Drug Safety in Pregnancy

Until the 2010s, the U.S. Food and Drug Administration (FDA) classified over-the-counter (OTC) and prescription drugs into 5 categories of safety for use during pregnancy (A, B, C, D, X). However, few well-controlled studies of therapeutic drugs have been done in pregnant women. Most information about drug safety during pregnancy is derived from animal studies, uncontrolled studies, and postmarketing surveillance. Consequently, the FDA classification system led to confusion and difficulty applying available information to clinical decisions. In December 2014, the FDA responded by requiring that the pregnancy categories A, B, C, D, and X be removed from the labeling of all drugs.

Instead of categories, the FDA now requires that drug labels provide information about the specific drug in a consistent format (called the final rule, or Pregnancy and Lactation Labeling (Drugs) Final Rule [PLLR]).

The information required by the FDA has 3 subsections:

• Pregnancy: Information relevant to the use of the drug in pregnant women (eg, dosing, fetal risks) and information about whether there is a registry that collects and maintains data on how pregnant women are affected by the drug

• Lactation: Information about using the drug while breastfeeding (eg, the amount of drug in breast milk, potential effects on the breastfed child)

• Females and males of reproductive potential: Information about pregnancy testing, contraception, and infertility as it relates to the drug

The pregnancy and lactation subsections each include 3 subheadings (risk summary, clinical considerations, and data) that provide more detail. The final rule does not apply to nonprescription (over-the-counter) drugs.

During pregnancy, medications are often required to treat certain disorders. In general, when potential benefit outweighs known risks, medications may be considered for treatment of disorders during pregnancy.

Not all medications or other substances in the maternal circulation cross the placenta (transfer) to the fetus. Some drugs that cross the placenta may have a direct toxic effect or a teratogenic effect. Drugs that do not cross the placenta may still harm the fetus by

• Constricting placental vessels and thus impairing gas and nutrient exchange

• Producing severe uterine hypertonia that results in anoxic injury

• Altering maternal physiology (eg, causing hypotension)

For a list of some medications with adverse effects during pregnancy, see table Safety of Selected Drugs in Pregnancy.

Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers (see Absorption). Whether and how quickly a drug crosses the placenta depend on the drug’s molecular weight, extent of its binding to another substance (eg, carrier protein), area available for exchange across the placental villi, and amount of drug metabolized by the placenta. Most drugs with a molecular weight of < 500 daltons readily cross the placenta and enter the fetal circulation. Substances with a high molecular weight (eg, protein-bound drugs) usually do not cross the placenta. One exception is immune globulin G, which may be used to treat disorders such as fetal alloimmune thrombocytopenia or fetal hemachromatosis. Generally, equilibration between maternal blood and fetal tissues takes at least 30 to 60 minutes; however, some drugs do not reach similar concentrations in the maternal and fetal circulation.

A drug’s effect on the fetus is determined largely by fetal age at exposure, placental permeability, maternal factors, drug potency, and drug dosage.

Fetal age affects the type of drug effect:

• Before the 20th day after fertilization: Drugs given at this time typically have an all-or-nothing effect, killing the embryo or not affecting it at all. Teratogenesis is unlikely during this stage.

• During organogenesis (between 20 and 56 days after fertilization): Teratogenesis is most likely at this stage. Drugs reaching the embryo during this stage may result in spontaneous abortion, a sublethal gross anatomic defect (true teratogenic effect), covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life), or an increased risk of childhood cancer (eg, when the mother is given radioactive iodine to treat thyroid cancer); or the drugs may have no measurable effect.

• After organogenesis (in the second and third trimesters): Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues. As placental metabolism increases, doses must be higher for adverse fetal effects to occur.

Maternal factors include those that affect drug absorption, distribution, metabolism, and excretion. For example, nausea and vomiting may decrease absorption of an oral drug.

The overall rate of major structural birth defects in the United States is approximately 3% (1); most malformations result from genetic, environmental, multifactorial, or unknown causes. It is difficult to determine the overall rate of congenital malformations caused by therapeutic drugs. As an example, in one study of 5504 cases of birth defects, only 20% had a definite cause and < 1% of cases with known causes were due to medications (2).

Immunization is as effective in women who are pregnant as in those who are not.

Influenza vaccine is recommended for all pregnant women during influenza season.

The tetanus-diphtheria-pertussis (Tdap) vaccine is recommended for all pregnant women during the third trimester.

