Pregnancy Safety
Complete guide to FDA pregnancy categories, safe medications, medicines to avoid, and the updated PLLR labeling system.
The legacy FDA system (still widely used for older medicines) classifies medications by fetal risk level.
Category A
Minimal Risk
Adequate and well-controlled studies in humans have failed to demonstrate a risk to the fetus in the first trimester, and there is no evidence of risk in later trimesters.
Examples:
Category B
Probably Safe
Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women.
Examples:
Category C
Use with Caution
Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans. Benefits may warrant use despite potential risks.
Examples:
Category D
Known Fetal Risk
There is positive evidence of human fetal risk based on adverse reaction reports or studies, but potential benefits may warrant use in pregnant women despite potential risks.
Examples:
Category X
Contraindicated
Studies in animals or humans have demonstrated fetal abnormalities, or positive evidence of fetal risk exists, and the risks clearly outweigh any possible benefit.
Examples:
In December 2014, the FDA finalized the Pregnancy and Lactation Labeling Rule (PLLR), which became effective June 30, 2015. For medicines approved after this date, the old letter categories were replaced with a narrative labeling system that provides more nuanced risk information.
The new PLLR labeling includes three subsections:
The first trimester (weeks 1–12) represents the period of organogenesis — when major organ systems form. This is the period of highest teratogenic risk for most medications. However, some medicines are harmful throughout pregnancy or in specific trimesters.
The Pregnancy and Lactation Labeling Rule (PLLR), implemented in 2015, replaced the simple letter category system with more detailed narrative labeling. The PLLR organizes pregnancy-related information into three subsections: Pregnancy (8.1), Lactation (8.2), and Females and Males of Reproductive Potential (8.3). This expanded format provides clinicians with more nuanced information including:
While the PLLR provides better information, it requires more interpretation than simple letter categories. Both systems will likely remain in use during the transition period — older medications still display letter categories while newer drugs use PLLR narratives.
First Trimester (Weeks 1-12): The most critical period for fetal development. All major organ systems form during this time, making the embryo particularly vulnerable to teratogens. Many medications must be avoided or used with extreme caution during this period. Common teratogens include certain anticonvulsants (valproic acid, phenytoin), warfarin, ACE inhibitors, retinoids, and lithium. Even seemingly minor exposures during this critical window can have major consequences.
Second Trimester (Weeks 13-26): Organ formation is largely complete, but continued development occurs. Many medications considered unsafe in the first trimester may be acceptable now. However, some medications affect later development — for example, ACE inhibitors can cause fetal renal damage when used in second or third trimester. This trimester is often when chronic medical conditions require active management.
Third Trimester (Weeks 27-Delivery): Continued growth and final preparation for birth. Specific concerns include NSAIDs (premature closure of ductus arteriosus after 20 weeks), benzodiazepines (neonatal sedation and withdrawal), opioids (neonatal abstinence syndrome), SSRIs (poor neonatal adaptation), and various medications affecting labor and delivery.
NSAIDs and Pregnancy: The FDA strengthened warnings in 2020 about NSAID use after 20 weeks gestation due to risks of low amniotic fluid and kidney problems in the fetus. NSAIDs after 30 weeks can cause premature closure of the ductus arteriosus and other complications. Acetaminophen remains the preferred analgesic during pregnancy, though recent research raises questions about possible developmental effects of frequent prenatal acetaminophen use.
Antidepressants and Pregnancy: Depression during pregnancy is itself a serious concern, with untreated depression increasing risks of preterm birth, low birth weight, and postpartum depression. SSRIs are most commonly used during pregnancy. Sertraline has the most safety data. Paroxetine is generally avoided due to cardiac defect concerns. SSRI use late in pregnancy can cause neonatal adaptation syndrome (transient symptoms in newborns).
Antibiotics and Pregnancy: Many antibiotics are safe during pregnancy. Penicillins, cephalosporins, and azithromycin are commonly used. Tetracyclines must be avoided (cause discoloration of fetal teeth and bone growth issues). Fluoroquinolones are typically avoided in pregnancy. Trimethoprim-sulfamethoxazole should be avoided in first trimester (folate antagonism) and near term (hyperbilirubinemia risk).
Antiepileptic Drugs and Pregnancy: Valproic acid is the most teratogenic anticonvulsant, with up to 11% rate of major malformations including neural tube defects. Phenytoin, carbamazepine, and phenobarbital carry significant teratogenic risks. Lamotrigine and levetiracetam have lower teratogenic risk and are often preferred in women of reproductive age. The dilemma: uncontrolled seizures also pose serious risks to both mother and fetus.
