Search

Background: Cladribine tablets are contraindicated during pregnancy; therefore, safety data on pregnancies exposed to this treatment are limited. CLEAR collects and describes pregnancy outcomes in this understudied population. Objectives: To describe the main features of the CLEAR study design, including the data sources and the methodological approach, and provide a status update. Design: CLEAR is a non-interventional, multi-database, comparative cohort study. Four cohorts are included: pregnancies of women with multiple sclerosis (MS) exposed to cladribine tablets (maternal cohort exposed); pregnancies of women with MS unexposed to any disease-modifying therapy (DMT; maternal cohort unexposed); pregnancies fathered by men with MS exposed to cladribine tablets; and pregnancies fathered by men with MS unexposed to any DMT. Methods: A staggered methodological approach, using data from Denmark, Finland, France, Germany, Norway, Scotland, and Sweden, will be applied to analyze the occurrence of major congenital anomalies (primary outcome) and selected pregnancy outcomes. The first interim analysis (performed using German pregnancy cohorts) was conducted when ⩾75 pregnant women (including 25 women from the maternal cohort exposed) were cumulatively reached across all participating countries. The end of the study period will be established once pregnancy counts reach 149 in the maternal cohort exposed and 298 in the maternal cohort unexposed in all countries combined, or 5 years after pregnancy counts are first assessed (whichever occurs first). Results: As of January 2024, data on pregnancies of women exposed to cladribine tablets (n = 28–36 (numbers are approximate due to masking of some counts)), and pregnancies of women unexposed to cladribine tablets (n = 2834) were available from Denmark, Finland, Germany, Scotland, and Sweden. Conclusion: The CLEAR study, using a staggered methodological approach, aims to provide further insight into the safety outcome data for cladribine tablets in pregnant women, as a regulatory commitment with the European Medicines Agency. Trial registration: EU PAS Register number, EUPAS25027. [ABSTRACT FROM AUTHOR]

Background: Women have a higher risk of developing multiple sclerosis (MS), potentially due to hormonal factors. Elevated testosterone levels, common in polycystic ovary syndrome (PCOS), might influence MS risk. Objective: To investigate the relationship between PCOS, as a proxy for elevated testosterone levels, and MS risk through phenotypic and genomic analysis. Methods: Cox regression models analysed the association between PCOS and MS risk. The genome-wide cross-trait analysis examined the genetic architecture. Results: In a Swedish cohort of 1,374,529 women, 77 (0.3%) with PCOS and 3,654 (0.3%) without PCOS were diagnosed with MS. After adjusting for birth year and obesity, no association was found between PCOS and MS (HR = 0.91, 95% CI = 0.72–1.15), which was confirmed by Mendelian randomization analysis, where genetically predicted PCOS propensity, sex hormone-binding globulin (SHBG), or testosterone levels did not causally affect MS risk (all p -values > 0.05). By exploring horizontal pleiotropy, we identified shared genetic regions and 19 independent pleiotropic SNPs for SHBG with MS and 11 for testosterone with MS. Conclusion: We did not find evidence for a causal role of PCOS, as a proxy of elevated testosterone, in reducing the risk of MS in women. The shared genetic loci between testosterone, SHBG, and MS provide biological insights. [ABSTRACT FROM AUTHOR]

ObjectiveThe authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes.MethodFollowing uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes.ResultsResults were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes.ConclusionsAnorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Background: In observational medication pregnancy safety studies, children are often followed from birth to 1 year of age. However, some major congenital malformations (MCM) may take longer to diagnose. Objectives: We aimed to investigate the proportion of children with detected MCMs at different lengths of follow‐up and compare them to the proportion detected at 1 year after birth. Methods: This population‐based register study included all singleton children liveborn in Sweden from 2006 to 2016. MCM were identified by ICD‐10 codes in the Medical Birth Register and National Patient Register, aligned to the EUROCAT classification system. Cumulative proportion of children with detected MCM at birth, 90 days, 1, 2, and 3 years was calculated and compared between children born preterm and at term. Results: In 1,138,113 liveborn children, the cumulative proportion of children with a detected MCM increased from 1.9% at birth to 3.1%, 3.9%, 4.4% and 4.7% at 90 days, 1, 2, and 3 years after birth, respectively, and varied by MCM subgroup. MCMs of the eye, ear‐face‐neck, nervous system and genitals were detected with the longest delay, with 31%–59% more detected at 3‐ versus 1‐year follow‐up. Compared to children born at term, the proportion of children with any MCM was 2.5 times higher amongst preterm children, with a higher proportion detected over the first 90 days for most MCM subgroups. Conclusions: The proportion of children with a detected MCM varied by MCM subgroup and follow‐up time. In pharmacoepidemiology studies of medication safety in pregnancy using Swedish national data, the length of child follow‐up should be chosen in accordance with the expected age at detection if a specific subgroup of MCM is under investigation, for example, eye and genital MCM require longer follow‐up for detection than abdominal wall and digestive system MCM. However, in most circumstances, 1 year of follow‐up is sufficient. [ABSTRACT FROM AUTHOR]

Purpose: To present the main findings of a post‐authorization safety study assessing pregnancy and infant outcomes after prenatal golimumab exposure in a real‐world setting. Methods: This observational population‐based cohort study included data from pregnancies ending in 2006–2018 (Finland) or 2019 (Denmark, Sweden). Infants born to women with rheumatic diseases or ulcerative colitis diagnoses were identified. Based on prescription fills from 90 days prior to pregnancy until delivery, infants were assigned to one of the four drug‐exposure cohorts: golimumab, other anti‐TNF biologics, other biologics, and nonbiologic systemic therapy, and the general population. Prevalence of adverse pregnancy outcomes, mortality, diagnoses of major congenital anomalies (MCA), and inpatient infections in the infants' first year of life were assessed. Odds ratios and 95% CIs were calculated for MCA and infection. Results: Among 134 infants in the golimumab cohort, none were stillborn or died in the first year of life. MCA were diagnosed in 4.5% of the infants in the golimumab cohort, versus 6.8%, 10.9%, 5.5%, and 4.6% in the other anti‐TNF biologics, other biologics, nonbiologic systemic therapy and general population cohorts, respectively. Inpatient infections were diagnosed in 11% of golimumab‐exposed infants, compared with 9%–11% of infants in the other cohorts. Unadjusted and selected adjusted comparisons showed no association between prenatal golimumab exposure and MCA or infection compared with the other exposure cohorts or general population. Conclusions: The number of infants with prenatal golimumab exposure was low, but results are reassuringly consistent with the evidence available for other anti‐TNF biologics. Continued monitoring is needed. [ABSTRACT FROM AUTHOR]

Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. This study examines women prescribed metformin before pregnancy and estimates the risk of continuing metformin and adding insulin versus starting insulin but discontinuing metformin in early pregnancy on outcomes of congenital malformations and nonlive births. Visual Abstract. Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. This study examines women prescribed metformin before pregnancy and estimates the risk of continuing metformin and adding insulin versus starting insulin but discontinuing metformin in early pregnancy on outcomes of congenital malformations and nonlive births. Background: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. Objective: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. Design: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). Setting: U.S. Medicaid health care administration database (2000 to 2018). Participants: 12 489 pregnant women who met the eligibility criteria. Measurements: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. Results: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). Limitation: Possible residual confounding by glycemic control and body mass index. Conclusion: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. Primary Funding Source: National Institutes of Health. [ABSTRACT FROM AUTHOR]

Purpose: To describe ADHD medication use trajectories around pregnancy in Norway and Sweden. Methods: We identified pregnancies resulting in births using linked data from birth and prescribed drug registers of Norway (2006–2019, N = 813 107) and Sweden (2007–2018, N = 1 269 146). We restricted to women who filled prescriptions for ADHD medication during pregnancy or in the year before or after. We described exposure as use versus no use, and total amount of drug dispensed in defined daily doses (DDDs). Group‐based trajectory modeling was used to identify distinct medication use trajectories. Results: In total, 13 286 women (0.64%) filled a prescription for ADHD medication. We identified four trajectory groups: continuers (5.7%), interrupters (23.8%), discontinuers (49.5%), and late initiators (21.0%). Discontinuers were younger, continuers were older on average. More women continued medication in recent years (2014–2019). Most discontinuers (60.7%) were nulliparous; more initiators and continuers had one or multiple previous births, respectively. Continuers were least likely to live with a partner (65.8%). Discontinuers were least likely (24.7%) and continuers most likely (37.6%) to smoke at the beginning of pregnancy. More continuers used amphetamine derivatives and were most likely to use other psychotropics. On modeling continuers, we identified three dose‐trajectory groups which suggested that most women reduced medication dose during pregnancy. Conclusions: Most pregnant women discontinued or interrupted their ADHD medication during pregnancy, but more continued in recent years. Continuers were more likely to have had previous births, less likely to have lived with a partner, and may have had additional comorbidities warranting the use of other psychotropics. [ABSTRACT FROM AUTHOR]