Short Term Coping-Behaviors and Postpartum Health in a Population-Based Study of Women with a Live Birth, Stillbirth, or Neonatal Death.

OBJECTIVE: Responding to the National Institutes of Health Working Group's call for research on the psychological impact of stillbirth, we compared coping-related behaviors by outcome of an index birth (surviving live birth or perinatal loss - stillbirth or neonatal death) and, among individuals with loss, characterized coping strategies and their association with depressive symptoms 6-36 months postpartum. METHODS: We used data from the Stillbirth Collaborative Research Network follow-up study (2006-2008) of 285 individuals who experienced a stillbirth, 691 a livebirth, and 49 a neonatal death. We conducted a thematic analysis of coping strategies individuals recommended following their loss. We fit logistic regression models, accounting for sampling and inverse probability of follow-up weights to estimate associations between pregnancy outcomes and coping-related behaviors and, separately, coping strategies and probable depression (Edinburgh Postnatal Depression Scale > 12) for those with loss. RESULTS: Compared to those with a surviving live birth and adjusting for pre-pregnancy drinking and smoking, history of stillbirth, and age, individuals who experienced a loss were more likely to report increased drinking or smoking in the two months postpartum (adjusted OR: 2.7, 95% CI = 1.4-5.4). Those who smoked or drank more had greater odds of probable depression at 6 to 36 months postpartum (adjusted OR 6.4, 95% CI = 2.5-16.4). Among those with loss, recommended coping strategies commonly included communication, support groups, memorializing the loss, and spirituality. DISCUSSION: Access to a variety of evidence-based and culturally-appropriate positive coping strategies may help individuals experiencing perinatal loss avoid adverse health consequences.

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants.

OBJECTIVE: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. STUDY DESIGN: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. RESULTS: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). CONCLUSION: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01029353.

Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018.

IMPORTANCE: Despite improvement during recent decades, extremely preterm infants continue to contribute disproportionately to neonatal mortality and childhood morbidity. OBJECTIVE: To review survival, in-hospital morbidities, care practices, and neurodevelopmental and functional outcomes at 22-26 months' corrected age for extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: Prospective registry for extremely preterm infants born at 19 US academic centers that are part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. The study included 10 877 infants born at 22-28 weeks' gestational age between January 1, 2013, and December 31, 2018, including 2566 infants born before 27 weeks between January 1, 2013, and December 31, 2016, who completed follow-up assessments at 22-26 months' corrected age. The last assessment was completed on August 13, 2019. Outcomes were compared with a similar cohort of infants born in 2008-2012 adjusting for gestational age. EXPOSURES: Extremely preterm birth. MAIN OUTCOMES AND MEASURES: Survival and 12 in-hospital morbidities were assessed, including necrotizing enterocolitis, infection, intracranial hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia. Infants were assessed at 22-26 months' corrected age for 12 health and functional outcomes, including neurodevelopment, cerebral palsy, vision, hearing, rehospitalizations, and need for assistive devices. RESULTS: The 10 877 infants were 49.0% female and 51.0% male; 78.3% (8495/10848) survived to discharge, an increase from 76.0% in 2008-2012 (adjusted difference, 2.0%; 95% CI, 1.0%-2.9%). Survival to discharge was 10.9% (60/549) for live-born infants at 22 weeks and 94.0% (2267/2412) at 28 weeks. Survival among actively treated infants was 30.0% (60/200) at 22 weeks and 55.8% (535/958) at 23 weeks. All in-hospital morbidities were more likely among infants born at earlier gestational ages. Overall, 8.9% (890/9956) of infants had necrotizing enterocolitis, 2.4% (238/9957) had early-onset infection, 19.9% (1911/9610) had late-onset infection, 14.3% (1386/9705) had severe intracranial hemorrhage, 12.8% (1099/8585) had severe retinopathy of prematurity, and 8.0% (666/8305) had severe bronchopulmonary dysplasia. Among 2930 surviving infants with gestational ages of 22-26 weeks eligible for follow-up, 2566 (87.6%) were examined. By 2-year follow-up, 8.4% (214/2555) of children had moderate to severe cerebral palsy, 1.5% (38/2555) had bilateral blindness, 2.5% (64/2527) required hearing aids or cochlear implants, 49.9% (1277/2561) had been rehospitalized, and 15.4% (393/2560) required mobility aids or other supportive devices. Among 2458 fully evaluated infants, 48.7% (1198/2458) had no or mild neurodevelopmental impairment at follow-up, 29.3% (709/2419) had moderate neurodevelopmental impairment, and 21.2% (512/2419) had severe neurodevelopmental impairment. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants born in 2013-2018 and treated at 19 US academic medical centers, 78.3% survived to discharge, a significantly higher rate than for infants born in 2008-2012. Among infants born at less than 27 weeks' gestational age, rehospitalization and neurodevelopmental impairment were common at 2 years of age.

Preeclampsia at delivery is associated with lower serum vitamin D and higher antiangiogenic factors: a case control study.

