JACC: ADVANCES VOL. 2, NO.

4, 2023

ª 2023 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ORIGINAL RESEARCH

CONGENITAL HEART DISEASE

Prenatal Congenital Heart Disease and

Placental Phenotypes
Preserved Neonatal Weight Despite Small Placentas

Angela Desmond, MD,a,b,* Helia Imany-Shakibai,b,* Deanna Wong, MD,b,c Lorna Kwan, MPH,d Gary Satou, MD,b,e
Mark Sklansky, MD,b,e Yalda Afshar, MD, PHDb,c,f

ABSTRACT

BACKGROUND Congenital heart disease (CHD) affects 8 in 1,000 live births with significant postnatal implications
including growth failure, neurodevelopmental delay, and mortality. The placenta develops concomitantly with the fetal
heart. High rates of placental pathology and discordant growth in pregnancies affected by CHD highlight the significance
of the fetal-placental-cardiac axis.

OBJECTIVES This study aimed to characterize the relationship between neonatal birthweight (BW), head circumfer-
ence, placental weight (PW), and placental pathology in pregnancies affected by CHD. PW:BW provides a surrogate to
assess placental efficiency, or nutrient exchange and delivery by the placenta, across CHD phenotypes.

METHODS Retrospective cohort of 139 live-born singletons with postnatally confirmed CHD with placental pathology.
Placental examination, infant BW, head circumference, and CHD categories (septal defects, right-sided defects, left-sided
defects, conotruncal anomalies, and others) were included. Chi-square, Fisher’s exact, or Kruskall-Wallis tests and
multinomial logistic regressions, as appropriate.

RESULTS Median birthweight and head circumference percentile was 33 and 35, respectively. Placental pathology was
documented in 37% of cases. PW to BW ratios were <10th percentile for 78% and <3rd percentile for 54% of the cohort,
with no difference between CHD categories (P ¼ 0.39 and P ¼ 0.56, respectively).

CONCLUSIONS Infants with CHD have preserved BW and head circumferences in the setting of small placentas and
increased prevalence of placental pathology, suggesting placental efficiency. Detection of abnormal placental growth
could add prenatal diagnostic value. Placental and neonatal discordant growth may allude to a vascular anomaly
predisposing fetuses to developing CHD. Further studies are needed to explore fetal nutrient delivery and utilization
efficiency. (JACC Adv 2023;2:100383) © 2023 The Authors. Published by Elsevier on behalf of the American College of
Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

From the aDivision of Neonatology, Department of Pediatrics, University of California-Los Angeles, Los Angeles, California, USA;
b
David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, USA; cDivision of Maternal Fetal
Medicine, Department of Obstetrics and Gynecology, University of California-Los Angeles, Los Angeles, California, USA;
d
Department of Urology, University of California-Los Angeles, Los Angeles, California, USA; eDivision of Pediatric Cardiology,
Department of Pediatrics, UCLA Mattel Children’s Hospital, Los Angeles, California, USA; and the fMolecular Biology Institute,
University of California-Los Angeles, Los Angeles, California, USA. *Drs Desmond and Imany-Shakibai share co-first authorship.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 15, 2022; revised manuscript received March 3, 2023, accepted March 31, 2023.

