Associations Between Maternal Antenatal Corticosteroid Treatment and Psychological Developmental and Neurosensory Disorders in Children.
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ABSTRACT:
SUBMITTER: Raikkonen K
PROVIDER: S-EPMC9403777 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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Associations Between Maternal Antenatal Corticosteroid Treatment and Psychological Developmental and Neurosensory Disorders in Children.
Räikkönen Katri K Gissler Mika M Tapiainen Terhi T Kajantie Eero E
JAMA network open 20220801 8
<h4>Importance</h4>Corticosteroids administered to women at risk of imminent preterm birth is one of the most effective ways to improve the prognosis of infants born preterm. Scant data about long-term neurodevelopmental and neurosensory outcomes among the treatment-exposed children are mixed, suggesting that not all domains of neurodevelopmental and neurosensory function may be equally affected. Moreover, the long-term outcomes may vary according to whether the treatment-exposed children are be ...[more]
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Project description:Importance:Maternal antenatal corticosteroid treatment is standard care to accelerate fetal maturation when birth before 34 weeks is imminent. Recently, expansion of the indications beyond 34 gestational weeks has been debated. However, data about long-term outcomes remain limited, especially among infants who after treatment exposure are born at term. Objective:To study if antenatal corticosteroid treatment is associated with mental and behavioral disorders in children born at term (≥37 weeks 0 days' gestation) and preterm (<37 weeks 0 days' gestation) and if unmeasured familial confounding explains these associations. Design, Setting, and Participants:Population-based retrospective cohort study using nationwide registries of all singleton live births in Finland surviving until 1 year and a within-sibpair comparison among term siblings. Children were born between January 1, 2006, and December 31, 2017, and followed up until December 31, 2017. Exposures:Maternal antenatal corticosteroid treatment. Main Outcomes and Measures:Primary outcome was any childhood mental and behavioral disorder diagnosed in public specialized medical care settings. Results:Of the 674 877 singleton children born in Finland during the study period, 670 097 were eligible for analysis. The median length of follow-up was 5.8 (interquartile-range, 3.1-8.7) years. Of the 14 868 (2.22%; 46.1% female) corticosteroid treatment-exposed children, 6730 (45.27%) were born at term and 8138 (54.74%) were born preterm; of the 655 229 (97.78%; 48.9% female) nonexposed children, 634 757 (96.88%) were born at term and 20 472 (3.12%) were born preterm. Among the 241 621 eligible term-born maternal sibpairs nested within this population, 4128 (1.71%) pairs were discordant for treatment exposure. Treatment exposure, compared with nonexposure, was significantly associated with higher risk of any mental and behavioral disorder in the entire cohort of children (12.01% vs 6.45%; absolute difference, 5.56% [95% CI, 5.04%-6.19%]; adjusted hazard ratio [HR], 1.33 [95% CI, 1.26-1.41]), in term-born children (8.89% vs 6.31%; absolute difference, 2.58% [95% CI, 1.92%-3.29%]; HR, 1.47 [95% CI, 1.36-1.69]), and when sibpairs discordant for treatment exposure were compared with sibpairs concordant for nonexposure (6.56% vs 4.17% for within-sibpair differences; absolute difference, 2.40% [95% CI, 1.67%-3.21%]; HR, 1.38 [95% CI, 1.21-1.58]). In preterm-born children, the cumulative incidence rate of any mental and behavioral disorder was also significantly higher for the treatment-exposed compared with the nonexposed children, but the HR was not significant (14.59% vs 10.71%; absolute difference, 3.38% [95% CI, 2.95%-4.87%]; HR, 1.00 [95% CI, 0.92-1.09]). Conclusions and Relevance:In this population-based cohort study, exposure to maternal antenatal corticosteroid treatment was significantly associated with mental and behavioral disorders in children. These findings may help inform decisions about maternal antenatal corticosteroid treatment.
