Preterm Birth and Antidepressant Medication Use during Pregnancy: A Systematic Review and Meta-Analysis

Introduction: Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth. Methods: We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect. Results: Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI) were 1.53 (1.40–1.66) for antidepressant use at any time and 1.96 (1.62–2.38) for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92–1.45)] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association. Discussion Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out

Antidepressants and Breast and Ovarian Cancer Risk: A Review of the Literature and Researchers\u27 Financial Associations with Industry

Background Antidepressant (AD) use has been purported to increase the risk of breast and ovarian cancer, although both epidemiological and pre-clinical studies have reported mixed results [1]–[6]. Previous studies in a variety of biomedical fields have found that financial ties to drug companies are associated with favorable study conclusions [7]. Methods and Findings We searched English-language articles in MEDLINE, PsychINFO, the Science Citations Index and the Cochrane Central Register of Controlled Clinical Trials (through November 2010). A total of 61 articles that assessed the relationship between breast and ovarian cancer and AD use and articles that examined the effect of ADs on cell growth were included. Multi-modal screening techniques were used to investigate researchers\u27 financial ties with industry. A random effects meta-analysis was used to pool the findings from the epidemiological literature. Thirty-three percent (20/61) of the studies reported a positive association between ADs and cancer. Sixty-seven percent (41/61) of the studies reported no association or antiproliferative effect. The pooled odds ratio for the association between AD use and breast/ovarian cancer in the epidemiologic studies was 1.11 (95% CI, 1.03–1.20). Researchers with industry affiliations were significantly less likely than researchers without those ties to conclude that ADs increase the risk of breast or ovarian cancer. (0/15 [0%] vs 20/46 [43.5%] (Fisher\u27s Exact test P = 0.0012). Conclusions Both the pre-clinical and clinical data are mixed in terms of showing an association between AD use and breast and ovarian cancer. The possibility that ADs may exhibit a bi-phasic effect, whereby short-term use and/or low dose antidepressants may increase the risk of breast and ovarian cancer, warrants further investigation. Industry affiliations were significantly associated with negative conclusions regarding cancer risk. The findings have implications in light of the 2009 USPSTF guidelines for breast cancer screening and for the informed consent process

Harnessing the Medicaid Analytic eXtract (MAX) to Evaluate Medications in Pregnancy: Design Considerations

Background: In the absence of clinical trial data, large post-marketing observational studies are essential to evaluate the safety and effectiveness of medications during pregnancy. We identified a cohort of pregnancies ending in live birth within the 2000–2007 Medicaid Analytic eXtract (MAX). Herein, we provide a blueprint to guide investigators who wish to create similar cohorts from healthcare utilization data and we describe the limitations in detail. Methods: Among females ages 12–55, we identified pregnancies using delivery-related codes from healthcare utilization claims. We linked women with pregnancies to their offspring by state, Medicaid Case Number (family identifier) and delivery/birth dates. Then we removed inaccurate linkages and duplicate records and implemented cohort eligibility criteria (i.e., continuous and appropriate enrollment type, no private insurance, no restricted benefits) for claim information completeness. Results: From 13,460,273 deliveries and 22,408,810 child observations, 6,107,572 pregnancies ending in live birth were available after linkage, cleaning, and removal of duplicate records. The percentage of linked deliveries varied greatly by state, from 0 to 96%. The cohort size was reduced to 1,248,875 pregnancies after requiring maternal eligibility criteria throughout pregnancy and to 1,173,280 pregnancies after further applying infant eligibility criteria. Ninety-one percent of women were dispensed at least one medication during pregnancy. Conclusions: Mother-infant linkage is feasible and yields a large pregnancy cohort, although the size decreases with increasing eligibility requirements. MAX is a useful resource for studying medications in pregnancy and a spectrum of maternal and infant outcomes within the indigent population of women and their infants enrolled in Medicaid. It may also be used to study maternal characteristics, the impact of Medicaid policy, and healthcare utilization during pregnancy. However, careful attention to the limitations of these data is necessary to reduce biases

Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States

Objective: To determine whether use of serotonin or non-serotonin reuptake inhibitors near to delivery is associated with postpartum hemorrhage. Design Cohort study. Setting 2000-07 nationwide Medicaid data (Medicaid Analytic eXtract). Population 106 000 pregnant women aged 12-55 with a diagnosis of mood or anxiety disorder. Women were categorized into four mutually exclusive exposure groups according to pharmacy dispensing data: current (delivery date), recent (1-30 days before delivery date), past (1-5 months before delivery date), and no exposure (reference group). Main outcome measures Risk of postpartum hemorrhage by timing of exposure and by serotonin or non-serotonin reuptake inhibitors, classes of antidepressant, and antidepressant types. Relative risks and 95% confidence intervals adjusted for delivery year, risk factors for postpartum hemorrhage, indicators of severity of mood/anxiety disorder, other indications for antidepressants, and other drugs. High dimensional propensity score (hdPS) methods were used to empirically identify and adjust for additional factors. Results: 12 710 (12%) women had current exposure to serotonin reuptake inhibitor monotherapy, and 1495 (1.4%) women had current exposure to non-serotonin reuptake inhibitor monotherapy. The risk of postpartum hemorrhage was 2.8% among women with mood/anxiety disorders but no exposure to antidepressants, 4.0% in the current users of serotonin reuptake inhibitors, 3.8% in the current users of non-serotonin reuptake inhibitors, 3.2% in the recent users of serotonin reuptake inhibitors, 3.1% in the recent users of non-serotonin reuptake inhibitors, 2.5% in the past users of serotonin reuptake inhibitors, and 3.4% in the past users of non-serotonin reuptake inhibitors. Compared with no exposure, women with current exposure to serotonin reuptake inhibitors had a 1.47-fold increased risk of postpartum hemorrhage (95% confidence interval 1.33 to 1.62) and women with current non-serotonin reuptake inhibitor exposure had a 1.39-fold increased risk (1.07 to 1.81). Results were similar with hdPS adjustment. Women with current exposure to serotonin reuptake inhibitors had an adjusted excess risk of 1.26% (0.90% to 1.62%), with a number needed to harm of 80, and for women with current exposure to non-serotonin reuptake inhibitors the excess risk was 1.03% (0.07% to 1.99%), with a number needed to harm of 97. For exposure to serotonin reuptake inhibitors the relative risk was 1.19 (1.03 to 1.38) for recent exposure and 0.93 (0.82 to 1.06) for past exposure; for non-serotonin reuptake inhibitors the figures were 1.17 (0.80 to 1.70) and 1.26 (1.00 to 1.59), respectively. Current exposure to selective serotonin reuptake inhibitor monotherapy was also associated with postpartum hemorrhage (1.42, 1.27 to 1.57), as was current serotonin norepinephrine (noradrenaline) reuptake inhibitor (1.90, 1.37 to 2.63) and tricyclic monotherapy (1.77, 0.90 to 3.47). All types of selective serotonin reuptake inhibitors available for analysis and venlafaxine, a serotonin norepinephrine reuptake inhibitor, were significantly associated with postpartum hemorrhage. Conclusions: Exposure to serotonin and non-serotonin reuptake inhibitors, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics, close to the time of delivery was associated with a 1.4 to 1.9-fold increased risk for postpartum hemorrhage. While potential confounding by unmeasured factors cannot be ruled out, these findings suggest that patients treated with antidepressants during late pregnancy are more likely to experience postpartum hemorrhage

A population-based study of stimulant drug treatment of ADHD and academic progress in children.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.We evaluated the hypothesis that later start of stimulant treatment of attention-deficit/hyperactivity disorder adversely affects academic progress in mathematics and language arts among 9- to 12-year-old children. We linked nationwide data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations. The study population comprised 11,872 children born in 1994-1996 who took standardized tests in both fourth and seventh grade. We estimated the probability of academic decline (drop of ≥ 5.0 percentile points) according to drug exposure and timing of treatment start between examinations. To limit confounding by indication, we concentrated on children who started treatment either early or later, but at some point between fourth-grade and seventh-grade standardized tests. In contrast with nonmedicated children, children starting stimulant treatment between their fourth- and seventh-grade tests were more likely to decline in test performance. The crude probability of academic decline was 72.9% in mathematics and 42.9% in language arts for children with a treatment start 25 to 36 months after the fourth-grade test. Compared with those starting treatment earlier (≤ 12 months after tests), the multivariable adjusted risk ratio (RR) for decline was 1.7 (95% confidence interval [CI]: 1.2-2.4) in mathematics and 1.1 (95% CI: 0.7-1.8) in language arts. The adjusted RR of mathematics decline with later treatment was higher among girls (RR, 2.7; 95% CI: 1.2-6.0) than boys (RR, 1.4; 95% CI: 0.9-2.0). Later start of stimulant drug treatment of attention-deficit/hyperactivity disorder is associated with academic decline in mathematicsPfizer Novartis University of Iceland Icelandic Centre for Research (RANNIS

Comparison of Different Approaches to Confounding Adjustment in a Study on the Association of Antipsychotic Medication With Mortality in Older Nursing Home Patients

