Comparison of the stability of glycoprotein acetyls and high sensitivity C-reactive protein as markers of chronic inflammation.

It has been suggested that glycoprotein acetyls (GlycA) better reflects chronic inflammation than high sensitivity C-reactive protein (hsCRP), but paediatric/life-course data are sparse. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we compared short- (over weeks) and long-term (over years) correlations of GlycA and hsCRP, cross-sectional correlations between GlycA and hsCRP, and associations of pro-inflammatory risk factors with GlycA and hsCRP across the life-course. GlycA showed high short-term (weeks) stability at 15 years (r = 0.75; 95% CI = 0.56, 0.94), 18 years (r = 0.74; 0.64, 0.85), 24 years (r = 0.74; 0.51, 0.98) and 48 years (r = 0.82 0.76, 0.86) and this was comparable to the short-term stability of hsCRP at 24 years. GlycA stability was moderate over the long-term, for example between 15 and 18 years r = 0.52; 0.47, 0.56 and between 15 and 24 years r = 0.37; 0.31, 0.44. These were larger than equivalent correlations of hsCRP. GlycA and concurrently measured hsCRP were moderately correlated at all ages, for example at 15 years (r = 0.44; 0.40, 0.48) and at 18 years (r = 0.55; 0.51, 0.59). We found similar associations of known proinflammatory factors and inflammatory diseases with GlycA and hsCRP. For example, BMI was positively associated with GlycA (mean difference in GlycA per standard deviation change in BMI = 0.08; 95% CI = 0.07, 0.10) and hsCRP (0.10; 0.08, 0.11). This study showed that GlycA has greater long-term stability than hsCRP, however associations of proinflammatory factors with GlycA and hsCRP were broadly similar.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

STUDY QUESTION: Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? SUMMARY ANSWER: Genetic instruments suggest that higher fasting insulin may increase infertility in women. WHAT IS KNOWN ALREADY: Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. STUDY DESIGN, SIZE, DURATION: This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). MAIN RESULTS AND THE ROLE OF CHANCE: In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. LIMITATIONS, REASONS FOR CAUTION: We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. WIDER IMPLICATIONS OF THE FINDINGS: Treatments for lower fasting insulin levels may reduce the risk of infertility in women. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Exposure to microplastics and human reproductive outcomes: A systematic review.

BACKGROUND: Microplastics, produced through degradation of environmental plastic pollution, have been detected in human tissues including placenta and fetal meconium. Cell culture and animal studies have demonstrated potential reproductive toxicity of these particles; however, their association with adverse fertility or pregnancy outcomes in humans is not known. OBJECTIVES: To synthesise evidence for the presence of microplastics in human reproductive tissue and their associations with environmental exposures and reproductive outcomes. SEARCH STRATEGY: MEDLINE, Embase, Emcare, CINAHL, ClinicalTrials.gov and ICTRP were searched from inception to 03/02/2023. SELECTION CRITERIA: Studies of human participants, assessing presence of microplastics in reproductive tissues, environmental exposures to microplastics, and fertility- or pregnancy-related outcomes. DATA COLLECTION AND ANALYSIS: Two independent reviewers selected studies and extracted data on study characteristics, microplastics detected, environmental exposures and reproductive outcomes. Narrative synthesis was performed due to methodological heterogeneity. MAIN RESULTS: Of 1094 citations, seven studies were included, covering 96 participants. Microplastics composed of 16 different polymer types were detected in both placental and meconium samples. Two studies reported associations between lifestyle factors (daily water intake, use of scrub cleanser or toothpaste, bottled water and takeaway food) and placental microplastics. One study reported associations between meconium microplastics and reduced microbiota diversity. One reported placental microplastic levels correlated with reduced birthweights and 1-minute Apgar scores. CONCLUSIONS: There is a need for high-quality observational studies to assess the effects of microplastics on human reproductive health.

Cross Sectional Survey of Antenatal Educators' Views About Current Antenatal Education Provision.