| S-EPMC7237984 | biostudies-literature
Project description:Antenatal corticosteroids (ACS) are used to treat women at risk of preterm birth to improve neonatal survival. Though affected children may be at long-term risk of neurobehavioural disorders, the driving mechanisms remain unknown. Animal studies have shown that ACS exposure can lead to overlapping changes in DNA methylation between the blood and the brain, identifying gene pathways for neurodevelopment, which highlights the potential to examine peripheral blood as a surrogate for inaccessible human brain tissue. We hypothesized that differential methylation will be identified in blood of term-born neonates following ACS. Mother-infant dyads that received ACS were retrospectively identified through the Ontario Birth Study at Sinai Health Complex and matched to untreated controls for maternal age, BMI, parity and foetal sex (n = 14/group). Genome-wide methylation differences were examined at single-nucleotide resolution in DNA extracted from dried bloodspot cards using reduced representative bisulfite sequencing approaches. 505 differentially methylated CpG sites (DMCs) were identified, wherein 231 were hypermethylated and 274 were hypomethylated. These sites were annotated to 219 genes, of which USP48, SH3PXD2A, NTM, CAMK2N2, MAP6D1 were five of the top ten genes with known neurological function. Collectively, the set of hypermethylated genes were enriched for pathways of transcription regulation, while pathways of proteasome activity were enriched among the set of hypomethylated genes. This study is the first to identify DNA methylation changes in human neonatal blood following ACS. Understanding the epigenetic changes that occur in response to ACS will support future investigations to delineate the effects of prenatal glucocorticoid exposure on human development.
| S-EPMC8967826 | biostudies-literature
Project description:BackgroundAntenatal Corticosteroid Treatment (ACT) improves the outcome of preterm infants, but may influence immune system development and risk of immune-related diseases. We investigated whether ACT is associated with infectious diseases in children born at term (≥37 gestational weeks), and very-to-moderate (<34 gestational weeks), and late (34-36 completed gestational weeks) preterm.MethodsAll singleton live births in Finland between 01/01/2006 and 31/12/2021, were followed-up until 31/12/2021. Exposure was maternal ACT. Primary outcomes were numbers of inpatient treatment days, episodes, and specialized care outpatient visits with any infectious disease diagnoses between ages 0 and 4 years. We considered mother- and child-related covariates, and conducted term-born co-sibling comparisons.FindingsData comprised 855,234 children. Of the 20,858 (2.4%) treatment-exposed children, 5981 (28.2%) were very-to-moderate preterm-born, 5809 (27.9%) late preterm-born, and 9069 (43.5%) term-born. Of the 271,767 term-born co-sibling pairs, 5010 (1.8%) were treatment-exposure-discordant, and 266,522 (98.1%) nonexposure-concordant. Among the term- and late preterm-born, treatment-exposed children had more inpatient treatment days than nonexposed children (term: 0.87 vs. 0.56 day/y, adjusted mean difference [aMD] 0.19, 95% CI 0.17-0.28; late preterm: 1.35 vs. 1.00 days/y, aMD 0.31,0.13-0.31), more inpatient treatment episodes (term: 0.43 vs. 0.33 episodes/y, aMD 0.06, 0.06-0.11; late preterm: 0.55 vs. 0.48 episodes/y, aMD 0.12, 0.06-0.18), and specialized care treatment visits (term: 1.46 vs. 0.95 visits/y, aMD 0.38; 0.34-0.43; late preterm: 1.63 vs. 1.28 visits/y, aMD 0.22, 0.12-0.32). Treatment-exposed and nonexposed very-to-moderate preterm-born children were similar in these outcomes, though they had less inpatient treatment days and episodes at 3-4 years. Differences remained in term-born co-sibling comparisons.InterpretationThese findings reinforce previous suggestions for careful consideration of risks and benefits of ACT.FundingAcademy of Finland, HiLIFE Fellows-Programme.
