STEPTRACKERPHARMACOLOGY + OBSTETRICS | DRUG SAFETY | HIGH-YIELD REVIEW

Drug Safety: Pregnancy, Lactation & the Elderly

Special populations change both the risk and the dose — know the teratogens by name and effect, what to avoid when breastfeeding, and why older adults are more sensitive.

FOCUS ON

Teratogen timing: weeks 3–8 (organogenesis) most vulnerable; earlier → all-or-none. Major teratogens: ACE inhibitors/ARBs (renal dysgenesis, oligohydramnios), valproate (neural tube defects), carbamazepine, phenytoin (fetal hydantoin), isotretinoin and vitamin A (craniofacial, CNS, heart), warfarin (nasal hypoplasia, stippled epiphyses), lithium (Ebstein anomaly), methotrexate, mycophenolate, thalidomide (limb defects), tetracyclines (teeth), aminoglycosides (ototoxicity), fluoroquinolones (cartilage), DES (clear cell adenocarcinoma), statins, misoprostol, ribavirin, alcohol, leflunomide. Safer in pregnancy: heparin (LMWH), labetalol, nifedipine, methyldopa, hydralazine, insulin, metformin, levothyroxine, penicillins, cephalosporins, azithromycin. Elderly: ↓ renal/hepatic clearance, ↑ fat, ↑ CNS sensitivity → avoid anticholinergics, long-acting benzodiazepines, first-generation antihistamines; watch falls, delirium, polypharmacy.

DRUG

FETAL / INFANT EFFECT

MECHANISM

SAFER CHOICE

ACE inhibitors · ARBs

Renal dysgenesis, oligohydramnios, skull hypoplasia (2nd/3rd trimester)

Fetal renal perfusion depends on angiotensin II

Labetalol, nifedipine, methyldopa

Valproate · carbamazepine

Neural tube defects, cognitive deficits (valproate worst)

Folate antagonism, HDAC inhibition

Lamotrigine, levetiracetam + folic acid

Phenytoin

Fetal hydantoin syndrome: cleft lip/palate, nail and digit hypoplasia, microcephaly

Arene oxide metabolites

—

Isotretinoin · high-dose vitamin A

Craniofacial, CNS and cardiac defects, miscarriage

Retinoic acid signaling

Two forms of contraception, pregnancy tests (iPLEDGE)

Warfarin

Nasal hypoplasia, stippled epiphyses, CNS bleeding

Crosses placenta, ↓ vitamin K–dependent bone proteins

LMWH

Lithium

Ebstein anomaly (apical displacement of tricuspid), neonatal hypothyroidism, diabetes insipidus

—

Fetal echo if continued

Methotrexate · mycophenolate · leflunomide

Miscarriage, craniofacial and limb defects

Antimetabolites

Stop before conception (leflunomide washout with cholestyramine)

Thalidomide · lenalidomide

Phocomelia (limb defects)

Anti-angiogenic

Strict REMS

Antibiotics to avoid

Tetracyclines (teeth, bone) · aminoglycosides (CN VIII) · fluoroquinolones (cartilage) · sulfonamides near term (kernicterus) · chloramphenicol (gray baby)

—

Penicillins, cephalosporins, azithromycin, nitrofurantoin (not at term)

DES · misoprostol · statins

Vaginal clear cell adenocarcinoma, uterine anomalies · abortion, Möbius · theoretical defects

—

Avoid

Alcohol · tobacco · cocaine

Fetal alcohol syndrome (smooth philtrum, thin upper lip, microcephaly, ID) · low birth weight · abruption

—

Abstinence

Breastfeeding cautions

Codeine/tramadol (ultrarapid metabolizers), lithium, chemotherapy, amiodarone, radioactive iodine, high-dose estrogen (↓ milk)

Lipophilic, low protein binding drugs enter milk

Most antibiotics, SSRIs (sertraline), heparin, insulin acceptable

Elderly high-risk drugs

Falls, delirium, urinary retention, constipation, bleeding, hypoglycemia

↓ clearance, ↑ sensitivity

Avoid diphenhydramine, TCAs, long-acting benzodiazepines, glyburide, muscle relaxants

Mechanism — timing of exposure

Weeks 0–2All-or-none: loss or normal

→

Weeks 3–8Organogenesis: structural defects

→

Fetal periodGrowth, function (kidney, brain, ears)

Safer in pregnancy

PROBLEM

SAFER DRUG

AVOID

Hypertension

Labetalol, nifedipine, methyldopa

ACEi, ARB

Anticoagulation

LMWH

Warfarin, DOACs

Diabetes

Insulin (metformin)

Most other oral agents

Hyperthyroidism

PTU (1st trimester) → methimazole

Radioactive iodine

Seizures

Lamotrigine, levetiracetam

Valproate

How it's tested

COMMON CONFUSIONPTU is preferred in the first trimester (methimazole causes aplasia cutis), then methimazole for the rest (PTU hepatotoxicity).

THE TRAPWomen planning pregnancy on valproate, isotretinoin, warfarin, ACE inhibitors or methotrexate need the drug switched before conception, not after a positive test.

YOUR APPROACHIdentify the population (pregnant, breastfeeding, elderly, renal/hepatic) → drug risk → safer alternative or dose change.

If you see… think…

Oligohydramnios and renal failure in a newborn → ACE inhibitor exposure

Neural tube defect, mother with epilepsy → valproate

Ebstein anomaly → lithium

Nasal hypoplasia, stippled epiphyses → warfarin

Limb reduction defects → thalidomide

Cleft palate, small nails and digits → phenytoin

Discolored teeth in a child exposed in utero → tetracycline

Clear cell vaginal adenocarcinoma in a young woman → DES exposure

Anticoagulant of choice in pregnancy → LMWH

Delirium in an elderly patient after diphenhydramine → anticholinergic burden