Annotated Abstracts of Journal Articles
2014, 3rd Quarter
Annotations by Leena Mittal, MD
Huybrechts KF, Palmsten K, Avorn J, et al
N Engl J Med 2014 Jun 19; 370(25):2397-407
ANNOTATION (Leena Mittal)
The Finding: This cohort study of 64,389 women nested within a large population-based cohort study of women enrolled in the nationwide Medicaid Analytic eXtract found no substantial increase in risk of cardiac malformations in infants of women with depression who use antidepressants (SSRI, SNRI, bupropion and TCA) in the first trimester when compared with women with depression without antidepressant use. This association was further attenuated by adjusting for a variety of factors including severity of depression, other indications for antidepressant use, sociodemographic factors, and health care utilization factors. In the unadjusted analysis, the relative risks of any cardiac defect with the use of SSRI was 1.25 (CI 1.13 to 1.38). However, these findings were attenuated by adjustment for women with depression only (RR 1.12 with CI 1.00-1.26) and a cohort that was fully adjusted for depression, depression severity, and other confounders (RR 1.06; 95% CI 0.93-1.22).
Strength and Weaknesses: The strengths of this study include its large sample size within a national database of Medicaid enrolees with the ability to link maternal and infant records as well as the use of propensity score matching to adjust for a large set of potential confounders. All major antidepressants were included. Additionally, this study controlled for the presence and severity of depression. While epidemiologic studies are often challenged to define exposure and timing of that exposure during pregnancy, these investigators enlisted secondary analyses limiting exposure to first trimester only and required women to have a filled prescription or refilled prescription which did not alter the findings substantially. The findings are further bolstered by the the replication of prior reports’ findings of associations between well-known risk factors for cardiac malformation such as diabetes, use of anticonvulsant, multifetal pregnancy.
Some of the limitations of this study include its use of a Medicaid population with is younger and more racially diverse than populations in prior studies, though the authors found no effect related to age or race. The data also included only live births, thus excluding pregnancies resulting in stillbirth, termination, or spontaneous abortion that could have been the result of more severe cardiac malformation. Additionally, the information on important lifetstyle factors such as smoking, alcohol use, and obesity was limited or absent.
Relevance: The use of psychotropics, especially antidepressants, during pregnancy is the focus of much scrutiny. Additionally, the role of untreated or unremitted symptoms of mental illness on pregnancy outcomes and infant outcomes has a growing body of literature. The decision about whether to initiate or continue an antidepressant during pregnancy should be made with careful consideration that balances the risk of that medication with the risk of the untreated symptoms, and this study adds to this discussion by carefully analyzing the risks of cardiac malformation associated with antidepressants.
This study calls into question previous findings from earlier epidemiologic studies that implicated paroxetine with a higher risk of right ventricular outflow tract obstructions in infants exposed in utero which resulted in the FDA eventually reclassifying the drug to Category D. Similarly, sertraline, one of the most commonly prescribed SSRIs used in pregnancy, was previously associated with ventricular septal defects. Given the increasing prevalence of antidepressant use (among other psychotropics) during pregnancy, this study adds to the large body of literature suggesting low absolute and relative risk of antidepressant use during pregnancy and specifically argues against teratogenic effects associated with common antidepressants.
Background: Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects.
Methods: We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders.
Results: A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41).
Conclusions: The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.)
ANNOTATION (Leena Mittal)
The Finding: This two-site, randomized controlled trial compared collaborative care for depression with usual care in women’s health settings. 205 patients were randomized to the intervention or usual care. The Depression Attention of Women Now intervention improved depression symptom and functional outcomes, adherence to depression treatment, and treatment satisfaction among women being treated in two academic, urban obstetric and gynecology clinics.
Strength and Weaknesses: This was a randomized controlled trial with blinded assessment in which patients were randomized to either a usual care or a collaborative care program for depression that was adapted specifically for obstetrics and gynecology clinics. The women were followed at 6, 12 and 18 month follow-up visits. This study demonstrated that this type of collaborative care model with depression care management, tracking and team meetings with psychiatrist, care manager, and site clinician is feasible and accepted by patients and improves outcomes. A notable strength of the findings is that the usual care group had access to antidepressant medication and mental health care referral, suggesting that the model itself is superior to usual care.
Only a small proportion of patients in either group were pregnant and postpartum status not designated. Given that the perinatal period (pregnancy and postpartum) is a time of higher risk for depression, the impact of this intervention as a function of perinatal status would be useful. Additionally, it would be useful to know if pregnant or postpartum women enrolled in this study at a lower rate than other women, or if this distribution was reflective of the clinic populations.
There was a delayed response noted as compared to previous trials as the two groups did not differ at 6-month follow-up visits, but the effects were seen at 12- and 18-month follow-ups. The authors attribute this to the high rates of poverty and PTSD in the study and usual care populations. This distinct population may limit the study’s generalizability to higher socioeconomic status populations or those with less chronic stress and PTSD.
Relevance: The authors note that more than a third of women seek care solely in women’s health or obstetrics/gynecology settings, making this trial especially applicable for women’s mental health care needs. There is a large body of literature on collaborative care models for depression in primary care settings across a variety of settings, but this is the largest randomized trial of such a model in a women’s health setting.
Objective: To evaluate an evidence-based collaborative depression care intervention adapted to obstetrics and gynecology clinics compared with usual care.
Methods: A two-site, randomized controlled trial included screen-positive women (Patient Health Questionnaire-9 score of at least 10) who met criteria for major depression, dysthymia, or both (Mini-International Neuropsychiatric Interview). Women were randomized to 12 months of collaborative depression management or usual care; 6-month, 12-month, and 18-month outcomes were compared. The primary outcomes were change from baseline to 12 months in depression symptoms and functional status. Secondary outcomes included at least 50% decrease and remission in depressive symptoms, global improvement, treatment satisfaction, and quality of care.
Results: Participants were, on average, 39 years old, 44% were nonwhite, and 56% had posttraumatic stress disorder. Intervention (n=102) compared with usual care (n=103) patients had greater improvement in depressive symptoms at 12 months (P<.001) and 18 months (P=.004). The intervention group compared with usual care group had improved functioning over the course of 18 months (P<.05), were more likely to have at least 50% decrease in depressive symptoms at 12 months (relative risk [RR] 1.74, 95% confidence interval [CI] 1.11-2.73), greater likelihood of at least four specialty mental health visits (6-month RR 2.70, 95% CI 1.73-4.20; 12-month RR 2.53, 95% CI 1.63-3.94), adequate dose of antidepressant (6-month RR 1.64, 95% CI 1.03-2.60; 12-month RR 1.71, 95% CI 1.08-2.73), and greater satisfaction with care (6-month RR 1.70, 95% CI 1.19-2.44; 12-month RR 2.26, 95% CI 1.52-3.36).
Conclusion: Collaborative depression care adapted to women’s health settings improved depressive and functional outcomes and quality of depression care.