| S-EPMC10583166 | biostudies-literature
Project description:BackgroundIdentifying modifiable risk factors for neuropsychological correlates of attention deficit hyperactivity disorder (ADHD) in early childhood can inform prevention strategies. Prenatal inflammatory states, such as maternal asthma and other atopic disorders, have been increasingly linked to enhanced risk for neurobehavioral disorders in children, with some studies suggesting sex-specific effects.ObjectivesTo assess the association between maternal active asthma and/or atopy in the antenatal period and child symptoms of ADHD during mid-childhood and, given the male-bias in ADHD prevalence, to examine modifying effects of child sex.Study designThe study sample includes 250 maternal-child pairs enrolled in the Boston-based Asthma Coalition on Community, Environment and Social Stress (ACCESS) pregnancy cohort. We defined antenatal active atopy based on maternal report of current asthma, allergic rhinitis or atopic dermatitis during and/or in the year before pregnancy. When children were approximately 6 years old, mothers completed a battery of standardized child behavior rating scales designed for evaluating symptoms of ADHD. We used multivariable quantile regression to assess the relations between maternal antenatal atopy and symptoms of ADHD among children.ResultsIn adjusted models, maternal atopy was significantly associated with greater risk for ADHD behaviors, as indicated by scores on the Conners' Parent Rating Scale-Revised ADHD index (β = 3.32, 95% CI: 0.33, 6.32). In sex-stratified models this association was stronger among girls (5.96, 95% CI = 0.95, 10.96) compared to boys (-2.14, 95% CI = -5.75, 1.45, p-interaction = 0.01). Among girls, we observed a similar finding for the Behavior Assessment System for Children 2nd Edition Parent Rating Scale Attention Problems subscale (β = 7.77, 95% CI = 1.57, 13.97). Results from other outcome subscales were similar in magnitude and direction, however, associations did not reach statistical significance at the p = 0.05 level.ConclusionsMaternal antenatal active atopy may be a risk factor for the development of ADHD-like symptoms, especially among girls.
| S-EPMC6660383 | biostudies-literature
Project description:Purpose: Evaluate fetal lung maturation and transcriptome after clinical treatment with antenatal corticosteroids compared to an alternative treatment with a slow release low-dose formulation. Methods: Lung mRNA profiles of rhesus macaques were generated by RNA sequencing. Reads that met quality thresholds were aligned to the rhesus macaque genome and number of reads per gene was counted. RNA-sequencing of the hippocampus was done. Differential expression analysis was done using read counts. Results: A relatively low dose of Beta-Ac increased lung compliance, surfactant concentration and relative airspace of the fetal lung equivalent to the clinical drug. By transcriptome analyses, the early suppression of genes associated with immune responses and the downregulation of genes associated with developmental pathways were less changed by Beta-Ac than the clinical drug. There were no significant differences between Beta-Ac and control while the clinical drug suppressed maturational pathways including genes involved in neurogenesis, neuronal differentiation and stem cell fate commitment. Conclusions: We report that low-dose betamethasone-acetate has decreased impact on lung transcriptome compared to the clinical treatment.
2019-06-21 | GSE118438 | GEO
Project description:IntroductionMaternal asthma in pregnancy is associated with adverse perinatal and child health outcomes; however, mechanisms are poorly understood.MethodsThe PRogramming of Intergenerational Stress Mechanisms (PRISM) prospective pregnancy cohort characterized asthma history during pregnancy via questionnaires and quantified placental DNAm using the Illumina Infinium HumanMethylation450 BeadChip. We performed epigenome-wide association analyses (n = 223) to estimate associations between maternal active or inactive asthma, as compared to never asthma, and placental differentially methylated positions (DMPs) and differentially variable positions (DVPs). Models adjusted for maternal pre-pregnancy body mass index, smoking status, parity, age and education level and child sex. P-values were FDR-adjusted.ResultsOne hundred and fifty-nine (71.3%) pregnant women reported no history of asthma (never asthma), 15 (6.7%) reported inactive, and 49 (22%) reported active antenatal asthma. Women predominantly self-identified as Black/Hispanic Black [88 (39.5%)] and Hispanic/non-Black [42 (18.8%)]. We identified 10 probes at FDR<0.05 and 4 probes at FDR<0.10 characterized by higher variability in maternal active asthma compared to never asthma mapping to GPX3, LHPP, PECAM1, ATAD3C, and ARHGEF4 and 2 probes characterized by lower variation mapping to CHMP4A and C5orf24. Amongst women with inactive asthma, we identified 52 probes, 41 at FDR<0.05 and an additional 11 at FDR <0.10, with higher variability compared to never asthma; BMP4, LHPP, PHYHIPL, and ZSCAN23 were associated with multiple DVPs. No associations were observed with DMPs.DiscussionWe observed alterations in placental DNAm in women with antenatal asthma, as compared to women without a history of asthma. Further research is needed to understand the impact on fetal development.
