Currently, the second-generation "atypical" antipsychotics, such as olanzapine (Zyprexa), aripiprazole (Abilify), and risperidone (Risperdal), are used far more frequently than are the first-generation "typical" antipsychotics, such as haloperidol. This is largely because the newer agents are used for a wider spectrum of illnesses that include bipolar disorder, anxiety disorders, and obsessive compulsive disorder, in addition to chronic psychotic illnesses such as schizophrenia.
As a result, a large number of women of reproductive age are being treated with atypicals, and given the persistent rate of unplanned pregnancies in the United States and globally, many women treated with atypicals become pregnant every year. But compared with the amount of reproductive safety information available for many classes of psychiatric medicines such as selective serotonin reuptake inhibitors (SSRIs), the reproductive safety data on both atypical and typical antipsychotics are relatively sparse.
The data on the older typical antipsychotics – from small-case series and one meta-analysis published in 1996 – do not suggest an increased risk for major malformations associated with first trimester exposure to this class (Am. J. Psychiatry 1996;153:592-606).
Atypical antipsychotics also include medications such as clozapine (Clozaril), ziprasidone (Geodon), paliperidone (Invega), quetiapine (Seroquel), asenapine (Saphris), lurasidone (Latuda), and iloperidone (Fanapt). The reproductive safety data on these drugs as a class include a small prospective study of 110 pregnancies in women treated with atypical antipsychotics (olanzapine, risperidone, quetiapine, and clozapine) during pregnancy, which found no signal for teratogenicity. The rate of major malformations was 0.9% in this group, which was not significantly different from the rate in the nonexposed group and was not higher than the 1%-3% baseline risk in the general population (J. Clin. Psychiatry 2005; 66:444-9).
However, this was a small sample and the findings were considered preliminary.
Because of the considerable use of atypicals to treat psychiatric disorders, the field has been waiting for more substantial information regarding the risks associated with fetal exposure to these newer drugs. Prompted by the lack of such data, the National Pregnancy Registry for Atypical Antipsychotics at Massachusetts General Hospital was established in 2008.
Now, the data we have been waiting for, from the registry and other sources, are beginning to emerge, and are providing some reassuring – though still preliminary – information regarding the risk for major congenital malformation risks associated with first trimester exposure to these drugs.
Published in August, a prospective observational cohort study conducted by the Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy in Germany compared the risk for major malformations and other adverse pregnancy outcomes among 561 women exposed to atypical antipsychotics, 284 women exposed to typical antipsychotics, and 1,122 pregnant women treated with medications known not to be harmful during pregnancy (the reference group) from January 1997 to March 2009.
After an effort to adjust for potential confounders, there was not a significant difference between the rates of major malformations, the primary endpoint, between those exposed to atypical antipsychotics (5.1%) or typical antipsychotics (4.2%) in the first trimester. The major malformation rate was higher among those exposed to typical antipsychotics than in the reference group, but the difference was not statistically significant. However, the major malformation rate was about twofold greater among those on atypicals compared to the reference group (odds ratio, 2.17), a significant difference. In the group exposed to atypicals, the most common major malformations were cardiovascular, and of the cardiac malformations, most (8 of 12) were atrial or ventricular septal defects (J. Clin. Psychopharmacol. 2013;33 453-62).
(The rate of symptoms suggesting "poor neonatal adaptation" were also significantly higher in the two antipsychotic-exposed groups.)
As the authors point out, cardiac septal defects are one of the most common congenital malformations, and this difference could be due to a detection bias, because women exposed to a medicine for which there are sparse reproductive safety data – particularly one in a relatively new class of drugs – may be more likely to get prenatal and postnatal diagnostic testing.
In the first presentation of the National Pregnancy Registry for Atypical Antipsychotics at an annual meeting in June, my coinvestigators and I concluded that atypical antipsychotics are unlikely to be major teratogens, like valproic acid. Based on 143 cases of first trimester exposure to atypicals, we described a risk with a very wide confidence interval with its outer bound being 5.5%. These data are considered preliminary at this point, and we plan to publish data based on a larger series with a nonexposed reference group in the next year.
Considering how widely the atypical antipsychotics are used across disease states by sexually active reproductive-age women, what can the clinician conclude based on the currently available reproductive safety data on atypical antipsychotics? Based on the 2005 study, the German study, and our report on the registry data, it is reasonable to conclude that second-generation antipsychotics are not major teratogens. They are not valproate (Depakote) or thalidomide. As I have noted in previous columns, when it comes to using psychiatric medicines, or most other medications for that case during pregnancy, there is no perfect decision and no decision is risk free. Given the importance of treating psychiatric illness during pregnancy and the evolving data that illustrate the adverse impact of untreated psychiatric illness on a wide range of neonatal and obstetrical outcomes – and on increasing the risk for postpartum psychiatric illness – one could consider a risk-benefit decision that places the use of atypical antipsychotics as not contraindicated.