text: A new study has found no direct link between antidepressant use during pregnancy and one type of birth defect. 
   
   The research, published in today’s issue of the New England Journal of Medicine, comes nine years after the U.S. Food and Drug Administration warned that exposure to selective serotonin reuptake inhibitors — the most commonly prescribed antidepressants — might increase the risk of heart malformations in the developing fetus. ||||| WEDNESDAY, June 18, 2014 (HealthDay News) -- Antidepressants taken during the first three months of pregnancy don't appear to increase the risk of heart defects in babies, new research suggests. 
   
   However, this latest study contradicts previous research that found that taking antidepressants in pregnancy can be risky. 
   
   The question is an important one because depression is common in pregnancy. It's diagnosed in 10 percent to 20 percent of pregnant women, and up to 13 percent of women take antidepressants while pregnant, according to the researchers. 
   
   "The most critical period in the development of an embryo or in the growth of a particular organ is during the time of most rapid cell division," said Krista Huybrechts, lead study author and epidemiologist at the Brigham and Women's Hospital, in Boston. So, it is in the first three months of pregnancy that the risk for developing major malformations is highest, she explained. 
   
   The U.S. government-funded research was published in the June 19 issue of the New England Journal of Medicine. 
   
   The current study's findings run counter to two previous studies that caused the U.S. Food and Drug Administration in 2005 to formally warn health care professionals that early prenatal exposure to paroxetine (Paxil) may increase the risk of heart malformations at birth. 
   
   Huybrechts and her team had some concerns about the earlier research and wanted to re-examine the evidence by designing their study differently. They tightened the focus and took more factors that could interfere with the data into account, she said. The team looked at whether antidepressants, including those called selective serotonin reuptake inhibitors, or SSRIs -- such as paroxetine (Paxil) and sertraline (Zoloft) -- are indeed associated with an increased risk of heart defects at birth. 
   
   The researchers tapped data from 46 states and Washington, D.C., from 2000 through 2007. They were able to use demographic information, such as age, income and education, as well as data about all physician services and hospitalizations, including diagnoses, procedures and filled outpatient prescriptions. 
   
   A total of almost a million women who had given birth were included in the study. They were all on Medicaid without supplementary private insurance. All of the women were between 12 to 55 years of age. Women were excluded if they had been treated with drugs that have been associated with birth defects (such as chemotherapy, lithium, retinoids and thalidomide) or if their infants had been diagnosed with a genetic abnormality. ||||| Data Source and Study Cohort 
   
   The study cohort was drawn from the Medicaid Analytic eXtract for 46 U.S. states and Washington, D.C., for the period of 2000 through 2007. Montana and Connecticut were excluded because of difficulty in linking data for mothers and infants, Michigan was excluded because of incomplete data, and data from Arizona were not available. The Medicaid Analytic eXtract data set contains individual-level demographic and Medicaid enrollment information, as well as data on all physician services and hospitalizations and the accompanying diagnoses and procedures and all filled outpatient medication prescriptions. 
   
   The development of our study cohort has been described previously.22 Briefly, we identified all completed pregnancies in women and adolescents 12 to 55 years of age (hereafter, “women”) and linked these pregnancies to liveborn infants. Using a validated algorithm,23 we estimated the date of the last menstrual period on the basis of the delivery date and diagnostic codes indicative of preterm delivery. Finally, we required all the women to be eligible for Medicaid, without supplementary private insurance or restricted benefits, from 3 months before the last menstrual period through 1 month after delivery. We excluded pregnancies in which the infant had received a diagnosis of a chromosomal abnormality (1609 pregnancies) and pregnancies in which the mother had been treated with known teratogens during the first trimester (i.e., lithium, antineoplastic agents, retinoids, and thalidomide; 2476 pregnancies). 
   
   Study Conduct 
   
   The study was approved by the institutional review board of Brigham and Women's Hospital, and the need for informed consent was waived. The authors vouch for the accuracy and completeness of the analyses reported as well as for the fidelity of the report to the study protocol. 
   
   Antidepressant Medications 
   
   The etiologically relevant window for exposure extended from the date of the last menstrual period through day 90 of pregnancy (first trimester). We determined maternal use of antidepressants by a review of pharmacy dispensing records, using the dispensing date and the number of days of supply. Women were considered to have had exposure if the days of supply overlapped with the first trimester. We defined the following exposure categories: any SSRI, paroxetine, sertraline, fluoxetine, tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors (SNRIs), bupropion, and other antidepressants (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The reference group consisted of women without exposure to antidepressants during the first trimester. 
   
   Cardiac Malformations 
   
   Congenital cardiac malformations were identified on the basis of the presence of inpatient or outpatient diagnostic codes from the International Classification of Diseases, Ninth Revision (ICD-9), in the maternal or infant records during the first 90 days after delivery. We used both maternal and infant codes because an infant's claims may be recorded under the mother's identification number for the first several months after birth.24 On the basis of previously reported associations,13,14,19 outcomes were grouped in the following categories: any cardiac malformation, right ventricular outflow tract obstruction, ventricular septal defect, and other cardiac malformation (Table S2 in the Supplementary Appendix). We excluded anomalies related to prematurity (e.g., patent ductus arteriosus, pulmonary-valve stenosis, and anomalies of the pulmonary artery in preterm infants).25 A given outcome was considered to be present if there was more than one date with the respective diagnostic codes recorded or if there was one diagnostic code and a code for a cardiac procedure or surgery (Table S3 in the Supplementary Appendix). The positive predictive values for these outcome definitions did not differ substantially according to exposure and ranged from 66.7 to 79.5% in a conservative validation study that was based on review of primary medical records in a subset of cases.26 
   
