Partial Identification of the Average Causal Effect in Multiple Study Populations: The Challenge of Combining Mendelian Randomization Studies.

BACKGROUND: Researchers often use random-effects or fixed-effects meta-analysis to combine findings from multiple study populations. However, the causal interpretation of these models is not always clear, and they do not easily translate to settings where bounds, rather than point estimates, are computed. METHODS: If bounds on an average causal effect of interest in a well-defined population are computed in multiple study populations under specified identifiability assumptions, then under those assumptions the average causal effect would lie within all study-specific bounds and thus the intersection of the study-specific bounds. We demonstrate this by pooling bounds on the average causal effect of prenatal alcohol exposure on attention deficit-hyperactivity disorder symptoms, computed in two European cohorts and under multiple sets of assumptions in Mendelian randomization (MR) analyses. RESULTS: For all assumption sets considered, pooled bounds were wide and did not identify the direction of effect. The narrowest pooled bound computed implied the risk difference was between -4 and 34 percentage points. CONCLUSIONS: All pooled bounds computed in our application covered the null, illustrating how strongly point estimates from prior MR studies of this effect rely on within-study homogeneity assumptions. We discuss how the interpretation of both pooled bounds and point estimation in MR is complicated by possible heterogeneity of effects across populations.

Bounding the average causal effect in Mendelian randomisation studies with multiple proposed instruments: An application to prenatal alcohol exposure and attention deficit hyperactivity disorder.

BACKGROUND: As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR. OBJECTIVES: We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected. METHODS: Using data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified. RESULTS: The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied. CONCLUSIONS: Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting.

COVID-19 vaccination in pregnancy: the impact of multimorbidity and smoking status on vaccine hesitancy, a cohort study of 25,111 women in Wales, UK.

BACKGROUND: Multimorbidity, smoking status, and pregnancy are identified as three risk factors associated with more severe outcomes following a SARS-CoV-2 infection, thus vaccination uptake is crucial for pregnant women living with multimorbidity and a history of smoking. This study aimed to examine the impact of multimorbidity, smoking status, and demographics (age, ethnic group, area of deprivation) on vaccine hesitancy among pregnant women in Wales using electronic health records (EHR) linkage. METHODS: This cohort study utilised routinely collected, individual-level, anonymised population-scale linked data within the Secure Anonymised Information Linkage (SAIL) Databank. Pregnant women were identified from 13th April 2021 to 31st December 2021. Survival analysis was employed to examine and compare the length of time to vaccination uptake in pregnancy by considering multimorbidity, smoking status, as well as depression, diabetes, asthma, and cardiovascular conditions independently. The study also assessed the variation in uptake by multimorbidity, smoking status, and demographics, both jointly and separately for the independent conditions, using hazard ratios (HR) derived from the Cox regression model. RESULTS: Within the population cohort, 8,203 (32.7%) received at least one dose of the COVID-19 vaccine during pregnancy, with 8,572 (34.1%) remaining unvaccinated throughout the follow-up period, and 8,336 (33.2%) receiving the vaccine postpartum. Women aged 30 years or older were more likely to have the vaccine in pregnancy. Those who had depression were slightly but significantly more likely to have the vaccine compared to those without depression (HR = 1.08, 95% CI 1.03 to 1.14, p = 0.002). Women living with multimorbidity were 1.12 times more likely to have the vaccine compared to those living without multimorbidity (HR = 1.12, 95% CI 1.04 to 1.19, p = 0.001). Vaccine uptakes were significantly lower among both current smokers and former smokers compared to never smokers (HR = 0.87, 95% CI 0.81 to 0.94, p < 0.001 and HR = 0.92, 95% CI 0.85 to 0.98, p = 0.015 respectively). Uptake was also lower among those living in the most deprived areas compared to those living in the most affluent areas (HR = 0.89, 95% CI 0.83 to 0.96, p = 0.002). CONCLUSION: Younger women, living without multimorbidity, current and former smokers, and those living in the more deprived areas are less likely to have the vaccine, thus, a targeted approach to vaccinations may be required for these groups. Pregnant individuals living with multimorbidity exhibit a slight but statistically significant reduction in vaccine hesitancy towards COVID-19 during pregnancy.