| S-EPMC9679966 | biostudies-literature
Project description:BackgroundAntenatal corticosteroids are considered the standard of care for pregnant women at risk for preterm birth, but studies examining their potential risks are scarce. We aimed to estimate the associations of antenatal corticosteroids with three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding, in pregnant women.MethodsOf 2,157,321 pregnant women, 52,119 at 24 weeks 0/7 days to 36 weeks 6/7 days of gestation were included in this self-controlled case series study during the study period of 2009-2018. We estimated incidence rates of three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding. Conditional Poisson regression was used to calculate incidence rate ratios (IRRs) for comparing incidence rates of the adverse events in each post-treatment period compared to those during the baseline period among pregnant women exposed to a single course of antenatal corticosteroid treatment.ResultsAmong 52,119 eligible participants who received antenatal corticosteroid treatment, the estimated incidence rates per 1000 person-years were 0.76 (95% confidence interval (CI): 0.69-0.83) for sepsis, 0.31 (95% CI: 0.27-0.36) for heart failure, and 11.57 (95% CI: 11.27-11.87) for gastrointestinal bleeding. The IRRs at 5 ~ 60 days after administration of antenatal corticosteroids were 5.91 (95% CI: 3.10-11.30) for sepsis and 4.45 (95% CI: 2.63-7.55) for heart failure, and 1.26 (95% CI: 1.02-1.55) for gastrointestinal bleeding; and the IRRs for days 61 ~ 180 were 2.00 (95% CI: 1.01-3.96) for sepsis, 3.65 (95% CI: 2.14-6.22) for heart failure, and 1.81 (95% CI: 1.56-2.10) for gastrointestinal bleeding.ConclusionsThis nationwide population-based study suggests that a single course of antenatal corticosteroids is significantly associated with a 1.3- to 5.9-fold increased risk of sepsis, heart failure, and gastrointestinal bleeding in pregnant women. Maternal health considerations, including recommendations for adverse event monitoring, should be included in future guidelines for antenatal corticosteroid treatment.
| S-EPMC10617183 | biostudies-literature
Project description:IntroductionSome types of antenatal maternal psychological distress may be associated with reduced fetal growth and birthweight. A stress-mediated reduction in placental blood flow has been suggested as a mechanism. Previous studies have examined this using ultrasound-derived arterial resistance measures in the uterine (UtA) and umbilical (UA) arteries, with mixed conclusions. However, a reduction in placental volume blood flow may occur before changes in arterial resistance measures are seen. Fetoplacental volume blood flow can be quantified non-invasively in the umbilical vein (UV). Our objective was to study whether specific types of maternal psychological distress affect the placental circulation, using volume blood flow quantification in addition to arterial resistance measures.MethodsThis was a prospective observational study of 104 non-smoking pregnant women (gestational age 30 weeks) with uncomplicated obstetric histories. Psychological distress was measured by General Health Questionnaire-28 (subscales anxiety and depression) and Impact of Event Scale-22 (subscales intrusion, avoidance and arousal). UtA and UA resistance measures and UV volume blood flow normalized for fetal abdominal circumference, were obtained by Doppler ultrasound.ResultsIES intrusion scores above the mean were associated with a reduction in normalized UV volume blood flow (corresponding to -0.61 SD; P?=?0.003). Adjusting for UA resistance increased the strength of this association (difference -0.66 SD; P<0.001). Other distress types were not associated with UV volume blood flow. Maternal distress was not associated with arterial resistance measures, despite adjustment for confounders.ConclusionsIntrusive thoughts and emotional distress regarding the fetus were associated with reduced fetoplacental volume blood flow in third trimester. Uterine and umbilical artery resistance measures were not associated with maternal distress. Our findings support a decrease in fetoplacental blood flow as a possible pathway between maternal distress and reduced fetal growth.
