OBJECTIVE: The aim of this study was to investigate the influence of maternal age on perinatal and obstetric outcome in women aged 40–44 years and those 45 years or older and to estimate whether adverse outcome was related to intercurrent illness and pregnancy complications. METHODS: National prospective, population-based, cohort study in women aged 40–44 years and those 45 years or older and in a control group of women aged 20–29 years who delivered during the period 1987–2001. Adjusted odds ratios (OR) were calculated after adjustments for significant malformations, maternal pre-existing diseases, and smoking. Main outcome measures were perinatal mortality, intrauterine fetal death, neonatal death, preterm birth, and preeclampsia. RESULTS: During the 15-year period, there were 1,566,313 deliveries (876,361 women were 20–29 years of age, 31,662 were 40–44 years, and 1,205 were ≥ 45 years). Perinatal mortality was 1.4%, 1.0%, and 0.5% in women 45 years or older, 40–44, and 20–29 years, respectively. Adjusted OR for perinatal mortality was 2.4 (95% confidence interval [CI] 1.5–4.0) in women aged 45 years or older, compared with 1.7 (95% CI 1.5–1.9) in women 40–44 years. Adjusted OR for intrauterine fetal death was 3.8 (95% CI 2.2–6.4) in women aged 45 years or older, compared with 2.1 (95% CI 1.8–2.4) in women 40–44 years. Preterm birth, gestational diabetes, and preeclampsia were more common among women 40–44 years of age and those 45 years or older. Perinatal mortality was increased in women with intercurrent illness or pregnancy complications compared with women without these conditions, but there was no evidence that these factors became more important with increasing age. CONCLUSION: Perinatal mortality, intrauterine fetal death, and neonatal death increased with age. There was also an increase in intercurrent illnesses and pregnancy complications with increasing age, but this did not entirely explain the observed increase in perinatal mortality with age. LEVEL OF EVIDENCE: II-3

Pregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA). This study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves. The main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P <10-7). Neither total nor coffee caffeine was associated with spontaneous PTD risk. Caffeine intake from different sources, measured repeatedly during pregnancy, was associated with lower BW (Marsal-28 g, Skjaerven-25 g, Gardosi-21 g per 100 mg/day additional total caffeine for a baby with expected BW 3,600 g, P <10-25). Caffeine intake of 200 to 300 mg/day increased the odds for SGA (OR Marsal 1.62, Skjaerven 1.44, Gardosi 1.27, P <0.05), compared to 0 to 50 mg/day. Coffee, but not caffeine, consumption was associated with marginally increased gestational length but not with spontaneous PTD risk. Caffeine intake was consistently associated with decreased BW and increased odds of SGA. The association was strengthened by concordant results for caffeine sources, time of survey and different SGA definitions. This might have clinical implications as even caffeine consumption below the recommended maximum (200 mg/day in the Nordic countries and USA, 300 mg/day according to the World Health Organization (WHO)) was associated with increased risk for SGA.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10⁻⁸, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10⁻⁸, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10⁻⁹, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10⁻⁸, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.