BACKGROUND:Antidepressant use is increasing during pregnancy but estimates of prevalence and patterns of prescribing are outdated. AIM:To describe the prevalence and patterns of antidepressant prescribing in and around pregnancy. DESIGN AND SETTING:This was a drug utilisation study using the UK's Clinical Practice Research Datalink (CPRD) GOLD Pregnancy Register. METHOD:Using primary care prescription records, individuals were identified who had been prescribed antidepressants in and around pregnancy between 1996 and 2018 and the prevalence of prescribing during pregnancy over time was described. Those with 'prevalent' or 'incident' antidepressant use were defined, where the 'prevalent' group contained individuals who were prescribed antidepressants both before and during pregnancy, whereas individuals in the 'incident' group were newly prescribed antidepressants during pregnancy. Patterns of prescribing were then qualitatively compared between these two groups. The study also investigated post-pregnancy prescribing, as well as characteristics associated with antidepressant discontinuation anytime during pregnancy. RESULTS:A total of 1 033 783 pregnancies were eligible: 79 144/1 033 783 (7.7%) individuals were prescribed antidepressants during pregnancy and 15 733/79 144 (19.9%) were in the 'incident' group. Antidepressant prescribing during pregnancy increased from 3.2% (556/17 653) in 1996 to 13.4% (3889/29 079) in 2018. Most women, both those whose antidepressants were 'prevalent' and 'incident' prescribed, discontinued their medication anytime during pregnancy (54.9% [34 801/63 411] and 59.9% [9427/15 733], respectively). Over half of those who discontinued during pregnancy were prescribed antidepressants in the 12 months after pregnancy (53.0%, 23 457/44 228). Younger age, previous stillbirth, and higher deprivation were associated with more frequent discontinuation anytime during pregnancy. CONCLUSION:Antidepressant prescribing during pregnancy has been increasing in the UK. Over half of the sample discontinued antidepressants at some point before the end of pregnancy, but post-pregnancy resumption of antidepressants was common. The results presented here highlight the benefit of counselling women when initiating antidepressants to support informed decision making.

BACKGROUND:The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that early life environmental exposures, especially during pregnancy, can impact long-term health. Research has largely relied on correlational evidence and has focussed on maternal factors, with less attention given to paternal, postnatal, and broader social determinants. This focus could complicate efforts to determine the most effective strategies for improving population health. METHODS AND FINDINGS:Using harmonised data across four population-based longitudinal cohort studies from the UK and Norway (births between 1991 and 2008), we took a systematic approach to explore associations of parental prenatal health behaviours (smoking, alcohol, and caffeine consumption) and low socioeconomic position (SEP) with 72 child health-related outcomes (e.g., related to body size and composition, cognitive function, mental health, blood pressure, allergy, etc.) from birth up to age 11. Where possible, cohort estimates were meta-analysed, yielding a maximum sample size of 232,139. We triangulated evidence of causality using different analytical approaches, including a Mendelian randomisation-informed approach using genetic risk scores, negative controls (maternal versus paternal and during versus post-pregnancy comparisons), and dose-response analyses. This comprehensive set of analyses generated more than 594,000 effect estimates. We developed a web app, 'EPoCH Explorer' to visualise and share our results in an accessible format. We did not find strong evidence for widespread or large effects of parental health behaviours on child health and wellbeing. Only 6% of analyses had a Cohen's D value >0.2 and FDR-adjusted P < 0.05. In most analyses, the effect estimate was similar for mothers and partners, with 51% showing a larger effect for mothers and 49% for partners. Despite the lack of widespread associations, we found consistent evidence of association between maternal smoking and small for gestational age, higher childhood body mass index (BMI), depressive symptoms, and behavioural issues, while partner smoking was consistently associated with childhood BMI and social communication difficulties. Overall, we found stronger evidence of child outcomes being associated with low SEP than with health behaviours: 15% of results for low SEP had a Cohen's D value >0.2 and FDR-P < 0.05, compared to 6% for parental smoking, 3% for alcohol, and 0.4% for caffeine. Sample sizes and statistical power varied across outcomes and there was limited ethnic diversity in our study samples. CONCLUSION:Our findings suggest that wider familial socioeconomic conditions may be a more important determinant of child health than specific parental health behaviours prenatally. Interventions to improve population health may be most effective if they target wider social inequalities, rather than individual behaviours and mothers specifically. We encourage researchers to use EPoCH Explorer to prioritise associations for exploration in their own datasets, thus enabling replication and cross-context comparison to validate and extend the generalisability of our findings.

