Social inequalities in pregnancy metabolic profile: findings from the multi-ethnic Born in Bradford cohort study.

BACKGROUND: Lower socioeconomic position (SEP) associates with adverse pregnancy and perinatal outcomes and with less favourable metabolic profile in nonpregnant adults. Socioeconomic differences in pregnancy metabolic profile are unknown. We investigated association between a composite measure of SEP and pregnancy metabolic profile in White European (WE) and South Asian (SA) women. METHODS: We included 3,905 WE and 4,404 SA pregnant women from a population-based UK cohort. Latent class analysis was applied to nineteen individual, household, and area-based SEP indicators (collected by questionnaires or linkage to residential address) to derive a composite SEP latent variable. Targeted nuclear magnetic resonance spectroscopy was used to determine 148 metabolic traits from mid-pregnancy serum samples. Associations between SEP and metabolic traits were examined using linear regressions adjusted for gestational age and weighted by latent class probabilities. RESULTS: Five SEP sub-groups were identified and labelled 'Highest SEP' (48% WE and 52% SA), 'High-Medium SEP' (77% and 23%), 'Medium SEP' (56% and 44%) 'Low-Medium SEP' (21% and 79%), and 'Lowest SEP' (52% and 48%). Lower SEP was associated with more adverse levels of 113 metabolic traits, including lower high-density lipoprotein (HDL) and higher triglycerides and very low-density lipoprotein (VLDL) traits. For example, mean standardized difference (95%CI) in concentration of small VLDL particles (vs. Highest SEP) was 0.12 standard deviation (SD) units (0.05 to 0.20) for 'Medium SEP' and 0.25SD (0.18 to 0.32) for 'Lowest SEP'. There was statistical evidence of ethnic differences in associations of SEP with 31 traits, primarily characterised by stronger associations in WE women e.g., mean difference in HDL cholesterol in WE and SA women respectively (vs. Highest-SEP) was -0.30SD (-0.41 to -0.20) and -0.16SD (-0.27 to -0.05) for 'Medium SEP', and -0.62SD (-0.72 to -0.52) and -0.29SD (-0.40 to -0.20) for 'Lowest SEP'. CONCLUSIONS: We found widespread socioeconomic differences in metabolic traits in pregnant WE and SA women residing in the UK. Further research is needed to understand whether the socioeconomic differences we observe here reflect pre-conception differences or differences in the metabolic pregnancy response. If replicated, it would be important to explore if these differences contribute to socioeconomic differences in pregnancy outcomes.

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Evaluating causal associations of chronotype with pregnancy and perinatal outcomes and its interactions with insomnia and sleep duration: a Mendelian randomization study.

IMPORTANCE: Observational studies suggest that chronotype is associated with pregnancy and perinatal outcomes. Whether these associations are causal is unclear. OBJECTIVE: To explore associations of a lifetime genetic predisposition to an evening preference chronotype with pregnancy and perinatal outcomes, and explore differences in associations of insomnia and sleep duration with those outcomes between chronotype. DESIGN SETTING AND PARTICIPANTS: We conducted two-sample Mendelian randomization (MR) using 105 genetic variants reported in a genome-wide association study (N=248 100) to instrument for lifelong predisposition to evening-versus morning-preference chronotypes. We generated variant-outcome associations in European ancestry women from UK Biobank (UKB, N=176 897), Avon Longitudinal Study of Parents and Children (ALSPAC, N=6826), Born in Bradford (BiB, N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, with linked data from the Medical Birth Registry of Norway (MBRN), N=57 430), and extracted equivalent associations from FinnGen (N=190 879). We used inverse variance weighted (IVW) as main analysis, with weighted median and MR-Egger as sensitivity analyses. We also conducted IVW analyses of insomnia and sleep duration on the outcomes stratified by genetically predicted chronotype. EXPOSURES: Self-reported and genetically predicted chronotype, insomnia and sleep duration. MAIN OUTCOMES AND MEASURES: Stillbirth, miscarriage, preterm birth, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, low birthweight and macrosomia. RESULTS: In IVW and sensitivity analyses we did not find robust evidence of effects of chronotype on the outcomes. Insomnia was associated with a higher risk of preterm birth among evening preference women (odds ratio 1.61, 95% confidence interval: 1.17, 2.21), but not among morning preference women (odds ratio 0.87, 95% confidence interval: 0.64, 1.18), with an interaction P-value=0.01. There was no evidence of interactions between insomnia and chronotype on other outcomes, or between sleep duration and chronotype on any outcomes. CONCLUSIONS AND RELEVANCE: This study raises the possibility of a higher risk of preterm birth among women with insomnia who also have an evening preference chronotype. Our findings warrant replications due to imprecision of the estimates. Key points: Question: Does an evening preference chronotype adversely affect pregnancy and perinatal outcomes? Is there an interaction between chronotype and either insomnia or sleep duration in relation to those outcomes?Findings: There was no evidence that evening preference was associated with pregnancy or perinatal outcomes. Women with a genetically predicted insomnia had a higher risk of preterm birth, if they also had a genetically predicted preference for evening chronotype.Meaning: The suggestive interaction between insomnia and evening preference on preterm birth, if replicated, supports targeting insomnia prevention in women of reproductive age with an evening chronotype.

Investigating effect modification between childhood maltreatment and genetic risk for cardiovascular disease in the UK Biobank.

