Pregnancy-Induced Pharmacokinetic Changes
pregnancy-induced pharmacokinetic changes that might occur that will affect her medication use and
Important physiologic changes occur in almost all maternal organs during
pregnancy to support the growth and development of the fetus. These physiologic
changes affect the cardiovascular, respiratory, and GI systems; plasma volume, renal
function, and hepatic enzymes can alter the absorption, distribution, metabolism, and
16 Alterations in the pharmacokinetics of drugs are influenced by
mainly by two factors: (a) maternal physiologic changes and (b) the effects of the
Pregnancy-induced changes affecting drug absorption are (a) a decrease in intestinal
motility owing to smooth muscle relaxation by progesterone, resulting in a 30% to
50% increase of gastric and intestinal emptying times; (b) a 40% decrease in gastric
acidity, which increases gastric pH; and (c) altered bioavailability or absorption
attributable to increased incidence of nausea and vomiting. Bioavailability may be
increased for acid-labile drugs and decreased for drugs that require acid medium for
stability. Prolonged gastric and intestinal emptying times may decrease the maximum
) of a drug and the time to reach Cmax
intestinal transit time may increase the area under the curve (AUC) and
bioavailability of a drug. In contrast, pregnancy-induced vomiting may decrease the
amount of drug ingested; it is therefore better to schedule medications during the
evening when the incidence of nausea and vomiting is lower, or to use the rectal
route for drug administration. In summary, the effect of pregnancy on drug absorption
is variable and depends greatly on the physicochemical properties of the drug.
Increased blood flow to the maternal skin, which helps dissipate fetal heat
production, may also increase the absorption of a topically (transdermal)
Changes in protein binding and increased plasma volume can theoretically increase
the apparent volume of distribution (Vd
) of drugs during pregnancy. Plasma volume
increases by 6 to 8 weeks’ gestation and continues to expand to 40% to 50% above
pregnancy volumes by 32 to 34 weeks’ gestation.
16,17 Plasma volume expands even
more with multiple gestations. The total body water (TBW) increases by 8 L; 40% of
this increase can be attributable to the mother and 60% to the fetal–placental unit.
This increase in TBW necessitates larger loading doses of water-soluble drugs (e.g.,
aminoglycosides) because of the increase in Vd. A decrease in the Cmax would be
Plasma albumin concentrations decrease during pregnancy, mostly because of
dilution by the increased plasma volume.
16,17 Albumin concentrations may also be
decreased as a result of decreased synthesis or increased catabolism.
18 These changes in protein binding generally result in
decreased protein binding, increased free fraction (fu
clearance of drugs when clearance is dependent on fu
18 When both fu and intrinsic clearance are increased as is the case
with increased cytochrome P-450 enzyme activity, both the total and free
concentrations are decreased (e.g., phenytoin, phenobarbital).
acid glycoprotein concentrations remain fairly unchanged.
Protein binding, activity of hepatic enzymes, and liver blood flow determine the
hepatic clearance of drugs. Increases in estrogen and progesterone during pregnancy
affect the hepatic metabolism by stimulating or decreasing different hepatic enzymes
of the cytochrome P-450 (CYP) system.
20 CYP3A4 and CYP2D6 activities are
increased during pregnancy, which results in increased metabolism of certain drugs
17,20 On the other hand, CYP1A2, xanthine oxidase, and
N-acetyltransferase activity are decreased, resulting in reduced hepatic elimination
of drugs such as theophylline and caffeine.
19,21 The clearance of caffeine can be
21 Hepatic blood flow as a percentage of the cardiac output is
decreased; however, the absolute rate (in L/minute) remains unchanged.
activity of nonhepatic enzymes (e.g., plasma cholinesterase) is also decreased.
extent of the effect on drug therapy of these hepatic physiologic changes during
pregnancy is difficult to quantify.
The glomerular filtration rate (GFR) begins to rise in the first half of the first
trimester and increases by 50% by the beginning of the second trimester.
blood flow also increases by 25% to 50% early during gestation. As a result, renal
drug excretion (e.g., β-lactams, enoxaparin, digoxin) can increase.
GFR necessitates dosage adjustments up to 20% to 65% for renally excreted drugs
throughout pregnancy to maintain therapeutic concentrations.
output and regional blood flow (e.g., renal blood flow) primarily are caused by
increased stroke volume and increased heart rate, which can increase drug
distribution and drug excretion.