Background:Contrary to previous findings, emerging studies support the increased likelihood of hazardous alcohol consumption in autistic adults when compared to neurotypical individuals. However, support services specifically for autistic people drinking hazardously are lacking. Examining the relationship of autistic features with alcohol consumption patterns longitudinally is essential to identify appropriate developmental points to offer support. Methods:We investigated this using both phenotypic and genetic exposures measured in participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Our exposures included three measures of autistic traits (a broad autism phenotype measure, Social Communication Disorders Checklist score and polygenic score reflecting genetic liability for autism). Our outcome was alcohol consumption, measured across five timepoints between the ages of 17 to 28 years. We used multilevel piecewise linear spline analyses to model both the mean and 10th, 50th (median) and 90th quantiles of alcohol consumption longitudinally. Results:There was little evidence that genetic liability for autism influenced alcohol consumption. However, we found that individuals with higher autistic traits drank less at the mean and 10th, 50th (median) and 90th percentiles of alcohol consumption compared to those with lower autistic traits. We did not find evidence of a relationship between social communication differences and alcohol consumption at the mean, 10th and 50th (median) percentiles. Conversely, there was evidence to suggest that individuals with greater social communication differences drank more at the 90th percentile compared to those with fewer social communication differences. Conclusion:Our findings indicate that social communication differences are associated with increased alcohol consumption in heavy drinkers, and that the relationship between autistic traits and alcohol consumption varies dependent on how traits are measured. This may explain the plurality of previous findings. Further research is needed to develop a more nuanced understanding of these associations across subpopulations of autistic traits and alcohol consumption.

BACKGROUND:Depression and anxiety during pregnancy is on the rise, thus more pregnant women are being offered antidepressants; however, uncertainties remain surrounding safety. AIM:To investigate the association between first trimester antidepressant use and miscarriage. DESIGN AND SETTING:Population-based cohort study using the UK Clinical Practice Research Datalink (CPRD) GOLD. METHOD:Pregnancies included in the CPRD GOLD Pregnancy Register between 1996 and 2018 were identified. Pregnancies in those with prescriptions for antidepressants overlapping with the first trimester were defined as 'exposed' and compared with pregnancies in those who were unexposed. Cox models, adjusted hazard ratios (aHRs), and absolute risk of miscarriage were calculated adjusted for confounders including depression, anxiety, smoking, and other health, lifestyle, and obstetric factors. RESULTS:Among the 1 021 384 eligible pregnancies, 73 540 patients were prescribed antidepressants in the first trimester (7.2%); 10 693/73 540 (14.5%) pregnancies ended in miscarriage among those prescribed antidepressants versus 116 641/947 844 (12.3%) in those not prescribed antidepressants. Antidepressant prescription during the first trimester was only modestly associated with miscarriage following adjustment (aHR 1.04, 95% confidence interval [CI] = 1.02 to 1.06). These findings translated to an absolute risk adjusted for confounders of 13.1% (95% CI = 13.0 to 13.2) for those not prescribed and 13.6% (95% CI = 13.3 to 13.8) for those prescribed antidepressants. Among those prescribed antidepressants in the 3 months before pregnancy and during the first trimester, the risk of miscarriage was the same as among those unexposed (aHR 1.00, 95% CI = 0.98 to 1.03). CONCLUSION:First trimester antidepressant use was associated with a small, clinically insignificant increased risk of miscarriage, with no evidence suggesting taking antidepressants before pregnancy and into the first trimester increases the risk of miscarriage.

