Second-generation or “atypical” antipsychotics, such as olanzapine (Zyprexa), aripiprazole (Abilify), and risperidone (Risperdal), are used far more frequently than are the first-generation or “typical” antipsychotics, such as haloperidol (Haldol). This is largely because the newer agents are associated with fewer side effects and, as a result, have been used for a wider spectrum of illnesses, including bipolar disorder, anxiety disorders, and obsessive compulsive disorder, in addition to chronic psychotic illnesses such as schizophrenia.

Consequently a large number of women of reproductive age are now being treated with atypical antipsychotic agents, and we are seeing an increasing number of women seeking consultations regarding the reproductive safety of these newer medications.  However, compared with the amount of reproductive safety data available for other classes of psychiatric medicines such as selective serotonin reuptake inhibitors (SSRIs), we have much less information on the reproductive safety of atypical and typical antipsychotics.

Over the last couple of years, we have seen a series of studies assessing the reproductive safety of this class of medications.  These studies have varied considerably in terms of size and methodology, and it has been difficult to piece together this information and to form evidence-based recommendations regarding the use of antipsychotic medications during pregnancy.  In the May issue of Obstetrics and Gynecology, a group of researchers has published a systematic review and meta-analysis of the adverse obstetric and neonatal outcomes associated with exposure to antipsychotics during pregnancy.

PubMed, Reprotox, and ClinicalTrials.gov were searched to identify case–control or cohort studies measuring birth outcomes associated with antipsychotic exposure during pregnancy.  Thirteen cohort studies, including 6,289 antipsychotic-exposed and 1,618,039 unexposed pregnancies, were included.

Looking at exposure to all antipsychotics (typical and atypical), antipsychotic exposure was associated with:

  • Increased risk of major malformations (odds ration [OR] 2.12, 95% confidence interval [CI] 1.25–3.57, P=.005)
  • Increased risk of cardiac defects (OR 2.09, 95% CI 1.50–2.91, P<.001)
  • Increased risk of preterm delivery (OR 1.86, 95% CI 1.45–2.39, P<.001)
  • Lower birth weight (weighted mean difference -57.89 g, 95% CI -103.69 to -12.10 g, P=.01)
  • Small for gestational age (OR 2.44, 95% CI 1.22–4.86, P=.01)

There was no significant difference in the risk of major malformations between typical (OR 1.55, 95% CI 1.21–1.99, P=.006) and atypical (OR 1.39, 95% CI 0.66–2.93, P=.38) antipsychotic medications.  Antipsychotic exposure was not associated with risk of large-for-gestational-age births, stillbirth, and spontaneous abortion.

Although the findings suggest that antipsychotic exposure during pregnancy is associated with an increased risk of adverse obstetric and neonatal outcomes, how we use this data to inform our decisions is not so straightforward.  Put simply, association does not necessarily imply causation.  We cannot say that antipsychotics caused these adverse outcomes.  It is possible, and likely, that other factors common in this population may have contributed to the outcomes. While this study included a large number of exposed pregnancies, the researchers were not able to adjust for potential confounding factors.

Probably the most important confounding factor is psychiatric illness itself.  The population of women who uses antipsychotic medications is heterogeneous, and a significant proportion of these suffer from a severe mental illness, such as schizophrenia.  We have seen multiple reports that demonstrate that women with severe or chronic mental illness have worse pregnancy outcomes (in the absence of exposure to psychotropic medications), so we cannot conclude if the worse outcomes we observe are the result of medication exposure or the result exposure to psychiatric illness and/or certain behaviors that go along with illness (i.e., poor prenatal care, smoking, substance use).

The Bottom Line

This is a particularly difficult clinical situation.  Many women who take antipsychotic medications have severe or refractory illness and cannot reasonably consider discontinuing the antipsychotic or have no other clinically effective alternatives.  Women who are pregnant or planning to conceive are forced to make decisions in the absence of adequate data regarding the reproductive safety of the antipsychotic medications.  While there is a tendency to consider discontinuing or avoiding medications in the mothers as the safest option, there is considerable evidence to indicate that untreated illness in the mother also carries significant risks.

So how does this study influence how clinicians should advise their patients regarding the use of antipsychotic medications during pregnancy?  What we can tell our patients is that several studies have raised concerns regarding the risk of certain adverse outcomes.  Reassuringly, the magnitude of the effects is small and we cannot rule out the possibility that other factors are involved.  While these findings may raise concerns, we clearly need more data to better understand how maternal illness may be contributing to this clinical picture and to fully appreciate the long-term implications of these clinical findings.

Moving Forward

In order to fill this void, the National Pregnancy Registry for Atypical Antipsychotics was created to evaluate the safety of atypical antipsychotic medications taken by women during pregnancy. The goal of this Registry is to gather information on the safety of these medications during pregnancy. Clinicians or women taking antipsychotic medications may CALL TOLL-FREE to learn more: 1-866-961-2388, or may email the Registry at registry@womensmentalhealth.org.

The registry is continuing to recruit pregnant women aged 18-45 years who are treated with one or more atypical antipsychotics, and will prospectively follow them for a spectrum of outcomes, including organ malformations and maternal or newborn complications. These drugs include aripiprazole (Abilify), clozapine (Clozaril), ziprasidone (Geodon), paliperidone (Invega), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), asenapine (Saphris), lurasidone (Latuda), and Iloperidone (Fanapt).

Ruta Nonacs

Coughlin CG, Blackwell KA, Bartley C, Hay M, Yonkers KA, Bloch MH.  Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy.  Obstet Gynecol. 2015 May;125(5):1224-35.