges for Severe prematurity in addition to Risks of hypoxia in a “near-term” fetus with
the fetus smallness and morbidity due to less reserve and possibility of severe
hemodynamic redistribution compromise due to inability to detect the
clinically “subtle” signs
Clinical challenges for Usually associated with maternal Maternal comorbidity is uncommon but
the mother comorbidity like preeclampsia increased risk of operative delivery
Challenge to clinician Optimizing the timing of delivery by Identifying the problem and optimizing the
balancing the odds of severe prematurity timing of delivery to avoid risk of fetal
with the risk of in utero compromise hypoxic injury
Clinical significance of Abnormal Dopplers in FGR
• Placental dysfunction
• Increased afterload for fetal heart
Umbilical artery High placental resistance • Progressive changes indicate
increased risk of hypoxia and acidosis
Lower PI of the MCA is

Middle cerebral artery Central compensatory mechanism indicative of fetal hypoxia
• Abnormal DV indicates
possibility of severe acidosis
Ductus Venosus Inflow of oxygenated blood to the fetus • Strongest short term
predictor of fetal death
Abnormal flows indicate

Aortic Isthmus Interface of cerebral and systemic resistance increased risk of neurological
dysfunction postnatally
• placental insufficiency due to other

reasons than defective early invasion of
High placental resistance trophoblastic cells
Maternal Uterine arteries from maternal side • Abnormal UtA Dopplers are associated
with high risk of intrapartum fetal distress
and emergency CS
Fig. 9.4 Clinical significance of abnormal Dopplers in FGR

9.1.3 Management of Fetal Growth aging fetal growth restriction is to optimize the
Restriction timing of delivery as the perfect balance between
not allowing nonreversible fetal damage due to
The problem in fetal growth restriction is that the the stress of nutritional and hemodynamic com-
fetus in utero is not being able to grow despite pensation while ensuring optimal maturity for an
having the capacity to do so otherwise. This intact postnatal survival and avoiding the risk of
translates into the fact that intrauterine environ- intrauterine fetal demise.
ment is not conducive for fetal growth and the The target of fetal monitoring is to achieve a
solution would involve an intervention such that reasonable maturity and hence at 37 weeks offer-
either that environment is modified or the fetus is ing delivery would be a prudent decision.
removed from that environment and allowed Continuing these pregnancies beyond 37 weeks
growth ex utero. Both these strategies may sound does not show any benefit, and if the Dopplers
logical but have inherent challenges. Modification are not severely compromised, even induction of
of in utero environment in advanced gestation has labor is acceptable at term. However, at earlier
extremely limited possibilities, e.g., treating gestation, decision to deliver is derived by multi-
maternal malnutrition and preventing smoking or factorial assessment, and the mode of delivery is
substance abuse, and as is evident, these are abdominal as these fetuses cannot be further sub-
issues pertinent to a very small fraction of cases jected to the stress of labor. Figure 9.5 summa-
with fetal growth restriction. Improving maternal rizes the challenges in managing FGR at different
diet seems to be a reasonable empirical “inter- gestational ages and the factors based on which
vention,” but unless the mother has definite mal- decisions to deliver may be taken.
nutrition, this is unlikely to be of palpable benefit As is evident from the preceding discussion,
based on the evidence provided by studies. There the decision to deliver a growth-restricted fetus is
are no proven medications as yet that can be taken while considering many factors, and in
started in the second half of pregnancy to improve reality, every clinical scenario will be different.
uteroplacental circulation. It is safe to say that till The wishes of the parents, the NICU facilities,
date, there is no proven “treatment” of fetal and the maternal condition are all confounding
growth restriction. It therefore remains a fact that variables in real life. In case there is a coexisting
finally the goal of management is to monitor a maternal medical condition, then the perinatal
fetus in utero till it becomes reasonable to deliver decisions are skewed in favor of maternal health.
and “relieve” the fetus of the “intrauterine” It is therefore not possible to have one blanket
growth restriction. This is the crux of the princi- algorithm covering management of fetal growth
ple of management of FGR. restriction. At best, one can follow the basic prin-
The growth-restricted fetus in utero copes ciples of healthcare of beneficence and non-
with the stresses on its system by developing maleficence and weigh the pros and cons of every
compensatory mechanisms. The severity of com- case before taking a final decision to deliver.
pensatory mechanisms correlate with neonatal Managing fetal growth restriction remains one of
morbidity, and decompensation finally results in the toughest challenges of present-day
intrauterine fetal demise. The challenge in man- healthcare.
• Closely monitor Dopplers-even absent end diastolic flow in umbilical

artery can justify a decision to deliver at this gestation as waiting for
further deterioration of Dopplers would compromise fetal health further.
32-37 • If umbilical Dopplers are normal but the cerebroplacental ratio is
weeks significantly reduced, monitoring has to be escalated and a decision for
delivery may be taken while considering multiple clinical factors like CTG
and BPP along with parental wishes and Neonatology counselling.
Challenge:
INTACT SURVIVAL
• Closely monitor Dopplers - umbilical artery Dopplers are expected to be

abnormal but at this gestation they cannot guide delivery decisions.
• In the absence of any maternal co morbidity, the trigger for delivery is
usually DV changes as the aim would be pull in utero as long as possible
28-32 weeks to achieve better maturity.
• With good NICU care, Aortic isthmus Dopplers may also be used to
determine timing of delivery as AOI changes precede DV changes by a
week or so but increase risk of neurological injury in the neonate.
Challenge: SURVIVAL
If possible INTACT SURVIVAL
• Detailed discussion of the situation with Neonatologist

• Delivery should be planned after explaining the risk of extreme
prematurity and smallness
Less than 28 weeks • Abnormal DV Doppler will be the trigger as it indicates risk of
IUFD if left in utero.
• The high risk of neonatal morbidity and mortality must be
discussed
Challenge: SURVIVAL
Fig. 9.5 Decisions to deliver in FGR based on gestational age
9.2 Fetal Overgrowth Conditions help in stabilizing the fetal growth velocity. In
some cases, there may be associated fetal anoma-
When the fetal biometry exceeds the expected cen- lies with an LGA fetus and some known genetic
tiles and is above the 90th centile for that stage for fetal overgrowth syndromes must be ruled out.
gestation, it is called “large for dates” or LGA Figure 9.6 shows an algorithm for workup for
(large for gestational age). It is reiterated here that fetal macrosomia.
in any suspicion of fetal growth disorder, the first In case the fetal overgrowth syndromes are
and foremost point to be checked is dating of the suspected, a genetic opinion may be sought, and
pregnancy. In case of mistaken dates, fetal growth specific genetic diagnosis can be obtained which
may be misinterpreted and a false diagnosis may helps in counseling the couple regarding the
be added. To avoid any such confusion, the preg- prognosis and recurrence in future pregnancies.
nancy dates must be reconfirmed. In case no specific cause is found and the fetus
If despite correction of dates the fetus appears is structurally normal, the condition may repre-
LGA, then the two important points to be checked sent a constitutional or familial trait. In such
are maternal sugars and fetal anatomy. Maternal cases, the fetal prognosis is good.
hyperglycemia increases the chances of fetal Unless maternal diabetes is confirmed, elective
macrosomia, and with the rising trend of mater- induction of labor due to suspected macrosomia is
nal diabetes, this is becoming increasingly com- still not recommended by current guidelines.
mon. If maternal diabetes is detected, then Every case of fetal macrosomia presents a tremen-
treating the same and achieving euglycemia can dous challenge to the obstetrician as macrosomia
9.2 Fetal Overgrowth Conditions 79
Large for dates Cheak dating
Confirmed LGA
Mistaken dates
Redate
Check maternal sugars
Check fetal anatomy
Maternal Normal
hyperglycemia LGA with fetal anomalies
? constitutional
Treat the
mother
Diabetic fetopathy
Genetic Overgrowth syndromes
Beckwith- Wiedeman Syndrome

polyamnios, omphalocele, macroglossia, Sotos Syndrome
placentomegaly, long umbilical cord, large
echogenic kidneys, pancreatic cystic dysplasia
Brain abnormalities,
macrocephaly
PerlmanSyndrome
Polyamnios, Simpson-Golabi-Behmel Syndrome
visceromegaly, large
Polyamnios, omphalocele, cystic hygroma,
Pallister-Killian Syndrome echogenic kidneys,
rhizomelic micromella, heart defects, diahragmatic hernia, large cystic kidneys,
cystic hygroma agenesis of the corpus callosum, Dandy
diaphragmatic hernia, increased NT,
facial abnormalities Walker malformation, and placentomegaly
Fig. 9.6 Algorithm for workup for an LGA fetus
is associated with increased risk of birth trauma

(e.g., shoulder dystocia, brachial plexus injuries), 3. Accurate dating of a pregnancy is vital
operative delivery, and also sudden stillbirth. It is in assessing fetal growth.
therefore imperative to identify the cases of LGA 4. Serial biometry with use of charts
fetuses accurately and conduct a thorough antena- depicting biometry centiles can help
tal workup to facilitate a good plan of perinatal assess growth patterns.
care by anticipating the challenges thereof. 5. Fetal growth restriction is more com-
mon than fetal overgrowth conditions.
6. Fetal growth restriction (FGR) can
occur due to various etiologies, and the
Key Learning Points in Fetal Growth currently classification of early versus
Disorders late FGR along with an understanding
1. Fetal growth is a steady process that of evolution of the condition provides
starts at conception and continues guidelines for management of
throughout life. FGR. Doppler studies are of paramount
2. There is an established “expected” pat- importance in FGR surveillance.
tern of growth which is defined as 7. Fetal overgrowth can occur due to
“physiological” at different stages of maternal metabolic disorders or fetal
life. Any deviations from this expected genetic conditions, and prognosis
pattern can lead to growth disorders. depends on inherent etiology.
Suggested Reading Figueras F, Gratacos E. An integrated approach to

fetal growth restriction. Best Pract Res Clin Obstet
Gynaecol. 2017;38:48–58.
Alfirevic Z, Stampalija T, Dowswell T. Fetal and
Gordijn SJ, Beune IM, Thilaganathan B, Papageorghiou
umbilical Doppler ultrasound in high-risk preg-
A, Baschat AA, Baker PN, Silver RM, Wynia K,
nancies. Cochrane Database Syst Rev. 2017;6(6):
Ganzevoort W. Consensus definition of fetal growth
CD007529.
restriction: a Delphi procedure. Ultrasound Obstet
American College of Obstetricians and Gynecologists.
Gynecol. 2016;48:333–9.
Practice Bulletin No. 173: Fetal Macrosomia.
ISUOG. Practice guidelines: diagnosis and manage-
American College of Obstetricians and Gynecologists’
ment of small-for-gestational age fetus and fetal
Committee on practice bulletins—obstetrics. Obstet
growth restriction. Ultrasound Obstet Gynecol.
Gynecol. 2016;128(5):e195–209.
2020;56:298–312.
The “First Trimester (11–14 Weeks)
Scan” 10
The first trimester of pregnancy is a very important and can be adopted in most clinical settings. It is
phase where fetal formation begins into a defini- thus imperative to invest in skill enhancement for
tive form and maternal adaptations to pregnancy first trimester ultrasound in all obstetric settings
start. We are all traditionally aware of the role of today.
the first trimester ultrasound in defining fetal via- The first trimester 11–14 weeks’ scan has now
bility and dating in early pregnancy. Today, the become a benchmark for a comprehensive fetal
first trimester scan has transcended its potential evaluation and has the following potential uses:
and can be optimized to define fetal structure so
well such that many fetal anomalies can not only 1. Reconfirmation of fetal viability and dating
be detected so early but those requiring prognosti- 2. Detailed structural assessment to diagnose
cating tests can be worked up early. The lethal fetal major anomalies, e.g., anencephaly, limb
anomalies are definitively defined and those agenesis, etc.
requiring pregnancy termination can be addressed 3. Screening for some anomalies that may
in the first trimester which makes the procedure become apparent later, e.g., intracranial trans-
safer— medically and socioethically. With the lucency for spina bifida
advancing maternal age in the general population 4. Screening for fetal aneuploidies by measuring
and prevalence of consanguinity in some regions, fetal nuchal translucency and other markers
the first trimester scan markers for aneuploidies like nasal bone, tricuspid valve blood flows,
and genetic syndromes have a potent role in and ductus venosus flows
screening for the same. Such screening facilitates 5. Basic workup of multifetal pregnancy like
decisions for definitive prenatal testing. confirmation of chorionicity and amnionicity,
Prediction of preterm births, fetal growth viability, and dating issues along with estab-
restriction, and maternal complications like pre- lishing any condition like early discordance in
eclampsia is possible with the ability to provide fetal growth or anatomy among the multiple
objective risk assessment in the first trimester by fetuses
use of ultrasound. Such prediction will help triag- 6. Evaluation of maternal uterine artery Doppler
ing women requiring special care and adequate as a screening tool for preeclampsia or fetal
preventive measures can be initiated early. This growth restriction in current pregnancy
optimization of the first trimester scan has a prac- 7. Evaluation of maternal cervix to assess risk of
tical advantage which is definitely cost-effective preterm birth

82 10 The “First Trimester (11–14 Weeks) Scan”
10.1 Reconfirmation of Fetal measurement of the fetal heart rate should be part
Viability and Dating of every scan report at 11–14 weeks.
Dating of a pregnancy is best done by the
Fetal viability is assessed by detecting a rhythmic crown-rump length (CRL) of the fetus in early
pulsation in the region of fetal cardia in early pregnancy, and again this is better done at
pregnancy. By the 11–14 weeks’ scan, the fetal 11–14 weeks as compared to very early scans
heart is a well-defined structure and the fetal simply because the fetus is a much better defined
heart beat is a convincing activity signifying fetal structure now and the possibility of error in mea-
viability. As soon as the fetus is visualized on the surement is very low if standard guidelines are
scan, one of the most important observations by followed.
the operator is to establish a definite fetal cardiac Several professional bodies have recom-
activity. Once this is noticed, the rate can be mea- mended guidelines to measure the fetal CRL cor-
sured by placing either an M-mode Doppler rectly as it is such an important parameter and the
(Fig. 10.1) or a pulse wave Doppler (Fig. 10.2) dating of a pregnancy finally rests on this mea-
across this region of activity, and the reading is surement. A few important common points to all
taken across one or two cycles depending on the are as follows:
machine settings and reported as “number of
beats per minute,” e.g., “148 bpm.” 1. The fetal CRL should be measured from the
It is a real-time assessment but a documenta- top of the crown to the bottom of the rump in
tion of the same by a convincing picture with the the midsagittal section without including
Fig. 10.1 FHR M-mode

10.1 Reconfirmation of Fetal Viability and Dating 83
Fig. 10.2 FHR by PW Doppler
limbs or yolk sac in the measurements and assessment of the reason for disparity.
(Fig. 10.3). However, in most cases, the error may be due to
2. The fetal attitude should be neutral and too suboptimal positioning of calipers in early preg-
much flexion underestimates the length, while nancy scans as the fetus is rather small, and
a highly extended fetus might appear to have unless one is very particular, it is possible to get a
a longer CRL as opposed to one in neutral rather oblique view of the fetus or a bit of “end-
position which is ideal (Fig. 10.4). on” appearance such that there is a scope of

3. As the fetus is not stationary and would be over−/underestimation. In most cases, for all
constantly moving through the examination, it practical purposes, the CRL defined at the
is advisable to take several measurements of 11–14 weeks’ scan is taken for dating the
the CRL and finally take an average of the pregnancy.
three best images to report the final CRL at An important rule in fetal care is to establish
that stage of gestation. the dating firmly by the 11–14 weeks’ scan and
NOT to change it repeatedly thereafter. The pur-
As it is evident that fetal appearance is better pose of dating a pregnancy is to establish the
defined at the 11–14 weeks’ scan, in some cases, limits of gestational age, and it is neither wise
there may be a disparity as compared to very nor correct to keep changing the same later on.
early pregnancy scans like 5–6 weeks. If there is Sometimes, a woman is not sure of her dates or
a convincing picture of a CRL measurement at is sure but the dates are not matching the fetal
those scans, then one has to refer the case to a age after we have redated her at 11–14 weeks’
specialize fetal care unit for detailed evaluation scan—in such cases, it is imperative to explain
Fig. 10.3 Correct measurement of CRL at 11–14 weeks’ scan
the situation to the woman and tell her the pro-

jected “EDD” which signifies the date when her
pregnancy will complete 40 weeks. It is very
useful to clarify this aspect to her now and even
advise her that during all future consultations,
she can make sure that these corrected dates are
used in her evaluation. In all subsequent fetal
scans, it is a good practice point to start the
report by stating the final EDD as allocated in
the first trimester so that future growth is cor-
roborated to this correct dating. This prevents
confusion lingering over such an important
issue in pregnancy.
Fig. 10.4 Extreme flexion affecting CRL measurement
10.2 Detailed Fetal Structural Assessment at the 11–14 Weeks’ Scan 85
10.2 Detailed Fetal Structural In cases where such a well-defined fetal

Assessment at head is either not seen or has some unusual
the 11–14 Weeks’ Scan appearance, one is alerted to the possibility of
major CNS anomalies. Some major anomalies
The fetus can be examined from “head to toe” to can be unequivocally diagnosed at the time of
complete a detailed structural evaluation at the first trimester scan such as absence of the
11–14 weeks’ scan. cranial vault—anencephaly (Fig. 10.6)—
improper cleavage of the forebrain leading to
Head The fetal head is evaluated in the trans- holoprosencephaly (Fig. 10.7) or outpouching
verse section and a smooth bony outline of the of the brain, and meninges through defects in
skull is seen along with a midline falx and cho- the cranial bones, encephaloceles (Fig. 10.8).
roid plexuses that seem to be filling the lateral Many of these problems have an adverse prog-
ventricles and give a characteristic “butterfly” nosis which are either lethal or carry risk of
appearance when the falx cerebri is seen as a severe neurodevelopmental delay. An early
midline division (Fig. 10.5). diagnosis of such problems helps in taking
Fig. 10.5 Normal fetal head at the 11–14 weeks’ scan

Fig. 10.6 Anencephaly in first trimester scan
Fig. 10.7 Holoprosencephaly in the first trimester

Fig. 10.8 Encephalocele in the first trimester
appropriate decisions in pregnancy at an early the Fetal Medicine Foundation, UK, and if that
stage. measurement is then applied to the first trimester
risk assessment protocol (Fig. 10.9).
Neck The fetal neck is evaluated in the midsag- In contrast, abnormal appearance of the fetal
ittal section in the first trimester of pregnancy. neck which can range from mild increase in the
The presence of any neck swelling or masses is “nuchal translucency” to appearance of large cys-
noted. The “nuchal translucency” or “NT” is the tic dilatations and even swelling enveloping the
collection of fluid posteriorly under the skin of entire fetus are features which increase the risk of
the fetal neck in the first trimester and is an structural and chromosomal abnormalities in the
important feature to be evaluated at the fetus. The different manifestations of abnormal
11–14 weeks’ scan as a marker for fetal aneuploi- appearance of the fetal neck in the first trimester
dies and structural anomalies. is shown in Fig. 10.10a–i.
A normal appearance of the fetal neck region Thorax The fetal thorax is evaluated in the axial
is very reassuring not only in terms of structural section in the first trimester (Fig. 10.11), and it usu-
assessment but also as a factor reducing the risk ally shows the fetal heart occupying the mediasti-
for fetal aneuploidies if the measurement is taken num and roughly one-third of the total area of the
according to a standard protocol as suggested by thoracic section flanked by two equal appearing
Fig. 10.9 Normal appearance of fetal neck in the first trimester
a b c d
e f g h
Fig. 10.10 (a–i) Increased NT or cystic hygroma in first trimester

lungs on either side. Presence of any lung masses or

pleural effusion is noted as signs of abnormalities
(Fig. 10.12) that warrant further workup.
Heart The first trimester is a good window for a

preliminary evaluation of the fetal heart. With the
advent of high-resolution machines and better
understanding of the anatomy of the fetal heart,
the possibilities of detailed imaging of the fetal
heart in the first trimester are increasing by leaps
and bounds such that first trimester fetal echocar-
diography is a definite reality in specialized fetal
medicine units. However, in general fetal medi-
cine practice, at least a four-chamber view of the
fetal heart along with a basic outflow tract evalu-
ation would suffice for a good practice protocol
that is practical, efficient, and easily reproducible
Fig. 10.11 Normal appearance of normal fetal thorax in
the first trimester with reasonable skill sets.
Fig. 10.12 Abnormal fetal thorax in the first trimester

Application of color flow to generate the fetal heart in the first trimester are seen in
“X” sign to represent the normal crossover of Fig. 10.13a–b. Any deviation from the normal
outflow tracts and the “Y” sign for the normal appearance such as disproportionate chambers
three-vessel trachea view further enhances the or obvious outflow abnormalities can be
detection rate for major cardiac anomalies in picked up at this stage of pregnancy
the first trimester. Normal appearances of the (Fig. 10.14a–d).
a b
Fig. 10.13 (a, b) Normal views of the fetal heart in the first trimester
a c
b d
Fig. 10.14 (a–d) Abnormal fetal heart views in the first trimester
Abdomen The evaluation of the fetal abdomen at this site and thus rule out any anterior abdomi-
includes an upper abdomen axial view at the level nal wall defects like exomphalos or gastroschisis
of the stomach to demonstrate a normal-sized (Fig. 10.16).
fetal stomach bubble which essentially indicates The physiological exomphalos of early preg-
a patent upper GI tract such that amniotic fluid is nancy is expected to have regressed by 11 weeks
being swallowed by the fetus and reaches the of gestation, and hence if the anterior abdominal
stomach to create the appearance of a “bubble” wall defect is seen after the completion of
on ultrasound. A very small or persistently absent 12 weeks, it is definitely pathological. These
stomach bubble in the first trimester scan indi- defects may be associated with other defects or
cates the possibility of an upper GI tract obstruc- fetal aneuploidies, and thus appropriate testing
tion or a poor swallowing effort by the fetus due and modification of care can be planned after this
to neuromuscular problems. It may be noted here condition is diagnosed early in pregnancy
that sometimes an absent stomach bubble may be (Fig. 10.17).
a transient finding and hence it should be evalu- In the lower abdomen, another hypoechoic
ated repeatedly over a period of time to establish area representing the fetal urinary bladder is also
definite, persistence absence of the same before noted in the first trimester. In case of doubt, dem-
labeling it in the diagnosis (Fig. 10.15). onstration of the umbilical arteries flanking this
cystic area is confirmation of this being the fetal
Another plane to evaluate the fetal abdomen is urinary bladder. The direct visualization of the
at the level of the umbilical cord insertion to fetal kidneys is possible around 12–13 weeks but
show a normal anterior abdominal wall contour may not be very clear in earlier first trimester
Fig. 10.15 Fetal stomach bubble in the first trimester

