Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: \"Bohlin\", \"EPIC overlap\" and \"Knight\". Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

UNASSIGNED: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes.
UNASSIGNED: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years.
UNASSIGNED: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS.
UNASSIGNED: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia.
UNASSIGNED: HorizonEurope; European Research Council.

OBJECTIVE: Motherhood affects women\'s mental health, encompassing aspects of both wellbeing and illbeing. This study investigated stability and change in wellbeing (i.e., relationship satisfaction and positive affect) and illbeing (i.e., depressive and anxiety symptoms) from pregnancy to three years postpartum. We further investigated the mutual and dynamic relations between these constructs over time and the role of genetic propensities in their time-invariant stability.
METHODS: This four-wave longitudinal study included 83,124 women from the Norwegian Mother, Father, and Child Cohort Study (MoBa) linked to the Medical Birth Registry of Norway. Data were collected during pregnancy (30 weeks) and at 6, 18 and 36 months postpartum. Wellbeing and illbeing were based on the Relationship Satisfaction Scale, the Differential Emotions Scale and Hopkins Symptoms Checklist-8. Genetics were measured by the wellbeing spectrum polygenic index. Analyses were based on random intercept cross-lagged panel models using R.
RESULTS: All four outcomes showed high stability and were mutually interconnected over time, with abundant cross-lagged predictions. The period of greatest instability was from pregnancy to 6 months postpartum, followed by increasing stability. Prenatal relationship satisfaction played a crucial role in maternal mental health postpartum. Women\'s genetic propensity to wellbeing contributed to time-invariant stability of all four constructs.
CONCLUSIONS: Understanding the mutual relationship between different aspects of wellbeing and illbeing allows for identifying potential targets for health promotion interventions. Time-invariant stability was partially explained by genetics. Maternal wellbeing and illbeing develop in an interdependent way from pregnancy to 36 months postpartum.

In women, shorter telomeres have been reported to be associated with conditions such as endometriosis and polycystic ovary syndrome, whereas other studies have reported the opposite. In men, studies mostly report associations between shorter telomeres and sperm quality. To our knowledge, no studies have thus far investigated the associations between TL and fecundability or the use of ART. This study is based on the Norwegian Mother, Father, and Child Cohort (MoBa) Study and uses data from the Medical Birth Registry of Norway (MBRN). We included women (24,645 with genotype data and 1,054 with TL measurements) and men (18,339 with genotype data and 965 with TL measurements) participating between 1998 and 2008. We investigated the associations between leukocyte TL and fecundability, infertility, and the use of ART. We also repeated the analyses using instrumental variables for TL, including genetic risk scores for TL and genetically predicted TL. Approximately 11% of couples had experienced infertility and 4% had used ART. TL was not associated with fecundability among women (fecundability ratio [FR], 0.98; 95% confidence interval [CI], 0.92-1.04) or men (FR, 0.99; CI, 0.93-1.06), nor with infertility among women (odds ratio [OR], 1.03; CI, 0.85-1.24) or men (OR, 1.05; CI, 0.87-1.28). We observed an increased likelihood of using ART with increasing TL among men (OR, 1.22; CI, 1.03-1.46), but not among women (OR, 1.10; CI, 0.92-1.31). No significant associations were observed using the instrumental variables. Our results indicate that TL is a poor biomarker of fecundability, infertility and use of ART in MoBa. Additional studies are required to replicate the association observed between TL and ART in men.