OBJECTIVES: Antenatal education (ANE) is part of National Health Service (NHS) care and is recommended by The National Institute for Health and Care Excellence (NICE) to increase birth preparedness and help pregnant women/birthing people develop coping strategies for labour and birth. We aimed to understand antenatal educator views about how current ANE supports preparedness for childbirth, including coping strategy development with the aim of identifying targets for improvement. METHODS: A United Kingdom wide, cross-sectional online survey was conducted between October 2019 and May 2020. Antenatal educators including NHS midwives and private providers were purposively sampled. Counts and percentages were calculated for closed responses and thematic analysis used for open text responses. RESULTS: Ninety-nine participants responded, 62% of these did not believe that ANE prepared women for labour and birth. They identified practical barriers to accessing ANE, particularly for marginalised groups, including financial and language barriers. Educators believe class content is medically focused, and teaching is of variable quality with some midwives being ill-prepared to deliver antenatal education. 55% of antenatal educators believe the opportunity to develop coping strategies varies between location and educators and only those women who can pay for non-NHS classes are able to access all the coping strategies that can support them with labour and birth. CONCLUSIONS FOR PRACTICE: Antenatal educators believe current NHS ANE does not adequately prepare women for labour and birth, leading to disparities in birth preparedness for those who cannot access non-NHS classes. To reduce this healthcare inequality, NHS classes need to be standardised, with training for midwives in delivering ANE enhanced.

Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis.

BACKGROUND: Few studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on women's health. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity. METHODS: We used genetic data from UK Biobank (273,238 women) and other consortia (EGG, GIANT, ReproGen and SSGAC) for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood and adulthood body size. We applied multivariable Mendelian randomization to account for genetic correlation and to estimate the causal effects of childhood and adulthood adiposity, independently of each other, on reproductive factors. Additionally, we estimated the effects of reproductive factors, independently of other relevant reproductive factors, on adulthood adiposity. RESULTS: We found a higher childhood body size leads to an earlier age at menarche, and an earlier age at menarche leads to a higher adulthood body size. Furthermore, we find contrasting and independent effects of childhood and adulthood body size on age at first birth (beta 0.22 SD (95% confidence interval: 0.14, 0.31) vs - 2.49 (- 2.93, - 2.06) per 1 SD increase), age at last birth (0.13 (0.06,0.21) vs - 1.86 (- 2.23, - 1.48) per 1 SD increase), age at menopause (0.17 (0.09, 0.25) vs - 0.99 (- 1.39, - 0.59) per 1 SD increase), and likelihood of having children (Odds ratio 0.97 (0.95, 1.00) vs 1.20 (1.06, 1.37) per 1 SD increase). CONCLUSIONS: Our findings demonstrate the importance of considering a lifecourse approach when investigating the inter-relationships between adiposity measures and reproductive events, as well as the use of 'age specific' genetic instruments when evaluating lifecourse hypotheses in a Mendelian randomization framework.

Sex differences in the severity and natural recovery of child PTSD symptoms: a longitudinal analysis of children exposed to acute trauma.

BACKGROUND: Higher levels of PTSD symptoms are present among trauma-exposed females v. males in adulthood; however, much less is known about the emergence of this sex difference during development. METHODS: In a multi-study sample of 7-18-year-olds (n = 3397), we examined the effect of sex and age on the severity of PTSD symptoms after a single incident trauma at 1 month (T1), and on symptom change after a natural recovery period of 3 (T2) and 6 months (T3). PTSD scores were harmonised across measurement types, and linear regressions were used to determine sex and age effects, adjusting for study level variance and trauma type. RESULTS: A sex × age interaction was observed at T1 (p < 0.001) demonstrating that older age was associated with greater PTSD symptom severity in females (ß = 0.008, p = 0.047), but less severe symptoms in males (ß = -0.011, p = 0.014). The same pattern was observed at T2 and T3, with sex differences beginning to emerge by age 12 years. PTSD symptoms decreased naturally by ~25% at T2 with little further improvement by T3. Further, females showed a greater reduction in symptoms at T3 than males, although the same effect was not observed at T2. CONCLUSIONS: Sex differences in PTSD symptoms become apparent during adolescence, due to opposing changes in susceptibility occurring in females and males with age. Understanding the factors contributing to these findings is likely to provide wider insight into sex-specific psychological vulnerability to trauma-related psychopathology.

Placental syndromes and maternal cardiovascular health.