Objectives To investigate the risk of miscarriage associated with first trimester antidepressant use. Design Population-based cohort study. Setting UK Clinical Practice Research Datalink (CPRD) GOLD. Participants 661 825 individuals who had 1 021 384 pregnancies in CPRD GOLD between 1996 and 2018. Main outcome measures Miscarriage defined as a pregnancy loss prior to 24 weeks' gestation. Results Among the eligible pregnancies, 73 540 were prescribed antidepressants in trimester one (7.2%); 14.7% antidepressant prescribed pregnancies ended in miscarriage, as opposed to 12.4% of those not prescribed antidepressants. Antidepressant use during trimester one was associated with miscarriage in the unadjusted models (hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.19 to 1.23), which attenuated following adjustment for covariates (aHR 1.04, 95% CI 1.02 to 1.06). These findings translated to an absolute risk adjusted for confounders of 13.1% (95% CI 13.0 to 13.2) in the unexposed compared to 13.6% (95% CI 13.3 to 13.8) in the first trimester antidepressant exposed. The propensity score matched model showed similar results (aHR 1.09, 95% CI 1.02 to 1.17, respectively). In those with depression or anxiety in the 12 months before pregnancy, our estimate didn't change (aHR 1.04, 95% CI 1.01 to 1.08). Conclusion First trimester antidepressant use was associated with a small yet clinically insignificant increase in risk of miscarriage, with no evidence suggesting taking antidepressants before pregnancy and into first trimester increases the risk of miscarriage. The conclusions are less clear for 'incident' antidepressant use in trimester one, however issues including gestational dating in early pregnancy and probable residual confounding prohibit us from interpreting this observation as causal.

Objectives To explore the association between antidepressant use during pregnancy and birth outcomes. Design Cohort study. Setting Electronic health record data. Participants 2 528 916 singleton births from the UK's Clinical Practice Research Datalink (1996-2018), Norway's Medical Birth Registry (2009-2020), and Sweden's Medical Birth Register (2006-2020). Main outcome measures Stillbirth, neonatal death, pre- and post-term delivery, small and large for gestational age, and low Apgar score five minutes post-delivery. Results A total of 120 209 (4.8%) deliveries were exposed to maternal antidepressant use during pregnancy. Maternal antidepressant use during pregnancy was associated with increased odds of stillbirth (adjusted pooled OR (aOR) 1.16, 95% CI 1.05 to 1.28), preterm delivery (aOR 1.26, 95% CI 1.23 to 1.30), and Apgar score < 7 at 5 minutes (aOR 1.83, 95% CI 1.75 to 1.91). These findings persisted in the discordant sibling analysis, but with higher uncertainty. The adjusted predicted absolute risk for stillbirth was 0.34% (95% CI 0.33 to 0.35) among the unexposed and 0.40% (95% CI 0.36 to 0.44) in the antidepressant exposed. Restricting to women with depression or anxiety, the association between antidepressant exposure and stillbirth attenuated (aOR 1.07, 95% CI 0.94 to 1.21). Paternal antidepressant use was modestly associated with preterm delivery and low Apgar score. Most antidepressants were associated with preterm delivery (except paroxetine) and Apgar score (except mirtazapine and amitriptyline). Conclusions Maternal antidepressant use during pregnancy may increase the risk of stillbirth, preterm delivery, and low Apgar score, although the absolute risks remained low. Confounding by severity of indication cannot be ruled out, as the severity of symptoms was not available. The modest association between paternal antidepressant use and both preterm delivery and low Apgar score suggests that residual confounding by familial environment cannot be ruled out.

