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.

Epigenetic aging and fecundability: the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is there an association between male or female epigenetic age acceleration (EAA) or deceleration (EAD) and fecundability? SUMMARY ANSWER: We do not find compelling evidence of an association between EAA or EAD and fecundability. WHAT IS KNOWN ALREADY: Prior research has shown that female accelerated epigenetic aging is associated with unfavorable clinical fecundity outcomes and use of in vitro fertilization, and that epigenetic aging in sperm cells is associated with unfavorable sperm parameters. Studies of epigenetic aging and fecundability among individuals who conceive naturally are lacking. STUDY DESIGN, SIZE, DURATION: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), a population-based pregnancy cohort which recruited pregnant couples between 1999 and 2008. We used data from 1657 couples (women and men) with planned naturally conceived pregnancies and available blood samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Methylation levels were measured in DNA from blood samples taken recruitment (at ∼18 gestational weeks) from pregnant women and their partners using the Illumina Methylation EPIC Array. To obtain a measure of EAA/EAD, we performed a linear regression of each of seven different established epigenetic biomarkers (DNAmAge by Horvath, DNAmAge by Hannum et al., PhenoAge by Levine et al., DunedinPoAm by Belsky et al., DunedinPACE by Belsky et al., DNAmTL by Lu et al., and GrimAge by Lu et al.) against chronological age. We fitted proportional probability regression models to obtain fecundability ratios (FRs) for each standard deviation increase in epigenetic aging, and obtained crude and adjusted (for body mass index, smoking, and education level) estimates. Results were evaluated at a false discovery rate (FDR) of 5%. We evaluated all models for non-linear associations using categories of epigenetic age where appropriate. MAIN RESULTS AND THE ROLE OF CHANCE: Although the DunedinPACE clock in males demonstrated slightly increasing fecundability with increasing EAA (adjusted FR 1.05 per one standard deviation increase in EAA, 95% CI 1.00-1.10), this was not robust when evaluated at an FDR of 5%. We found evidence of non-linearity between biological aging and fecundability in two models in females and three models in males, but non-linear associations were weak and conflicting. LIMITATIONS, REASONS FOR CAUTION: As MoBa is a pregnancy cohort, our findings may not be generalizable to all couples attempting conception. Fecundability is a couple-level measure, and any impacts of epigenetic aging in each partner may be obscured by effects of the other partner. WIDER IMPLICATIONS OF THE FINDINGS: Our findings contrast with those of prior studies, which have indicated an association between EAA and unfavorable clinical fertility outcomes in populations using fertility treatments, possibly due to less important effects of epigenetic aging among couples who conceive naturally. More research is needed on the association between blood-based EAA and clinical fertility parameters in both sexes. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Research Council of Norway through its Medical Student Research Program funding scheme (project number 271555/F20), its Centres of Excellence funding scheme (project number 262700), and a grant from the Women's Health Program (320656). Co-funding was also received from the Strategic Research Council (SRC), FLUX consortium, decision numbers 345130 and 345131; the National Institute on Aging (R01AG075208); grants to the Max Planck-University of Helsinki Center from the Max Planck Society (decision number 5714240218), Jane and Aatos Erkko Foundation, Faculty of Social Sciences at the University of Helsinki, and Cities of Helsinki, Vantaa, and Espoo; and the European Research Council; and the European Research Council (ERC Synergy, BIOSFER, grant number 101071773, and the Horizon 2020 research and innovation program, grant number 947684). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

The relationship between cesarean delivery and fecundability: a population-based cohort study.