The placental syndromes gestational hypertension, preeclampsia and intrauterine growth restriction are associated with an increased cardiovascular risk to the mother later in life. In this review, we argue that a woman's pre-conception cardiovascular health drives both the development of placental syndromes and long-term cardiovascular risk but acknowledge that placental syndromes can also contribute to future cardiovascular risk independent of pre-conception health. We describe how preclinical studies in models of preeclampsia inform our understanding of the links with later cardiovascular disease, and how current pre-pregnancy studies may explain relative contributions of both pre-conception factors and the occurrence of placental syndromes to long-term cardiovascular disease.

Interventions, outcomes and outcome measurement instruments in stillbirth care research: A systematic review to inform the development of a core outcome set.

BACKGROUND: A core outcome set could address inconsistent outcome reporting and improve evidence for stillbirth care research, which have been identified as an important research priority. OBJECTIVES: To identify outcomes and outcome measurement instruments reported by studies evaluating interventions after the diagnosis of a stillbirth. SEARCH STRATEGY: Amed, BNI, CINAHL, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycINFO, and WHO ICTRP from 1998 to August 2021. SELECTION CRITERIA: Randomised and non-randomised comparative or non-comparative studies reporting a stillbirth care intervention. DATA COLLECTION AND ANALYSIS: Interventions, outcomes reported, definitions and outcome measurement tools were extracted. MAIN RESULTS: Forty randomised and 200 non-randomised studies were included. Fifty-eight different interventions were reported, labour and birth care (52 studies), hospital bereavement care (28 studies), clinical investigations (116 studies), care in a multiple pregnancy (2 studies), psychosocial support (28 studies) and care in a subsequent pregnancy (14 studies). A total of 391 unique outcomes were reported and organised into 14 outcome domains: labour and birth; postpartum; delivery of care; investigations; multiple pregnancy; mental health; emotional functioning; grief and bereavement; social functioning; relationship; whole person; subsequent pregnancy; subsequent children and siblings and economic. A total of 242 outcome measurement instruments were used, with 0-22 tools per outcome. CONCLUSIONS: Heterogeneity in outcome reporting, outcome definition and measurement tools in care after stillbirth exists. Considerable research gaps on specific intervention types in stillbirth care were identified. A core outcome set is needed to standardise outcome collection and reporting for stillbirth care research.

Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review.

Diseases diagnosed in adulthood may have antecedents throughout (including prenatal) life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of disease prevention strategies. Mendelian randomisation (MR) is increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes. This systematic literature review explores MR methods used to perform lifecourse investigations and reviews previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted searches in PubMed, Embase, Medline and MedRXiv databases. Thirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures in the interpretation of "standard" MR techniques, five presented methods for repeat measures of the same exposure, and four described methodological approaches to handling multigenerational exposures. A further 127 studies presented the results of an applied research question. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. The remaining mostly estimated maternal effects. There is a growing body of research focused on the development and application of MR methods to address lifecourse research questions. The underlying assumptions require careful consideration and the interpretation of results rely on select conditions. Whilst we do not advocate for a particular strategy, we encourage practitioners to make informed decisions on how to approach a research question in this field with a solid understanding of the limitations present and how these may be affected by the research question, modelling approach, instrument selection, and data availability.

Interventions to enhance medication adherence in pregnancy- a systematic review.

BACKGROUND: Sub-optimal medication adherence in pregnant women with chronic disease and pregnancy-related indications has the potential to adversely affect maternal and perinatal outcomes. Adherence to appropriate medications is advocated during and when planning pregnancy to reduce risk of adverse perinatal outcomes relating to chronic disease and pregnancy-related indications. We aimed to systematically identify effective interventions to promote medication adherence in women who are pregnant or planning to conceive and impact on perinatal, maternal disease-related and adherence outcomes. METHODS: Six bibliographic databases and two trial registries were searched from inception to 28th April 2022. We included quantitative studies evaluating medication adherence interventions in pregnant women and women planning pregnancy. Two reviewers selected studies and extracted data on study characteristics, outcomes, effectiveness, intervention description (TIDieR) and risk of bias (EPOC). Narrative synthesis was performed due to study population, intervention and outcome heterogeneity. RESULTS: Of 5614 citations, 13 were included. Five were RCTs, and eight non-randomised comparative studies. Participants had asthma (n = 2), HIV (n = 6), inflammatory bowel disease (IBD; n = 2), diabetes (n = 2) and risk of pre-eclampsia (n = 1). Interventions included education +/- counselling, financial incentives, text messaging, action plans, structured discussion and psychosocial support. One RCT found an effect  of the tested intervention on self-reported antiretroviral adherence but not objective adherence. Clinical outcomes were not evaluated. Seven non-randomised comparative studies found an association between the tested intervention and at least one outcome of interest: four found an association between receiving the intervention and both improved clinical or perinatal outcomes and adherence in women with IBD, gestational diabetes mellitus (GDM), and asthma. One study in women with IBD reported an association between receiving the intervention and maternal outcomes but not for self-reported adherence. Two studies measured only adherence outcomes and reported an association between receiving the intervention and self-reported and/or objective adherence in women with HIV and risk of pre-eclampsia. All studies had high or unclear risk of bias. Intervention reporting was adequate for replication in two studies according to the TIDieR checklist. CONCLUSIONS: There is a need for high-quality RCTs reporting replicable interventions to evaluate medication adherence interventions in pregnant women and those planning pregnancy. These should assess both clinical and adherence outcomes.