Paternal exposures (and other non-maternal factors) around pregnancy could have important effects on offspring health. One challenge is that data on partners are usually from a subgroup of mothers with data, potentially introducing selection bias, limiting generalisability of findings. We aimed to investigate the potential for selection bias in studies using partner data.We characterise availability of data on father/partner and mother health behaviours (smoking, alcohol, caffeine and physical activity) around pregnancy from three UK cohort studies: the Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford and the Millennium Cohort Study. We assess the extent of sample selection by comparing characteristics of families where fathers/partners do and do not participate. Using the association of parental smoking during pregnancy and child birthweight as an example, we perform simulations to investigate the extent to which missing father/partner data may induce bias in analyses conducted only in families with participating fathers/partners.In all cohorts, father/partner data were less detailed and collected at fewer timepoints than mothers. Partners with a lower socio-economic position were less likely to participate. In simulations based on ALSPAC data, there was little evidence of selection bias in associations of maternal smoking with birthweight, and bias for father/partner smoking was relatively small. Missing partner data can induce selection bias. In our example analyses of the effect of parental smoking on offspring birthweight, the bias had a relatively small impact. In practice, the impact of selection bias will depend on both the analysis model and the selection mechanism.

A bstract Background Hypotheses about what phenotypes to include in causal analyses (that in turn can have clinical and policy implications) can be guided by hypothesis-free approaches, leveraging the epigenome for example. Materials & methods: Minimally adjusted epigenome-wide association studies (EWAS) using ALSPAC data were performed for example conditions, dysmenorrhea and heavy menstrual bleeding (HMB). Differentially methylated CpGs were searched in the EWAS Catalog and associated traits identified. Traits were compared between those with and without the example conditions in ALSPAC. Results: Seven CpG sites were associated with dysmenorrhea and two with HMB. Smoking and adverse childhood experience score were associated with both conditions in the hypothesis-testing phase. Conclusion: Hypothesis-generating EWAS can help identify associations for future analyses. P lain language summary To make a positive impact on policy and clinical practice, it is important that epidemiologists, those who study population health, can identify characteristics that might increase the risk of medical conditions. However, it can be difficult to know which associations should be investigated and decisions can often be biased by pre-formed opinions about what is relevant. In this study, we wanted to look for potential risk factors for dysmenorrhea (painful periods) and heavy menstrual bleeding (HMB) using a hypothesis-free approach (in other words, minimal adjustment for potential confounders), leveraging epigenetic data from a sub-sample of the Avon Longitudinal Study of Parents and Children (ALSPAC) and generating hypotheses about associations, then testing these hypotheses in the wider ALSPAC cohort. This meant looking for differentially methylated CpGs between those with and without the conditions of interest using an epigenome-wide association study (EWAS), seeing which phenotypes were associated with the CpGs in the EWAS Catalog, and testing these hypotheses in the ALSPAC cohort using measurements of each phenotype. For dysmenorrhea, we found seven differentially methylated CpGs and for HMB, we found two. These CpGs were associated with several phenotypes, which we could proxy in the wider ALSPAC cohort, creating hypotheses we tested using regression analyses. In the hypothesis-testing phase, we found that smoking and adverse childhood experience score were associated with dysmenorrhea and HMB. With this under-utilised approach, we can identify phenotypes that may be risk factors for under-studied conditions, that can be explored in other cohorts using analyses that can assess causality. T weetable abstract Leveraging EWAS data can help identify novel potential risk factors for understudied conditions such as dysmenorrhea and heavy menstrual bleeding for future examination in causally motivated analyses: a proof-of-concept study in the Children of the 90’s cohort (ALSPAC)