The CDC recommends COVID-19 vaccination for all people 5 years and older, including people who are pregnant, breastfeeding, trying to get pregnant, or might become pregnant in the future. Evidence about the safety and effectiveness of COVID-19 vaccination during pregnancy has been growing. These data suggest that the benefits of receiving a COVID-19 vaccine outweigh any known or potential risks of vaccination during pregnancy. (See also CDC: COVID-19 Vaccines While Pregnant or Breastfeeding.)

In August 2023, the US Food and Drug Administration approved use of a respiratory syncytial virus (RSV) vaccine in pregnant individuals between 32 to 36 weeks of gestation, with a warning to avoid use prior to 32 weeks. Clinical trials have found increased rates of preterm birth, preeclampsia in pregnant patients, and low birth weight and jaundice in infants following prenatal administration of RSV vaccine versus placebo; further study is needed to evaluate these potential risks (3).

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, hepatitis B, measles, mumps, plague, poliomyelitis, rabies, typhoid, and yellow fever may be given during pregnancy if risk of infection is substantial.

Live-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 vaccine is another attenuated live-virus vaccine that can potentially infect the fetus; risk is highest between 13 weeks and 22 weeks gestation. This vaccine is contraindicated during pregnancy.

Pregnancy is associated with an increased risk of severe COVID-19. For pregnant patients with early mild to moderate COVID-19, the United States National Institutes of Health (NIH)45), if indicated. The American College of Obstetricians and Gynecologists

Antivirals for influenza

Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are commonly used during pregnancy because the prevalence of clinical depression during pregnancy is high (7 to 12% in one review) (6). Physiologic and psychosocial changes during pregnancy can affect depression (possibly worsening it) and possibly reduce the response to antidepressants. Ideally, a multidisciplinary team that includes an obstetrician and a psychiatric specialist should manage depression during pregnancy.

Pregnant women who are taking antidepressants should be asked about depressive symptoms at each prenatal visit, and appropriate fetal testing should be done. It may include the following:

• A detailed evaluation of fetal anatomy during the second trimester

To reduce the risk of withdrawal symptoms in the neonate, clinicians should consider tapering the dose of all antidepressants to the lowest effective dose during the third trimester. However, the benefits of tapering must be carefully balanced against the risk of symptom recurrence and postpartum depression. Postpartum depression is common, often unrecognized, and should be treated promptly. Periodic visits with a psychiatrist and/or social workers may be helpful.

1. 1. Centers for Disease Control and Prevention (CDC): Update on overall prevalence of major birth defects--Atlanta, Georgia, 1978-2005. MMWR Morb Mortal Wkly Rep 57(1):1-5, 2008.

2. 2. Feldkamp ML, Carey JC, Byrne JLB, Krikov S, Botto LD: Etiology and clinical presentation of birth defects: population based study. BMJ 357:j2249, 2017. Published 2017 May 30. doi:10.1136/bmj.j2249

3. 3. U.S. Food and Drug Administration (FDA): FDA Approves First Vaccine for Pregnant Individuals to Prevent RSV in Infants. FDA News Release, August 21, 2023.

4. 4. Garneau WM, Jones-Beatty K, Ufua MO, et al: Analysis of clinical outcomes of pregnant patients treated with nirmatrelvir and ritonavir for acute SARS-CoV-2 infection. JAMA Netw Open 5(11):e2244141, 2022. Published 2022 Nov 1. doi:10.1001/jamanetworkopen.2022.44141

5. 5. Liggins GC, Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50(4):515-525, 1972.

6. 6. Bennett HA, Einarson A, Taddio A, et al: Prevalence of depression during pregnancy: systematic review [published correction appears in Obstet Gynecol 103(6):1344, 2004]. Obstet Gynecol 103(4):698-709, 2004. doi:10.1097/01.AOG.0000116689.75396.5f

1. The FDA's Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling: This document discusses the change in labeling for pregnancy, which eliminates the pregnancy categories (A, B, C, D, X) and replaces them with more helpful and detailed information. The new labeling requires a summary of the risks of drug use during pregnancy and lactation, data to support that summary, and relevant information to help health care professionals make prescribing decisions and advise women about drug use during pregnancy and lactation.

2. Teratogen Information System: This web site provides resources to help clinicians determine the risks of drugs (and of environmental exposures [eg, vaccines, infections]) during pregnancy. It provides expert information about > 1700 drugs (including 200 of the most frequently prescribed drugs). Clinical and experimental literature is summarized, and based on that information, teratogenic risk is assigned. A subscription is required.