The relationships between women's reproductive factors: a Mendelian randomisation analysis.

BACKGROUND: Women's reproductive factors include their age at menarche and menopause, the age at which they start and stop having children and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors. METHODS: We used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomisation (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap. RESULTS: LDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06-0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (beta (B) = 0.09 SD, 95% confidence intervals (CI) = 0.06,0.11), age at first birth (B = 0.07 SD, CI = 0.04,0.10), age at last birth (B = 0.06 SD, CI = 0.04,0.09) and age at menopause (B = 0.06 SD, CI = 0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B = 0.21 SD, CI = 0.13,0.29), age at last birth (B = 0.72 SD, CI = 0.67, 0.77) and a lower number of births (B = -0.38 SD, CI = -0.44, -0.32). CONCLUSION: This study presents evidence that women's reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman's entire reproductive history, including the causal interplay between reproductive factors.

Exploring the causal role of intimate partner violence and abuse on depressive symptoms in young adults: a population-based cohort study.

BACKGROUND: Previous studies have shown an association between experience of intimate partner violence and abuse (IPVA) and depression. Whether this is a causal relationship or explained by prior vulnerability that influences the risk of both IPVA and depression is not known. METHODS: We analysed data from the Avon Longitudinal Study of Parents and Children prospective cohort (N = 1764 women, 1028 men). To assess the causal association between IPVA at 18-21 years old and logged depressive symptom scores at age 23, we used (i) multivariable linear regression, (ii) inverse probability of treatment weighting (IPTW), and (iii) difference-in-difference (DiD) analysis, which compared the mean change in logged depressive symptom scores between ages 16 and 23 between those who experienced IPVA and those who did not. RESULTS: Women who experienced IPVA had on average 26% higher depressive symptom scores after adjustment for measured confounders (ratio of geometric means 1.26, 95% CI 1.13 to 1.40). In men, the difference was 5% (ratio of geometric means 1.05, 95% CI 0.92 to 1.21). Results from IPTW analysis were similar. In the DiD analysis, there was no evidence that being exposed to IPVA affected the change in depressive symptom scores over time compared to being in the non-exposed group for either women (difference-in-differences 1%, -12 to 16%) or men (-1%, -19 to 20%). CONCLUSIONS: Multivariable linear regression and IPTW suggested an association between IPVA and higher depressive symptom score in women but not men, but DiD analysis indicated a null effect in both women and men. This suggests the causal origins of higher depressive symptoms in this young adult population are likely to reflect prior vulnerability that leads to both higher depressive symptoms and increased risk of IPVA exposure.

Cardiovascular health in the menopause transition: a longitudinal study of up to 3892 women with up to four repeated measures of risk factors.

