Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum.

Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=0.403, P=2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no rg between female infertility and reproductive hormones (P>0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P=1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.

Maternity healthcare professionals' experiences of supporting women in decision-making for labour and birth: a qualitative study.

OBJECTIVES: To explore and characterise maternity healthcare professionals' (MHCPs) experience and practice of shared decision-making (SDM), to inform policy, research and practice development. DESIGN: Qualitative focus group study. SETTING: Large Maternity Unit in the Southwest of England. PARTICIPANTS: MHCPs who give information relating to clinical procedures and pregnancy care relating to labour and birth and are directly involved in decision-making conversations were purposively sampled to ensure representation across MHCP groups. DATA COLLECTION: A semistructured topic guide was used. DATA ANALYSIS: Reflexive thematic analysis was undertaken. RESULTS: Seven focus groups were conducted, comprising a total of 24 participants (3-5 per group). Two themes were developed: contextualising decision-making and controversies in current decision-making. Contextual factors that influenced decision-making practices included lack of time and challenges faced in intrapartum care. MHCPs reported variation in how they approach decision-making conversations and asked for more training on how to consistently achieve SDM. There were communication challenges with women who did not speak English. Three controversies were explored: the role of prior clinical experience, the validity of informed consent when women were in pain and during life-threatening emergencies and instances where women declined medical advice. CONCLUSIONS: We found that MHCPs are committed to SDM but need better support to deliver it. Structured processes including Core Information Sets, communication skills training and decision support aids may help to consistently deliver SDM in maternity care.

Mapping cell-to-tissue graphs across human placenta histology whole slide images using deep learning with HAPPY.

Accurate placenta pathology assessment is essential for managing maternal and newborn health, but the placenta's heterogeneity and temporal variability pose challenges for histology analysis. To address this issue, we developed the 'Histology Analysis Pipeline.PY' (HAPPY), a deep learning hierarchical method for quantifying the variability of cells and micro-anatomical tissue structures across placenta histology whole slide images. HAPPY differs from patch-based features or segmentation approaches by following an interpretable biological hierarchy, representing cells and cellular communities within tissues at a single-cell resolution across whole slide images. We present a set of quantitative metrics from healthy term placentas as a baseline for future assessments of placenta health and we show how these metrics deviate in placentas with clinically significant placental infarction. HAPPY's cell and tissue predictions closely replicate those from independent clinical experts and placental biology literature.

Hypertensive disorders of pregnancy and midlife maternal cognition in a prospective cohort study.

Hypertensive disorders of pregnancy (HDP) are associated with an increased risk of cardiovascular disorders, with recent evidence linking pre-eclampsia with vascular dementia. We examined associations of HDP with cognitive performance measured in midlife, in a prospective cohort study, the Avon Longitudinal Study of Parents and Children. Six cognitive function domains were measured 20 years after pregnancy at a mean age of 51 years. The cognition tests were repeated at clinics in the following two years. Cognitive function domains measured were immediate and delayed verbal episodic memory, working memory, processing speed, verbal intelligence, and verbal fluency. Exposures were pre-eclampsia, gestational hypertension (GH), and a combined category of any HDP, all compared to normotensive pregnancy. Of 3393 pregnancies included in the analysis, GH was experienced by 417 (12.3%) and pre-eclampsia by 57 (1.7%). GH was associated with lower verbal episodic memory, in the delayed logic memory test (-0.16 SDs; 95% CI -0.30, -0.03; p = .015) and there was weak evidence of an association with the immediate logic memory test (-0.13 SDs; -0.27, 0.001; p = .058). However, we did not see steeper declines by age for women with GH and there was no evidence of associations with other cognitive domains or for pre-eclampsia with any domains. Results were not substantially changed after controlling for midlife blood pressure. Our findings suggest that a history of GH is associated with slightly reduced episodic memory 20 years after pregnancy, but we found no evidence of a quicker age-related decline compared to women with normotensive pregnancies.

Parental infertility and offspring cardiometabolic trajectories: a pooled analysis of three European cohorts.