Objective To describe the prevalence and patterns of antidepressant prescribing in and around pregnancy. Design Drug utilisation study. Setting Primary care in the United Kingdom (UK). Population Women with a pregnancy between 1996 and 2018 in the UK Clinical Practice Research Datalink (CPRD) GOLD Pregnancy Register. Methods Using primary care prescription records, we identified individuals who had been prescribed antidepressants in and around pregnancy and described changing prevalence of prescribing during pregnancy over time. We defined 'prevalent' or 'incident' antidepressant use, where 'prevalent' users were prescribed antidepressants both before and during pregnancy, and 'incident' users were newly prescribed antidepressants during pregnancy, and then compared patterns of prescribing between these two groups. We also investigated characteristics associated with antidepressant discontinuation anytime during pregnancy and post-pregnancy prescribing. Main outcome measures Antidepressant prescribing during pregnancy. Results A total of 1,033,783 pregnancies were identified: 79,144 (7.7%) were prescribed antidepressant during pregnancy and 15,733 of these (19.9%) were incident users. Antidepressant prescribing during pregnancy increased from 3.2% in 1996 to 13.4% in 2018. Most women, both 'prevalent' and 'incident' users, discontinued antidepressants anytime during pregnancy (54.8% and 59.9%, respectively). The majority of those who discontinued during pregnancy resumed in the 12 months after pregnancy (53.0%). Younger age, previous stillbirth, and higher deprivation were associated with more frequent discontinuation anytime during pregnancy. Conclusions Antidepressant use during pregnancy appears to be increasing in the UK. Most women discontinued antidepressants at some point before the end of pregnancy, but post-pregnancy resumption of antidepressants was common. Funding Wellcome Trust 218495/Z/19/Z. Key words Antidepressants, drug utilisation, pregnancy, epidemiology. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement FZM was supported by a Wellcome Trust PhD studentship (218495/Z/19/Z). GCS was supported by a Medical Research Council (MRC) grant (MR/S009310/1). LB was supported by an NIHR Clinical Lectureship in General Practice (CL-2022-16-001). VNS was supported by an NIHR clinical fellowship (ACF-2016-25-503). PMD and DR were supported by the NIHR Research Bristol Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. FZM, GCS, KEE, PMD and DR are members of the UK MRC Integrative Epidemiology Unit, funded by the MRC (MC\_UU\_00032/02, MC\_UU\_00032/04, and MC\_UU\_00032/6) and the University of Bristol. For Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders of this project had no role in the design or conduct (including analysis or interpretation) of this study, or in the decision to submit this manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: CPRD has ethics approval from the Health Research Authority to support research using anonymised patient data. This particular study was approved by CPRD's Independent Scientific Advisory Committee (ISAC) in 2021 [ISAC number: 21_000362]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.

Background Antidepressants are among the most common prescriptions in women of childbearing age and prescribing has increased in recent decades. Some evidence suggests that many women discontinue antidepressants on becoming pregnant. Understanding patterns of antidepressant prescribing in pregnancy is crucial for both clinicians and those researching associations between antidepressant use during pregnancy and outcomes. Methods Using the Clinical Practice Research Datalink (CPRD) Pregnancy Register, we defined a cohort of eligible pregnancies and using primary care prescription data, identified which out of these were prescribed antidepressants in the 12 months before, during, and the 12 months after pregnancy. Prevalent and incident users were categorised among those who were prescribed antidepressants during pregnancy. Prevalent users were those who had at least one prescription of antidepressants in the 3 months prior to pregnancy and incident users were those who did not have any antidepressant prescriptions in the 3 months prior to pregnancy. We investigated patterns of prescribing within pregnancy among those two groups: discontinuation, dose changes, medication switching, and continuation with no changes to their regimen. Results Between 1996 and 2018, 30,804 pregnancies were exposed to antidepressants, of which 24,219 (79%) had been prescribed antidepressants in the 3 months prior to pregnancy (prevalent users). Incident users during pregnancy (no prescriptions in the 3 months before the start of pregnancy) made up the remaining 21%. Discontinuation of antidepressants during pregnancy was most common (78% and 81% for prevalent and incident users, respectively). Among those who did not discontinue their antidepressants during pregnancy, decreasing dose was more common among prevalent users, however among incident users, increasing dose was more common. In both prevalent and incident users, not making any changes to their regimen was the most common pattern (47% and 69%, respectively). When investigating the 12 months after pregnancy, the majority of those who discontinued during pregnancy resumed antidepressants in the immediate postpartum period (64%). Conclusion The majority of women in the UK prescribed antidepressants in pregnancy are prevalent users who already have prescriptions for these medications before their pregnancy. A substantial proportion of these prescriptions are discontinued in early pregnancy but are reinitiated after the end of pregnancy.

