Dataset Information

Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium.

ABSTRACT: Importance:Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety. Objective:To examine the risk of congenital malformations associated with intrauterine exposure to stimulants. Design, Setting, and Participants:Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017. Exposures:Methylphenidate and amphetamines dispensed during the first trimester. Main Outcomes and Measures:Major congenital malformations and subgroup of cardiac malformations. Results:In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64). Conclusions and Relevance:These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.

SUBMITTER: Huybrechts KF

PROVIDER: S-EPMC5838573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAntenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure.MethodsThe Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records.Results and discussionThe Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS.

Project description:BackgroundThe prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths.Methods and findingsA population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates.ConclusionsBased on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy.

Dataset Information

Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium.

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