BACKGROUND: Women experience adverse changes in cardiovascular health in mid-life; whether the menopausal transition influences these remains strongly debated. The aim of this study was to examine associations of reproductive age (time since final menstrual period (FMP)) with change in carotid intima media thickness (CIMT) and cardiovascular risk factors and determine the role of chronological and reproductive age. METHODS: We used data from 1702 women from a pregnancy-based UK cohort who had up to four repeat cardiovascular health measures between mean age 51 (SD = 4.0) and 56 (SD = 3.6) years and experienced a natural menopause. Multilevel models were used to assess the relationship between cardiovascular measures and time since FMP (reproductive age), whilst adjusting for the underlying effects of chronological age and confounders (socioeconomic factors, body mass index, smoking, alcohol, parity, age at menarche). In addition, we looked at the relationship between cardiovascular measures by chronological age according to menopausal stages (pre-menopause, peri-menopause and post-menopause) using information from women who had and had not experienced menopause (N = 3892). RESULTS: There was no strong evidence that reproductive age was associated with CIMT (difference in mean 0.8 µm/year, 95% CI - 0.4, 2.1), whereas there was a strong positive association of chronological age (7.6 µm/year, 95% CI 6.3, 8.9). Consistent with this, we found weaker linear associations of reproductive compared with chronological age for atherosclerotic risk factors, such as with systolic blood pressure (- 0.1 mmHg/year, 95% CI - 0.3, 0.1, and 0.4 mmHg/year, 95% CI 0.2, 0.5, respectively) and non-HDL-cholesterol (0.02 mmol/l/year, 95% CI 0.005, 0.03, and 0.06, 95% CI 0.04, 0.07, respectively). In contrast, associations with fat mass (0.06 kg/m2/year, 95% CI 0.03, 0.10, and 0 kg/m2/year, 95% CI - 0.04, 0.04, respectively) and C-reactive protein (0.01, 95% CI 0.001, 0.02, and 0.01, 95% CI - 0.001, 0.02 natural logged mg/l/year, respectively) were stronger for reproductive compared with chronological age. Both reproductive and chronological age were (weakly) positively associated with glucose (0.002, 95% CI 0.0001, 0.003, and 0.002, 95% CI 0.0001, 0.003 natural logged mmol/l/year, respectively). CONCLUSIONS: Our results suggest that going through the menopausal transition does not further increase women's risk of atherosclerosis (measured by CIMT) beyond effects of ageing. Menopausal transition may, in additional to ageing, modestly increase adiposity and glucose levels and therefore a possible associated diabetes risk.

Associations between Adverse Childhood Experiences and the novel inflammatory marker glycoprotein acetyls in two generations of the Avon Longitudinal Study of Parents and Children birth cohort.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with increased risk of non-communicable diseases in adulthood, potentially mediated by chronic low-grade inflammation. Glycoprotein acetyls (GlycA) is a marker of chronic and cumulative inflammation. We investigated associations between ACEs and GlycA at different ages, in two generations of the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. METHODS: ALSPAC offspring's total ACE scores were generated for two age periods using prospectively collected data: 0-7y and 0-17y. GlycA was measured using high-resolution proton nuclear magnetic resonance at mean ages 8y, 18y, and 24y. Sample sizes ranged from: n = 5116 (8y) to n = 3085 (24y). ALSPAC mothers (n = 4634) retrospectively reported ACEs experienced before age 18y and GlycA was assessed at mean age 49y. We used multivariable linear regression to estimate associations between ACEs (total ACE score and individual ACEs) and subsequent GlycA in both samples, adjusting for key confounders. RESULTS: Mean GlycA levels were similar in offspring and mothers and over time. In offspring, there was no evidence that ACEs (total score or individual ACE) were associated with GlycA at age 8y or 18y, or 24y after adjustment for maternal age at birth and parity, maternal marital status, household occupational social class, maternal education, maternal smoking, own ethnicity, sex, and age in months. In mothers, there was evidence of a positive association between the total ACE score and GlycA at age 49y (adjusted mean difference 0.007 mmol/L; 95%CI: 0.003, 0.01). Emotional neglect was the only individual ACE associated with higher GlycA after adjusting for confounders and other ACEs. CONCLUSION: Results suggest the association between ACEs and GlycA may emerge in middle age. Future research should explore the extent to which inflammation in adulthood mediates well-documented associations between ACEs and adverse health outcomes in later life.

Mode of delivery and maternal sexual wellbeing: A longitudinal study.

