Erin A.S. Clark

Antenatal Betamethasone for Women at Risk for Late Preterm Delivery

BACKGROUND Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. METHODS We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. RESULTS The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001). CONCLUSIONS Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications. (Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.).

Maternal Prenatal Weight Gain and Autism Spectrum Disorders

BACKGROUND: The rising population of individuals identified with an autism spectrum disorder (ASD) calls for further investigation of its underlying etiology. A disturbance in the fetal steroid hormone environment may be a mechanism in which environmental and genetic risk factors interact. The mother, fetus, and placenta collectively create the fetal steroid environment. Prepregnancy BMI and pregnancy weight gain have served as markers for fetal steroid hormone exposure in other disease states. This study’s objective is to determine whether prepregnancy BMI and pregnancy weight gain are associated with increased ASD risk across study designs and cohorts while controlling for important confounding variables. METHODS: A population-based Utah ASD cohort (n = 128) was ascertained in a 3-county surveillance area and gender- and age-matched to 10 920 control subjects. A second, research-based ASD cohort of Utah children (n = 288) and their unaffected siblings (n = 493) were ascertained through participation in an ASD genetics study. Prenatal variables were obtained from birth certificate records. RESULTS: ASD risk was significantly associated with pregnancy weight gain (adjusted odds ratio = 1.10, 95% confidence interval: 1.03 to 1.17; adjusted odds ratio = 1.17, 95% confidence interval: 1.01 to 1.35 for each 5 pounds of weight gained), but not prepregnancy BMI, in population and research-based cohorts, respectively. When analyses were restricted to ASD cases with normal IQ, these associations remained significant. CONCLUSIONS: ASD risk associated with a modest yet consistent increase in pregnancy weight gain suggests that pregnancy weight gain may serve as an important marker for autism’s underlying gestational etiology. This justifies an investigation into phenomena that link pregnancy weight gain and ASD independent of prepregnancy BMI.

The association of innate immune response gene polymorphisms and puerperal group A streptococcal sepsis

OBJECTIVE The objective of the study was to determine whether single-nucleotide polymorphisms (SNPs) that influence the maternal innate immune response are associated with puerperal group A streptococcal sepsis. STUDY DESIGN Subjects with confirmed puerperal group A streptococal infection were prospectively identified in 2 tertiary care hospitals over 18 years. Controls were racially matched subjects with term, uncomplicated deliveries. Thirty-eight polymorphisms associated with the innate immune response to bacterial infection were analyzed. Allele and genotype frequencies for subjects and controls were compared. RESULTS Forty-eight women with puerperal group A streptococcal infection were identified. DNA was obtained for 28 subjects and 54 controls. Allele frequencies were significantly different between subjects and controls for polymorphisms in Toll-like receptor (TLR) 9-1486 (P = .03) and heat shock protein (HSP) 70-2 1267 (P = .003). Genotype frequencies were significantly different between subjects and controls for TLR9-1486 (P = .025), HSP70-2 1267 (P = .02), and interleukin (IL)-1beta-511 (P = .016). CONCLUSION Puerperal group A streptococcal sepsis may be associated with innate immune response gene polymorphisms in TLR9, HSP70-2, and IL1beta.

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery

BACKGROUND The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section. METHODS In this trial conducted at 14 centers in the United States, we studied 2013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture. We randomly assigned 1019 to receive 500 mg of intravenous azithromycin and 994 to receive placebo. All the women were also scheduled to receive standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks. RESULTS The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval [CI], 0.38 to 0.68; P<0.001). There were significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P=0.02), wound infection (2.4% vs. 6.6%, P<0.001), and serious maternal adverse events (1.5% vs. 2.9%, P=0.03). There was no significant between-group difference in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, P=0.63). CONCLUSIONS Among women undergoing nonelective cesarean delivery who were all receiving standard antibiotic prophylaxis, extended-spectrum prophylaxis with adjunctive azithromycin was more effective than placebo in reducing the risk of postoperative infection. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; C/SOAP ClinicalTrials.gov number, NCT01235546 .).

Effect of umbilical cord milking on morbidity and survival in extremely low gestational age neonates

OBJECTIVE Delayed umbilical cord clamping benefits extremely low gestational age neonates (ELGANs) but has not gained wide acceptance. We hypothesized that milking the umbilical cord (MUC) would avoid resuscitation delay but improve hemodynamic stability and reduce rates for composite outcome of severe intraventricular hemorrhage, necrotizing enterocolitis, and/or death before discharge. STUDY DESIGN We implemented a joint neonatal/maternal-fetal quality improvement process for MUC starting September 2011. The MUC protocol specified that infants who were born at <30 weeks of gestation undergo MUC 3 times over a duration of <30 seconds at delivery. Obstetric and neonatal data were collected until discharge. We compared the MUC group to retrospective ELGAN cohort delivered at our center between January 2010 and August 2011. Analysis was intention-to-treat. RESULTS We identified 318 ELGANs: 158 eligible for MUC and 160 retrospective control neonates. No adverse events were reported with cord milking. There was no difference in neonatal resuscitation, Apgar scores, or admission temperature. Hemodynamic stability was improved in the MUC group with higher mean blood pressures through 24 hours of age, despite less vasopressor use (18% vs 32%; P < .01). The initial hematocrit value was higher (50% vs 45%; P < .01), and red cell transfusions were fewer (57% vs 79%; P < .01) in MUC vs control infants. Presence of the composite outcome was significantly less in MUC vs the historic control infants (22% v 39%; odds ratio, 1.81; 95% confidence interval, 1.06-3.10). There were also reductions in intraventricular hemorrhage, necrotizing enterocolitis, and death before hospital discharge. CONCLUSION MUC improves early hemodynamic stability and is associated with lower rates of serious morbidity and death among ELGANs.

Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis

BackgroundBecause of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB.ResultsWe reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies.For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 – 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity.ConclusionsIL6 SNP rs1800795 genotype CC is protective against PTB in women of European descent. It is not significant in other heterogeneous or admixed populations, or in fetal genotype analysis.Population structure is an important confounding factor that should be controlled for in studies of PTB.

Impact of preterm PROM and its complications on long-term infant outcomes

There is increasing evidence that preterm premature rupture of membranes (PPROM) is associated with increased risk for adverse neurodevelopmental outcomes through multiple mechanisms, including preterm birth and its antecedent etiologies. Intrauterine infection is a particularly important risk factor for adverse neurodevelopmental outcomes after PPROM. This review focuses on the long-term neurodevelopmental outcomes after PPROM, the possible etiologic mechanisms of neurological injury, and the effect of antenatal and perinatal interventions using available evidence.

Genetic Variants Associated With Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants

PURPOSE To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants. METHODS Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis. RESULTS Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 × 10(-5)) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P = 2.9 × 10(-7)). CONCLUSIONS Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.

Pregnancy‐induced changes in the pharmacokinetics of caffeine and its metabolites

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30‐95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC‐MS/MS. There was a significant increase in dose‐normalized caffeine serum and urine concentrations between the first and third trimesters (P < .05 and P < .01, respectively). Normalized theophylline concentrations also increased significantly in the third trimester in serum (P < .001) and in urine (P < .05). The caffeine urine/serum concentration ratio also increased in the last trimester (P < .05). No significant difference was found in normalized paraxanthine or theobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism.

Magnesium sulfate, chorioamnionitis, and neurodevelopment after preterm birth.

To assess the neuroprotective effect of magnesium sulfate (MgSO4) in preterm children exposed to chorioamnionitis.