ISSN 2772-963X https://doi.org/10.1016/j.jacadv.2023.100383

2 Desmond et al JACC: ADVANCES, VOL. 2, NO. 4, 2023

Placental Phenotypes in Congenital Heart Disease JUNE 2023:100383

C
ABBREVIATIONS ongenital heart disease (CHD) is the Infants born with CHD are more commonly small
AND ACRONYMS leading cause of major birth defects for gestational age (SGA) compared to those without
affecting approximately 8 per 1,000 CHD. 13 In a large database investigation for infants
CHD = congenital heart disease 1
live births. Despite significant advance- born in California, 16.3% of infants with CHD were
DM = diabetes mellitus
ments in prenatal diagnostics and postnatal SGA, compared to 8.1% of infants without CHD.16 In-
HTN = hypertension
care, CHD remains a leading cause of infant fants born with CHD have demonstrated decreased
PW:BW = placental weight to morbidity and mortality, with studies growth velocity, particularly brain growth velocity, in
birthweight
showing one per 814 deaths attributable to the third trimester.17 A fetal imaging study revealed a
SGA = small for gestational age 2
CHD. Many children with CHD are subse- 13% reduction in brain volume in fetuses with CHD
quently diagnosed with deficits in various domains compared to controls. 18
of neurodevelopment. Despite existing literature on placental to birth-
The development of CHD is multifactorial and re- weight ratios, there are few studies of placental to
mains poorly understood. Etiologies likely extend birthweight ratios in pregnancies affected by CHD
beyond described genetic, epigenetic, and environ- and none include preterm births. The dynamic,
mental factors. Recent insights demonstrate a plau- intricate fetal-placental-cardiac axis of circulation in
sibility of concomitant placental anomalies. 3,4 The the context of CHD remains poorly understood. This
placenta is a major vascular organ that significantly study aims to characterize the relationship between
influences fetal organogenesis, development, and neonatal growth and placental size and pathology in
growth. 5 The fetal heart and maternal placenta pregnancies affected by CHD and to assess placental
develop concurrently by formation of a tubular heart efficiency in this population.
and a primitive placental villous tree by 21 days of
gestation.6-8 Shared regulatory and signaling path- METHODS
ways exist in the development of the fetal heart and
placenta.9 This was a retrospective cohort study that examined
A body of literature suggests a link between vas- all pregnancies that underwent prenatal echocardi-
culogenesis and angiogenesis in the fetal heart and ography with pediatric cardiology at the University of
10
placenta. Placental vascular abnormalities have California-Los Angeles (UCLA) for suspected CHD af-
been detected at high rates in pregnancies affected by ter screening ultrasonography and were referred for
CHD. In particular, fetal vascular malperfusion and suspected CHD between January 2011 and September
maternal vascular malperfusion lesions were found in 2021. All singleton pregnancies delivered at UCLA
20% and 23% of placentas from pregnancies affected (Ronald Reagan UCLA Medical Center or UCLA Santa
by fetal CHD, respectively, while they were not found Monica Medical Center) that resulted in a live birth
in any control pregnancies.11 Umbilical venous flow, a with confirmed CHD on postnatal echocardiography
measure of fetal placental blood flow and a surrogate and had placental pathology collected at delivery
for placental function, has been shown to be lower in were included. Institutional Review Board approval
fetuses with CHD compared to controls. 12 was obtained (UCLA IRB #19-001754) and informed
The placenta, the exclusive source of nutrients and consent was waived given the retrospective nature of
oxygen to the developing fetus, is instrumental in the study.
prenatal growth and development. A large placenta is Chart review was conducted to obtain maternal
not necessarily indicative of adequate fetal growth demographic information and comorbidities,
since placental pathology (infarction, thrombosis, placental weight and pathology, neonatal birth-
chorangiosis), blood flow resistance, and nutrient weight, and postnatal CHD diagnosis. Risk factors and
exchange and utilization are also influential. These maternal comorbidities collected include hyperten-
factors are aberrant in the setting of CHD. sive diseases of pregnancies, pre-eclampsia, diabetes,
Placental weight to birthweight (PW:BW) ratios teratogenic exposure, and family history of CHD.19,20
have been studied and correlated with short- and Placentas were sent to pathology for gross and
long-term outcomes for infants. In the perinatal microscopic histopathologic examination at the time
period, high PW:BW correlates with increased of birth. Gynecologic and perinatal pathologists at
admission rate to the neonatal intensive care unit, UCLA performed histologic examination. The
lower Apgar scores, and higher cesarean births.13 In placental size was measured, and the trimmed weight
adulthood, high PW:BW is associated with risk of was recorded. All placentas were fixed in 10% buff-
hypertension and death from cardiovascular ered formalin. Sections submitted included 2 sections
causes.14,15 of umbilical cord, 2 sections of membrane, 3 full
JACC: ADVANCES, VOL. 2, NO. 4, 2023 Desmond et al 3
JUNE 2023:100383 Placental Phenotypes in Congenital Heart Disease