BACKGROUND: Previous studies have found that women who undergo cesarean delivery have fewer pregnancies. Cesarean delivery is also more common among women with lower fecundability. The potential role of cesarean delivery in reduced fecundability is not known. OBJECTIVE: This study aimed to assess the bidirectional relationship between cesarean delivery and fecundability. STUDY DESIGN: This was a prospective cohort study based on data from the Norwegian Mother, Father, and Child Cohort study linked with the Medical Birth Registry of Norway. We estimated the fecundability ratio (per cycle probability of pregnancy) and relative risk of infertility (time to pregnancy ≥12 months) by mode of delivery in the previous delivery among 42,379 women. For the reverse association, we estimated the relative risk of having a cesarean delivery by fecundability (the number of cycles women needed to conceive) among 74,024 women. RESULTS: The proportion of women with infertility was 7.3% (2707/37,226) among women with a previous vaginal delivery and 9.9% (508/5153) among women with a previous cesarean delivery, yielding an adjusted relative risk of 1.21 (95% confidence interval, 1.10-1.33). Women with a previous cesarean delivery also had a lower fecundability ratio (0.90; 95% confidence interval, 0.88-0.93) than women with a previous vaginal delivery. When assessing the reverse association between fecundability and cesarean delivery, we found that women who did not conceive within 12 or more cycles had a higher risk for cesarean delivery (adjusted relative risk, 1.57; 95% confidence interval, 1.48-1.66) than women who conceived within the first 2 cycles. The associations remained after controlling for sociodemographic and clinical risk factors and were observed across parity groups. CONCLUSION: Among women with more than 1 child, those who had a previous cesarean delivery subsequently had a lower fecundability ratio and an increased infertility risk than those who had a vaginal delivery. However, women who needed a longer time to conceive were also more prone to be delivered by cesarean delivery, indicating a bidirectional relationship between cesarean delivery and fecundability. This could suggest a common underlying explanatory mechanism and that the surgical procedure itself may not or only partly directly influence fecundability.

Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

Body mass index and subfertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: What is the association between BMI and subfertility? SUMMARY ANSWER: We observed a J-shaped relationship between BMI and subfertility in both sexes, when using both a standard multivariable regression and Mendelian randomization (MR) analysis. WHAT IS KNOWN ALREADY: High BMI in both women and men is associated with subfertility in observational studies and this relationship is further substantiated by a few small randomized controlled trials of weight reduction and success of assisted reproduction. Women with low BMI also have lower conception rates with assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Cohort study (the Norwegian Mother, Father and Child Cohort Study), 28 341 women and 26 252 men, recruited from all over Norway between 1999 and 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women (average age 30, average BMI 23.1 kg/m2) and men (average age 33, average BMI 25.5 kg/m2) had available genotype data and provided self-reported information on time-to-pregnancy and BMI. A total of 10% of couples were subfertile (time-to-pregnancy ≥12 months). MAIN RESULTS AND THE ROLE OF CHANCE: Our findings support a J-shaped association between BMI and subfertility in both sexes using multivariable logistic regression models. Non-linear MR validated this relationship. A 1 kg/m2 greater genetically predicted BMI was linked to 18% greater odds of subfertility (95% CI 5% to 31%) in obese women (≥30.0 kg/m2) and 15% lower odds of subfertility (-24% to -2%) in women with BMI <20.0 kg/m2. A 1 kg/m2 higher genetically predicted BMI was linked to 26% greater odds of subfertility (8-48%) among obese men. Low genetically predicted BMI values were also related to greater subfertility risk in men at the lower end of the BMI distribution. A genetically predicted BMI of 23 and 25 kg/m2 was linked to the lowest subfertility risk in women and men, respectively. LIMITATIONS, REASONS FOR CAUTION: The main limitations of our study were that we did not know whether the subfertility was driven by the women, men or both; the exclusive consideration of individuals of northern European ancestry; and the limited amount of participants with obesity or BMI values <20.0 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: Our results support a causal effect of obesity on subfertility in women and men. Our findings also expand the current evidence by indicating that individuals with BMI values <20 kg/m2 may have an increased risk of subfertility. These results suggest that BMI values between 20 and 25 kg/m2 are optimal for a minimal risk of subfertility. 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 project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). It was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. D.A.L. is a UK National Institute for Health Research Senior Investigator (NF-SI-0611-10196) and is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545). The funders had no role in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

The demographics of assisted reproductive technology births in a Nordic country.