OBJECTIVE: To assess whether parental infertility is associated with differences in cardiometabolic trajectories in offspring. DESIGN: Pooled observational analysis in three prospective cohorts. SETTING: Three nationwide pregnancy cohorts. PATIENTS: A total of 14,609 singletons from the UK Avon Longitudinal Study of Parents and Children, the Portuguese Geraçao 21, and the Amsterdam Born Children and Their Development study. Each cohort contributed data up to ages 26, 12, and 13 years, respectively. INTERVENTION: Parental infertility is defined as time-to-pregnancy of ≥12 months (n = 1,392, 9.5%). MAIN OUTCOME MEASURES: Trajectories of body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol (LDL-C) level, high-density lipoprotein cholesterol (HDL-C) level, triglycerides level, and glucose level were compared in the offspring of couples with and without infertility. Trajectories were modeled using mixed-effects models with natural cubic splines adjusting for cohort, sex of the offspring, and maternal factors (age, BMI, smoking, educational level, parity, and ethnicity). Predicted levels of cardiometabolic traits up to 25 years of age were compared with parental infertility. RESULTS: Offspring of couples with infertility had increasingly higher BMI (difference in mean predicted levels by age 25 years: 1.09 kg/m2, 95% confidence interval [0.68-1.50]) and suggestively higher diastolic blood pressure at age 25 years (1.21 mmHg [-0.003 to 2.43]). Their LDL-C tended to be higher, and their HDL-C values tended to be lower over time (age: 25 years, LDL-C: 4.07% [-0.79 to 8.93]; HDL-C: -2.78% [-6.99 to 1.43]). At age 17 years, offspring of couples with infertility had higher waist circumference (1.05 cm [0.11-1.99]) and systolic blood pressure (age: 17 years; 0.93 mmHg [0.044-1.81]), but these differences attenuated at later ages. No intergroup differences in triglyceride and glucose level trajectories were observed. Further adjustment for paternal age, BMI, smoking, and educational level, and both parents' histories of diabetes and hypertension in the cohort with this information available (Avon Longitudinal Study of Parents and Children) did not attenuate intergroup differences. CONCLUSION: Offspring of couples with infertility relative to those of fertile couples have increasingly higher BMI over the years, suggestively higher blood pressure levels, and tend to have greater values of LDL-C and lower values of HDL-C with age.

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.

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.

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.

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.

Menstrual cycle features in mothers and daughters in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Problematic menstrual cycle features, including irregular periods, severe pain, heavy bleeding, absence of periods, frequent or infrequent cycles, and premenstrual symptoms, are experienced by high proportions of females and can have substantial impacts on their health and well-being. However, research aimed at identifying causes and risk factors associated with such menstrual cycle features is sparse and limited. This data note describes prospective, longitudinal data collected in a UK birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), on menstrual cycle features, which can be utilised to address the research gaps in this area. Data were collected across 21 timepoints (between the average age of 28.6 and 57.7 years) in mothers (G0) and 20 timepoints (between the average age of 8 and 24 years) in index daughters (G1) between 1991 and 2020. This data note details all available variables, proposes methods to derive comparable variables across data collection timepoints, and discusses important limitations specific to each menstrual cycle feature. Also, the data note identifies broader issues for researchers to consider when utilising the menstrual cycle feature data, such as hormonal contraception, pregnancy, breastfeeding, and menopause, as well as missing data and misclassification.

Childhood socioeconomic position and sex-specific trajectories of metabolic traits across early life: prospective cohort study.

BACKGROUND: Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life. METHODS: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25 years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models. FINDINGS: Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7 years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and -0.02SD (95% CI: -0.16, 0.13) among males. Between 7 and 25 years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25 years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively. INTERPRETATION: Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females. FUNDING: The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.

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.

Early Childhood Violence Exposure Patterns in The Drakenstein Child Health Study (DCHS).

Background: Research has highlighted high rates of exposure to violence among South African youth. However, work to date has been largely cross-sectional, focused on violence exposure during the adolescence period, and has been limited to specific types of violence exposure. We examined violence exposure in South African preschool children between 3 and 6 years of age, capturing both direct and indirect forms of violence, and tested for potential sex differences across the several types of exposures. Methods: Lifetime direct and indirect exposure to domestic and community violence was measured by parental report when children were 3.5 years (N = 530), 4.5 years (N = 749) and 6 years of age (N= 417) in a South African birth cohort located in a peri-urban community. Results: There are three main findings. First, a large proportion of children (72%-75%) were reported as having been exposed to some form of direct or indirect violent experience in their homes or communities from a young age. Second, there was significant polyvictimization,  with 49% of the children being exposed to more than one type of violence by age 6. Third, by 4.5 years of age, there was evidence that boys were more likely than girls to be exposed to domestic victimisation (28% vs. 17%) and polyvictimization (38% vs. 28%). Conclusions: These findings highlight the high levels of violence exposure in young South African children, particularly among boys, and the need for prevention at both the community and individual levels.

Quality of relationships in mothers and their partners in the Avon Longitudinal Study of Parents and Children.

