Pregnancy and drugs
Prescribing for pregnant patients requires balancing the risk of drug exposure to the foetus against the risk of untreated maternal disease. Many conditions (epilepsy, hypertension, diabetes, mental health) require ongoing treatment through pregnancy. This guide covers the FDA PLLR labelling system, teratogenic mechanisms, trimester-specific PK changes, high-risk drugs, and breastfeeding safety. Key resources: NCBI drug use in pregnancy review ↗ and the FDA PLLR Final Rule ↗.
FDA Pregnancy and Lactation Labelling Rule (PLLR)
The PLLR (effective June 2015) ↗ replaced the letter system (A/B/C/D/X) with narrative risk summaries and requires the following subsections in labelling (8.1–8.3):
Pregnancy
Risk summary (human data, animal data, background risk); clinical considerations (dose adjustments, maternal and foetal/neonatal adverse reactions); data section. Must include information about pregnancy exposure registries if available.
Lactation
Risk summary (presence of drug in human milk, effects on breastfed infant, effects on milk production); clinical considerations (minimising infant exposure — timing of dose, pumping and discarding milk); data. See the NLM LactMed database ↗ for drug-specific lactation data.
Females and Males of Reproductive Potential
Pregnancy testing requirements, contraception requirements, infertility effects. Required for drugs known to affect reproduction or development (e.g. REMS programmes: isotretinoin iPLEDGE, thalidomide STEPS).
All approved drug labelling is accessible via DailyMed ↗. For drugs approved before the PLLR, manufacturers must update labelling at the next significant revision.
Teratogenicity — mechanisms and risk windows
A teratogen is any agent that causes structural or functional abnormalities in the developing embryo or foetus. The MotherToBaby (OTIS) ↗ fact sheet service and the CDC birth defects programme ↗ are key population-level resources.
"All or nothing": exposure causes embryo death or complete recovery (no structural defects). Few drug exposures are clinically relevant in this window.
Highest risk for structural teratogenesis. Each organ system has a critical developmental window. Heart: weeks 3–6. Neural tube: weeks 3–4. Limbs: weeks 4–7. Palate: weeks 6–9.
Lower risk for gross malformation (organogenesis complete). Still vulnerable to: functional teratogenesis (neurodevelopment), growth restriction, foetotoxicity (ACE inhibitors), and premature labour (NSAIDs).
Mechanisms of teratogenesis
Retinoic acid receptors mediate isotretinoin teratogenicity — RAR-β activation disrupts cranial neural crest migration.
Methotrexate, trimethoprim, and valproate inhibit folate metabolism → neural tube defects. Periconceptional folic acid supplementation (400–4000 µg/day) reduces NTD risk. CDC folic acid ↗.
ACE inhibitors and ARBs inhibit the foetal renin-angiotensin system in T2/T3 → foetal renal tubular dysgenesis, oligohydramnios, limb contractures, skull hypoplasia.
Cocaine, misoprostol, and some vasoactive drugs can disrupt foetal blood supply → limb reduction defects, intestinal atresia via ischaemia.
PK changes across trimesters
| PK parameter | Change in T3 | Clinical consequence | Example |
|---|---|---|---|
| GFR / renal clearance | ↑ 40–60% | ↑ clearance of renally eliminated drugs → lower Css | Lamotrigine: dose may double; amoxicillin: shorter t½ |
| Plasma volume | ↑ 40–50% | ↑ Vd for hydrophilic drugs → dilutional ↓ Cmax | Iron supplementation needs increase; heparin Vd increases |
| CYP3A4 | ↑ ~35% | ↑ clearance of CYP3A4 substrates → subtherapeutic levels | Nifedipine, indinavir, midazolam: lower AUC in late pregnancy |
| CYP2D6 | ↑ ~35% | ↑ metabolism of antidepressants, beta-blockers | Paroxetine, metoprolol: may need dose increase |
| CYP1A2 | ↓ ~30% | ↓ clearance of CYP1A2 substrates → ↑ exposure | Clozapine, caffeine: accumulate in pregnancy |
| Albumin (haemodilution) | ↓ ~15% | ↑ free fraction of highly bound drugs | Phenytoin: total level falls but free level may be unchanged |
| Gastric emptying | ↓ (T1 nausea) | ↑ tmax, ↓ Cmax for oral drugs in T1 | Iron tablets: slower absorption; antiemetics needed |
All changes reverse within 1–4 weeks postpartum — dose reductions may be needed immediately after delivery to avoid toxicity (e.g. lamotrigine levels rise rapidly post-delivery → seizure risk if dose not reduced).
High-risk drug classes in pregnancy
Isotretinoin (Accutane)
Highly potent teratogen — causes craniofacial, cardiac, CNS, and thymic defects in virtually all exposed embryos. iPLEDGE REMS requires 2 forms of contraception, monthly negative pregnancy tests, and counselling. FDA iPLEDGE ↗.
