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Drugs and Environmental Agents in Pregnancy and Lactation: Teratology and Epidemiology
Key Points
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The critical period of organ development extends from day 31 to day 71 after the first day of the LMP.
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Infants of epileptic women taking certain anticonvulsants, such as valproic acid, have double the rate of malformations of unexposed infants. The risk of fetal hydantoin syndrome is less than 10%.
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The risk of malformations after in utero exposure to isotretinoin is 25%, and an additional 25% of infants will develop mental retardation.
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Heparin is the drug of choice for anticoagulation during pregnancy except for women with artificial heart valves, who should receive coumadin despite the 5% risk of warfarin embryopathy.
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Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can cause fetal renal failure in the second and third trimesters, leading to oligohydramnios and hypoplastic lungs.
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Vitamin B 6 25 mg three times a day is a safe and effective therapy for first-trimester nausea and vomiting. Doxylamine 12.5 mg three times a day is also effective in combination with B 6 .
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Most antibiotics are generally safe in pregnancy, although aminoglycosides are known to be ototoxic to the fetus. Trimethoprim may carry an increased risk in the first trimester, and tetracyclines taken in the second and third trimesters may cause tooth discoloration.
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Aspirin in analgesic doses inhibits platelet function and prolongs bleeding time, increasing the risk of peripartum hemorrhage but is not associated with congenital defects.
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Fetal alcohol syndrome occurs in infants of mothers who drink heavily during pregnancy. A safe level of alcohol intake during pregnancy has not been determined.
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Cocaine has been associated with increased risk of miscarriage, abruptio placentae, and congenital malformations, in particular, microcephaly and limb defects.
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Most drugs are safe during lactation because subtherapeutic amounts, approximately 1% to 2% of the maternal dose, appear in breast milk. Short-term (<2 days) use of codeine is safe during breastfeeding.
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Only a small amount of prednisone crosses the placenta, so it is the preferred corticosteroid for most chronic maternal illnesses such as lupus. In contrast, betamethasone and dexamethasone readily cross the placenta and are preferred for acceleration of fetal lung maturity.
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Exposure to high-dose ionizing radiation at any stage during gestation causes microcephaly and mental retardation Diagnostic exposures below 5 rads after 12 weeks of gestation do not pose increased teratogenic risks.
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Lead levels in blood have decreased in recent years in all except some immigrant populations. Blood levels below 25 μg/dL in women of reproductive age minimizes the risk of fetal growth restriction during pregnancy.
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Mercury in high levels deleteriously affects the fetal nervous system. For this reason pregnant and nursing women should avoid shark, swordfish, king mackerel, and tilefish. Exposures to mercury can further be limited by restricting ingestion of certain other seafood (shrimp, canned tuna, salmon, pollock, catfish) to 12 oz/week.
Overview
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Virtually all drugs cross the placenta to some degree, with the exception of large molecules such as heparin and insulin but also vaccines.
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The incidence of major malformations in the general population is 2% to 3%.
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The classic teratogenic period is from day 31 after the last menstrual period (LMP) in a 28-day cycle to 71 days from the LMP. During this critical period, organs are forming, and teratogens may cause malformations that are usually overt at birth.
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Before day 31, exposure to a teratogen produces an all-or-none effect.
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FDA categories lists five categories of labeling for drug use during pregnancy. The risk increases from A (controlled studies show no risk) to X (contraindicated during pregnancy). These categories were designed for prescribing physicians and not to address inadvertent exposure. For example, isotretinoin and oral contraceptives are both category X based on lack of benefit for oral contraceptives during pregnancy, yet oral contraceptives do not have any teratogenic risk with inadvertent exposure.
Basic Principles of Teratology
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Wilson’s six general principles of teratogenesis provide a framework for understanding how structural or functional teratogens may act.
Genotype and Interaction With Environmental Factors
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The first principle is based on the concept that susceptibility to a teratogen depends on the genotype of the conceptus and on the manner in which the genotype interacts with environmental factors. Not all fetuses exposed to a specific drug at a similar dose and gestational age will develop congenital malformations.
Timing of Exposure
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The second principle is that susceptibility of the conceptus to teratogenic agents varies with the developmental stage at the time of exposure. Most structural defects occur during the second to the eighth weeks of development after conception, during the embryonic period.