| S-EPMC3577751 | biostudies-literature
Project description:Phenylketonuria (PKU), a rare metabolic disorder, causes cognitive impairment unless treated with a strict, protein-restricted diet, but few studies have examined the relationship between treatment compliance and parental wellbeing. In the present study, 46 primary caregivers of children with PKU completed measures of psychological distress, parenting stress (related to caring for a child with an illness), resilience, perceived social support and child dependency. Treatment adherence was assessed using the proportion of blood phenylalanine concentrations within target range in the preceding year. Results indicated that 59% of caregivers showed clinical levels of psychological distress, which was predicted by their parenting stress and resilience. Whilst the proportion of blood phenylalanine concentrations in range was not associated with parental distress, it was predicted by child age and caregiver's perceived support from family. Despite experiencing high levels of distress, the results indicated that caregivers' ability to adhere to treatment was not affected. Interventions to reduce parenting stress and boost caregiver resilience may have a positive effect on parental wellbeing. Additionally, interventions to promote treatment adherence benefit parents of older children, with a focus on promoting support from family members. Further research with larger sample sizes and longitudinal designs is needed to further establish causal mechanisms.
| S-EPMC5740045 | biostudies-literature
Project description:BackgroundAntenatal corticosteroids (ACS) are highly effective at improving outcomes for preterm newborns. Evidence suggests the benefits of ACS may vary with the time interval between administration-to-birth. However, the optimal ACS administration-to-birth interval is not yet known. In this systematic review, we synthesised available evidence on the relationship between ACS administration-to-birth interval and maternal and newborn outcomes.MethodsThis review was registered with PROSPERO (CRD42021253379). We searched Medline, Embase, CINAHL, Cochrane Library, Global Index Medicus on 11 Nov 2022 with no date or language restrictions. Randomised and non-randomised studies of pregnant women receiving ACS for preterm birth where maternal and newborn outcomes were reported for different administration-to-birth intervals were eligible. Eligibility screening, data extraction and risk of bias assessment were performed by two authors independently. Fetal and neonatal outcomes included perinatal and neonatal mortality, preterm birth-related morbidity outcomes and mean birthweight. Maternal outcomes included chorioamnionitis, maternal mortality, endometritis, and maternal intensive care unit admission.FindingsTen trials (4592 women; 5018 neonates), 45 cohort studies (at least 22,992 women; 30,974 neonates) and two case-control studies (355 women; 360 neonates) met the eligibility criteria. Across studies, 37 different time interval combinations were identified. There was considerable heterogeneity in included administration-to-birth intervals and populations. The odds of neonatal mortality, respiratory distress syndrome and intraventricular haemorrhage were associated with the ACS administration-to-birth interval. However, the interval associated with the greatest improvements in newborn outcomes was not consistent across studies. No reliable data were available for maternal outcomes, though odds of chorioamnionitis might be associated with longer intervals.IntepretationAn optimal ACS administration-to-birth interval likely exists, however variations in study design limit identification of this interval from available evidence. Future research should consider advanced analysis techniques such as individual patient data meta-analysis to identify which ACS administration-to-birth intervals are most beneficial, and how these benefits can be optimised for women and newborns.FundingThis study was conducted with funding support from the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Sexual and Reproductive Health and Research (SRH), a co-sponsored programme executed by the World Health Organization.
| S-EPMC10050784 | biostudies-literature