BACKGROUND: Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. METHODS: This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases (N = 56). Women without a finding of preeclampsia were controls (N = 341). RESULTS: Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower (P = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies (P < 0.001). CONCLUSIONS: Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

Surgery-Associated Infections among Infants Born Extremely Preterm.

OBJECTIVE: To assess the burden of invasive infection following surgery (surgery-associated infections [SAI]) among infants born extremely premature. STUDY DESIGN: This was an observational, prospective study of infants born at gestational age 22-28 weeks hospitalized for >3 days, between April 1, 2011, to March 31, 2015, in academic centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. SAI was defined by culture-confirmed bacteremia, fungemia, or meningitis ≤14 days following a surgical procedure. RESULTS: Of 6573 infants, 1154 (18%) who underwent surgery were of lower gestational age (mean [SD]: 25.5 [1.6] vs 26.2 [1.6], P < .001), lower birth weight (803 [220] vs 886 [244], P < .001), and more likely to have a major birth defect (10% vs 3%, P < .001); 64% had 1 surgery (range 1-10 per infant). Most underwent gastrointestinal procedures (873, 76%) followed by central nervous system procedures (150, 13%). Eighty-five (7%) infants had 90 SAIs (78 bacteremia, 5 fungemia, 1 bacteremia and meningitis, 6 meningitis alone). Coagulase-negative staphylococci were isolated in 36 (40%) SAI and were isolated with another organism in 5 episodes. Risk of SAI or death ≤14 days after surgery was greater after gastrointestinal compared with central nervous system procedures (16% vs 7%, adjusted relative risk [95% CI]: 1.95 [1.15-3.29], P = .01). Death ≤14 days after surgery occurred in 141 of the 1154 infants; 128 deaths occurred after gastrointestinal surgeries. CONCLUSIONS: Surgical procedures were associated with bacteremia, fungemia, or meningitis in 7% of infants. The epidemiology of invasive postoperative infections as described in this report may inform the selection of empiric antimicrobial therapy and postoperative preventive care.

Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial.

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.

Outcomes Following Post-Hemorrhagic Ventricular Dilatation among Infants of Extremely Low Gestational Age.

OBJECTIVE: To assess outcomes following post-hemorrhagic ventricular dilatation (PHVD) among infants born at ≤26 weeks of gestation. STUDY DESIGN: Observational study of infants born April 1, 2011, to December 31, 2015, in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and categorized into 3 groups: PHVD, intracranial hemorrhage without ventricular dilatation, or normal head ultrasound. PHVD was treated per center practice. Neurodevelopmental impairment at 18-26 months was defined by cerebral palsy, Bayley Scales of Infant and Toddler Development, 3rd edition, cognitive or motor score <70, blindness, or deafness. Multivariable logistic regression examined the association of death or impairment, adjusting for neonatal course, center, maternal education, and parenchymal hemorrhage. RESULTS: Of 4216 infants, 815 had PHVD, 769 had hemorrhage without ventricular dilatation, and 2632 had normal head ultrasounds. Progressive dilatation occurred among 119 of 815 infants; the initial intervention in 66 infants was reservoir placement and 53 had ventriculoperitoneal shunt placement. Death or impairment occurred among 68%, 39%, and 28% of infants with PHVD, hemorrhage without dilatation, and normal head ultrasound, respectively; aOR (95% CI) were 4.6 (3.8-5.7) PHVD vs normal head ultrasound scan and 2.98 (2.3-3.8) for PHVD vs hemorrhage without dilatation. Death or impairment was more frequent with intervention for progressive dilatation vs no intervention (80% vs 65%; aOR 2.2 [1.38-3.8]). Death or impairment increased with parenchymal hemorrhage, intervention for PHVD, male sex, and surgery for retinopathy; odds decreased with each additional gestational week. CONCLUSIONS: PHVD was associated with high rates of death or impairment among infants with gestational ages ≤26 weeks; risk was further increased among those with progressive ventricular dilation requiring intervention.

Behavior Profiles at 2 Years for Children Born Extremely Preterm with Bronchopulmonary Dysplasia.

OBJECTIVE: To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior. RESULTS: Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P < .001) and pervasive developmental problems (P < .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values < .05). CONCLUSIONS: BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

Interpregnancy interval and risk of stillbirth: a population-based case control study.

PURPOSE: We examined the association between interpregnancy intervals (IPIs) and stillbirth (defined as fetal death ≥20 weeks), as both short and long IPIs have been associated with adverse perinatal outcomes. Prior pregnancy loss is also a known risk factor for stillbirth, and women who suffer a prior loss often have shorter IPIs. For these reasons, we also sought to quantify the proportion of the association between prior pregnancy loss and subsequent stillbirth risk that may be attributed to a short IPI. METHODS: We used data from the Stillbirth Collaborative Research Network, a multisite case-control study conducted in 2006-2008, restricted to singleton pregnancies among multiparous or multigravid women (985 controls and 291 cases). We accounted for complex sample design and nonparticipation with weighted multivariable logistic regression. RESULTS: In the adjusted models, IPIs <6 months, as compared with a reference of 18-23 months, were associated with increased odds of stillbirth (aOR 1.6, 95% CI: 0.8, 3.4). Long IPIs (60-100 months) were also associated with an increased odds of stillbirth (aOR 2.4, 95% CI: 1.2, 4.5). After control for covariates, about one-fifth (21.2%) of the association of prior pregnancy loss (stillbirth, ectopic pregnancy, molar pregnancy, or spontaneous abortion) and stillbirth may be attributable to a short IPI. CONCLUSIONS: Our results suggest that women who experience a prior pregnancy loss may benefit from additional counseling on adequate birth spacing to reduce subsequent stillbirth risk.