Evaluating Messaging on Prenatal Health Behaviors Using Social Media Data: Systematic Review.

BACKGROUND: Social media platforms are increasingly being used to disseminate messages about prenatal health. However, to date, we lack a systematic assessment of how to evaluate the impact of official prenatal health messaging and campaigns using social media data. OBJECTIVE: This study aims to review both the published and gray literature on how official prenatal health messaging and campaigns have been evaluated to date in terms of impact, acceptability, effectiveness, and unintended consequences, using social media data. METHODS: A total of 6 electronic databases were searched and supplemented with the hand-searching of reference lists. Both published and gray literature were eligible for review. Data were analyzed using content analysis for descriptive data and a thematic synthesis approach to summarize qualitative evidence. A quality appraisal tool, designed especially for use with social media data, was used to assess the quality of the included articles. RESULTS: A total of 11 studies were eligible for the review. The results showed that the most common prenatal health behavior targeted was alcohol consumption, and Facebook was the most commonly used source of social media data. The majority (n=6) of articles used social media data for descriptive purposes only. The results also showed that there was a lack of evaluation of the effectiveness, acceptability, and unintended consequences of the prenatal health message or campaign. CONCLUSIONS: Social media is a widely used and potentially valuable resource for communicating and evaluating prenatal health messaging. However, this review suggests that there is a need to develop and adopt sound methodology on how to evaluate prenatal health messaging using social media data, for the benefit of future research and to inform public health practice.

COVID-19 vaccination in pregnancy: views and vaccination uptake rates in pregnancy, a mixed methods analysis from SAIL and the Born-In-Wales Birth Cohort.

BACKGROUND: Vaccine hesitancy amongst pregnant women has been found to be a concern during past epidemics. This study aimed to (1) estimate COVID-19 vaccination rates among pregnant women in Wales and their association with age, ethnicity, and area of deprivation, using electronic health record (EHR) data linkage, and (2) explore pregnant women's views on receiving the COVID-19 vaccine during pregnancy using data from a survey recruiting via social media (Facebook, Twitter), through midwives, and posters in hospitals (Born-In-Wales Cohort). METHODS: This was a mixed-methods study utilising routinely collected linked data from the Secure Anonymised Information Linkage (SAIL) Databank (Objective 1) and the Born-In-Wales Birth Cohort participants (Objective 2). Pregnant women were identified from 13th April 2021 to 31st December 2021. Survival analysis was utilised to examine and compare the length of time to vaccination uptake in pregnancy, and variation in uptake by; age, ethnic group, and deprivation area was examined using hazard ratios (HR) from Cox regression. Survey respondents were women who had a baby during the COVID-19 pandemic or were pregnant between 1st November 2021 and 24th March 2022 and participating in Born-In-Wales. Codebook thematic analysis was used to generate themes from an open-ended question on the survey. RESULTS: Population-level data linkage (objective 1): Within the population cohort, 8203 (32.7%) received at least one dose of the COVID-19 vaccine during pregnancy, 8572 (34.1%) remained unvaccinated throughout the follow-up period, and 8336 (33.2%) received the vaccine postpartum. Younger women (< 30 years) were less likely to have the vaccine, and those living in areas of high deprivation were also less likely to have the vaccine (HR = 0.88, 95% CI 0.82 to 0.95). Asian and Other ethnic groups were 1.12 and 1.18 times more likely to have the vaccine in pregnancy compared with White women (HR = 1.12, 95% CI 1.00 to 1.25) and (HR = 1.18, 95% CI 1.03 to 1.37) respectively. Survey responses (objective 2): 207 (69%) of participants stated that they would be happy to have the vaccine during pregnancy. The remaining 94 (31%) indicated they would not have the vaccine during pregnancy. Reasons for having the vaccine included protecting self and baby, perceived risk level, and receipt of sufficient evidence and advice. Reasons for vaccine refusal included lack of research about long-term outcomes for the baby, anxiety about vaccines, inconsistent advice/information, and preference to wait until after the pregnancy. CONCLUSION: Potentially only 1 in 3 pregnant women would have the COVID-19 vaccine during pregnancy, even though 2 in 3 reported they would have the vaccination, thus it is critical to develop tailored strategies to increase its acceptance rate and decrease vaccine hesitancy. A targeted approach to vaccinations may be required for groups such as younger people and those living in higher deprivation areas.

