Perinatal mortality by gestational week and size at birth in singleton pregnancies at and beyond term: a nationwide population-based cohort study

Background: Whether gestational age per se increases perinatal mortality in post-term pregnancy is unclear. We aimed at assessing gestational week specific perinatal mortality in small-for-gestational-age (SGA) and non-SGA term and post-term gestations, and specifically to evaluate whether the relation between post-term gestation and perinatal mortality differed before and after ultrasound was introduced as the standard method of gestational age estimation. Methods: A population-based cohort study, using data from the Medical Birth Registry of Norway (MBRN), 1967–2006, was designed. Singleton births at 37 through 44 gestational weeks (n = 1 855 682), excluding preeclampsia, diabetes and fetal anomalies, were included. Odds ratios (OR) with 95% confidence intervals (CI) for perinatal mortality and stillbirth in SGA and non-SGA births by gestational week were calculated. Results: SGA infants judged post-term by LMP had significantly higher perinatal mortality than post-term non-SGA infants at 40 weeks, independent of time period (highest during 1999–2006 [OR 9.8, 95% CI: 5.7-17.0]). When comparing years before (1967–1986) versus after (1987–2006) ultrasound was introduced, there was no decrease in the excess mortality for post-term SGA versus non-SGA births (ORs from 6.1 [95% CI: 5.2-7.1] to 6.7 [5.2-8.5]), while mortality at 40 weeks decreased significantly (ORs from 4.6, [4.0-5.3] to 3.2 [2.5-3.9]). When assessing stillbirth risk (1999–2006), more than 40% of SGA stillbirths (11/26) judged to be ≥41 weeks by LMP were shifted to lower gestational ages using ultrasound estimation. Conclusions: Mortality risk in post-term infants was strongly associated with growth restriction. Such infants may erroneously be judged younger than they are when using ultrasound estimation, so that the routine assessment for fetal wellbeing in the prolonged gestation may be given too late

Adjusting for outcome risk factors in immigrant datasets: total or direct effects?

Background When quantifying differences in health outcomes between immigrants and non-immigrants, it is common practice to adjust for observed differences in outcome risk factors between the groups being compared. However, as some of these outcome risk factors may act as mediators on the causal path between the exposure and outcome, adjusting for these may remove effects of factors that characterize the immigrants rather than removing a bias between immigrants and non-immigrants. Methods This study investigates the underlying conditions for which adjusting for outcome risk factors in regression models can lead to the estimation of either total or direct effect for the difference in health outcomes between immigrants and non-immigrants. For this investigation, we use modern tools in causal inference to construct causal models that we believe are highly relevant in an immigrant dataset. In these models, the outcome risk factor is modeled either as a mediator, a selection factor, or a combined mediator/selection factor. Unlike mediators, selection factors are variables that affect the probability of being in the immigrant dataset and may contribute to a bias when comparing immigrants and non-immigrants. Results When the outcome risk factor acts both as a mediator and selection factor, the adjustment for the risk factor in regression models leads to the estimation of what is known as a “controlled” direct effect. When the outcome risk factor is either a selection factor or a mediator alone, the adjustment for the risk factor in regression models leads to the estimation of a total effect or a controlled direct effect, respectively. In all regression analyses, also adjusting for various confounding paths, including mediator-outcome confounding, may be necessary to obtain valid controlled direct effects or total effects. Conclusions Depending on the causal role of the outcome risk factors in immigrant datasets, regression adjustment for these may result in the estimation of either total effects or controlled direct effects for the difference in outcomes between immigrants and non-immigrants. Because total and controlled direct effects are interpreted differently, we advise researchers to clarify to the readers which types of effects are presented when adjusting for outcome risk factors in immigrant datasets.publishedVersio

Perinatal mortality by gestational week and size at birth in singleton pregnancies at and beyond term: a nationwide population-based cohort study

