Traditional null hypothesis significance testing (NHST) incorporating the critical level of significance of 0.05 has become the cornerstone of decision‐making in health care, and nowhere less so than ...in obstetric and gynecological research. However, such practice is controversial. In particular, it was never intended for clinical significance to be inferred from statistical significance. The inference of clinical importance based on statistical significance (p < 0.05), and lack of clinical significance otherwise (p ≥ 0.05) represents misunderstanding of the original purpose of NHST. Furthermore, the limitations of NHST—sensitivity to sample size, plus type I and II errors—are frequently ignored. Therefore, decision‐making based on NHST has the potential for recurrent false claims about the effectiveness of interventions or importance of exposure to risk factors, or dismissal of important ones. This commentary presents the history behind NHST along with the limitations that modern‐day NHST presents, and suggests that a statistics reform regarding NHST be considered.
IMPORTANCE Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure ...to valproate may increase the risk of autism. OBJECTIVE To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism autistic disorder, Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 95% CI, 1.7-4.9) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 95% CI, 2.7-10.0). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 95% CI, 0.9-3.2), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 95% CI, 1.4-6.0) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
Introduction
We hypothesized that children with Down syndrome who were born after the implementation of first‐trimester combined screening for trisomy 13, 18, and 21 and a second‐trimester ultrasound ...scan in Denmark would show a milder syndrome phenotype. We investigated the birth biometry, prevalence of congenital malformations, and early childhood morbidity of children with Down syndrome before and after implementation of this screening program.
Material and methods
A nationwide register‐based study of all live born singletons with Down syndrome in Denmark from 1995 to 2018. In interrupted time series analyses, we studied the temporal developments in birth biometry, prevalence of congenital malformations, and early childhood morbidity related to the implementation of a national prenatal screening program.
Results
We included 602 singletons with Down syndrome born before and 308 after implementation of the screening program. Z‐scores of birthweight and head circumference increased over time before screening, but this temporal development changed after implementation by −0.05 (95% confidence interval CI: −0.11 to 0.01) and −0.05 (95% CI −0.12 to 0.02), respectively. Just after implementation, the prevalence of non‐severe congenital heart disease decreased (relative change in odds 0.48 95% CI: 0.24–0.94). For severe congenital heart disease, atrioventricular septal defect, and non‐heart malformations, this change was 1.16 (95% CI: 0.56–2.41), 0.95 (95% CI: 0.43–2.03), and 0.98 (95% CI: 0.33–2.76), respectively. For all malformations, pre‐existing temporal developments did not change following implementation of screening. The implementation was associated with higher odds of admission to a neonatal intensive care unit (relative change 1.98 95% CI: 0.76–5.26) and an increased risk of hearing impairment (risk difference 3.4% 95% CI: −0.4% to 7.1%). In contrast, the implementation was not associated with the incidence of hospital admissions by 2 years of age or with the probability of a thyroid disorder.
Conclusions
After implementation of a national prenatal screening program, we did not observe a milder Down syndrome phenotype apart from an apparent reduction in the proportion of children with non‐severe congenital heart disease; this result is, however, limited by small numbers.
We hypothesized that children with Down syndrome would have a milder phenotype if born following the implementation of first‐trimester combined screening and second‐trimester ultrasonography in Denmark. Overall, this hypothesis was not supported by our results.
Obesity, affecting one in three pregnant women worldwide, is not only a major obstetric risk factor. The resulting low‐grade inflammation may have a long‐term impact on the offspring's HPA axis ...through dysregulation of maternal, placental and fetal corticosteroid metabolism, and children born of obese mothers have increased risk of diabetes and cardiovascular disease. The long‐term effects of maternal obesity on offspring neurodevelopment are, however, undetermined and could depend on the specific effects on placental and fetal cortisol metabolism. This systematic review evaluates how maternal obesity affects placental cortisol metabolism and the offspring's HPA axis. Pubmed, Embase and Scopus were searched for original studies on maternal BMI, obesity, and cortisol metabolism and transfer. Fifteen studies were included after the screening of 4556 identified records. Studies were small with heterogeneous exposures and outcomes. Two studies found that maternal obesity reduced placental HSD11β2 activity. In one study, umbilical cord blood cortisol levels were affected by maternal BMI. In three studies, an altered cortisol response was consistently seen among offspring in childhood (n = 2) or adulthood (n = 1). Maternal BMI was not associated with placental HSD11β1 or HSD11β2 mRNA expression, or placental HSD11β2 methylation. In conclusion, high maternal BMI is associated with reduced placental HSD11β2 activity and a dampened cortisol level among offspring, but the data is sparse. Further investigations are needed to clarify whether the HPA axis is affected by prenatal factors including maternal obesity and investigate if adverse effects can be ameliorated by optimising the intrauterine environment.
