Anatomical and Physiological Alterations of Pregnancy

Journal of Pharmacokinetics and Pharmacodynamics
https://doi.org/10.1007/s10928-020-09677-1(0123456789().,-volV)(0123456789().
,- volV)
REVIEW PAPER
Anatomical and physiological alterations of pregnancy

Jamil M. Kazma1 • John van den Anker2,3 • Karel Allegaert4,5 • André Dallmann6 •
Homa K. Ahmadzia1
Received: 8 October 2019 / Accepted: 28 January 2020

Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
The extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes
affect almost all organ systems, including the cardiovascular, respiratory, renal, gastrointestinal, and hematologic system.
The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting
signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect
the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In
addition, the teratogenic effects of medications are often extrapolated from animals, which further adds uncertainties.
Unfortunately, pregnant women are only rarely included in clinical drug trials, while doses, regimens, and side effects are
often extrapolated from studies conducted in non-pregnant populations. In this comprehensive review, we present the
changes occurring in each system with its effects on the pharmacokinetic variables. Understanding these physiological
changes throughout normal pregnancy helps clinicians to optimize the health of pregnant women and their fetuses.
Furthermore, the information on pregnancy-related physiology is also critical to guide study design in this vulnerable
‘orphan’ population, and provides a framework to explore pregnancy-related pathophysiology such as pre-eclampsia.
Keywords Pregnancy Physiology Pharmacokinetics Pharmacology Anatomy
Introduction
The amount of drug prescriptions and herbal medicine use

in pregnancy has substantially increased during recent
decades. This change has been more evident during the first
trimester, where the average drug usage has increased by
& Homa K. Ahmadzia
[email protected] 62.5% between 1976 and 2008 [1–4].
The risks of pharmacotherapy in pregnancy are two-
1
Division of Maternal-Fetal Medicine, Department of fold: for the pregnant woman and her fetus; altered phar-
Obstetrics & Gynecology, The George Washington macokinetics and pharmacodynamics may lead to inade-
University School of Medicine and Health Sciences,
Washington, DC, USA quate therapeutic response or maternal toxicity, and
2 maternal–fetal transmission may impair fetal organ for-
Division of Clinical Pharmacology, Children’s National
Hospital, Washington, DC, USA mation or cause fetal demise. Studies on the pharmacoki-
3 netics and safety of drugs during pregnancy are scarce
Pediatric Pharmacology and Pharmacometrics, University of
Basel Children’s Hospital, Basel, Switzerland [4, 5]. Therefore, practitioners need to balance the risks and
4 benefits of each drug before deciding to prescribe.
Department of Development and Regeneration, and
Department of Pharmaceutical and Pharmacological Pharmacokinetics (PK) of a drug includes the processes
Sciences, Leuven, Belgium of drug absorption, distribution, metabolism, and excretion
5
Department of Clinical Pharmacy, Erasmus MC, Rotterdam, (ADME), whereas pharmacodynamics (PD) describes the
The Netherlands mechanism of action and the pharmacological effect(s) of a
6
Clinical Pharmacometrics, Research & Development, drug [6]. Several physiological and anatomical changes
Pharmaceuticals, Bayer AG, Leverkusen, Germany that occur during pregnancy may alter some or all of these
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ADME processes (Table 1). Clinicians often lack the the understanding of a drug’s PK and PD profile in preg-
knowledge on how and why drug disposition is altered in nant women. Yet, although PBPK models have retrospec-
pregnancy, and for that reason, determining the ‘‘appro- tively demonstrated a good predictive performance, in vivo
priate’’ doses to result in appropriate target exposure is concentration data from clinical trials are still needed for
difficult [7]. confirmation and increasing the confidence in these models
The increase in plasma volume, weight gain, and change which requires interdisciplinary collaboration between
in fat composition, as well as other effects on the renal, clinicians and pharmacometricians [14]. In vivo data on
cardiovascular, and gastrointestinal systems play a pivotal fetal exposure are generally limited to single umbilical cord
role in determining the PK variables of a drug. Random- blood sampling at delivery, preferably with paired maternal
ized controlled trials for drugs rarely include pregnant sampling.
women as clinical investigators encounter barriers that Even if coping well with the logistics of conducting a
span across medical, logistical, legal, and ethical arenas randomized controlled trial including pregnant women to
[5, 8]. The doses of most drugs currently used in pregnancy study mechanisms governing a drug’s PK and PD, the
are extrapolated from studies conducted in men and non- effects of the physiological changes in pregnancy will need
pregnant women. Also, post-marketing surveillance and to be taken into consideration in the study design, data
results from retrospective studies are used to determine the collection and interpretation. In this review we provide an
safety profile of drugs [9, 10]. The fact that studies deter- overview of the systems that are affected in pregnancy and
mining teratogenicity of drugs were historically based on how each can contribute to changing certain variables
animal-model studies, adds complexity to extrapolate the related to the pharmacokinetics and pharmacodynamics of
findings to the human species [11]. A recent review showed frequently used drugs during pregnancy.
that less than 0.5% of all registered clinical trials target the
use of pharmaceutical drugs among pregnant women. Most Cardiovascular system
of these clinical trials were conducted in the therapeutic
areas of anesthesia and analgesia, preterm birth and The cardiovascular system undergoes several significant
tocolysis, pre-eclampsia and pregnancy-induced hyperten- anatomical and physiological changes during pregnancy.
sion in descending order [12]. The heart is displaced more laterally and to the upper left
The placenta and potential fetal drug exposure add of the chest by the effect of the progressively elevated
additional complexity to this situation. Various methods diaphragm. Moreover, the left ventricle muscle wall is
can be used to study whether and to which extent a drug enlarged to accommodate the increase in blood volume,
crosses the placenta, such as cell cultures, organ-on-a-chip and as a result, the ejection fraction remains unchanged,
techniques, ex vivo experiments and in silico models [13]. maintaining compliance [15]. In terms of hemodynamic
Ideally, the information obtained from such experiments is variables, the end-systolic volume and end-diastolic vol-
integrated in pharmacometric models, such as physiologi- ume are increased, whereas the end-systolic and end-di-
cally based pharmacokinetic (PBPK) models, to improve astolic pressures remain the same [15]. On cardiac exam,
Table 1 The different pharmacokinetic variables and the physiologic changes that affect these variables during pregnancy
Pharmacokinetic variable Physiologic change that affects it Direction of change [38]
Absorption Nausea and vomiting Decreased