F I G U R E 1 Study Population

CHD ¼ congenital heart disease.

thickness sections of grossly normal appearing appropriate growth curve. CHD diagnoses were
placenta from the chorionic plate to the basal plate, determined by postnatal echocardiography reports.
and additional submitted sections of any grossly Each diagnosis was then classified as one of the
abnormal placenta. Sections underwent routine pro- following: septal defects, right-sided heart defects,
cessing, were paraffin-embedded, sectioned at 3 to left-sided heart defects, conotruncal anomalies, or
5 m m, and stained with hematoxylin and eosin. The other (total anomalous pulmonary venous return, si-
pathologists categorized the histopathologic lesions tus inversus, heterotaxy, dilated cardiomyopathy,
according to the Amsterdam criteria after the multiple anomalies not fitting any one category).
consensus statement was published.21 Placental pa- PW:BW ratios were calculated and percentiles were
thology reports were reviewed to extract placental assigned based on established nomograms. 22 All
weight and presence of the following pathologies: abstracted information was stored in a de-identified
thrombosis, infarction, chorangiosis, and villous research database.
hypomaturation. Placental weight percentiles were All maternal and neonatal variables were summa-
assigned based on sex and gestational age from rized with frequencies or median (IQR). Chi-square
established nomograms. test (or Fisher’s exact test if appropriate) was used
Birthweight percentiles were assigned based on to analyze categorical variables and Kruskal-Wallis
gestational age at birth using the World Health Or- test was used to analyze and compare continuous
ganization and Fenton growth curves, for term and variables across the 5 CHD diagnoses. We also
preterm (<37 weeks’ gestational age) infants, checked for associations between PW:BW ratio with
respectively. SGA was assigned if the birthweight the maternal variables with a Kruskal-Wallis test, and
percentile was <the 10th percentile on the then ran a multinomial logistic regression of PW:BW
4 Desmond et al JACC: ADVANCES, VOL. 2, NO. 4, 2023

Placental Phenotypes in Congenital Heart Disease JUNE 2023:100383

T A B L E 1 Maternal Demographics and Clinical Characteristics

Right Left Conotruncal Other

All Septal Defect Heart Defect Heart Defect Anomalies Anomaliesa
(N ¼ 139,100%) (n ¼ 27,19%) (n ¼ 13,9%) (n ¼ 38,27%) (n ¼ 41,29%) (n ¼ 20,14%) P Value

Age, y 32 (27-36) 34 (29-40) 35 (25-39) 30 (27-35) 32 (26-36) 31 (25-35) 0.156b

Race/ethnicity 0.498c
Non-white 96 (69) 21 (78) 7 (54) 28 (74) 26 (63) 14 (70)
White 43 (31) 6 (22) 6 (46) 10 (26) 15 (37) 6 (30)
Comorbidities
Diabetes mellitus 12 (9) 2 (7) 1 (8) 2 (5) 4 (10) 3 (15) 0.797c
Gestational diabetes 23 (17) 7 (26) 4 (31) 3 (8) 8 (20) 1 (5) 0.082c
Chronic hypertension 14 (10) 4 (15) 2 (15) 3 (8) 2 (5) 3 (15) 0.445c
Gestational hypertension 26 (19) 8 (30) 1 (8) 7 (18) 7 (17) 3 (15) 0.492c
Category of pregnancy induced 0.395c
hypertension
Gestational hypertension 4 (15) 0 (0) 0 (0) 2 (29) 2 (29) 0 (0)
Pre-eclampsia/Eclampsia 21 (81) 8 (100) 1 (100) 4 (57) 5 (71) 3 (100)
HELLP 1 (4) 0 (0) 0 (0) 1 (14) 0 (0) 0 (0)
Family history of CHD 16 (11) 2 (7) 2 (15) 4 (11) 5 (12) 3 (15) 0.909c
Assisted reproductive technology 3 (2) 1 (4) 1 (8) 0 (0) 0 (0) 1 (5) 0.092c
Medication/teratogen exposure 4 (3) 0 (0) 0 (0) 1 (3) 1 (2) 2 (10) 0.457c
Substance abuse 0.446c
Smoking 3 (2) 0 (0) 1 (8) 0 (0) 1 (2) 1 (5)
Alcohol 2 (1) 1 (4) 0 (0) 0 (0) 1 (2) 0 (0)
None 134 (96) 26 (96) 12 (92) 38 (100) 39 (96) 19 (95)