Fig. 10.16 Normal abdominal insertion of the umbilical cord
a b c
Fig. 10.17 (a–c) Exomphalos seen at the 11–14 weeks’ scan
scans. Presence of a normal-sized fetal urinary is a marker for fetal aneuploidies, while more
bladder is an indirect indicator of functioning than 14 mm is more likely to be caused by blad-
fetal kidneys which are producing urine that is der outflow obstruction.
filling the bladder (Fig. 10.18a–b). Persistent nonvisualization of the fetal bladder
The longitudinal diameter of the fetal urinary in the first trimester scan may be indicative of
bladder is less than 7 mm in the first trimester, bilateral renal agenesis or nonfunctioning kid-
and when it exceeds 7 mm, it is labeled as “mega- neys. The liquor amnii in the first trimester is also
cystis” (Fig. 10.19a, b). Megacystis below 14 mm produced by the placenta and fetal membranes so
a b
Fig. 10.18 (a–c) Normal fetal urinary bladder in the first trimester
a b
Fig. 10.19 (a, b) Megacystis in the first trimester
body, and all the three segments—arms, fore-

it is not a good indicator of renal function. In arms, and hands—are well visualized as shown
cases where the fetal bladder is not seen in the in Fig. 10.20.
first trimester scans, it is useful to recall the
mother at 16 weeks for a detailed reassessment of Both fetal lower limbs are also similarly seen
fetal kidneys. (Fig. 10.21a–d), and it is a good practice to docu-
ment an image of both legs simultaneously in the
Limbs The first trimester scan provides an opti- report. Such documentation is very reassuring
mal opportunity to evaluate the fetal limbs—all and helps establish the presence of limbs at this
three segments of all four limbs can be clearly stage of fetal evaluation in cases of rare evolving
demonstrated at this stage. Simultaneous visual- anomalies arising due to transverse limb amputa-
ization of both upper limbs and both lower limbs tion by amniotic bands, etc.
is possible in the first trimester scan so this is
actually a better time to detect major anomalies Spine The fetal spine is evaluated in the sagittal
of the fetal limbs like agenesis or hypoplasia of or coronal section (Fig. 10.22a, b) in the first tri-
limb segments. Both upper limbs are seen arising mester where a normal contour along with a com-
from the fetal trunk in the axial section of the plete overlying skin cover is highly reassuring.
a b
Fig. 10.20 Normal upper limbs in the first trimester
a b
Fig. 10.21 (a, b) Normal lower limbs in the first trimester
a b
Fig. 10.22 (a, b) Normal fetal spine in the first trimester
Abnormal contours with major bends along the significant clinical impact on the fetal well-being,
longitudinal axes may represent kyphoscoliosis or and such early diagnosis allows to explain the prog-
even open spina bifida (Fig. 10.23a–c). The abnor- nosis to the parents and get relevant workup done.
malities in spinal contour that present very obvi- Open spina bifida may or may not be directly
ously even in the first trimester are likely to have seen in the first trimester, but there is a screening
10.3 Screening for Spina Bifida by IT (Intracranial Translucency) 95
a b c
Fig. 10.23 (a–c) Abnormal fetal spine in the first trimester
Fig. 10.24 Intracranial translucency
marker for these abnormalities called intracranial first trimester of pregnancy. In the same section
translucency or “IT” which has emerged as a use- that is used to evaluate the fetal NT, the fetal
ful marker in triaging fetuses who need recall for brain stem, fourth ventricle, and the cisterna
an early anatomy assessment at 16 weeks. magna are seen as almost parallel spaces. The IT
appears as a hypoechoic area and represents the
fourth ventricle of the fetal brain at the
10.3 Screening for Spina Bifida by 11–14 weeks of gestation. A normal appearing IT
IT (Intracranial Translucency) (Fig. 10.24) is reassuring, while a collapsed IT
represents compression of the fourth ventricle
The “intracranial translucency” (IT) actually rep- due to caudal displacement of the brain stem in
resents the appearance of the fourth ventricle in a open neural tube defects. The actual defect may
midsagittal view of the fetal head and neck in the not be big enough to be clearly seen on the first
trimester scan, but an abnormal IT raises the For purposes of risk allocation for fetal aneu-
index of suspicion for such problems and facili- ploidies, it is mandatory that fetal CRL is between
tates an earlier detection with better follow-up. 45 and 84 mm and the NT is measured according
to the criteria defined by the FMF. Since the exact
measurement of the NT is vital to get a correct
10.4 Markers for Fetal Aneuploidy risk assessment for fetal aneuploidies, it is imper-
Screening in the ative upon all operators to learn this technique
11–14 Weeks’ Scan perfectly. The Fetal Medicine Foundation web-
site which has been referenced in the “suggested
The 11–14 weeks’ scan is a landmark for screen- reading” section at the end of this chapter has
ing for fetal aneuploidies. The various markers clear description of the technique and a certifica-
assessed at this scan with the background of tion process for this scan.
maternal age can provide a screening test for tri- This process has been one of the most suc-
somy 21 with a sensitivity of up to 85–90% for a cessful self-learning strategies in which the oper-
false-positive rate of less than 5%. ator can follow instructions and improvise his/her
The details of fetal aneuploidy screening and own images and once a satisfactory level of
risk assessment protocol issues are given in Chap. confidence is gained, one can send images for an
4 (“Principles of Screening for Fetal online assessment by an FMF expert. This evalu-
Aneuploidies”). In this chapter, we will empha- ation provides feedback regarding the quality of
size upon the correct imaging for these markers the images, and if the images are satisfactory, the
during the conduct of the first trimester scan. operator is certified to conduct the NT measure-
ment for risk assessment by the FMF UK. The
process comes highly recommended for all oper-
10.4.1 Fetal NT ators who want to conduct a meaningful NT scan
as this certification helps in standardizing image
As per the guidelines given in by the Fetal procurement and reduces interoperator variabil-
Medicine Foundation (FMF UK), it is expected ity (Fig. 10.25).
that the image would be magnified to an extent
that the ultrasound screen is occupied almost
entirely by the head and the neck of the fetus in 10.4.2 Fetal Nasal Bone
“midsagittal” view. The attitude of the fetus
should be such that the neck is aligned in line The fetal nasal bone can be assessed in the same
with the head. The fluid between the chin and the view as the NT and the magnification, attitude,
chest of the fetus indicates that the neck is not too and gain criteria are similar as described above.
flexed and it should not be too extended but rather To demarcate the nasal bone, it is useful to hold
in a “neutral position.” The image should have the scan probe in the direction of the nose, and
adequate contrast which is attained by reducing with very fine lateral tilts, one can observe a sec-
the “gain” settings, and the sharp margins of the ond line parallel to the skin of the nose. This par-
lines behind the neck should be seen. The fetal allel line arrangement, also called the “equal”
NT is then measured placing “plus-shaped” cali- sign, has the skin as the upper line and the lower
pers in a manner that the horizontal line of the line representing the nasal bone, seen normally
caliper merges with the inner borders of the area brighter than the skin as seen in Fig. 10.26.
representing the nuchal fluid. If the gain settings If the lower line is not seen or is not brighter
are not optimal, this sharp margin will not be than the skin, then the nasal bone is deemed as
delineated and the measurement will be errone- absent or hypoplastic, respectively. It has been
ous. The calipers have to be adjusted such that clearly stated in literature that for purposes of
each movement changes the measurement by risk calculation, “absent” or “hypoplastic” nasal
0.1 mm. bone is deemed as a common entity.
10.4 Markers for Fetal Aneuploidy Screening in the 11–14 Weeks’ Scan 97
Fig. 10.25 Fetal NT
Fig. 10.26 Fetal NB

10.4.3 Tricuspid Blood Flow tole, no backflow is expected but sometimes there
may be small physiological jets. In case the
The blood flow across the tricuspid valve is regurgitant jet speed is 60 cm/s or more and if
expected to be unidirectional and a normal flow this jet occupies more than half of systole, then it
pattern is seen in Fig. 10.27. is considered as tricuspid regurgitation as seen in
The presence of tricuspid regurgitation is con- Fig. 10.28.
sidered as a minor marker for fetal aneuploidies
and is also associated with a higher risk of fetal
cardiac anomalies. 10.4.4 Ductus Venosus Blood Flow
The correct method of evaluation of tricuspid
blood flow according to the FMF criteria is on the The fetal ductus venosus (DV) is a continuation
axial section of the fetal thorax with the apical of the umbilical vein and forms a narrow conduit
four-chamber cardiac view occupying 75–80% of before joining the IVC. Due to the narrow cali-
the screen. The pulse wave Doppler with a gate ber, the blood flow through the DV shows “alias-
size of 2–3 mm is placed across the tricuspid ing” upon application of color Doppler and is
valve with the angle aligned ideally along the thus identified. It is better to measure the DV
direction of blood flow but never more than 30° blood flow when the fetus is not moving and with
away. The sweep speed is adjusted to 2–3 cm/s a smaller sample gate of 0.5–1 mm in size owing
and flow pattern is noted. During ventricular sys- to the small size of this vessel (Fig. 10.29).
Fig. 10.27 Normal tricuspid flow

10.4 Markers for Fetal Aneuploidy Screening in the 11–14 Weeks’ Scan 99
Fig. 10.28 Tricuspid regurgitation
Fig. 10.29 Fetal DV flow in the first trimester

The fetal DV can be identified in the midsagit- placentae in twins are seen distinctly separate,
tal section of the fetal abdomen with color then the assignment of “dichorionicity” is easy.
Doppler as a small area of aliasing between the However, if the placentae are close by, the
umbilical vein and IVC. A low-frequency wall “lambda” sign (Fig. 10.30a, b) denotes dichori-
motion filter (50–70 Hz) helps in getting the tri- onicity, while the “T” sign represents monochori-
phasic wave of this vessel which is affected by onicity (Fig. 10.31). Individual fetal evaluation
the right atrial activity. will be similar to that in singletons, and specific
The DV pulsatility index is used as a parame- protocols for multiple pregnancy evaluation in
ter for risk calculation in the scan-based fetal general are described in Chap. 11 (“Multiple
aneuploidy risk assessment protocol. Abnormal Pregnancy Evaluation”).
DV flow indices are associated with higher risk In cases of triplets, the “Benz” sign denotes
of aneuploidies, fetal cardiac anomalies, and triamnionicity (Fig. 10.32). Chorionicity will be
even risk of fetal demise. determined by assessment of the “lambda sign”
or “T sign” at the interface of the different pla-
centae. Triamniotic triplets can therefore be
10.5 Basic Workup of Multifetal trichorionic, dichorionic, or monochorionic.
Pregnancy at the 11–14- Chorionicity is the most important prognostic
Week Scan factor for multifetal pregnancy and this is opti-
mally achieved at the 11–14 weeks’ scan. Not
The most important aspect of multifetal preg- allocating chorionicity in a first trimester scan for
nancy assessment in the first trimester remains multiple pregnancy should be considered a sub-
the assessment of number of fetuses and estab- optimal evaluation.
lishment of chorionicity unequivocally. If both
a b
Fig. 10.30 (a, b) Dichorionic twins—lambda sign

10.5 Basic Workup of Multifetal Pregnancy at the 11–14-Week Scan 101
Fig. 10.31 Monochorionic twins—T sign
Fig. 10.32 Triamniotic triplets in the first trimester

10.6 Evaluation of Uterine Artery eral at the level of the internal cervical os. The
Doppler in First uterine artery is identified by color Doppler at
Trimester Scan this level and is interrogated with pulse wave
Doppler using a sample gate of 2 mm and an
The uterine artery Doppler flow is an important angle of insonation less than 30°. The systolic
parameter representing uteroplacental resistance peak velocity more than 60 cm/s confirms that
and thus has become an effective marker for the vessel is the uterine artery as shown in
screening for risk of conditions related to utero- Fig. 10.33. This process is repeated on both (left
placental insufficiency like maternal preeclamp- and right) sides and the pulsatility indices of both
sia and fetal growth restriction. The evaluation of uterine arteries are measured. The mean PI is
uterine artery Doppler flows in the first trimester used to calculate the risk of preeclampsia in the
is done by obtaining a sagittal section of the uter- first trimester along with other biochemical and
ine cavity and then moving the probe slightly lat- biophysical parameters.
Fig. 10.33 Uterine artery Doppler in the first trimester

10.7 Evaluation of Maternal Cervix in First Trimester Scan 103
10.7 Evaluation of Maternal empty bladder. It is important to identify the

Cervix in First Trimester Scan internal and external os, cervical canal, and endo-
cervical mucosa. The details of cervical length
The evaluation of maternal cervix in the first tri- assessment are given in the chapter on cervical
mester is ideally done transvaginally with an assessment in pregnancy (Chap. 12) (Fig. 10.34).
Fig. 10.34 Maternal cervix in the first trimester

Suggested Reading Ratha C, Khurana A. “First things first”: images for

a proper nuchal translucency in the first trimester
11–13+6 weeks scan. J Fetal Med. 2014;1(2):1–3.
First trimester scan guidelines on www.fetalmedicine.org.
https://doi.org/10.1007/s40556-014-0015-x.
Nicolaides KH. First-trimester screening for chromo-
Ratha C, Khurana A. “First things first”: fetal nasal bone
somal abnormalities. Semin Perinatol. 2005;29:190–4.
imaging in the first trimester 11–13+6 weeks scan.
Nicolaides KH. Turning the pyramid of prenatal care.
J Fetal Med. 2015;2(1). https://doi.org/10.1007/
Fetal Diagn Ther. 2011;29:183–9.
s40556-015-0034-2.
Nicolaides KH, et al. The 11-14 week scan. Baillieres Best
Pract Res Clin Obstet Gynaecol. 2000;14:581–94.
Multiple Pregnancy Evaluation
in Fetal Medicine Clinic 11
Multiple pregnancy or multifetal pregnancy is a 11.1 Establishing the Diagnosis

condition where there are more than one fetuses and Chorionicity
in the mother’s womb at the same time. The most of Multifetal Pregnancy
common type of multiple pregnancies is twin
pregnancy and triplets, quadruplets, pentuplets, Finding more than one fetal poles in the gravid
and so on are serially rarer to be seen. According uterus is the most unequivocal method of diag-
to the classical “Hellin’s rule,” the incidence of nosing multifetal pregnancy in today’s medical
twins was considered to be 1 in 89, and the inci- practice. It can be done any time since early
dence of other multifetal pregnancies appeared to pregnancy (6–8 weeks), and the best time to
be 1 in 89 raised to the power (n-1), where n is unequivocally diagnose and allocate chorionic-
the number of fetuses in utero simultaneously. ity to a multifetal pregnancy is before 14 weeks
This was accepted for many years as long as of gestation. The number of fetal poles can be
nature was responsible for multifetal gestation counted and the pregnancy may be labeled as
due to wither multiple ovulation simultaneously twins, triplets, quadruplets, and so on. However,
or postzygotic splitting. In today’s world, this law clinically, this labeling remains incomplete
does not hold so good. The incidence of multife- unless the chorionicity or amnionicity is defined
tal pregnancy has increased significantly in the because these are important prognostic markers.
last century primarily due to the advent of assisted In fetal medicine, multiple pregnancy nomen-
reproductive techniques (ART) which rely heav- clature can only be complete if it includes three
ily on multifollicular ovulation although other points:
factors contributing to lifestyle changes and even
better diagnostic techniques have contributed to 1. Number of fetuses
the same. As early pregnancy ultrasound is gain- 2. Number of placentae (chorionicity)
ing favor with obstetricians, most multifetal preg- 3. Number of amniotic sacs (amnionicity)
nancies are diagnosed in early pregnancy.
Ultrasound has emerged as one of the most Figure 11.1 shows some examples of the dif-
important diagnostic, prognostic, and even a ferent types of multiple gestations based on
therapy-guiding tool for multifetal pregnancy in amnionicity and chorionicity (DCDA, MCDA,
present-day prenatal care protocols. MCMA, QCQA, TCTA)

106 11 Multiple Pregnancy Evaluation in Fetal Medicine Clinic
Fig. 11.1 Ultrasound appearance of multifetal gestation in first trimester
It is important to understand the rational basis Hence, BEFORE we proceed any further on the
of such classification rather than just learning the discussion of multiple pregnancy, we have to
names. Although this fact has been stated time learn to establish CHORIONICITY.
and again, over and over by experts, it is still not The best time to determine chorionicity by
uncommon to find ultrasound reports and case USG is the first trimester of pregnancy when one
notes on multifetal pregnancy where chorionicity can assign chorionicity with a sensitivity and
and amnionicity are either not mentioned or specificity of 100% and 99.8%, respectively, as
erroneous due to nonadherence of some basic per current literature. In situations that each fetus
rules. One must realize that each fetus derives its has its own placenta, ultrasound will be able to
nutritional and metabolic support from the pla- demonstrate separate placentae or the “lambda
centa (chorion) so whenever there are more than sign” or “twin peak” sign (Fig. 11.2a, b) which is
one fetuses attached to one common placenta, the hallmark of polychorionicity. When two
this support has to be shared by two or more fetuses are sharing one placenta, then the inter-
fetuses, and nature may not always be fair to each twin membrane is seen arising from the fetal sur-
such that the “share” of individual fetuses may be face of the placenta without any intervening
unequal. This is a simple way of understanding chorionic tissue—the “T sign” which indicates
why multifetal gestation is more than a mere monochorionicity (Fig. 11.2c, d). These signs
mechanical overload on the womb. Also, each may disappear after 14–16 weeks of gestation
fetus is an individual entity and can have its own and hence the need for checking them earlier on
share of complications related to structure, devel- in pregnancy.
opment, chromosomal or genetic composition, or Once chorionicity is established, it is strongly
growth trajectory. This can lead to “discordance” recommended that this is well documented and
in coexisting multiple fetuses and thus severe preserved in the antenatal notes for future refer-
management dilemmas arise. The clinician will ence in case of any confusion because this is
agree that CHORIONICITY remains the most extremely a vital information in making critical
important clinical criterion which will dictate decisions about multiple pregnancy management
management decisions in multifetal pregnancy. later. It is considered a good practice to take at
11.2 Dating of a Multifetal Pregnancy 107
a b
c d
Fig. 11.2 (a–d) Ultrasound signs of chorionicity (a, b Lambda sign; c, d T sign)
least one picture of these important signs of cho- accurate. In twin pregnancies, there may however
rionicity and keep the picture also for reference be discrepancy in the CRL of two fetuses, and in
later. In any case that chorionicity is not estab- such situations, the larger of the CRLs should be
lished in early pregnancy and if the typical signs used to estimate gestational age. Similarly, in
are lost by the time a clinician encounters the higher-order multiples, the CRL of the largest
case, it is better to allocate “monochorionicity” fetus is considered for dating as per the current
and manage accordingly so as to not miss any guidelines. This is an area of active research and
potential complication. there may be some revision of protocol if alter-
nate convincing evidence arises.
If the woman presents after 14 weeks’ gesta-
11.2 Dating of a Multifetal tion, the larger head circumference should be
Pregnancy used. Twin pregnancies conceived via in vitro
fertilization should be dated using the embryonic
Accurate dating of a pregnancy is important in age from fertilization. It is therefore important to
planning maternal and fetal care optimally. It is take a detailed history of the periconception
an accepted fact that dating of a pregnancy should period to ascertain that the events that determine
be done by early pregnancy CRL as sometimes the dating of pregnancy are well documented and
the mother’s recollection of dates may not be match the assigned gestational age calculation.
11.3 Systematic Labeling normal fetuses, there is scope for confusion

of Fetuses in Multifetal unless labeling is unequivocal. Studies have
Gestation shown that assigning laterality, placental posi-
tion, and intertwin membrane orientation can
Each fetus is identified and labeled in an unam- help in systematically labeling twins as A and B
biguous manner such that on serial evaluations (Fig. 11.3).
at different points in time, the individual fetal In higher-order multiples, it is useful to label
parameters are correlated correctly without any the first fetus as the one closest to the cervix and
confusion. This is of particular significance in then work clockwise and define the orientation,
follow-up of biometry as well as aneuploidy placental positions, and cord attachments of each
screening results allocation. Anatomical dis- fetus sequentially. This labeling is followed in all
crepancies may be easier to detect and distin- future examinations to ensure consistency of fetal
guish between fetuses, but in structurally evaluation.
Twin 1 :
Anterior Placenta
Lower cord insertion
Twin 2 : Maternal left
Posterior Placenta
Higher cord
insertion
Maternal right
Fig. 11.3 Systematic labeling of twins

11.4 Aneuploidy Screening in Multifetal Pregnancy 109
11.4 Aneuploidy Screening the maternal serum biochemistry. In

in Multifetal Pregnancy MONOCHORIONIC twins, the average NT of
both fetuses is considered as one entity which is
In twin pregnancies, the first trimester combined combined with serum biochemistry to assign one
screening test (NT scan along with serum bio- risk to both fetuses with the assumption that this
chemistry) can be used for risk assessment of is a monozygotic pregnancy. The maternal serum
aneuploidy after defining chorionicity. biochemistry is only used in twins in the first tri-
It may be noted here that for all practical pur- mester, but it cannot be used when dealing with
pose, chorionicity is assumed to be a surrogate higher-order multiple pregnancies as it is not reli-
marker for zygosity while assigning risk of aneu- able in those cases.
ploidy to multiple fetuses in a multifetal preg- In higher-order multiples, the combination of
nancy. There is however a fundamental flaw in maternal age and the aneuploidy markers at the
this approach because we must understand that NT scan should be used as biochemical screening
even dichorionic twins may be monozygotic. If a becomes unreliable. Serum biochemical screen-
zygote splits within the first 72 h, it may develop ing tests are not validated for triplets and higher-
into two fetuses with two placentae and therefore order multiples.
continue as a dichorionic twin pair while both Figure 11.4 illustrates the use of NT in calcu-
fetuses have originated from one zygote and are lation of risk in multifetal pregnancies.
hence monozygotic. It is reasonable to accept Twin pregnancies in the second trimester and
monochorionic twins as monozygotic but all higher-order multiple pregnancies should be
dichorionic twins are not definitely dizygotic. offered aneuploidy screening based on ultra-
The problem is that we cannot assign zygosity by sound parameters as the primary method. In
ultrasound and therefore we accept chorionicity polychorionic pregnancies, each fetus gets an
as a surrogate marker for zygosity during risk individual risk for aneuploidies, and there may be
allocation. discordance in the NT values leading to discor-
In DICHORIONIC twins, each fetus is allo- dant risks for both fetuses. It is important to
cated a separate risk based on its NT along with inform women and their partners in advance of
MCDA twins
DCDA twins
Final NT = NT1+NT2
NT1, NT2
2
MCTA triplets
TCTA triplets
Final NT = NT1+NT2+NT3
NT1, NT2, NT3
3
DCTA triplets
Final NT = NT1 , avg. NT of the MC pair ( NT2+NT3)
2
Fig. 11.4 Method of NT calculation for risk assessment in multiple pregnancy

the potentially complex decisions that they will guided CVS and amniocentesis help in confirm-
need to make on the basis of the results of coming the fetal chromosomal status. A summary of
bined screening, bearing in mind the increased a screening protocol is displayed in Fig. 11.5
risk of invasive testing in twins, the possible dis- about aneuploidy screening for twin
cordance between dichorionic twins for fetal pregnancies.
aneuploidy, and the risks of selective fetal If such invasive procedures are contemplated,
reduction. then it is better to check all the fetal sacs or pla-
In monochorionic twins, as they are both theo- centae. This recommendation is based on the
retically assumed to have similar karyotypes, the theoretical fact that even monozygotic pregnan-
risks are allocated after taking an average of the cies which split very early may develop into
NT of both fetuses such that both have a similar dichorionic gestation so chorionicity does not
risk for aneuploidy. confirm zygosity. Details of invasive procedures
Cell-free fetal DNA can be offered in twin are given in a subsequent chapter. In multiple
pregnancy after checking with the specific labs pregnancy, special care must be taken to label the
regarding this facility. This can act as a secondary fetuses correctly and label their samples accord-
screening method as it may reduce the need for ingly so that there is no confusion in interpreting
unnecessary invasive testing. However, if the the results and appropriate solutions may be pro-
results of cell-free DNA suggest high risk of vided in case of discordant results for fetal aneu-
aneuploidy, invasive testing is warranted. As such ploidy. In cases of confirmed aneuploidy in one
this method is not validated for triplets or above. fetus along with a normal co-twin, the parents
These are methods of screening for aneuploidies may opt for selective fetal reduction. Only if the
and help in allocating risk for aneuploidies for labeling of fetuses is accurate such a procedure
each fetus. In high-risk fetuses, ultrasound- can be carried out correctly.
Suggested screening protocol : aneuploidies in multiple gestation
Confirm viability and dating(6-8 weeks)
Chorionicity
First trimester bloods(free beta hCG+PAPP-A) at 10-11 Low risk
weeks (window 10-14 weeks) FOR TWINS
NT scan at 12 weeks(window 11-14 weeks)
NIPT
High risk
Low Risk CVS to confirm

