Methodological challenges in pregnancy pharmacoepidemiology : the case of antiseizure medication and offspring neurodevelopment

This thesis is driven by the overarching aim of elucidating methodological challenges inherent in pharmacoepidemiology during pregnancy, with a particular focus on antiseizure medications. In Study I, a substantial surge in antiseizure medication use in the United Kingdom is observed, notably linked to increases in psychiatric indications. This shift in the medication landscape raises questions about the predominant contributors to this rise and underscores the necessity of understanding evolving patterns in drug utilization during pregnancy. In Study II, a large-scale examination of associations between specific antiseizure medications and neurodevelopmental conditions across Sweden and the United Kingdom emphasizes the importance of considering drug classes and shared confounders, providing valuable insights into the possible causal effect of these drugs. Study III explores the intricate interplay between epilepsy and psychiatric conditions, unveiling a heightened risk of neurodevelopmental conditions in individuals diagnosed with epilepsy. These findings shed light on the complex within-individual links between these conditions, potentially explaining the observed higher likelihood of neurodevelopmental diagnoses in children of women using antiseizure medications in pregnancy. In Study IV, a critical evaluation of drug safety studies warns against indication-based sampling, advocating for comprehensive regression adjustments to mitigate biases. Finally, Study V introduces the marginalized between-within model, a novel approach to derive absolute measures of occurrence in sibling analysis, enhancing the interpretability of findings. This thesis, collectively, calls for a concerted effort to improve the methodology of pharmacoepidemiology during pregnancy, fostering a more nuanced understanding of medication risks, and ultimately enhancing maternal and fetal health outcomes

Birth weight and grip strength in young Swedish males: a longitudinal matched sibling analysis and across all body mass index ranges

Low birth weight is associated with a lower grip strength later in life. However, associations between birth weight among infants born at-term and factors driving associations between birth weight and grip strength are largely unknown. A cohort of 144,369 young men born at-term, including 10,791 individuals who had at least one male sibling/s, were followed until conscription where they performed a grip strength test. We used linear and non-linear regression analyses in the full cohort, and fixed-effects regression analyses in the sibling cohort, to address confounding by factors that are shared between siblings. After adjustment, each unit increase in birth weight z-score was associated with increases of 17.7 (95% CI, 17.2-18.2) and 13.4 (10.1-16.6) newton grip strength, which converts to approximately 1.8 and 1.4 kilogram-force in the full and within-families cohorts, respectively. The associations did not vary with young adulthood BMI. Birth weight, within the at-term range, is robustly positively associated with grip strength in young adulthood among men across all BMI categories and associations appears to be mainly driven by factors that are not shared between siblings. These findings underline the importance of recognizing the influence of low birth weight, also within the at-termrange, on young adulthood muscle strength

Maternal smoking and smokeless tobacco use during pregnancy and offspring development:Sibling analysis in an intergenerational Swedish cohort

BACKGROUND: The association between maternal smoking in pregnancy and offspring intellectual disability (ID) is less well understood than that of smoking and fetal growth restriction. As fetal growth and cognitive development may share similar confounding structures, comparison of the two associations may improve understanding of the causal nature of the association with ID. Furthermore, comparisons of smoking with smokeless tobacco use may aid identification of mechanisms of action. METHODS: This was a cohort study of all Swedish births between 1999 and 2012 (n = 1 070 013), with prospectively recorded data. We assessed the association between maternal smoking during pregnancy and offspring outcomes ID and born small for gestational age (SGA). Analyses were repeated for snus use in pregnancy. Using a sibling design, we estimated within-family effects that control for shared sibling characteristics. RESULTS: Those exposed to maternal smoking in pregnancy had increased odds of ID [odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.16-1.33] and SGA (OR = 2.19, 95% CI: 2.11-2.27) after confounder adjustment. Within-family effects were found for SGA (OR = 1.44, 95% CI: 1.27-1.63) but not ID (OR = 0.92, 95% CI: 0.74-1.14). For snus use, the results for ID were similar to smoking. We found increased odds of offspring SGA among mothers who used snus in pregnancy in sensitivity analyses but not in primary analyses. CONCLUSIONS: Our findings are consistent with a causal effect of maternal smoking in pregnancy on risk of offspring born SGA but not on risk of ID. We found no evidence for a causal effect of snus use in pregnancy on ID and inconclusive evidence for SGA

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics

Elective and nonelective cesarean section and obesity among young adult male offspring : A Swedish population-based cohort study