A method is described for the design, evaluation, and application of internal control targets and probes for use in probe-based nucleic acid diagnostic assays (i.e., PCR-ELISA). The technique is a modified version of oligonucleotide-directed mutagenesis in conjunction with PCR amplification to develop a novel probe-annealing sequence in a cloned IS1111a gene fragment of Coxiella burnetii. The internal control probe-recognition site with its complementary probe was identical to the wild-type-specific probe in length, base composition, location, and annealing temperature. Neither the internal control nor the wild-type probes annealed to the recognition sequence of the other. As both of the amplified nucleic acid fragments, internal control and wild type, were identical in length and base composition, the amplification conditions for the diagnostic assay were not affected. This allowed small copy numbers of the internal control clone to be loaded into a diagnostic assay without negatively affecting it. In a single reaction we were able to differentiate between an assay reporting a true or false-negative signal. A negative signal is defined as the absence of detectable pathogen genetic material (true) or inhibition/failure of the reaction (false).

Background Observational evidence shows that maternal (and paternal) health behaviours around pregnancy are associated with offspring health. It is often difficult to infer whether associations represent causal effects or arise due to confounding. We have conducted a multi-cohort, multi-exposure, multi-outcome study, applying several approaches that can strengthen causal inference. We have developed a web-app to make our results available to the research community. Methods In a reduced phenome-wide association study (PheWAS), we separately regressed over 200 child health outcomes on up to four parental health behaviour classes at several timepoints, or polygenic risk scores (PRS) for these health behaviours. To increase power, we ran the PheWAS in four cohorts and meta-analysed results (maximum N=106,396). Finally, we developed a web-app (EPoCH) to search, visualize and download results. Results Our EPoCH web-app facilitates triangulation of approaches to strengthen causal inference. Users are shown associations (effect estimates and 95% confidence intervals): 1) adjusted for various confounders; 2) from different cohorts, allowing cross-context comparisons; 3) for (i) maternal and paternal exposures, and (ii) pre- and post-natal exposures, enabling negative control comparisons; 4) for different pregnancy exposure timepoints, enabling exploration of the importance of exposure timing; 5) for different doses of ordinal exposures, enabling exploration of dose-response effects; 6) for PRS, facilitating Mendelian Randomisation analyses. Conclusion The EPoCH app provides a useful resource for improving causal inference in parental prenatal effects research. Findings can help identify the most appropriate prenatal targets for more effective interventions to improve child health.

Background There are challenges in studying the effects of partner exposures around pregnancy on child health. We explored potential sources of bias in the effects of parental prenatal health behaviours on child health, to describe and quantify some of these challenges, as well as suggest ways in which they might be mitigated. Methods First, we characterised the availability of data on partner and mother health behaviours in the prenatal period from three UK cohort studies: the Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Millennium Cohort Study (MCS). Second, we assessed the potential for sample selection in these cohorts by comparing characteristics of families where the partner did and did not participate. Third, using parental smoking during pregnancy and child birthweight as an example, we ran simulation studies of several DAGs to explore the extent that missing partner data and selection can affect estimates. We then explored the ‘real life’ impact of partner sample selection on estimates of maternal effect. Results In all cohorts, data on partner prenatal health behaviours was less detailed and collected less frequently than maternal prenatal health behaviours. Partners participated in ALSPAC and MCS for the majority of pregnancies. Of 14,472 pregnancies in ALSPAC, and 18,241 pregnancies in MCS, 12,997 (78%) and 13,145 (71%) had a cohort participating partner, respectively. However, partner participation was much lower in BiB: 3131/11,538 pregnancies (27%) had a cohort participating partner. Consistently across all cohorts, in pregnancies with cohort participating partners, mothers were more likely to be living with their partner before birth of the child, be white and have a university degree. They were consistently less likely to have no qualifications and their babies were less likely to be born preterm or have a low birthweight. We saw relatively stable effect estimates within cohorts for associations between maternal smoking and offspring birthweight regardless of whether we used the full sample, the sample where fathers participated (selected either through stratification or adjusting for partner smoking), or the sample where fathers did not participate. Conclusion Overall, these results show partner selection is unlikely to cause strong selection bias in estimates of maternal effects. This suggests that, although inclusion of partner data with high levels of non-random missingness has the potential to introduce selection bias, in practice, the biasing effect appears to be small. This also has implications for studies of partner effects in their own right.