STUDY QUESTION: What are the socio-demographic characteristics of families in Norway who have children after assisted reproductive technology (ART), and have these characteristics changed over time? SUMMARY ANSWER: Parents who conceive through ART in Norway tend to be advantaged families, and their socio-demographic profile has not changed considerably over the period 1985-2014. WHAT IS KNOWN ALREADY: A small number of studies show that couples who conceive through ART tend to be socio-economically advantaged. STUDY DESIGN, SIZE, DURATION: Norwegian Population Register, the Medical Birth Register and the national data bases were linked to study all live births in Norway between 1985 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The sample consisted of 1 757 768 live births. Simple bivariate analyses were performed to describe the socio-demographic characteristics of parents who conceived through ART and changes in these characteristics over the time period 1985-2014. We used linear probability models to estimate the association between parental income and giving birth after ART from 2000 to 2014, before and after adjustment for maternal age at delivery, education and area of residence. MAIN RESULTS AND THE ROLE OF CHANCE: Parents conceiving through ART were more likely to be older, with the highest levels of income and education, and married. Their socio-demographic profiles did not change considerably during the period 1985-2014. In the unadjusted model, parents belonging to the top income quartile were 4.2 percentage points more likely (95% CI: 4.1 to 4.3) to have conceived through ART than parents who belonged to the bottom income quartile. Adjustment for maternal age only partially reduced the income disparities (for the top income quartile by 35% (ß = 2.7 with 95% CI: 2.5 to 2.8)). Additional adjustment for maternal education, marital status and area of residence did not further attenuate the associations. LIMITATIONS, REASONS FOR CAUTION: The data does not enable us to tell whether the lower numbers of children conceived through ART amongst more disadvantaged individuals is caused by lower success rates with ART treatment, lower demand of ART services or barriers faced in access to ART. The study focuses on Norway, a context characterised by high subsidisation of ART services. WIDER IMPLICATIONS OF THE FINDINGS: Even though in Norway access to ART services is highly subsidised, the results highlight important and persisting social inequities in use of ART. The results also indicate that children born after ART grow up in resourceful environments, which will benefit their development and well-being. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by European Research Council agreement n. 803959 (to A.G.), by Economic and Social Research Council grant ES/M001660/1 and by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Maternal history of miscarriages and measures of fertility in relation to childhood asthma.

BACKGROUND: It remains unclear what underlies the greater risk of asthma reported among children conceived by assisted reproductive technologies (ART). OBJECTIVE: Our aim was to clarify the role of parental subfertility and unmeasured confounding on the association between ART and childhood asthma, and to examine the possibility for common mechanisms underlying parental subfertility and miscarriages influencing asthma pathogenesis. METHODS: We used data from national Norwegian health registries (n=474 402) and the Norwegian Mother and Child Cohort Study (MoBa) (n=75 797). We used log-linear regression to estimate overall associations, and fixed-effects logistic regression to estimate associations within siblings. RESULTS: ART offspring had greater asthma risk, the adjusted relative risk (aRR) was 1.20 (95% CI 1.09 to 1.32) in the registry-based cohort, and 1.42 (95% CI 1.14 to 1.76) in MoBa. The sibling analysis yielded similar associations, although the CI included the null value. The elevated asthma risk among ART offspring was attenuated when they were compared with spontaneously conceived offspring with time to conception >12 months, aRR 1.22 (95% CI 0.95 to 1.57). Asthma risk also increased with maternal history of early miscarriages (≤12 weeks), with an aRR of 1.07 (95% CI 1.03 to 1.11) for one, aRR 1.18 (95% CI 1.10 to 1.26) for two and aRR 1.24 (95% CI 1.12 to 1.37) for three or more. CONCLUSION: Our findings indicate that both parental subfertility and characteristics related to the ART procedure itself might increase offspring asthma risk, although this needs to be confirmed in future studies, and further suggest that common mechanisms underlying parental subfertility and recurrent miscarriages might influence offspring asthma pathogenesis.

A Prospective Study of the Association between Physical Activity and Lower Urinary Tract Symptoms in Parous Middle-Aged Women: Results from the Avon Longitudinal Study of Parents and Children.

PURPOSE: We examined prospective associations between physical activity and a range of lower urinary tract symptoms in parous middle-aged women. MATERIALS AND METHODS: We used prospectively collected data on women participating in the ALSPAC (Avon Longitudinal Study of Parents and Children). Physical activity levels were self-reported at a mean ± SD age of 37.2 ± 4.6 years and translated into MET hours per week. A total of 4,126 and 2,770 women reported symptoms of lower urinary tract symptoms, including stress, urgency and mixed incontinence, at 3 and 11.5 years of followup, respectively. RESULTS: The prevalence of any lower urinary tract symptoms at 3 and 11.5 years of followup was 15% and 23% at a mean age of 40.5 and 49.3 years, respectively. At 3 years of followup women in the highest category of physical activity (43.2 MET hours or more per week) had lower odds of stress incontinence (aOR 0.51, 95% CI 0.32-0.80) than women in the lowest category (0 MET hours per week). At 11.5 years of followup women in the highest category of physical activity had lower odds of stress incontinence (aOR 0.56, 95% CI 0.39-0.82), urgency incontinence (aOR 0.34, 95% CI 0.20-0.67) and mixed incontinence (aOR 0.34, 95% CI 0.19-0.63) compared to women in the lowest physical activity category. CONCLUSIONS: Greater physical activity is associated with reduced odds of lower urinary tract symptoms, especially stress incontinence, among middle-aged parous women. Further research is necessary to examine the impact of different types of physical activity on lower urinary tract symptoms.

