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Drugs in Pregnancy
Sep 02, 08 Clinical UpdatesThe most commonly used drugs include antiemetics, antacids, antihistamines, analgesics, antimicrobials, diuretics, hypnotics, tranquilizers, and social and illicit drugs.
The FDA classifies drugs into 5 categories of safety for use during pregnancy (see Table 1: Normal Pregnancy, Labor, and Delivery: FDA Categories of Drug Safety During Pregnancy). However, few well-controlled studies of therapeutic drugs have been conducted in pregnant women. Most information about drug safety during pregnancy is derived from animal studies and uncontrolled studies in people (eg, postmarketing reports). During pregnancy, drugs are often required to treat certain disorders (see Table 2: Pregnancy Complicated by Disease: Drugs With Adverse Effects During Pregnancy). Despite widespread concern about drug safety, exposure to therapeutic drugs accounts for only 2 to 3% of all fetal congenital malformations; most malformations result from genetic, environmental, or unknown causes.
Not all maternal drugs cross the placenta to the fetus. Those that do can have a direct toxic or teratogenic effect (for known and suspected teratogens, see Table 2: Normal Pregnancy, Labor, and Delivery: Known or Suspected Teratogens).
Those that do not cross the placenta may still harm the fetus by constricting placental vessels and thus impairing gas and nutrient exchange, by producing severe uterine hypertonia resulting in anoxic injury, or by altering maternal physiology (eg, causing hypotension).
Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers. Whether and how quickly a drug crosses the placenta depend on the drug’s mol wt, extent of its binding to another substance (eg, carrier protein), area available for exchange across the villi, and amount of drug metabolized by the placenta. Most drugs with a mol wt
< 500 daltons readily cross the placenta and enter fetal circulation. Substances with a high mol wt (eg, protein-bound drugs) usually do not cross the placenta. The exception is immune globulin G, which is occasionally used to treat disorders such as fetal alloimmune thrombocytopenia. Generally, equilibration between maternal blood and fetal tissues takes at least 40 min.
Table 1
FDA Categories of Drug Safety During Pregnancy
Category - Description
A - Controlled human studies show no fetal risks; these drugs are the safest.
B - Animal studies show no risk to the fetus and no controlled human studies have been conducted, or animal studies show a risk to the fetus but well-controlled human studies do not.
C - No adequate animal or human studies have been conducted, or adverse fetal effects have been shown in animals but no human data are available.
D - Evidence of human fetal risk exists, but benefits may outweigh risks in certain situations (eg, life-threatening disorders, serious disorders for which safer drugs cannot be used or are ineffective).
X - Proven fetal risks outweigh any possible benefit.
A drug’s effect on the fetus is determined largely by fetal age at exposure, drug potency, and drug dosage. Fetal age affects the type of drug effect:
- Before the 20th day after fertilization: Drugs given at this time may have an all-or-nothing effect, killing the embryo or not affecting it at all. Teratogenesis is not likely during this stage.
- During organogenesis (between 20 and 56 days after fertilization): Teratogenesis is most likely at this stage. Drugs reaching the embryo at this stage may result in abortion, a sublethal gross anatomic defect (true teratogenic effect), or covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life), or the drugs may have no measurable effect.
- After organogensis (in the 2nd and 3rd trimesters): Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues.
Vaccines: Immunization is as effective in women who are pregnant as in those who are not. Influenza vaccine is recommended for all pregnant women in the 2nd or 3rd trimester during influenza season. Other vaccines should be reserved for situations in which the woman or fetus is at significant risk of exposure to a hazardous infection and risk of adverse effects from the vaccine is low. Vaccinations for cholera, hepatitis A and B, measles, mumps, Plague, poliomyelitis, rabies, tetanus-diphtheria, typhoid, and yellow fever may be given during pregnancy if risk of infection is substantial.
Known or Suspected Teratogens ACE inhibitors - Methimazole Alcohol - Methotrexate Aminopterin - Norprogesterones Androgens - Penicillamine Carbamazepine - Phenytoin Coumarins - Radioactive iodine Danazol - Streptomycin Diethylstilbestrol - Tetracycline Etretinate - Thalidomide Isotretinoin - Trimethadione Lithium - ValproateLive-virus vaccines should not be given to women who are or may be pregnant. Rubella vaccine, an attenuated live-virus vaccine, may cause subclinical placental and fetal infection. However, no defects in neonates have been attributed to rubella vaccine, and women vaccinated inadvertently during early pregnancy need not be advised to terminate pregnancy based solely on theoretical risk from the vaccine. Varicella is another attenuated live-virus vaccine that can potentially infect the fetus; risk is highest between 13 wk and 22 wk gestation. This vaccine is contraindicated during pregnancy. Vitamin A: In the amount typically present in prenatal vitamins (5000 IU/day), vitamin A has not been associated with teratogenic risk. However, doses > 10,000 IU/day during early pregnancy may increase risk of congenital malformations. Social and illicit drugs: Cigarette smoking and use of alcohol during pregnancy can cause significant problems in fetuses and neonates. Although marijuana’s main metabolite can cross the placenta, recreational use of this drug does not appear to consistently increase risk of congenital malformations, fetal growth restriction, or postnatal neurobehavioral abnormalities. Many mothers of children with congenital heart defects used amphetamines during pregnancy, suggesting a possible teratogenic association. Women who used cocaine during pregnancy have had perinatal complications, including abruptio placentae and stillbirth; however, no consistent teratogenic effects have been shown. Whether consuming large amounts of caffeine can increase risk of perinatal complications is unclear. Consuming caffeine in small amounts (eg, 1 cup of coffee/day) appears to pose little or no risk to the fetus, but some data, which did not account for tobacco or alcohol use, suggest that consuming large amounts (> 7 cups of coffee/day) increases risk of stillbirths, preterm deliveries, low birth weight, and spontaneous abortions. Decaffeinated beverages theoretically pose little risk to the fetus. Use of the dietary sugar substitute aspartame during pregnancy is often questioned. The most common metabolite of aspartame, phenylalanine, is concentrated in the fetus by active placental transport; toxic levels may cause mental retardation. However, when ingestion is within the usual range, fetal phenylalanine levels are far below toxic levels. Thus, moderate ingestion of aspartame (eg, no more than 1 liter of diet soda per day) during pregnancy appears to pose little risk of fetal toxicity. However, in pregnant women with phenylketonuria, intake of phenylalanine and thus aspartame is prohibited. Haywood L. Brown, MDAlso in this section:
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