Mechanisms of Teratogenesis
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The third principle is that teratogenic agents act in specific ways—that is, via specific mechanisms —on developing cells and tissues in initiating abnormal embryogenesis (pathogenesis).
Manifestations
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The fourth principle is that irrespective of the specific deleterious agent, the final manifestations of abnormal development are malformation, growth restriction, functional disorder, and death.
Agent
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The fifth principle is that access of adverse environmental influences to developing tissues depends on the nature of the influence ( agent ).
Dose Effect
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The final principle is that manifestations of abnormal development increase in degree from the no-effect level to the lethal level as dosage increases.
Medical Drug Use
Effects of Specific Drugs
Estrogens and Progestins
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Studies have not confirmed any teratogenic risk for oral contraceptives or progestins.
Androgenic Steroids
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Androgens may masculinize a developing female fetus.
Spermicides
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A meta-analysis of reports of spermicide exposure has concluded that the risk of birth defects is not increased.
Antiepileptic Drugs
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Women with epilepsy who take antiepileptic drugs (AEDs) during pregnancy have approximately double the general population risk of malformations in offspring.
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Valproic acid and carbamazepine each carry approximately a 1% risk of neural tube defects (NTDs) and other anomalies.
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Fewer than 10% of offspring show the fetal hydantoin syndrome, which consists of microcephaly, growth deficiency, developmental delays, mental retardation, and dysmorphic craniofacial features.
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Valproate should not be used as a first-choice drug in women of reproductive age.
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Of 1532 infant exposures to newer-generation antiepileptic drugs, 1019 were to lamotrigine, and 3.7% presented with major birth defects. Of 393 infants exposed to oxcarbazepine, the rate was 2.8%, and for 108 exposed to topiramate, the rate was 4.6%. None of these differences were statistically different from controls.
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Most authorities agree that the benefits of AEDs during pregnancy outweigh the risks of discontinuation of the drug if the patient is first seen during pregnancy.
Isotretinoin
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Isotretinoin is a significant human teratogen.
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The risk of structural anomalies in patients studied prospectively is now estimated to be about 25%, and an additional 25% have mental retardation alone.
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In 88 pregnancies prospectively ascertained after discontinuation of isotretinoin, no increased risk of anomalies was noted.
Vitamin A
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Cases of birth defects have been reported after exposure to levels of 25,000 IU or more of vitamin A during pregnancy.
Psychoactive Drugs
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No clear risk has been documented for most psychoactive drugs with respect to overt birth defects.
Lithium
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A prospective study of 148 women exposed to lithium in the first trimester showed no difference in the incidence of major anomalies compared with controls. Polyhydramnios may be a sign of fetal lithium toxicity.
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Discontinuation of lithium may pose an unacceptable risk of increased morbidity in women who have had multiple episodes of affective instability. These women should be offered appropriate prenatal diagnosis with ultrasound, including fetal echocardiography.
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We recommend that women exposed to lithium be offered a detailed fetal ultrasound examination including fetal echocardiography.
Antidepressants
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No increased risk of major malformations has been found after first-trimester exposure to fluoxetine in several studies. However, one study showed a twofold increased risk of ventricular septal defects and two other studies found an increased risk of cardiac defects after exposure to paroxetine.
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When considering the use of antidepressant drugs during pregnancy, it should be noted that among women who maintained their medication throughout pregnancy, 26% relapsed compared with 68% who discontinued medication.
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Fetal alcohol spectrum disorders are 10 times more common in offspring exposed to selective serotonin reuptake inhibitors than in unexposed offspring.
Anticoagulants
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Warfarin embryopathy occurs in about 5% of exposed pregnancies and includes nasal hypoplasia, bone stippling seen on radiologic examination, ophthalmologic abnormalities including bilateral optic atrophy, and mental retardation.
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The risk for pregnancy complications is higher when the mean daily dose of warfarin is more than 5 mg.
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Because heparin does not have an adverse effect on the fetus, it should be the drug of choice for patients who require anticoagulation during pregnancy, except in women with artificial heart valves.
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Women with mechanical heart valves, especially the first-generation valves, require warfarin anticoagulation because heparin is neither safe nor effective.
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Low-molecular-weight heparins may have substantial benefits over standard unfractionated heparin. Enoxaparin is cleared more rapidly during pregnancy, so twice-daily dosing is advised.
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