BACKGROUND: Whether gestational age per se increases perinatal mortality in post-term pregnancy is unclear. We aimed at assessing gestational week specific perinatal mortality in small-for-gestational-age (SGA) and non-SGA term and post-term gestations, and specifically to evaluate whether the relation between post-term gestation and perinatal mortality differed before and after ultrasound was introduced as the standard method of gestational age estimation. METHODS: A population-based cohort study, using data from the Medical Birth Registry of Norway (MBRN), 1967–2006, was designed. Singleton births at 37 through 44 gestational weeks (n = 1 855 682), excluding preeclampsia, diabetes and fetal anomalies, were included. Odds ratios (OR) with 95% confidence intervals (CI) for perinatal mortality and stillbirth in SGA and non-SGA births by gestational week were calculated. RESULTS: SGA infants judged post-term by LMP had significantly higher perinatal mortality than post-term non-SGA infants at 40 weeks, independent of time period (highest during 1999–2006 [OR 9.8, 95% CI: 5.7-17.0]). When comparing years before (1967–1986) versus after (1987–2006) ultrasound was introduced, there was no decrease in the excess mortality for post-term SGA versus non-SGA births (ORs from 6.1 [95% CI: 5.2-7.1] to 6.7 [5.2-8.5]), while mortality at 40 weeks decreased significantly (ORs from 4.6, [4.0-5.3] to 3.2 [2.5-3.9]). When assessing stillbirth risk (1999–2006), more than 40% of SGA stillbirths (11/26) judged to be ≥41 weeks by LMP were shifted to lower gestational ages using ultrasound estimation. CONCLUSIONS: Mortality risk in post-term infants was strongly associated with growth restriction. Such infants may erroneously be judged younger than they are when using ultrasound estimation, so that the routine assessment for fetal wellbeing in the prolonged gestation may be given too late

Preeclampsia in pregnancy and later use of antihypertensive drugs

We explored the association between preeclampsia and later use of antihypertensive drugs in a population-based study with data from the Medical Birth Registry of Norway and the Norwegian Prescription Database. The study cohort consisted of 980,000 women having 2.1 million pregnancies during 1967–2012. Hazard ratios (HRs) with 95 % confidence intervals (95 % CI) were estimated in multivariate time-dependent Cox proportional hazards regression models. Overall, the HR of later use of antihypertensive drugs was 2.0 (95 % CI 2.0–2.0) in women with one preeclamptic pregnancy compared to women without preeclamptic pregnancies. The HR increased by increasing number of preeclamptic pregnancies, both term and preterm pregnancies. In women with two or more preeclamptic pregnancies, the HR was 2.8 (2.7–3.0). The overall HR after 40 years of follow-up for women with one preeclamptic pregnancy was 1.3 (1.2–1.4) and for two or more preeclamptic pregnancies the HR was 1.6 (1.1–2.1). The first 5 years after the first birth, the HR of being dispensed antihypertensive drugs was higher in preterm [8.4 (7.7–9.1)] than term preeclamptic pregnancies [4.3(4.0–4.6)]. However, after 10 years, this difference was no longer present. The HR of later use of antihypertensive drugs increased with the number of preeclamptic pregnancies, and in the first 10 years the HR was higher after a preterm than a term preeclamptic pregnancy. Although the HR decreased with time since first birth, the risk was still elevated after 40 years. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited

Use of asthma medication during pregnancy and risk of specific congenital anomalies: A European case-malformed control study

Background. Pregnant women with asthma need to take medication during pregnancy. Objective. We sought to identify whether there is an increased risk of specific congenital anomalies after exposure to antiasthma medication in the first trimester of pregnancy. Methods. We performed a population-based case-malformed control study testing signals identified in a literature review. Odds ratios (ORs) of exposure to the main groups of asthma medication were calculated for each of the 10 signal anomalies compared with registrations with nonchromosomal, nonsignal anomalies as control registrations. In addition, exploratory analyses were done for each nonsignal anomaly. The data set included 76,249 registrations of congenital anomalies from 13 EUROmediCAT registries. Results. Cleft palate (OR, 1.63; 95% CI, 1.05-2.52) and gastroschisis (OR, 1.89; 95% CI, 1.12-3.20) had significantly increased odds of exposure to first-trimester use of inhaled β2-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled β2-agonists were found for spina bifida, cleft lip, anal atresia, severe congenital heart defects in general, or tetralogy of Fallot. None of the 4 literature signals of exposure to inhaled steroids were confirmed (cleft palate, cleft lip, anal atresia, and hypospadias). Exploratory analyses found an association between renal dysplasia and exposure to the combination of long-acting β2-agonists and inhaled corticosteroids (OR, 3.95; 95% CI, 1.99-7.85). Conclusions. The study confirmed increased odds of first-trimester exposure to inhaled β2-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting β2-agonists and inhaled corticosteroids. Use of inhaled corticosteroids during the first trimester of pregnancy seems to be safe in relation to the risk for a range of specific major congenital anomalies.publishedVersio

Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases

AbstractBackgroundPrenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring.MethodsWe performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967–2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004–2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models.ResultsThe following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2–2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5–1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3–2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4–1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1–1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5–1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4–1.6 for male offspring]), none of the associations differed significantly by offspring sex.ConclusionsSeveral maternal somatic diseases with immune components were found to increase the risk of ADHD in offspring. The associations could involve several causal pathways, including common genetic predisposition and environmental factors, and increased insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD

Male to female ratios in autism spectrum disorders by age, intellectual disability and attention-deficit/hyperactivity disorder