High risk
fetal karyotype
Genetic sonogram as part of the

anomaly scan
Amniocentesis/FBS to
Low Risk High risk confirm fetal karyotype
Reassure and continue regular antenatal care
Fig. 11.5 Aneuploidy screening protocol for multiple pregnancies

11.5 Screening for Fetal Anomalies in Multifetal Pregnancy 111
11.5 Screening for Fetal ible with a good quality of life, it may be reason-
Anomalies in Multifetal able to consider termination of the pregnancy.
Pregnancy Thus, timely screening for fetal anomalies in
multiple pregnancies is important so that such
The principles of ultrasound screening for fetal issues can be detected at the earliest possible ges-
anomalies in the first and second trimester have tational age. The decision to continue or discon-
been described in previous chapters. The same tinue the pregnancy will depend on the type of
parameters have to be used for twins, triplets, and anomaly and the decision of the parents so effec-
higher-order multiple fetuses too. The only tive diagnosis and timely counseling must be
important precaution to be exercised by the arranged to plan further care. Figure 11.6 pres-
ultrasound operators is to carefully follow the ents the possible plan of care when fetal anoma-
structure of each twin separately as sometimes lies are detected in twin pregnancy.
there can be an error of judgment due to fetal In case of any anomaly detected, the chal-
movements and the same fetus may get evaluated lenges of management in twin pregnancy are
twice. To avoid such errors, a practical approach different and more complex than those faced in
is to start with the first fetus and complete its singleton gestations. In multifetal pregnancy,
evaluation before shifting focus to the next one. the potential effect of any intervention in the
Utmost care and caution is needed during multi- interest of an anomalous fetus puts the normal
fetal assessment to avoid any confusion. If during co-twin at some degree of risk. Some anomalies
anytime of the scan the operator feels lost or is are lethal and may lead to fetal compromise in
unsure of the fetus being evaluated, it is better to utero—while this may be acceptable in dichori-
recheck the orientation and labeling and restart onic gestation, a single fetal demise can be cata-
the examination if needed—much like the “recen- strophic in a monochorionic pair due to the
ter” application on Google Maps!! complications of a shared placenta. Hence, the
These issues may seem mundane and one decisions to manage such problems are also
might wonder why a simple fact like this even based primarily on chorionicity and thereafter
merits a mention in a textbook for specialists! It on the type of anomaly based on the system
is therefore vital to understand that while text- involved, its potential to affect the course of
book pictures and theoretical learning deal with present pregnancy, and its subsequent viability
individual fetuses distinctly, during real-time and functional effects.
scans, the fetuses are moving independent of If a particular anomaly can lead to problems
each other and may even change position signifi- like polyhydramnios thus increasing the risk to
cantly while the scan is in progress. This poses a the normal co-twin or if there is a high risk of
practical challenge to the operator. With experi- intrauterine fetal demise in a monochorionic pair,
ence and practice, such problems get minimized selective fetal reduction may be done to amelio-
but it is always better to be prudent in this regard. rate the effects of the anomalous fetus and
The incidence of structural abnormalities in improve the prognosis of the normal co-twin.
multiple pregnancies is more than that found in Procedures like selective fetal reduction entail
singleton gestations. One or both of the co-twins many considerations and risks, and these have
may be affected in a twin pregnancy. If both twins been explained in detail in the chapter on invasive
are anomalous and the anomalies are not compat- procedures.
Anomaly detected in twin pregnancy
Both fetuses One normal/

anomalous One anomalous
One manageable/ one uncorrectable

Both lethal or
uncorrectable anomalies
Does the uncorrectable anomaly lead

to polyamnios or risk of IUFD?
Consider termination of
pregnancy
No
Yes
Continue pregnancy with

Consider selective fetal reduction:
adequate conunselling in the
method depends on chorionicity
interest of the better co-twin
Fig. 11.6 Management plan for anomaly detected in twin pregnancy
11.6 Planning a Rational A standard fetal care plan for DCDA twins
Follow-up for Serial can be formulated as shown in the following
Monitoring of Multiple flowchart in Fig. 11.7. Individual issues like dat-
Pregnancy ing, labeling, and screening for aneuploidies and
anomalies have been explained earlier. It has
11.6.1 DICHORIONIC DIAMNIOTIC been established that although in the first and sec-
Twins ond trimesters, the growth rate of twins is not sig-
nificantly different from that of singletons, there
This is by far the commonest type of multifetal is usually slower fetal growth, even in uncompli-
pregnancy encountered in clinical practice and cated twin gestations, in the third trimester, as
accounts for 97–98% of such cases. The need and compared to uncomplicated singleton fetuses.
importance of determining chorionicity in early Twin pregnancies are more likely to be affected
pregnancy have been explained earlier and are by fetal growth restriction, and therefore such
being reiterated only to reaffirm its importance. pregnancies should be monitored with serial
An early pregnancy scan should be ideally ultrasound examinations for growth and Dopplers
done between 9 and 14 weeks of gestation, and in the third trimester.
the unequivocal evidence of dichorionicity like In uncomplicated DCDA twin pregnancies,
the “lambda” sign must be detected and docu- with adequate feto-maternal surveillance, preg-
mented in the patient’s note for future reference nancy can be continued till term, and at term the
in case she changes her center of care and books obstetrician can plan the time and mode of deliv-
in another unit later in pregnancy. ery based on obstetric indications.
11.6 Planning a Rational Follow-up for Serial Monitoring of Multiple Pregnancy 113
DICHORIONIC TWINS: Follow up protocol
6-8 weeks Viability, dating and

Systematic Labelling of fetuses number of fetuses
11-14 weeks Chorionicity
Aneuploidy screening
18-20 weeks TIFFA
Biometry
AF volume
24-26 weeks Cervical length
28-30 weeks Growth and Complicated DCDA :selective IUGR -

Doppler Mild discrepancy/advanced gestation (>32 weeks) —
try to continue pregnancy as long as possible to
32-34 weeks AF volume achieve better fetal maturity
Severe discrepancy/early gestation (<26 weeks) —

consider continuing in the interest of better maturity
36-37 weeks for the better growing co twin even at risk of IUFD of
the IUGR fetus
Uncomplicated : Plan for delivery at term

At gestations between 26-32 weeks better to consult
Mode of delivery :Obstetric indications neonatologists, parents and take a call on a case-to-
case basis as multiple factors are involved.
Fig. 11.7 Fetal care protocol for DCDA twins
If one or both fetuses are not growing opti- Discordant growth in twins presents a major
mally, on serial follow-up, FGR or discordant clinical dilemma for the managing team. A fine
growth may be detected in DCDA twins. balance has to be achieved between allowing the
“Discordance” in fetal growth in twins is defined pregnancy to continue so that better maturity is
as any of the following parameters: achieved especially for the normal or better grow-
ing co-twin and the risks of fetal compromise
1. In the first trimester, discrepancy of ≥20% in that may become palpable for the smaller fetus
the CRL (crown-rump length) may be implying added dangers of adverse effects on neu-
observed and is predictive of later weight rodevelopmental outcome due to in utero hemody-
discordance. namic and possibly, metabolic compromise.
2. An intertwin AC (abdominal circumference) The decision to deliver discordant DCDA twins
difference ≥20 mm, irrespective of gesta- is dependent on the extent of discrepancy such that
tional age, has been reported to have 83% if a fair prognosis for intact survival exists for both
positive predictive value to detect a difference fetuses, an elective preterm delivery may be justi-
in birth weight ≥20%. fied for the normal growing co-twin to prevent fur-
3. The percentage of the intertwin weight differ- ther in utero compromise of its growth-restricted
ence in comparison to the weight of the larger partner. However, if there is severe discordancy in
twin: (difference of EFW of twins/EFW of early gestation, it may be reasonable to continue
larger fetus X 100)%. Discordance of 20% or pregnancy in the interest of the normal co-twin
more is considered clinically significant and even at the risk of an intrauterine fetal demise
suggests selective FGR. (IUFD) of the growth-restricted fetus.
11.6.2 MONOCHORIONIC The sharing of placenta by two fetuses leads

DIAMNIOTIC Twins to some unique complications in MC twins, and
understanding the basic pathophysiology of these
Monochorionic diamniotic (MCDA) twins are the complications is vital to planning reasonable care
second most common variety of multifetal preg- for these conditions. The placental size, position,
nancies encountered in clinical practice. The most and architecture are definitely important in prog-
important difference in MC and DC twins is the nosticating any pregnancy, but its typical vascu-
common placenta between two fetuses in the MC lature is the most important determinant of
pair unlike DC twins where each fetus has its own prognosis of a MC pregnancy. As explained
independent placenta. Therefore, the chances of earlier in this chapter, sharing the placenta in
complications are higher and the type of problems terms of its area and vascularity can inherently
faced by monochorionic twins is rather unique. lead to “discordance” in natural allocation of
The need for closer monitoring of monochori- resources to the twins and therefore increase the
onic pregnancies has been realized, and the fol- possibility of fetal problems.
low-up protocol for any monochorionic The placenta is a very vascular organ with
pregnancy recommends at least two-weekly multiple interconnecting or “anastomotic” ves-
reviews from 16 weeks of gestation onward. The sels formed during its development. When two
situation would change if any complication was fetuses are connected through the placenta, these
associated, but as a general consensus, uncompli- interconnections or anastomoses form pathways
cated MC twins can be followed up based on the or “shunts” capable of bidirectional blood flow,
plan displayed in Fig. 11.8. but the direction depends on the pressure gradient
MONOCHORIONIC TWINS: Follow up protocol
6-8 weeks
Systematic Labelling of fetuses Viability, dating and
Chorionicity number of fetuses
11-14 weeks
Aneuploidy screening
16 weeks
Biometry TTTS screening TIFFA
18 weeks Biometry
AF volume
20 weeks Cervical length
Umbilical artery PI
MCA PSV
22 weeks
24 weeks
Fetal Growth
Single deepest pool of liquor
26 weeks
Umbilical artery PI
MCA PSV
28 weeks
30 weeks
32 weeks
Uncomplicated : Plan for delivery at 36-37 weeks
34 weeks Mode of delivery :Obstetric indications
36 weeks
Fig. 11.8 Fetal care protocol in uncomplicated MC twins

11.6 Planning a Rational Follow-up for Serial Monitoring of Multiple Pregnancy 115
across these vessels. There are three types of fetus which is toward the “venous” predominance
“shunts” that are possible: becomes the “recipient,” while the fetus toward
the “arterial” predominance becomes the “donor.”
1. Arterioarterial (A-A) shunts Blood thus flows from the donor to the recipient
2. Venovenous shunts (V-V) shunts leading to the condition known as “twin-to-twin
3. Arteriovenous (A-V) shunts transfusion syndrome” or TTTS. TTTS affects
about 15% of all monochorionic twin pregnan-
Figure 11.9 shows the monochorionic pla- cies and is a result of unbalanced AV anastomo-
centa with different types of anastomoses. The ses in the placenta. Figure 11.10 illustrates the
pressure gradient across A-A or V-V shunts is pathophysiology of TTTS.
minimal such that they do not cause much hemo- The donor becomes progressively hypovole-
dynamic changes, but the A-V shunts have a defi- mic, oliguric, and growth restricted. The recipi-
nite pressure gradient such that the blood flows ent becomes overperfused and at risk of cardiac
preferentially from the arterial to the venous side. failure. Both fetuses are at risk of mortality in this
If such shunting is “balanced” across two condition, if left untreated. TTTS is classified
fetuses who share a placenta (monochorionic), into five stages based on a system of staging pro-
then the pressure compensation maintains circu- posed by Prof. Ruben Quintero in 1999. These
latory balance, but if these shunts are “unbal- stages are the following:
anced,” then blood tends to flow toward the fetus
which has more venous connections. Thus, blood • Stage I: Significant difference in amniotic
is “pumped” toward one fetus preferentially—the fluid volumes (polyamnios-oligoamnios)
Twin 1
Twin 2
Placenta in MC twins
A-A anastomosis : equal pressures – bidirectional flow
V-V anastomosis : equal pressure – bidirectional flow
A-V anastomosis : Pressure gradient - unidirectional flow from A to V
Fig. 11.9 Monochorionic placenta with vascular anastomoses

Twin 2 : Recipient
Twin 1 :Donor
Predominantly arteries Predominantly Veins
Blood flows from A to V: Blood flows from A to V:

hence “donates” blood to hence “receives” blood
co twin from co twin
Pathophysiology of TTTS
At risk of hypovolemia, At risk of hypovolemia,
oliguria, oligoamnios and polyuria, polyamnious and
renal failure congestive heart failure
Fig. 11.10 Pathophysiology of twin-to-twin transfusion syndrome
between the two sacs but urine still visible should mention the comparative fluid levels in
within the donor twin’s bladder during ultra- both sacs (whether normal/oligo/poly) and the
sound. There is a 40% risk of fetal mortality. presence or absence of fetal bladder and the fetal
• Stage II: In addition to the features of stage I, Doppler features as the preliminary features
the donor’s bladder is “empty” as no urine is which help in diagnosing TTTS. Once TTTS is
detected in the bladder during scans. Fetal diagnosed and staged, management of the condi-
Dopplers are normal so far. tion is another challenge. Stage I TTTS may be
• Stage III: In stage III, abnormal Doppler stud- managed conservatively with serial review, but
ies of the umbilical artery, ductus venosus, or stage II or III warrants definitive treatment like
umbilical vein are seen in addition to stage II LASER photocoagulation of anastomotic vessels
features. in the placenta. This procedure helps in effec-
• Stage IV: Ascites or frank hydrops in either tively “dichorionizing” a monochorionic placenta
twin. The risk of fetal mortality increases to and hence is an effective treatment of TTTS
60% by now. which allows salvaging both the fetuses. It is
• Stage V: Demise of either fetus. In case there however a very skill-intensive procedure and
is one surviving twin, there is a 19–26% risk should be undertaken only by operators specifi-
of neurological morbidity in this fetus. cally trained for the same. Details of such fetal
therapeutic procedures are discussed in a sepa-
The progression of TTTS through these stages rate chapter later in the book.
is a logical sequence of events that happen due to In some cases single fetal salvage may be
the drastic hemodynamic imbalance in the donor done by Radiofrequency ablation or Bipolar cord
and recipient as shown in the table below coagulation of the worse affected twin. Decisions
(Table 11.1). regarding which procedure to be performed and
It is imperative that all ultrasound scan reports when have to be considered with the merits of
pertaining to monochorionic twins must mention each individual case and cannot be randomly
the presence or absence of TTTS signs in addi- generalized.
tion to the general issues of viability and biome- The important point to remember here is that
try. In particular, all scan reports of MC twins TTTS potentially affects both donor and recipi-
11.7 Twin Reversed Arterial Perfusion (TRAP) Sequence 117
Table 11.1 Stage-wise progression and ultrasound findings in TTTS

TTTS
Stage Donor physiology Recipient physiology USG findings
Stage I Receives less blood flow, decreased Receives more blood Donor: Oligoamnios, small bladder
GFR, decreased urine output volume, hyperdynamic Recipient: Polyamnios, large bladder
although renal functions are circulation, polyuria
maintained
Stage II Receives further less blood flow, Receives more blood Donor: Severe oligoamnios, absent
decreased GFR, critically decreased volume, hyperdynamic bladder echo
urine output such that renal circulation, polyuria, Recipient: Polyamnios, large bladder
functions are affected and almost no and increased stress on
urine is formed, fetal growth the fetal heart
restriction starts to set in
Stage III Fetal growth restriction sets in with Early signs of cardiac Donor: FGR, umbilical artery
anuria and abnormal umbilical compensation to the dopplers PI is raised or AREDF seen
artery dopplers hyperdynamic state and Recipient: Cardiomegaly, tricuspid
hypervolemia are seen regurgitation, abnormal ductus
venosus flows
Stage IV Severe FGR with renal compromise Cardiac Donor: Severe FGR with anuria
decompensation, Recipient: Hydrops fetalis
congestive heart failure
Stage V Death or risk of residual neurological morbidity if alive USG signs of neurological damage
may not present immediately but
take several weeks to manifest
ent adversely, and if left untreated, both fetuses latory pathways and therefore the risk of neuro-
are at risk of morbidity and mortality. Death of logical damage is minimized.
any one fetus in a MC pair causes a risk of neuro-
logical deficit to the surviving co-twin because
there is some exsanguination from the live fetus 11.7 Twin Reversed Arterial
to the dead co-twin at the time of the latter’s Perfusion (TRAP) Sequence
demise. This leads to a transient ischemia in the
tissues of the surviving fetus, and since brain is This is another unique complication associated
very sensitive to hypoxia, it may get irreversibly with MC twins where one fetus is normally
affected in some cases accounting for 19–26% formed but the other one is an acardiac, amor-
risk of neurological morbidity in these cases. phous mass which does not have a heart of its
Therefore, any intervention toward fetal therapy own (hence “acardiac”) and its circulation is
must be attempted only before a fetal demise based on abnormal arterioarterial and venove-
because these adverse events occur at the time of nous anastomoses that is supported by the car-
the fetal demise and even if subsequent proce- diac activity of the “pump twin.” As shown in
dures are done, the risk for residual neurological Fig. 11.11, the pathophysiology of the TRAP
damage exists. The basic premise of therapeutic sequence is based on the “reversed arterial per-
procedures is to disconnect the circulations of the fusion” of the acardiac mass. This mass receives
fetuses, and this is only meaningful if done when blood through the umbilical artery that in turn is
both have their inherent circulations active. filled by blood from the heart of the normal
Although the result of some procedures like twin. The blood is returned by the umbilical
radiofrequency ablation and bipolar cord cauter- vein, and through the placenta, this again circu-
ization is the demise of one fetus, this iatrogenic lates to the other fetus, thus putting the “pump
reduction is beneficial to the live co-twin because twin” at risk of congestive heart failure due to
as the connecting vascular channels are sealed, hyperdynamic circulation, while this acardiac
there is no exsanguination into the other’s circu- mass may grow into bigger proportions. The
Pathophysiology of TRAP sequence
Normal twin
Inflow: Umbilical vein
Outflow: Umbilical artery
Pumb: fetal heart
Acardiac twin
Inflow: Umbilical artery
Outflow: Umbilical vein
Pumb: No internal pump,
supported by noraml twin’s heart
Fig. 11.11 Pathophysiology of the TRAP sequence
TRAP itself may have different names based on vage may be done by ablating the vessels of the
the parts formed or absent, e.g., acephalus, acardiac twin by either LASER or RFA or
anceps, acormus, or truly amorphous. Like all BPCC. The details of these procedures are given
monochorionic complications, this is also a in the chapter on fetal therapy.
double whammy—the pump twin may develop It is important to be aware of this condition as
hydrops due to volume overload, and the acar- many times the presence of a second mass with-
diac mass may grow so much that delivering it out cardiac activity is erroneously diagnosed as a
will become challenging as it may not have the missed miscarriage of one twin, and subsequently
“limb handles” or any structure that can be when this presumably nonviable fetus starts
grasped easily to deliver. In some cases, the growing in dimensions and even developing skel-
TRAP may spontaneously cease growing if the etal elements, then it leads to clinical dilemma
arterial supply is hampered naturally. Many of due to ignorance of the cause (Figs. 11.12, 11.13,
these pregnancies continue successfully, but if and 11.14).
the acardiac mass continues to grow in size and When diagnosed early and correctly, a reason-
vascularity, co-twin demise is the result of the able plan of care can be formulated to lead to a
sequence of changes. In such cases, fetal sal- good perinatal outcome.
11.7 Twin Reversed Arterial Perfusion (TRAP) Sequence 119
Fig. 11.12 Monoamniotic twin pregnancy showing cord insertions of the twins, no intervening membrane
Fig. 11.13 Conjoined twins
Fig. 11.14 Higher-order multiple gestation

11.8 Monochorionic There is no effective method of monitoring

Monoamniotic (MCMA) MCMA twins to prevent cord entanglement or
Twins consequent fetal demise, and hence many profes-
sional bodies recommend elective delivery by
Monochorionic twins are monozygotic twins that caesarean section at 32 weeks after steroid over
split after 72 h of fertilization such that they for fetal lung maturity. This approach is definitely
retain a common placenta. MCDA twins (com- not ideal and controversial, but considering the
mon placenta-different sacs) result from splitting unique and unpredictable nature of clinical prob-
between 3 and 8 days. If the zygote splits between lems in the context of MCMA twins, such man-
8 and 12 days, then it results in MCMA (common agement may be justifiable.
placenta and common sac).
As a simple analogy, DCDA twins have their
own rooms and own kitchens, while MCDA 11.8.1 Conjoined Twins
twins have separate rooms but a common
kitchen—hence the problems of unequal sharing If a single zygote splits into two fetuses after
and distribution!! MCMA twins share not only 13 days of fertilization, complete separation is
the kitchen but also their room!! The MCMA not achieved, and the two fetuses are joined to
twins may have further unique problems like each other and often found to be sharing organs
“cord entanglement” which can be benign if it too. Depending on the common, shared organs,
remains loose and does not disrupt circulation or conjoined twins may be called craniopagus, tho-
may cause intermittent hypoxic episodes and is racopagus, ischiopagus, etc.
potentially lethal causing intrauterine fetal If multiple fetal parts are seen on ultrasound
demise of one or both co-twins. scan and found to be moving simultaneously with
Diagnosis of a monoamniotic twin pregnancy no relative motion, conjoined twins are sus-
is based on exclusion of the possibility of an pected. A thorough ultrasound imaging eventu-
intervening membrane between the fetuses, and ally confirms the diagnosis which is corroborated
sometimes it may take more than one occasion to by the presence of a four-vessel umbilical cord.
firmly establish this diagnosis. Presence of cord The prognosis of conjoined twins is uniformly
entanglement is a confirmatory sign, but nonvisu- bad and postnatal complex surgery is warranted to
alization of the membrane despite a thorough separate them—the results of which have not
search in a monochorionic twin pregnancy latest been very encouraging. Most parents opt to dis-
by 11–14 weeks’ scan should enable one to con- continue pregnancies with conjoined fetuses and
firm the diagnosis of MCMA pregnancy. hence an early diagnosis becomes clinically an
Approximately 1% of monozygotic twins are important issue. Delivering a conjoined pair of
monoamniotic and the overall incidence is about twins is a technical challenge as the size of the
1 in 12,500 births. Perinatal mortality is high in fetuses grows and can cause serious damage to
MCMA twins due to cord entanglement (in maternal structures in the process of vaginal
almost 50% cases), congenital anomalies, pre- expulsion or caesarean section. A “bifid” fetal
term birth, or even twin-twin transfusion syn- pole in early pregnancy is an early indicator of the
drome, which is difficult to diagnose and possibility of “conjoined” twins. By 11–14 weeks,
managed in these cases. again this diagnosis can be unequivocally estab-
lished although it may be possible earlier too.
Further Reading 121
11.9 Higher-Order Multiples