Gastric motility Delayed absorption
Distribution Increase in body weight Increased
Increase in fat deposition Increased for lipophilic drugs
Increase of plasma volume Increased
Decrease of plasma albumin Increased for unbound drugs
Metabolism Change in hepatic drug metabolizing enzymes Variable; depends on specific enzyme
Excretion Increase of hepatic blood flow Increased clearance for high excretion ratio drugs
Increase of renal blood flow Increased clearance for unchanged drugs
Increase of glomerular filtration rate Increased clearance of unchanged drugs
Transport Placental drug metabolism Variable
Placental transport
Accumulation in amniotic fluid
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there is evidence of changes in physiology, including mild During the third trimester, the enlarging size of the
tachycardia, peripheral edema, jugular venous distention, gravid uterus compresses the vena cava [19, 24]. In addi-
and lateral displacement of cardiac apex [16]. As for heart tion, the blood flow to the utero-placental circulation is also
sounds, a louder first sound with the exaggerated splitting at its peak in the third trimester [25]. Both factors con-
of the second sound and a third heart sound can be heard tribute to decreasing the preload and might lead to a
[16]. Also, systolic murmurs can be heard at the left lateral decrease in cardiac output during the third trimester.
sternal border in 90% of pregnant women, and this is However, this is offset by the increase in the resting heart
considered a flow murmur, reflecting the increased blood rate. Moreover, there is preferential blood flow to the
volume passing through the aortic and pulmonary valve uterus and placenta (up to tenfold increase in uterine
[17]. arterial blood flow) near term [26–29]. During labor, the
Cardiac output denotes the amount of work performed cardiac output increases again as a result of increased blood
by the heart and is the product of stroke volume and heart volume accompanying contractions, and the phenomenon
rate. It is affected by the blood volume, heart rate, and of ‘‘auto-transfusion’’ as blood from the utero-placental
autonomic regulation of the heart and vessels, yet the exact unit is shunted back to the maternal circulation immedi-
contribution of each remains controversial [18, 19]. Car- ately after delivery [30].
diac output increases in a non-linear fashion at the begin- The systolic blood pressure remains the same, but
ning of the pregnancy, reaches its peak by early third diastolic blood pressures decrease during pregnancy,
trimester which can be up to 45% in a singleton pregnancy, reaching a nadir at 24–26 weeks and then rises again [23].
then decreases slightly towards term (Table 2) [20, 21]. Blood pressure variations are common, and it is dependent
That early increase is more pronounced in multiple gesta- on the position of the mother and on the systemic vascular
tions [22]. During the first trimester, there is a reduction in resistance which decreases due to the interplay of proges-
the systemic vascular resistance (afterload) stimulating the terone, nitric oxide, endothelin, and estrogen [31]. The
sympathetic nervous system and leading to an increase in mean arterial pressure is determined by the systemic vas-
heart rate. Thus, a reduction in afterload is responsible for cular resistance and cardiac output and serves as an indi-
the increase in cardiac output during the first trimester as cator of organ perfusion. The autoregulation compensates
opposed to the previous attribution to change in stroke the decrease systemic vascular resistance by increasing the
volume [20, 23]. cardiac output [32]. In the case of pulmonary pressures, the
Table 2 Summary of key

