Down syndrome and associated atrioventricular septal defects in a nationwide Norwegian cohort: Prevalence, time trends, and outcomes.

INTRODUCTION: The prevalence of Down syndrome (DS) is approximately 1 per 1000 births and is influenced by increasing maternal age over the last few decades. DS is strongly associated with congenital heart defects (CHDs), especially atrioventricular septal defect (AVSD). Our objectives were to investigate the prevalence of live-born infants with DS having a severe CHD in the Norwegian population over the last 20 years and compare outcomes in infants with AVSD with and without DS. MATERIAL AND METHODS: Information on all births from January 1, 2000 to December 31, 2019 was obtained from the Medical Birth Registry of Norway. We also obtained data on all infants with severe CHDs in Norway registered in Oslo University Hospital's Clinical Registry for Congenital Heart Defects during 2000-2019 and accessed individual-level patient data from the electronic hospital records of selected cases. Infants with AVSD and DS were compared to infants with AVSD without chromosomal defects. Crude and adjusted odds ratios (ORs) of infant mortality and need for surgery during the first year of life, with associated 95% confidence intervals (CIs), were estimated by logistic regression. RESULTS: A total of 1 177 926 infants were live-born in Norway during the study period. Among these, 1456 (0.1%) had DS. The prevalence of infants with DS having a severe CHDs was relatively stable, with a mean of 17 cases per year. The most common CHD associated with DS was AVSD (44.4%). Infants with AVSD and DS were more likely to have cardiac intervention during their first year of life compared to infants with AVSD without chromosomal defects (adjusted OR [aOR]: 2.52; 95% CI 1.27, 4.98). However, we observed no difference in infant mortality during first year of life between the two groups (aOR: 1.08; 95% CI 0.43, 2.70). CONCLUSIONS: The prevalence of live-born infants with severe CHDs and DS has been stable in Norway across 20 years. Infants with AVSD and DS did not have higher risk of mortality during their first year of life compared to infants with AVSD without chromosomal defects, despite a higher risk of operative intervention.

Association of oxytocin augmentation and duration of labour with postpartum haemorrhage: A cohort study of nulliparous women.

OBJECTIVE: Both duration of labour and use of oxytocin for augmentation are known risk factors for postpartum haemorrhage but distinguishing between the significance of these factors is complex. In this study, we aimed to investigate the association between both labour duration and oxytocin augmentation, for postpartum haemorrhage. DESIGN: A cohort study based on a secondary analysis of a cluster-randomised trial. PARTICIPANTS AND SETTING: Term nulliparous women with a single foetus in cephalic presentation, spontaneous onset of active labour and a vaginal birth. The participants were originally included in cluster-randomised trial conducted in Norway from December 1, 2014, to January 31, 2017, that aimed to compare the frequency of intrapartum caesarean sections when adhering to the WHO partograph versus Zhang's guideline. MEASUREMENTS: The data were analysed through four statistical models. Model 1 investigated the effect of oxytocin augmentation as a dichotomous variable (yes/no); Model 2 investigated the effect of the duration of oxytocin augmentation; Model 3 investigated the effect of the maximum dose of oxytocin; and Model 4 investigated the effect of both the duration of augmentation and the maximum dose of oxytocin. All four models included duration of labour divided into five time-intervals. We used binary logistic regression to estimate the odds ratios of postpartum haemorrhage, defined as blood loss of ≥ 1000 ml, including a random intercept for hospital and mutually adjusting for oxytocin augmentation and labour duration in addition to maternal age, maternal marital status, maternal higher education level, maternal smoking habits in the first trimester, maternal body mass index and birth weight. FINDINGS: Model 1 found a significant association between the use of oxytocin and postpartum haemorrhage. In Model 2, oxytocin augmentation of ≥ 4.5 h was associated with postpartum haemorrhage. In Model 3, we found an association between a maximum dose of oxytocin of ≥ 20 mU/min and postpartum haemorrhage. Model 4 showed that a maximum dose of oxytocin ≥ 20 mU/min was associated with postpartum haemorrhage both for those augmented < 4.5 h and for those augmented ≥ 4.5 h. Duration of labour was associated with postpartum haemorrhage in all models if lasting ≥ 16 h. KEY CONCLUSIONS: We found both oxytocin augmentation and labour duration to be associated with postpartum haemorrhage. Oxytocin doses of ≥ 20 mU/min and a labour duration of ≥ 16 h showed an independent association. IMPLICATION FOR PRACTICE: The potent drug oxytocin should be carefully administered, as doses of ≥ 20 mU/min were associated with an increased risk of PPH, regardless of the duration of oxytocin augmentation.