(Triplets, Quadruplets, Key Learning Points in Multiple Pregnancy
and So on) 1. Multiple pregnancy incidence has
increased significantly due to multiple
The incidence of higher-order multiple is ris- reasons and is a regular entity in fetal
ing steadily especially due to assisted reproduc- medicine clinics.
tive techniques that cause “superovulation” or 2. Identification, prognostication, and
multiple embryo transfers during IVF. Higher- management of multiple pregnancy
order multiples pose severe challenges to the cases pose a daunting challenge to
clinical management not only due to exaggerated clinicians.
mechanical effects of a pregnancy with more than 3. CHORIONICITY is the most important
two fetuses but also due to some specific issues prognostic factor in multifetal preg-
like lack of robust aneuploidy screening methods, nancy and MUST be established by the
technical difficulties in scanning each individual first trimester of pregnancy.
fetus for anomalies, increased risk of preterm 4. Dating, risk assessment, and serial
birth, and add-on problems of “monochorionic- fetal surveillance in multifetal preg-
ity” if some fetuses are sharing their placentae. nancy are based on protocols defined by
Higher-order multiple pregnancy must be diag- chorionicity.
nosed early, and assessment of number of fetuses 5. Systematic labeling of multiple fetuses
and chorionicity should be clearly completed by helps in proper monitoring of the fetuses
11 weeks. Labeling of these fetuses is done by in serial assessments.
identifying the first sac closest to the cervix and 6. Monochorionic pregnancies carry risk
then moving anticlockwise or clockwise from of specific complications and need spe-
thereon and defining each placental position, cord cialized management.
insertion, and fetal orientation. Potential problems 7. Higher-order multiple pregnancies need
with higher-order multiples must be discussed in careful identification and management.
detail with the parents in early pregnancy.
Care for higher-order multiple should be
arranged in close coordination of a fetal medicine
center and an obstetric care center with a tertiary Suggested Reading
level neonatalogy backup. Aneuploidy screen-
ing is scan-based and biochemical tests do not Algeri P, et al. Selective IUGR in dichorionic twins: what
perform well in higher-order multiples. Offering can Doppler assessment and growth discordancy say
serial two-weekly scans is justified as clinical about neonatal outcomes? Med: J. Perinat; 2017.
Dias T, et al. First-trimester ultrasound determination of
assessment of growth is fallacious in these cases. chorionicity in twin pregnancy. Ultrasound Obstet
Maternal discomfort can be considerable and Gynecol. 2011;10(1):89.
despite recommended precautions, the risk of Khalil A, et al. ISUOG Practice Guidelines: role of ultra-
preterm birth is above 30%. sound in twin pregnancy. Ultrasound Obstet Gynecol.
2016;47:247–63.
In order to improve perinatal outcomes in Lewi L, et al. Clinical outcome and placental character-
higher-order multiples, iatrogenic fetal reduction istics of monochorionic diamniotic twin pairs with
to twins is a justifiable option, and the technique early- and late-onset discordant growth. Am J Obstet
is discussed in the chapter on prenatal interven- Gynecol. 2008;199:511.
tions (Chap. 15).
Placenta, Cord, Amniotic Fluid,
and Cervix 12
The human placenta is a pregnancy-specific

organ that is the connecting bridge between the Box 12.1: Interesting Trivia About the
mother and the fetus. The placenta provides a Human Placenta
platform for exchange of oxygen and nutrients • Human beings are “viviparous” mam-
for the fetus and is a vascular structure that also mals—they give birth to their little ones
regulates fetal hemodynamics as a pressure and as opposed to “oviparous” animals
volume interface. The placenta is the first organ which lay eggs and hatch them exter-
to form in the feto-maternal unit as it is required nally. The placenta is the organ which
for supplying the bioenergetic needs of the devel- allows in vivo growth of the human
oping fetus. The placenta itself is a temporary fetus.
organ, but its effects on the life of the fetus as • Human “placental” tissues include
well as the mother are coming to be recognized amnion, chorion, and allantois which
as extremely important and long-standing after represent the amniotic sac, placenta, and
more and more studies are being conducted on umbilical cord, respectively.
the molecular basis of maternal-fetal health. • The placenta is discoidal and
There is a wealth of information available about hemochorial.
the evolution, metabolomics, and genomics of • The presence of live ectopic pregnan-
the placenta which is now considered central in cies indicates that placenta, not uterus,
the mechanism of fetal development and mater- is the critically important factor in
nal adaptations to pregnancy. maternofetal physiology.
It is always interesting to delve a bit into the • The placenta, though transient, is con-
basics of biology which establish a link of our sidered a highly “mutable” organ. The
understanding of human life as part of the evolu- higher evolution of the placenta in the
tionary story of living beings. We remember that “eutherian” mammals has enabled an
we are part of the group of “mammals” in the ani- evolutionary advantage leading to dif-
mal kingdom. Some interesting trivia about the ferentiation of several taxonomic orders.
placenta are given in Box 12.1. which are worth a
quick recapitulation at this stage.

124 12 Placenta, Cord, Amniotic Fluid, and Cervix
12.1 Evaluation of the Placenta some distinctly disturbing features as shown in

in Pregnancy Fig. 12.2a, b.
This appearance of small cystic spaces in a
The placenta can be evaluated by ultrasound, and bulky placental mass is suggestive of molar
the appearance of this organ changes progres- changes and warrants a battery of investigations.
sively during different stages of pregnancy. A highly elevated hCG level in maternal serum
Figure 12.1 shows how the placenta appears as a corroborates the diagnosis although confirmation
small hyperechoic area near the fetal pole in early is only by histopathological examination of the
pregnancy and gradually develops as a well- placenta. Although a complete mole warrants
defined entity by the end of the first trimester. evacuation of the uterus, a partial mole or a coex-
In the late first trimester, the size of the pla- istent twin fetus with a complete molar preg-
centa in comparison to the uterine cavity is such nancy may present management dilemmas in the
that it is spread over more than half of the longi- pregnancy.
tudinal axis and hence may appear invariably Such pregnancies must be managed in centers
“low lying” although it may not be a truly pla- with expertise to address all the complications
centa previa. It is therefore better not to label the which include fetal aneuploidy, severe fetal
position of the placenta in the first trimester. It growth restriction, early preeclampsia, and inva-
suffices to mention “normal appearances” of the sive mole. Detailed counseling and thorough fol-
placenta in the first trimester unless there are low-up is necessary in these cases.
a
Early placenta
Yolk sac
Fetal pole
Intrauterine gestational sac
b
fetus
Placenta at 12 weeks
Umbiliacl cord
Fig. 12.1 (a, b) Placental appearance in early pregnancy—6 weeks and 12 weeks
12.3 Location and Edges 125
a b
Fig. 12.2 (a) Partial molar placenta. (b) Complete molar placenta
12.2 Placenta in Second Trimester A “low-lying” placenta (Fig. 12.4) is defined

as one where the lower edge is seen within 3 cm
By the second trimester, the placenta is a well- from the internal os or may even be partially or
defined organ seen on ultrasound, and it is impera- completely covering it as in placenta previa. A
tive that a proper placental evaluation accompanies complete placenta previa (Fig. 12.5) is an impor-
fetal evaluation during the midtrimester fetal scan. tant diagnosis to make although partial previas
The points to be noted with respect to the placenta and other types of “low-lying” placentae are
and mentioned in the report of a second trimester expected to “move” away from the internal os as
pregnancy scan are placental location, size, any the pregnancy progresses due to development of
remarkable morphologic changes, cord insertion, the lower uterine segment. Therefore, these cases
and associated cord issues. “Grading” of the pla- need to be reassessed in the third trimester,
centa which was done in earlier times is no longer around 32 weeks, to check the placental location
part of placental evaluation. and modify care as needed.
It is important to alert the obstetrician about a
low-lying placenta in any case so that a rational
12.3 Location and Edges follow-up may be maintained. If the lower edge
of the placenta is seen clearly on transabdominal
The placenta may be present on the anterior scanning, then it is highly reassuring. However,
(Fig. 12.3a), posterior (Fig. 12.3b), or lateral in case of any doubts at all, especially in posterior
walls of the uterus as observed during the scan, placentae, a transvaginal assessment must be
and its lower edges must be defined with respect done in order to correctly assign placental
to the internal os of the cervix. location.
Fig. 12.3 (a) Anterior placenta. (b) Posterior placenta

12.3 Location and Edges 127
Fig. 12.4 Low-lying placenta
Fig. 12.5 Complete placenta previa

12.4 Size reveals that both low and high placental weight
with respect to fetal weight are associated with
Assessment of placental size is generally sub- fetal growth restriction and even have been cor-
jective during antenatal ultrasound. The size of related to later hypertension and cardiovascular
the placenta typically correlates with fetal size disease.
but there is scope for a large degree of variation When the thickness of the placenta is more
too. A relatively large placenta for birth weight than 5 cm, it is classified as a “large placenta”
may indicate that the placenta was compensat- (Fig. 12.6). Such large placentae are commonly
ing for inefficient transport mechanisms due to seen in cases of fetal hydrops, intrauterine infec-
defects at the cellular level. However, a small tions, fetal anemia, or maternal diabetes. If all
placenta also indicates restriction in provision such associations are ruled out, it may be a physi-
of nutrients to the fetus. A review of literature ological variant too.
Fig. 12.6 Large placenta

12.5 Morphology of the Placenta 129
12.5 Morphology of the Placenta color Doppler (Fig. 12.8a–d) with multiplanar
imaging can help in such assessment.
The “normal” appearance of the placenta has Based on the above factors, recently, an
been discussed in an earlier section, and we will ultrasound-based classification of placenta accreta
delve a bit into the details of the structural evalu- spectrum (PAS) has been suggested (Ref: Cali
ation of a placenta during the midtrimester scan et al.) which appears to be feasible and also corre-
(Fig. 12.7). lates with the severity of adverse clinical outcomes
The distinct, hypoechoic basal layer is indica- as the stage progresses. Table 12.1 lists the differ-
tive of a normal interface in the myometrium, ent features of the progressive stages of PAS (0–3).
whereas absence of this layer beneath the pla- Whenever morbid adherence is suspected, it is
centa raises the possibility of morbid adherence. prudent to alert the obstetrician to be prepared
Presence of placental lakes, obvious “dropout during the process of delivery anticipating risks
areas” in uterine myometrium, and vascular con- and the need for added interventions. MRI has
nections across the myometrio-chorial interface been suggested by some authors to aid in the
are factors corroborating the diagnosis of mor- ultrasound diagnosis of morbid adherence, but
bidly adherent placenta. The common risk factors the sensitivity of both is limited by multiple fac-
for morbid adherence are cases with previous tors and hence it is better to be prepared for clini-
uterine surgery or scars (caesarean sections, cal emergencies in such cases.
transcavitary myomectomy or curettage, etc.) Some other placental conditions encountered
and low-lying placentae. In low-lying placentae, in clinical practice that can be diagnosed on ante-
a thorough assessment of the vesicouterine inter- natal ultrasound are chorangiomas (Fig. 12.9)
face should be done to look for these signs, and and placental cysts (Fig. 12.10).
Echogenic placenta
Hypoechonic Basal layer
Fig. 12.7 Normal placental morphology

a b
c d
Fig. 12.8 (a–d) Assessment of placenta to rule out morbid adherence
Table 12.1 USG-based classification of PAS (Ref: Cali While placental cysts are relatively benign,
et al. Prenatal Ultrasound Staging System for Placenta chorangiomas either can be asymptomatic or
Accreta Spectrum Disorders. Ultrasound Obstet Gynecol. may contribute to hyperdynamic circulation in
2019 Jun;53(6):752–760)
the fetus leading to polyhydramnios and a risk of
PAS0 Placenta previa with no US signs of fetal hydrops necessitating interventions like
invasion or placenta previa with placental
lacunae but no evidence of abnormal occluding its feeding vessel to stop its growth and
uterine-bladder interface effects.
PAS1 Presence of at least two ultrasound signs Sometimes, echogenic rims are seen lining the
among placental lacunae, loss of the clear placental cotyledons (Fig. 12.10), and this is con-
zone, or bladder wall interruption
sidered as a sign of placental ageing by some
PAS2 PAS1 + uterovesical hypervascularity
authors in the literature of yester years. Now it is
PAS3 PAS1/PAS2 + evidence of increased
vascularity in the inferior part of the known that such appearance of placenta does not
lower uterine segment potentially directly correlate with clinical outcomes, and
extending in the parametrial region hence clinical decision-making based on these
placental appearances is not recommended.
12.5 Morphology of the Placenta 131
Fig. 12.9 Chorangioma
Fig. 12.10 Echogenic rims in placental cotyledons

a b
Fig. 12.11 Marginal cord insertion (a) as compared to central insertion (b)
12.6 Umbilical Cord Insertion between the mother and the fetus and allows for
transport of oxygen, nutrients, and metabolites.
Umbilical cord insertion site on the placenta also The length and flexibility of the umbilical cord
must be checked as part of the placental evalua- make it possible for the fetus to move freely in
tion because the insertion site has clinical signifi- the amniotic cavity while maintaining its nutri-
cance. The site of cord insertion can be tion and other functions. This free movement is
investigated by making a transverse sweep across necessary for optimum psychomotor develop-
the uterine cavity from the fetus toward the pla- ment of the fetus. The length of the normal
centa. Majority of placentae (90–91%) have a umbilical cord is anything between 50 and 75 cm,
“central” or eccentric cord insertion. There may but it is difficult to assess the exact length—espe-
be abnormalities like marginal (7%) or velamen- cially in long cords. Very short umbilical cords
tous (1–2%) insertions which are associated with may be suspected if the fetus is not freely moving
high risk for poor fetal outcomes (Fig. 12.11). at around the uterine cavity, and this is sometimes
Marginal insertion is defined as the cord inserted seen with body stalk anomalies.
less than 2 cm away from an edge of the placenta, The normal umbilical cord of the fetus has
while velamentous insertion is defined as inser- three vessels—two umbilical arteries and one
tion of the cord in the membranes rather than the umbilical vein. Usually, the left umbilical vein
bulk of the placenta. remains patent throughout fetal life, while the
right umbilical vein naturally regresses by the
seventh week of gestation.
12.7 Assessment of Umbilical The normal umbilical cord configuration is seen
Cord Morphology either by using color flow across the transverse sec-
tion of lower abdomen demonstrating two perivesi-
The assessment of the structure of the umbilical cal umbilical arteries (Fig. 12.12) or as a transverse
cord is also important along with its insertion section of the free loop of the cord (Fig. 12.13)
site. This umbilical cord is the only connection demonstrating the “Mickey mouse” sign.
12.7 Assessment of Umbilical Cord Morphology 133
Fig. 12.12 Two umbilical arteries continuing into umbilical cord
Fig. 12.13 Mickey mouse sign

a b
Fig. 12.14 (a, b) SUA
12.8 Single Umbilical Artery SGA fetus and hence warrants serial growth fol-
low-up. Once all of the above are sorted, parents
Umbilical cord abnormalities can have important can be reassured that majority of the babies with
prognostic implications for perinatal outcome. SUA will have a normal antenatal course and a
One of the common abnormalities is the finding good postnatal outcome.
of a single umbilical artery (SUA) whereby the
cord has only two vessels—one artery and one
vein. The reported incidence of SUA varies from 12.9 Persistent Right
0.5% at the time of second trimester prenatal Umbilical Vein
ultrasound and in umbilical cord specimens from
live-born infants to 2.1% in fetal deaths, autop- This happens rarely and is seen in 0.08–0.5%
sies, or aborted fetuses. cases. The diagnosis of persistent right umbilical
The cause of a SUA could be either a primary vein (PRUV) is tricky as the umbilical cord on
agenesis or a secondary thrombotic atrophy of cross section has three vessels and the two arter-
one umbilical artery or the persistence of the ies are demonstrated perivesically in the normal
original single allantoic artery of the body stalk. manner. However, the clincher for diagnosis is to
Depending on the cause, the prognosis would notice the course of the umbilical vein intraab-
vary, but it is not realistically possible to defini- dominally—it curves toward the stomach in the
tively establish this cause during antenatal scans. transverse abdominal view instead of curving
The diagnosis of SUA is based on the findings away from the stomach (Fig. 12.15).
of the perivesical view revealing only one patent The extrahepatic PRUV has a poorer progno-
vessel or two lumens seen on transverse section sis as it is often associated with absent DV lead-
of the cord (Fig. 12.14a–b). ing to high risk of fetal hydrops. The intrahepatic
Diagnosis of a single umbilical artery (SUA) PRUV may have a fairly good prognosis
leads to a lot of anxiety, but it is important to (Fig. 12.16).
remember that is most commonly (70%) a nor- Other umbilical cord abnormalities like cord
mal variant unless proved otherwise. SUA is an cysts (Fig. 12.17) and umbilical vein varices may
indication to ensure that there are no other associ- be seen on antenatal ultrasound.
ated structural anomalies (30%) as it may be Problems like true knots (Fig. 12.18) are com-
associated with multisystem abnormalities of the monly evident only after delivery in most cases as
VACTERL group and those associated with tri- detection of true knots in utero is more of a chance
somy 18. SUA is also associated with a risk of finding and practically one cannot interrogate the
12.9 Persistent Right Umbilical Vein 135
Confirmed diagnosis of Single Umbilical artery
Algorithm for management

Detailes anomaly scan - TIFFA
normal
abnormal Neonatology
Assessment
KT, counsel Fetal echo

according to final
diagnosis
Serial growth follow up in third trimester
abnormal normal
Manage according to Doppler and Delivery at term as per

serial monitoring Obstetric indications
Fig. 12.15 Algorithm for follow up after diagnosis of single umbilical artery
Normal LUV : curves

away from the stomach
S S
PRUV : curves towards
p p the stomach
i i
n n
e e
stomach
Fig. 12.16 PRUV
entire length of the umbilical cord in all cases, at remains a rather subjective and debatable entity,
all gestations. Most of the times, knots in the cord and literature is divided on whether umbilical
are incidental diagnoses and may be missed cord coiling is a cause or effect of fetal problems.
despite regular scans if the affected part of the In addition to all the above findings is the inci-
cord is not in the visual field of the operator. dental finding of a “nuchal cord”—a loop of cord
Another aspect commonly associated with either around or across the fetal neck. This is just
umbilical cord anatomy is the degree of coiling— an observation and should not be the sole guide
hyper- or hypocoiling. The cord “coiling index” decisions regarding delivery. This is considered a
a b
Fig. 12.17 Umbilical cord cyst: (a) gray scale, (b) color Doppler
Fig. 12.18 True knot in umbilical cord discovered after delivery
normal variation in the cord position—it may slip tion of cord abnormalities should prompt a thor-
off or may cause tightening in labor which will ough fetal examination as these conditions could
anyway be detected as fetal heart rate pattern result in fetal growth restriction and even fetal
abnormalities during intrapartum monitoring and death. Early diagnosis and surveillance can mini-
then the decisions to deliver may be justified. mize fetal mortality and help make decisions.
The examination of the umbilical cord is an The isolated cord abnormalities generally have a
important part of fetal ultrasound, and the detec- good prognosis.
12.10 Amniotic Fluid 137
12.10 Amniotic Fluid (Fig. 12.21) and more than normal is known as
“polyamnios”.
Amniotic fluid is the liquor in the amniotic cavity The common causes of oligoamnios are hypo-
which provides spaces, buoyancy, mechanical perfusion of fetal kidneys due to fetal growth
cushioning, and temperature maintenance of the restriction or fetal anomalies like bilateral renal
fetal environment. In early pregnancy, most of agenesis or donor twin in TTTS. Polyamnios on
the amniotic fluid is formed by the placenta and the other hand may be due to fetal, maternal, or
its membranes, while after 16 weeks of gestation, placental causes. Fetal anomalies like open
the fetal urine becomes a major contributor. neural tube defects, cleft lip and/or palate, ante-
Assessment of amniotic fluid levels is part of rior abdominal wall defects, and neuromuscular
every fetal assessment. In the first trimester, the disorders leading to fetal akinesia, fetal GI
assessment is rather subjective, but in the second obstructions, fetal anemia, or recipient twin in
half of pregnancy, a quantitative amniotic fluid TTTS may have polyamnios. Maternal factors
assessment can be made based on either a “single like hyperglycemia due to uncontrolled diabetes
deepest pool” (Fig. 12.19) or a four-quadrant and placental chorangiomas can cause
amniotic fluid index (Fig. 12.20). polyamnios.
Both methods are acceptable methods of With this background, it may be understood
assessing amniotic fluid but it is important that that reporting only “oligoamnios” or “polyam-
the normal values be adjusted based on the nios” in an antenatal scan leaves scope for a lot
method used. more information pertaining to the suggested
The normal range of AFI based on SDP is cause of these problems. It is therefore impera-
2–8 cm while that on 4Q AFI is 5–25 cm. Values tive on the reporter to make a note of fetal anat-
less than normal are called “oligoamnios” omy, placental morphology, and possibility of
Fig. 12.19 SDP

Fig. 12.20 4Q AFI
No measurable liquor pocket
Fig. 12.21 Severe oligoamnios

12.11 Assessment of Cervix 139
fetal growth restriction or hypoperfusion or even at a high risk of preterm birth. Cervical assess-
macrosomia to indicate any plausible etiological ment is done most accurately by the transvaginal
conditions. In an average grown fetus with no method with a high frequency (5 MHz). By gen-
other associated features as described above, tly placing the probe in the anterior vaginal for-
mild liquor disturbances may be physiological. nix, a sagittal view of the cervix is obtained
However, even when unexplained, severe oli- (Fig. 12.22).
goamnios or polyamnios could be potentially The internal os, external os, cervical canal, and
lethal. Severe oligo leads to postural limb defects endocervical mucosa are identified without exert-
and pulmonary hypoplasia, while severe poly puts ing undue pressure on the cervix with the probe
the fetus at risk of preterm birth along with mater- because this will falsely elongate the cervix.
nal health risks due to overdistension of the uterus. Sometimes, one may find a short cervix
Such cases have to be dealt with by a dedicated (Fig. 12.23) with or without funneling of mem-
maternal-fetal medicine team of experts with ade- branes. A cervical length of less than 25 mm at
quate investigations, counseling, and follow-up. 24 weeks on TVS in singleton pregnancy
increases the risk of preterm birth by sixfold and
the risk escalates with the degree of shortness.
12.11 Assessment of Cervix Cervical funneling may add to the risk and
funneling is progressively seen, characterized by
The length and integrity of the maternal cervix the appearance of membranes at the level of
are important determinants of in utero safety of internal os resembling the alphabets—Y, V, and
the pregnancy. A short cervix places the woman U (Fig. 12.24a–c), respectively.
Fig. 12.22 Cervical length