Cardiovascular disease (CVD) is influenced by genetic and environmental factors. Childhood maltreatment is associated with CVD and may modify genetic susceptibility to cardiovascular risk factors. We used genetic and phenotypic data from 100,833 White British UK Biobank participants (57% female; mean age = 55.9 years). We regressed nine cardiovascular risk factors/diseases (alcohol consumption, body mass index [BMI], low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes, and stroke) on their respective polygenic scores (PGS) and self-reported exposure to childhood maltreatment. Effect modification was tested on the additive and multiplicative scales by including a product term (PGS*maltreatment) in regression models. On the additive scale, childhood maltreatment accentuated the effect of genetic susceptibility to higher BMI (Peffect modification: 0.003). Individuals not exposed to childhood maltreatment had an increase in BMI of 0.12 SD (95% CI: 0.11, 0.13) per SD increase in BMI PGS, compared to 0.17 SD (95% CI: 0.14, 0.19) in those exposed to all types of childhood maltreatment. On the multiplicative scale, similar results were obtained for BMI though these did not withstand to Bonferroni correction. There was little evidence of effect modification by childhood maltreatment in relation to other outcomes, or of sex-specific effect modification. Our study suggests the effects of genetic susceptibility to a higher BMI may be moderately accentuated in individuals exposed to childhood maltreatment. However, gene*environment interactions are likely not a major contributor to the excess CVD burden experienced by childhood maltreatment victims.

Weekend effect of air pollutants in small and medium-sized cities: The role of policies stringency to COVID-19 containment.

Although the pattern of air pollutants has been extensively studied during the COVID-19 pandemic, the weekend effect has been rarely investigated. In order to understand the impact of policies stringency as well as the interruption-recovery pattern, the aim of the study was to investigate the levels of air pollutants (O3, NO2, SO2, PM2.5, PM10) and PM2.5/PM10 ratio before and after the COVID-19 pandemic in four cities in the state of Rio Grande do Sul, Brazil, evaluating the weekend effect at these two scenarios and also identifying how the restriction measures applied locally had an impact on this effect. For this, daily data from two years of monitoring of air pollutants were collected and the weekend effect was calculated based on the levels from Monday to Friday (weekday) and Saturday and Sunday (weekend). There was a positive weekend effect for almost all criteria air pollutants in the four cities, and an intrinsic relation between the weekend effect and the restriction measures adopted. A negative weekend effect was observed in the scenario characterized by less restrictive and more permissive policies for daily and occupational activities. Conversely, when more stringent measures were implemented, this trend was reversed and higher intensities of positive weekend effect were observed as restrictions increased. In conclusion, the COVID-19 perturbation to air quality changed as regions tighten and loosen restrictions on human mobility. These insights that can guide responsible authorities about future strategies and policies for air quality control.

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.

Investigating causal relations between sleep duration and risks of adverse pregnancy and perinatal outcomes: linear and nonlinear Mendelian randomization analyses.

BACKGROUND: Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use Mendelian randomization (MR) and multivariable regression to examine nonlinear effects of sleep duration on stillbirth (MR only), miscarriage (MR only), gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and low/high offspring birthweight. METHODS: We used data from European women in UK Biobank (N=176,897), FinnGen (N=~123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration and investigated its effects using two-sample, and one-sample nonlinear (UK Biobank only), MR. We compared MR findings with multivariable regression in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks. RESULTS: In UK Biobank, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and low offspring birthweight. Shorter and longer duration increased stillbirth and low offspring birthweight; shorter duration increased perinatal depression. For example, longer sleep duration was related to lower risk of low offspring birthweight (odds ratio 0.79 per 1 h/day (95% confidence interval: 0.67, 0.93)) in the shortest duration group and higher risk (odds ratio 1.40 (95% confidence interval: 1.06, 1.84)) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration on any outcome using two-sample MR. In multivariable regression, risks of all outcomes were higher in the women reporting <5 and ≥10 h/day sleep compared with the reference category of 8-9 h/day, despite some wide confidence intervals. Nonlinear models fitted the data better than linear models for most outcomes (likelihood ratio P-value=0.02 to 3.2×10-52), except for gestational diabetes. CONCLUSIONS: Our results show shorter and longer sleep duration potentially causing higher risks of stillbirth, perinatal depression and low offspring birthweight. Larger studies with more cases are needed to detect potential nonlinear effects on hypertensive disorders of pregnancy, preterm birth and high offspring birthweight.

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.

Longitudinal changes in reproductive hormones through the menopause transition in the Avon Longitudinal Study of Parents and Children (ALSPAC).

We characterised changes in reproductive hormones-LH, FSH, SHBG and AMH-by chronological age and time around the menopause (reproductive age) in mid-life women and explored their associations with lifestyle and reproductive factors. We used data from 1608 women from a UK cohort who had repeat hormone measures and experienced a natural menopause. Multilevel models were used to assess: (i) changes in hormones (outcomes) by reproductive age and chronological age (these age variables being the key exposures) and (ii) associations of body mass index (BMI), smoking, alcohol intake, parity and age at menarche with changes in hormones by reproductive age. Both LH and FSH increased until ~ 5 and 7 years postmenopause, respectively, after which they declined, but not to premenopausal levels. SHBG decreased slightly until ~ 4 years postmenopause and increased thereafter. AMH decreased markedly before menopause and remained low subsequently. For all hormones, the best fitting models included both reproductive and chronological age. BMI, smoking and parity were associated with hormone changes; e.g., higher BMI was associated with slower increase in LH and FSH and decrease in AMH. Reproductive and chronological age contribute to changes in LH, FSH, SHBG and AMH across mid-life in women, and BMI, smoking and parity are associated with these hormone changes.