What are the risks of teratogenic exposure during pregnancy?

Teratogenic Risks During Pregnancy

The risks of teratogenic exposure during pregnancy include major structural birth defects (2-3% of all births), spontaneous abortion, fetal death, intrauterine growth restriction, and functional neurological impairments, with severity depending critically on timing of exposure, dose, and specific agent involved. 1

Critical Timing Windows

First Trimester (Weeks 0-12): Highest Risk Period

• Weeks 0-2: "All-or-nothing" phenomenon occurs—exposure results in either spontaneous abortion or normal development with no intermediate outcomes 1
• Weeks 3-12 (Organogenesis): Period of maximum vulnerability to structural malformations, including major congenital anomalies affecting all organ systems 1
• This is when medications should ideally be avoided unless proven safe 2, 3

Second and Third Trimesters

• Risk shifts from structural malformations to functional defects and growth abnormalities 1
• Continuing central nervous system development remains vulnerable, along with gonads, teeth, palate, eyes, and ears 1
• Potential outcomes include stillbirth, intrauterine growth retardation, and functional defects of late-forming tissues 1

Specific Teratogenic Agents and Their Risks

Proven Highly Teratogenic Medications (Must Avoid)

Methotrexate, Cyclophosphamide, and Mycophenolate

• Cause embryotoxicity and proven teratogenicity with miscarriage or major birth defects during first trimester exposure 1
• Require discontinuation 1-3 months (methotrexate), 3 months (cyclophosphamide), or 1.5 months (mycophenolate) before conception 1
• Effective contraception is mandatory while taking these medications 1

ATRA (All-Trans Retinoic Acid) and Retinoids

• Considered highly teratogenic, particularly isotretinoin which causes miscarriage and severe birth defects 1
• Must be avoided during first trimester; can potentially be used in second/third trimesters if absolutely necessary 1

Arsenic Trioxide (ATO)

• High embryotoxic potential demonstrated in animal models 1
• Associated with low birth weight, spontaneous abortion, and stillbirth in human populations exposed environmentally 1
• Cannot be recommended at any stage of pregnancy 1

Warfarin

• Crosses placental barrier and causes fatal hemorrhage to fetus 4
• First trimester exposure causes embryopathy with nasal hypoplasia and chondrodysplasia punctata 4
• Second/third trimester exposure causes central nervous system abnormalities including dorsal midline dysplasia, agenesis of corpus callosum, Dandy-Walker malformation, optic atrophy, mental retardation, and blindness 4
• Additional rare defects include urinary tract anomalies, cardiac defects, polydactyly, cleft palate/lip, and microcephaly 4

Thalidomide and Analogues (Pomalidomide)

• Induces high frequency of severe birth defects including amelia (absent limbs), phocomelia (short limbs), bone hypoplasticity, external ear abnormalities, facial palsy, eye abnormalities, and congenital heart defects 5
• Mortality at or shortly after birth occurs in approximately 40% of affected infants 5
• Pomalidomide crosses the placenta and is teratogenic in animal studies at doses near human therapeutic levels 5

Antiepileptic Drugs

• Valproate, phenytoin, carbamazepine, and phenobarbital are teratogenic 1
• Risk of congenital anomalies increases with higher doses and polytherapy 1
• Monotherapy at lowest effective dose should be used when treatment cannot be avoided 1

Methimazole

• Possible teratogenicity in first trimester; propylthiouracil is preferred during this period 1

Chemotherapy Agents: Trimester-Specific Risks

First Trimester

• Older alkylators (thiotepa, busulfan, chlorambucil, nitrogen mustard) and antimetabolites (aminopterin, methotrexate) have most pronounced teratogenic potential 1
• Associated with fetal malformations, increased abortion risk, and low birth weight 1

Second and Third Trimesters

• Anthracyclines, 5-fluorouracil, cytarabine, and vinca alkaloids have least teratogenic potential 1
• Taxanes and platinum compounds appear relatively safe based on limited case reports 1
• Daunorubicin preferred over idarubicin due to less placental transfer 1
• Still carries increased risk of stillbirth, growth retardation, and premature delivery 1

Radiation Exposure

Critical Thresholds

• Fetal exposure should be kept below 5-10 cGy (50-100 mGy) 1
• Below this threshold: very low risk of mutations and no increased rate of malformations above general population baseline (3-5%) 1
• Above this threshold: deterministic effects including fetal death, malformations, and growth disturbances 1

Timing-Dependent Effects

• Weeks 2-8: highest risk of teratogenicity 1
• Weeks 8-25: association with intellectual deficit (lower risk after week 15) 1
• After week 25: minimal risks 1

Imaging Modality Safety

• Ultrasound without Doppler: safest, no known fetal risks 1
• MRI without gadolinium: preferred if additional imaging needed 1
• Gadolinium must be avoided: crosses placenta, accumulates in fetal urinary tract, potentially teratogenic in animal models 1
• CT abdomen/pelvis: 13-25 mGy fetal dose (below threshold but should be avoided when possible) 1

Dose-Response Relationships

Five Critical Determinants of Teratogenic Risk 6

1. Genotype of the conceptus: genetic susceptibility varies
2. Developmental stage at exposure: timing is critical
3. Mechanism of action: six major pathways identified 7
4. Drug access to developing tissues: placental transfer and metabolism
5. Dose of exposure: nearly all teratogen-induced defects are preventable if dose-response is clearly defined 6

Mechanisms of Teratogenicity

Six Major Pathogenic Mechanisms 7

• Folate antagonism
• Neural crest cell disruption
• Endocrine disruption
• Oxidative stress
• Vascular disruption
• Specific receptor- or enzyme-mediated teratogenesis

Pregnancy-Compatible Medications

Safe Throughout Pregnancy 1

• Hydroxychloroquine (at standard daily doses)
• Azathioprine (up to 2 mg/kg/day in patients with normal thiopurine metabolism)
• Cyclosporine and tacrolimus (at lowest effective dose with trough level monitoring)
• Sulfasalazine (up to 2 g/day with mandatory folic acid supplementation)
• Colchicine (1-2 mg/day)
• TNF inhibitors and certain biologics (per specific guidelines)

NSAIDs: Trimester-Specific Safety 1

• First and early second trimester: No evidence of increased miscarriage or teratogenicity risk; ibuprofen has most reassuring data 1
• Short-term use (7-10 days) in second trimester: appears safe with nonselective NSAIDs with short half-life (e.g., ibuprofen) at lowest effective dose 1
• Must discontinue after gestational week 28: increased sensitivity to risks including oligohydramnios and ductus arteriosus narrowing/occlusion 1

Common Pitfalls and Critical Warnings

Methylene Blue in Pregnancy

• Teratogenic effects include jejunal/ileal atresia (most common), fetal demise, hyperbilirubinemia, hemolytic anemia, and respiratory distress 1
• Should only be used when risks clearly outweigh benefits, with multidisciplinary discussion 1

Combination Medication Risks

• Seemingly unrelated prescription and over-the-counter medications may utilize similar teratogenic mechanisms, resulting in additive increased risk 7

Baseline Birth Defect Rate

• General population baseline: 3-5% of children manifest developmental defects 1, 6
• Teratogen-induced malformations account for 2-3% of all birth defects 6
• Approximately 10% of birth defects are due to teratogenic exposures 8

Undetermined Risks

• More than 90% of drugs approved in recent decades have undetermined human teratogenic risks 7
• Absence of evidence is not evidence of safety