Medications and Teratogenic Exposures — Nelson Textbook of Pediatrics (2024), Chapter 117.4

1. Definitions and Scope

• Pregnancy loss
• Congenital malformation
• Functional impairment (e.g., developmental delay)

• Medications (e.g., thalidomide, isotretinoin)
• Infections (e.g., rubella, CMV, Zika virus)
• Physical agents (e.g., radiation)
• Recreational exposures (e.g., alcohol, smoking)
• Maternal conditions (e.g., pregestational diabetes, hyperthermia, maternal PKU)
• Environmental chemicals (e.g., lead, mercury)

2. Principles That Modify Teratogenic Risk

• Timing of exposure: Exposure during embryogenesis (weeks 2–8 of gestation) carries the highest risk of structural malformation; later exposures (2nd/3rd trimester) more often impair organ function rather than structure (e.g., ACE inhibitors/ARBs later in pregnancy cause oligohydramnios, IUGR, renal failure, and Potter sequence rather than structural defects).
• Dose/threshold effects: Some agents (notably radiation) have a threshold below which no injury occurs; diagnostic imaging doses rarely approach this threshold, so diagnostic radiologic studies should not be withheld from a pregnant patient when medically needed.
• Genetic susceptibility: Maternal and fetal genetic variants affect metabolism of teratogens and can raise or lower individual risk — the same agent/dose does not consistently produce the same outcome across pregnancies.
• Delayed manifestation: Some effects are not evident at birth. Classic example: diethylstilbestrol (DES) exposure in utero caused vaginal/cervical clear-cell adenocarcinoma in female offspring only in the 2nd–3rd decade of life.
• Protective exposures: Not all modifications are harmful — folic acid fortification of cereal-grain products (mandatory in the US since 1998) plus 0.4–0.8 mg/day supplementation has reduced neural tube defect (NTD) birth prevalence by an estimated 1,300+ births/year.

3. Regulatory Framework

4. Specific Drug Classes Discussed in Detail

Antidepressants

• SSRIs (fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine), SNRIs (venlafaxine, duloxetine), and TCAs are used for maternal depression/anxiety.
• Associated with increased risk of congenital heart defects, preterm birth, persistent pulmonary hypertension of the newborn (PPHN), and respiratory distress — though absolute risk is low even if relative risk is elevated.
• Paroxetine carries the highest birth-defect risk among SSRIs; sertraline shows a comparatively lower PPHN risk.
• Poor Neonatal Adaptation Syndrome (PNAS): transient neonatal signs (feeding/sleep problems, irritability, abnormal tone, jitteriness, GI symptoms, respiratory distress) appearing within 48 hours and lasting 2–6 days. Occurs in ~30% of infants exposed to SSRIs/SNRIs and 20–50% exposed to TCAs. Management is supportive (small frequent feeds, swaddling, skin-to-skin contact); breastfeeding may reduce PNAS risk.
• Untreated maternal depression itself carries independent risks (fetal death, preterm birth, growth problems), complicating attribution of causality.

Antiepileptic Drugs

• Most infants of women with epilepsy are born without malformation, but several agents raise risk.
• Valproate carries the highest risk (>10% of infants exposed in the first trimester have congenital malformations) — NTDs, congenital heart defects, hypospadias, orofacial clefts, clubfoot, plus long-term cognitive delay and autism spectrum features.
• Lamotrigine has the lowest risk among commonly compared agents.
• High-dose folic acid (≥4 mg/day) may partially reduce NTD risk with valproate exposure.
• Clinical implication: since ~50% of pregnancies are unintended, antiepileptic choice in reproductive-age women/adolescents should favor lower-teratogenic-risk agents when seizure control allows.

Opioids

• Rising use in pregnancy; associated with spontaneous abortion, PROM, preeclampsia, placental abruption, fetal death, preterm delivery, and SGA infants.
• Neonatal Opioid Withdrawal Syndrome (NOWS)/Neonatal Abstinence Syndrome (NAS): occurs after birth in infants exposed to opioids (including methadone/buprenorphine maintenance). Signs: irritability/crying, poor state control, hypertonicity, tremors/jitteriness, poor feeding, vomiting/diarrhea, hiccups, tachypnea, fever. Managed with nonpharmacologic comfort measures first, escalating to pharmacologic treatment if needed (detailed further in Chapter 145, Table 145.2).

Alcohol

• Produces Fetal Alcohol Spectrum Disorder (FASD), with Fetal Alcohol Syndrome at the severe end (growth deficiency, characteristic facial features, neurocognitive deficits, confirmed prenatal exposure).
• No known safe level of alcohol exposure in pregnancy — complete abstinence is recommended.

Antihypertensives (ACE inhibitors / ARBs)

• 2nd/3rd trimester exposure decreases fetal renal function → oligohydramnios, growth deficiency, pulmonary hypoplasia, hypocalvaria, renal dysplasia, and death (Potter sequence).

Radiation (Section 117.5, closely linked)

• Background fetal exposure ~0.1 rad; most radiographs <0.1 rad, most CT scans <5 rad.
• Malformations/growth restriction generally require ≥25 rad before 25 weeks' gestation — well above diagnostic imaging doses.
• No increase in genetic abnormalities was seen in offspring of atomic bomb survivors exposed as fetuses.
• Diagnostic MRI and ultrasound have no demonstrated harmful fetal effect (no ionizing radiation).
• Pregnancy termination should not be recommended solely on the basis of diagnostic radiation exposure.

5. Table 117.5 — Factors Associated With Stillbirth (selected)

6. Table 117.6 — Agents Affecting Fetal Structure (Teratogens causing malformation)

7. Table 117.7 — Agents Affecting Neonatal Function (not structural teratogens)

8. Clinical Take-Home Points (per Nelson)

1. Always weigh maternal benefit against fetal risk before prescribing in pregnancy — never withhold necessary treatment purely from teratogenic fear.
2. Counsel women of reproductive age (especially adolescents on chronic medication) about lower-teratogenic-risk alternatives given the high rate of unintended pregnancy.
3. Reassure families that most birth defects have no identifiable teratogenic cause.
4. Refer complex exposure questions to MotherToBaby, TERIS, or Reprotox rather than relying on outdated pregnancy category letters.