Associations of Binge Drinking With the Risks of Ischemic Heart Disease and Stroke: A Study of Pooled Norwegian Health Surveys.

Norwegian health survey data (1987-2003) were analyzed to determine if binge drinking increases the risk of incident major events from ischemic heart disease (IHD) and stroke. Among current drinkers reporting average alcohol intakes of 2.00-59.99 g/day (n = 44,476), frequent binge drinking (≥5 units at least once per month) was not associated with a greater risk of IHD (adjusted hazard ratio (HR) = 0.91, 95% confidence interval (CI): 0.76, 1.09) or stroke (adjusted HR = 0.98, 95% CI: 0.81, 1.19), in comparison with participants who reported that they never or only infrequently (less than once per month) had episodes of binge drinking. Participants with an average alcohol intake of 2.00-59.99 g/day had a lower risk of IHD in comparison with participants with very low intakes (<2.00 g/day), both among frequent binge drinkers (adjusted HR = 0.67, 95% CI: 0.56, 0.80) and among never/infrequent binge drinkers (adjusted HR = 0.75, 95% CI: 0.67, 0.84). The findings suggest that frequent binge drinking, independent of average alcohol intake, does not increase the risk of incident IHD or stroke events. However, the findings should be interpreted in light of the limitations of the study design.

Maternal and offspring genetic risk score analyses of fetal alcohol exposure and attention-deficit hyperactivity disorder risk in offspring.

BACKGROUND: Studies investigating the effects of prenatal alcohol exposure on childhood attention-deficit hyperactivity disorder (ADHD) symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolize alcohol. We used genetic variants from the alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), as proxies for fetal alcohol exposure to investigate their association with risk of offspring ADHD symptoms around age 7-8 years. METHODS: We used data from 3 longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR), and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH and ALDH genes were calculated for mothers (NALSPAC  = 8196; NMOBA  = 13,614), fathers (NMOBA  = 13,935), and offspring (NALSPAC =8,237; NMOBA =14,112; NGENR =2,661). Associations between maternal GRS and offspring risk of ADHD symptoms were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status. RESULTS: The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR = 0.99, 95%CI 0.97-1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across all the cohorts was as follows: ORDRINKING  = 0.98, 95% CI 0.94-1.02; ORNO DRINKING  = 0.99, 95% CI 0.97-1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa. CONCLUSIONS: We did not find evidence for a causal effect of fetal alcohol exposure on risk of ADHD symptoms in offspring. The results may be affected by limited power to detect small effects and outcome assessment.

Breastfeeding and the origins of health: Interdisciplinary perspectives and priorities.

