Bipolar disorder and pregnancy: what considerations need to be kept in mind?
Medication decisions during pregnancy are always a challenge, and, since many pregnancies are unplanned, considerations should start well before pregnancy occurs and should be addressed again if the patient becomes pregnant. Patients with bipolar disorder who stop medication during pregnancy can have a relapse rate of 80% for depression, 16% for mania, and 4% for mixed episodes during the postpartum period (Figure).1 However, many bipolar medications can have harmful effects during pregnancy.
Ranking Treatment Options
Valproate is the most teratogenic bipolar medication and should be avoided in women of childbearing potential until all other options have been exhausted.2,3 Use of valproate in pregnancy has been a source of concern internationally.4,5 Valproate (but not lamotrigine) also is associated with lower intelligence scores in young children who were exposed to it in utero6 and is associated with an elevated risk of autism spectrum disorder and attention-deficit/hyperactivity disorder.7
Carbamazepine is almost as teratogenic as valproate and is associated with increased spina bifida and vitamin K deficiencies late in pregnancy.8 The data on lamotrigine suggest low risk of fetal harm as monotherapy, but cleft palate is a concern.9,10
Lithium has fewer malformation risks than valproate and carbamazepine. In a large study, the adjusted risk ratio for any cardiac abnormality was 1.65 compared with unexposed babies.11 The risk rises with higher doses, but it still has been shown to be lower than previously thought. For Ebstein’s anomaly, the risk ratio was 2.66. In absolute numbers, the risk was 0.6% for lithium-exposed infants vs 0.18% for those not exposed. In the most recent meta-analysis, the absolute risk of any cardiac abnormality was 1.2%. The increased risk was limited to lithium exposure in the first trimester.12
Note that these observational studies involved comparisons of women with bipolar disorder taking lithium vs those not taking lithium. Rates of cardiac abnormalities are lower in women without bipolar disorder. The study results were often unclear if they excluded women who were on other teratogenic medications or were misusing any substances like alcohol. The authors12 concluded that the risks of lithium exposure during pregnancy are low. The risks associated with mood episode relapse following lithium cessation or lowering the level below the therapeutic range appear, for most women, to exceed the harms of fetal abnormalities or other pregnancy complications associated with continuing lithium.
Thus, lithium is preferred over valproate and carbamazepine. For some patients, lithium should be the first choice. For bipolar depression, the second-generation antipsychotics (eg, lurasidone, quetiapine, cariprazine) are reasonable choices, although the data on safety in pregnancy for the newer drugs are limited. Depot antipsychotics should not be routinely used in pregnancy; infants may show extrapyramidal symptoms for months. Anticholinergic drugs should not be prescribed to pregnant women except for acute, short-term need.
Antipsychotics in pregnancy seem relatively safe with respect to congenital malformations.13 There is a high risk, however, of gestational diabetes with olanzapine (the second worst option is quetiapine).14
Electroconvulsive therapy (ECT) during pregnancy warrants more caution than previously thought. It causes fetal heart rate reduction, uterine contraction, and premature labor in up to one-third of cases. In a large survey of case reports, ECT was found to have a child mortality rate of 7%.15 ECT can be used for severe depression, catatonia, medication-resistant illness, extremely high risk for suicide, psychotic agitation, and severe physical decline due to malnutrition, dehydration, or other life-threatening conditions.
Avoid valproate in any woman with the potential to become pregnant. Should the patient become pregnant, it may be too late to discontinue it before harm is done. High-dose folate (4-5 mg daily) has been recommended if valproate or carbamazepine are essential, but the protective effect occurs only if used prior to conception.16
Lamotrigine may be considered for bipolar depression.
Prescribe as few drugs as possible—ideally only 1 medication. When pregnancy unexpectedly occurs during treatment, it is usually best to continue the regimen to avoid exposure to additional agents—except if the patient is on valproate or carbamazepine. In such cases, switching to something safer should be considered. Adjust doses as pregnancy progresses. Blood volume expands 30% in the third trimester. Plasma level monitoring is helpful.
Dr Osser is associate professor of psychiatry at Harvard Medical School and co-lead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.
1. Maina G, Rosso G, Aguglia A, Bogetto F. Recurrent rates of bipolar disorder during the postpartum period: a study on 276 medication-free Italian women. Arch Womens Ment Health. 2014;17(5):367-372.
2. Jentink J, Loane MA, Dolk H, et al; EUROCAT Antiepileptic Study Working Group. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010;362(23):2185-2193.
3. Balon R, Riba M. Should women of childbearing potential be prescribed valproate? a call to action. J Clin Psychiatry. 2016;77(4):525-526.
4. Sher J, Frank JW, Doi L, de Caestecker L. Failures in reproductive health policy: overcoming the consequences and causes of inaction. J Public Health. 2018;41(2):e209-e215.
5. Leistikow N, Smith MH, Payne JL, Osborne LM. Is valproate reasonable? Am J Psychiatry. 2021;178(1):99.
6. Cummings C, Stewart M, Stevenson M, Morrow J, Nelson J. Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child. 2011;96(7):643-647.
7. Wiggs KK, Rickert ME, Sujan AC, et al. Antiseizure medication use during pregnancy and risk of ASD and ADHD in children. Neurology. 2020;95(24):e3232-e3240.
8. Jentink J, Dolk H, Loane MA, et al; EUROCAT Antiepileptic Study Working Group. Intrauterine exposure to carbamazepine and specific congenital abnormalities: systematic review and case-control study. BMJ. 2010;341:c6581.
9. Dolk H, Wang H, Loane M, et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital abnormalities. Neurology. 2016:86(18):1716-1725.
10. Vajda FJE, Dodd S, Horgan D. Lamotrigine in epilepsy, pregnancy, and psychiatry—a drug for all seasons? J Clin Neurosci. 2013:20(1):13-16.
11. Patorno E, Huybrechts KF, Bateman BT, et al. Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med. 2017;376(23):2245-2254.
12. Fornaro M, Maritan E, Ferranti R, et al. Lithium exposure during pregnancy and the postpartum period: a systematic review and meta-analysis of safety and efficacy outcomes. Am J Psychiatry. 2020;177(1):76-92.
13. Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry. 2016;73(9):938-946.
14. Park Y, Hernández-Díaz S, Bateman BT, et al. Continuation of atypical antipsychotic medications during early pregnancy and the risk of gestational diabetes. Am J Psychiatry. 2018:175(6):564-574.
15. Leiknes KA, Cooke MJ, Jarosch-von Schwender L, Harboe I, Høie B. Electroconvulsive therapy during pregnancy: a systematic review of case studies. Arch Womens Ment Health. 2015;18(1):1-39.
16. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry. 13th ed. Wiley Blackwell; 2018:610. ❒