Fig. 12.23 Short cervix without funneling
a b
Fig. 12.24 (a) Y-shaped internal os. (b) 24b V-shaped internal os. (c) U-shaped internal os
Further Reading 141
Suggested Reading
Key Learning Points in Placenta, Cervix, and
Cord Issues Baergen RN. Pathology of the umbilical cord, in manual of
1. Evaluation of the placenta is vital to pathology of the human placenta. 2nd ed. New York:
Springer; 2011.
prognosticating pregnancy outcome— Cali, et al. Prenatal ultrasound staging system for pla-
at every stage of pregnancy, there are centa Accreta Spectrum disorders. Ultrasound Obstet
objective methods of evaluating the pla- Gynecol. 2019 Jun;53(6):752–60.
centa, and these features should be Cervical assessment guidelines as given in the website of
the Fetal Medicine Foundation, UK. www.fmf.org.
included in the obstetric scan report. Desforges, et al. Placental nutrient supply and fetal
2. Placental position and signs of morbid growth. Int J Dev Biol. 2010;54(2–3):377–90.
adherence must be noted during all Jansson, et al. Role of the placenta in fetal programming:
obstetric scans. underlying mechanisms and potential interventional
approaches. Clin Sci (Lond). 2007;113(1):1–13.
3. Umbilical cord variations and anoma-
lies add information that can alter the
prognosis and follow-up protocol in
pregnancy.
4. Amniotic fluid assessment can be done
objectively in the second half of preg-
nancy, and liquor abnormalities are
associated with adverse pregnancy
outcomes.
5. Cervical length by TVS is an important
predictor of preterm birth.
Basics of Genetics in Fetal
Medicine 13
Genetics is the study of hereditary characteristics each concept to its basics. In this chapter, these
which are passed from one generation to another genetic concepts have been presented in a simpli-
through genes. With growing understanding of fied language as important points to facilitate
the human genome, a lot has been deciphered of such understanding.
what was once considered a mystery. Yet, while For a start, we are aware that “genes” are car-
this rapid expansion of knowledge and technol- riers of information that describe or define our
ogy in genetics has helped us become better characteristics.
equipped with information to answer many clini-
cal questions, it is the same ever-progressing sci- • Genes are strands of DNA (deoxyribonucleic
ence that makes us feel inadequate time and again acid) which carry information regarding
as clinicians. There is a constant need to update which proteins will be formed in the body, and
oneself and more importantly, the developments the flow of biological information is thus
in the science of genetics have taught us that maintained in the sequence DNA →
expression of genes is different from mere pres- RNA → protein. If the information on the
ence of genes, and thus the actual answers are at gene is wrong, the wrong protein will be
much more complex levels than what appear at formed and will lead to wrong functions.
the surface. • Chromosomes are structures that carry many
In short, genetics intimidates the average genes. In fact, it may be appropriate to say that
ObGyn clinician, and yet without a basic under- genes are “packed” into chromosomes so that
standing of genetics, one cannot hope to practice their transfer from one cell to another can hap-
meaningful fetal medicine. This chapter in this pen at the time of cell division.
book therefore aims at providing an “insight into • The number of chromosomes in a cell of an
genetics” to practitioners in ObGyn and fetal organism is specific and fixed for that species.
medicine. The description here is nowhere close As human beings, we have 46 chromosomes
be “complete” or “sufficient” as the field of in our cells—23 pairs (22 autosomes and 1
genetics is unimaginably wide but the informa- pair of sex chromosomes—XX in female, XY
tion given here is definitely “necessary” because in male). A depiction of all the chromosomes
without understanding these fundamental con- in the cell is known as karyotype. A karyotype
cepts, one cannot hope to address any genetic is obtained from culture of amniocytes which
query from patients. Most clinicians find it diffi- allows these cells to multiply by mitosis. The
cult to comprehend the contemporary technical culture is then arrested and the chromosomes
genetic jargon of genetic tests, and there is a need are studied in “metaphase” after staining with
for overcoming this apprehension by connecting “Giemsa” stain that causes a banding pattern

144 13 Basics of Genetics in Fetal Medicine
known as G-banding. Individual chromo- • Translocation means that a portion of one

somes are identified and placed on the karyo- chromosome is detached and reattached to
gram in descending order of size from another chromosome (Fig. 13.3).
chromosome pairs 1 to 23. The standard turn- Translocations may be “balanced” when there
around time for karyotyping on amniotic fluid is no net loss or gain of chromosomal material
samples is about 2–3 weeks. or “unbalanced.” Balanced translocations are
Figure 13.1 shows a normal human karyo- usually compatible with a normal phenotype
type obtained from the culture of amniocytes. although carriers of such translocations may
Twenty-two autosomes are shown in pairs, produce gametes carrying “unbalanced” chro-
while the 23rd pair depicting the sex chromo- mosomal material, thus leading to adverse
somes is hidden in concordance with the fetal outcomes like miscarriages or fetal
PCPNDT Act in India which prevents prenatal abnormalities.
sex determination. • There may sometimes be a “deletion” or
• Any abnormality in the “number” of chromo- “duplication” or “inversion” of a part of the
somes is called “aneuploidy” (Fig. 13.2). This chromosome, and this in turn can lead to a
may be a single chromosome being extra (tri- defect in the formation of proteins if these
somy, e.g., Down syndrome is “trisomy 21” as problems affect the area of the chromosome
there are three chromosomes instead of the which carries the genes responsible for spe-
normal two in the 21st pair) or absent (mono- cific protein formation.
somy, e.g., Turner’s syndrome is seen when • In some cases, more than one cell lines may be
one X chromosome is missing). When an detected and this is called “mosaicism,” e.g., a
entire extra set of chromosomes is present, the certain percentage of cells may be euploid,
condition is termed as “triploidy.” while some cells may be aneuploid in the
• Structural aberrations in chromosomes may same fetus. Mosaicism poses a challenge in
be “deletions,” “duplications,” or “transloca- counseling as the phenotype may differ, and it
tion” of certain regions. Deletions or duplica- is difficult to predict the severity of the afflic-
tions will affect the genes present in that tion based on mere numbers. Such counseling
region of the chromosome and hence will usu- should be done in consultation with a clinical
ally have significant impact on phenotype. geneticist who can help the parents arrive at an
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
Fig. 13.1 Normal karyotype

13 Basics of Genetics in Fetal Medicine 145
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
Fig. 13.2 Abnormal karyotype: trisomy 21
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
Fig. 13.3 Balanced translocation
informed decision regarding continuation or analysis by karyotype are dependent on the

discontinuation of the pregnancy along with a indication.
clear plan for follow-up in future Sometimes, the abnormality in the chromo-
pregnancies. some may be smaller such that the “resolu-
• The abovementioned chromosomal abnormal- tion” of the standard karyotype is not enough
ities can be detected on a “karyotype” as to detect problems of size smaller than
shown in the figures above. The results of fetal 4–5 MB (mega bases)—such as a “microdele-
diagnosis using conventional cytogenetic tion.” This requires a higher-resolution study
of the chromosomes—a technique which can information as compared to conventional

scan the chromosomal regions up to karyotype in evaluation of fetal anomalies and
10—100 kB (kilo bases)!! is becoming widely recommended as one of
To understand this concept better, let us the first-line investigations in fetal structural
take a very simple day-to-day example. anomalies, in evaluation of stillbirth, and in
Checking chromosomes on karyotyping is early miscarriages. The advantages in the lat-
similar to checking a rack of books on a ter two indications are that microarray can be
library shelf—you check the number of books performed on non-vital tissue also as it is a
and can make out if a particular book is miss- DNA-based analysis and does not need an
ing or extra or inverted or majorly damaged. active culture. In cases of stillbirths and mis-
However, just by looking at the rack, you may carriages, culture failure of fetal cells would
not be able to detect whether all the pages of generally be the limiting factor for conven-
each book are present and in correct order. tional karyotyping in the past leading to loss
For that you would require more intensive of vital information. As our understanding of
scrutiny like opening each book and counting fetal genetics is improving and the signifi-
its pages. This is what is done in a microarray cance of this additional yield of information is
where the chromosome is examined further being understood, cytogenetic microarray is
closely and even a single missing page may being prescribed in amniotic fluid samples in
be detected. This page, depending on which cases where there are confirmed fetal struc-
area of the book it belongs to, may or may not tural anomalies out chromosomal problems
be “significant”—for example, a page which beyond aneuploidies. The standard turnaround
is a divider between two chapters and is miss- time for CMA on amniotic fluid samples is
ing may still allow the book to serve its func- about 7–10 days.
tion, but if the page containing a crucial In evaluation of childhood intellectual dis-
chapter is missing, then the purpose of the ability, cytogenetic microarray is now the rec-
book itself gets defeated. Similarly, changes ommended first-line test in genetic
in small parts of chromosomes may or may evaluation.
not be significant depending on the area they The results of CMA are either normal
belong to, and this information is given in the (Fig. 13.4) or abnormal/pathogenic (Fig. 13.5)
report after the clinical geneticists analyze the or sometimes uncertain. The uncertainty arises
microarray. due to detection of copy number “variants of
• This higher-resolution scanning of chromo- unknown significance.” Whatever copy num-
somes to detect smaller changes in the “seg- ber variants are detected on the CMA are com-
ments” of the chromosomes is called pared with standard genetic databases to check
“microarray.” In this test, “subkaryotypic” if they are confirmed pathogenic variants or
abnormalities are detected like microdeletions variants of unknown significance (VOUS).
and microduplications which may be missed The VOUS definitely pose a challenge in
on a routine karyotype. Figure 13.4 shows the counseling especially in prenatal cases, and
results of chromosomal microarray analysis therefore it is strongly recommended that such
which is normal, i.e., no clinically significant counseling be done in close coordination with
deletions or duplications or other chromo- a clinical geneticist who has access to a wide
somal abnormalities in the given sample. range of databases and follows the updated
Due to the higher resolution of scanning standard guidelines in reporting and
the chromosomes, microarray yields more counseling.
13.1 Fluorescence in Situ Hybridization (FISH) 147
Fig. 13.4 Cytogenetic microarray: normal report
Fig. 13.5 Abnormal results on CMA
13.1 Fluorescence in Situ cence in situ hybridization involves use of probes

Hybridization (FISH) that bind to specific areas of the fetal DNA and
can thus be used to detect the number of chromo-
This is a molecular technique for rapid detection somes (useful in aneuploidies) or specific dele-
of issues like aneuploidies and can yield results tions or translocations. The probes are colored
in 48–72 h which is significantly earlier than and they “hybridize” with cellular DNA (thus
karyotyping or even microarray. FISH or fluores- called FISH) resulting in a pattern as shown in
a
b
Normal Patient
SNRPN (small nuclear ribonucleoprotein polypeptide N (15q11)-critical region

PML (Promyelocytic Leukemia) (15q24)-control region
Fig. 13.6 (a) Normal FISH. (b) Abnormal FISH—Down syndrome. (c) Comparative normal and abnormal FISH
Fig. 13.6. Normal FISH is shown in Fig. 13.6a, spots, one for each of the two chromosomes, are
while abnormal FISH results are shown in visualized in normal subjects, while trisomies are
Fig. 13.6b, c. When the nuclei of fetal cells are revealed by the presence of an extra spot and
examined under fluorescent microscope, two monosomies by the absence of one spot.
13.2 Quantitative Fluorescent PCR (QfPCR) 149
13.2 Quantitative Fluorescent primers are used to visualize the amplified seg-
PCR (QfPCR) ments and these can be quantified as peak DNA
scanners. Normal euploid fetal cells are expected
Quantitative fluorescent PCR is another rapid diag- to show two peak areas (peak ratio 1:1) for each
nostic test for fetal aneuploidies, and it is based on chromosome analyzed (Fig. 13.7), while trisomies
the amplification of chromosome- specific DNA are visualized either as an extra peak or as a 2:1
sequences (STR, short tandem repeats). Fluorescent ratio peak between the two areas (Fig. 13.8).
Sample File Sample Name Panel SQI OS SQ

KT41197333 AF D10 10.fsa KT41197333 AF Devvser Extend v2 Mix 2
21A 21B 18C 13B 21D
105 175 245 315 385 455
8000
0
ar 38851 ar 52185 ar 20618 ar 22863 ar 20772 ar 13958 ar 17102
sz 103.71 sz 133.11 sz 174.74 sz 242.76 sz 325.11 sz 402.65 sz 461.78
ar 38981 ar 24043 ar 17263 ar 22366 ar 19155 ar 12530 ar 15715

sz 109.37 sz 137.40 sz 186.97 sz 248.60 sz 333.28 sz 411.99 sz 465.58
X1 XY2 13A 18D-2 13D
140 210 280 350 420 490
6000
0
ar 31907 ar 16339 ar 31724 ar 11329 ar 13658
sz 146.99 sz 187.46 sz 261.09 sz 391.31 sz 458.23
ar 16024 ar 10143 ar 12829

sz 191.39 sz 405.71 sz 473.46
21l 18B 21C 18M 13C
140 210 280 350 420 490
4400
0
ar 14022 ar 25938 ar 15172 ar 15606 ar 10857 ar 16187 ar 7224
sz 127.42 sz 159.65 sz 206.91 sz 235.36 sz 303.99 sz 375.66 sz 450.81
ar 15239 ar 28137 ar 15050 ar 11311 ar 15187 ar 8015

sz 131.34 sz 162.96 sz 210.98 sz 320.87 sz 379.79 sz 454.45
13K T1 XY3 X3 X9 21H 18J
105 175 245 315 385 455
4400
0
ar 11904 ar 17592 ar 18628 ar 12259 ar 13973 ar 11207 ar 13558
sz 131.47 sz 181.18 sz 242.17 sz 289.05 sz 321.87 sz 383.45 sz 453.98
ar 10923 ar 9992 ar 13301

sz 143.46 sz 387.62 sz 460.47
Fig. 13.7 Normal QfPCR

Sample File Sample Name Panel SQI OS SQ

KT41197958 AF H10 22.fsa KT41197958 AF Devvser Extend v2 Mix 2
21A 21B 18C 13B 21D
105 175 245 315 385 455
6000
0
ar 50246 ar 26966 ar 12368 ar 8921 ar 14940 ar 4990 ar 4833
sz 103.80 sz 133.19 sz 182.90 sz 242.67 sz 321.01 sz 398.85 sz 463.74
ar 24616 ar 4642 ar 8641 ar 4172 ar 8974

sz 137.47 sz 199.23 sz 256.56 sz 404.42 sz 469.17
ar 7375
sz 260.49
X1 XY2 13A 18D-2 13D

140 210 280 350 420 490
4300
0
ar 17113 ar 8957 ar 7833 ar 5481 ar 9201
sz 142.99 sz 195.56 sz 257.28 sz 387.24 sz 469.53
ar 15242 ar 7439 ar 8111 ar 4746

sz 151.17 sz 199.60 sz 264.90 sz 391.38
21l 18B 21C 18M 13C
140 210 280 350 420 490
4400
0
ar 15612 ar 46248 ar 20261 ar 16552 ar 18358 ar 5526
sz 131.43 sz 162.93 sz 214.88 sz 308.06 sz 375.64 sz 454.50
ar 23756 ar 7752
sz 135.20 sz 320.64
13K T1 XY3 X3 X9 21H 18J
105 175 245 315 385 455
4500
0
ar 23754 ar 10415 ar 11600 ar 6838 ar 7459 ar 7379 ar 8101
sz 119.72 sz 181.18 sz 242.19 sz 289.09 sz 321.88 sz 379.49 sz 446.63
ar 9404 ar 6102 ar 6324 ar 12562 ar 6519

sz 201.44 sz 297.15 sz 338.34 sz 383.48 sz 461.40
Fig. 13.8 Abnormal QfPCR—trisomy 21
QfPCR has some advantages over FISH in many samples can be processed at the same time,
that it is able to report even on fewer fetal cells, the whole process taking less than an hour.
and since the analysis can easily be automated,
Ratio
0
0.5
1
1.5
2
2.5
01-001.138225 TNFRSF 4-3* - 404nt
01-001.949449 GABRD-6* - 148nt
01-002.331696 PEX10-2* - 315nt
01-002.928350 ACTRT2-1* - 136nt
04-001.700130 TACC3-4* - 453nt
04-001.872455 WHSC1-2* - 199nt
04-001.902193 WHSC1-6* - 445nt
04-001.950156 WHSC1-22* - 238nt
05-001.311706 TERT-13* - 364nt
05-001.346495 TERT-2* - 268nt
05-001.391037 CLPTM1L-5* - 251nt
Fig. 13.9 MLPA results—normal

05-001.931281 IRX4-5* - 372nt
05-001.785306 CTNND2-2* - 413nt
Dependent Probe
05-176.493894 NSD1-1* - 264nt

13.3 Multiplex Ligation-
05-176.619619 NSD1-14* - 232nt

Amplification (MLPA)
05-176.654366 NSD1-23* - 181nt

07-019.123766 TWIST1-1* - 355nt
07-019.125427 TWIST1-up* - 256nt
07-073.090003 ELN-4* - 388nt
07-073.094914 ELN-6* - 339nt
07-073.115357 ELN-27* - 469nt
08-116.700557 TRPS1-3* - 226nt
08-117.837051 EIF3H-1* - 130nt parison to other rapid diagnostic tests, MLPA
tified using just a single pair of primers. In com-
Thus, many sequences can be amplified and quan-
with only a single primer pair. The MLPA tech-
a variation of the multiplex polymerase chain reac-
or MLPA is another rapid diagnostic test which is
not amplify the target DNA, but only the probes.

multiple targets with a single primer pair—it does
Multiplex ligation-dependent probe amplification
nique facilitates the amplification and detection of

tion that permits amplification of multiple targets
08-118.918440 EXT1-2* - 274nt

11-030.212260 FSHB-3* - 170nt
11-031.285887 DCDC1-4* - 175nt
11-031.789032 PAX6-2* - 159nt
15-022.716791 SNRPN-u5* - 396nt
13.3 Multiplex Ligation-Dependent Probe Amplification (MLPA)
KT41188469 MDD
15-022.750781 SNRPN-CpG isl* - 219nt
KT41188469 MDD
15-023.135402 UBE3A-10* - 346nt
15-023.201527 UBE3A-1* - 287nt
16-003.717675 CREBBP-31* - 141nt
16-003.800566 CREBBP-3* - 298nt
17-002.361823 METTL16-1* - 436nt
17-002.443762 PAFAH1B1-1* - 187nt
17-002.488280 PAFAH1B1-2* - 323nt
and tissue sample
Distribution Type: Reference Samples | Exp: 16092021

17-002.531787 PAFAH1B1-11* - 292nt
17-017.525905 RAl1-1* - 244nt
17-017.636976 RAl1-3* - 421nt
1. Aneuploidy detection
morphisms) detection
17-017.654897 RAl1-6* - 165nt

17-017.816505 TOM1L2-1* - 193nt
20-010.571165 JAG1-21* - 281nt
20-010.602274 JAG1-1* - 483nt
22-017.621598 CLTCL1-3* - 205nt
4. Detection of gene copy number
22-017.847478 CDC45-1* - 476nt

22-018.156405 GNB1L-8* - 331nt
22-018.453612 DGCR8-2* - 154nt
MLPA has a variety of applications:
22-019.079428 ZNF74-2* - 211nt

22-019.266745 MED15-10* - 461nt
BRCA1, BRCA2, hMLH1, and hMSH2
22-019.565377 SNAP29-3* - 380nt

22-049.413270 ARSA-1* - 306nt
ics, this technique has found many clinical uses.
22-049.491410 SHANK3-18* - 428nt

5. Detection of duplications and deletions in
3. Chromosomal characterization of cell lines
2. Mutations and SNP (single nucleotide poly-
a sample MLPA report and in current-day genet-
fast, cheap, and simpler to perform. Figure 13.9 is
requires a very small quantity of DNA, and it is
151
human cancer predisposition genes such as

13.4 Clinical Exome Sequencing sions, more areas might get highlighted.
(CEX) Similarly, the known regions of the genome today
will be increased tomorrow once newer genes are
The human genome consists of many genes and identified so the scope of the “clinical exome.”
every gene has “exons” which are the segments Figure 13.10 is a sample report of clinical
of DNA coding for proteins and “introns” which exome sequencing, and it reveals the presence of
are the noncoding regions in the gene. All the a “homozygous” genetic abnormality at a partic-
exons of a person’s genome comprise “whole ular location of a gene which is classified as
exome” of the individual, while the clinically pathogenic because there is a known condition
known exons could be grouped under “clinical (in this case, Vici syndrome), associated with this
exome.” “Sequencing” is a process of reading the particular variation, inherited in an autosomal
genetic material in an orderly manner to detect recessive manner. This test has become a very
any mistakes in the expected pattern. The test is important investigative tool for recurrent prob-
performed on DNA and large sequences are read lems in families with background consanguinity
to detect any possibility if errors like “point and even otherwise where genetic conditions are
mutations” or “point deletions” may not have suspected. In many cases, it helps unravel the so-
been detected otherwise. If we go back to the called “unexplained” causes for problems like
example of books in the library, if microarray multiple children in a family with neurodevelop-
was counting the pages, gene sequencing is like mental delay, recurrent neonatal deaths, and
reading the lines of the pages. Whole genome similar clinical situations. In some fetal anoma-
sequencing would be like reading the entire book, lies with a normal karyotype or normal microar-
whole exome sequencing would be like reading ray, the possibility of “genetic” abnormalities
important chapters, and clinical exome remains, and in the absence of known handles, a
sequencing could perhaps e compared to reading clinical exome sequencing can help in looking at
specific, marked, highlighted headings. These possible genetic aberrations. As with microar-
highlighted zones might be altered if several peo- rays, the CEX is also expected to give results that
ple gave their inputs and after a few more revi- are normal, abnormal, or uncertain. Application
CLINICAL EXOME SEQUENCING
CLINICAL INFORMATION
Fetus of presented with clinical indications of primary microcephaly, lisencephaly, colopoephaly

and dilated third ventricle. Fetus of has been evaluated for pathogenic gene variations.
RESULT SUMMARY
Pathogenic variant causative of the reported phenotype was detected
Gene and Disease

Variant Zygosity Inheritance Classification
Transcript (OMIM)
Vici
EPG5 (-) c.420_421insTCTA Homozygous syndrome Autosomal Pathogenic
(ENST0000028 (p.Vall41SerfsTer20) (OMIM recessive
2041.5) 242840)
No other pathogenic or likely pathogenic variants were detected in the screened genes as per the current
literature and human genome variation database including Clinvar, 5000 Exome Global MAF and COSMIC.
Fig. 13.10 Clinical exome report

13.5 Targeted Mutation Analysis 153
of this test on fetal samples has to be considered cific for the specific mutation we are looking for. It
very carefully. Empirical clinical exome on fetal will identify any abnormality in that region alone
samples is generally not recommended as it takes and will not give any other information regarding
about 3–6 weeks (depending on the lab services) the rest of the genome. Hence, the objective and
to get the results and in the absence of definite limitation of such testing must be clearly under-
phenotype, variations of uncertain significance stood. This is recommended in single gene disor-
are difficult to understand or manage reasonably. ders where parents are known carriers because the
Clinical exome sequencing yields most fruit- risk of recurrence of autosomal recessive condi-
ful results in cases with definite phenotype, and tions is 25% and autosomal dominant conditions is
then the information is corroborated to allocate a 50% in subsequent pregnancies. Ideally, parental
genetic characteristic to that phenotype. Hence, it carrier status must be established to justify the pre-
is more useful in evaluation of an index child natal testing, but in some cases, if that has not been
with abnormalities or the parents of such a child possible, prenatal diagnosis can be targeted based
for “carrier status” in the absence of the index on the index sibling’s report.
sample. It is a good practice to discuss with a Figure 13.11 is a sample report of targeted
clinical geneticist and then only plan for such mutation analysis for the sickle cell anemia gene.
tests so that they can be appropriately interpreted Most obstetricians are intimidated by the myr-
and help in clinical management. iad of genetic tests available and the novelty of
genetic jargon which seems to be ever expanding.
However, as you may have understood by now,
13.5 Targeted Mutation Analysis the basics of genetics and its applications are
simple, logical, and goal-oriented. Instead of get-
Targeted mutation analysis is a method to directly ting carried away by the fancy of doing the latest
test a very specific area within the gene where a or newest test for your patient, it is better to
known defect is expected to be found. Single gene review the primary indication of testing and then
disorders with known abnormalities, e.g., sickle plan a test appropriately. The following table
cell anemia, spinal muscular atrophy, thalassemia, (Table 13.1) effectively summarizes the contem-
etc., can all be detected by targeted mutation anal- porary genetic tests and their applications and
ysis. This is a DNA-based test and is highly spe- limitations.
Previous child carrier for sickle cell anemia.
Test Performed – β Thalassemia Panel