During pregnancy, the serum creatinine concentration is lower because of the
increased GFR, resulting in normal serum creatinine values of 0.3 to 0.7 mg/dLin the
20 A normal value for serum creatinine in nonpregnant
22 Similar changes occur with serum urea nitrogen and uric
acid (UA) concentrations. These differences have important implications when
assessing renal function during pregnancy. A serum creatinine indicative of normal
renal function in a nonpregnant woman may be indicative of renal insufficiency in a
woman who is pregnant in her third trimester.
PLACENTAL–FETAL COMPARTMENT EFFECT
Maternal and fetal drug concentrations are dependent on the amount of drug that
crosses the placenta, the extent of metabolism by the placenta, and fetal distribution
and elimination of drug (Fig. 49-1).
17,20 Diffusion across the placenta is the main
mechanism of drug transfer; nonionized lipophilic substances are more readily
transferred, whereas less lipid-soluble (e.g., ionized) substances less readily cross
17 Highly protein-bound or large-molecular-weight drugs (e.g., heparin
and insulin) do not cross the placenta. Both the immature fetal liver and placenta can
metabolize drugs. Fetal drug accumulation can be problematic secondary to limited
metabolic enzymatic activity along with the concern that approximately half of the
blood flow from the umbilical vein bypasses the fetal liver and goes to the cardiac
17 Another mechanism that can also lead to prolonged
effects of drugs in the fetal compartment is ion trapping. This phenomenon occurs
because the fetal plasma pH is more acidic than the maternal plasma, causing weak
bases (e.g., usually nonionized and lipophilic substances) to diffuse across the
placental barrier and become ionized in the more acidic fetal blood. The net effect is
movement of drugs from the maternal to fetal compartment. This equilibrium between
the maternal and fetal compartments becomes important when therapeutic fetal drug
concentrations are desired (e.g., digoxin therapy for intrauterine fetal arrhythmias).
Drugs are eliminated by the fetus primarily through diffusion back to the maternal
compartment. As the fetal kidney matures, metabolites of drugs are excreted into the
Figure 49-1 FDA Labeling. (Source:
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.htm
S.C.’s thyroid function should be checked regularly to assess the need for an
increase in her levothyroxine dosage. During S.C.’s pregnancy, an increase in the Vd
of thyroid hormones in the vascular, hepatic, and fetal–placental units, an increase in
thyroxine-binding globulin resulting from a rise in estrogen, and an increase in
placental transport and maternal metabolism of thyroxine will occur.
with hypothyroidism who are taking oral thyroid hormones before pregnancy, similar
to S.C., will require an increase in their dosage by about 30% to 50% throughout
their pregnancy and then will need decreased dose adjustments postpartum.
CASE 49-1, QUESTION 5: S.C. is currently 8 weeks pregnant and has become increasingly concerned
regarding the teratogenicity potential of levothyroxine use during pregnancy?
Prevalence of Congenital Malformations
The largest concern with medication use during pregnancy is the risk of congenital
malformations, defined as “structural abnormalities of prenatal origin that are present
at birth and that seriously interfere with viability or physical well-being.”
Congenital anomalies or birth defects are estimated to occur in 120,000 babies born
10 Some drug-induced defects relate to changes in functions or conditions
that are not structural abnormalities (e.g., mental retardation, central nervous system
[CNS] depression, deafness, tumors, or biochemical changes).
congenital anomalies include the four major manifestations of abnormal fetal
development, which include growth alterations, functional deficits, structural
malformations, and fetal death.
The background incidence of birth defects in the general population must be taken
into consideration when interpreting the risk of drug-induced birth defects. The
prevalence of major congenital malformations discovered at or shortly after birth in
the general population is approximately 3%.
25 This number has been derived from
large epidemiologic studies completed during the past several decades and depends
on how terms are defined (e.g., major versus minor congenital malformations), the
thoroughness with which the infant is examined, and how long the exposed person is
25 The collection of malformations data is a complicated task
subject to numerous errors and biases. Some studies examined only “significant
anomalies,” others “major malformations,” whereas still others reported only “live
births” or “single births” or “birth weights greater than 500 g.” Stillbirths and
spontaneous abortions, both often associated with congenital malformations, often
were excluded from epidemiologic data. Neurodevelopmental delays and growth
retardation also are potential long-term effects that will not be diagnosed in the
immediate postpartum period. The prevalence of congenital anomalies is likely
greater than 3% if minor anomalies and long-term adverse effects are considered.
Despite the significant impact of drug-induced birth defects, it is difficult and
unethical to conduct randomized, controlled trials to assess the risk of fetal exposure
to drugs in humans. Much of the data available are derived from epidemiologic
studies, anecdotal experiences in humans, and animal studies. Because birth defects
are species-specific and influenced by many factors including genetic predisposition,
the data must be carefully interpreted and the results not overgeneralized.
