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Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth.

ABSTRACT: OBJECTIVE:To evaluate the association of magnesium sulfate (MgSO4) exposure and candidate gene polymorphisms with adverse neurodevelopmental outcomes following preterm birth. STUDY DESIGN:We performed a nested case-control analysis of a randomized trial of maternal MgSO4 before anticipated preterm birth for the prevention of cerebral palsy (CP). Cases were children who died within 1?year of life or were survivors with abnormal neurodevelopment at age 2 years. Controls were race- and sex-matched survivors with normal neurodevelopment. We analyzed 45 candidate gene polymorphisms in inflammation, coagulation, and vascular regulation pathways and their association with (1) psychomotor delay, (2) mental delay, (3) CP, and (4) combined outcome of death/CP. Logistic regression analyses, conditional on maternal race and child sex, and adjusted for treatment group, gestational age at birth and maternal education, were performed. RESULTS:Four hundred and six subjects, 211 cases and 195 controls, were analyzed. The strongest association was for IL6R (rs 4601580) in which each additional copy of the minor allele was associated with an increased risk of psychomotor delay (adjusted odds ratio 3.3; 95% confidence interval, 1.7-6.5; p?

SUBMITTER: Clark EAS

PROVIDER: S-EPMC6129012 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth.

Clark Erin A S EAS Weiner Steven J SJ Rouse Dwight J DJ Mercer Brian M BM Reddy Uma M UM Iams Jay D JD Wapner Ronald J RJ Sorokin Yoram Y Malone Fergal D FD O'Sullivan Mary J MJ Peaceman Alan M AM Hankins Gary D V GDV Dudley Donald J DJ Caritis Steve N SN

American journal of perinatology 20180306 10

<h4>Objective</h4>To evaluate the association of magnesium sulfate (MgSO<sub>4</sub>) exposure and candidate gene polymorphisms with adverse neurodevelopmental outcomes following preterm birth.<h4>Study design</h4>We performed a nested case-control analysis of a randomized trial of maternal MgSO<sub>4</sub> before anticipated preterm birth for the prevention of cerebral palsy (CP). Cases were children who died within 1 year of life or were survivors with abnormal neurodevelopment at age 2 years. ...[more]

PMID: 29510423

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Project description:ObjectiveTo test the primary hypothesis that extremely preterm children antenatally exposed to both magnesium sulfate and antenatal corticosteroids have a lower rate of severe neurodevelopmental impairment or death compared with those exposed to antenatal corticosteroids alone.MethodsThis was a prospective observational study of children born at 22 0/7-26 6/7 weeks of gestation from 2011 to 2014 at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network hospitals (N=3,093). The primary outcome was severe neurodevelopmental impairment or death at 18-26 months of corrected age follow-up based on exposure to antenatal corticosteroids and magnesium sulfate or antenatal corticosteroids alone. Secondary outcomes included components of severe neurodevelopmental impairment by exposure group and comparisons of severe neurodevelopmental impairment or death between children exposed to both antenatal corticosteroids and magnesium sulfate with those exposed to magnesium sulfate alone or to neither antenatal corticosteroids nor magnesium sulfate. Logistic regression models adjusted for background characteristics.ResultsChildren exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of severe neurodevelopmental impairment or death (813/2,239, 36.3%) compared with those exposed to antenatal corticosteroids alone (225/508, 44.3%; adjusted odds ratio [aOR] 0.73; 95% CI 0.58-0.91), magnesium sulfate alone (47/89, 53%; aOR 0.49; 95% CI 0.29-0.82), or neither therapy (121/251; 48.2%; aOR 0.66, 95% CI 0.49-0.89). Similarly, children exposed to both antenatal corticosteroids and magnesium sulfate had a lower rate of death compared with either or neither therapy, but the rate of severe neurodevelopmental impairment among survivors did not differ between exposure groups.ConclusionIn children born between 22 0/7 and 26 6/7 weeks of gestation, exposure to both antenatal corticosteroids and magnesium sulfate was associated with lower rates of severe neurodevelopmental impairment or death and death compared with exposure to antenatal corticosteroids alone.Clinical trial registrationClinicalTrials.gov, NCT00063063.

Project description:ImportanceSurvival of infants born extremely preterm (EP) (<28 weeks' gestation) has increased since the early 1990s. It is necessary to know whether increased survival is accompanied by increased neurodevelopmental disability.ObjectiveTo examine changes in major (ie, moderate or severe) neurodevelopmental disability and survival free of major neurodevelopmental disability at 2 years in infants born EP.Design, setting, and participantsFour prospective longitudinal cohort studies comprising all EP live births at 22 to 27 weeks' gestation from April 1, 2016, to March 31, 2017, and earlier eras (1991-1992, 1997, and 2005), and contemporaneous term-born controls in the state of Victoria, Australia. Among 1208 live births during the periods studied, data were available for analysis of 2-year outcomes in 1152 children: 422 (1991-1992), 215 (1997), 263 (2005), and 252 (2016-2017). Data analysis was performed from September 17, 2020, to April 15, 2021.ExposuresExtreme preterm live birth.Main outcomes and measuresSurvival, blindness, deafness, cerebral palsy, developmental delay, and neurodevelopmental disability at 2 years' corrected age. Developmental delay comprised a developmental quotient less than -1 SD relative to the control group means on the Bayley Scales for each era. Major neurodevelopmental disability comprised blindness, deafness, moderate to severe cerebral palsy, or a developmental quotient less than -2 SDs. Individual neurodevelopmental outcomes in each era were contrasted relative to the 2016-2017 cohort using logistic regression adjusted for gestational age, sex, birth weight z score, and sociodemographic variables. Changes in survival free of major neurodevelopmental disability over time were also assessed using logistic regression.ResultsSurvival to 2 years was highest in 2016-2017 (73% [215 of 293]) compared with earlier eras (1991-1992: 53% [225 of 428]; 1997: 70% [151 of 217]; 2005: 63% [170 of 270]). Blindness and deafness were uncommon (<3%). Cerebral palsy was less common in 2016-2017 (6%) than in earlier eras (1991-1992: 11%; 1997: 12%; 2005: 10%). There were no obvious changes in the rates of developmental quotient less than -2 SDs across eras (1991-1992: 18%; 1997: 22%; 2005: 7%; 2016-2017: 15%) or in rates of major neurodevelopmental disability (1991-1992: 20%; 1997: 26%; 2005: 15%; 2016-2017: 15%). Rates of survival free of major neurodevelopmental disability increased steadily over time: 42% (1991-1992), 51% (1997), 53% (2005), and 62% (2016-2017) (odds ratio, 1.30; 95% CI, 1.15-1.48 per decade; P < .001).Conclusions and relevanceThese findings suggest that survival free of major disability at age 2 years in children born EP has increased by an absolute 20% since the early 1990s. Increased survival has not been associated with increased neurodevelopmental disability.

Project description:BackgroundPreterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.MethodsProteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.FindingsIL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.InterpretationIL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.FundingNICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.

Dataset Information

Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth.

Publications

Genetic Variation, Magnesium Sulfate Exposure, and Adverse Neurodevelopmental Outcomes Following Preterm Birth.

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