Values are median (IQR) or n (%). aOther includes total anomalous pulmonary venous return, situs inversus, heterotaxy, dilated cardiomyopathy, multiple anomalies not fitting any one
category. bKruskal-Wallis. cFisher’s exact.
CHD ¼ congenital heart disease; HELLP ¼ hemolysis, elevated liver enzymes, low platelets.

ratio on the 5 CHD diagnoses, controlling for the singleton births, delivery at a study hospital, avail-
following covariates: maternal DM, maternal gesta- able placental pathology). Table 1 displays the spec-
tional DM, maternal chronic hypertension (HTN), trum of CHD diagnostic categories in this population.
pregnancy induced HTN (none, gestational HTN, pre- The most common lesions were conotruncal anoma-
eclampsia, hemolysis, elevated liver enzymes, low lies and left-sided heart defects, composing 29% and
platelets), family history of CHD, and assisted repro- 27% of the cohort, respectively.
ductive technology. In post hoc analyses, we MATERNAL DEMOGRAPHICS AND CLINICAL
compared the same variables between single CHARACTERISTICS. Maternal demographic and
ventricle vs double ventricle physiology, and be- clinical risk factors for our cohort are summarized in
tween left sided vs non-left-sided defects, and ran a Table 1 and compared to the general pregnant popu-
logistic regression for each comparison with the same lation in Table 2. The median maternal age was
covariates as the multinomial logistic regression. 32 years old, which is significantly higher than
Additionally, we compared placental weight percen- average age at delivery of first pregnancy.23 Family
tile between placental infarction vs without infarc- history of CHD was identified in 11% of cases. DM or
tion. We separately stratified the cohort by SGA status gestational diabetes affected 25% of pregnancies,
to compare across CHD diagnoses to explore potential which is significantly higher than the general preg-
interactions with SGA status. We also compared our nant population.28 Hypertensive diseases of preg-
study population with published reports for several nancy were present in 19% of the cohort, of which
maternal characteristics. 81% were categorized as pre-eclampsia or eclampsia.
RESULTS No statistically significant differences were detected
between CHD groups.
A total of 500 pregnant people had prenatal echo- BIRTHWEIGHT AND PLACENTAL PATHOLOGY. Table 3
cardiograms for a suspected fetal CHD at the institu- displays neonatal and placental characteristics
tion between January 2011 and September 2021 across CHD groups. The median gestational age at
(Figure 1), of which 139 met criteria for our study (live, delivery for the entire cohort was 38 weeks, with no
JACC: ADVANCES, VOL. 2, NO. 4, 2023 Desmond et al 5
JUNE 2023:100383 Placental Phenotypes in Congenital Heart Disease

significant difference between CHD groups. The me-

T A B L E 2 Comparison of Our Study Population to General Pregnant Population
dian birthweight was 2,920 g and median birthweight
percentile was 33 based on gestational age. The me- Our Study General Pregnant
Population Population P Value
dian head circumference was 33 cm and median head
Maternal age, y 31.5  6.5 27.1  6.523 <0.0001
circumference percentile was 35 based on gestational
Assisted reproductive technology 2.2% 1.6%24 0.4904a
age. Twenty-seven percent of the infants studied Substance abuse
with CHD were SGA (Table 3), which is significantly Smoking 2.2% 7.2%25 0.0215
27
higher than 11% in the general population. Birth- Alcohol 1.4% 13.5%26 <0.0001
weight, SGA diagnosis, and head circumference were SGA 27% 11%27 <0.0001

