Clozapine in Pregnancy and Breastfeeding: What the Evidence Shows

The Clozaril label states that published studies "over decades of use with clozapine during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes".¹ The one clozapine-specific cohort estimate found is imprecise. In a Finnish register study, 106 pregnancies were exposed to clozapine in early pregnancy, and the adjusted odds ratio for major malformations was 2.00, with a 95% confidence interval of 0.30 to 13.35.²

An interval that wide is too imprecise to draw a conclusion. It's compatible with a lower risk, no difference, or a much higher risk. Decisions about clozapine around a pregnancy are made with the psychiatrist and the obstetric team, ideally before conception.

What the label says about clozapine in pregnancy

The label warns that newborns exposed to antipsychotic drugs, including clozapine, during the third trimester "are at risk for extrapyramidal and/or withdrawal symptoms following delivery". The reported symptoms are agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. "Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization".¹

The label states that "There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide". It gives the estimated background risk in the US general population as 2 to 4% for major birth defects and 15 to 20% for miscarriage in clinically recognized pregnancies.¹

The label names the National Pregnancy Registry for Atypical Antipsychotics, which monitors pregnancy outcomes in women exposed to these drugs, and encourages clinicians to advise patients to register by calling 1-866-961-2388.¹

Stopping clozapine when pregnant

Section 8.1 of the label does not mention stopping or continuing clozapine in pregnancy. It states that there are risks to the mother from untreated schizophrenia and from exposure to antipsychotics.¹ A 2022 systematic review of clozapine continuation in pregnancy found only two eligible studies, both rated as poor quality, and the number of clozapine-exposed patients "was too small for separate statistical analysis".³

A woman who learns she's pregnant while taking clozapine contacts her psychiatrist promptly, and the dose isn't changed without the prescriber.

Clozapine and birth defects: what the studies can show

The Finnish study used national register data from 1996 to 2017. Major malformations were recorded in 37.7 per 1,000 of the 106 clozapine-exposed pregnancies and 43.7 per 1,000 unexposed pregnancies. The crude odds ratio was 0.88 (95% CI 0.32 to 2.41) and the adjusted odds ratio was 2.00 (95% CI 0.30 to 13.35).²

A 2021 systematic review of 42 studies described the data as "of limited quality and quantity" and concluded that "data thus far do not support that clozapine is teratogenic".⁴ An analysis of international pharmacovigilance reports identified 494 report combinations involving adverse pregnancy outcomes with clozapine and found no signal of disproportionate reporting compared with other antipsychotics. Its authors cautioned that this "is not automatically equivalent to the relative safety of clozapine during pregnancy".⁵ A prospective comparative study of 151 pregnancy outcomes included 6 with clozapine exposure.⁶

The larger figures describe the drug class

The registry named in the label reported in 2021 on second-generation antipsychotics as a class. Among 640 live births in the exposure group, 16 (2.50%) had confirmed major malformations, compared with 14 of 704 (1.99%) in the control group, for an odds ratio of 1.48 (95% CI 0.625 to 3.517).⁷ A cohort of 1,341,715 pregnancies found an adjusted relative risk of malformations overall of 1.05 (95% CI 0.96 to 1.16) for atypical antipsychotics.⁸ Both figures are class-level, and neither abstract gives an estimate for clozapine.

Clozapine and gestational diabetes

A 2017 review stated that "rates of gestational diabetes are twice as high in pregnant women using clozapine".⁹ The cohort data don't isolate clozapine. In Swedish registers, 169 women filled prescriptions for olanzapine and/or clozapine, and the adjusted odds ratio for gestational diabetes was 1.94 (95% CI 0.97 to 3.91), which was not statistically significant.¹⁰

A later Swedish study grouped olanzapine, clozapine and quetiapine together and found adjusted risk ratios for gestational diabetes of 1.8 and 1.6 against two comparison groups. Clozapine was recorded for 29 pregnancies in that group of 1,710.¹¹

Newborn effects: mostly case reports

The 2017 review wrote that clozapine accumulation in fetal serum "possibly contributes to increased rates of floppy infant syndrome at delivery, decreased foetal heart rate variability, and seizures in infancy", and that "The majority of these data come from case reports and case series".⁹ A case series of four pregnancies in three women found partial placental passage and a mean neonatal clozapine half-life of 92 hours.¹² The label tells clinicians to monitor exposed newborns for extrapyramidal and withdrawal symptoms.¹

Clozapine and breastfeeding

The label states: "Clozapine is present in human milk. There is one case report of sedation and a report of agranulocytosis in an infant exposed to clozapine through human milk". It asks that the benefits of breastfeeding "be considered along with the mother’s clinical need for CLOZARIL and any potential adverse effects on the breastfed child", and says exposed infants "should be monitored for excess sedation and neutropenia".¹

LactMed, the lactation database of the National Institute of Child Health and Human Development, states that because published experience is limited and sedation and adverse hematologic effects have been reported in breastfed infants, "other agents are preferred". It adds that "breastfeeding is not contraindicated during clozapine use" and that "some sources recommend that women taking clozapine not breastfeed". If a mother taking clozapine does breastfeed, it advises close monitoring for excessive sedation and periodic monitoring of the infant's white blood cell count. Only the LactMed summary was retrieved for this page.¹³

A combined analysis reported a mean breast milk penetration ratio of 3.19 for clozapine (range 2.79 to 4.32), the second highest after amisulpride.¹⁴ How the baby is fed is decided with the psychiatrist and the baby's doctor.

Limitations of the evidence

This evidence has limitations. First, the clozapine-specific data are case reports, case series and a cohort of 106 exposed pregnancies. Second, the registry and large-cohort figures describe second-generation antipsychotics as a class, and the gestational diabetes estimate pooled olanzapine with clozapine and was not statistically significant. Nevertheless, the label and the 2021 systematic review agree that the available data have not established a risk of major birth defects, and the decision is made case by case with the psychiatrist and obstetric team, before conception where possible.

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

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