Reproductive Safety of Second Generation Antipsychotics

An update on the reproductive safety of second-generation antipsychotics offers valuable information for clinicians prescribing these medications to reproductive-aged individuals.

May 2023
Reproductive Safety of Second Generation Antipsychotics

Atypical antipsychotics are increasingly used in women of reproductive age as primary or adjunctive therapy across a wide range of psychiatric disorders (including bipolar disorder, schizophrenia, unipolar depression, and anxiety disorders), thus increasing the need for accurate reproductive safety information for these medications.

The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) is a timely and ideal mechanism for collecting important reproductive safety data on second-generation antipsychotics (SGAs).

The Registry is the first hospital-based pregnancy registry in North America to systematically and prospectively examine the risk of malformations among infants exposed in utero to SGAs. The objective of this report is to present updated results from the NPRAA since the last publication describing reproductive safety data for this class of psychotropics.

Methods

This ongoing prospective cohort follows pregnant women with psychiatric illness, ages 18 to 45, who are exposed and not exposed to SGAs during pregnancy. These medications include aripiprazole, aripiprazole lauroxil, asenapine, clozapine, iloperidone, lurasidone, olanzapine, olanzapine pamoate, paliperidone, quetiapine, risperidone, ziprasidone, brexpiprazole, cariprazine, and paliperidone palmitate.

The exposed group consists of women who used at least one SGA during the first trimester of pregnancy. The comparison group consists of women with a history of psychiatric problems who are being treated with a variety of psychotropic medications other than SGAs.

Participants are interviewed by telephone 3 times throughout pregnancy: at enrollment, at 7 months, and at 3 months postpartum. The initial interview reports on demographic characteristics, medication use and dosage changes (if any, before and during pregnancy), social habits (smoking, alcohol consumption, and illicit drug use), medical, psychiatric, and family history of defects. of birth.

The 7-month interview collects data on changes in medication or dosage and medical problems during pregnancy. During the final postpartum interview, information on pharmacotherapy, labor, delivery, and neonatal health outcomes is obtained.

Outcomes data are also obtained through review of medical records from obstetrics, labor and delivery, and pediatrics.

The primary outcome is the presence of a major malformation identified within 6 months of birth. Major malformation is defined as a structural abnormality with surgical, clinical or cosmetic significance.

Clear chromosomal and single-gene abnormalities were excluded. Other exclusions included minor malformations, deformities, birthmarks, physiological characteristics due to prematurity, and any findings on prenatal ultrasound or at surgery (or autopsy) that were not identified by an examining pediatrician (or other medical professional).

Secondary outcomes include neonatal, obstetric, and neurobehavioral outcomes that are not included in this analysis.

Results

Between the start of the NPRAA in November 2008 and the data analysis cutoff point on April 9, 2020, a total of 1,906 women were enrolled.

For this analysis, 1311 individuals were eligible based on completion of the postpartum interview; 621 had first trimester exposure to an atypical antipsychotic, and 690 had no exposure to an atypical antipsychotic during pregnancy.

The remaining women in the sample were ineligible because they either had not completed their postpartum interview or dropped out of the study, were lost to follow-up, or had a spontaneous or therapeutic abortion without known major malformation. An additional 48 women were not included because they were exposed to an atypical antipsychotic during their second or third trimester, but not during the first trimester.

Exposed participants were older at the onset of their primary psychiatric diagnosis and had a lower proportion of lifetime illness than those not exposed to an atypical antipsychotic.

Women in the exposed group were more likely to have a diagnosis of bipolar disorder than those in the unexposed group; those in the unexposed group were more likely to have a primary diagnosis of major depression or anxiety.

In order of prevalence, the most used atypical antipsychotics in the exposed group were quetiapine, aripiprazole and lurasidone. Among the 640 babies exposed to SGAs, 16 major malformations were identified.

In the comparison group of 704 unexposed babies, 14 major malformations were identified. The prevalence in the exposed group was estimated at 2.50% compared to 1.99% in the non-exposed group.

Discussion

Based on the current data of this work, the estimated odds ratio for major malformations was 1.48 (95% CI 0.625–3.517). Therefore, this odds ratio estimate is likely to be lower than for other important teratogens, although more modest effects cannot be ruled out.

The current findings are consistent with some, but not all, studies. Two large epidemiological studies reported a 1.5- to 2-fold increase in the risk of major malformations. Furthermore, they also found a significant increase in heart defects, primarily atrial and ventricular septal defects, among infants exposed to SGAs.

Although cardiac septal defects are among the most common congenital malformations in the general population, it is also highly likely that detection bias plays an important role in the preponderance of cardiac defects.

Pregnant women on atypical antipsychotic medications are more likely to be offered fetal echocardiography and increased monitoring compared with women not on such medications. Interestingly, they did not see a significant increase in heart defects in this analysis.

It is also reassuring that these findings are consistent with one of the largest studies to date involving a sample of more than one million women. In that study, the estimated hazard ratio, after adjusting for psychiatric conditions, was 1.05 (95% CI 0.96–1.16) among infants exposed versus not exposed to SGAs, demonstrating no increased risk of malformations. important for medication as a class.

Furthermore, a characteristic of a teratogen is that it tends to cause a specific type or pattern of malformations. They found no preponderance of a single type of major malformation or specific pattern of malformations between the exposed and unexposed groups. However, the absolute risk of a malformation in the unexposed group was 1.99%, which was lower than expected and may be due to random error or higher rates of healthy behavior in women who choose to enroll in a pregnancy record.

In conclusion, the authors’ results suggest that the use of atypical antipsychotics during the first trimester does not substantially increase the risk of major malformations.

An important clinical implication of these findings is that for women with major mood disorders and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, as is recommended for continued treatment in women. pregnant women with other serious and chronic medical conditions, such as epilepsy.