System Parameter Direction of change (quantitative) [30, 183, 184]
physiological changes during
pregnancy Cardiovascular Cardiac output Increased (20–45%)
Heart rate Increased (10 to 20 bpm)
Stroke volume Increased (20% to 30%)
Plasma volume Increased (30% to 50%)
Blood pressure
Systolic No change
Diastolic Decreased (10 mmHg)
Respiratory Respiratory rate No change
Residual volume Decreased
Tidal volume Increased (up to 40%)
Minute ventilation Increased (up to 50%)
Functional residual capacity Decreased (20%)
Oxygen consumption Increased (20%)
FEV1 Unchanged
Gastrointestinal Serum albumin Decreased (20% to 40%)
Gastric emptying Prolonged
Hepatic artery blood flow No change
Renal Glomerular filtration rate Increased (up to 50%)
Renal plasma flow Increased (up to 50%)
Total body water Increased (up to 20%, 75% in ECF and 25% in blood)
FEV1 forced expiratory volume at end of 1 s, ECF extracellular fluid
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pulmonary vascular resistance is decreased; however, the There is a controversy as to whether gastric emptying
pulmonary capillary wedge pressure remains the same. and motility are delayed during pregnancy and if that
This is advantageous because it allows to accommodate the impacts the peak serum concentration of oral medication.
increased cardiac output. In case of a pulmonary vascular Some studies showed that the delay is a result of increased
disease during pregnancy, the increased resistance would progesterone and estrogen levels, causing the relaxation of
lead to pulmonary artery hypertension which will not tol- smooth muscle cells in the alimentary tract [48, 49]. This
erate the increased cardiac output and would result in right decrease can often lead to constipation and bloating and
sided heart failure [33]. Supine hypotension is a known cause discomfort to patients in addition to its role in aug-
physiological change that occurs in 10% of women during menting nausea and vomiting during pregnancy resulting
pregnancy as a result of compression of great vessels by the theoretically in a delay in the peak concentration of oral
gravid uterus [34] and must not be mistaken for true drugs in the system. Other studies have noted delayed
hypotension. gastric emptying specifically early in pregnancy [50, 51],
There is an increase in the plasma volume during compared to those showing no delay in motility throughout
pregnancy to accommodate the increased needs of the pregnancy [50, 52]. Absorption of certain medications,
placenta and the fetus [35, 36]. The plasma volume such as acetaminophen, can be affected by delayed gastric
increase is evident as early as 6–8 weeks, and continues to emptying during pregnancy. Furthermore, concomitant use
increase throughout the pregnancy, peaking at 32 weeks of some medications may alter absorption profiles for both
[37]. This also causes an increase in the apparent volume of pregnant and non-pregnant patients [53]. For example, due
distribution of drugs, which implies that hydrophilic drugs to the fact that iron supplements and proton pump inhibi-
would require a higher initial dose and maintenance dose to tors may decrease levothyroxine absorption, patients are
obtain plasma concentration levels that are comparable to instructed not to take them concurrently [54].
those in non-pregnant women [38]. In addition, there is a The physiological effect of pregnancy on liver enzymes
13% decrease in albumin concentration from non-pregnant involved in drug metabolism varies [55, 56]. Several phase
levels by 32 weeks [39], which may cause an increase in I enzymatic activities are either enhanced or decreased. For
the unbound drug concentration; this is very important example, activity of the CYP2D6 enzyme is increased
clinically as drugs which are highly bound would have resulting in increased clearance of fluoxetine, one of its
much higher concentrations of their free form during substrates, which might require dose adjustment to reach a
pregnancy (i.e. digoxin and phenytoin) [28, 30]. In addi- pharmacological effect [57]. Other phase I enzymes, such
tion, the a1-glycoprotein, which is a binding protein for as CYP2A6, 2C9 and 3A4 appear to be induced as well
many basic compounds, slightly decreases during healthy resulting in decreased plasma concentrations of drugs
pregnancy [40]. metabolized via these enzymes, such as cotinine, phenytoin
and midazolam [58–60]. Of note, as illustrated for pheny-
Gastrointestinal system toin [59], a highly protein-bound anticonvulsant, the
increase in total drug clearance can be further enhanced by
Heartburn is common during pregnancy. This can be increases in the free fraction which stems itself from
attributed to the decrease in gastric secretion pH, increase reduced serum albumin levels. On the other hand, a
in the amount of secretions along with a decrease in the decreased activity of drug metabolizing enzyme CYP1A2
lower esophageal sphincter tone [41]. Lower esophageal will result in a decrease in the clearance of caffeine,
sphincter tone decreases as a result of progesterone action olanzapine, and clozapine, and thus dose adjustment is
on smooth muscle cells and is responsible not only for the needed to avoid toxic concentrations [57]. The activity of
heartburn symptom but also contributes to nausea and essential enzymes in the phase II metabolism pathway of
vomiting [42]. Nausea and vomiting of pregnancy is also the liver, including many members of the uridine diphos-
common in around 80% of pregnant patients but with phate glucuronosyltransferase (UGT) 1 family [61] is also
variable severity and presentation [43, 44]. It can present as altered. For example, UGT1A1 appears to be induced by
early as the 2nd week and last up until the 2nd trimester, increased progesterone concentrations during pregnancy,
and in some cases until 37 weeks’ gestation or full term while others, such as UGT2B7 appear to be unchanged
[45–47]. This is important to keep in mind as clinicians [62]. Labetalol, an a-1 and b-adrenoreceptor blocker and a
need to control the symptoms before the absorption of substrate of UGT1A1, is an important drug for treating
medication and bioavailability of oral drugs is altered. For elevated blood pressure in pregnancy (Table 3) [63]. It is
that reason, it is recommended that patients take their believed to have a lower availability due to increased
medication at a time when nausea is minimal to avoid hepatic clearance and first pass excretion, with a
decreased bioavailability of the drug due to lower con- bioavailability averaging 20–40%. Its clearance is depen-
centrations at the absorption site [38]. dent on phase II metabolism that is enhanced during the
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Table 3 Pharmacokinetic variables of selected clinical drugs commonly used pregnancy

