Teratogen
A teratogen is any medication, chemical, infectious agent, physical factor, or maternal condition that can increase the risk of permanent structural or functional abnormalities in the embryo or fetus when exposure occurs during pregnancy. Teratogenic risk depends on dose, timing of exposure, coexisting maternal–fetal factors, and fetal genetic susceptibility.
Human development is especially vulnerable during organogenesis, roughly the third to eighth week after conception (about 5–10 weeks of gestation calculated from the last menstrual period). Later exposures may not produce major structural malformations, but can still impair growth, brain development, or organ function.
Most congenital anomalies do not have a clearly identified cause. Epidemiologic estimates suggest that known environmental and teratogenic exposures account for roughly 5–10 % of congenital anomalies, with the remainder due to chromosomal or single-gene disorders, multifactorial inheritance, or unknown causes. The true proportion may be underestimated because many environmental effects are difficult to prove in humans.
Selected human teratogens and critical periods
In the table below, conceptual age refers to weeks after fertilization, whereas gestational age refers to weeks from the last menstrual period (approximately 2 weeks greater than conceptual age). Ranges are approximate and represent periods of highest known susceptibility; risk outside these windows may still be present.
| Teratogen / exposure | Category / common use | Principal fetal effects (examples) | Highest-risk conceptual age (weeks post-fertilization) | Approx. gestational age (weeks from LMP) |
|---|---|---|---|---|
| Alcohol (ethanol) | Chronic heavy use or binge drinking | Fetal alcohol spectrum disorders (FASD): growth restriction, microcephaly, characteristic facial features (short palpebral fissures, smooth philtrum, thin upper lip), structural cardiac defects, and long-term neurodevelopmental impairment. | ~3–8 weeks for classic facial and major structural anomalies; brain growth and neurobehavioral effects may be impacted throughout pregnancy. | ~5–10 weeks (facial/structural); continuing vulnerability for CNS through 2nd and 3rd trimesters. |
| Isotretinoin (13-cis-retinoic acid) | Systemic retinoid for severe acne | Craniofacial malformations (microtia/anotia, ear canal atresia, micrognathia), conotruncal cardiac defects, thymic and parathyroid hypoplasia or aplasia, CNS anomalies, intellectual disability. | Approx. 3–5 weeks (organogenesis of craniofacial structures, heart, great vessels); teratogenic risk across the first trimester. | Approx. 5–7+ weeks (highest), with clinically important risk throughout ~5–10 weeks of gestation. |
| Valproate (valproic acid) | Antiseizure and mood-stabilizing medication | Neural tube defects (especially lumbosacral spina bifida), craniofacial anomalies, cardiac defects, limb anomalies, and later cognitive and behavioral impairment. | ~3–4 weeks (neural tube closure), with additional risk across the remainder of the first trimester. | ~5–6 weeks (NTDs); ongoing risk for other malformations to ~10 weeks. |
| Thalidomide | Immunomodulatory drug; historically sedative | Severe limb reduction defects (phocomelia), radial ray anomalies, ear and eye anomalies, facial nerve palsy, and cardiac defects. | Classic sensitive period approximately 20–36 days after conception (~3–5 weeks), with specific day ranges associated with upper versus lower limb defects. | ~5–7 weeks (≈34–50 days) of gestation. |
| Warfarin | Vitamin K antagonist anticoagulant | “Warfarin embryopathy”: nasal hypoplasia, stippled epiphyses (chondrodysplasia punctata), limb hypoplasia, growth restriction. Later exposures associated with CNS anomalies, ocular defects, and fetal/neonatal bleeding. | Approx. 4–7 weeks for classic embryopathy; CNS/ocular injury possible with later second- and third-trimester exposures. | Approx. 6–9 weeks (embryopathy); later effects with exposure beyond ~12 weeks. |
| ACE inhibitors / ARBs | Antihypertensives (e.g., for chronic hypertension) | “ACE-inhibitor fetopathy”: renal dysgenesis or renal failure, oligohydramnios and pulmonary hypoplasia, limb contractures, skull ossification defects, neonatal hypotension and renal insufficiency. | Primarily later pregnancy once fetal kidneys are the major source of amniotic fluid—approximately after 10–12 weeks post-conception. | Highest risk with sustained exposure during the second and third trimesters (~12–32+ weeks). |
| Maternal pregestational diabetes (poorly controlled) |
Maternal metabolic disease present before conception | Increased risk of major congenital malformations, particularly cardiac defects, neural tube defects, caudal regression syndrome, skeletal and genitourinary anomalies; risk correlates with periconceptional glycemic control. | ~3–7 weeks (organogenesis of heart, neural tube, caudal structures), when maternal hyperglycemia is most critical. | ~5–9 weeks of gestation (periconceptional period and early first trimester). |
| Maternal hyperthermia | High fever, saunas/hot tubs, environmental heat | Increased risk of neural tube defects, other midline defects, miscarriage, and possibly cardiac and craniofacial anomalies with significant early first-trimester hyperthermia. | Approx. 3–4 weeks (neural tube closure); earlier or later effects possible depending on timing and duration. | Approx. 5–6 weeks of gestation for NTD risk. |
| Rubella virus (primary maternal infection) | Viral teratogen; congenital rubella syndrome | Classic triad of sensorineural hearing loss, cataracts, and cardiac defects (e.g., PDA); also microcephaly, growth restriction, “blueberry muffin” rash, and other anomalies. | Highest risk with infection from conception through about 8 weeks post-conception; risk of deafness persists with infection up to ~12–16 weeks. | Approx. 2–10 weeks (major anomalies); up to ~14–18 weeks for isolated hearing loss. |
| Zika virus | Arboviral infection (mosquito-borne, sexual transmission) | Severe microcephaly, intracranial calcifications, cortical malformations, ventriculomegaly, ocular anomalies, arthrogryposis, growth restriction, fetal demise. | Greatest risk with infection in early pregnancy, especially first trimester (roughly 2–11 weeks post-conception), though later infection can also cause brain and eye injury. | Approx. 4–13 weeks of gestation (highest); susceptibility may extend into the second trimester. |
Clinical note
Evaluation of a pregnancy exposed to a potential teratogen usually includes careful dating, determination of the exact timing and dose of exposure, targeted ultrasound (and, when appropriate, fetal MRI), and genetic counseling. Many medications and exposures are not proven teratogens, and abrupt discontinuation of maternal therapy may be harmful; decisions should be individualized.
References