Objective To examine the gender distribution in ASD in adults compared with children and the impact of comorbid intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) on the male to female ratio (MFR). Methods We estimated the MFR and the male prevalence ratio (PR) for ASD in adults and children using the Medical Birth Registry of Norway, including all individuals born during 1967–2011. We examined variation with age, comorbid ID and ADHD as defined by diagnoses in the Norwegian Patient Registry during 2008–2015 and/or a dispensed prescription for ADHD medication. Results The sample included 1,701,206 adults and 804,146 children, including 8,995 (0.5%) adults and 8,056 (1.0%) children with ASD, 53,822 (3.2%) adults and 26,967 (3.4%) children with ADHD and 9,178 (0.5%) adults and 5,038 (0.6%) children with ID. The MFR for ASD was 3.67 in children and 2.57 in adults, corresponding to a male PR in ASD of 1.54 (95% CI 1.53–1.56) and 1.41 (1.39–1.24), respectively. Comorbid ID decreased the MFR and the male PR in both adults and children, whereas comorbid ADHD significantly increased the male PR in children. The MFR and the population prevalence of ASD, ADHD and ID decreased from children to younger adults and yet further to older adults. Conclusion We found a lower MFR and male PR in adults than in children. Findings suggest the strong male predominance seen in childhood/clinical studies of ASD diminishes in adult samples, possibly reflecting the influence of non-aetiological factors such as later diagnosis in females, diagnostic biases and diagnostic trends.publishedVersio

Association between pregravid physical activity and family history of stroke and risk of stillbirth: Population-based cohort study

Objectives: To evaluate whether family history of disease and pregravid lifestyle and cardiovascular risk factors are associated with subsequent stillbirth delivery. Design: Prepregnancy cohort study. Setting: Cohort Norway regional health surveys (1994–2003) linked to Medical Birth Registry of Norway for deliveries through 2012. Participants: 13 497 singleton births (> 22 weeks gestation) in 8478 women. Main outcome measure: Risk of stillbirth evaluated by Poisson regression. Results: Mean (SD) length of follow-up was 5.5 (3.5) years. In analyses adjusting for baseline age and length of follow-up, ≥3 hours of baseline past-year vigorous physical activity per week (resulting in shortness of breath/sweating) was associated with increased risk of stillbirth compared with 18.5 and <25 kg/m2). Vigorous activity of ≥3 hours per week (IRR of 4.50; 95% CI 1.72 to 11.79) and a family history of stroke (IRR of 3.81; 95% CI 1.31 to 11.07) were more strongly related to stillbirth risk among women with a normal BMI than that observed for all women combined. Established risk factors also associated with stillbirth risk. Conclusions: The study identified physical activity and family history of stroke as potential new risk factors for stillbirth delivery.publishedVersio

Cesarean delivery in Norwegian nulliparous women with singleton cephalic term births, 1967–2020: a population-based study

Background Nulliparous women contribute to increasing cesarean delivery in the Nordic countries and advanced maternal age has been suggested as responsible for rise in cesarean delivery rates in many developed countries. The aim was to describe changes in cesarean delivery rates among nulliparous women with singleton, cephalic, term births by change in sociodemographic factors across 50 years in Norway. Methods We used data from the Medical Birth Registry of Norway and included 1 067 356 women delivering their first, singleton, cephalic, term birth between 1967 and 2020. Cesarean delivery was described by maternal age (5-year groups), onset of labor (spontaneous, induced and pre-labor CD), and time periods: 1967–1982, 1983–1998 and 1999–2020. We combined women’s age, onset of labor and time period into a compound variable, using women of 20–24 years, with spontaneous labor onset during 1967–1982 as reference. Multivariable regression models were used to estimate adjusted relative risk (ARR) of cesarean delivery with 95% confidence interval (CI). Results Overall cesarean delivery increased both in women with and without spontaneous onset of labor, with a slight decline in recent years. The increase was mainly found among women   = 35 years. In women with spontaneous onset of labor, the ARR of CD in women >  = 40 years decreased from 14.2 (95% CI 12.4–16.3) in 1967–82 to 6.7 (95% CI 6.2–7.4) in 1999–2020 and from 7.0 (95% CI 6.4–7.8) to 5.0 (95% CI 4.7–5.2) in women aged 35–39 years, compared to the reference population. Despite the rise in induced onset of labor over time, the ARR of CD declined in induced women >  = 40 years from 17.6 (95% CI 14.4–21.4) to 13.4 (95% CI 12.5–14.3) while it was stable in women 35–39 years. Conclusion Despite growing number of Norwegian women having their first birth at a higher age, the increase in cesarean delivery was found among women < 35 years, while it was stable or decreased in older women. The increase in cesarean delivery cannot be solely explained by the shift to an older population of first-time mothers.publishedVersio