ABSTRACT Background and aims Previous studies suggest an association between maternal tobacco and caffeine consumption during and outside of pregnancy and offspring mental health. We aimed to separate effects of the maternal environment (intrauterine or postnatal) from pleiotropic genetic effects. Design Secondary analysis of a longitudinal study. We 1) validated smoking and caffeine genetic risk scores (GRS) derived from published GWAS for use during pregnancy, 2) compared estimated effects of maternal and offspring GRS on childhood mental health outcomes, and 3) tested associations between maternal and offspring GRS on their respective outcomes. Setting We used data from a longitudinal birth cohort study from England, the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants Our sample included 7921 mothers and 7964 offspring. Measurements Mental health and non-mental health phenotypes were derived from questionnaires and clinical assessments: 79 maternal phenotypes assessed during and outside of pregnancy, and 71 offspring phenotypes assessed in childhood (<10 years) and adolescence (11-18 years). Findings The maternal smoking and caffeine GRS were associated with maternal smoking and caffeine consumption during pregnancy (2nd trimester: Psmoking = 3.0×10−7, Pcaffeine = 3.28×10−5). Both the maternal and offspring smoking GRS showed evidence of association with reduced childhood anxiety symptoms (βmaternal = -0.033; βoffspring= -0.031) and increased conduct disorder symptoms (βmaternal= 0.024; βoffspring= 0.030), after correcting for multiple testing. Finally, the maternal and offspring smoking GRS were associated with phenotypes related to sensation seeking behaviours in mothers and adolescence (e.g., increased symptoms of externalising disorders, extraversion, and monotony avoidance). The caffeine GRS showed weaker evidence for associations with mental health outcomes. Conclusions We did not find strong evidence that maternal smoking and caffeine genetic risk scores (GRS) have a causal effect on offspring mental health outcomes. Our results confirm that the smoking GRS also captures liability for sensation seeking personality traits.

Background: Heavy alcohol consumption often co-occurs with mental health problems; this could be due to confounding, shared biological mechanisms, or causal effects. Polygenic risk scores (PRS) for alcohol use can be used to explore this association at critical life stages. Design: We characterized a PRS reliably associated with patterns of adult alcohol consumption by 1) validating whether it predicts own alcohol use at different life-stages (pregnancy, adolescence) of interest for mental health impact. Additionally, we explored associations of alcohol PRS on mental health phenotypes 2) within-individuals (using own alcohol PRS on own phenotypes) and 3) intergenerationally (using maternal alcohol PRS on offspring phenotypes). We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 960-7841). Additional substance abuse behaviors and mental health/behavioral outcomes were investigated (alcohol phenotypes n = 22; health phenotypes n = 91). Findings: Maternal alcohol PRS was associated with consumption during pregnancy (strongest signal: alcohol frequency at 18 weeks' gestation: beta = 0.041, 95%CI = 0.0.02-0.06), p = 1.01 x 10(-5), adjusted R-2 = 1.6 %), offspring alcohol PRS did not predict offspring alcohol consumption. We found evidence for an association of maternal alcohol PRS with own perinatal depression (OR = 1.10, 95% CI = 1.02 to 1.18, p = 0.022) and decreased offspring intellectual ability (beta=-0.209, 95% CI -0.38 to -0.04, p=0.016). Conclusions: These alcohol PRS are a valid proxy for maternal alcohol use in pregnancy. Offspring alcohol PRS was not associated with drinking in adolescence. Consistently with results from different study designs, we found evidence that maternal alcohol PRS are associated with both prenatal depression and decreased offspring intellectual ability.