Prospective Cohort Study of Breastfeeding and the Risk of Childhood Asthma.

OBJECTIVES: To study whether the duration of breastfeeding and time for introduction of complementary foods was associated with the risk of childhood asthma. STUDY DESIGN: We used data from the Norwegian Mother and Child Study, a nationwide prospective cohort study that recruited pregnant women from across Norway between 1999 and 2008. Children with complete data of breastfeeding up to 18 months and current age >7 years were eligible (n = 41 020). Asthma as the primary outcome was defined based on ≥2 dispensed asthma medications at age 7 years registered in the Norwegian Prescription Database. We used log-binomial regression models to obtain crude relative risks (RRs) in the main analysis, and adjusted for selected confounders in multivariable analyses. RESULTS: For duration of any breastfeeding, 5.9% of infants breastfed <6 months (adjusted RR [aRR] 1.05, 0.93-1.19) and 4.6% breastfed 6-11 months (aRR 0.96, 0.87-1.07) had dispensed asthma medications at age 7 years compared with 4.6% of infants breastfed ≥12 months (Ptrend .62). Infants still breastfed at 6 months, but introduced to complementary foods <4 months and 4-6 months, had an aRR of 1.15 (0.98-1.36) and 1.09 (0.94-1.27) respectively, compared with infants fully breastfed for 6 months (Ptrend .09). Ages at introduction of solids or formula separately were not significant predictors (Ptrend .16 and .08, respectively). CONCLUSIONS: We found no association between duration of breastfeeding or age of introduction to complementary foods and asthma at age 7 years.

Perinatal risk factors for development of celiac disease in children, based on the prospective Norwegian Mother and Child Cohort Study.

BACKGROUND & AIMS: There have been inconsistent reports of prenatal and perinatal factors that affect risk for development of celiac disease. We assessed the association of fetal growth, birth weight, and mode of delivery with development of celiac disease within the Norwegian Mother and Child (MoBa) Cohort Study. METHODS: The MoBa cohort contains pregnancy information on 95,200 women and data on their 114,500 children, which were collected in Norway from 1999 through 2008; it is linked to the Medical Birth Registry. Women and children with celiac disease were identified from the National Patient Registry and from women's responses to MoBa questionnaires. We calculated odds ratios (ORs) for celiac disease by using a multivariable logistic regression model, adjusting for maternal celiac disease, sex of children, and children's age (model 1); in a second model, we adjusted for age of gluten introduction and duration of breastfeeding (model 2). RESULTS: We identified 650 children with celiac disease and 107,828 controls in the MoBa database. We found no association between birth weight or height with celiac disease (born small for gestational age was not associated). Celiac disease was not associated with mode of delivery (cesarean section, model 1: OR, 0.84; 95% confidence interval [CI], 0.65-1.09, and model 2: OR, 0.83; 95% CI, 0.63-1.09). Maternal celiac disease, adjusted for age and sex of the children (OR, 12.45; 95% CI, 8.29-18.71) and type 1 diabetes (model 1: OR, 2.58; 95% CI, 1.19-5.53, and model 2: OR, 2.61; 95% CI, 1.14-5.98) were associated with development of celiac disease in children, whereas maternal type 2 diabetes and gestational diabetes were not. CONCLUSIONS: On the basis of analysis of the Norwegian MoBa cohort, development of celiac disease in children is significantly associated with sex of the child, maternal celiac disease, and type 1 diabetes but not with intrauterine growth.

Reproductive outcomes in women and men conceived by assisted reproductive technologies in Norway: prospective registry based study.

