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Annotated Abstracts of Journal Articles
2014, 1st Quarter

Women's Mental Health

Annotations by Christina Wichman, DO, FAPM
March 2014

Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism

Hviid A, Melbye M, Pasternak B
N Engl J Med 2013 Dec 19; 369(25):2406-15

ANNOTATION (Christina Wichman)

The Finding: Children exposed to antidepressants during pregnancy had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2-1.9) of being diagnosed with an ASD compared with unexposed children. The association was similar regardless of type of antidepressant, timing of antidepressant exposure, and dosage of antidepressant. Because maternal psychiatric disorder carries a risk for ASD in the offspring, the researchers attempted to separate the effect of medication from that of the underlying indication for treatment. When the researchers included only the children of women with a diagnosis of mood disorder, the adjusted hazard ratio (aHR) decreased to 1.2 (95% CI 0.7-2.1). The risk was further reduced when exposed children were compared to their unexposed siblings (aHR = 1.1; 95% CI 0.5-2.3).

Strength and Weaknesses: This study utilized the Danish population registry, linking drug use during pregnancy and ASD in offspring, and included a very large cohort (n = 626,875 live births, including 52 cases of ASD in offspring of women with SSRI exposure during pregnancy). It should be noted that overall prevalence of SSRI use in pregnancy was 0.97%, significantly lower than prevalence quoted in the United States. It inherently has issues involved with registry/database review of data (i.e., medication prescribed was actually filled and taken, offspring diagnosed with ASD actually met criteria for diagnosis, etc.).

Relevance: Given the number of factors that may influence risk for autism spectrum disorders, it is difficult to differentiate the impact of prenatal exposure to antidepressants from other prenatal exposures and genetic factors. It appears that the association between prenatal antidepressant exposure and ASD in the offspring observed in previous studies may be the result of confounding factors, specifically the underlying indication for antidepressant use.


Background: Studies have raised concern about an association between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and an increased risk of autism spectrum disorders in the offspring.

Methods: We conducted a cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009. Using Danish population registries, we linked information on maternal use of SSRIs before and during pregnancy, autism spectrum disorders diagnosed in the offspring, and a range of potential confounders. We used a survival analysis of the time to diagnosis in the offspring with Poisson regression to estimate rate ratios of autism spectrum disorders according to maternal use of SSRIs.

Results: During 5,057,282 person-years of follow-up, we identified 3892 cases of autism spectrum disorder (incidence rate, 77.0 per 100,000 person-years). A total of 52 cases during 42,400 person-years of follow-up involved offspring of women who were exposed to SSRIs during their pregnancy (incidence rate, 122.6 per 100,000 person-years). As compared with no use of SSRIs both before and during pregnancy, use during pregnancy was not associated with a significantly increased risk of autism spectrum disorders (fully adjusted rate ratio, 1.20; 95% confidence interval [CI], 0.90 to 1.61). Among women who received SSRIs before pregnancy but not during pregnancy, the corresponding fully adjusted rate ratio was 1.46 (95% CI, 1.17 to 1.81).

Conclusions: We did not detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring. On the basis of the upper boundary of the confidence interval, our study could not rule out a relative risk up to 1.61, and therefore the association warrants further study. (Funded by the Danish Health and Medicines Authority.)

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Longitudinal pattern of depressive symptoms around natural menopause
Freeman EW, Sammel MD, Boorman DW, Zhang R
JAMA Psychiatry 2014 Jan; 71(1):36-43

ANNOTATION (Christina Wichman)

The Finding: The overall prevalence of high (>16) CES-D scores decreased from 10 years before to 8 years after the final menstrual period (FMP), with an overall decrease of 15% per year. The pattern of depressive symptoms were strongly modified by a personal history of depression; women with a history of depression were more than 13 times more likely to have high depressive symptoms compared to women without a personal history of depression. Both groups had higher risk of depressive symptoms in the years before FMP and less risk each year after FMP.

Strength and Weaknesses: This study was able to investigate within-woman changes in depressive symptoms relative to FMP for 10 years before and 8 years after natural menopause in a population-based sample. The CES-D was utilized for reporting of depressive symptoms; while a cut-off of 16 or higher (standard measure of depressive symptoms, but may not indicate a clinical diagnosis of depression) was defined as the high depressive symptom group, a higher cut point of 25 was noted to have similar results.

Relevance: In this study, the final menstrual period proved to be pivotal; there was a higher risk of depressive symptoms before the FMP and lower risk after the FMP. This is consistent with other studies demonstrating an increased risk of depressive symptoms during the menopause transition. However, it was also noted that risk of depressive symptoms continued to decline after menopause, as compared to levels at FMP.


Importance: An increased risk of depressive symptoms has been associated with the transition to menopause, but the risk of depressive symptoms in the early postmenopausal years has not been well characterized.

Objectives: To identify within-woman changes in depressive symptoms during a 14-year period around menopause, determine associations of a history of depression with the pattern of depressive symptoms, and evaluate the rate of change in reproductive hormones as predictors of depressive symptoms following menopause.

Design, Setting, and Participants: A randomly identified, population-based sample in Philadelphia County, Pennsylvania, of 203 late-reproductive-age women who were premenopausal at baseline and reached natural menopause.

Main Outcomes and Measures: Center for Epidemiologic Studies Depression Scale.

Results: The prevalence of high scores on the Center for Epidemiologic Studies Depression Scale decreased from 10 years before to 8 years after the final menstrual period (FMP), with a decrease of approximately 15% of baseline per year (odds ratio, 0.85; 95% CI, 0.81-0.89; P<.001). Relative to the FMP, the risk of depressive symptoms was higher in the years before and lower in the years after the FMP. Among women with a history of depression, the likelihood of depressive symptoms was more than 13 times greater overall and 8 times greater after menopause compared with women with no depression history. Among women who first experienced depressive symptoms approaching menopause, the risk of depressive symptoms declined after the FMP, with a significantly lower risk the second year after menopause. The risk of depressive symptoms after menopause decreased by 35% for each unit (SD) increase before the FMP in the log rate of change of follicle-stimulating hormone (odds ratio, 0.65; 95% CI, 0.46-0.91; P=.01).

Conclusions and Relevance: The FMP was pivotal in the overall pattern of decreasing depressive symptoms in midlife women, with higher risk before and lower risk after the FMP. A history of depression strongly increased the risk both before and after menopause. Women who had no history of depression before the menopause transition had a low risk of depressive symptoms 2 or more years after the FMP.

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