Variants Detected
Clinical
Variants identified HGVS Name Genotype
Significance
Homozygous Sickle Cell
Hb S HBB:c.20A>T Anemia
(EHbS/EHbS)
Heterozygous
Hb S HBB:c.20A>T Sickle Cell trait
(E/EHbS)
Heterozygous
Hb S HBB:c.20A>T (E/EHbS) Sickle Cell trait
Fig. 13.11 Targeted mutation analysis report

Table 13.1 Summary of different tests available for genetic evaluation

Large deletion/ Micro deletion/ Known point Many possible
Aneuploidy duplication/translocation duplication mutation genetic mutations
Karyotype Yes Yes No No No
Microarray Yes Yes Yes No Not
nonspecifically
FISH Yes May not detect if probe Only if probe is Only if probe Not
is not of that region specific for that region is specific for nonspecifically
that region
QfPCR Yes May not detect if probe Only if probe is No Not
is not of that region specific for that region nonspecifically
MLPA Yes May not detect if probe Only if probe is Only if probe Not
is not of that region specific for that region is specific for nonspecifically
that region
Clinical No May not detect if probe May not detect if Yes Yes
exome is not of that region probe is not of that
sequencing region
Targeted No Only if probe is specific Only if probe is Yes No
mutation for that region specific for that region
analysis
Key Learning Points in Basics of Genetics Suggested Reading

1. Understanding basics of genetics is
Benn P, et al. Position statement from the Chromosome
mandatory for a fetal medicine Abnormality Screening Committee on behalf of
practitioner. the Board of the International Society for Prenatal
2. The possibilities of prenatal diagnosis Diagnosis. Prenat Diagn. 2015;35(8):725–34.
by genetic techniques are rapidly Ranganath P et al. Genetic update for the next generation
clinician 2017 (a compilation of articles from genet-
increasing, and there is a dire necessity ics clinics). Society for Indian Academy of Medical
to keep oneself updated on the latest Genetics.
advances. Van den Veyver IB. Recent advances in prenatal genetic
3. Although clinicians can understand the screening and testing. F1000Res. 2016;5:2591. https://
doi.org/10.12688/f1000research.9215.1.
basics of molecular testing and genetic
conditions, it is useful to consult a clini-
cal geneticist while planning and inter-
preting genetic tests and their results.
Recurrent Fetal Problems: Looking
for Solutions 14
In some unfortunate couples, pregnancy outcome of the illness. As each of the previous doctors has
is affected by problems in the fetus or the child looked at only one aspect of the situation, their
after birth that recur in subsequent pregnancies opinions are also limited in relevance to the entire
and thus pose unique challenges. The classical case scenario when viewed in its totality. While
problem of “recurrent pregnancy loss” is usually every individual consultation in the past may be
a condition of a pregnancy failure due to inability important at that situation and its advice appro-
to sustain the fetus in utero largely due to mater- priate for the limited issue being addressed at that
nal reasons and is largely an obstetric problem. point, they are like pieces of a jigsaw puzzle, and
When we talk of recurrent “fetal problems,” we unless they are all put together in a coherent man-
are considering an entirely different subset of ner, the complete picture is often missed. Let us
problems where pregnancies may be affected by consider the following case as an example of the
“fetal conditions” and in some cases may even go point being made here.
up to term asymptomatically, but the “fetal out-
come” may be adverse—either manifesting in
pregnancy, immediately in the neonatal period, or Case 1
much later. Typical presentations may be: Mrs X, 28 years old, consanguineous mar-
riage (second degree), G3P2 L0 had two
1. Recurrent neonatal/childhood problems lead- previous full-term deliveries at term. First
ing to neurodevelopmental delay and/or death child—male, 3 kg birth weight, and deliv-
2. Recurrent fetal anomalies causing miscar- ered vaginally—was “normal” for a month
riage or warranting termination of pregnancy or so and then developed seizures, failure
3. Recurrent fetal growth restriction or severe to thrive, and neurodevelopmental delay
early onset maternal preeclampsia leading to and died at the age of 3 years. Second
early delivery and hence severe prematurity or child—baby girl delivered by elective LSCS
in utero fetal demise at term (indication—to avoid possibility of
“birth injury” which may be related to the
These cases become important in fetal medi- outcome of the first child). This child was
cine because they generally arrive at the fetal asymptomatic till 1 month of age but then
medicine clinic with huge files full of investiga- developed the same symptoms as the first
tion reports and opinions from a variety of clini- child and followed almost a similar time-
cians who have dealt either with the previous line to her death at the age of 3 years.
pregnancies or with the children at various stages

156 14 Recurrent Fetal Problems: Looking for Solutions
Now she is 18 weeks pregnant and has been of empirical genetic testing in the fetus can yield
referred to fetal medicine clinic for the solution ofa lot of uninterpretable information. Moreover,
her problems based on her history. The couple we need to collect fetal cells through an amnio-
arrive at the fetal medicine clinic with a lot of centesis which carries potentially an added and
hope that they will have a healthy baby this time!! procedure-related risk of miscarriage. Hence,
This clinical scenario is not uncommon in fetal such invasive testing is only justified when we are
medicine clinics. We are now well equipped with sure that it will help us get a final result.
wonderful scan machines and a lot of knowledge If we had the DNA of the previous children,
in fetal anatomy physiology, genetic, etc. as high- that would be an ideal situation in order to estab-
lighted in the preceding chapters, yet this situationlish the primary cause in the person first affected
frustrates us due to our helplessness in providing or the “proband”—in this case, the expected
a definitive solution in this scenario. You may be mutation in “homozygous “state. If that homozy-
wondering why—and the reasons are many. Let gosity is proven in the proband, then both parents
us list out the problems in the given scenario: could be checked to confirm that they too carry
the same mutation in “heterozygous” state and
1. There are two cases of deaths following severe we know that they are asymptomatic in this
morbidity in their children so the case is regard. Therefore, this proves that individuals
“recurrent.” who harbor a heterozygous mutation are asymp-
2. We do not know the exact “cause” of the tomatic carriers and those who are “homozy-
problem. gous” for the mutation are likely to be affected.
3. Both children were “structurally” normal with This sounds logical but sadly in most such cases,
average weight at birth—therefore, a “nor- the proband DNA is not available and hence such
mal” anomaly scan at 18 weeks or normal testing becomes impractical. Instead, we try to do
growth scans thereafter cannot reassure us in an empirical search for mutations in the parents
this pregnancy regarding the final outcome. by “clinical” or “whole” exome sequencing. This
4. There is a risk of “recurrence” but we have no test usually takes about 4–6 weeks to give results
way to predict it as we do not know the exact and only after these results, we can plan targeted
cause!! prenatal testing.
The “frustration” about starting such a workup
Once all these points are analyzed, the most plan at 18 weeks is thus obvious because though
obvious solution to our problems is knowing the we may be able to find the exact cause of the
exact cause of the past problems and then finding problem, we may even be able to establish the
a method of ruling out that cause in this preg- genetic status of the fetus, but in those 25% cases
nancy. As both cases had an almost similar clini- that are likely to be affected, termination of preg-
cal presentation, the etiology is likely to be the nancy is no longer an option in most clinical set-
same, and in a consanguineous couple where we ups due to the advanced gestational age! The
expect both partners to have many similarities in treatment options for such genetic conditions are
the gene pool, this condition could be an autoso- extremely limited, and it seems ironical to finally
mal recessive genetic disorder. Both parents may know the reason for the suffering in the past and
be asymptomatic carriers (heterozygous) of the not being able to offer any solution at present.
disease-causing gene, and when the two disease- This brings us to few important aspects on ret-
causing genes come together (homozygous)—at a rospective analysis of the case:
theoretical recurrence risk of 25%—the child will
manifest the disease. Therefore, in the given case 1. When a child has unidentified reasons for
in this pregnancy also, there is a theoretically 25% “failure to thrive” or “neurodevelopmental
chance of recurrence of the disease. We know that delay,” possibility of genetic etiology should
fetal DNA testing can help us detect fetal genes— be kept in mind—especially in recurrent
however unless we know our “target,” the results cases.
14 Recurrent Fetal Problems: Looking for Solutions 157
2. The pediatricians/pediatric neurologists need Now, she has been referred to the fetal medi-
to be sensitized to the need for arriving at a cine clinic at 11 weeks for advice regarding fetal
genetic diagnosis if possible—ideally by care in the present pregnancy. In this case, unlike
involving a clinical geneticist. the previous scenario, the pattern of presentation
3. In cases where parents have cost concerns and appears to be different in each pregnancy. The
are unable to invest in major genetic tests, a possibilities are that this may be just by chance
simple cost-effective method of “DNA storage” with no relation whatsoever between the different
in suspicious cases can be adopted which then pregnancies, but as clinicians, we do understand
can be used for genetic analysis anytime later. that recurrence of such problems needs further
4. Cultural practices can hinder the investigation of workup before we label it as “just by chance.”
such cases. In many societies, where such mis- Ideally, if the previous affected pregnancies
haps are considered “inauspicious,” families would have been investigated, we may have had
destroy all such data following the death of a information regarding the exact cause for each
child and sometimes change the doctors and do mishap, and then we would predict the chances of
not reveal such history!! It is, therefore, very the present pregnancy being affected. However,
important to explain this possibility to the par- in the absence of such information, we again
ents clearly and reiterate the need for preserving have to pick up clues from the available resources
all clinical notes, pictures, and relevant informa- and form a plan of care.
tion for future workup too. This practice can Upon analyzing the history in this case, we
only change by better counseling and generating can make the following observations:
awareness about genetic conditions so that
superstitions are replaced by rational behavior. 1. There is likely to be a “recurrent” pathology.
2. Unlikely to be infections—fetal infections
generally do not “recur,” and to consider
Case 2 the rare possibility of a different terato-
Mrs Y, 29 years old, nonconsanguineous genic infection each time, the history is not
marriage, G6 P1L1 A3, is now 11 weeks corroborative.
pregnant. First pregnancy was terminated 3. Each time the fetal presentation is different
due to large cystic hygroma detected at including early pregnancy losses too.
12 weeks; second pregnancy was a sponta-
neous miscarriage at 8 weeks; third preg- This brings us to consider the possibility
nancy resulted in a full-term normal delivery of “chromosomal” rather than “genetic” etiol-
of a structurally normal child; now 4 years ogy, and one condition which can explain such
with normal developmental milestones, recurrence is if one of the parents is a carrier
fourth pregnancy was terminated due to of a balanced translocation. Therefore, in such
multiple fetal defects (bilateral ventriculo- cases, parental karyotyping can be a reasonable
megaly, absent stomach bubble, bilateral investigation.
club feet, and unilateral cleft palate and lip) The parent who carries the balanced translo-
detected at the 16 weeks’ scan; and fifth cation in his or her karyotype is generally asymp-
pregnancy was a spontaneous miscarriage tomatic. However, this individual can form
detected at 10 weeks after cardiac activity gametes with either normal, “balanced,” or
was documented at 7 weeks. There is no sig- “unbalanced” rearrangements. While the “nor-
nificant history of maternal medical disor- mal” or “balanced” gametes can lead to success-
ders, infections, or teratogenic drug intake. ful pregnancies, the “unbalanced” translocations
Ultrasound scan reports are available for contribute to a zygote which is incompatible with
all pregnancies but no further workup done normal life and result in malformations and/or
in any of the previous cases. miscarriage. This concept has been discussed in
detail in the chapter on the basics of genetics.
It is already a proven fact that chromosomal

abnormalities contribute mostly to early preg- Case 3
nancy miscarriages. This is possible even with Mrs Z, 30 years old, nonconsanguineous
parents who have normal karyotype because the marriage, G4 P1L0A2, is now 12 weeks
etiology of such aberrations is usually “nondis- pregnant. First pregnancy was a missed
junction” during the meiosis while the gametes miscarriage at 12 weeks with a structurally
are being formed. The chances of recurrence of normal fetus and second pregnancy was a
miscarriage is considerably higher when any of fetal demise at 24 weeks with early onset
the parents carry chromosomal translocations, FGR, large jellylike placenta, and high
and this can also result in variable fetal presenta- resistance flows in uterine arteries seen on
tions like in the case above. Conducting a fetal scan at 20 weeks of gestation. The fetus had
karyotype in any case of multiple fetal malforma- “echogenic bowel” reported on the anom-
tions or unexplained miscarriage is thus a reason- aly scan and fetal karyotype was normal.
able investigation in arriving at a final diagnosis In her third pregnancy, she again had early
regarding the cause. onset FGR and had developed severe pre-
In this case, we have no proven reason so far eclampsia at 24 weeks. She had to be deliv-
but each time fetus has presented with structural ered at 27 weeks due to rapid deterioration
anomalies or a miscarriage. The pregnancy is of maternal parameters—600 g male baby,
now at 11 weeks of gestation so we can proceed succumbed to complications of extreme
for a detailed first trimester fetal scan and check prematurity in the NICU on day 3. Fetus
the fetal structure. If any anomaly is detected, was structurally normal and had a normal
then a fetal karyotyping can be offered. If the karyotype.
scan is normal, a combined screening test for
aneuploidies can be offered and the fetus can be
reviewed at 17–18 weeks for a detailed midtri- She has now arrived at 12 weeks to the fetal
mester anomaly scan. It may be useful to discuss medicine clinic in view of the previous history of
the possibility of parental karyotyping in the “fetal losses” hoping for a solution in the present
meantime because if indeed one of them is carry- pregnancy. This is again a common scenario in
ing a balanced translocation, then it becomes the fetal medicine clinic, and only after a system-
mandatory to check fetal chromosomes and offer atic “history taking” exercise, one realizes that
a microarray even of scans and screening tests are the problem in this case scenario may not be
normal. Scans detect structural normalcy and all totally of “fetal” origin.
chromosomal rearrangements do not manifest as Points to ponder in this case are the following:
detectable structural malformations. While inher-
iting translocations, subkaryotypic microdele- 1. Although the final outcome has been a fetal
tions may be caused which can only be detected loss in each pregnancy in this case, the fetus
by a microarray and sometimes these may have has remained structurally and chromosomally
functional significance. normal but suffered intrauterine growth
If the parental karyotype is normal and fetal restriction probably due to severe placental
scans and growth continue to reveal a structurally insufficiency.
normal, average growing fetus, then the preg- 2. Such recurrent uteroplacental insufficiency
nancy can be continued with expectant antenatal points at the possibility of maternal causes
care for both mother and fetus with serial leading to the vascular complications, e.g.,
surveillance. maternal thrombophilias.
14 Recurrent Fetal Problems: Looking for Solutions 159
The evidence on the “causal” association of ine artery Doppler, history, biophysical, and
fetal loss due to maternal thrombophilias is yet to biochemical markers, and women at high risk for
be firmly established, but there is a general accep- preterm preeclampsia can be offered low-dose
tance that pregnancy complications can be a aspirin from 12 weeks to 36 weeks to reduce the
result of maternal antibodies or prothrombotic incidence and complications of the disease.
conditions. Altered levels of placental biomark- As illustrated in the above case, if the diagno-
ers have been proven in several studies on preg- sis of a prothrombotic condition could have been
nancy outcomes with maternal autoimmune, unequivocally diagnosed before pregnancy, then
prothrombotic conditions. It has also been shown optimum thromboprophylaxis methods could
that normal values of placental biomarkers in have been instituted in a proper, evidence-based
early pregnancy have a good negative predictive care scheme.
value for adverse pregnancy outcomes. However, As clinicians, we are often confronted with
since the physiological changes of pregnancy situations that “should have been” or “could have
make the diagnosis of such conditions difficult, been” worked up differently, but the hard fact is
the ideal time to diagnose them is in the nonpreg- that patients present to us in any given scenario
nant state. So in the given scenario, it would have and we have to pick up pieces of clues and indi-
been a good idea to have checked for such condi- cators from the available history and documents
tions in the “interconception” period. However, and frame the most reasonable care plan for the
now that she is already at 12 weeks of gestation, next pregnancy. In cases of recurrent fetal prob-
it will be useful to offer her a comprehensive first lems, cases present as either with confirmed diag-
trimester screening where in addition to fetal nosis or with reasons to suspect some diagnosis.
parameters, a maternal risk assessment for pre- The following flowchart (Fig. 14.1) gives us a
eclampsia can be done by a combination of uter- scheme of how to proceed such cases.
Presentation of genetic
diseases in prenatal
population
Suspected Know genetic

genetic disorder disorder with
molecular dianosis
proven
Strong clinical Theoretical CVS/Amniocentesis –
signs/symptoms/pedigree assumption IDEAL for direct testing on fetal
prenatal samples
diagnosis
Previous known congenital malformations

Previous unexplained IUFD
Previous unexplained neonatal deaths
Index child work up if
Previous probable metabolic disorders
possible
Previous child with mental retardation/developmental delay
Unexplained severe IUGR
Parental carrier screening
Targetted gene sequencing /

panel testing / clinical exome
sequencing
Fig. 14.1 Flowchart of care planning in cases of recurrent fetal problems

As is clear, the most important determinant of

ensuring a good fetal outcome in a case with past • Establishing the primary diagnosis
fetal problems is the knowledge of what exactly requires a complete workup of the index
is the cause of the previous problems—the “pri- case, and this must be considered even
mary diagnosis.” Only if this is known, the future while caring for a pregnancy where the
plan of care can be truly “appropriate.” In mater- fetal prognosis is so poor that a termina-
nal causes, we realized that prepregnancy investi- tion is warranted.
gations are more helpful. Similarly, in fetal • Termination of pregnancy should be
causes, the “index case” workup would yield associated with adequate fetal testing
vital information that can help us in the future. So and storage of DNA if needed to facili-
the “golden window” for workup in cases of tate future tests.
recurrent fetal problems is the “interconceptional • Planning care in subsequent pregnan-
period.” So pediatricians, physicians, surgeons, cies with history of fetal problems is
or neurologists dealing with children with unex- best done preconceptionally so a com-
plained developmental delay or metabolic prob- prehensive preconception counseling
lems or congenital anomalies must suggest at and workup should be suggested in
least one visit to a fetal medicine specialist for a these cases.
“prepregnancy” counseling. A complete prepreg-
nancy workup can go a long way in improving
the overall perinatal outcome in cases of recur-
rent fetal problems. We may not be able to cure everything in
fetal medicine, but we can certainly care.
Key Points to Remember

• Fetal problems may be recurrent—
either in a similar pattern or in differing
patterns depending on the primary cause
of the problem.
• The exact recurrence risk depends on
the primary etiology.
• Genetic or chromosomal issues can be
tested in a fetus but the best results are
obtained only when the primary diagno-
sis is known.
Invasive Prenatal Diagnostic
and Therapeutic Procedures 15
Prenatal diagnosis of fetal conditions by “invad- Table 15.1 Invasive prenatal procedure checklist
ing” the gestational sac is done in cases where • Indication
there is a need to evaluate fetal cells or fluids • Pretest counseling
directly. These procedures are generally • Rhesus status check—anti-D for Rh-negative
ultrasound-guided needle procedures performing mothers
• Maternal HIV and Hep B screening
which requires great skill and training. While
• Consent
conducting the procedure is considered techni-
• Legal forms (e.g., PCPNDT forms in India)
cally challenging, the clinician must realize that • Lab requisition forms
conduct of the procedure itself is a small part in • Result analysis
the entire scheme of fetal health management. • Posttest counseling
The indication of the procedure, the decision of
which tests are to be performed on the fetal sam-
ples, and the final interpretation of the results of records. In some countries, prenatal tests come
these tests are actually the most important prog- under specific legal sections and demand special-
nostic factors for any prenatal test. It is therefore ized documentation. These points are enumer-
important for the doctor to understand the fetal ated in Table 15.1.
health issue in depth and be clear about how is a
fetal sample testing going to help in the further
management of the case before embarking upon 15.1 Indication
an invasive prenatal test. These tests carry poten-
tial risks to the pregnancy—both to the mother The “indication” for any invasive prenatal tests is
and fetus—and hence need to be regulated by the pressing reason which justifies a potentially
judicious protocols. In this chapter, we will dis- “risky” procedure in a pregnancy. This is by far
cuss the common prenatal invasive procedures— the most important aspect while planning any
both diagnostic and therapeutic. prenatal invasive procedure. There has to be an
Before we start discussing each and every pre- unequivocally pressing reason to obtain a fetal
natal invasive procedure, some common “check- sample for testing either the genetic or biochemi-
list points” need to be scrutinized. This checklist cal composition which is going to affect antenatal
is a quick reminder of all the important aspects of care or decisions regarding continuation of
prenatal invasive testing and should be handy in pregnancy.
every clinic for reference by the entire medical Common indications for prenatal diagnostic
team—including nursing and support staff who procedures are to obtain fetal cells or DNA for
help in the documentation and maintenance of karyotyping, genetic analysis, or biochemical

162 15 Invasive Prenatal Diagnostic and Therapeutic Procedures
analysis. Cases are selected based on preliminary The point about checking rhesus status has been
screening tests such that those with high risk are placed separately to make sure that any clinician,
offered invasive tests. Fetal abnormalities war- whenever contemplating a prenatal invasive pro-
rant chromosomal/genetic testing to rule out cedure, does not forget this point.
associated syndromes and establish prognosis. In rhesus negative women, a pretest indirect
Some genetic conditions like sickle cell anemia, Coombs test must be done to assess her antibody
beta thalassemia, or some metabolic syndromes status. If not isoimmunized, then appropriate
may be known in the family, and thus high risk of dose of anti-D should be administered for post-
recurrence warrants prenatal testing. procedure prophylaxis. It is important to date and
Every case has to be individually worked up document the dose given for future reference in
and if a justifiable indication exists, a prenatal that pregnancy.
invasive procedure can be planned.
15.4 Maternal HIV and Hepatitis B