   Covariates 
   
   The information on covariates that were being taken into consideration in the adjustment for confounding or that were being used for stratification was obtained during the baseline period (from the time before the last menstrual period through the end of the first trimester). In addition to sociodemographic information (year of delivery, state of residence, age, race, and parity), we considered known or suspected risk factors for congenital cardiac malformations and proxies for such risk factors: multiple gestation, chronic maternal illness (hypertension, diabetes, epilepsy, and renal disease), use of suspected teratogenic medications, use of other psychotropic medications (anticonvulsant, antipsychotic, anxiolytic, and hypnotic agents; other benzodiazepines; and barbiturates), use of antidiabetic and antihypertensive medications, and the number of distinct prescription drugs used, excluding antidepressants, as a general marker of coexisting conditions.27 To address confounding by the underlying indication, we considered proxies for depression severity (number of depression diagnoses received as an outpatient and as an inpatient) and other indications for antidepressant use (other mental health disorders, pain-related diagnoses, sleep disorders, the premenstrual tension syndrome, smoking, and the chronic fatigue syndrome). 
   
   Statistical Analysis 
   
   We compared the distributions of sociodemographic, clinical, and health care utilization characteristics among the various exposure groups, and we calculated the absolute risks of cardiac malformations. Logistic-regression analysis was used to estimate odds ratios for cardiac malformations and their corresponding 95% confidence intervals. Because the odds ratio is an excellent approximation of the risk ratio in the case of rare outcomes, the results are referred to as relative risks.28 Use of the robust variance estimator to account for correlations within women with multiple pregnancies did not change the confidence intervals appreciably, so correlation structures were omitted from all the analyses. 
   
   Results are presented for analyses performed according to three levels of adjustment: an unadjusted analysis; an analysis restricted to women with a depression diagnosis, to control for the potential effect of the underlying illness or factors associated with it; and an analysis restricted to women with a depression diagnosis and performed with the use of propensity-score stratification to further control for proxies of depression severity and other potential confounders.29 Propensity scores were derived from the predicted probability of treatment estimated in a logistic-regression model that contained all the covariates listed above without additional variable selection. We created 100 equally sized propensity-score strata, dropped uninformative strata (i.e., all strata that did not contain at least one treated woman and one untreated woman), and stratified the outcome models according to these propensity-score strata. In all cases, less than 0.5% of treated women and less than 0.1% of untreated women were included in the dropped strata. 
   
   In confirmatory analyses, we used a high-dimensional propensity-score algorithm, which evaluates thousands of diagnoses, procedures, and pharmacy-claim codes to identify and prioritize covariates that serve as proxies for unmeasured confounders. A total of 200 empirically identified confounders were selected and were combined with investigator-identified covariates to improve adjustment for confounding.30 No adjustments were made for multiple comparisons. 
   
   We performed prespecified subgroup and sensitivity analyses to evaluate the robustness of the primary results (for any cardiac malformation). Because the cohort we studied was younger and more racially diverse than cohorts in previous studies,13,14 we tested for effect modification according to age (<30 years vs. ≥30 years) and race or ethnic group (white vs. nonwhite). We conducted dose–response analyses for low, medium, and high doses of antidepressants using the first and highest doses dispensed (Table S4 in the Supplementary Appendix).31 In the analysis of SSRIs, we stratified the analysis according to the use of just that drug class versus the use of multiple antidepressant classes. 
   
   To evaluate the effect of potential misclassification of exposure, we redefined exposure status as having had one or more prescriptions filled during the first trimester (as compared with days of supply that overlap with the first trimester); we redefined the reference group as women with no antidepressant exposure throughout pregnancy. To evaluate the effect of potential misclassification of outcome, we restricted the outcome to inpatient diagnoses only and extended infant follow-up to 1 year. We corrected odds ratios for outcome misclassification using sensitivities and specificities consistent with the positive predictive values estimated in the internal validation study.26,32 To further assess whether outcomes were well captured, we evaluated some well-known associations in our data set — in particular, associations between cardiac malformations and maternal diabetes, use of an anticonvulsant agent, or multifetal pregnancy.33
target: – An estimated 8% to 13% of pregnant woman are on antidepressants, and not without warning: The FDA in 2005 amended antidepressants' labels to indicate that babies born to moms taking them could suffer an increased risk of heart defects. But causation hadn't been proven, and the latest study on the topic indicates those warnings may be baseless. The latest study, published in the New England Journal of Medicine, followed 949,504 pregnant women, 64,389 (6.8%) of whom used antidepressants during the first trimester—the period of the most rapid cell division, when the risk of developing such defects is highest, WebMD explains. What Krista Huybrechts of Brigham and Women's Hospital did differently: She and her team took into consideration factors that could lead to heart defects, like the mother's age and whether she had diabetes. The Boston Herald reports that among babies whose mothers did not take antidepressants, 72.3 per 10,000 were born with a cardiac defect, compared with 90.1 per 10,000 infants whose mothers did. After controlling for risk factors, "there is no evidence to support a substantial increased risk of cardiac malformations overall," says Huybrechts. Still, she cautions that antidepressant use during pregnancy poses a "whole range of other potential adverse outcomes." To wit, one expert pointed to "serious flaws" with the study. For one, it didn't flag miscarriages, which are linked to antidepressants. "It may be that the most severely affected pregnancies are miscarrying," he noted.