Drug decisions for women of childbearing age

Decisions about medication during pregnancy are always a challenge and, since many pregnancies are unplanned, considerations must begin well in advance of pregnancy and must be addressed again if the patient becomes pregnant. Patients with bipolar disorder who discontinue treatment during pregnancy may 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 drugs can have harmful effects during pregnancy.

Ranking of treatment options

Valproate is the most teratogenic bipolar drug and should be avoided in women of childbearing potential until all other options have been exhausted.2.3 The use of valproate during pregnancy has been of international concern.4.5 Valproate (but not lamotrigine) is also associated with lower intelligence scores in young children who have been exposed to it in utero6 and is associated with a high 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 in late pregnancy.8 Lamotrigine data suggests a low risk of fetal harm as monotherapy, but cleft palate is a concern.9.10

Lithium presents less risk of malformation than valproate and carbamazepine. In a large study, the adjusted relative risk for any heart abnormalities was 1.65 compared to unexposed babies.11 The risk increases with higher doses, but it has always been found to be lower than previously thought. For Ebstein’s anomaly, the relative risk was 2.66. In absolute numbers, the risk was 0.6% for infants exposed to lithium against 0.18% for those not exposed. In the most recent meta-analysis, the absolute risk of any heart abnormalities was 1.2%. The increased risk was limited to exposure to lithium during the first trimester.12

Note that these observational studies involved comparisons of women with bipolar disorder taking lithium versus those not taking lithium. The rates of heart abnormalities are lower in women without bipolar disorder. The results of the study were often not clear whether they excluded women who took other teratogenic drugs or abused substances like alcohol. Authors12 concluded that the risks of exposure to lithium during pregnancy are low. The risks associated with relapse of the mood episode after discontinuing lithium or lowering the level below the therapeutic range appear, for most women, to outweigh the harms of fetal abnormalities or other complications of the disease. pregnancy associated with continued lithium.

Thus, lithium is preferred over valproate and carbamazepine. For some patients, lithium should be the first choice. For bipolar depression, second generation antipsychotics (eg, lurasidone, quetiapine, cariprazine) are reasonable choices, although data on the safety in pregnancy of newer drugs is limited. Long-acting antipsychotics should not be used routinely during pregnancy; infants can have extrapyramidal symptoms for months. Anticholinergic drugs should not be prescribed for pregnant women, except in cases of acute short-term need.

Antipsychotics during pregnancy appear to be relatively safe for birth defects.13 There is, however, a high risk 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 a reduction in fetal heart rate, uterine contraction, and preterm labor in up to a third of cases. In a large investigation of case reports, ECT was found to have an infant mortality rate of 7%.15 ECT can be used for severe depression, catatonia, drug resistant illnesses, extremely high risk of suicide, psychotic agitation, and severe physical decline due to malnutrition, dehydration, or other conditions. potentially fatal.

Recomendations

Avoid valproate in any woman who may become pregnant. If the patient becomes pregnant, it may be too late to stop it before harm is done. High doses of folate (4 to 5 mg per day) have been recommended if valproate or carbamazepine are essential, but the protective effect only appears if used before conception.16

Lamotrigine may be considered for bipolar depression.

Prescribe as few drugs as possible, ideally just one drug. When pregnancy unexpectedly occurs during treatment, it is usually best to continue treatment to avoid exposure to other agents, unless the patient is taking valproate or carbamazepine. In such cases, moving to something more secure should be considered. Adjust the doses as the pregnancy progresses. Blood volume increases by 30% in the third trimester. Monitoring of the plasma level is useful.

Dr Osser is Associate Professor of Psychiatry at Harvard Medical School and Co-Chief Psychiatrist, United States Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. The author does not report any conflict of interest regarding the subject of this article.

The references

1. Maina G, Rosso G, Aguglia A, Bogetto F. Recurrent rates of bipolar disorder in the postpartum period: a study of 276 Italian women without medication. Arch Women’s Mental Health. 2014; 17 (5): 367-372.

2. Jentink J, Loane MA, Dolk H, et al; EUROCAT Antiepileptic Study Working Group. Monotherapy with valproic acid in pregnancy and major birth defects. N English J Med. 2010; 362 (23): 2185-2193.

3. Balon R, Riba M. Should valproate be prescribed for women of childbearing age? a call to action. J Clin Psychiatry. 2016; 77 (4): 525-526.

4. Sher J, Frank JW, Doi L, de Caestecker L. Reproductive health policy failures: 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. Arche Say Child. 2011; 96 (7): 643-647.

7. Wiggs KK, Rickert ME, Sujan AC, et al. Use of antiepileptic drugs in 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 anomalies: systematic review and case-control study. BMJ. 2010; 341: c6581.

9. Dolk H, Wang H, Loane M, et al. Use of lamotrigine during pregnancy and risk of cleft mouth and other birth defects. 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. Use of lithium during pregnancy and risk of heart defects. N English 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 the safety and efficacy results. Am J Psychiatry. 2020; 177 (1): 76-92.

13. Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Use of antipsychotics during pregnancy and risk of birth defects. JAMA Psychiatry. 2016; 73 (9): 938-946.

14. Park Y, Hernández-Díaz S, Bateman BT, et al. Continuation of atypical antipsychotics in early pregnancy and 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 in pregnancy: a systematic review of case studies. Arch Women’s Mental 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. ??

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