15.2 Pretest Counseling Screening
Prior to the procedure, the couple should be told Mother to fetus transmission of HIV and hepati-
about the purpose of the procedure (clear indica- tis B is a palpable risk which increases in the set-
tion/severity of the disorder) and the potential ting of a prenatal invasive procedure. In case of
complications, including technical problems that HIV-positive women, adequate antiretroviral
might necessitate a second procedure. The medications can be started to prevent fetal trans-
genetic risk versus the procedure-related risk and mission. There are no specific methods of pre-
test accuracy should be weighed before deciding venting mother to child transmission for hepatitis
to undergo the test. They should be told about the B, and hence in women positive for hepatitis B,
time required before results will be available and appropriate counseling and case selection is
the accuracy and limitations of the diagnostic important. The risks of fetal transmission have to
test(s) planned, including possible inability to be carefully weighed against the benefit of prena-
make a diagnosis. Alternatives that may yield the tal diagnosis.
same or similar information but are less invasive
options should also be discussed. It imperative to
understand whether termination would be war- 15.5 Consent
ranted following confirmation of the affliction
and whether termination is acceptable to the cou- The principles of consent for any medical pro-
ple. Since the clinician has a broad idea of the cedure apply similarly for prenatal invasive pro-
expected results, it is prudent to counsel hypo- cedures. A clear, written consent is mandatory
thetically regarding all possible outcomes prior prior to conducting any invasive prenatal proce-
to undertaking the test so that the overall experi- dure. The consent should be taken after a
ence of the test is satisfactory. detailed pretest counseling with the patient
being aware of the reason for the test, the
expected results and plan of care thereafter, the
15.3 Rhesus Status Check risks entailed in the procedure, and the other
clinical options including the specific condi-
Prenatal invasive procedures involve the possibil- tions of avoiding the test. The clinician should
ity of increasing feto-maternal transfusion and provide the patient enough time to decide volun-
therefore potentially can cause isoimmunization tarily whether to accept or decline the invasive
unless specific precautions are taken. It is most test. A copy of this consent should be carefully
important not to do harm in any medical process. filed in her clinical notes.
15.6 Amniocentesis 163
15.6 Amniocentesis this gestation making it an appropriate window to

obtain fetal samples. Third trimester amniocente-
Amniocentesis is one of the most commonly per- sis is associated with higher risk of the need for
formed invasive prenatal diagnostic procedures. multiple punctures and blood-stained fluid
This involves aspirating 10–20 ml of amniotic although it does not increase the risk of emer-
fluid through a transabdominal puncture of the gency delivery.
amniotic cavity using a 20–22 G hollow needle. A 22 G spinal needle is most commonly used
It can be performed safely any time after 15 weeks to aspirate amniotic fluid through a transabdomi-
of gestation in the pregnancy. The ideal time for nal approach under real-time ultrasound guid-
amniocentesis for prenatal diagnosis is ance by continuous needle tip visualization
16–20 weeks as there are technical safety issues (Fig. 15.1). Care is taken to avoid a transplacental
at earlier and later gestations. Amniotic fluid route whenever possible and with appropriate
aspiration prior to 15 weeks of gestation has been skill and experience, the risk of fetal/cord injury
associated with risk of talipes and fetal respira- is minimal. The aspirated fluid is straw colored
tory problems. After 16 weeks, the fetal mem- and contains cells of fetal origin. Most of the
branes get well apposed with the uterine walls, cells floating in amniotic fluid are epithelioid
thus eliminating the possibility of “tenting” of although fibroblastoid and amniotic fluid-specific
the membranes during entry of the needle, thus cells are also present. It is estimated that at
making the procedure safer. The other advantage 16 weeks, there are more than 200,000 cells/mL
is that the availability of fetal cells is adequate by of amniotic fluid of which only 3–4 cells/mL are
Amniocentesis
• Aseptic precautions
• Avoid placenta
• Needle thickness 22G
• Continuous needle tip
visualisation
Complications:
• Failed procedure/
Dry tap
• Bloody tap
• Multiple punctures
Fig. 15.1 Amniocentesis

capable of attaching to a culture substrate and any time after 10 weeks of gestation technically,
yielding colonies. Before 15 weeks, there is a sig- but practically, it is done between 11 and
nificant decline in cloning efficiency (fewer than 14 weeks after a detailed structural evaluation
1.5 clone forming cells/mL fluid). This sample is and aneuploidy risk assessment of the fetus.
sent to the lab in sterile falcon tubes, and as per Since the sample obtained has solid tissue, a
the indication of the procedure, genetic, cytologi- thicker needle is used for CVS as compared to
cal, or biochemical testing can be performed to amniocentesis. Usually, 18 G or 20 G disposable
obtain the desired prenatal diagnosis. spinal needle of adequate length (7.5–15 mm) is
Amniocentesis carries 0.1–1% added risk of mis- used. The needle is passed through anterior
carriage depending on the operator experience. abdominal wall into the substance of the chorion
Frequent complications are bloody tap, dry tap, or a frondosum under continuous needle tip visualiza-
failure to culture cells in the lab from the sample. tion under ultrasound guidance. Unlike amnio-
centesis where the needle is static in the amniotic
fluid, in CVS the needle is moved up and down
15.7 Chorionic Villus Sampling gently to break the villi, and a strong negative
(CVS) pressure suction by a 20 cc syringe is needed to
aspirate the villi. Figure 15.2 shows the needle
The placenta has cells of both maternal and fetal position and sample aspiration in CVS.
origin. In earlier gestations, the chorionic villi in The earlier age of performance of CVS along
the developing placenta can be used to obtain with the technical details like use of a thicker nee-
fetal cells and DNA. This procedure can be done dle for CVS is the reason for a marginally higher
• Transabdominal access under

Chorionic Villus sampling (CVS)
USG guidance
• 18 G long spinal needle
• Chorionic villi aspirated and

transported to lab in sterile
media
• Sample used to extract fetal

DNA and cells for prenatal
diagnosis
chorionic villi
USG guided needle aspiration of chorionic villi
Chorionic villi in collection medium
Fig. 15.2 Chorionic villus sampling

15.8 Fetal Blood Sampling 165
risk of miscarriage after CVS as compared to umbilical vein in the cord either transplacen-
amniocentesis. Operator skill and experience is an tally near the cord insertion in an anterior pla-
important factor affecting the procedure- related centa or in a free loop of the cord in posterior
risk of pregnancy loss. The distinct advantage of placenta. A 22 G long spinal needle is used.
CVS is the earlier gestation age of performance Extreme care is needed while performing this
allowing an earlier prenatal diagnosis. It is also procedure as it carries a higher risk of fetal
known that the yield of fetal cells and DNA from loss as compared to CVS and amniocentesis
CVS is much greater than 20 ml of amniotic fluid. (Fig. 15.3).
However, the possibility of placental mosaicism, Although the needle is thinner, the target is the
maternal cell contamination, and culture failure at umbilical cord, and there is a possibility of intra-
CVS may necessitate repeat procedure in the form uterine bleeding from the cord or inadvertent
of amniocentesis in some cases. puncture of the umbilical arteries leading to fetal
bradycardia.
Fetal blood sampling is therefore done only
15.8 Fetal Blood Sampling for pressing indications where either amniocente-
sis is not possible like severe oligoamnios or
Fetal blood sampling provides an unequivo- prior to intrauterine transfusion to confirm fetal
cal fetal sample for prenatal diagnosis. Fetal hematocrit and plan the exact volume of
blood can be obtained by tapping the fetal transfusion.
• Transabdominal access under USG guidance

Fetal Blood Sampling
• 22 G long spinal needle
• Fetal blood aspirated in 1-2ml heparinised syringes
22 G long spinal needle

• Transported in Heparin tubes for karyotyping
• For DNA based studies sample is transported in EDTA

tubes as heparin insterferes with DNA extraction
• Common indications of FBS–fetal infective agents PCR,

Umbilical cord loops karyotyping, pre transfusion hematocrit estimation
Fig. 15.3 Fetal blood sampling

Table 15.2 Common invasive fetal therapeutic procedures

Procedure Indication Instruments/technique Intended benefit
Aspiration of Pleural effusion USG-guided needle aspiration Relieving the pressure due to
abnormal fluid Selected fetal cysts using 22 G long needle the abnormal fluid collection
collection in fetus causing significant Assessment of the fluid to
pressure effects ascertain its nature and guide
further treatment
Intrauterine blood Fetal anemia Transabdominal percutaneous Increase the fetal hemoglobin
transfusion USG-guided procedure with 20 G and prevent risk of hydrops or
long spinal needle—intravascular IUFD
or intraperitoneal
Selective fetal Fetal anomalies in twin Fetal intracardiac KCl in cases of Reduce the abnormal fetus to
reduction pregnancies or multichorionic pregnancies help in the unhindered growth
high-order multifetal Interstitial LASER/radiofrequency and development of the
pregnancies ablation or bipolar cord cautery in normal fetus
monochorionic pregnancy Optimize the perinatal
outcome of higher-order
multifetal pregnancy by
reducing it to twins
Placental Severe twin-to-twin Fetoscopy-guided LASER Stop the physiological effects
anastomoses transfusion in MCA photocoagulation of placental of the TTTS which would
ablation twins anastomoses otherwise adversely affect
both fetuses
Fetal Congenital Fetoscopy-guided balloon Maintain prenatal lung
endotracheal diaphragmatic hernia placement in fetal trachea with volume to minimize the risk
balloon occlusion with risk of severe lung occlusion of the lumen of lung hypoplasia and
hypoplasia improve the outcome of
postnatal surgery
Open fetal Open neural tube Hysterotomy for repair of fetal Prevent neurological damage
surgery defects in fetus meningomyelocele followed by due to tentorial herniation in
reposition of fetus in utero and ONTD
closure of uterine incision
15.9 Invasive Prenatal

Threapeutic Procedures 2. All invasive procedures carry a
procedure-related risk of pregnancy loss
Some invasive procedures are done in the antena- and hence must be undertaken after
tal period with the aim of “treating” certain fetal careful consideration and appropriate
conditions. Fetal therapy is a highly specialized pretest counseling.
area and a detailed discussion on this count is 3. Appropriate documentation of the
beyond the scope of this book. A synopsis of counseling, consent, and conduct of the
common procedures done for fetal therapy is pre- procedure must be maintained as per
sented in Table 15.2. local guidelines.
4. Invasive therapeutic procedures present
several dilemmas in view of the guarded
Key Learning Points in Invasive Procedures fetal prognosis, and all the factors must
for Prenatal Diagnosis and Therapy be discussed ideally in a multidisci-
1. Invasive prenatal diagnosis is a power- plinary team setting prior to embarking
ful method to obtain definitive informa- on such a procedure.
tion for fetal conditions.
Rhesus Isoimmunization and Fetal
Infections 16
16.1 Rhesus Isoimmunization Now when a rhesus negative woman carries a

rhesus negative fetus, there is no mismatch, and
Rhesus isoimmunization is a common clinical no clinical problems are anticipated even if there
problem seen in maternal-fetal clinics. The rhe- is any feto-maternal bleed. However, if a rhesus
sus blood group system is based on the presence negative woman is carrying a rhesus positive
or absence of “D-antigen” on the red blood cells fetus, then the clinical outcome depends on
(RBCs) of an individual. Women who are rhesus whether or not she has anti-rhesus or anti-D anti-
negative do not have the D antigen on their RBCs, bodies. If she has these antibodies, then the anti-
while those who are rhesus positive do have this. bodies can destroy fetal red blood cells causing
Unlike the ABO blood groups, the antibody fetal anemia and severe cardiovascular dysfunc-
against the rhesus antigen (anti-D antibody) does tion in the fetus leading to hemolytic jaundice,
not “naturally” exist in the system, and it is pro- hydrops fetalis, and eventually fetal demise. It is
duced by rhesus negative individuals as a therefore important to remember the following
response to exposure to the D-antigen. This expo- facts about rhesus isoimmunization:
sure to D-antigen to rhesus negative individuals
can occur either by mismatched blood/blood 1. First pregnancy in a rhesus negative mother
product exposure or through feto-maternal hem- with a rhesus positive fetus is uneventful.
orrhage in cases of a rhesus negative woman car- 2. ANY pregnancy in a nonisoimmunized rhe-
rying a rhesus positive fetus. sus negative mother with a rhesus positive
When a woman is rhesus negative, she is fetus is uneventful.
“homozygous” negative as rhesus negativity is a 3. ANY pregnancy in an isoimmunised rhesus
recessive trait. If her partner is also rhesus nega- negative mother with a rhesus negative
tive, then all their kids will be rhesus negative and fetus is uneventful.
this will not cause a clinical problem. If, how- 4. If an isoimmunised rhesus negative mother
ever, a rhesus negative woman is carrying the has a rhesus POSITIVE fetus, then fetus is
child of a rhesus positive father, the child may be at risk of anemia.
rhesus positive or negative depending on the
zygosity of the father and the assortment of It is therefore imperative that for any rhesus
genes. If the father is “homozygous” positive, all negative woman, her anti-D antibody status
children borne by this couple will be rhesus posi- MUST be checked at the time of first booking.
tive, while if the father is “heterozygous,” 50% EVERY rhesus negative woman MUST be
children will be rhesus positive and 50% rhesus offered an INDIRECT COOMBS TEST at book-
negative (Fig. 16.1). ing. If she is rhesus negative, nonimmunized with

168 16 Rhesus Isoimmunization and Fetal Infections
Inheritance of the rhesus factor
Father
Homozygous Mother Father
Mother
Rhesus positive Rhesus negative Heterozygous
Rhesus negative
Rhesus positive
100% children rhesus positive 50% children 50% children

rhesus negative rhesus positive
Fig. 16.1 Inheritance pattern of the rhesus blood group
Table 16.1 Indications to offer additional antenatal anti-

D in rhesus negative women If a rhesus negative pregnant woman is found
1. Antepartum bleeding to be isoimmunised, then her fetus is at risk of
2. Invasive procedures like amniocentesis, CVS, etc. hemolysis in case it is rhesus positive. Now
3. Maternal abdominal blunt trauma establishing the rhesus type of the fetus through
4. External cephalic version invasive testing is counterproductive as it can
5. In cases of miscarriage/termination/ectopic increase the fetomaternal bleed and worsen the
pregnancy isoimmunization. Noninvasive prenatal testing
can help in establishing the fetal rhesus genotype
a partner who is rhesus positive, ICT must be and if this facility is available, it must be called
repeated at 28 weeks and routine anti-D prophy- for. If the fetus in utero is found to be rhesus neg-
laxis may be given to prevent isoimmunization. ative, then we do not anticipate any problems in
This is repeated at 34 weeks and following deliv- the current pregnancy and no specific monitoring
ery within 72 h if the baby is rhesus positive. is needed.
Apart from routine antenatal anti-D, there are If however it is confirmed that the fetus of an
some indications for additional anti-D prophy- isoimmunized mother is rhesus positive or if
laxis to unimmunized rhesus negative women facilities to detect fetal rhesus type is unavail-
when at higher risk of isoimmunization. Such able, it is prudent to put the fetus under surveil-
conditions are listed in Table 16.1. lance for detecting any adverse effects of the
16.1 Rhesus Isoimmunization 169
antibodies like fetal anemia. Quantifying the needed to be transfused for correction of fetal
antibody titer in the mother has a limited role as anemia. Further details on fetal transfusion are
any which way the final common pathway of given in the chapter on fetal therapy. Following
fetal affliction is through fetal hemolysis and transfusion, the fetus is kept on serial monitoring
subsequent anemia so monitoring the same is and in rare cases, repeat transfusion may be
easier and more productive. Fetal anemia can be needed after a few weeks.
detected by monitoring the peak systolic veloc- Fetal blood transfusion is an example of suc-
ity (PSV) of the fetal middle cerebral artery cessful fetal therapy and the outcomes in well-
(MCA) on Doppler examination. The MCA- selected cases are very good. This intervention is
PSV (Fig. 16.2) rises in cases of fetal anemia lifesaving for the fetus and helps in prolonging
and the value can be plotted on nomograms for intrauterine gestation till a stage where the risks
the corresponding gestational age. The method of extreme prematurity are avoided. Delivery
of conducting fetal MCA flow assessment has may be considered by 34 weeks if anemia recurs
been described in detail in the chapter of fetal in a transfused fetus, but the final decision to
Dopplers in this book. deliver between 34 and 37 weeks will depend on
In cases of severe fetal anemia, it is usually the composite inputs from the neonatologist,
above 1.5 MOM for that stage of gestation and fetal medicine specialist, obstetrician, and the
warrants treatment in the form of fetal blood parents.
transfusion. Fetal blood transfusion is done using Although treatment of fetal anemia is possi-
O negative, leuko-depleted, gamma-irradiated, ble, there are inherent challenges, and it is best to
packed RBCs with very high hematocrit. The prevent rhesus isoimmunization by optimum pro-
high hematocrit allows for a lesser volume phylaxis with passive ant-D immunization.
Fig. 16.2 MCA Doppler showing PSV

16.2 Fetal Infections the body of the host and cause disease. The disease
process involves specific tissue response leading
The fetus in utero can be infected by parasitic to organ damage and dysfunction. Although there
organisms that can gain entry into the fetal system are many organisms that can cause fetal infections,
through different routes as shown in Fig. 16.3. the common concerns are always with infections
While transcervical or transamniotic infections do of the “TORCH” group and few others such as
occur in special circumstances, their impact is usu- parvovirus, varicella, Zika virus, etc.
ally manifested as chorioamnionitis and effects are As these infections are spread transplacen-
systemic at the maternal level. tally, the chances of “infection” are less when the
There are some specific “fetal infections” which mother gets infected in the first trimester as the
are vertically transmitted through the placenta to the placental mass itself is less at that time as com-
fetus in utero after a maternal infection in pregnancy. pared to the second or third trimester. However, if
The primary infection in the mother or even the anti- the infection does cross the placenta, the “effects”
bodies may not be detected unless looked for specifi- of the infection are more severe in the first tri-
cally as the mother herself remains asymptomatic in mester than later.
these conditions. The fetus, however, may be signifi- As stated earlier, the mother may remain
cantly affected by these conditions and show several asymptomatic while being the primary host of
changes that can lead to serious risks of morbidity as the infections that could affect the fetus, but the
well as mortality. It is therefore important to be fetus may get severely affected depending on the
aware of the panorama of fetal manifestations as a kind of organism and the stage of pregnancy that
sign of response to maternal infection. the infection sets in. These fetal infections are
An infection is caused by organisms like diagnosed after some nonspecific stigmata of
viruses, bacteria, fungi, and parasites which enter infective process are noticed on the antenatal
Routes of fetal infection
Placenta Transplacental transmission

following
maternal hematogenous infection
Uterus
Fetus
Transamniotic transmission following

Amniotic fluid Percutaneous procedures (IATROGENIC)
Transcervical transmission following

maternal vaginal infection
Fig. 16.3 Routes of fetal infection

16.2 Fetal Infections 171
ultrasound assessment. Table 16.2 lists some of cates an old infection, while low avidity indicates
the findings on fetal ultrasound which indicate a a recent infection—usually within 3–6 months.
high possibility of fetal infection. This helps in dating the timing of infection with
These signs are rather nonspecific and seen in the period of gestation and thus anticipating the
most congenital infections. Whenever fetal infec- effect on the fetus in the present pregnancy. The
tion is suspected, a preliminary maternal serol- summary of maternal serology interpretation is
ogy is done to assess maternal immune status for given in Table 16.3.
these infections and either rule out the possibility Maternal serology is used as the first screening
or determine which infection to be looked for in method to anticipate if there could be fetal infec-
the fetus. tion in the current pregnancy after a suspicion is
Maternal serology is done by assessing the raised usually by ultrasound findings suggestive
IgM and IgG levels for the specific infection sus- of infection or rarely when the mother has fever
pected. IgM is produced as an acute response to with rashes or lymphadenopathy in pregnancy.
infection and usually indicates a recent infection. The “gold standard” for diagnosing fetal
IgG is the second line of antibodies, indicating infection is by isolating the pathogen or its spe-
old infection and some degree of immunity— cific nucleic acid from the amniotic fluid or fetal
even for the fetus as it can cross the placenta. IgG blood sample. Such a test understandably carries
avidity testing is an additional test that helps in a good “positive predictive value” for fetal “infec-
timing the infection such that high avidity indi- tion” but does not always correlate with fetal
“affection” as the fetal infection may be asymp-
tomatic in few cases. One also needs to under-
Table 16.2 Common signs of fetal infection on antenatal stand here that despite being “asymptomatic” of
ultrasound
having no discernible ultrasound features of
1. Fetal growth restriction
infection in fetal life, there may be long-term
2. Oligo−/polyamnios
sequelae manifesting in childhood for fetuses
3. Large placenta with calcifications
infected in utero.
4. Hyperechogenic fetal bowel
5. Fetal visceral calcifications On the other hand, if the fetal sample tests
6. Fetal hepatosplenomegaly negative for the infective agent, it does not rule
7. Fetal brain changes (calcification/cysts/ out the possibility of infection as there may be
ventriculomegaly, etc.) technical limitations to detecting the infective
8. Fetal ascites/hydrops agent in fetal samples. Sometimes the timeline of
9. Fetal anemia the infection is unclear due to nonspecific symp-
Table 16.3 Interpretation of maternal serology testing regarding congenital infections

Antibodies Indication Expectation Treatment
IgM No recent infection Not immune If vaccine available—can
negative No past infection be given
IgG
negative
IgM Recent infection for the first time Expect severe sequelae if Treat primary infection if
positive fetal infection possible
IgG
negative
IgM Recent infection with development of Do IgG AVIDITY AVIDITY test helps in
positive some immunity reinfection Low avidity—recent timing the infection
IgG infection
positive High avidity–old infection
(>3–6 months)
IgM Past infection/immunity NO TREATMENT NO VACCINE NEEDED
negative NEEDED
IgG
positive
toms in the mother, and sometimes the serology results of organism nucleic acid PCR or culture
may be “false positive” due to cross-reaction following fetal sampling.
with other antibodies leading to negative results The principles described above are applicable
on fetal sampling. Repeating invasive tests for in general to most intrauterine infections with
mere clarifications carries logistic limitations minor individual variations. Table 16.4 shows
which clinicians will understand, and therefore some individual details of the common congeni-
the “diagnosis” of fetal infection is limited to the tal infections that are encountered in regular clin-
cohort of cases that show confirmed positive ical practice.
Table 16.4 Overview of common congenital infections