not significantly different between CHD diagnostic Comorbidities

Diabetes mellitus 8.6% 1.3%28 <0.0001a
cohorts or in the post hoc sub analyses comparing
Gestational diabetes 16.6% 7.6%28 <0.0001
single ventricle vs double ventricle physiology and
Chronic hypertension 10.1% 0.9%-1.5%29
left-sided defects vs non-left-sided defects Hypertensive disorders of pregnancy 18.7% 4-8%30
(Supplemental Tables 1 and 2, respectively). Category of pregnancy induced hypertension
Median placental weight was 407 g, which is <3rd Gestational hypertension 2.9% 3%31
percentile for males or females born at 38 weeks’ Pre-eclampsia 15.1% 2%-8%32

gestational age. Over half of the infants in our study Eclampsia 0% 0.82%31
HELLP 0.7% 0.9%33
had placental weights <3rd percentile and over two-
thirds had placental weights <10th percentile based Values are mean  SD or %. Bold values indicate significant as defined by P < 0.05. aFisher’s exact.
on sex and gestational age (Table 3). Infants with left- HELLP ¼ hemolysis, elevated liver enzymes, low platelets; SD ¼ standard deviation; SGA ¼ small for gesta-
tional age.
sided heart defects had the lowest median placental
weight at 384 g; however, there was no statistically
significant difference in placental weight across CHD
categories. The majority (89%) of infants in our
significantly associated (P ¼ 0.08-0.96). However, in
cohort who were SGA had placental weights <3rd
multivariate analysis, neither PW:BW ratio nor the
percentile compared to less than one-half (47%) in the
other covariates were associated with defect category
non-SGA cohort of our population (Table 4). There
(P ¼ 0.70 for PW:BW and 0.89 for family history),
was no significant difference in distribution of
single vs double ventricle (P ¼ 0.63 and P ¼ 0.14), or
placental weight percentiles across CHD diagnostic
left vs non-left-sided defect (P ¼ 0.82 and P ¼ 0.80)
categories or when infants with left-sided defects
(data not shown).
were compared to those without left-sided defects or
The most common placental pathology in this
those with single ventricle were compared to those
population was infarction, which was diagnosed in
with double ventricle physiology (Table 3,
20% of all CHD cases. Placental thrombosis and
Supplemental Tables 1 and 2, respectively). Within
chorangiosis were present in 7% and 6% of the cohort,
our non-SGA cohort, those with left-sided defects had
respectively (Table 3). There was no significant dif-
a higher frequency of placental weights #3rd
ference in the incidence of placental pathology be-
percentile (54%) compared to those without left-
tween CHD diagnostic groups. When we looked at
sided defects (44%) (Table 4).
placental weights and PW:BW in those with placental
PW to BW ratios were <3rd percentile for over half
infarction vs those without infarction, we found no
of the cohort and <10th percentile for almost 80% of
significant difference (Supplemental Table 3).
the cohort, with no significant difference between
CHD category (P ¼ 0.39 and P ¼ 0.56, respectively) DISCUSSION
(Table 3) or between those with single ventricle and
double ventricle physiology (P ¼ 0.88 and P ¼ 0.50, Despite an increased incidence of placental pathology
respectively) (Supplemental Table 1). Comparing in- in our cohort of pregnancies complicated by fetal
fants with left-sided heart defects to those without, CHD, we demonstrate small placentas regardless of
those with left-sided heart defects tended to have lesion type in comparison to neonatal birthweight
PW:BW ratio <3rd percentile more commonly than and head circumference, suggesting increased
those without (66% vs 50%, P ¼ 0.09) (Supplemental placental efficiency (Central Illustration). At first
Table 2). glance, our population of neonates with CHD had
In the bivariate analysis with PW:BW ratio, only normal in-utero growth exemplified by a median
family history of CHD was significantly associated birthweight percentile of 33. However, 27% of our
with PW:BW ratio where those with a history had population was SGA, which is a significantly higher
smaller ratios (P ¼ 0.02). The other variables were not rate than stated in prior studies examining fetal
6 Desmond et al JACC: ADVANCES, VOL. 2, NO. 4, 2023

Placental Phenotypes in Congenital Heart Disease JUNE 2023:100383

T A B L E 3 Birth Characteristics for Infants With CHD and Corresponding Placental Findings