Selective prescribing of conventional antipsychotic medication (APM) to frailer patients is thought to have led to overestimation of the association with mortality in pharmacoepidemiologic studies relying on claims data. The authors assessed the validity of different analytic techniques to address such confounding. The cohort included 82,012 persons initiating APM use after admission to a nursing home in 45 states with 2001–2005 Medicaid/Medicare data, linked to clinical data (Minimum Data Set) and institutional characteristics. The authors compared the association between APM class and 180-day mortality with multivariate outcome modeling, propensity score (PS) adjustment, and instrumental variables. The unadjusted risk difference (per 100 patients) of 10.6 (95% confidence interval (CI): 9.4, 11.7) comparing use of conventional medication with atypical APM was reduced to 7.8 (95% CI: 6.6, 9.0) and 7.0 (95% CI: 5.8, 8.2) after PS adjustment and high-dimensional PS (hdPS) adjustment, respectively. Results were similar in analyses limited to claims-based Medicaid /Medicare variables (risk difference = 8.2 for PS, 7.1 for hdPS). Instrumental-variable estimates were imprecise (risk difference = 8.8, 95% CI: −1.3, 19.0) because of the weak instrument. These results suggest that residual confounding has a relatively small impact on the effect estimate and that hdPS methods based on claims alone provide estimates at least as good as those from conventional analyses using claims enriched with clinical information

Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study

Objective: To provide absolute and relative risk estimates of neonatal abstinence syndrome (NAS) based on duration and timing of prescription opioid use during pregnancy in the presence or absence of additional NAS risk factors of history of opioid misuse or dependence, misuse of other substances, non-opioid psychotropic drug use, and smoking. Design: Observational cohort study. Setting: Medicaid data from 46 US states. Participants: Pregnant women filling at least one prescription for an opioid analgesic at any time during pregnancy for whom opioid exposure characteristics including duration of therapy: short term (<30 days) or long term (≥30 days); timing of use: early use (only in the first two trimesters) or late use (extending into the third trimester); and cumulative dose (in morphine equivalent milligrams) were assessed. Main outcome measure Diagnosis of NAS in liveborn infants. Results: 1705 cases of NAS were identified among 290 605 pregnant women filling opioid prescriptions, corresponding to an absolute risk of 5.9 per 1000 deliveries (95% confidence interval 5.6 to 6.2). Long term opioid use during pregnancy resulted in higher absolute risk of NAS per 1000 deliveries in the presence of additional risk factors of known opioid misuse (220.2 (200.8 to 241.0)), alcohol or other drug misuse (30.8 (26.1 to 36.0)), exposure to other psychotropic medications (13.1 (10.6 to 16.1)), and smoking (6.6 (4.3 to 9.6)) than in the absence of any of these risk factors (4.2 (3.3 to 5.4)). The corresponding risk estimates for short term use were 192.0 (175.8 to 209.3), 7.0 (6.0 to 8.2), 2.0 (1.5 to 2.6), 1.5 (1.0 to 2.0), and 0.7 (0.6 to 0.8) per 1000 deliveries, respectively. In propensity score matched analyses, long term prescription opioid use compared with short term use and late use compared with early use in pregnancy demonstrated greater risk of NAS (risk ratios 2.05 (95% confidence interval 1.81 to 2.33) and 1.24 (1.12 to 1.38), respectively). Conclusions: Use of prescription opioids during pregnancy is associated with a low absolute risk of NAS in the absence of additional risk factors. Long term use compared with short term use and late use compared with early use of prescription opioids are associated with increased NAS risk independent of additional risk factors

Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006‐2016: A study in the five Nordic countries, United States, and Australia

Publisher's version (útgefin grein)Purpose: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. Methods: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. Results: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). Conclusions: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED.This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS) (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366). Linkage of Danish data was supported by the Danish Council for Independent Research (Project No: DFF‐6110‐00019) and Karen Elise Jensens Fond (2016), and grant NNF18OC0052029 from Novo Nordisk Fonden (Li). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). We thank Anders Engeland (Norwegian Institute of Public Health, University of Bergen, Norway), Anna Heino (National Institute for Health and Welfare, Finland), Mette Nørgaard (Aarhus University, Denmark), Pär Karlsson (Karolinska Institutet, Sweden), Jennifer Yland (Harvard T.H. Chan School of Public Health, USA), Gregory Brill and Helen Mogun (Brigham and Women's Hospital & Harvard Medical School, USA) for providing assistance with analyses. The authors would like to thank the NSW Ministry of Health, the Australian Government Department of Health and Ageing and the Department of Human Services for providing data. The authors also thank the Centre for Health Record Linkage (CHeReL) and the Australian Institute for Health and Welfare for conducting the linkage of records.Peer Reviewe

Antipsychotic drug use in pregnancy: A multinational study from ten countries

Aim: To compare the prevalence and trends of antipsychotic drug use during pregnancy between countries across four continents

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations : A Multinational Study