OBJECTIVES: To investigate the association between mode of delivery and subsequent maternal sexual wellbeing. DESIGN: Prospective birth cohort study. SETTING: Avon (in Bristol area), UK. POPULATION: Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS: Mode of delivery was abstracted from obstetric records and sexual wellbeing measures were collected via a self-report questionnaire. Missing data were imputed using multiple imputation, and ordinal logistic regression models for ordered categorical outcomes were adjusted for the covariates maternal age at delivery, pre-pregnancy body mass index, diabetes during pregnancy, socio-economic position, parity, depression and anxiety. MAIN OUTCOME MEASURES: Sexual enjoyment and frequency at four time points postpartum (between 33 months and 18 years) and two types of sex-related pain (pain in the vagina during sex and elsewhere after sex) at 11 years postpartum. RESULTS: We found no association between mode of delivery and sexual enjoyment (e.g. adjusted odds ratio [OR] 1.11, 95% confidence interval [95% CI] 0.97-1.27 at 33 months) or sexual frequency (OR 0.99, 95% CI 0.88-1.12 at 33 months). Caesarean section was associated with an increased odds of pain in the vagina during sex at 11 years postpartum as compared with vaginal delivery in the adjusted model (OR 1.74, 95% CI 1.46-2.08). CONCLUSIONS: These findings provide no evidence supporting associations between caesarean section and sexual enjoyment or frequency. However, mode of delivery was shown to be associated with dyspareunia, which may not be limited to abdominal scarring.

Identifying potential causal effects of age at menopause: a Mendelian randomization phenome-wide association study.

Age at natural menopause (ANM) is associated with a range of health-related traits, including bone health, female reproductive cancers, and cardiometabolic health. Our objective was to conduct a Mendelian randomization phenome-wide association study (MR-pheWAS) of ANM. We conducted a hypothesis-free analysis of the genetic risk score (GRS) for ANM with 18,961 health-related traits among 181,279 women in UK Biobank. We also stratified the GRS according to the involvement of SNPs in DNA damage response. We sought to replicate our findings in independent cohorts. We conducted a negative control MR-pheWAS among men. Among women, we identified potential effects of ANM on 221 traits (1.17% of all traits) at a false discovery rate (P value ≤ 5.83 × 10-4), and 91 (0.48%) potential effects when using Bonferroni threshold (P value ≤ 2.64 × 10-6). Our findings included 55 traits directly related to ANM (e.g. hormone replacement therapy, gynaecological conditions and menstrual conditions), and liver function, kidney function, lung function, blood-cell composition, breast cancer and bone and cardiometabolic health. Replication analyses confirmed that younger ANM was associated with HbA1c (adjusted mean difference 0.003 mmol/mol; 95% CI 0.001, 0.006 per year decrease in ANM), breast cancer (adjusted OR 0.96; 95% CI 0.95, 0.98), and bone-mineral density (adjusted mean difference - 0.05; 95% CI - 0.07, - 0.03 for lumbar spine). In men, 30 traits were associated with the GRS at a false discovery rate (P value ≤ 5.49 × 10-6), and 11 potential effects when using Bonferroni threshold (P value ≤ 2.75 × 10-6). In conclusion, our results suggest that younger ANM has potential causal effects on a range of health-related traits.

Changes in women's physical function in mid-life by reproductive age and hormones: a longitudinal study.

BACKGROUND: Whether women's physical function in mid-life is related to their reproductive age is not known. The objectives of this study were to examine and compare changes in physical function in women by reproductive age, measured as time since final menstrual period (FMP), and chronological age, and to explore associations with repeatedly assessed levels of reproductive hormones. METHODS: We used data from 2319 UK women with up to three repeated measurements of physical function (median length of follow up: 2 years), focusing on changes occurring in women experiencing a natural menopausal transition. The main outcome was a composite physical function score that incorporated assessments of strength (grip strength), balance (one-leg stand) and cardiorespiratory fitness (timed chair rises). Associations with time since FMP, age, and time-updated measures of anti-Müllerian hormone, follicle-stimulating hormone and luteinizing hormone were assessed by multilevel models and generalised estimating equations models adjusted for the underlying effects of chronological age and confounding by education, age at first birth and smoking. RESULTS: The results showed that, adjusted for these confounders, time since FMP (- 0.21 SD per 10 years, 95% CI - 0.37, - 0.06) and chronological age (- 0.31 SD per 10 years, 95% CI - 0.46, - 0.15) were inversely associated with the physical function composite score. Grip strength seemed to be the main contributor to the decline in the composite score by time since FMP. There was no strong evidence of associations between any of the three reproductive hormones and the composite score. CONCLUSIONS: Physical function in women in mid-life declined with both chronological and reproductive age. The decline with reproductive age was independent of chronological age but did not seem to be driven by changes in reproductive hormones.