Septal Right Left Conotruncal Other

Total Defect Heart Defect Heart Defect Anomalies Anomalies
(N ¼ 139) (n ¼ 27) (n ¼ 13) (n ¼ 38) (n ¼ 41) (n ¼ 20) P Value

Gestational weeks at delivery 38 (37-39) 38 (36-39) 38 (37-39) 38 (37-39) 39 (37-39) 38 (37-39) 0.453a
Birthweight (g) 2,920 2,830 3,320 2,800 3,015 2,840 0.597a
(2,400–3,418) (2,415–3,220) (2,582–3,440) (2,405–3,279) (2,550–3,435) (2,405–3,328)
Birthweight percentile 33 (8–65) 26 (4–71) 58 (21–65) 32 (5–65) 30 (8–60) 34 (11–75) 0.679a
SGA 38 (27) 8 (30) 2 (15) 12 (32) 11 (27) 5 (25) 0.842b
Head circumference (cm) 33.0 32.5 33.5 33.0 33.1 33.1 0.616a
(32.0–34.5) (31.0–34.0) (32.5–36.0) (31.4–34.1) (32.0–34.5) (32.0–36.0)
Head circumference percentile 35.3 34.6 37.4 26.6 35.9 22.7 0.563a
(5.6–75.5) (5.6–82.0) (12.5–96.3) (3.5–61.5) (4.4, 66.3) (12.3–89.0)
Placental characteristics
Placental weight 407 401 427 384 423 430 0.601a
(336–514) (308–504) (385–543) (348–451) (307–510) (374–518)
Placental weight percentile 0.491b
<3 81 (58) 16 (59) 7 (54) 25 (66) 25 (61) 8 (40)
<10 14 (10) 3 (11) 0 (0) 2 (5) 5 (12) 4 (20)
25/50/75/>90 44 (32) 8 (30) 6 (46) 11 (29) 11 (27) 8 (40)
Placental weight to birthweight ratio 0.14 0.14 0.15 0.14 0.14 0.15 0.295a
(0.12–0.16) (0.13–0.18) (0.14–0.16) (0.12–0.16) (0.12–0.16) (0.14–0.16)
Placental weight to birthweight percentile
<3 75 (54) 14 (52) 5 (38) 25 (66) 22 (54) 9 (45) 0.394b
<10 109 (78) 21 (78) 10 (77) 32 (84) 33 (80) 13 (65) 0.556b
Thrombosis 10 (7) 1 (4) 2 (15) 2 (5) 4 (10) 1 (5) 0.680b
Infarction 28 (20) 6 (22) 2 (15) 7 (18) 8 (20) 5 (25) 0.960b
Chorangiosis 8 (6) 0 (0) 1 (8) 4 (11) 1 (2) 2 (10) 0.236b
Villus: hypomature 5 (4) 2 (7) 1 (8) 2 (5) 0 (0) 0 (0) 0.239b

Values are median (IQR) or n (%). aKruskal-Wallis. bFisher’s exact.

CHD ¼ congenital heart disease; SGA ¼ small for gestational age.

growth in the setting of CHD and higher than the infarction in 17 to 28% of CHD pregnancies. 35,36 Sur-
general population average of 11%. prisingly, we did not find significantly lower birth-
We found that 37% of the placentas in our cohort weights for infants from pregnancies with placental
had pathology, an incidence higher than 26% to 28% infarction. In the context of increased pathology, we
cited in all pregnancies, but lower than 57% to 78% then examined the relationship between placental
cited in pregnancies affected by fetal CHD.11,34,35 The size and fetal growth in our cohort.
frequency of infarction (20%) in our cohort is similar The PW:BW ratio is inversely proportional to
to other studies that found evidence of placental placental efficiency. 37 In other words, a low PW:BW

T A B L E 4 Placental Weight Percentiles Categorized by CHD Defect Stratified by Infant SGA Status

Septal Right Left Conotruncal Other

Total Defect Heart Defect Heart Defect Anomalies Anomalies
(N ¼ 139) (n ¼ 27) (n ¼ 13) (n ¼ 38) (n ¼ 41) (n ¼ 20)