Breastfeeding and human milk (HM) are critically important to maternal, infant and population health. This paper summarizes the proceedings of a workshop that convened a multidisciplinary panel of researchers to identify key priorities and anticipated breakthroughs in breastfeeding and HM research, discuss perceived barriers and challenges to achieving these breakthroughs and propose a constructive action plan to maximize the impact of future research in this field. Priority research areas identified were as follows: (1) addressing low breastfeeding rates and inequities using mixed methods, community partnerships and implementation science approaches; (2) improving awareness of evidence-based benefits, challenges and complexities of breastfeeding and HM among health practitioners and the public; (3) identifying differential impacts of alternative modes of HM feeding including expressed/pumped milk, donor milk and shared milk; and (4) developing a mechanistic understanding of the health effects of breastfeeding and the contributors to HM composition and variability. Key barriers and challenges included (1) overcoming methodological limitations of epidemiological breastfeeding research and mechanistic HM research; (2) counteracting 'breastfeeding denialism' arising from negative personal breastfeeding experiences; (3) distinguishing and aligning research and advocacy efforts; and (4) managing real and perceived conflicts of interest. To advance research on breastfeeding and HM and maximize the reach and impact of this research, larger investments are needed, interdisciplinary collaboration is essential, and the scientific community must engage families and other stakeholders in research planning and knowledge translation.

Association of coincident self-reported mental health problems and alcohol intake with all-cause and cardiovascular disease mortality: A Norwegian pooled population analysis.

BACKGROUND: The disease burden attributable to mental health problems and to excess or harmful alcohol use is considerable. Despite a strong relationship between these 2 important factors in population health, there are few studies quantifying the mortality risk associated with their co-occurrence in the general population. The aim of this study was therefore to investigate cardiovascular disease (CVD) and all-cause mortality according to self-reported mental health problems and alcohol intake in the general population. METHODS AND FINDINGS: We followed 243,372 participants in Norwegian health surveys (1994-2002) through 2014 for all-cause and CVD mortality by data linkage to national registries. The mean (SD) age at the time of participation in the survey was 43.9 (10.6) years, and 47.8% were men. During a mean (SD) follow-up period of 16.7 (3.2) years, 6,587 participants died from CVD, and 21,376 died from all causes. Cox models estimated hazard ratios (HRs) with 95% CIs according to a mental health index (low, 1.00-1.50; high, 2.01-4.00; low score is favourable) based on the General Health Questionnaire and the Hopkins Symptom Checklist, and according to self-reported alcohol intake (low, <2; light, 2-11.99; moderate, 12-23.99; high, ≥24 grams/day). HRs were adjusted for age, sex, educational level, marital status, and CVD risk factors. Compared to a reference group with low mental health index score and low alcohol intake, HRs (95% CIs) for all-cause mortality were 0.93 (0.89, 0.97; p = 0.001), 1.00 (0.92, 1.09; p = 0.926), and 1.14 (0.96, 1.35; p = 0.119) for low index score combined with light, moderate, and high alcohol intake, respectively. HRs (95% CIs) were 1.22 (1.14, 1.31; p < 0.001), 1.24 (1.15, 1.33; p < 0.001), 1.43 (1.23, 1.66; p < 0.001), and 2.29 (1.87, 2.80; p < 0.001) for high index score combined with low, light, moderate, and high alcohol intake, respectively. For CVD mortality, HRs (95% CIs) were 0.93 (0.86, 1.00; p = 0.058), 0.90 (0.76, 1.07; p = 0.225), and 0.95 (0.67, 1.33; p = 0.760) for a low index score combined with light, moderate, and high alcohol intake, respectively, and 1.11 (0.98, 1.25; p = 0.102), 0.97 (0.83, 1.13; p = 0.689), 1.01 (0.71, 1.44; p = 0.956), and 1.78 (1.14, 2.78; p = 0.011) for high index score combined with low, light, moderate, and high alcohol intake, respectively. HRs for the combination of a high index score and high alcohol intake (HRs: 2.29 for all-cause and 1.78 for CVD mortality) were 64% (95% CI 53%, 74%; p < 0.001) and 69% (95% CI 42%, 97%; p < 0.001) higher than expected for all-cause mortality and CVD mortality, respectively, under the assumption of a multiplicative interaction structure. A limitation of our study is that the findings were based on average reported intake of alcohol without accounting for the drinking pattern. CONCLUSIONS: In the general population, the mortality rates associated with more mental health problems and a high alcohol intake were increased when the risk factors occurred together.

Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study.

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.