Drug Trimester Comparison Overall observed PK changes References
group
VD CL t1/2
Ampicillin 3rd Post-partum :38%à :50%à ;12%à [185]

à
Cefazolin 2nd Post-partum NR : 31 ;35%à [186]
Enoxaparin All Non-pregnant :48%à :49%à :13% [187]
Fluoxetine 3rd Historical NR NR NR [188]
controls
Lamotrigine 3rd Non-pregnant NR :140à NR [189]
Levothyroxine All No grouping NR No change in dose NR [190]
Labetalol 1st/term Post-partum :90% :40%à and 60%à NR [191]
respectively
Nifedipine 3rd Non-pregnant : (Magnitude :308% ; (Magnitude [192]
unspecified) unspecified)
Phenytoin 3rd Post-partum NR :256% NR [59]
PK pharmacokinetics, NR not reported, VD volume of distribution, CL clearance, t1/2 half-life, IV intravenous, IM intramuscular
à
Statistically significant
second and third trimester compared to the post-partum bipolar patients, is one of the renally cleared drugs of
period, which is similar to metabolism of acetaminophen which its clearance is doubled during the third trimester of
during pregnancy [62, 64]. As a consequence, labetalol is pregnancy, with a fast return to pre-pregnancy clearance in
often dosed using twice or three times daily regimens. the first 2 weeks after delivery [71, 72]. Other drugs,
among the many that can be affected, include cephalos-
Renal system porins, piperacillin, atenolol, and digoxin [71]. Although
the change in GFR is uniform as the pregnancy progresses,
During pregnancy, the kidneys are in a state of glomerular it is noted that the renally-excreted drugs are not affected
hyperfiltration since there is increased plasma volume, equally, and that is because of the role of renal transporters
increased effective renal plasma flow (eRPF), and responsible for secretion and reabsorption in the tubules
decreased renal plasma oncotic pressure. The eRPF and changes in the plasma protein binding of some drugs
increases by about 80% at the end of the first trimester as a [73].
result of massive vasodilation from relaxin-mediated nitric Urinalysis in pregnancy may show glucosuria resulting
oxide release [65, 66]. This is clinically manifested by a from increased GFR and impaired resorption at the proxi-
decrease in creatinine levels by an average of 0.4 mg/dL mal tubule level. However, even though it might be
reflecting an increased glomerular filtration rate (GFR), physiologic, the finding of glucosuria always warrants
which can be up to 50% from baseline [67]. At the investigation for pregnancy related diabetes mellitus [74].
beginning of pregnancy, the GFR and eRPF both increase, For the same reason, proteinuria is commonly found on
however, the eRPF declines during late pregnancy while urinalysis during pregnancy with values below the thresh-
the GFR plateaus from the second trimester till birth and old of 300 mg/dL, and any value above that would require
returns to normal levels in the postpartum period [67, 68]. investigational studies to rule out pregnancy-specific
Frequency and urgency, which are common symptoms abnormalities. This cut-off is double that of the non-preg-
seen even early in pregnancy, are believed to be due to nant states [75, 76].
these changes in GFR and eRPF [69]. Later in pregnancy Water and sodium regulation is changed during preg-
frequency and urgency are also secondary to the physical nancy. Despite the rise in all components of the renin-
compression of the bladder by the growing uterus and angiotensin system, resistance to pressor effects contribute
fetus. Serum creatinine is a rapid evaluation of glomerular to a more substantial increase in extracellular volume along
filtration, though a 24-h urine collection sample is the more with water and sodium retention [77]. As a result, plasma
accurate assessment of creatinine clearance [70]. osmolarity is slightly decreased from 290 mOsm/kg to 280
Furthermore, this physiological change can be deemed mOsm/kg and sodium to 136 mEq/L [78]. The body retains
cumbersome when dealing with renally cleared drugs. sodium despite the increased filtration by the kidneys,
Lithium, which is prescribed as a mood stabilizer for
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through upregulation of mechanisms responsible for reab- increased in mid-pregnancy, stimulating the release of
sorption in the distal tubules. insulin-like growth factors which contribute to the
In addition to the physiological changes, there are sev- acromegalic features of some women during pregnancy
eral anatomical modifications to be noted in pregnancy. [95].
The size of the kidney increases by 1 cm at the end of the Pregnancy is a state of hypercortisolism. Corticotropin-
pregnancy, as a result of the increase in vasculature and releasing hormone is synthesized by the placenta and
plasma volume [79]. Moreover, the renal calyces and increased until term [96]. This corticotropin-releasing
ureters are dilated in more than 80% of pregnant women by hormone stimulates the release of both placental and
mid-gestation and more commonly on the right side. pituitary adrenocorticotropic hormone, and characteristi-
Clinically, this is reflected by an increased risk of cally, the former is insuppressible by the low-dose dex-
ascending urinary tract infection from urine stasis and amethasone test [97, 98]. Moreover, the hepatic production
sonographic difficulties in differentiating pathology from of cortisol-binding globulins is upregulated under the effect