Causes of congenital malformations are generally classified into one of five
categories: (a) monogenic origin, (b) chromosomal abnormalities, (c) multifactorial
inheritance, (d) environmental factors, and (e) unknown.
chromosomal-related defects account for approximately 25% of all congenital
malformations in live-born infants (monogenetic, 7.5%–20%; chromosomal, 5%–
24–26 Multifactorial inheritance refers to defects that are polygenic in origin; it
has an environmental component. One surveillance program estimated that this
interaction between genetic and environmental factors causes 23% of defects.
Congenital dislocation of the hip is an example of a defect in this category: The
depths of the acetabular socket and joint laxity are genetically determined, and a
frank breech malposition is one of the environmental factors.
however, the environmental factors in multifactorial inheritance are unknown.
Environmental factors account for approximately 10% of malformations.
include maternal conditions, mechanical effects, chemicals and drugs, and certain
infectious agents. Maternal diseases associated with malformations include diabetes,
phenylketonuria, virilizing tumors, and maternal hyperthermia. About 9% (range,
6.6%–13.0%) of infants of diabetic mothers develop major congenital defects,
primarily consisting of cardiovascular, neural tube, and skeletal malformations.
Mechanical effects, such as intrauterine compression and abnormal cord constriction,
may result in fetal deformations.
Probably, the best known of the teratogenic viruses is rubella, which can cause a
fetal rubella syndrome consisting of cataracts, heart disease, and deafness.
exposure to rubella in the first trimester can cause defects in up to 85% of fetuses.
Cytomegalovirus infection occurs in 0.5% to 1.5% of newborns in the United States,
resulting in deafness and mental retardation in 5% to 10% of these infants.
Characteristics of cytomegalic inclusion disease, the syndrome produced by
cytomegalovirus, include intrauterine growth restriction (IUGR), microcephaly, and
at times chorioretinitis, seizures, blindness, and optic atrophy.
Herpes simplex 1 and 2 and varicella are also associated with malformations.
The protozoan generally accepted as a teratogen is Toxoplasma gondii which may
24 Most infants infected with T. gondii show no symptoms and
develop normally. When toxicity does occur, the anomalies may consist of
hepatosplenomegaly, icterus, maculopapular rash, chorioretinitis, cerebral
calcifications, and hydrocephalus or microcephalous.
presence of T. gondii in cat litter, women should avoid cleaning or touching cat litter
while pregnant. Treponema pallidum (syphilis) can cross the placenta and cause
congenital syphilis as well as other defects, such as hydrocephaly, chorioretinitis,
In utero exposure to syphilis after the fourth month of pregnancy
is associated with higher risk.
The final category, defects of unknown cause, comprises the greatest percentage of
congenital malformations, accounting for about 60% to 65% of the total.
Medication Use in Pregnancy and Teratogenicity
The term teratogen is used to denote an agent that has the potential under certain
exposure conditions to produce abnormal development in the fetus.
have the general perception that use of any medication during a pregnancy can harm
22 This thought may lead to consideration of terminating wanted
pregnancies or withholding necessary drug therapy during the course of the
pregnancy. The extent to which a drug will affect the development of the fetus
depends on the physical and chemical properties of the drug as well as the dose,
duration, route, and timing of exposure and the genetic composition and biologic
susceptibility of the mother and fetus.
33 Numerous drugs have been associated with
congenital anomalies, but only in a few cases has a consensus been reached that a
specific agent is teratogenic. Table 49-1
lists those agents generally considered
or suspected to be proven human teratogens. Not all these teratogens will cause
developmental toxicity with every exposure, however.
Because every pregnancy has the risk of an abnormal outcome regardless of drug
exposure, the objective of evaluating data on drug exposure during pregnancy is to
ascertain whether a particular drug increases the risk of developmental toxicity in the
fetus beyond the background rate. The following basic principles of teratogenicity
should be applied when assessing the potential for teratogenicity of drugs.
After fertilization, the development of the embryo and fetus is divided into three main
stages: pre-embryonic period, embryonic period, and fetal period.
weeks after fertilization or the pre-embryonic period (0–14 days), little is known
about the effects of drugs on human development. Exposure to a teratogenic agent
during this period usually produces an “all or none” effect on the ovum31
either dies from exposure to a lethal dose of a teratogenic drug or regenerates
completely after exposure to a sublethal dose. Some animal studies have suggested,
however, that exposure to some drugs during the preimplantation stage can halt
growth and development before implantation.