Moderate alcohol drinking in pregnancy increases risk for children's persistent conduct problems: causal effects in a Mendelian randomisation study.

BACKGROUND: Heavy alcohol use during pregnancy can cause considerable developmental problems for children, but effects of light-moderate drinking are uncertain. This study examined possible effects of moderate drinking in pregnancy on children's conduct problems using a Mendelian randomisation design to improve causal inference. METHODS: A prospective cohort study (ALSPAC) followed children from their mother's pregnancy to age 13 years. Analyses were based on 3,544 children whose mothers self-reported either not drinking alcohol during pregnancy or drinking up to six units per week without binge drinking. Children's conduct problem trajectories were classified as low risk, childhood-limited, adolescence-onset or early-onset-persistent, using six repeated measures of the Strengths and Difficulties Questionnaire between ages 4-13 years. Variants of alcohol-metabolising genes in children were used to create an instrumental variable for Mendelian randomisation analysis. RESULTS: Children's genotype scores were associated with early-onset-persistent conduct problems (OR = 1.29, 95% CI = 1.04-1.60, p = .020) if mothers drank moderately in pregnancy, but not if mothers abstained from drinking (OR = 0.94, CI = 0.72-1.25, p = .688). Children's genotype scores did not predict childhood-limited or adolescence-onset conduct problems. CONCLUSIONS: This quasi-experimental study suggests that moderate alcohol drinking in pregnancy contributes to increased risk for children's early-onset-persistent conduct problems, but not childhood-limited or adolescence-onset conduct problems.

Prenatal alcohol exposure and childhood atopic disease: a Mendelian randomization approach.

BACKGROUND: Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations are likely to be confounded. OBJECTIVE: We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding. METHODS: In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol). RESULTS: After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio [OR] per category increase in intake: 0.91 [95% CI, 0.82-1.01] and 0.87 [95% CI, 0.78-0.98], respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 [95% CI, 0.66-1.47]) or hay fever (OR, 1.11 [95% CI, 0.71-1.72]), nor with any other atopic outcome. CONCLUSION: We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood.

Exploring causal associations between alcohol and coronary heart disease risk factors: findings from a Mendelian randomization study in the Copenhagen General Population Study.

AIMS: To explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors. METHODS AND RESULTS: We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (-4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [-2.0% (-2.1, -1.8)] was not present in the IV analyses [0.6% (-3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [-0.13 kg/m(2) (-0.16, -0.10)] and with triglycerides [-0.4% (-0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m(2) (0.59, 2.15)] and the strong inverse association with triglycerides [-14.9% (-25.6, -4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose. CONCLUSION: Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.

Analyzing Questions About Alcohol in Pregnancy Using Web-Based Forum Topics: Qualitative Content Analysis.

BACKGROUND: Prenatal alcohol exposure represents a substantial public health concern as it may lead to detrimental outcomes, including pregnancy complications and fetal alcohol spectrum disorder. Although UK national guidance recommends abstaining from alcohol if pregnant or planning a pregnancy, evidence suggests that confusion remains on this topic among members of the public, and little is known about what questions people have about consumption of alcohol in pregnancy outside of health care settings. OBJECTIVE: This study aims to assess what questions and topics are raised on alcohol in pregnancy on a web-based UK-based parenting forum and how these correspond to official public health guidelines with respect to 2 critical events: the implementation of the revised UK Chief Medical Officers' (CMO) low-risk drinking guidelines (2016) and the first COVID-19 pandemic lockdown (2020). METHODS: All thread starts mentioning alcohol in the "Pregnancy" forum were collected from Mumsnet for the period 2002 to 2022 and analyzed using qualitative content analysis. Descriptive statistics were used to characterize the number and proportion of thread starts for each topic over the whole study period and for the periods corresponding to the change in CMO guidance and the COVID-19 pandemic. RESULTS: A total of 395 thread starts were analyzed, and key topics included "Asking for advice on whether it is safe to consume alcohol" or on "safe limits" and concerns about having consumed alcohol before being aware of a pregnancy. In addition, the Mumsnet thread starts included discussions and information seeking on "Research, guidelines, and official information about alcohol in pregnancy." Topics discussed on Mumsnet regarding alcohol in pregnancy remained broadly similar between 2002 and 2022, although thread starts disclosing prenatal alcohol use were more common before the introduction of the revised CMO guidance than in later periods. CONCLUSIONS: Web-based discussions within a UK parenting forum indicated that users were often unclear on guidance and risks associated with prenatal alcohol use and that they used this platform to seek information and reassurance from peers.

