3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.5 Teratogenicity and developmental abnormalities associated with psychotropic drug use in pregnancy
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Written by Resident Doctor Committee · Published
Forms of harm and timing
Teratogenicity is structural malformation while organs form. Exposure after that window can still affect growth, brain development and how the baby adapts after birth.
Organogenesis happens mainly 3 to 8 weeks after conception. The neural tube usually closes by about day 28 after conception, which is about six weeks by obstetric dating.
Background risk
The background major malformation rate is 2 to 3%, so drug risks are given as absolute numbers against it: doubling 2% gives 4%.
Confounding by indication arises because maternal illness itself affects outcomes, and treated and untreated pregnancies differ in that illness.
Valproate
Valproate is the most teratogenic psychotropic in common use.
Outcome | Risk after exposure |
|---|---|
Major malformation after first-trimester exposure | About 10%, several times background |
Spina bifida | 1 to 2% |
Neurodevelopmental problems | 30 to 40% |
Malformations include neural tube defects, orofacial clefts, cardiac defects, hypospadias and limb defects.
Neurodevelopmental problems include delayed walking or speech, autism and lower intelligence quotient (IQ). They are far more common than malformations.
Risk is dose dependent and rises with daily doses above 1 g. No dose is free of risk, and the risk is not confined to early pregnancy.
Valproate taken with carbamazepine raises neural tube defect risk more than either drug alone. Both act through folate antagonism, yet folic acid does not remove valproate's risks.
Valproate is contraindicated for psychiatric indications in pregnancy. Anyone able to become pregnant who takes it needs Pregnancy Prevention Programme safeguards.
Other anticonvulsants
Drug | Major malformation risk | Pattern |
|---|---|---|
Carbamazepine | About 5% | Neural tube and craniofacial defects |
Topiramate | Increased | Orofacial clefts, hypospadias, small for gestational age |
Phenytoin | Increased | Craniofacial, digit and nail abnormalities |
Lamotrigine | Near background | No consistent pattern |
Orofacial clefts after first-trimester exposure are most clearly linked with valproate, carbamazepine and topiramate. The early benzodiazepine cleft signal was not confirmed.
Since 2024 the Medicines and Healthcare products Regulatory Agency (MHRA) has required a pregnancy prevention programme for topiramate.
Lithium
Ebstein's anomaly is apical displacement of the tricuspid leaflets with an atrialised right ventricle. It is classically linked with first-trimester lithium exposure.
Reporting bias inflated early estimates of a 400-fold risk. Lithium raises the risk of Ebstein's and other cardiac defects two- to threefold on a low baseline, to well under one in a hundred pregnancies.
Stopping lithium abruptly raises the risk of relapse, especially postpartum.
Antidepressants and benzodiazepines
Selective serotonin reuptake inhibitors (SSRIs) show no large class-wide malformation risk.
Paroxetine has the most consistent SSRI link with cardiac malformations, mainly septal defects. It is usually avoided in women planning a pregnancy.
Benzodiazepine malformation findings are inconsistent.
Neonatal effects of late exposure
Exposure | Neonatal picture | Course |
|---|---|---|
Late SSRI | Discontinuation features: jitteriness, irritability, shrill cry, feeding problems | Starts soon after birth and settles within days; worst with short half-life agents such as paroxetine |
Regular late benzodiazepine | Floppy infant syndrome: hypotonia, hypothermia, poor sucking, apnoea, sedation | Lasts days with long-acting agents such as diazepam |