normal changes like hydronephrosis [80–82]. of estrogen, ensuring an increased half-life and decreased
hepatic clearance [99]. Consequently, cortisol levels are
Endocrinology system increased, and mainly, a cortisol surge occurs at labor
[100].
The several metabolic changes occurring during pregnancy The total triiodothyronine and tetraiodothyronine levels
are essential for meeting the demands of the growing fetus are increased during pregnancy as a result of an estrogen-
and placenta. By the third trimester, the basal metabolic induced increase in thyroid-binding globulin, decreased
rate is increased by 20% [83]. There exists a state of hepatic clearance and an increase in production of hor-
hyperinsulinism from hyperplasia of islet cells in the pan- mones by the thyroid gland [101, 102]. These hormones
creas along with a state of peripheral insulin resistance. play a pivotal role in fetal neurogenesis. In particular, early
Human placental lactogen and the human placental growth pregnancy levels of thyroid hormones are positively cor-
hormone are thought to contribute to insulin resistance related with cognitive and behavioral development in
[84, 85]. The former acts as an insulin-like and anti-insulin infancy and childhood [103]. Historically, there has been
molecule causing pancreatic cells to secrete insulin, and at some controversy about treating subclinical maternal
the same time inducing peripheral resistance to insulin hypothyroidism and improvement of neurodevelopmental
[84]. This ensures glucose availability for the fetus by outcomes. A recent clinical trial definitively showed that
keeping the postprandial glucose levels elevated [86, 87]. neurodevelopmental outcome through 5 years of age is not
Also, augmentation of hepatic gluconeogenesis in the third significantly improved in the treatment arm [104]. There-
trimester contributes to sustaining the postprandial glucose fore, the American Congress of Obstetrics and Gynecology
levels [88]. Patients with pre-existing insulin resistance or along with the American Thyroid Association do not rec-
diabetes will need to adjust their insulin medication to ommend universal screening of thyroid dysfunction during
higher doses as the pregnancy progresses [89]. pregnancy [105, 106]
Maternal lipid levels are increased under the effect of The thyroid gland is increased in size during pregnancy.
insulin resistance and estrogen [90]. During the first part of In addition, an iodine deficiency state ensues because of the
pregnancy, lipid synthesis is favored, and stored fat is active transport of iodine across the placenta to the fetus,
increased. However, during the third trimester, the fat increased renal excretion and increased consumption of
stored will be used by the mother for energy production iodine by the mother’s thyroid [107]. Despite the increase
[91]. This is important since fatty acids and glycerol serve in total hormones, the free-from remains stable, maintain-
as the nutritive fuel for the mother, whereas glucose and ing a euthyroid status in the pregnant woman [108]. In the
amino acids are preferentially utilized by the fetus [86]. case of hypothyroidism, the dose of levothyroxine, if
In addition to the metabolic status, several hormone- required, should be increased by 30% in early pregnancy to
secreting organs like the pituitary and thyroid undergo meet the maternal demands, and then usually returns to
drastic changes. Estrogen induces hyperplasia and hyper- pre-pregnancy doses postpartum to avoid excessive
trophy of lactotrophs resulting in an enlarged pituitary exogenous thyroid hormone exposure [109].
gland with prolactin levels subsequently increasing as well
[92, 93]. Also, there is a decrease in gonadotrophs from Hematologic changes
increased progesterone and estrogen. However, the corti-
cotrophs and thyrotrophs remain the same [94]. The pla- As discussed earlier, the plasma volume increases in
centa also contributes to the hormonal milieu, by secreting pregnancy nonlinearly and non-monotonically. It increases
its form of the growth hormone synthesized by the syn- by 15% in the first trimester, and more rapidly during the
cytiotrophoblast. The placental growth hormone is second trimester, continuing at a slower rate during the
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third trimester till it plateaus in the few weeks before maybe that the thrombosis of pelvic veins offers an
delivery [110, 111]. As a result, there is an average gain of advantage for facilitating normal postpartum involution, as
30 to 50% (or more than one liter) of blood volume com- anti-thrombin falls and reaches a nadir at 12 h postpartum
pared to non-pregnant levels [112]. This is advantageous before rising again and plateauing at 72 h [132, 133]. Low-
for mother and fetus in response to the increased metabolic molecular-weight-heparin has become the traditional drug
demands of pregnancy, and more importantly, it serves as a of choice for treating venous thromboembolism in preg-
protective buffer to minimize consequences of large vol- nancy. Most women go on twice daily dosing for antico-
ume blood loss encountered during delivery. agulation during pregnancy or postpartum, however, a
As for blood components, the upregulation of erythro- population pharmacokinetic study was able to show effi-
