In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and motherchild linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population.
The authors have no conflicts of interest.T A B L E 1 Sociodemographic and clinical characteristics of patients who completed vs. did not complete an indicated obstetric referral. Characteristic Successful Referral (n=126) Unsuccessful Referral (n=18) P value a Demographic characteristic Age, years (interquartile range [IQR]) 25 [21-31] 23 [21-28] 0.17 Prefer to speak Mayan language, %
Introduction Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. Objective To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. Methods This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005-2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel-Haenszel (MH) meta-analyses. ResultsThe total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98-1.34) for major congenital malformations and 1.72 (1.02-2.91) for stillbirth, which attenuated to 1.25 (0.74-2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03-1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67-1.42) for autism spectrum disorders, and 1.00 (0.78-1.29) for intellectual disability. Conclusions Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.Szimonetta Komjáthiné Szépligeti and Pär Karlsson contributed equally to the study.
Objective: To investigate an association between childbirths affected by vaginal bleeding within 20 gestational weeks and women's subsequent risks of diabetes and cardiovascular diseases. Design: Cohort study in Denmark, 1979-2018. Setting: Danish nationwide registries. Participants: Between 1979 and 2017, we identified 3,085,955 pregnancies among 1,329,331 women. Of these pregnancies, 69,230 ended in childbirth affected by vaginal bleeding (VB) within 20 gestational weeks; 2,180,855 ended in VB-unaffected childbirth; 578,355 ended in termination, and 258,430 ended in a miscarriage. Main outcome measures: The outcomes were diabetes types 1 and 2, hypertension, ischaemic heart disease, including myocardial infarction, atrial fibrillation or flutter, heart failure, ischaemic and haemorrhagic stroke, coronary artery bypass grafting, and percutaneous coronary intervention. We computed the incidence rates per 10,000 person-years and cumulative incidences of cardiovascular outcomes at up to 40 years of follow-up. Hazard ratios (HRs) with 95% confidence intervals adjusted for age, calendar year, reproductive history, baseline comorbidities, and socioeconomic factors were computed using conventionally and inverse probability of treatment weighted Cox proportional hazards regression. Results: At the end of the follow-up, among women with VB-affected vs VB-unaffected childbirths, the cumulative risks of the outcome events were 4.5% vs 3.5% for diabetes type 1; 13.8% vs 11.1% for diabetes type 2; 25.1% vs 21.4% for hypertension; 10.6% vs 8.2% for ischaemic heart disease, including 2.9% vs 2.6% for myocardial infarction; 5.3% vs 4.4% for atrial fibrillation or flutter; 2.3% vs 2.0% for heart failure; 5.1% vs 4.0% for ischaemic stroke; 1.8% vs 1.4% for haemorrhagic stroke; 0.5% vs 0.4% for coronary artery bypass graft; and 2.4% vs 1.9% for percutaneous coronary intervention. Adjusted HRs were 1.2 to 1.3-fold increased for diabetes types 1 and 2, hypertension, ischaemic heart disease, atrial fibrillation or flutter, heart failure, ischaemic and haemorrhagic stroke as well as a coronary artery bypass grafting. Following women's first pregnancies and in sensitivity analyses, the HRs remained increased. For comparisons of VB-affected childbirths with terminations, HRs were up to 1.3-fold increased for diabetes and 1.1-fold increased for hypertension, ischaemic heart disease, atrial fibrillation or flutter, and haemorrhagic stroke. HRs were unity when we compared having VB-affected childbirth with having a miscarriage. Conclusions: Women's risks of diabetes types 1 and 2 and multiple cardiovascular outcomes were increased on the relative scale following childbirths affected by VB within 20 gestational weeks when compared with VB-unaffected childbirths and terminations, but not when compared with miscarriages.
Background The birth of a child affected by a threatened abortion (TAB) in utero is associated with autism spectrum disorder; association with other neurological disorders is unknown. Methods This nationwide registry-based cohort study included singletons live-born in Denmark (1979–2010), followed through 2016. The outcomes were epilepsy, cerebral palsy (CP) and attention-deficit/hyperactivity disorder (ADHD). We used Cox regression to compute hazard ratios (HRs), adjusted for birth year, birth order, parental age, morbidity, medication use and maternal socio-economic factors. To remove time-invariant family-shared confounding, we applied sibling analyses. Results The study population included 1 864 221 singletons live-born in 1979–2010. Among the TAB-affected children (N = 59 134) vs TAB-unaffected children, at the end of follow-up, the cumulative incidence was 2.2% vs 1.6% for epilepsy, 0.4% vs 0.2% for CP and 5.5% vs 4.2% for ADHD (for children born in 1995–2010). The adjusted HRs were 1.25 [95% confidence interval (CI) 1.16–1.34] for epilepsy, 1.42 (95% CI 1.20–1.68) for CP and 1.21 (95% CI 1.14–1.29) for ADHD. In the sibling design, the adjusted HRs were unity for epilepsy (full siblings: 0.96, 95% CI 0.82–1.12; maternal: 1.04, 95% CI 0.90–1.20; paternal: 1.08, 95% CI 0.93–1.25) and ADHD (full: 1.08, 95% CI 0.92–1.27; maternal: 1.04, 95% CI 0.90–1.20; paternal: 1.08, 95% CI 0.93–1.25). For CP, HRs shifted away from unity among sibling pairs (full: 2.92, 95% CI 1.33–6.39; maternal: 2.03, 95% CI 1.15–3.57; paternal: 3.28, 95% CI 1.36–7.91). Conclusions The birth of a child affected by TAB in utero was associated with a greater risk of CP, but not epilepsy or ADHD.
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