Funding Information: Submitted: February 18, 2022; accepted September 20, 2022. Published online: January 16, 2023. Relevant financial relationships: Dr Bröms has been a speaker for Takeda and has been involved in projects at Centre for Pharmacoepidemiology, Karolinska Institutet, partly financed by Janssen, Pfizer, and UCB, all unrelated to this project. Dr Hernandez-Diaz is an investigator on grants to her institution from Takeda for unrelated studies, has received personal consulting fees from UCB and Roche outside the submitted work, and has served as an epidemiologist with the North America AED pregnancy registry and as a scientific advisor for the National Pregnancy Registry for Psychiatric Medication and for Pregistry, which are funded by multiple companies. Dr Huybrechts reports being an investigator on research grants to her institution from Takeda and UCB for unrelated studies. Mr Karlsson is employed at the Centre for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, and contract research organizations) for performance of drug safety and drug utilization studies, with no relation to the work reported in this article. Dr Nørgaard is employed at the Department of Clinical Epidemiology, Aarhus University Hospital, which receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of these studies has any relation to the present study. Dr Reutfors is employed at the Centre for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, and contract research organizations) for performance of drug safety and drug utilization studies, with no relation to the work reported in this article. Dr Sørensen is employed at the Department of Clinical Epidemiology, Aarhus University Hospital, which receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of these studies have any relation to the present study. Dr Zoega is employed at the Centre for Big Data Research in Health, UNSW Sydney, which received funding from AbbVie Australia in 2020 to conduct research, unrelated to this study. AbbVie did not have any knowledge of, or involvement in, this study. Dr Kieler is employed at the Centre for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, and contract research organizations) for performance of drug safety and drug utilization studies, with no relation to the work reported in this article. Drs Bateman, Einarsdóttir, Engeland, Furu, Gissler, Klungsøyr, and Lahesmaa-Korpinen; Mr Kristiansen; and Ms Mogun report no conflicts of interest. Funding/support: This study was supported by the Söderström-König Foundation (SLS-664411); the Swedish Society of Medicine (SLS-689141); and the Stockholm Region (clinical postdoc appointment SLL-20170670); partly supported by the Research Council of Norway through its Centres of Excellence funding scheme (Project# 262700); NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS; Project# 83539); the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS; Project# 273366); UNSW Scientia Award (to H.Z.); The Drugs and Pregnancy project, funded by the Finnish Institute for Health and Welfare (THL), the Finnish Medicines Agency (FIMEA), and the Social Insurance Institution of Finland (Kela); the National Institute of Child Health and Human Development (R21 HD092879); and the National Institute of Mental Health (R01 MH116194). Role of the sponsor: The funding sources had no role in the design and conduct of the study or in the decision to publish. Previous presentation: An oral presentation of this work (title: ADHD Drugs During Pregnancy and the Risk of Congenital Malformations: A Study from the International Pregnancy Safety Study [InPreSS] Consortium) was made at the International Conference of Pharmacoepidemiology and Drug Safety; Montreal, Canada; August 26-30 2017. Ethical approval: The study was approved by the Regional Ethical Review Board in Stockholm, Sweden (2015/1826-31/2); the National Bioethics Committee in Iceland (VSNb201860017/03.01); the Steering Committee of the Drugs and Pregnancy Project; the Norwegian Data Inspectorate and the Regional Ethics Committee for Medical Research of South/East Norway); and the Danish Data Protection Agency (2015-57-0002). The use of the US data was approved by the Institutional Review Board of Brigham and Women’s Hospital, which granted a waiver of informed consent. Additional information: The data in this study were obtained from national health registers in Denmark, Iceland, Norway, and Sweden and the US Medicaid Analytic eXtract and cannot be made publicly available in their entirety due to national laws and data privacy. ORCID: Gabriella Bröms: https://orcid.org/0000-0002-2423-1968; Johan Reutfors: https://orcid. org/0000-0003-1372-4262; Mika Gissler: https:// orcid.org/0000-0001-8254-7525; Kari Klungsøyr: https://orcid.org/0000-0003-2482-1690; Mette Nørgaard: https://orcid.org/0000-0001-6110-5891; Anders Engeland: https://orcid.org/0000-0001-5620-9207; Anna-Maria Lahesmaa-Korpinen: https://orcid.org/0000-0003-1062-2893; Krista Huybrechts: https://orcid.org/0000-0001-5805-8430; Kari Furu: https://orcid.org/0000-0003-2245-0179; Kristjana Einarsdóttir: https://orcid.org/0000-0003-4931-7650; Henrik Toft Sørensen: https:// orcid.org/0000-0003-4299-7040; Helga Zoega: https://orcid.org/0000-0003-0761-9028 Supplementary material: Available at Psychiatrist.com. Publisher Copyright: © 2023 The Authors. Published by Physicians Postgraduate Press, Inc.Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure. Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors. Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16). Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.Peer reviewe