Annotated Abstracts of Journal Articles
2015, 4th Quarter
Annotations by Christina Wichman, DO, FAPM and Robin Valpey, MD
Boukhris T, Sheehy O, Mottron L, Bérard A
JAMA Pediatr 2015; 14:1-8
ANNOTATION (Neeta Shenai)
The Finding: The use of any antidepressant during the second and third trimester was associated with an increased risk of autism spectrum disorders (ASDs) (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of SSRIs during the second and/or third trimester was associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93).
Strength: This was a large, register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort. A very large number of singleton full-term infants (145,456) were analyzed.
• Antidepressant exposure was defined as having at least one prescription filled at any time during pregnancy or a prescription filled before pregnancy that overlapped the first day of gestation, however it could not confirm whether or not women actually took the medication.
• While a very large number of births were analyzed, only 1054 children (0.7%) were diagnosed with ASD. The numbers of children diagnosed with ASD were very small (n=31 with any antidepressant and n=22 with SSRIs) as compared to the 145,456 records reviewed. Children were identified as having ASD if at least one diagnosis of ASD was documented in the medical record, but independent clinical confirmation was not completed.
• The study does not fully account for the fact that women suffering from psychiatric illnesses already have a greater risk of having children with ASD. Although the authors controlled for maternal depression, there are not reliable measures of severity. Women who choose to take antidepressants during pregnancy are inherently a different group of women than those who choose not to take medications during pregnancy, despite having the same diagnosis. Therefore, it makes it very difficult to determine if the increased risk is due to the antidepressant medications or because women were experiencing more severe depression.
Relevance: Given the number of factors that may account for an increased risk for ASDs, it is difficult (if not impossible) to differentiate the impact of in utero exposure to antidepressants from other exposures and genetic factors. The association between in utero antidepressant exposure and ASD may be, all or at least in part, the result of confounding factors, specifically the underlying indication for antidepressant use.
Importance: The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.
Objective: To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression.
Design, Setting, and Participants: We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145 456 singleton full-term infants born alive and whose mothers were covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015.
Exposures: Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes.
Main Outcomes and Measures: Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs.
Results: During 904 035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97).
Conclusions: Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.
Cohen LS, Viguera AC, McInerney KA, et al
Am J Psychiatry 2015 Oct 6 [Epub ahead of print]
ANNOTATION (Meredith Leigh Spada)
The Finding: This 2015 study utilizes data from the first hospital-based pregnancy registry for second-generation antipsychotics in North America that prospectively evaluates risk of malformations among infants exposed in utero to antipsychotics. Of the three infants in the exposed group that developed major malformations, two of the malformations were cardiac in nature (transposition of the great arteries and ventricular septal defect), with the third being an imperforate hymen. All three infants were notably exposed to multiple agents, including other non-antipsychotic psychotropics. While the unadjusted odds ratio conveyed a 1.25 times greater risk for infants exposed to second-generation antipsychotics compared to those infants not exposed, adjustment for a number of confounding variables decreased this risk closer to 1, indicating that this preliminary finding may be an overestimate.
Strength and Weaknesses: The most notable strengths of this study involve its design, particularly related to its prospective analysis and the use of both medical records and participant interviews to provide in-depth information regarding the outcomes. The comparison group, consisting of women with psychiatric illnesses who are not using medications, helps to limit potential confounding from any pathophysiologic or behavioral contributions for those with psychiatric illness. The study additionally looked at clinically relevant factors such as chronicity of illness, which again facilitates the generalizability and relevance to the psychiatric patient population.
Weaknesses include the current size of the registry, as determining a statistically significant increased risk in rare malformations would take far more subjects than currently enrolled. In addition, determining risks related to specific agents is difficult given that a large number of subjects in both groups (79% in exposed and 44% in unexposed groups) were exposed to multiple psychiatric medications, including multiple antipsychotics. Finally, generalizability is further challenged by the potential selection bias, as the majority of participants were white, married, college-educated women who were motivated to participate in a longitudinal study.
Relevance: The data from this first American pregnancy registry looking at second-generation antipsychotic agents enables a prospective and longitudinal evaluation of the potential effect of these agents on infants exposed in utero. Second-generation antipsychotics are being used for a variety of reasons in clinical practice, ranging from sleep aid to mood stabilization and treatment of agitation or depression. As their clinical use becomes more common, the information obtained will enable better risk-benefit discussions with pregnant women regarding exposure to infants. This is particularly relevant now that the old classification of reproductive safety is being replaced with a system that details all available data of known risk of fetal exposure in order to facilitate such discussions with pregnant women and their families.
Objective: Second-generation antipsychotics are used to treat a spectrum of psychiatric illnesses in reproductive-age women. The National Pregnancy Registry for Atypical Antipsychotics was established to determine the risk of major malformations among infants exposed to second-generation antipsychotics during pregnancy relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.
Method: Women were prospectively followed during pregnancy and the postpartum period; obstetric, labor, delivery, and pediatric medical records were obtained. Eligible enrollees were pregnant women ages 18-45. The Registry is based at the Center for Women’s Mental Health at Massachusetts General Hospital. Women were recruited through provider referral, self-referral, and the Center’s web site.
Results: As of December 2014, 487 women were enrolled: 353 who used second-generation antipsychotics and 134 comparison women. Medical records were obtained for 82% of participants. A total of 303 women had completed the study and were eligible for inclusion in the analysis. Of 214 live births with first-trimester exposure to second-generation antipsychotics, three major malformations were confirmed. In the control group (N=89), one major malformation was confirmed. The absolute risk of major malformations was 1.4% for exposed infants and 1.1% for unexposed infants. The odds ratio for major malformations comparing exposed infants with unexposed infants was 1.25 (95% CI=0.13-12.19).
Conclusions: The results suggest that it would be unlikely for second-generation antipsychotics to raise the risk of major malformations more than 10-fold beyond that observed in the general population or among control groups using other psychotropic medications. If the estimate stabilizes around the null with ongoing data collection, findings may be reassuring for both clinicians and women trying to make risk-benefit treatment decisions about using atypical antipsychotics during pregnancy. These findings are timely given the renewed focus of regulatory agencies on reproductive safety.