Objectives: To determine whether the perinatal outcomes of women or men who were conceived by assisted reproductive technologies are different compared with their peers who were naturally conceived. Design: Prospective registry based study. Setting: Medical Birth Registry of Norway. Participants: People born in Norway between 1984 and 2002 with a registered pregnancy by the end of 2021. Exposure: People who were conceived by assisted reproductive technologies and have had a registered pregnancy. Main outcome measures: Comparing pregnancies and births of people who were conceived by assisted reproductive technologies and people who were naturally conceived, we assessed mean birth weight, gestational age, and placental weight by linear regression, additionally, the odds of congenital malformations, a low 5 min Apgar score (<7), transfer to a neonatal intensive care unit, delivery by caesarean section, use of assisted reproductive technologies, hypertensive disorders of pregnancy and pre-eclampsia, preterm birth, and offspring sex, by logistic regression. The occurrence of any registered pregnancy from people aged 14 years until age at the end of follow-up was assessed using Cox proportional regression for both groups. Results: Among 1 092 151 people born in Norway from 1984 to 2002, 180 652 were registered at least once as mothers, and 137 530 as fathers. Of these, 399 men and 553 women were conceived by assisted reproductive technologies. People who were conceived by assisted reproductive technologies had little evidence of increased risk of adverse outcomes in their own pregnancies, increased use of assisted reproductive technologies, or any difference in mean birth weight, placental weight, or gestational age. The only exception was for an increased risk of the neonate having a low Apgar score at 5 min (adjusted odds ratio 1.86 (95% confidence interval 1.20 to 2.89)) among women who were conceived by assisted reproductive technologies. Odds were slightly decreased of having a boy among mothers conceived by assisted reproductive technologies (odds ratio 0.79 (95% confidence interval 0.67 to 0.93)). People conceived by assisted reproductive technologies were slightly less likely to have a registered pregnancy within the follow-up period (women, adjusted hazard ratio 0.88 (95% CI 0.81 to 0.96); men, 0.91 (0.83 to 1.01)). Conclusions: People conceived by assisted reproductive technologies were not at increased risk of obstetric or perinatal complications when becoming parents. The proportion of people conceived by assisted reproductive technologies with a registered pregnancy was lower than among people who were naturally conceived, but a longer follow-up is required to fully assess their fertility and reproductive history.

Infertility and Risk of Cardiovascular Disease: A Prospective Cohort Study.

Background Certain symptoms associated with infertility are associated with cardiovascular disease, including menstrual cycle irregularity, early menopause, and obesity; however, few studies have investigated the association between infertility and cardiovascular disease risk. Methods and Results Participants in the NHSII (Nurses' Health Study II) who reported infertility (12 months of trying to conceive without success, including women who subsequently conceived) or who were gravid, with no infertility were followed from 1989 until 2017 for development of incident, physician-diagnosed coronary heart disease (CHD) (myocardial infarction, coronary artery bypass grafting, angioplasty, stent) and stroke. Time-varying Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs and were adjusted a priori for potential confounding variables. Among 103 729 participants, 27.6% reported having ever experienced infertility. Compared with gravid women who had not reported infertility, women with a history of infertility had greater risk of CHD (HR, 1.13 [95% CI, 1.01-1.26]) but not stroke (HR, 0.91 [95% CI, 0.77-1.07]). The association between history of infertility and CHD was strongest among women who reported infertility at an earlier age (HR for infertility first reported at ≤25 years, 1.26 [95% CI, 1.09-1.46]; HR at 26-30 years, 1.08 [95% CI, 0.93-1.25]; HR at >30 years, 0.91 [95% CI, 0.70-1.19]). When we investigated specific infertility diagnoses, elevated risk of CHD was observed among women whose infertility was attributed to an ovulatory disorder (HR, 1.28 [95% CI, 1.05-1.55]) or endometriosis (HR, 1.42 [95% CI, 1.09-1.85]). Conclusions Women with infertility may be at an increased risk of CHD. Risk differed by age at first infertility diagnosis and was restricted to ovulatory- and endometriosis-related infertility.

Association between perinatal mortality and morbidity and customised and non-customised birthweight centiles in Denmark, Finland, Norway, Wales, and England: comparative, population based, record linkage study.