Background: Previous studies have suggested that cesarean section (CS) is associated with offspring overweight and obesity. However, few studies have been able to differentiate between elective and nonelective CS, which may differ in their maternal risk profile and biological pathway. Therefore, we aimed to examine the association between differentiated forms of delivery with CS and risk of obesity in young adulthood. Methods and findings: Using Swedish population registers, a cohort of 97,291 males born between 1982 and 1987 were followed from birth until conscription (median 18 years of age) if they conscripted before 2006. At conscription, weight and height were measured and transformed to World Health Organization categories of body mass index (BMI). Maternal and infant data were obtained from the Medical Birth Register. Associations were evaluated using multinomial and linear regressions. Furthermore, a series of sensitivity analyses were conducted, including fixed-effects regressions to account for confounders shared between full brothers. The mothers of the conscripts were on average 28.5 (standard deviation 4.9) years old at delivery and had a prepregnancy BMI of 21.9 (standard deviation 3.0), and 41.5% of the conscripts had at least one parent with university-level education. Out of the 97,291 conscripts we observed, 4.9% were obese (BMI ≥ 30) at conscription. The prevalence of obesity varied slightly between vaginal delivery, elective CS, and nonelective CS (4.9%, 5.5%, and 5.6%, respectively), whereas BMI seemed to be consistent across modes of delivery. We found no evidence of an association between nonelective or elective CS and young adulthood obesity (relative risk ratio 0.96, confidence interval 95% 0.83–1.10, p = 0.532 and relative risk ratio 1.02, confidence interval 95% 0.88–1.18, p = 0.826, respectively) as compared with vaginal delivery after accounting for prepregnancy maternal BMI, maternal diabetes at delivery, maternal hypertension at delivery, maternal smoking, parity, parental education, maternal age at delivery, gestational age, birth weight standardized according to gestational age, and preeclampsia. We found no evidence of an association between any form of CS and overweight (BMI ≥ 25) as compared with vaginal delivery. Sibling analysis and several sensitivity analyses did not alter our findings. The main limitations of our study were that not all conscripts had available measures of anthropometry and/or important confounders (42% retained) and that our cohort only included a male population. Conclusions: We found no evidence of an association between elective or nonelective CS and young adulthood obesity in young male conscripts when accounting for maternal and prenatal factors. This suggests that there is no clinically relevant association between CS and the development of obesity. Further large-scale studies are warranted to examine the association between differentiated forms of CS and obesity in young adult offspring. Trial registration: Registered as observational study at ClinicalTrials.gov Identifier: NCT03918044

The association between birth by cesarean section and adolescent cardiorespiratory fitness in a cohort of 339,451 Swedish males

Birth by cesarean section is increasing worldwide and associates with offspring morbidities capable of adversely impacting cardiorespiratory fitness later in life. Whether birth by cesarean section associates with lower levels of cardiorespiratory fitness later in life is unknown and is of interest to public health. Four Swedish national registers were linked to follow 339,451 singleton males, born between 1973–1987 until December 31 2005, for Watt-maximum achieved on a cycle ergometer test at conscription into the Swedish military. Main exposure was birth by cesarean section which was compared to vaginal birth. A sub-population of 45,999 males born between 1982–1987 was identified to explore differentiated associations between elective and non-elective cesarean section with Watt-maximum. Within-family analyses of 34,252 families with 70,632 biological male siblings, who conscripted during the study period, were performed to explore the role of familial confounding on Watt-maximum. Swedish males born by cesarean section achieved lower mean Watt-maximum (− 2.32 W, 95%C.I. − 2.90 to − 1.75) and displayed excess odds of low cardiorespiratory fitness (aOR = 1.08, 95%C.I. 1.05 to 1.11) at conscription in the eighteenth life-year compared to males born vaginally after adjusting for birth characteristics, maternal morbidities and parental socioeconomic position. In the sub-population, males born 1982–1987, there was a greater negative association of elective cesarean section with cardiorespiratory fitness (− 4.42 W, 95%C.I. − 6.27 to − 2.57, p < 0.001) than non-elective cesarean sections (− 1.96 W, 95%C.I. − 3.77 to − 0.16, p = 0.033) as compared to vaginal births. No associations between modes of cesarean delivery and cardiorespiratory fitness levels persisted in the within-family analyses where biological male siblings were compared whilst controlling for factors shared within families. Males born by cesarean section had lower levels of cardiorespiratory fitness eighteen years later compared to males born vaginally. These findings appear to be largely explained by factors of familial confounding

Preschool environment and preschool teachers physical activity and their association with childrens activity levels at preschool