Since the beginning of the COVID-19 pandemic, discussions on social media and blogs have indicated that women have experienced menstrual changes, including altered menstrual duration, frequency, regularity, and volume (heavier bleeding and clotting), increased dysmenorrhea, and worsened premenstrual syndrome. There have been a small number of scientific studies of variable quality reporting on menstrual cycle features during the pandemic, but it is still unclear whether apparent changes are due to COVID-19 infection/illness itself, or other pandemic-related factors like increased psychological stress and changes in health behaviours. It is also unclear to what degree current findings are explained by reporting bias, recall bias, selection bias and confounding factors. Further research is urgently needed. We provide a list of outstanding research questions and potential approaches to address them. Findings can inform policies to mitigate against gender inequalities in health and society, allowing us to build back better post-COVID.

Background Precise estimates of prevalence vary, but menstrual symptoms such as menorrhagia (heavy or prolonged bleeding) and dysmenorrhea (pain associated with period) are experienced by a large proportion of adolescent girls. Risk factors, co-morbidities and potential impacts of these menstrual problems on other areas of health and wellbeing are not well-characterised. We aimed to describe the prevalence of menorrhagia and dysmenorrhea in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort and to identify associations between these symptoms and other traits. Methods Cases of both dysmenorrhea and menorrhagia were identified using self-report questionnaires administered nine times between the ages of 8 and 17 years (n = 4,222 responded to at least one). Cases were defined as respondents who had reported to have visited the doctor for the symptom, any time during puberty. We used the ALSPAC cohort’s corresponding epigenetic data resource, ARIES, to identify differences in methylation between cases for each symptom and those who never had reported it (controls), to identify traits associated with each symptom. These identified traits were then explored in the full ALSPAC cohort, using logistic regression. Results Of the 4,222 adolescents who had responded to at least one of the puberty questionnaires, almost 70% (n = 2,915) had experienced dysmenorrhea at least once during puberty and over 50% (n = 2,123) had experienced menorrhagia. Of these, 22% (n = 641) and 25% (n = 527) visited the doctor for dysmenorrhea and menorrhagia, respectively. These symptoms showed significant overlap with one another, but remained distinctive. The epigenetic findings revealed potential associations with novel traits, including inflammatory markers and child abuse. In ALSPAC, both symptoms were shown to be associated with increased C-reactive protein and higher average adverse childhood experience (ACE) score, among other traits including prenatal smoke exposure, higher average body mass index and lower socioeconomic position. Discussion The prevalence of both dysmenorrhea and menorrhagia is high in ALSPAC, highlighting an important and neglected area for population health research and intervention. These findings may suggest that exposure to ACE may go on to increase likelihood of enduring more severe menstrual symptoms in adolescence, potentially mediated by higher BMI and circulating inflammatory proteins. The implication of ACE adds to the growing body of evidence that they negatively affect long-term health. This study overall describes novel associations between menstrual symptoms and early life exposures that warrant further investigation.

The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the schizophrenia-associated 'A' allele (N = 22) or the alternative 'C' allele (N = 18) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequence task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation. Average MST learning and sleepdependent performance improvements were similar across genotype groups, albeit more variable in the AA group. During sleep after learning, CC participants showed increased slow-wave (SW) and spindle amplitudes, plus augmented coupling of SW activity across recording electrodes. SW and spindles in those with the AA genotype were insensitive to learning, whilst SW coherence decreased following MST training. Accordingly, NREM neurophysiology robustly predicted the degree of overnight motor memory consolidation in CC carriers, but not in AA carriers. We describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in the coordinated neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of schizophrenia-associated common genetic variants on neural circuit oscillations and function.