Objectives: To compare the risk of adverse perinatal outcomes according to infants who are born small for gestational age (SGA; <10th centile) or large for gestational age (LGA; >90th centile), as defined by birthweight centiles that are non-customised (ie, standardised by sex and gestational age only) and customised (by sex, gestational age, maternal weight, height, parity, and ethnic group). Design: Comparative, population based, record linkage study with meta-analysis of results. Setting: Denmark, Finland, Norway, Wales, and England (city of Bradford), 1986-2019. Participants: 2 129 782 infants born at term in birth registries. Main outcome measures: Stillbirth, neonatal death, infant death, admission to neonatal intensive care unit, and low Apgar score (<7) at 5 minutes. Results: Relative to those infants born average for gestational age (AGA), both SGA and LGA births were at increased risk of all five outcomes, but observed relative risks were similar irrespective of whether non-customised or customised charts were used. For example, for SGA versus AGA births, when non-customised and customised charts were used, relative risks pooled over countries were 3.60 (95% confidence interval 3.29 to 3.93) versus 3.58 (3.02 to 4.24) for stillbirth, 2.83 (2.18 to 3.67) versus 3.32 (2.05 to 5.36) for neonatal death, 2.82 (2.07 to 3.83) versus 3.17 (2.20 to 4.56) for infant death, 1.66 (1.49 to 1.86) versus 1.54 (1.30 to 1.81) for low Apgar score at 5 minutes, and (based on Bradford data only) 1.97 (1.74 to 2.22) versus 1.94 (1.70 to 2.21) for admission to the neonatal intensive care unit. The estimated sensitivity of combined SGA or LGA births to identify the three mortality outcomes ranged from 31% to 34% for non-customised charts and from 34% to 38% for customised charts, with a specificity of 82% and 80% with non-customised and customised charts, respectively. Conclusions: These results suggest an increased risk of adverse perinatal outcomes of a similar magnitude among SGA or LGA term infants when customised and non-customised centiles are used. Use of customised charts for SGA/LGA births-over and above use of non-customised charts for SGA/LGA births-is unlikely to provide benefits in terms of identifying term births at risk of these outcomes.

The Relationship of Maternal Gestational Mass Spectrometry-Derived Metabolites with Offspring Congenital Heart Disease: Results from Multivariable and Mendelian Randomization Analyses.

Background: It is plausible that maternal pregnancy metabolism influences the risk of offspring congenital heart disease (CHD). We sought to explore this through a systematic approach using different methods and data. Methods: We undertook multivariable logistic regression of the odds of CHD for 923 mass spectrometry (MS)-derived metabolites in a sub-sample of a UK birth cohort (Born in Bradford (BiB); N = 2605, 46 CHD cases). We considered metabolites reaching a p-value threshold <0.05 to be suggestively associated with CHD. We sought validation of our findings, by repeating the multivariable regression analysis within the BiB cohort for any suggestively associated metabolite that was measured by nuclear magnetic resonance (NMR) or clinical chemistry (N = 7296, 87 CHD cases), and by using genetic risk scores (GRS: weighted genetic risk scores of single nucleotide polymorphisms (SNPs) that were associated with any suggestive metabolite) in Mendelian randomization (MR) analyses. The MR analyses were performed in BiB and two additional European birth cohorts (N = 38,662, 319 CHD cases). Results: In the main multivariable analyses, we identified 44 metabolites suggestively associated with CHD, including those from the following super pathways: amino acids, lipids, co-factors and vitamins, xenobiotics, nucleotides, energy, and several unknown molecules. Of these 44, isoleucine and leucine were available in the larger BiB cohort (NMR), and for these the results were validated. The MR analyses were possible for 27/44 metabolites and for 11 there was consistency with the multivariable regression results. Conclusions: In summary, we have used complimentary data sources and statistical techniques to construct layers of evidence. We found that pregnancy amino acid metabolism, androgenic steroid lipids, and levels of succinylcarnitine could be important contributing factors for CHD.

Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study.

OBJECTIVE: To investigate the association between smoking and infertility. DESIGN: Prospective study. SETTING: Nationwide cohort. PATIENTS: 28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study. INTERVENTION: Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization. MAIN OUTCOME MEASURE: Infertility (time-to-pregnancy ≥12 months). RESULTS: Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11-1.28; ORadjusted 1.12; 95% CI, 1.03-1.21), also after adjusting for the partner's tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88-0.99; ORadjusted 0.89; 95% CI, 0.84-0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75-0.91; ORadjusted, 0.83; 95% CI, 0.75-0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization. CONCLUSIONS: We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.