Objective The aim of this study was to investigate the association between preschool playground size, formalized physical activity (PA) policies, time spent outdoors and preschool teachers levels of PA and childrens objectively assessed levels of PA and sedentary time (ST) during preschool hours. Methods In total, 369 children and 84 preschool teachers from 27 preschools in Sodermalm municipally, Stockholm Sweden wore an Actigraph GT3X+ accelerometer during 7 consecutive days. Preschool environmental and structural characteristics were measured via the Environment and Policy Evaluation Self-Report ( EPAO-SR) instrument and time in- and outdoors was recorded by preschool teachers during the PA measurements. Weight and height of children were measured via validated scales and parents filled out a questionnaire on demographical and descriptive variables. Linear mixed models, nested on preschool level, were used to assess the association between predictors and outcomes. Results The mean child age was 4.7 years (SD 0.8) and 45% were girls. We found that children were more active in preschools with a formalized PA policy, compared to preschools without such a policy, but not less sedentary. The association between policy and activity seemed to be more pronounced when accounting for other environmental factors. Similar associations were found in children spent most time outdoors (uppermost quartile) compared with children spent least time outdoors (Lowermost quartile). Preschool teachers light PA (LPA) (beta = 0.25, P = 0.004) and steps (beta = 0.52, P&amp;lt;0.001) were associated with childrens LPA and steps while the preschool playground size showed no association with PA in children, when accounting for other environmental factors. Conclusion The current study showed that preschool structural characteristics such as formalized PA policies and more time spent outdoors were positively associated with childrens PA. These findings suggest that formalized PA policies and time outdoors may be of importance for promoting childrens PA during preschool hours.Funding Agencies|Lindhes Advokatbyra; Sodermalm municipally</p

Physical activity through a classroom-based intervention : A pragmatic non-randomized trial among swedish adolescents in an upper secondary school

Schools are an important arena to curb the decline in physical activity (PA) in youth. School-based interventions with accelerometer-measured PA are warranted. This study aimed to increase accelerometer-measured PA in adolescents following a 12-month school-based intervention. Two school-classes of 16–18-year-old Swedish students were allocated to intervention group and control group. Accelerometer-measured PA was gathered at baseline, 6-and 12-month follow-up. Mixed-effects linear regression was used to investigate between-group and within-group differences in mean minutes per day (min/day) of moderate to vigorous PA (MVPA), light PA (LPA) and sedentary time (ST). Fifty-seven students participated (intervention group = 31, control group = 26). At 12-month follow-up, the intervention group performed 5.9 (95% CI: −4.3, 16.2) min/day more in MVPA, 1.8 (95% CI: −17.9, 14.2) min/day less in LPA, and 4.1 (95% CI: −27.3, 19.2) min/day less in ST compared to the control group. Within the intervention group, there was no significant change in PA. Within the control group, LPA decreased (95% CI: −19.6, −0.2; p = 0.044) and ST increased (95% CI: 1.8, 30.8; p = 0.028). Although no between-group differences in PA were statistically significant, the within-group changes may suggest a preventive impact on the decline in PA during adolescence

Birth Weight and Cardiorespiratory Fitness Among Young Men Born at Term : The Role of Genetic and Environmental Factors

Background: Preterm delivery and low birth weight are prospectively associated with low cardiorespiratory fitness (CRF). However, whether birth weight, within the at-term range, is associated with later CRF is largely unknown. Thus, the aim of the current study was to examine this issue and whether such association, if any, is explained by shared and/or nonshared familial factors. Methods and Results: We conducted a prospective cohort study, including 286 761 young male adults and a subset of 52 544 siblings born at-term. Objectively measured data were retrieved from total population registers. CRF was tested at conscription and defined as the maximal load obtained on a cycle ergometer. We used linear and nonlinear and fixed-effects regression analyses to explore associations between birth weight and CRF. Higher birth weight, within the at-term range, was strongly associated with increasing CRF in a linear fashion. Each SD increase in birth weight was associated with an increase of 7.9 (95% CI, 7.8-8.1) and 6.6 (95% CI; 5.9-7.3) Wmax in the total and sibling cohorts, respectively. The association did not vary with young adulthood body mass index. Conclusions: Birth weight is strongly associated with increasing CRF in young adulthood among men born at-term, across all categories of body mass index. This association appears to be mainly driven by factors that are not shared between siblings. Hence, CRF may to some extent be determined already in utero. Prevention of low birth weight, also within the at-term-range, can be a feasible mean of increasing adult CRF and health

HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden : A registry-based cohort study

Background: The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality. Methods and findings: This cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins.In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%).A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens. Conclusions: Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic