Table 1.

Reproductive safety profile of psychotropic drugs used in bipolar disorder

Medication	Potential fetal/newborn risk summary	Clinical recommendation
Mood stabilizers
Lithium	Small risk of Ebstein’s anomaly (0.1%–0.05% live births) with first-trimester exposure No evidence of behavioral or cognitive problems in children exposed to lithium till 5 years of age	Fetal echocardiography Frequent serum lithium monitor in view of fluid shifts over pregnancy
Valproic acid Divalproate	Increased rate of congenital malformations (approximate 10%), including neural tube defects Linked to neurodevelopmental disorders in children with in-utero exposure	Use in pregnancy for BD banned in several countries Must be avoided in pregnancy High-dose folic acid supplementation (4 mg/day) advised prior to conception
Carbamazepine	Congenital malformations: Around 3%–6% Risk of bleeding diathesis in neonates due to Vitamin K deficiency	If possible, use in pregnancy should be avoided High-dose folic acid supplementation (4 mg/day) advised prior to conception Oral Vitamin K supplementation for newborn
Oxcarbazepine	Congenital malformations: Around 3% Risks appear to be low, though more data is required Possible link to autism with in-utero exposure but need more studies
Lamotrigine	Risk of major congenital malformations in most studies (2%–3%) is comparable to baseline population rates No significant neurobehavioral sequelae	Preferred agent to use, if clinically indicated (e.g., bipolar depression or depression predominant course) Dose may be increased due to enhanced clearance rates across pregnancy stages
FGAs
Haloperidol Trifluoperazine	Increased risk of preterm labor and reduced birth weight; but not always clinically significant No increased risk of congenital malformations or neurodevelopmental delays	May watch for extrapyramidal and other adverse effects Appear safe to use in pregnancy, though FGA use is often restricted to acute care rather than prophylaxis in BD
SGAs
Olanzapine Quetiapine Aripiprazole Risperidone	Risk of congenital malformations for most SGAs: Around 3.5%, not substantially different from general population rates (2%–3.5%) Risperidone is associated with possible small increase in risk, but needs replication Increased risk of maternal weight gain, gestational diabetes mellitus, and large-for-gestational-age baby	Relatively safe to use in pregnancy, especially olanzapine, quetiapine, and aripiprazole Periodic monitor for maternal glucose and weight with olanzapine/quetiapine Ultrasound for fetal size in late pregnancy
Clozapine Ziprasidone Lurasidone	Limited/scarce quality data on safety in pregnancy	Weekly monitoring for agranulocytosis for infants who were exposed to clozapine in utero till six months after birth
SSRIs
Fluoxetine Escitalopram Sertraline Paroxetine Fluvoxamine	Small increased risk of spontaneous abortion, preterm labor, and lower weight at birth Small increased absolute risk (2/1000 births) of congenital cardiac defect with first-trimester paroxetine exposure Conflicting evidence for persistent pulmonary hypertension of newborn with third-trimester exposure Mild poor neonatal adaptation syndrome in about one-third of cases with exposure during late pregnancy	Largely safe to use in pregnancy, if indicated Paroxetine use may be avoided
Antidepressant drugs (other than SSRIs)
Bupropion Mirtazapine Venlafaxine Duloxetine	Less data on their safety as compared to SSRIs Reported risks of congenital malformation appear similar to SSRIs in limited available data
Benzodiazepines
Clonazepam Lorazepam Alprazolam Midazolam diazepam Chlordiazepoxide	Older evidence pointed to association with oral cleft defects, which was not found in recent meta-analytic evidence Third-trimester exposure associated with neonatal toxicity and withdrawal symptoms Case reports of floppy infant syndrome	Regular or high-dose use should be avoided as far as possible Tapering of dose should be considered before delivery Use in acute care, no role in prophylaxis

FGAs=First-generation antipsychotics, SGAs=Second-generation antipsychotics, SSRIs=Selective serotonin reuptake inhibitors, BD=Bipolar disorder