poiesis, induced by erythropoietin hormone from the cacy of once-daily dosing, adjusted to weight, in treatment
maternal kidneys, increases red blood cell (RBC) mass. of venous thromboembolism [134]. Often women are
However, this increase lags behind that of the plasma continued on low-molecular-weight-heparin for a duration
volume resulting in dilutional anemia, or more clinically of at least 6 weeks depending on the indication. Further
known as ‘‘anemia of pregnancy’’ [113]. One advantage of research is needed in the area of optimal anticoagulation
this is that the blood viscosity decreases, with increasing dosing especially for women with active thromboembolism
carrying capacity of the RBCs, ensuring a more efficient who have additional comorbidities such as morbid obesity.
exchange between mother and fetus [114]. The hemoglobin
averages at 12.5 g/dL, and despite physiologic anemia, any Respiratory system
value below 11 g/dL should be investigated [115]. Iron
requirements increase by the latter half of the pregnancy, Increasing progesterone during pregnancy induces a
and it is imperative to start the patient on iron supplements change in the threshold of the respiratory center of the
early on in pregnancy especially in the subset of patients brain, increasing the sensitivity to carbon dioxide, which is
who are anemic at the start of their pregnancy to avoid reflected by the slope of the ventilation curve in response to
maternal and neonatal morbidity, particularly low birth the changes in alveolar carbon dioxide [135, 136]. In
weight or severe hemorrhage [116–118]. addition to that, progesterone also mediates dilation of the
Lymphocytes are higher in pregnancy, averaging around respiratory airways and hyperemia and edema of the
15,000/mm3, and this value is even higher as we approach mucosal surfaces causing nasal congestion, resulting in
labor and delivery [119]. For that reason, diagnosing an rhinitis of pregnancy [137–139]. The effect of estrogen is
infection, especially at the time of delivery like by upregulating the progesterone receptors in the central
chorioamnionitis using the lab values, may be difficult and nervous system, particularly in the medulla and hypotha-
the clinician should always support the lab values with the lamus, where the respiratory control center resides [140].
clinical picture. In addition to looking at the number of Anatomically, the upward displacement of the dia-
band cells or immature cells which are not elevated in phragm as a result of the growing gravid uterus leads to a
pregnancy [30]. Although studies have documented chan- decrease in functional residual capacity [141]. Not only the
ges in platelet count, their level remains within the normal mechanical effect causes this change, but it has been shown
range [120]. It is believed that the drop in platelets is due to that the displacement occurs earlier in pregnancy when the
hemodilution along with an element of hypersplenism from uterus is not enlarged, and it is attributed to the effect of
splenic enlargement, reaching up to 50% during the first progesterone and relaxin on inducing the ligamentous
trimester, and resulting in platelets sequestration attachments of the lower ribs to relax [142]. Other
[121–123]. anatomical changes include an increase in the subcostal
Pregnancy is a hypercoagulable state as evident by angle by 50% by the end of pregnancy from 68.5 to 103.5°,
upregulation of procoagulation factors like all clotting and the transverse diameter of the rib cage increases by
factors, and especially thrombin (factor II) and fibrinogen 2 cm [142]. Eventually, the chest wall compliance
(factor I) [124–126]. Moreover, regulatory proteins decreases by the third trimester due to increased abdominal
responsible for anticoagulation such as protein S and anti- content; however, lung compliance remains the same
thrombin are decreased during pregnancy, and there is [143, 144]. Despite the changes in the anatomy, inspiratory
increased resistance to activated protein C [127]. The result and expiratory maximum pressure values remain preserved
of the interplay between coagulation and anticoagulation throughout pregnancy [141]. Dyspnea is a common pre-
pathway is evident, and this might play a role in decreasing sentation during pregnancy as this physiological dyspnea
blood loss during delivery and afterwards. However, occurs in 50–70% of patients by the third trimester [145].
pregnant women are at increased risk of venous throm- As for the pulmonary function tests, the tidal volume is
boembolism in both pregnancy and postpartum period, and increased by up to 50% (or 650 mL) of the non-pregnant
that is a leading cause of maternal death [128–131]. It is values, but the respiratory rate remains the same.
123
Consequently, the minute ventilation, which is the product from mother to fetus and vice versa [160, 161]. It is well
the tidal volume and respiratory rate follow with the trend established that uncharged, lipophilic drugs with a rela-
and increases to up to 50% [146]. The functional residual tively low molecular weight can pass readily, and the
capacity (FRC) decreases by 20 to 30 percent during amniotic fluid surrounding the fetus can also be considered
pregnancy, as a result of diaphragm elevation decreasing a site for drug distribution and accumulation [6]. However,