Maternal body mass index and risk of obstetric, maternal and neonatal outcomes: A cohort study of nulliparous women with spontaneous onset of labor.

INTRODUCTION: This study investigates associations between maternal body mass index (BMI) early in pregnancy and obstetric interventions, maternal and neonatal outcomes. MATERIAL AND METHODS: This is a cohort study of nulliparous women originally included in a cluster randomized controlled trial carried out at 14 Norwegian obstetric units between 2014 and 2017. The sample included 7189 nulliparous women with a singleton fetus, cephalic presentation and spontaneous onset of labor at term, denoted as group 1 in the Ten-Group Classification System. The women were grouped according to the World Health Organization BMI classifications: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), pre-obesity (BMI 25.0-29.9), obesity class I (BMI 30.0-34.9), and obesity classes II and III (BMI ≥35.0). We used binary logistic regression to estimate crude and adjusted odds ratios (ORs) of the interventions and outcomes, with associated 95% confidence intervals (CIs), comparing women in different BMI groups with women of normal weight. RESULTS: We found an increased risk of intrapartum cesarean section in women of obesity class I and obesity classes II and III, with adjusted OR of 1.70 (95% CI 1.21-2.38) and 2.31 (95% CI 1.41-3.77), respectively. Women in obesity groups had a gradient of risk of epidural analgesia and use of continuous CTG (including STAN), with adjusted OR of 2.39 (95% CI 1.69-3.38) and 3.28 (95% CI 1.97-5.48), respectively. Women in obesity classes II and III had higher risk of amniotomy (adjusted OR = 1.42, 95% CI 1.02-1.96), oxytocin augmentation (adjusted OR = 1.54, 95% CI 1.11-2.15), obstetric anal sphincter injuries (adjusted OR = 2.21, 95% CI 1.01-4.85) and postpartum hemorrhage ≥1000 mL (adjusted OR = 2.20, 95% CI 1.29-3.78). We found a reduced likelihood of spontaneous vaginal delivery for pre-obese women (adjusted OR = 0.85, 95% CI 0.74-0.97) and no associations between maternal BMI and neonatal outcomes. CONCLUSIONS: Obese women in Ten-Group Classification System group 1 had increased risks of obstetric interventions and maternal complications. There was a gradient of risk for intrapartum cesarean section, with the highest risk for women in obesity classes II and III. No associations between maternal BMI and neonatal outcomes were observed.

Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a complex condition. Causal factors are not established, although underlying psychological or immunological susceptibility has been proposed. We studied primary care diagnoses for children with CFS/ME, with children with another hospital diagnosis (type 1 diabetes mellitus [T1DM]) and the general child population as comparison groups. METHODS: All Norwegian children born 1992-2012 constituted the study sample. Children with CFS/ME (n = 1670) or T1DM (n = 4937) were identified in the Norwegian Patient Register (NPR) (2008-2014). Children without either diagnosis constituted the general child population comparison group (n = 1337508). We obtained information on primary care diagnoses from the Norwegian Directorate of Health. For each primary care diagnosis, the proportion and 99 % confidence interval (CI) within the three groups was calculated, adjusted for sex and age by direct standardization. RESULTS: Children with CFS/ME were more often registered with a primary care diagnosis of weakness/general tiredness (89.9 % [99 % CI 88.0 to 91.8 %]) than children in either comparison group (T1DM: 14.5 % [99 % CI: 13.1 to 16.0 %], general child population: 11.1 % [99 % CI: 11.0 to 11.2 %]). Also, depressive disorder and anxiety disorder were more common in the CFS/ME group, as were migraine, muscle pain, and infections. In the 2 year period prior to the diagnoses, infectious mononucleosis was registered for 11.1 % (99 % CI 9.1 to 13.1 %) of children with CFS/ME and for 0.5 % (99 % CI (0.2 to 0.8 %) of children with T1DM. Of children with CFS/ME, 74.6 % (1292/1670) were registered with a prior primary care diagnosis of weakness / general tiredness. The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %. CONCLUSIONS: This large nationwide registry linkage study confirms that the clinical picture in CFS/ME is complex. Children with CFS/ME were frequently diagnosed with infections, supporting the hypothesis that infections may be involved in the causal pathway. The long time span often observed from the first diagnosis of weakness / general tiredness to the diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated to infections and it has been suggested that vaccination can trigger the disease. However, little is known about the specific association between clinically manifest influenza/influenza vaccine and CFS/ME. As part of a registry surveillance of adverse effects after mass vaccination in Norway during the 2009 influenza A (H1N1) pandemic, we had the opportunity to estimate and contrast the risk of CFS/ME after infection and vaccination. METHODS: Using the unique personal identification number assigned to everybody who is registered as resident in Norway, we followed the complete Norwegian population as of October 1, 2009, through national registries of vaccination, communicable diseases, primary health, and specialist health care until December 31, 2012. Hazard ratios (HRs) of CFS/ME, as diagnosed in the specialist health care services (diagnostic code G93.3 in the International Classification of Diseases, Version 10), after influenza infection and/or vaccination were estimated using Cox proportional-hazards regression. RESULTS: The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk. The adjusted HR of CFS/ME after pandemic vaccination was 0.97 (95% confidence interval [CI]: 0.91-1.04), while it was 2.04 (95% CI: 1.78-2.33) after being diagnosed with influenza infection during the peak pandemic period. CONCLUSIONS: Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME. We found no indication of increased risk of CFS/ME after vaccination. Our findings are consistent with a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME.

Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012.

BACKGROUND: The aim of the current study was to estimate sex- and age-specific incidence rates of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) using population-based registry data. CFS/ME is a debilitating condition with large impact on patients and their families. The etiology is unknown, and the distribution of the disease in the general population has not been well described. METHODS: Cases of CFS/ME were identified in the Norwegian Patient Register (NPR) for the years 2008 to 2012. The NPR is nationwide and contains diagnoses assigned by specialist health care services (hospitals and outpatient clinics). We estimated sex- and age-specific incidence rates by dividing the number of new cases of CFS/ME in each category by the number of person years at risk. Incidence rate ratios were estimated by Poisson regression with sex, age categories, and year of diagnosis as covariates. RESULTS: A total of 5,809 patients were registered with CFS/ME during 2008 to 2012. The overall incidence rate was 25.8 per 100,000 person years (95% confidence interval (CI): 25.2 to 26.5). The female to male incidence rate ratio of CFS/ME was 3.2 (95% CI: 3.0 to 3.4). The incidence rate varied strongly with age for both sexes, with a first peak in the age group 10 to 19 years and a second peak in the age group 30 to 39 years. CONCLUSIONS: Early etiological clues can sometimes be gained from examination of disease patterns. The strong female preponderance and the two age peaks suggest that sex- and age-specific factors may modulate the risk of CFS/ME.

Folic acid supplementation and interpregnancy interval.

BACKGROUND: Maternal folic acid supplementation between subsequent pregnancies may be important to reduce the risk of low folate status associated with short interpregnancy intervals. We examined how the prevalence of preconception folic acid use for a given pregnancy in Norwegian women varied according to the time interval from the previous pregnancy. METHODS: Analysis was based on 48 855 pairs of pregnancies with the second pregnancy included in the Norwegian Mother and Child Cohort Study (birth years 1999-2009). Interpregnancy interval was defined as the time from birth of a child to the conception of the subsequent sibling. Preconception folic acid use was defined as any use of folic acid-containing supplements within the last 4 weeks before the second pregnancy. RESULTS: The prevalence of preconception folic acid use was 31%. Among women with a term birth (≥37 weeks) in the previous pregnancy (92%), those with interpregnancy intervals ≤12 and ≥49 months were associated with up to 35% lower prevalence of preconception folic acid use for the second pregnancy, relative to the reference group (13-24 months). The low use in short intervals was mainly attributable to lower proportion of planned pregnancies and fewer women with higher education. Among women with a preterm birth (<37 weeks) in the previous pregnancy (8%), preconception folic acid use significantly decreased with increasing pregnancy spacing. CONCLUSIONS: Our finding of a lower preconception folic acid use in women with both short and long interpregnancy intervals might help identifying those with higher risk of folate deficiency and preventing unwanted pregnancy outcomes.