The Association Between Constipation and Lower Urinary Tract Symptoms in Parous Middle-Aged Women: A Prospective Cohort Study.

Objective: To examine the prospective association between constipation and risk of developing lower urinary tract symptoms (LUTS) in parous middle-aged women. Materials and Methods: The study uses data from 3,729 women from the Avon Longitudinal Study of Parents and Children who provided self-reports of medication intake for constipation at two time points (Baseline): 2001-2003 and 2003-2005. Women with LUTS at baseline were excluded. After 10 years of follow-up, women provided self-reports of LUTS using an adapted version of the International Consultation on Incontinence Questionnaire on Female LUTS. LUTS were categorized according to International Continence Society definitions as stress urinary incontinence (UI), urgency UI, mixed UI, nocturia, increased daytime frequency, urgency, hesitancy, and intermittency. LUTS were considered present if symptoms were reported to occur at least "sometimes" for all subtypes, except for increased daytime frequency (≥9 times) and nocturia (≥2 times nightly). Results: At follow-up, the prevalence of any LUTS was 40%. Women (mean age 43.3 years, standard deviation 0.5), who took medication for constipation at either time point had increased risks of urgency (adjusted relative risks [RRs] = 1.35; 95% confidence interval [CI] 1.04-1.95) and hesitancy (adjusted RR = 1.72; 95% CI 1.04-3.01) compared with women who reported not using medication for constipation at either time point. The risk of urgency (adjusted RR = 1.94; 95% CI 1.15-3.29) and hesitancy (adjusted RR = 1.78; 95% CI 1.03-4.19) was greater for women who reported taking medication for constipation at both time points. There was no evidence that constipation was associated with stress UI, urgency UI, mixed UI, nocturia, increased daytime frequency, and intermittency. Conclusion: Constipation is prospectively associated with an increased risk of urgency and hesitancy among parous middle-aged women. If further research finds evidence that this association is causal, this implies that women should seek treatment to alleviate constipation to reduce their consequent risk of developing these LUTS.

Birthing parents had a lower risk of testing positive for SARS-CoV-2 in the peripartum period in Norway, 15th of February 2020 to 15th of May 2021.

Hospital infection control measures against COVID-19 may come into conflict with patients' need for support. In Norway, some hospitals have restricted access for partners of women giving birth. We investigated the incidence rate of SARS-CoV-2 among birthing parents compared to similarly aged women and men in the general population; and the additional risk posed by allowing partners in. Birthing parents often shared infection status and had a slightly lower incidence rate than the general population in the peripartum period. They should not be considered a high-risk group for SARS-CoV-2 infections.

Parental income and mental disorders in children and adolescents: prospective register-based study.

BACKGROUND: Children with low-income parents have a higher risk of mental disorders, although it is unclear whether other parental characteristics or genetic confounding explain these associations and whether it is true for all mental disorders. METHODS: In this registry-based study of all children in Norway (n = 1 354 393) aged 5-17 years from 2008 to 2016, we examined whether parental income was associated with childhood diagnoses of mental disorders identified through national registries from primary healthcare, hospitalizations and specialist outpatient services. RESULTS: There were substantial differences in mental disorders by parental income, except for eating disorders in girls. In the bottom 1% of parental income, 16.9% [95% confidence interval (CI): 15.6, 18.3] of boys had a mental disorder compared with 4.1% (95% CI: 3.3, 4.8) in the top 1%. Among girls, there were 14.2% (95% CI: 12.9, 15.5) in the lowest, compared with 3.2% (95% CI: 2.5, 3.9) in the highest parental-income percentile. Differences were mainly attributable to attention-deficit hyperactivity disorder in boys and anxiety and depression in girls. There were more mental disorders in children whose parents had mental disorders or low education, or lived in separate households. Still, parental income remained associated with children's mental disorders after accounting for parents' mental disorders and other factors, and associations were also present among adopted children. CONCLUSIONS: Mental disorders were 3- to 4-fold more prevalent in children with parents in the lowest compared with the highest income percentiles. Parents' own mental disorders, other socio-demographic factors and genetic confounding did not fully explain these associations.