36 Although the damage can be repaired,
intrauterine growth may be retarded in the offspring.
During the embryonic period (14–56 days after fertilization), when organogenesis
occurs, the embryo is most susceptible to the effects of teratogens or other
25,31 Exposure during this sensitive period may produce major morphologic
changes (Fig. 49-2). These stages of development differ significantly from other
species, and knowledge of these stages is essential for the interpretation of the
relationship between congenital malformations and drugs. For example, if a specific
drug exposure occurs after the time of organ development, then a structural defect in
that organ is less likely to be caused by that specific drug.
The fetal period (57 days to term) includes most of the stages of histogenesis and
functional maturation, although the latter continues for some time after birth.
structural changes are still possible during histogenesis, but anomalies are more
likely to involve growth and functional aspects such as mental development and
All teratogens follow a toxicologic dose–response curve.
threshold dose below which adverse effects will not occur. The threshold dose is the
dosage in which the incidence of structural malformations, rate of fetal death, growth
restriction, and functional deficits does not exceed the background rate in the general
25 Conversely, developmental toxicity may occur when the fetus is
exposed to doses above the maximum or threshold dose. There may be an increase in
the severity and incidence of malformations when the fetus is exposed to increasingly
higher dosages. For example, the risk for major congenital malformations, including
NTD and minor anomalies, is increased statistically in patients taking valproic acid
dosages greater than 1,000 mg/day during the first trimester.
EXTRAPOLATION FROM ANIMAL STUDIES
In the absence of human trials, data derived from animal studies are used to assess
the level of risk of developmental toxicity in humans. Most newly marketed drugs
often have to rely on preclinical data to develop an estimation of teratogenic risk
based on animal studies until human data become available.
experimental animal data is expressed as multiples of the human dose using plasma
or serum AUC or dose per unit based on body surface area.
have a low risk for teratogenicity if the toxic dose in animals (based on AUC or
mg/m2 comparison) is greater than 10 times the anticipated human dose.
assessment using animal data is more complicated than just considering the dosage
alone. Other major factors, including the effects of metabolism and active
metabolites, species differentiation, route of administration, and type of defects, must
The most potent teratogenic agent will not produce malformations with every
25 The teratogenic potential of some drugs is influenced by the genotype of
both the mother and fetus. Although the effects of known teratogens can be
predictable in the general population, the possibility of individual assessment is
difficult. The same dose of a teratogenic agent exposed at the same gestational
window will produce variable outcomes in different people. Genetic variability can
confer differences in cell sensitivities, placental transport, drug metabolism, enzyme
composition, and receptor binding, which may affect how much active drug will
41 One study showed an increased susceptibility to the teratogenic
effect of phenytoin, most likely caused by elevated levels of oxidative metabolites
(epoxides). These epoxides are normally eliminated from the systemic circulation by
enzymes called microsomal epoxide hydrolase. Women who are homozygous for the
recessive allele produce low levels of epoxide hydrolase, which may expose the
fetus to higher levels of epoxides. These fetuses may be at a higher risk for fetal
Drugs with Suspected or Proven Teratogenic Effects in Humans
Alcohol Growth restriction, mental retardation, mid-facial hypoplasia, renal and cardiac
Androgens (testosterone) Masculinization of female fetus
Pulmonary hypoplasia, hypocalvaria, oligohydramnios, fetal kidney anuria, and
Antithyroid drugs Fetal and neonatal goiter with iodine use; small risk of aplasia cutis with
β-Blockers IUGR and decrease in placental weight in β-blockers with intrinsic
sympathomimetic activity if used in second and third trimesters
Carbamazepine Neural tube defects (NTDs), minor craniofacial defects, fingernail hypoplasia
Cigarette smoking IUGR, functional and behavioral deficits
Cocaine Bowel atresias; heart, limbs, face, and genitourinary tract malformations;
microcephaly; cerebral infarctions; growth restriction
Corticosteroids (systemic) Oral cleft lip and palates if used during organogenesis
Cyclophosphamide Craniofacial, eye, and limb defects; IUGR; neurobehavioral deficits
Diethylstilbestrol Vaginal carcinoma and other genitourinary defects
Lamotrigine Oral cleft lip and cleft palate
Methotrexate CNS and limb malformations
Misoprostol Möbius sequence (high doses) and spontaneous abortions
Nonsteroidal anti-inflammatory
Constriction of the ductus arteriosus, oral clefts, cardiac defects, and possible
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