Name of infective Possible postnatal effects of fetal Preventive
agent Type of agent infection Management and prognosis vaccine
Cytomegalovirus DNA virus of Sensorineural hearing deafness NO effective treatment No
the herpes even in apparently asymptomatic available in regular practice
family cases and long-term neurological Only under research
disability settings, valacyclovir and
hyperimmune globulin are
being used
Toxoplasma Parasite Chorioretinitis and neurological Spiramycin can reduce No
Toxoplasma disability vertical transmission in
gondii pregnancy
Treatment of fetal infection
in utero is by a combination
of pyrimethamine and
sulfadiazine
Rubella RNA virus of Congenital cataract, hearing loss, No effective treatment Yes
Togaviridae neurological disability, and cardiac available. Infection in the
family malformations first trimester may justify
termination of pregnancy
due to severe adverse effects
Herpes simplex DNA virus Direct teratogenicity is low Acyclovir can be given to No
virus although some cases of treat both primary and
neurological abnormalities are recurrent herpes infections
known. Peripartum transmission in pregnancy
can lead to ophthalmic and
neurological sequelae
Varicella zoster DNA virus of Rarely, fetus is affected with fetal Acyclovir can be given to Yes
the herpes varicella syndrome—limb defects, treat maternal symptoms
family dermatological scarring, eye Passive immunity can be
abnormalities, neurological provided by
disability immunoglobulin to
minimize the effect of
maternal infection
Parvovirus B19 Single- Anemia with thrombocytopenia Fetal blood transfusion (both No
stranded RBC and platelets) can help
DNA virus prevent in utero hydrops and
demise
Treponema Spirochete Congenital syphilis—many Benzathine penicillin No
pallidum Treponema manifestations, e.g., skeletal
pallidum abnormalities, corneal scarring,
neurological disability, etc.
Zika virus RNA virus of Microcephaly and even in the No effective treatment No
the Flavivirus absence of microcephaly, there known
type may be neurological disability due
to brain abnormalities that are part
of the congenital Zika virus
syndrome
Suggested Reading 173
As is evident from the preceding discussion,

the suspicion of fetal infection when based on 5. Fetal infections are caused by transpla-
ultrasound findings and serology reports war- cental transfer of the TORCH organ-
rants a detailed counseling of the couple regard- isms following maternal infection
ing all the possibilities including the uncertainty which may be asymptomatic.
of the final outcome. It is often disappointing 6. Suspicion of fetal infections is mostly
for the parents when the possibility of long-term based on typical ultrasound findings or
sequelae is discussed even in the absence of ultra- in cases of maternal fever with rash.
sound signs and yet it is imperative on the fetal 7. Maternal serology helps suspect fetal
medicine consultant to share the information. A infection although confirmation is by
multidisciplinary team approach helps in such sit- amniotic fluid PCR.
uations including the obstetrician, neonatologist, 8. Individual infections carry different
and infectious diseases physician along with the prognosis based on the organism and
fetal medicine consultant. gestational age at the time of infection.
9. Some infections like rubella and vari-
cella are preventable by immunization
Key Learning Points and preconceptional immunization is a
1. Rhesus isoimmunization is a prevent- good practice.
able condition if appropriate precau-
tions are taken in the rhesus negative
pregnancies. Suggested Reading
2. Universal blood group/Rh screening for
pregnant women and ICT for rhesus Mari G, Deter RL, Carpenter RL, et al. Noninvasive diag-
negative women must be promoted. nosis by Doppler ultra-sonography of fetal anemia due
3. Fetal MCA-PSV is an effective, nonin- to maternal red-cell alloimmunization. Collaborative
Group for Doppler Assessment of the Blood Velocity
vasive method of screening for fetal of Anemic Fetuses. N Engl J Med. 2000;342:9–14.
anemia. ISUOG Practice guidelines. Role of ultrasound in
4. Fetal blood transfusion in carefully congenital infection. Ultrasound Obstet Gynecol.
selected cases is a lifesaving interven- 2020;56:128–51.
tion for anemic fetuses.
Potential for Assessing Maternal
Morbidity in Fetal Medicine Clinics 17
The mother and the fetus are inseparable in preg- In cases of impaired placentation, there is
nancy—in fact, the “separation” marks the end of inadequate trophoblastic invasion of maternal
pregnancy! So while “fetal medicine” is the study spiral arterioles, and the uteroplacental bed
of health and disease conditions of the fetus, it is remains a high resistance zone. Blood flow pat-
very important to realize that the maternal health terns through the uterine arteries are indicative of
and disease conditions can have a bearing on the distal resistance in the uteroplacental bed. In
fetal health and vice versa. case of high resistance, the spectral flow pattern
Fetal medicine is definitely the science deal- of the uterine artery shows impeded flow in dias-
ing with health issues of the fetus in utero, but the tole with high pulsatility indices. This is reflec-
fact remains that these health issues are inte- tive of suboptimal placentation and is effectively
grated with the mother as long as “fetal” life con- predictive of the risk of preeclampsia in the
tinues. There are some maternal health issues mother in that pregnancy.
which may be predicted or detected due to the Uterine artery Doppler in the second trimester
clinical assessment in fetal medicine clinics. In is usually done transabdominally. The ultrasound
this chapter, we discuss some such maternal med- probe is moved laterally in the lower segment,
ical disorders like preeclampsia, hyperglycemia, and color Doppler is used to identify the uterine
and some autoimmune conditions. artery at the apparent crossover with the external
iliac arteries (Fig. 17.1).
Then pulse wave Doppler is used to get a
17.1 Uterine Artery Doppler waveform which may be representative of good
Studies Predict Risk diastolic flow (Fig. 17.2) or high resistance flow
of Preeclampsia (Fig. 17.3).
High resistance flows in the uterine artery
Preeclampsia is a pregnancy-specific syndrome have been associated with the risk of developing
which involves hypertension and proteinuria or preeclampsia in the current pregnancy. Several
maternal organ dysfunction. The exact etiology studies have correlated the uterine artery Doppler
may have remained a matter of speculation parameters with the risk of developing pre-
through the past century, but the central role of eclampsia and the predictability is definitely bet-
impaired placentation in the disease is well estab- ter in later gestations. The placentation is
lished—whether this is the cause or effect of a completed in two waves, and sometimes an
primary pathology remains elusive to a final abnormal flow in the first trimester may improve
explanation. following the second wave of trophoblastic

176 17 Potential for Assessing Maternal Morbidity in Fetal Medicine Clinics
Fig. 17.1 Identifying the uterine artery with color Doppler
invasion—hence, the possibility of “false- UK, has suggested a multimodality screening

positive” prediction is higher earlier on in model which includes maternal mean arterial
pregnancy. pressure, uterine artery Doppler, and biomark-
The ASPRE trial established that it is possi- ers like PlGF (placental growth factor) in the
ble to effectively prevent preterm preeclampsia first trimester to predict the risk of maternal pre-
or delay the onset and severity of symptoms if eclampsia. This algorithm allows the risk assess-
prophylactic low-dose aspirin is started appro- ment in any pregnancy, and the “high-risk”
priately in the high-risk group before 16 weeks— group can be offered chemoprophylaxis (150 mg
or in other words, before the onset of the second aspirin daily at bedtime started before 16 weeks
wave of placentation. This has increased the and continued till 36 weeks of gestation) to
importance of screening for preeclampsia in the reduce the incidence and severity of the
first trimester. The Fetal Medicine Foundation, condition.
17.1 Uterine Artery Doppler Studies Predict Risk of Preeclampsia 177
Fig. 17.2 Normal uterine artery flows
Fig. 17.3 High resistance flows in uterine artery

17.2 Hyperglycemia in Pregnancy The clinical details of fetal macrosomia and

polyamnios have been dealt with in separate
Pregnancy is known to be a diabetogenic state chapters in this book, but here the mention of
and women who have subclinical glucose intoler- these entities is made to highlight that sometimes
ance may develop frank hyperglycemia in preg- they could instigate a retrospective diagnosis of a
nancy. The current classification of hyperglycemia maternal medical disorder during a routine fetal
in pregnancy (HIP) includes two entities—diabe- evaluation.
tes mellitus in pregnancy (DIP), diagnosed before Such an incidental diagnosis is of paramount
20 weeks, and gestational diabetes mellitus importance in GDM where appropriate glycemic
(GDM), identified in the second or third trimester control can help in optimizing both maternal and
of gestation. Most obstetric units have their own fetal outcomes of the pregnancy.
screening protocols for GDM, and it is usually
delayed until the late second or early third trimes-
ter of pregnancy, because the diabetogenic effects 17.3 Maternal Autoimmune
of pregnancy increase with gestation and, there- Diseases
fore, delayed testing maximizes the detection
rate. Sometimes, during a fetal scan, congenital heart
Sometimes, during a routine fetal assessment, block or fetal anemia may be discovered leading
detection of fetal macrosomia and/or polyhy- to the discovery of presence of maternal antibod-
dramnios alerts the clinician toward the possibil- ies as the etiology of these conditions. In most of
ity of maternal hyperglycemia (Fig. 17.4). High these cases, the mother herself may be asymp-
levels of maternal glucose can pass through the tomatic and her condition is diagnosed only
placenta and lead to fetal hyperglycemia with based on suspicion during fetal evaluation. This
fetal release of insulin, insulin-like growth fac- chance finding also has significant impact on
tors, and growth hormone. This sequence eventu- both maternal and fetal health.
ally leads to increased fetal subcutaneous fat An incidental diagnosis of fetal heart block in
deposition and larger fetal size. a structurally normal fetal heart raises the suspi-
Polyhydramnios and Macrosomia
Estimated fetal weight (g)
5000
95%
4000
3000 5%
2000
1000
0
10 18 26 34
Gestational age (w)
High suspicion of maternal hyperglycemia
Fig. 17.4 Clinical features in fetus due to maternal hyperglycemia

17.3 Maternal Autoimmune Diseases 179
Congenital heart block in a

structurally normal fetal heart
Suspicion of maternal autoantibodies
Fig. 17.5 Fetal heart block
cion of the presence of maternal anti-Ro/anti-La The fetal prognosis of course depends on the
antibodies which can cross the placenta and lead stage of the pathology and gestational age at
to autoimmune-mediated congenital heart block diagnosis. Early gestational age with advanced
(Fig. 17.5). This can be progressive leading to heart block is generally associated with high fetal
fetal hydrops and may ultimately be lethal to the mortality, while stage I CHB may sometimes be
fetus. reversible with antenatal steroids and may lead to
The anti-Ro/SSA and anti-La/SSB antibodies a live birth although postnatal issues may arise.
were initially related to patients with Sjögren’s These fetuses have a passively acquired autoim-
syndrome (SS) and systemic lupus erythemato- munity that may be associated with serious neo-
sus (SLE), but subsequent studies have shown natal complications like neonatal lupus or need
that anti-Ro antibodies can be detected in many for a pacemaker. Nevertheless, once maternal
other autoimmune diseases. These diseases are diagnosis is established and the mother is put
usually multifaceted, complex entities with vari- under care of a rheumatologist, the outlook for
able phenotypes, clinical presentations, and future pregnancies improves due to optimal pre-
relapsing-remitting courses. Their primary diag- conceptional care and planning.
nosis is therefore important as it has significant Diagnosis of fetal anemia is possible by the
impact on the woman’s health with long-term raised fetal MCA peak systolic velocity (PSV)
effects on multiple organ systems. Pregnancy that has been discussed in detail in a previous
provides an opportunity for this detection in chapter. However, sometimes an incidental find-
asymptomatic women through findings in fetal ing of fetal anemia becomes the starting point of
evaluation. diagnosing maternal isoimmunization or parvo-
virus infection, while the mother may be asymp-

tomatic otherwise. Maternal isoimmunization Key Learning Points
may be due to anti-D antibodies in rhesus nega- 1. Fetal medicine clinics also provide a
tive women or due to atypical red cell antibodies method of detecting maternal problems
which can be present even in rhesus positive as sometimes they may present indi-
women and often remain unsuspected. rectly in asymptomatic women.
Similarly, the diagnosis of severe fetal growth 2. Comprehensive maternal-fetal evalua-
restriction with oligoamnios or even intrauterine tion helps in identifying maternal mor-
fetal demise associated with significant uteropla- bidity which can be then addressed,
cental insufficiency can lead to the diagnosis of thus minimizing long-term health risks
maternal antiphospholipid antibodies or other for the mother.
forms of maternal thrombophilias.
There are few studies linking the possibility of
myasthenia gravis in women who have fetuses
Suggested Reading
affected with arthrogryposis multiplex
congenita. Tranquilli AL, Dekker G, Magee L, et al. The classifica-
As the readers may have realized by now that tion, diagnosis and management of the hypertensive
many issues discussed in this chapter are repeti- disorders of pregnancy: a revised statement from the
ISSHP. Pregnancy Hypertens. 2014;4:97–104.
tions of clinical issues dealt elsewhere in the O’Gorman N, Wright D, Poon LC, et al. Multicenter
book, the purpose of this repetition was to high- screening for preeclampsia by maternal factors and
light that some maternal conditions may be biomarkers at 11-13 weeks’ gestation: comparison
unraveled only if the associated fetal issue is to NICE guidelines and ACOG recommendations.
Ultrasound Obstet Gynecol. 2017;49:756–60.
properly identified and worked upon. The course Rolnik DL, Wright D, Poon LC, et al. Aspirin versus
of the present pregnancy would depend on many placebo in pregnancies at high risk for preterm pre-
factors, but definitely the course of future preg- eclampsia. N Engl J Med. 2017;377(7):613–22.
nancies can be optimized by adequate multidisci- Hod M, Kapur A, Sacks DA, et al. The International
Federation of Gynecology and Obstetrics (FIGO)
plinary care. Opportunistic diagnosis of maternal Initiative on gestational diabetes mellitus: a prag-
medical disorders provides an effective window matic guide for diagnosis, management, and care. Int J
to institute corrective medical and lifestyle mea- Gynaecol Obstet. 2015;131(Suppl 3):S173–211.
sures so as to improve the woman’s health in the Brito-Zerón P, Izmirly PM, Ramos-Casals M, et al. The
clinical spectrum of autoimmune congenital heart
long term. block. Nat Rev Rheumatol. 2015;11(5):301–12.
Essentials of Counseling in Fetal
Medicine 18
Counseling is one of the most important aspects undergo, the purpose of the test, and the possible
of clinical practice in Fetal medicine. Counseling outcomes, then they are much better equipped to
is the part where there is effective communica- handle the results and even in case of an adverse
tion between the doctor and the patient after a report, the anxiety levels are not unduly high.
particular fetal assessment is done. All clinicians Pretest counseling can be done at the same sit-
will agree that unless this communication is done ting as we mostly do for fetal scans or may be
well, the final goal of “care” remains unachieved. scheduled in advance for some specific proce-
Not only in fetal medicine, but also in every field dures where the stakes are higher and the parents
of clinical medicine, effective doctor-patient may need some time and further deliberation
communication is the crux of satisfactory treat- before they can reach a decision of whether or not
ment. Achieving great technical skills, using to go ahead with a test or procedure.
state-of-the-art machinery, and writing accurate Supplementing oral advice with written informa-
reports are all very important accomplishments tion in the form of information leaflets is a good
in fetal medicine practice, but unless you are able idea as sometimes parents are so stressed during
to explain the results to the most important stake- the consultation that they may not understand or
holders in fetal care—the parents—there remains retain every piece of information that you have
a lacuna in the process which starts with lack of shared with them. If they take home leaflets, they
understanding the exact situation and may snow- can read them later and understand the situation
ball into misconceptions and wrong decisions in better.
pregnancy. Therefore, effective counseling—
both “pretest” and “posttest” sessions—are vital
in every fetal medicine clinic to ensure good fetal 18.2 Pretest Counseling for Fetal
care. Scans
It is good practice to do a pretest counseling for

18.1 Pretest Counseling fetal scans. Prior to placing your probe on the
mother, it would be very useful to spend a few
Every fetal evaluation test—be it an ultrasound minutes explaining the nature of the scan, what
scan or a serum screening test—MUST begin are the goals of the scan, the expected time frame,
with a “pretest” counseling. If the parents are what can be seen, what cannot be seen, and the
explained what is the test that they are about to expected results. The fact that some part of the

182 18 Essentials of Counseling in Fetal Medicine
evaluation may require a transvaginal approach 18.3 Posttest Counseling for Fetal
at times can also be mentioned at the outset to Scans
mentally prepare her for that possibility. It makes
the patient feel as ease and she is far more relaxed Once the scan is complete and you have made the
during the session as compared to a situation report, it is useful to meet the parents, explain the
where a doctor walks in directly without any report, and address any of their concerns with
priming and starts a technical scan with the regard to the scan. Even if everything is “normal”
patient very nervous and anxious about the according to you, it is a good practice to mention
happenings. the points evaluated on the scan and the limits of
It is also important to explain that sometimes the scan. After addressing any particular query
fetal position may not be favorable temporarily that they may have, the next time for fetal evalu-
and we may have to let her go for a walk and ation can be mentioned. If that is the last routine
review after sometime when the fetus may have scan for this pregnancy, then the parents may be
turned into a better position. These points, how- informed so and requested to revert with the out-
ever trivial they may appear, are important as come of pregnancy as it is equally important to
some parents can get very nervous when you say follow-up the final results of your fetal evaluation
a sentence like “I can’t see the heart as baby is not and care.
moving inside”!! It may be an innocent statement In case there are any fetal “markers” or
of fact but carries unimaginable potential to “anomalies” are found, then a detailed explana-
unnerve your patient. Correct choice of words tion of that specific issue and its impact on fur-
remains forever important, but timing a few such ther fetal evaluation and the pregnancy in general
points in the pretest counseling will help you has to be made. As discussed in previous chap-
immensely in increasing overall patient ters, all problems have specific care plans and
satisfaction. multidisciplinary teams have to be constituted for
Many parents walk in for fetal scans expect- executing those plans. The obstetrician remains
ing to be entertained by looking at the fetus in the most important clinician in the care of a preg-
real time. While it is acceptable to allow them nancy, and in the event of any fetal problem, it is
to experience this joy, what is most important is important to inform and involve the obstetrician
for everyone to realize that fetal scans are NOT about the alteration in fetal care. As such findings
a PR exercise—they have scientific indications may be discovered in the middle of a busy clini-
and until those goals are achieved, a mere dis- cal day and it may not be possible to arrange a
play of the fetal activity on screen is not going joint multidisciplinary meeting right away, it is
to lead us to the right consequence. Hence, doc- rational to do a preliminary counseling of the par-
tors have to explain to the parents that first the ents at the FM clinic, give them information leaf-
clinical agenda has to be fulfilled, the technical lets, and arrange for a MDT meeting at a later
checklist has to be completed, and only then we date with all relevant subspecialists.
can “show” them the fetus for their satisfaction.
Such pretest counseling will help gain their
cooperation in allowing you to complete your 18.4 Pretest Counseling for Fetal
clinical work without interruption and will also Screening Tests
keep them prepared that we may find some
issues which will then necessitate further dis- Screening tests, as defined earlier, are tests done
cussion. If we do not prepare them prior to the on “apparently normal” people to pick out “low-
scan, every little point can become a cause of risk” population that can be reassured and “high-
major anxiety, frustration, and discontent with risk” population that needs further testing and
far-reaching consequences. evaluation. It is therefore very crucial that before
18.4 Pretest Counseling for Fetal Screening Tests 183
undertaking any screening tests, the parents nancy, there are possibilities of problems in some
understand that the results may come “high risk” cases and hence some tests are done to look for
and this is not a diagnosis but only a probability those women who have higher chances of these
of a problem and hence needs further problems and such tests are called “screening
investigation. tests.” Most of the time, difficulties arise in the
At this session, it may be useful to address the process of screening due to neglect of the “pretest
point that the screening test is being offered to counseling.” These few extra minutes spent in
her as part of a routine care process. Many women explaining the rationale of a screening test to the
get very anxious the moment the doctor uses couple goes a very long way in ensuring compli-
terms like “chromosomal abnormalities” and get ance and reasonable reactions to the results of the
defensive by stating that they do not have any test (Fig. 18.1).
such problems in the family or get nervous why By “counseling” clinicians generally mean
suddenly there is this discussion about “prob- “explaining” the results of the fetal evaluation to
lems.” It is therefore useful to open the discussion the couple and sometimes their family members.
on a positive note and explain that although Most doctors think of counseling as an act of
everything looks normal at this stage of preg- “talking” to the patient, whereas if you look into
A Allot a quiet and comfortable

space in the clinic for counselling
sessions
M Meet the couple and introduce

yourself
I Introduce sensitively the reason for

having this session
C Check what are their concerns
A Answer all their queries and
explain the next possible steps
B Be sure that they have understood
L Leaflets with written information

can be handed over for better
understanding
E Expect a decision regarding future

care for the fetus — either right
away or after they think over the
issue
Fig. 18.1 AMICABLE checklist for counseling sessions

184 18 Essentials of Counseling in Fetal Medicine
the actual meaning of counseling, it involves

“listening” to the other person’s concerns and Key Learning Points
then advising them further to help them reach a 1. Counseling remains the cornerstone of
decision. It is important to realize in all fetal effective clinical service—until your
medicine consultations that we are not commu- patient understands the course of man-
nicating with the “patient” per se. We are com- agement, the job of a doctor is
municating with the mother or the parents about unfinished.
a baby yet to be born! As such, there is a rather 2. Your patients may not remember exactly
abstract idea in most people about the existence what you said to them but they will
of this fetus, and the attachment is so emotional remember how you made them feel—if
that parents often find it difficult to individualize you are able to convey your intentions
this fetus and discuss anything that could be a in planning her care, your patient will
“problem” to the fetus! Most fetal medicine con- not lose faith in you.
sultations start with a high baseline anxiety, and 3. Remember, most of the discontent in
the onus lies on the fetal medicine doctor to medical practice today is because of
moderate the emotional quotient and bring the poor communication between doctors
discussion to a rational platform. It will be cor- and patients—talking to your patient is
rect to state that appropriate counseling by the not a waste of your time; it is the very
fetal medicine specialist can be “lifesaving” for purpose of your practice!
a fetus!!

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Fetal

ISBN 978-981-19-6098-7 ISBN 978-981-19-6099-4 (eBook)

© Springer Nature Singapore Pte Ltd. 2022

Hyderabad, India Chinmayee Ratha

1 Introduction to Fetal Medicine ������������������������������������������������������ 1

Chinmayee Ratha, MS (ObGyn), FRCOG, FIMSA, FICOG is the

Ashok Khurana commenced his medical studies at All India Institute of

Ultrasound in Medicine and Biology. He is also a member of the FOGSI

Fetal medicine is a branch of medicine dealing

© Springer Nature Singapore Pte Ltd. 2022 1

© Springer Nature Singapore Pte Ltd. 2022 5

A normal pregnancy is a journey of a zygote 3.1 4–6 Weeks of Gestation

Fig. 3.1 Timeline for fetal evaluation in a normal pregnancy

© Springer Nature Singapore Pte Ltd. 2022 7

Although fetal monitoring at this stage is largely

Routine or follow up third

© Springer Nature Singapore Pte Ltd. 2022 13

Apparently normal population

High risk for a condition

Low risk for a condition

High risk for a condition

Fig. 4.1 Screening concept

Primary Intermediate Secondary

High Risk Diagnostic

Fig. 4.2 Concept of intermediate risk

4.7 Cell-Free Fetal DNA Test 4.8 The Midtrimester Genetic

based on the prevalence of these markers in nor-

© Springer Nature Singapore Pte Ltd. 2022 23

Fig. 5.1 Ultrasound probe, machine electricity source

Fig. 5.2 Hyperechoic “Hyperechoic” –

Fig. 5.3 Gain settings: high and low

Fig. 5.4 2D/3D pictures

Fig. 5.5 M-mode

excursions of the valves and the myocardium.

Fig. 5.6 Fetal MRI

supply should be connected to prevent potentially

© Springer Nature Singapore Pte Ltd. 2022 31

Fig. 6.1 Early pregnancy scan

Table 6.1 Biometric parameters in early pregnancy ultrasound

Yolk sac Diameter: The longest diameter of the

Table 6.1 (continued)

Fetal heart Beats per minute: Measured using

Any adnexal Dimensions: Linear measurements at

6.2 Significance of Early 6.3 “Dating Is a New

• Biparietal diameter (BPD)

These measurements when calculated together

6.5 Biparietal Diameter Fig. 6.2 BPD

This is the length between the two parietal emi-

6.6 Head Circumference Similarly at times, the head shape is some-

a b Two methods of measuring HC

Fig. 6.3 (a) HC. (b) Methods to measure HC

b BPD = OFD : Branchycephaly

Fig. 6.4 (a) Dolichocephaly. (b) Brachycephaly

Both these methods are acceptable in clinical

Biometry can be represented in centiles, or as p

±2.5 SD from mean or as Z-score deviations e

depending on which method adheres to local pro- stomach

Table 6.4 Important points while measuring the fetal AC

skeletal dysplasia and that required detailed

Hyderabad, India Chinmayee Ratha

1 Introduction to Fetal Medicine �� 1

A normal pregnancy is a journey of a zygote 3.1 4–6 Weeks of Gestation

4.7 Cell-Free Fetal DNA Test 4.8 The Midtrimester Genetic

6.2 Significance of Early 6.3 “Dating Is a New

6.5 Biparietal Diameter Fig. 6.2 BPD

6.6 Head Circumference Similarly at times, the head shape is some-

Fetal face is examined in the median sagittal 7.4.4 Fetal Neck

7.4.5 Fetal Thorax 7.4.6 Fetal Heart

7.4.9 Fetal Limbs ing unhindered movements of the limbs through-

7.5 Scope of the Midtrimester It is important to explain the limitations of the

become crucial in planning management of 8.1 Fetal Circulation

8.2 Umbilical Artery Doppler 8.3 Fetal Middle Cerebral Artery