Alcohol consumption and PSA-detected prostate cancer risk--a case-control nested in the ProtecT study.

Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98-0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93-0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99-1.08; p(difference) =0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix.

Vaccine effectiveness for prevention of covid-19 related hospital admission during pregnancy in England during the alpha and delta variant dominant periods of the SARS-CoV-2 pandemic: population based cohort study.

Objective: To estimate vaccine effectiveness for preventing covid-19 related hospital admission in individuals first infected with the SARS-CoV-2 virus during pregnancy compared with those of reproductive age who were not pregnant when first infected with the virus. Design: Population based cohort study. Setting: Office for National Statistics Public Health Data Asset linked dataset, providing national linked census and administrative data in England, 8 December 2020 to 31 August 2021. Participants: 815 477 females aged 18-45 years (mean age 30.4 years) who had documented evidence of a first SARS-CoV-2 infection in the NHS Test and Trace or Hospital Episode Statistics data. Main outcome measures: Hospital admission where covid-19 was recorded as the primary diagnosis. Cox proportional hazards models, adjusted for calendar time of infection, sociodemographic factors, and pre-existing health conditions related to uptake of the covid-19 vaccine and risk of severe covid-19 outcomes, were used to estimate vaccine effectiveness as the complement of the hazard ratio for hospital admission for covid-19. Results: Compared with pregnant individuals who were not vaccinated, the adjusted rate of hospital admission for covid-19 was 77% (95% confidence interval 70% to 82%) lower for pregnant individuals who had received one dose and 83% (76% to 89%) lower for those who had received two doses of vaccine. These estimates were similar to those found in the non-pregnant group: 79% (77% to 81%) for one dose and 83% (82% to 85%) for two doses of vaccine. Among those who were vaccinated >90 days before infection, having two doses of vaccine was associated with a greater reduction in risk than one dose. Conclusions: Covid-19 vaccination was associated with reduced rates of hospital admission in pregnant individuals infected with the SARS-CoV-2 virus, and the reduction in risk was similar to that in non-pregnant individuals. Waning of vaccine effectiveness occurred more quickly after one than after two doses of vaccine.

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis.

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.

Current guidelines recommend pregnant women to limit caffeine intake to less than 200 mg daily, even though there is no clear proof of its effects on human development. A biological explanation for how exposure to caffeine during pregnancy influences development would help clarify if recommended limits are justified. An epigenetic mechanism, called DNA methylation (DNAm), has been suggested as a potential biological explanation for how caffeine intake during pregnancy influences health development. DNAm can switch genes 'on' or 'off' in response to environmental influences and therefore act as a bridge between genes and the environment. Studies have found that smoking during pregnancy is connected to over 6000 changes in DNAm at birth, with lasting effects into adulthood. To explore the link between caffeine intake during pregnancy and DNAm at birth, we analyzed data from 3725 mother­child pairs living in different European countries. We looked at effects from coffee, tea and cola intake during pregnancy on children's DNAm at birth. We found one change in DNAm to be connected to total caffeine and another to cola consumption during pregnancy. These few connections do not provide convincing evidence that caffeine intake during pregnancy impacts children's DNAm at birth. However, because mothers in our study consumed little caffeine, it is possible that results would be different in studies with participants consuming high amounts of caffeine during pregnancy. Potentially, our study did not include enough people to find very small changes in DNAm that are connected to caffeine consumption during pregnancy.