Non-SGA infants (n ¼ 101)

Placental weight percentile <3 47 (47) 9 (47) 5 (45) 14 (54) 15 (50) 4 (27)
Placental weight percentile <10 12 (12) 2 (11) 0 (0) 2 (8) 4 (13) 4 (27)
Placental weight percentile 25/50/75 39 (39) 8 (42) 6 (55) 8 (31) 11 (37) 6 (40)
Placental weight percentile 90 3 (3) 0 (0) 0 (0) 2 (8) 0 (0) 1 (7)
SGA infants (n ¼ 38)
Placental weight percentile <3 34 (89) 7 (88) 2 (100) 11 (92) 10 (92) 4 (80)
Placental weight percentile <10 2 (5) 1 (13) 0 (0) 0 (0) 1 (9) 0 (0)
Placental weight percentile 25/50/75 2 (5) 0 (0) 0 (0) 1 (8) 0 (0) 1 (20)
Placental weight percentile 90 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Values are n (%).

JACC: ADVANCES, VOL. 2, NO. 4, 2023 Desmond et al 7
JUNE 2023:100383 Placental Phenotypes in Congenital Heart Disease

C ENTR AL I LL U STRA T I O N Small, Efficient Placentas in Fetal CHD Pregnancies

Desmond A, et al. JACC Adv. 2023;2(4):100383.

may correspond to higher placental efficiency or with CHD adjusts to extract or utilize nutrients more
nutrient extraction from the fetus. We found that 78% effectively (Figure 2). Further studies are needed to
of the cohort we studied had PW:BW ratios <10th determine whether the placental transfer of oxygen
percentile; furthermore, 54% had ratios <3rd and nutrients in CHD is enhanced and how it ac-
percentile. These are quite comparable to findings in complishes this favorable phenotype.
a smaller study that found 77% of PW:BW <3rd Previous imaging studies in CHD pregnancies have
percentile and 49% of PW:BW <10th percentile in shown that despite normal fetal estimated size and
CHD pregnancies.36 This suggests that despite small weight, brain size can be disproportionately low.9 It is
placental size, the developing fetuses receive enough hypothesized that this is a result of longstanding
oxygen and nutrients to grow, as exemplified by decreased cerebral perfusion secondary to prolonged
disproportionately higher birthweight percentiles. hypoxia. This is in opposition to the acute or subacute
The placenta may adapt to deliver nutrients in a more insufficiency seen with gestational hypertension
efficient way to the developing fetus with CHD, even leading to the well-documented brain sparing physi-
in the setting of increased placental pathology. An ology. In our population of infants with CHD, we
alternative explanation is that the developing fetus found median head circumference percentile to be
8 Desmond et al JACC: ADVANCES, VOL. 2, NO. 4, 2023

Placental Phenotypes in Congenital Heart Disease JUNE 2023:100383

F I G U R E 2 Plausible Mechanisms for the Fetal-Placental-Cardiac Axis in CHD

CHD ¼ congenital heart disease.

