Background

There is increased risk of cardiovascular, metabolic, and hypertensive disorders in later life in the preterm population. We studied school-age children who had been born extremely premature who had undergone endocrine, cardiovascular, and anthropometric evaluations.

Methods

School age measurements of salivary cortisol, adrenal androgens, blood pressure, and anthropometric markers were correlated with DNA methylation of 11-betahydroxysteroid dehydrogenase type 2 (11BHSD2), leptin, and the LINE1 repetitive DNA element.

Results

We observed a modest correlation between log AUC for salivary cortisol and methylation of leptin in preterm infants and a negative correlation between methylation of region 1 of the glucocorticoid receptor (GR in term-born infants. There was an association between LINE1 methylation and cortisol response to awakening and a negative correlation between LINE1 and systolic blood pressure at 6-7 years. Methylation of the GR promoter region showed a positive association with systolic blood pressure at 6-7 years of age.

Conclusions

These results show that extremely preterm birth, followed by complex patterns of endocrine, cardiovascular, and metabolic exposures during early postnatal life, is associated with lasting changes in DNA methylation patterns in genes involved in hypothalamic pituitary adrenal axis function, adrenal hormonal regulation, and cardiometabolic risk.

Impact

Preterm infants have significant environmental and physiological exposures during early life that may have lasting impact on later function. Alterations in hypothalamic pituitary adrenal axis (HPA) function have been associated with these exposures. We examined the associated changes in DNA methylation of important genes involved in HPA function, metabolism, and global DNA methylation. The changes we saw in DNA methylation may help to explain associated cardiovascular, metabolic, and growth disturbance in these children in later life.

Evaluate the spectrum of neurodevelopmental outcome in a contemporary cohort of extremely preterm infants. We hypothesize that the rate of severe neurodevelopmental impairment (NDI) decreases over time. Retrospective analysis of neurodevelopmental outcome of preterm infants ≤27 weeks' gestational age (GA) from a Neonatal Research Network center that completed neurodevelopmental follow-up assessments between April 1, 2011, and January 1, 2015. The Bayley Scales of Infant Development-III (BSID III) and a standardized neurosensory examination were performed between 18 and 26 months' adjusted age. Outcome measures were neurologic examination diagnoses, BSID III cognitive and motor scores, sensory impairment, and the composite outcome of NDI, based on the BSID III cognitive score (analyzed by using a cutoff of <85 or <70), BSID III motor score of <70, moderate or severe cerebral palsy (CP), bilateral blindness, and hearing impairment. Two thousand one hundred and thirteen infants with a mean GA of 25.0 ± 1.0 weeks and mean birth weight of 760 ± 154 g were evaluated. The 11% lost to follow-up were less likely to have private insurance, late-onset sepsis, or severe intraventricular hemorrhage. Neurologic examination results were normal in 59%, suspect abnormal in 19%, and definitely abnormal in 22%. Severe CP decreased 43% whereas mild CP increased 13% during the study. The rate of moderate to severe NDI decreased from 21% to 16% when using the BSID III cognitive cutoff of <70 (P = .07) or from 34% to 31% when using the BSID III cognitive cutoff of <85 (P = .67). Extremely preterm children are at risk for NDI. Over time, the rate of moderate to severe NDI did not differ, but the rates of severe CP decreased, and mild CP increased.

Background

Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children.

Methods

Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30' later, evening).

Results

For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01).

Conclusion

Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).

Background

Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes.

Methods

We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death.

Results

Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively).

Conclusions

The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633 .).

Objective

To describe discordance in antenatal corticosteroid use and resuscitation following extremely preterm birth and its relationship with infant survival and neurodevelopment.

Study design

A multicenter cohort study of 4858 infants 22-26 weeks of gestation born 2006-2011 at 24 US hospitals participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, with follow-up through 2013. Survival and neurodevelopmental outcomes were available at 18-22 months of corrected age for 4576 (94.2%) infants. We described antenatal interventions, resuscitation, and infant outcomes. We modeled the effect on infant outcomes of each hospital increasing antenatal corticosteroid exposure for resuscitated infants born at 22-24 weeks of gestation to rates observed at 25-26 weeks of gestation.

Results

Discordant antenatal corticosteroid use and resuscitation, where one and not the other occurred, were more frequent for births at 22 and 23 but not 24 weeks (rate ratio [95% CI] at 22 weeks: 1.7 [1.3-2.2]; 23 weeks: 2.6 [2.2-3.2]; 24 weeks: 1.0 [0.8-1.2]) when compared with 25-26 weeks. Among infants resuscitated at 23 weeks, adjusting each hospital's rate of antenatal corticosteroid use to the average at 25-26 weeks (89.2%) was projected to increase infant survival by 7.1% (95% CI 5.4-8.8%) and survival without severe impairment by 6.4% (95% CI 4.7-8.1%). No significant change in outcomes was projected for infants resuscitated at 22 weeks, where few (n = 22) resuscitated infants received antenatal corticosteroids.

Conclusions

Infants born at 23 weeks were more frequently resuscitated without antenatal corticosteroids than other extremely preterm infants. When resuscitation is intended, consistent provision of antenatal corticosteroids may increase infant survival and survival without impairment.

Trial registration

ClinicalTrials.govNCT00063063 (Generic Database) and NCT00009633 (Follow-Up Study).

Objective

The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP).

Summary background data

The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown.

Methods

We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches.

Results

Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%.

Conclusions

There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

Objective

To estimate risk of necrotizing enterocolitis (NEC) for extremely low birth weight (ELBW) infants as a function of preterm formula (PF) and maternal milk intake and calculate the impact of suboptimal feeding on the incidence and costs of NEC.

Study design

We used aORs derived from the Glutamine Trial to perform Monte Carlo simulation of a cohort of ELBW infants under current suboptimal feeding practices, compared with a theoretical cohort in which 90% of infants received at least 98% human milk.

Results

NEC incidence among infants receiving ≥98% human milk was 1.3%; 11.1% among infants fed only PF; and 8.2% among infants fed a mixed diet (P = .002). In adjusted models, compared with infants fed predominantly human milk, we found an increased risk of NEC associated with exclusive PF (aOR = 12.1, 95% CI 1.5, 94.2), or a mixed diet (aOR 8.7, 95% CI 1.2-65.2). In Monte Carlo simulation, current feeding of ELBW infants was associated with 928 excess NEC cases and 121 excess deaths annually, compared with a model in which 90% of infants received ≥98% human milk. These models estimated an annual cost of suboptimal feeding of ELBW infants of $27.1 million (CI $24 million, $30.4 million) in direct medical costs, $563 655 (CI $476 191, $599 069) in indirect nonmedical costs, and $1.5 billion (CI $1.3 billion, $1.6 billion) in cost attributable to premature death.

Conclusions

Among ELBW infants, not being fed predominantly human milk is associated with an increased risk of NEC. Efforts to support milk production by mothers of ELBW infants may prevent infant deaths and reduce costs.