Alcohol Intake and Hypertensive Disorders of Pregnancy: A Negative Control Analysis in the ALSPAC Cohort.

Background Alcohol intake increases blood pressure yet estimates of associations between maternal intake and hypertensive disorders of pregnancy (HDP) are sparse and range from null to a protective effect. Here we estimated the association of maternal drinking during pregnancy with preeclampsia and gestational hypertension (separately and jointly, as HDP). We used partner's alcohol intake as a negative control exposure, beverage type-specific models, and a range of sensitivity analyses to strengthen causal inference and reduce the influence of bias. Methods and Results We performed a longitudinal analysis of prospectively collected data on self-reported alcohol intake and presence of HDP from the UK ALSPAC (Avon Longitudinal Study of Parents and Children) cohort. Multivariable multinomial regression models were adjusted for confounders and mutually adjusted for partner's or maternal alcohol intake in the negative control analysis. We also performed a beverage type analysis of the effect of beer and wine separately on HDP risk, owing to different social patterning associated with different drinks. Sensitivity analyses assessed the robustness of results to assumptions of no recall bias, no residual confounding, and no selection bias. Of the 8999 women eligible for inclusion, 1490 fulfilled the criteria for HDP (17%). Both maternal and partner's drinking were associated with decreased HDP odds (mutually adjusted odds ratio [OR], 0.86; [95% CI, 0.77-0.96], P=0.008 and OR, 0.82; [95% CI, 0.70-0.97], P=0.018, respectively). We demonstrate the validity of the negative control analyses using the same approach for smoking as the exposure. This confirmed an inverse association for maternal but not partner's smoking, as expected. Estimates were more extreme for increasing levels of wine intake compared with increasing levels of beer. Multiple sensitivity analyses did not alter our conclusions. Conclusions We observed an inverse relationship between alcohol intake during pregnancy and risk of HDP for both maternal and, more surprisingly, partner's drinking. We speculate that this is more likely to be due to common environmental exposures shared between pregnant women and their partners rather than a true causal effect. This warrants further investigation using different study designs, including Mendelian randomization.

The Frequency of Infant-Feeding Presentations at English Emergency Departments During the SARS-CoV-2 Pandemic: A Nation-Wide Electronic Health Records Study.

OBJECTIVES: To examine the frequency and distribution of infant feeding-related presentations at emergency departments (EDs) before and during the SARS-CoV-2 pandemic. SETTING: Attendances at 48 major EDs in England in two 50-week periods before and during the COVID-19 pandemic: period 1, April 2, 2019 to March 10, 2020 and period 2, April 1, 2020 to March 10, 2021. METHODS: We estimated the change in frequency of ED presentations by age group and diagnosis before and after the start of the SARS-CoV-2 pandemic in England. We compared changes in the frequency of attendances of infant-feeding related presentations by infant age, sex, ethnicity, deprivation, rurality, arrival mode, arrival time, acuity, mother's age, gravidity and mental health, birth length of stay, attendance duration, and disposal (i.e., admission or discharge). RESULTS: While total ED attendances fell by 16.7% (95% CI -16.8% to -16.6%), infant attendances increased for feeding problems (+7.5% 95% CI 2.3% to 13.0%), neonatal jaundice (+12.8%, 95% CI 3.3% to 23.3%) and gastro-esophageal reflux (+9.7%, 95% CI 4.4% to 15.2%). These increases were more pronounced amongst first babies (+22.4%, 95% CI 13.1% to 32.5%), and where the stay in hospital after birth was brief (0-1 days, +20.1%, 95% CI 14.8% to 25.7%). Our analysis suggests that many of these attendances were of low acuity. CONCLUSIONS: While ED attendances reduced dramatically and systematically with the COVID-19 pandemic, presentations for infant feeding issues increased, implying growth in the unmet needs of new mothers and infants.