UNASSIGNED: Blood total mercury concentration (BTHg) predominantly contains methyl Hg from seafood, and less inorganic Hg. Measured BTHg is often available only in a small proportion of large cohort study samples. Associations between estimated dietary intake of total Hg (THg) and lower birth weight within strata of maternal seafood intake was previously reported in the Norwegian Mother, Father, and Child Cohort Study (MoBa). However, maternal seafood consumption was associated with increased birth weight, indicating negative confounding by seafood in the association between THg intake and birth weight. Using predicted BTHg as a proxy for measured BTHg, we hypothesized that predicted BTHg would be associated with decreased birth weight.
UNASSIGNED: To develop and validate a prediction model for BTHg in MoBa and to examine the association between predicted BTHg and birth weight in the MoBa population.
UNASSIGNED: Using linear regression, measured maternal BTHg (n = 1437) was used to build the best fitting model (highest R-squared value). Model validation (n = 1436) was based on correlation and weighted Kappa (Кw). Associations between predicted BTHg in the MoBa population (n = 86,775) or measured BTHg (n = 3590) and birth weight were assessed by multivariate linear regression models.
UNASSIGNED: The best fitting model had R-squared = 0.3 and showed strong correlation (r = 0.53, p < 0.001) between predicted and measured BTHg. Cross-classification (quintiles) showed 73 % correctly classified and 3.3 % grossly misclassified, with Кw of 0.37. Measured BTHg was not associated with birth weight. Predicted BTHg was significantly associated with higher birth weight. There were no trends in birth weight with increasing quintiles of measured or predicted BTHg after stratification into high or low seafood consumption.
UNASSIGNED: The results indicate that prediction of BTHg did not overcome negative confounding of the association between Hg exposure and birth weight by seafood intake. Furthermore, effect on birth weight of toxicological concern is unexpected in our observed BTHg range.

BACKGROUND: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted.
METHODS: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health.
RESULTS: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (β =  - 0.11, 95% CI [- 0.12, - 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (β =  - 0.07, 95% CI [- 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding.
CONCLUSIONS: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

BACKGROUND: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery.
METHODS: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation.
RESULTS: Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]).
CONCLUSIONS: Our results suggest that continued smoking during pregnancy causes higher placental weights.

OBJECTIVE: To examine the association between early-life smoking exposure and later risk of inflammatory bowel disease [IBD].
METHODS: We followed 115663 participants from the Norwegian Mother, Father and Child [MoBa] and All Babies in Southeast Sweden [ABIS] cohorts from birth [1997-2009] through 2021. IBD was identified through national patient registers. Validated questionnaire data defined maternal smoking during pregnancy, maternal environmental tobacco smoke [ETS] exposure during pregnancy, and child ETS exposure by ages 12 and 36 months. Cox regression was used to estimate adjusted hazard ratios [aHRs] for sex, maternal age, education level, parental IBD, and origin. Cohort-specific estimates were pooled using a random-effects model.
RESULTS: During 1 987 430 person-years of follow-up, 444 participants developed IBD [ABIS, 112; MoBa, 332]. Any vs no maternal smoking during pregnancy yielded a pooled aHR of 1.30 [95% CI = 0.97-1.74] for offspring IBD. Higher level of maternal smoking during pregnancy (compared with no smoking, average ≥6 cigarettes/day: pooled aHR = 1.60 [95% CI = 1.08-2.38]) was associated with offspring IBD, whereas a lower smoking level was not (average 1-5 cigarettes/day: pooled aHR = 1.09 [95% CI = 0.73-1.64]). Child ETS exposure in the first year of life was associated with later IBD (any vs no ETS, pooled aHR = 1.32 [95% CI = 1.03-1.69]). Estimates observed for child ETS exposure by 36 months were similar but not statistically significant.
CONCLUSIONS: In this prospective Scandinavian cohort study, children exposed to higher levels of maternal smoking during pregnancy or ETS during the first year of life were at increased risk of later IBD.

OBJECTIVE: Is age at menarche associated with fecundability?
CONCLUSIONS: Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability.
BACKGROUND: Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive.
METHODS: We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies.
METHODS: We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants\' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive.
RESULTS: We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years.
CONCLUSIONS: The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate.
CONCLUSIONS: Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly.
BACKGROUND: This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union\'s Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests.
BACKGROUND: N/A.

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).
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.
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.
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.