Identifying children with autism spectrum disorder at 18 months in a general population sample.

BACKGROUND: Previous research on clinical and high-risk samples suggests that signs of autism spectrum disorder (ASD) can be detected between 1 and 2 years of age. We investigated signs of ASD at 18 months in a population-based sample and the association with later ASD diagnosis. METHODS: The study sample includes 52,026 children born 2003 through 2008 and is a subset of children that participated in the Norwegian Mother and Child Cohort (MoBa), a population-based longitudinal study, and the Autism Birth Cohort (ABC), a sub-study on ASD. Parents completed all 23 items from the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months. RESULTS: The M-CHAT 6-critical-item criterion and the 23-item criterion had a specificity of 97.9% and 92.7% and a sensitivity of 20.8% and 34.1%, respectively. In the 173 children diagnosed with ASD to date, 60 children (34.7%) scored above the cut-off on either of the screening criteria. The items with the highest likelihood ratios were 'interest in other children', 'show objects to others' and 'response to name'. CONCLUSION: Even though one-third of the children who later received an ASD diagnosis were identified through M-CHAT items, the majority scored below cut-off on the screening criteria at 18 months. The results imply that it might not be possible to detect all children with ASD at this age.

Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders.

BACKGROUND: This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders (ASDs). METHODS: The cohort sample (n = 89 836) was derived from the population-based prospective Norwegian Mother and Child Cohort Study and its substudy of ASDs, the Autism Birth Cohort (ABC) study. The nationwide registry data were derived from the Medical Birth Registry of Norway (n = 507 856). The children were born in 1999­2007, and seven prenatal and perinatal exposures were selected for analyses. RESULTS: ASDs were reported for 234 (0.26%) children in the cohort and 2072 (0.41%) in the nationwide population. Compared with the nationwide population, the cohort had an under-representation of the youngest women (<25 years), those who had single status, mothers who smoked during pregnancy, and non-users of prenatal folic acid supplements. The ratios of the adjusted odds ratios (ORs) in the cohort over the adjusted ORs in the nationwide population were as follows; primipara pregnancy: 1.39/1.22, prenatal folic acid use: 0.85/0.86, prenatal smoking: 1.20/1.17, preterm birth (<37 weeks): 1.48/1.42, low birthweight (<2500 g): 1.60/1.58, male sex: 4.39/4.59 (unadjusted only); and caesarean section history: 1.03/1.04. CONCLUSIONS: Associations estimated between ASDs and perinatal and prenatal exposures in the cohort are close to those estimated in the nationwide population. Self-selection does not appear to compromise validity of exposure-outcome associations in the ABC study.

Maternal body composition, smoking, and hyperemesis gravidarum.

PURPOSE: To study associations between maternal prepregnant body mass index (BMI), smoking, and hyperemesis gravidarum (hyperemesis). METHODS: The sample consisted of 33,467 primiparous women from the Norwegian Mother and Child Cohort Study (1999-2008). Data on hyperemesis, BMI, education, maternal age, eating disorders, maternal and paternal smoking habits were obtained from questionnaires. All associations were studied by logistic regression. RESULTS: Altogether, 353 (1.1%) women had hyperemesis. Among non-smokers, both underweight and obese women were more likely to develop hyperemesis than normal-weighted women: odds ratio (OR), 2.36; 95% confidence interval (95% CI), 1.43-3.88 and OR, 1.48; 95% CI, 1.00-2.20, respectively. No associations were found among smokers. Women who smoked daily (OR, 0.44; 95% CI, 0.32-0.60) or occasionally (OR, 0.64; 95% CI, 0.44-0.93) had lower risk of hyperemesis than non-smokers. No effect of partner's smoking habits was observed. CONCLUSIONS: Both underweight and obesity were associated with hyperemesis, but only among non-smokers. Maternal prepregnant smoking reduced the risk of hyperemesis, whereas partner's smoking habits had no effect.