outward recoil of the chest. Pregnant women are at risk of newer studies are showing evidence of drug transporters in
hypoxemia during general anesthesia induction as a result the placenta that can be responsible for active transmission
of this decrease in FRC [147, 148]. The expiratory reserve of drugs from the mother to the fetus [162]. In fact, mul-
volume and residual volume make up the FRC, and both tiple drug transporters, such as P-glycoprotein and the
decrease by about 20% [149]. On the other hand, the breast cancer resistance protein, are expressed in the
inspiratory capacity, which is defined as the maximum membrane of the fetal syncytiotrophoblasts and endothe-
inhaled volume from FRC, is increased by 10% and the lium at varying levels during gestation [13].
total lung capacity (a combination of Inspiratory Capacity Although the maternal and fetal blood never meet, many
and FRC) remains the same. These changes do not differ nutrients, waste products, and other molecules can and
between singleton and twin pregnancy [150]. should pass through the brush border (apical) membrane of
In pregnancy there is a state of respiratory alkalosis with syncytiotrophoblast cells at the interface [163]. Three types
maternal pH ranging between 7.42–7.46 [151]. Arterial of drug transport categories are recognized: the complete
blood gases change as a result of the increase in minute transfer (type 1 drugs), which indicates that a drug can
ventilation. The PaO2 is increased from 93 to 106 mmHg, readily cross the placenta, and its concentration will rapidly
and the PaCO2 is decreased from 37 to 30 mmHg by the equilibrate between mother and fetus, or exceeding transfer
end of the third trimester [151–153]. The latter decrease (type 2 drugs) in which greater concentration is reached in
provides an advantageous gradient between mother and the fetus compared to the mother, and the last is incomplete
fetus, allowing CO2 of the fetus to be transferred to the transfer where the drug is unable to pass through the pla-
mother. Fetal acidemia, among other factors, can affect centa completely [164].
local placental transportation of weakly basic compounds Like any other molecule, drugs depend on particular
like the anesthetic drugs bupivacaine and meperidine, and mechanisms to pass through the cell membrane. Simple
can result in the entrapment of these compounds in their diffusion, like in the cases of midazolam and acet-
ionic form [154, 155]. The renal system compensates by aminophen, is the most common mechanism of drug
increasing the excretion of bicarbonate, which its serum transport across the placenta, especially for type 1 drugs.
levels decrease from 23 to 18 mEq/L in late pregnancy Other mechanisms are facilitated diffusion like in the case
[156]. Moreover, the chronic state of respiratory alkalosis of cephalosporins and corticosteroids, and active transport
in pregnancy would shift the oxyhemoglobin curve to the like the case of norepinephrine or dopamine [164]. How-
right, which facilitates the oxygen diffusion across the ever, despite the possibility of drug transport, some medi-
placenta [157]. cations cannot cross the barrier and reach the fetus. An
Volatile anesthetic agents with minimum alveolar con- example of that is doxorubicin, a chemotherapeutic agent
centration (MAC) values more than 1.5 MAC can lead to involved in several hematologic malignancy treatment
dilation of uterine arteries and also reduce uterine tone, and protocols [165]. The transfer of molecules across the pla-
pregnancy has been associated with increased sensitivity to centa is also dependent on size, where drugs with a
these agents. Most induction agents, opioids, and neuro- molecular weight [ 1000 Da (e.g. low-molecular-weight-
muscular blockade can be used in pregnancy. Thiopental is heparin and insulin) usually do not cross the placenta
the most commonly used agent during rapid-sequence [166, 167]. Monoclonal antibodies are a specific group of
intubation in pregnancy with a lower dose than generally drugs used to treat oncological or a variety of inflammatory
used [158]. More recently, propofol is also used as an diseases, or to prevent infections in mother or infant (in-
alternative agent in early pregnancy after showing no ter- fluenza, pertussis).The human placenta has the capacity of
atogenicity in animal studies [159]. active transfer of antibodies from mother to fetus, and this
may result in developmental toxicology [168, 169]. How-
Placenta ever, the extent of transfer may also depend on biochemical
modifications like PEGylation of the Fc fragment of the
The placenta was perceived initially as a protective barrier antibody. Furthermore, there is some controversy over their
at the maternal–fetal interface. It was not until fetal mal- use in pregnant women with chronic conditions where the
formations were attributed to thalidomide exposure in the potential benefits outweigh the risks [170].
early 1960s that physicians started discovering the trans-
port of xenobiotics and other drugs across the placenta
123
Summary of physiological changes and model angiotensin II receptor blocker agents and often these are
applications initiated by a primary care provider at some point beyond
the 6 weeks after delivery. Caution is warranted for using
In addition to the previous changes described (Tables 1, 2), thiazide drugs postpartum if they are breastfeeding due to a