35th percentile, which is close to the 33rd percentile community. Our study population likely includes
we found for weight, suggesting proportional head pregnancies complicated by more critical and ductal
and total body growth. For those with left-sided heart dependent lesions. Excluding dyads that did not have
defects, head circumference tended to be smaller placentas sent for pathology introduces another
(27th percentile compared to birthweight of 32nd source of selection bias. We examined the 135 dyads
percentile) (Central Illustration). who were excluded based on not having placental
The strengths of our study include a diverse, large pathology and report delivery dates and distribution
sample size that included preterm and term de- of fetal cardiac anomalies in Supplemental Table 4.
liveries. Our population encompassed a heteroge- The ineligible group had more right-sided defects and
neous and comprehensive very complex group of conotruncal defects compared to our study popula-
CHD diagnoses. tion. Prior to the Amsterdam criteria, there was less
standardization of placental pathology analysis.
STUDY LIMITATIONS. Despite several strengths, our Furthermore, we did not analyze any in utero
study had limitations. Namely, this stems from the placental imaging, quantitative, or qualitative anal-
retrospective nature of the study design. Here in, we ysis; we used the post-birth placental pathology as a
investigated maternal-fetal dyads from a single, high- surrogate. We chose to use separate growth curves for
volume quaternary care center that is a catchment preterm and term infants in our study and this likely
area for pregnancies affected by complex CHD. All detected a higher incidence of SGA and smaller head
cases had prenatally diagnosed CHD. We excluded 119 circumferences than we would have if we had chosen
out of 500, or roughly 1 in 4, on basis of delivery at a to use the Fenton growth curve for all infants. This
different institution, which introduces selection bias; choice impacts the results comparing SGA to non-SGA
however, it selects for the most high-risk lesions. infants. We did not study or control for nutritional
Lower risk CHD lesions were able to deliver in the status during pregnancy, which could impact BW:PW.
JACC: ADVANCES, VOL. 2, NO. 4, 2023 Desmond et al 9
JUNE 2023:100383 Placental Phenotypes in Congenital Heart Disease

Finally, our small sample size has the potential to FUNDING SUPPORT AND AUTHOR DISCLOSURES
introduce type II errors. Clinically important differ-
ences, such as median birth weight of those with left- Dr Desmond is supported by the T15L013976 (AD) National Library Of
Medicine of the National Institutes of Health under Award Number
sided heart defects being 520 g less than those with
T15LM013976. Dr Afshar has served as a consultant to Mirview; and is
right-sided heart defects, did not meet statistical supported by the National Institute of Health K12HD000849 awarded
significance. to the Reproductive Scientist Development Program by the Eunice
Kennedy Shriver National Institute of Child Health and Human
CONCLUSIONS Development. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National
Institutes of Health. All other authors have reported that they have no
We demonstrate low placental weights in pregnancies relationships relevant to the contents of this paper to disclose.
complicated by CHD with disproportionately low
PW:BW ratios, suggesting that fetal growth was not as ADDRESS FOR CORRESPONDENCE: Dr Yalda Afshar,
compromised as one would expect. The etiology of UCLA Health, 200 Medical Plaza, Suite 430, Los
this phenomenon is not yet well understood but may Angeles, California 90095, USA. E-mail: YAfshar@
provide invaluable insight into the development mednet.ucla.edu.
CHD. An abnormal maternal blood flow pattern could
contribute to a vascular phenotype leading to
abnormal placental growth and pathology, predis- PERSPECTIVES
posing fetuses to developing CHD. Plausibly, early
detection of abnormal placental growth could add
COMPETENCY IN MEDICAL KNOWLEDGE: Understanding
prenatal diagnostic value. More so, antenatal fetal
the implications of placental pathology on fetal growth in-utero
surveillance and delivery planning for fetal growth
and development in the setting of CHD allows for personalized
restriction (FGR) with CHD vs without CHD should be
patient-centered care for a uniquely poised and vulnerable
considered and a consideration for a more personal-
population. Our study demonstrates low placental to birthweight
ized approach to FGR in the setting of CHD, in place of
ratios in pregnancies affected by CHD. We do not yet know
grouping this cohort with all FGR antenatal
whether maternal factors or altered fetal hemodynamics are
management.
responsible for the placental changes.
While we demonstrate preservation of total birth-
weight, the head circumference was proportional,
TRANSLATIONAL OUTLOOK: In utero imaging to trend
suggesting a lack of head sparing, a likely result of
placental and fetal growth through gestation in pregnancies
chronic hypoxia throughout gestation vs a later hit,
affected by CHD would be useful and could influence antenatal
possibly predisposing these neonates to decreased
surveillance, monitoring, and delivery planning. Future studies
growth trajectory and neurodevelopmental delays in
looking at underlying molecular mechanisms that preserve
childhood. Further studies investigating placental
growth and early developmental hallmarks of the fetal-placenta-
growth during pregnancy and following the growth of
cardiac axis are needed to understand disease etiology, inter-
infants and children with a history of abnormal
ventions, and prevention of CHD.
placental size and pathology over time will be
important.

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