A dynamic approach for reconstructing missing longitudinal data using the linear increments model.

Missing observations are commonplace in longitudinal data. We discuss how to model and analyze such data in a dynamic framework, that is, taking into consideration the time structure of the process and the influence of the past on the present and future responses. An autoregressive model is used as a special case of the linear increments model defined by Farewell (2006. Linear models for censored data, [PhD Thesis]. Lancaster University) and Diggle and others (2007. Analysis of longitudinal data with drop-out: objectives, assumptions and a proposal. Journal of the Royal Statistical Society, Series C (Applied Statistics, 56, 499-550). We wish to reconstruct responses for missing data and discuss the required assumptions needed for both monotone and nonmonotone missingness. The computational procedures suggested are very simple and easily applicable. They can also be used to estimate causal effects in the presence of time-dependent confounding. There are also connections to methods from survival analysis: The Aalen-Johansen estimator for the transition matrix of a Markov chain turns out to be a special case. Analysis of quality of life data from a cancer clinical trial is analyzed and presented. Some simulations are given in the supplementary material available at Biostatistics online.

Assessing quality of life in a randomized clinical trial: correcting for missing data.

BACKGROUND: Health-related quality of life is a topic of current interest. This paper considers a randomized phase III study of radiation therapy with concurrent chemotherapy (docetaxel) versus radiation therapy alone in non-small cell lung cancer, stage III A/B. Longitudinal data on quality of life have been obtained through repeated administration of a multi-item questionnaire (EORTC QLQ-C30) developed by the European Organisation for Research and Treatment of Cancer. Missingness in the data is owing to patients having failed to complete the questionnaire at some of the scheduled filling-in times. METHODS: We have analysed a monotone (in terms of missingness) subset of the data as regards estimation of the mean score of a summary measure of self-reported quality of life in a hypothetical drop-out-free population at different points in time. Missingness is a difficult issue of great importance. We have therefore chosen to compare three different methods that are relatively easy to implement: the linear-increments method, the inverse-probability-weighting method and the Markov-process method. Single imputation has been applied in a supplementary analysis to fill in for all the non-consecutive missing score values prior to the execution of the estimation procedure. RESULTS: For the response in focus, the observed mean score at a certain time is larger than the estimated mean scores, which implies that the true mean score is easily overestimated unless the missingness is appropriately adjusted for. Comparison of the treatment arms shows a significant difference in mean score at the end of treatment. CONCLUSION: Use of proper methodology developed for analysing data subject to missingness is necessary to reduce potential estimation bias. The quality of life of patients receiving radiation therapy with concurrent chemotherapy (docetaxel) appears somewhat worse than that of patients receiving radiation therapy alone in the period during which treatment is given. The conclusions are robust for the choice of statistical methods.

Estimating stage occupation probabilities in non-Markov models.

We study non-Markov multistage models under dependent censoring regarding estimation of stage occupation probabilities. The individual transition and censoring mechanisms are linked together through covariate processes that affect both the transition intensities and the censoring hazard for the corresponding subjects. In order to adjust for the dependent censoring, an additive hazard regression model is applied to the censoring times, and all observed counting and "at risk" processes are subsequently given an inverse probability of censoring weighted form. We examine the bias of the Datta-Satten and Aalen-Johansen estimators of stage occupation probability, and also consider the variability of these estimators by studying their estimated standard errors and mean squared errors. Results from different simulation studies of frailty models indicate that the Datta-Satten estimator is approximately unbiased, whereas the Aalen-Johansen estimator either under- or overestimates the stage occupation probability due to the dependent nature of the censoring process. However, in our simulations, the mean squared error of the latter estimator tends to be slightly smaller than that of the former estimator. Studies on development of nephropathy among diabetics and on blood platelet recovery among bone marrow transplant patients are used as demonstrations on how the two estimation methods work in practice. Our analyses show that the Datta-Satten estimator performs well in estimating stage occupation probability, but that the censoring mechanism has to be quite selective before a deviation from the Aalen-Johansen estimator is of practical importance.