Diabetes Medications and Pregnancy: Type 1 and pre-existing type 2 diabetes require careful management during pregnancy. Insulin is the preferred treatment as it does not cross the placenta. Metformin has been studied and appears safe, with many guidelines now supporting its use in pregnancy. Other oral diabetes medications generally lack adequate safety data in pregnancy.
Hypertension Medications and Pregnancy: ACE inhibitors and ARBs are contraindicated due to fetal renal damage. Beta-blockers (especially labetalol), methyldopa, and calcium channel blockers (nifedipine) are commonly used. Severe pre-eclampsia and pregnancy-induced hypertension require careful management with multidisciplinary care.
Pregnancy exposure registries collect data on outcomes of women exposed to specific medications during pregnancy. These registries provide critical real-world safety data that informs prescribing decisions. Women taking these medications during pregnancy are encouraged to enroll in registries to contribute to the knowledge base. Notable registries include the Antiepileptic Drug Pregnancy Registry, National Pregnancy Registry for Atypical Antipsychotics, and registries for specific HIV medications, biologics, and other drugs.
Medication use during breastfeeding requires consideration of drug transfer into breast milk, infant exposure, and potential effects on the nursing infant. The LactMed database (a free National Library of Medicine resource) provides comprehensive information on drug-breastfeeding compatibility. Most medications transfer into breast milk in some amount, but many are still compatible with breastfeeding.
Factors affecting drug transfer to breast milk include molecular weight, lipid solubility, protein binding, pKa, and maternal plasma concentration. The relative infant dose (RID) — the dose received by the infant relative to the maternal dose adjusted for body weight — helps assess safety. RID below 10% is generally considered acceptable, while higher RIDs require careful evaluation.
Some medications are contraindicated during breastfeeding (cytotoxic chemotherapy, radiopharmaceuticals, lithium with certain limitations). Many medications previously considered contraindicated are now known to be compatible with breastfeeding when used appropriately. Consultation with healthcare providers familiar with lactation pharmacology helps individual decision-making.
Women on chronic medications who plan pregnancy benefit from preconception medication review. This evaluation considers:
Vaccines deserve specific attention. Some vaccines are recommended during pregnancy (Tdap, influenza, COVID-19), while others are contraindicated (MMR, varicella, live attenuated influenza). Maternal vaccination provides important protection for both mother and infant through transferred maternal antibodies. The CDC and ACOG provide detailed pregnancy vaccine recommendations.
Untreated mental illness during pregnancy carries significant risks: increased preterm birth, low birth weight, postpartum depression, impaired maternal-infant bonding, and in severe cases, suicide. Treatment decisions must weigh these risks against potential medication risks. Many psychiatric medications can be safely continued during pregnancy with appropriate monitoring. Psychotherapy provides important non-medication treatment options. Multidisciplinary care including psychiatry, obstetrics, and pediatrics optimizes outcomes.
Alcohol, tobacco, and illicit substance use during pregnancy carry significant risks. Alcohol causes fetal alcohol spectrum disorders (FASD) — no amount is considered safe. Tobacco use increases preterm birth, low birth weight, and SIDS risk. Opioid use can cause neonatal abstinence syndrome. Cannabis use during pregnancy is increasingly common but has documented developmental risks. Cocaine, methamphetamine, and other stimulants pose serious risks. Comprehensive treatment for substance use disorders, often including medication-assisted treatment, is available for pregnant women.
The FDA replaced the A/B/C/D/X system with the Pregnancy and Lactation Labeling Rule (PLLR) for medicines approved after June 2015. However, older medicines still use the letter system, and the categories remain widely referenced in clinical practice.
Generally considered safe: acetaminophen (for pain/fever), antacids (calcium-based), most prenatal vitamins. Generally avoid: ibuprofen (NSAIDs, especially after 20 weeks), aspirin (high doses), most antihistamines (first trimester). Always consult your OB-GYN.
Yes. Category D means there is evidence of fetal risk, but the benefits may outweigh the risks in certain situations — for example, seizure medications (phenytoin) in a mother with epilepsy. The prescriber makes an individualized risk-benefit decision.
Many antidepressants are Category C. SSRIs have been studied extensively. There is some evidence of neonatal adaptation syndrome with third-trimester SSRI use (not birth defects). Untreated severe depression also carries risks. This is a conversation to have with your psychiatrist and OB.