trimester-specific changes are summarized in Fig. 1. It is potential for decreasing breast milk production. The opti-
important to note that these percent changes are compared mal pharmacologic management of diseases in this critical
to pre-pregnancy state. These trimester-specific changes period of recovery from pregnancy is not well studied and
may not be valid in disease states like preeclampsia. it is a new front to discover, as breastfeeding and subse-
Pathophysiological changes during preeclampsia result in quent maturational changes in intestinal absorption of the
an additional increase in body weight due to water reten- infant is an additional factor in the complex model.
tion [171], an additional decrease in albumin [172] and
impaired GFR (about - 15%) when compared to the nor- Application of mechanistic models for pregnancy
mal physiological increase in GFR [173].
During the postpartum period, many of these physio- Several modeling tools may help to shed light on changes
logical changes return back to normal and for some this in pharmacokinetics and pharmacodynamics stemming
return may be gradual. For example, blood volume mainly from the herein discussed physiologic alterations.
decreases rapidly in the first few days under effect of Mechanistic models, such as PBPK models constitute a
diuresis, and continues to decrease gradually over a period strong tool to leverage the accumulated knowledge about
of 8 weeks [174]. Labor increases the cardiac output, along physiologic alterations in pregnant women within a bio-
with its components (heart rate and stroke volume), to an logically plausible framework. For example, previous
additional 80% from pre-labor values, and eventually car- studies have demonstrated that information obtained from
diac output will return to normal within 6–8 weeks of ex vivo perfused placental cotyledons can be integrated in
pregnancy [175]. Postpartum GFR normalizes to pre- PBPK models to successfully predict and quantify fetal
pregnancy estimates within 4 weeks after delivery [173]. exposure to antiretroviral drugs [177, 178]. Other appli-
Moreover, as uterine size decreases, the FRC also returns cations encompass the prediction of a maximum recom-
to normal within 1 to 2 weeks. In cases of chronic medical mended dosage of lithium for pregnant women for
conditions, such as hypertension, women either resume treatment of bipolar disorder [179]; the prediction of a
their pre-pregnancy medications in the postpartum period worst-case scenario for maternal exposure to the toxic
or commonly stay on labetalol or nifedipine (Table 3) metabolite N-acetyl-p-benzoquinone imine (NAPQI) fol-
[176]. There is limited data for safety with breastfeeding lowing acetaminophen intake at various stages throughout
and use of angiotensin-converting enzyme inhibitors and pregnancy [180]; and the prediction of caffeine
60
Relative change [%]
40
20
−20
Body Fat Body Plasma HCT Cardiac AAG Albumin GFR Renal
weight mass water volume output blood
flow
First trimester Second trimester Third trimester
Fig. 1 Percentage Change in Physiological Parameters across the Dallmann et al. to reflect the first, second and third trimester [193].
Three Trimesters. Percent changes have been calculated at 12, 26 and HCT hematocrit, AAG a-1 acid glycoprotein, GFR glomerular
38 weeks based on the individual trend lines as described by filtration rate
123
pharmacokinetics and pharmacodynamics in the fetus to needed to better understand optimal dosing, so that toxic-
support the identification of potential cut-offs for caffeine ities are minimized for the mother and the fetus.
intake during pregnancy [181]. While PBPK models typi-
cally focus on pharmacokinetic and pharmacodynamic
processes at the organ level, biologically based dose–re- Funding The project was funded by NHLBI Grant (K23HL141640).
sponse (BBDR) models shift the focus to a finer biological
scale by incorporating data on biological processes at the Compliance with ethical standards
cellular and molecular level. These models can be used to
study the interactions between compounds and the bio- Conflict of interest The authors declare that they have no conflict of
logical system and to link exposure to a quantifiable bio- interest.
logical response. For example, a BBDR model for the
thyroid endocrine system was recently used to evaluate
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Anatomical and Physiological Alterations of Pregnancy

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Journal of Pharmacokinetics and Pharmacodynamics

Anatomical and physiological alterations of pregnancy

Received: 8 October 2019 / Accepted: 28 January 2020

Keywords Pregnancy Physiology Pharmacokinetics Pharmacology Anatomy

The amount of drug prescriptions and herbal medicine use

Absorption Nausea and vomiting Decreased

Table 2 Summary of key

Table 3 Pharmacokinetic variables of selected clinical drugs commonly used pregnancy

Ampicillin 3rd Post-partum :38%à :50%à ;12%à [185]

25:483–495. https://doi.org/10.2174/138161282566619032013 32. Melchiorre K, Sharma R, Thilaganathan B (2012) Cardiac

Pharm 18:977–979. https://doi.org/10.1177/1060028084018 practice. Clin J Am Soc Nephrol 4:528–534. https://doi.org/10.

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