Being silenced, loneliness and being heard: understanding pathways to intimate partner violence & abuse in young adults. a mixed-methods study.

BACKGROUND: International research shows the significance and impact of intimate partner violence and abuse (IPVA) as a public health issue for young adults. There is a lack of qualitative research exploring pathways to IPVA. METHODS: The current mixed-methods study used qualitative interviews and analysis of longitudinal cohort data, to explore experiences of pathways to IPVA. Semi-structured Interviews alongside Life History Calendars were undertaken to explore 17 young women's (19-25 years) experiences and perceptions of pathways to IPVA in their relationships. Thematic analysis was undertaken. Based on themes identified in the qualitative analysis, quantitative analysis was conducted in data from 2127 female and 1145 male participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. We fitted regression models to assess the association of child maltreatment, parental domestic violence, and peer-to-peer victimisation, by age 12, with loneliness during adolescence (ages 13-14), and the association of loneliness during adolescence with IPVA (age 18-21). Mediation analysis estimated the direct effects of maltreatment on IPVA, and indirect effects through loneliness. FINDINGS: All women interviewed experienced at least one type of maltreatment, parental domestic violence, or bullying during childhood. Nearly all experienced IPVA and most had been multi-victimised. Findings indicated a circular pathway: early trauma led to isolation and loneliness, negative labelling and being silenced through negative responses to help seeking, leading to increased experiences of loneliness and intensifying vulnerability to further violence and abuse in young adulthood. The pathway was compounded by intersectionality. Potential ways to break this cycle of loneliness included being heard and supported, especially by teachers. Quantitative analysis confirmed an association between child maltreatment and loneliness in adolescence, and an association between loneliness in adolescence and experience of IPVA in young adult relationships. CONCLUSION: It is likely that negative labelling and loneliness mediate pathways to IPVA, especially among more disadvantaged young women. The impact of early maltreatment on young people's wellbeing and own relationships is compounded by disadvantage, disability and ethnicity. Participants' resilience was enabled by support in the community.

Puberty timing and markers of cardiovascular structure and function at 25 years: a prospective cohort study.

BACKGROUND: Whether earlier onset of puberty is associated with higher cardiovascular risk in early adulthood is not well understood. Our objective was to examine the association between puberty timing and markers of cardiovascular structure and function at age 25 years. METHODS: We conducted a prospective birth cohort study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were born between April 1, 1991, and December 31, 1992. Exposure of interest was age at peak height velocity (aPHV), an objective and validated growth-based measure of puberty onset. Outcome measures included cardiovascular structure and function at age 25 years: carotid intima-media thickness (CIMT), left ventricular mass index (LVMI) and relative wall thickness (RWT), pulse wave velocity (PWV) and systolic blood pressure (SBP). Multiple imputation was used to impute missing data on covariates and outcomes. Linear regression was used to examine the association between aPHV and each measure of cardiac structure and function, adjusting for maternal age, gestational age, household social class, maternal education, mother's partner's education, breastfeeding, parity, birthweight, maternal body mass index, maternal marital status, maternal prenatal smoking status and height and fat mass at age 9. All analyses were stratified by sex. RESULTS: A total of 2752-4571 participants were included in the imputed analyses. A 1-year older aPHV was not strongly associated with markers of cardiac structure and function in males and females at 25 years and most results spanned the null value. In adjusted analyses, a 1-year older aPHV was associated with 0.003 mm (95% confidence interval (CI) 0.00001, 0.006) and 0.0008 mm (95% CI - 0.002, 0.003) higher CIMT; 0.02 m/s (95% CI - 0.05, 0.09) and 0.02 m/s (95% CI - 0.04, 0.09) higher PWV; and 0.003 mmHg (95% CI - 0.60, 0.60) and 0.13 mmHg (95% CI - 0.44, 0.70) higher SBP, among males and females, respectively. A 1-year older aPHV was associated with - 0.55 g/m2.7 (95% CI - 0.03, - 1.08) and - 0.89 g/m2.7 (95% CI - 0.45, - 1.34) lower LVMI and - 0.001 (95% CI - 0.006, 0.002) and - 0.002 (95% CI - 0.006, 0.002) lower RWT among males and females. CONCLUSIONS: Earlier puberty is unlikely to have a major impact on pre-clinical cardiovascular risk in early adulthood.