ACE inhibitors / ARBs
Foetal renin-angiotensin system inhibition in T2/T3 → foetal renal tubular dysgenesis, oligohydramnios, neonatal renal failure, skull/limb hypoplasia. May be used in T1 if no suitable alternative, with close monitoring. NCBI ACE inhibitor fetopathy review ↗.
Antiepileptics (AEDs)
Valproate: highest NTD risk (1–2%), also autism risk — avoid in females of childbearing potential when possible (EMA restriction). Lamotrigine: dose requires monitoring (CLR doubles in T3); generally preferred in T1 compared to valproate. Levetiracetam: growing safety data, now commonly used. NCBI AED pregnancy registry data ↗.
NSAIDs
NSAIDs in T3 (especially after 20 weeks) → premature closure of the ductus arteriosus and foetal renal dysfunction → oligohydramnios. FDA NSAID warning ↗: avoid after 20 weeks unless no alternative. Occasional use in T1/T2 generally considered low risk.
Drug transfer in breastfeeding
The relative infant dose (RID) is the primary metric for assessing infant exposure:
Most antihypertensives (nifedipine, labetalol), many antibiotics (amoxicillin, cephalexin), SSRIs with low RID (sertraline ~0.5%), short-acting NSAIDs (ibuprofen ~0.1%), most antihistamines.
Opioids (codeine — URM risk; prefer short-term morphine at lowest dose), lithium (RID ~17-30%), clozapine (agranulocytosis risk in infant).
Amiodarone (iodine load; long t½), cytotoxic chemotherapy (maternal plasma levels fluctuate; discontinue breastfeeding during active treatment), isotretinoin, radioiodine (I-131).
The NLM LactMed ↗ (free) and e-lactancia.org ↗ (Spanish resource, English available) provide evidence-based drug-by-drug lactation assessments.
Pregnancy exposure registries
Pregnancy exposure registries (PERs) prospectively collect data from women who take specific drugs during pregnancy. They are the primary source of human teratogenicity data for newer drugs. The FDA pregnancy registry list ↗ maintains an index of active registries. Key examples:
- North American AED Pregnancy Registry ↗ — antiepileptic drug safety
- MotherToBaby (OTIS) ↗ — broad drug and disease exposure registry; patient helpline
- OTIS — Organisation of Teratology Information Specialists ↗
- Bayer pregnancy registries (rivaroxaban, others) ↗
Frequently asked questions
What happened to the old FDA Pregnancy Categories (A, B, C, D, X)?
FDA replaced the A/B/C/D/X letter system in 2015 with the Pregnancy and Lactation Labelling Rule (PLLR). The new labelling provides narrative information in three subsections: Pregnancy (including a pregnancy exposure registry), Lactation, and Females and Males of Reproductive Potential. The new system is more informative than the oversimplified letter categories, which were widely misinterpreted as a linear safety ranking.
Is it safe to breastfeed while taking medications?
Many medications are compatible with breastfeeding. Key factors determining infant exposure via breast milk: molecular weight (low MW drugs transfer more readily), lipophilicity (lipophilic drugs concentrate in hindmilk), protein binding (only free drug transfers), oral bioavailability of the drug in the infant, and the relative infant dose (RID = infant dose via milk / maternal dose, weight-adjusted). An RID <10% is generally considered acceptable. The LactMed database (NCBI) and e-lactancia.org provide drug-specific breastfeeding guidance.
What is the teratogenic risk window?
The embryonic period (days 18–55 post-conception, approximately weeks 4–10 from last menstrual period) is the period of maximum risk for structural teratogenesis — organ systems are developing (organogenesis). Before day 18 (pre-implantation / early embryo), exposure typically causes an "all-or-nothing" effect (implantation failure or normal development). After week 10, the foetus is less susceptible to structural malformations but remains vulnerable to functional teratogenesis, growth restriction, and neurodevelopmental effects throughout pregnancy.
How does pregnancy change pharmacokinetics?
Pregnancy causes major PK changes: increased GFR (+50% in T3) → increased renal clearance of renally eliminated drugs (e.g. lamotrigine dose increases by 2–3× in late pregnancy); increased plasma volume → dilutional effect, lower Cmax for loading doses; increased CYP3A4, CYP2D6 activity; reduced CYP1A2, CYP2C19 activity; reduced albumin (haemodilution) → higher free fraction of bound drugs; delayed gastric emptying in T1. These changes peak in the third trimester and reverse rapidly after delivery.
Which drugs are absolutely contraindicated in pregnancy?
Absolutely contraindicated drugs (high evidence of human teratogenicity or foetotoxicity) include: isotretinoin (retinoids — craniofacial, cardiac defects; iPLEDGE REMS), thalidomide (limb defects; STEPS programme), ACE inhibitors/ARBs in T2/T3 (foetal renal dysgenesis, oligohydramnios), warfarin in T1 and near term, methotrexate (foetal death, multiple defects), valproate (neural tube defects, autism; avoid in women of childbearing potential per EMA), and misoprostol in early pregnancy (labour induction). This is not an exhaustive list — always verify with OTIS, MotherToBaby, or LactMed.