Maternal obesity affects the offspring's cortisol metabolism differently before and after birth. Around birth, the placental enzyme HSD11β2 that catalyses active cortisol into cortisone is downregulated and the umbilical cortisol level is decreased. In childhood, the offspring's HPA axis becomes overloaded with an increased cortisol steepness which triggers a cortisol blunt in adulthood. Thus, maternal obesity might increase the risk of cognitive and affective disabilities in exposed children.
Genetic counseling about Down syndrome is suggested to include information on a future family life. However, there is an insufficient knowledge on the potential impact of parenting a child with Down ...syndrome on parents’ everyday practices. We aimed to address this gap by exploring the experienced everyday practices of parents in families where a child has Down syndrome. Taking a qualitative approach, we conducted semi‐structured interviews with 25 parents of children with Down syndrome aged 4–12 years. Using reflexive thematic analysis, we identified two themes concerned with the parents’ practice. The first, ‘Supporting our child’, describes how the parents perceived their child as a valuable human being and how this perception founded parents’ support of the child's development and social interactions. The second, ‘Managing our family life’, demonstrates how the parents acted to manage a family life that had become the ‘new normal’ including being alert toward the child, shaping the practical and logistical framework of daily life, and balancing between being at home and away from home. Overall, the analysis presents an everyday practice aimed at a desirable future for the child with Down syndrome and at a management of everyday life on the family's own terms. In conclusion, this study provides specific knowledge on parents’ everyday practice, which may inform genetic counseling about Down syndrome and be of value to service providers.
Introduction
Maternal demographics have evolved, and more women than ever enter pregnancy with preexisting comorbidity and with potentially complex medication exposure, including polypharmacy ...(concomitant intake of multiple medications). This study aims to describe the evolution of medication use in pregnancy in Denmark from 1998 to 2018 with special focus on polypharmacy, patterns of use, and underlying demographics.
Material and methods
A Danish nationwide historical registry study based on all clinically recognized pregnancies with a gestation ≥10 weeks between 1998 and 2018. Medication use was estimated by redemption of prescriptions during pregnancy.
Results
Among a total of 1 402 327 clinically recognized pregnancies, redemption of at least one prescription medication during pregnancy increased from 56.9% in 1998 to 63.3% in 2018, coinciding with an increased use of polypharmacy (from 24.8% in 1998 to 35.2% in 2018). The prevalence of pregnant women who used medications for chronic conditions increased more than the prevalence of women treated for occasional or short‐time conditions. Redemption of one or multiple prescription medications during pregnancy was mostly seen among pregnant women ≥35 years of age. However, pregnant women <25 years old exhibited the largest increase in medication use during the study period.
Conclusions
Medication use in general, and polypharmacy in particular, increased from 1998 to 2008, possibly as the result of an increased prevalence of pregnant women with chronic conditions requiring pharmacological treatment. Notably, a marked maternal age‐based discrepancy in usage pattern was observed, highlighting the need for further research in this area. The rise in the prevalence of polypharmacy during pregnancy underscores the need for pharmacovigilance to monitor adverse effects. Future studies should investigate the patterns of polypharmacy and the accompanying maternal and fetal risks.
Prescription medication use during pregnancy rose from 1998 to 2018, coinciding with an increased prevalence of pharmacologically treated chronic conditions among pregnant women. This trend also heightened polypharmacy, with age‐related different medication patterns among pregnant women.
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