Quality of relationship between partners is associated with a wide range of physical and psychological outcomes like anxiety and depression. There are relatively few longitudinal studies with detailed and repeated measures for quality of relationship, particularly in both partners. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a large birth cohort study in the UK with five post-partum repeated measures of quality of relationship between mothers and their partners assessed using the Intimate Bond Measure (IBM). The Measure includes two subscales named "Care" and "Control". These were measured at 2.75, 6, 9, 12, and 18 years post-partum (baseline N for mothers: 8675; baseline N for partners: 5499). The aims of this data note are to provide a comprehensive overview on the existing IBM data in ALSPAC and to describe both its strengths and limitations for future users. The internal consistency of the subscales were high (Cronbach's alpha 0.95 and 0.88 for the Care and Control subscales) in both mothers and their partners at the baseline. In the Care subscale, all 12 items were highly correlated with the overall score (r>0.62) at the baseline, but in the Control subscale there were three items that had relatively low correlations with the total subscale (r<0.46). This should be taken into account in future research. The longitudinal nature of this data on both mothers and partners will enable detailed explorations of the causes and consequences of differences in quality of relationship.

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.

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.

Is Height2.7 Appropriate for Indexation of Left Ventricular Mass in Healthy Adolescents? The Importance of Sex Differences.

BACKGROUND: Left ventricular mass (LVM) is an important predictor of cardiovascular risk. In adolescence, LVM is commonly indexed to height2.7, although some evidence suggests that this may not fully account for sex differences. METHODS: We investigated appropriate allometric scaling of LVM to height, total lean mass, and body surface area, in a UK birth cohort of 2039 healthy adolescents (17±1 years). Allometric relationships were determined by linear regression stratified by sex, following log transformation of x and y variables [log(y)=a+b×log(x)], b is the allometric exponent. RESULTS: Log (LVM) showed linear relationships with log(height) and log(lean mass). Biased estimates of slope resulted when the sexes were pooled. The exponents were lower than the conventional estimate of 2.7 for males (mean [95% CI]=1.66 [1.30-2.03]) and females (1.58 [1.27-1.90]). When LVM was indexed to lean mass, the exponent was 1.16 (1.05-1.26) for males and 1.07 (0.97-1.16) for females. When LVM was indexed to estimated body surface area, the exponent was 1.53 (1.40-1.66) for males and 1.34 (1.24-1.45) for females. CONCLUSIONS: Allometric exponents derived from pooled data, including men and women without adjustment for sex were biased, possibly due to sex differences in body composition. We suggest that when assessing LVM, clinicians should consider body size, body composition, sex, and age. Our observations may also have implications for the identification of young individuals with cardiac hypertrophy.

Maternal Risk of Cardiovascular Disease After Use of Assisted Reproductive Technologies.

Importance: The use of assisted reproductive technologies (ARTs) is steadily increasing worldwide. The outcomes associated with treatment for an individual's long-term health, including risk of cardiovascular disease (CVD), remain largely unknown, due to the small number of studies and their limited follow-up time. Objective: To study whether the risk of CVD is increased among individuals who have given birth after ART compared with those who have given birth without ART. Design, Setting, and Participants: A registry-based cohort study was conducted using nationwide data from Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1985-2015). Data analysis was conducted from January to August 2022. A total of 2 496 441 individuals with a registered delivery in the national birth registries during the study period were included, and 97 474 (4%) of these gave birth after ART. Exposures: Data on ART conception were available from ART quality registries and/or medical birth registries. Main Outcomes and Measures: Information on CVD was available from patient and cause of death registries. The risk of CVD was estimated with Cox proportional hazards regression, adjusting for age, calendar year of start of follow-up, parity, diagnosis of polycystic ovary syndrome, diabetes, chronic hypertension, and country. Results: Median follow-up was 11 (IQR, 5-18) years. The mean (SD) age of women with no use of ART was 29.1 (4.9) years, and the age of those who used ART was 33.8 (4.7) years. The rate of any CVD was 153 per 100 000 person-years. Individuals who gave birth after using ART had no increased risk of CVD (adjusted hazard ratio [AHR], 0.97; 95% CI, 0.91-1.02), with evidence of heterogeneity between the countries (I2 = 76%; P = .01 for heterogeneity). No significant differences in the risk of ischemic heart disease, cerebrovascular disease, stroke, cardiomyopathy, heart failure, pulmonary embolism, or deep vein thrombosis were noted with use of ART. However, there was a tendency for a modest reduction in the risk of myocardial infarction (AHR, 0.80; 95% CI, 0.65-0.99), with no notable heterogeneity between countries. Conclusions and Relevance: The findings of this study suggest that women who gave birth after ART were not at increased risk of CVD over a median follow-up of 11 years compared with those who conceived without ART. Longer-term studies are needed to further examine whether ART is associated with higher risk of CVD.