Reproductive Safety of Second-Generation Antipsychotics: Current Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics

Cohen, Lee S.; Viguera, Adele C.; McInerney, Kathryn A.; Freeman, Marlene P.; Sosinsky, Alexandra Z.; Moustafa, Danna; Marfurt, Samantha P; Kwiatkowski, Molly A.; Murphy, Shannon; Farrell, Adriann M.; Chitayat, David; Hernández–Dı́az, Sonia

doi:10.1176/appi.ajp.2015.15040506

Cited by 168 publications

(77 citation statements)

References 38 publications

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“…Registry studies have been small (<250 exposed women) and have yielded mixed results; one study 4 reported higher than expected rates of malformations (particularly cardiac), whereas another study 5 did not find this association. Results from epidemiologic studies have also yielded inconsistent evidence.…”

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confidence: 95%

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations

et al. 2016

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IMPORTANCE The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations. OBJECTIVE To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs. DESIGN, SETTING, AND PARTICIPANTS This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015. EXPOSURES Use of APs during the first trimester, the etiologically relevant period for organogenesis. MAIN OUTCOMES AND MEASURES Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery. RESULTS Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4–33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5–48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6–54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24–1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81–1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96–1.16) for atypical APs and 0.90 (95% CI, 0.62–1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02–1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88–1.81) was found for risperidone that was independent of measured confounders. CONCLUSIONS AND RELEVANCE Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.

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Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations

et al. 2016

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“…Weighing these options against each other, the recommendation has often been to discontinue treatment, especially during the first trimester 1. However, during the past decade more safety data have accumulated suggesting that antipsychotics are relatively safe to use in pregnancy 1, 2, 3. It has also been demonstrated that discontinuing ongoing maintenance treatment for severe mood and psychotic disorders during pregnancy carries a high risk of disease recurrence 2.…”

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confidence: 99%

“…However, during the past decade more safety data have accumulated suggesting that antipsychotics are relatively safe to use in pregnancy 1, 2, 3. It has also been demonstrated that discontinuing ongoing maintenance treatment for severe mood and psychotic disorders during pregnancy carries a high risk of disease recurrence 2. Thus, for women with substantial psychiatric morbidity and good treatment response, maintained use of an antipsychotic during pregnancy might often represent the best risk–benefit option.…”

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Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (−76%; confidence interval (CI), −83%, −66%; P < 0.001) and aripiprazole (−52%; CI, −62%, −39%; P < 0.001), but not for olanzapine (−9%; CI, −28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

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“…Discussions about the use of medications in pregnancy should include the risks of treatment and of not receiving treatment. While available safety data should be taken into consideration (19–21), knowledge about which medications have been effective for the patient in the past is extremely helpful in clinical decision-making. In women with bipolar disorder, prophylaxis with lithium during pregnancy is recommended due to established efficacy, though with known maternal and infant risks (22).…”

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confidence: 99%

“…In women with bipolar disorder, prophylaxis with lithium during pregnancy is recommended due to established efficacy, though with known maternal and infant risks (22). If using antipsychotics, data suggests that neither first or second generation antipsychotics are considered major teratogens (19, 21) though second generation agents may have greater efficacy and fewer short term side effects in the treatment of bipolar disorder (23). Women who require antipsychotic medications are at higher risk for adverse maternal and perinatal outcomes compared to the general population and should be monitored (24).…”

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confidence: 99%