Outcome of Preterm Infants with Transient Cystic Periventricular Leukomalacia on Serial Cranial Imaging Up to Term Equivalent Age.

OBJECTIVE: To determine the outcome of preterm infants whose cystic periventricular leukomalacia "disappeared" on serial screening cranial imaging studies. STUDY DESIGN: Infants ≤26 weeks of gestation born between 2002 and 2012 who had cranial imaging studies at least twice, the most abnormal study at <28 days of age and another closest to 36 weeks, were reviewed. The outcome of late death (after 36 weeks postmenstrual age) or neurodevelopmental impairment (NDI) in surviving infants at 18-26 months corrected age was compared between the infants with no cystic periventricular leukomalacia on both studies and cystic periventricular leukomalacia that disappeared (cystic periventricular leukomalacia at <28 days but not at 36 weeks), persisted (cystic periventricular leukomalacia on both studies), or appeared late (cystic periventricular leukomalacia only at 36 weeks). Predictors of NDI were evaluated by logistic regression. RESULTS: Of 7063 eligible infants, 433 (6.1%) had cystic periventricular leukomalacia. Among the 433 infants with cystic periventricular leukomalacia, cystic periventricular leukomalacia disappeared in 76 (18%), persisted in 87 (20%), and 270 (62%) had late cystic periventricular leukomalacia. Loss to follow-up ranged between 3% and 13%. Death or NDI was more common in infants with disappeared cystic periventricular leukomalacia compared with those with no cystic periventricular leukomalacia (38 of 72 [53%] vs 1776 of 6376 [28%]; OR [95% CI] 2.8 [1.8-4.6]). Disappeared, persistent, and late cystic periventricular leukomalacia were all also independently associated with NDI (OR 1.17, 1.21, and 1.16, respectively). CONCLUSIONS: Infants with "disappeared" cystic periventricular leukomalacia are at increased risk of adverse outcome similar to infants with persistent or late cystic periventricular leukomalacia.

Antecedents and Outcomes of Abnormal Cranial Imaging in Moderately Preterm Infants.

OBJECTIVES: To describe the frequency and findings of cranial imaging in moderately preterm infants (born at 290/7-336/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics. STUDY DESIGN: We used data from the Neonatal Research Network Moderately Preterm Registry, including the most severe early (≤28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age, antenatal steroid use, and center. RESULTS: Among 7021 infants, 4184 (60%) underwent cranial imaging. These infants had lower gestational ages and birth weights and higher rates of small for gestational age, outborn birth, cesarean delivery, neonatal resuscitation, and treatment with surfactant, compared with those without imaging (P < .0001). Imaging abnormalities noted in 15% of the infants included any intracranial hemorrhage (13.2%), grades 3-4 intracranial hemorrhage (1.7%), cystic periventricular leukomalacia (2.6%), and ventriculomegaly (6.6%). Histologic chorioamnionitis (OR, 1.47; 95% CI, 1.19-1.83), gestational age (0.95; 95% CI, 0.94-0.97), antenatal steroids (OR, 0.55; 95% CI, 0.41-0.74), and cesarean delivery (OR, 0.66; 95% CI, 0.53-0.81) were associated with abnormal imaging. The center with the highest rate of cranial imaging, compared with the lowest, had a higher risk of abnormal imaging (OR, 2.08; 95% CI, 1.10-3.92). On the classification and regression-tree model, cesarean delivery, center, antenatal steroids, and chorioamnionitis, in that order, predicted abnormal imaging. CONCLUSION: Among the 60% of moderately preterm infants with cranial imaging, 15% had intracranial hemorrhage, cystic periventricular leukomalacia or late ventriculomegaly. Further correlation of imaging and long-term neurodevelopmental outcomes in moderately preterm infants is needed.

Neurodevelopmental and Behavioral Outcomes in Extremely Premature Neonates With Ventriculomegaly in the Absence of Periventricular-Intraventricular Hemorrhage.

Importance: Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective: To characterize the outcomes of extremely preterm neonates younger than 27 weeks' gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks' postmenstrual age. Design, Setting, and Participants: This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks' gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks' postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures: The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results: Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance: Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease. OBJECTIVE: We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks' postmenstrual age. STUDY DESIGN: Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks' gestational age with a birthweight of ≥401 g born from Jan. 1, 2006, through Dec. 31, 2014, were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks' postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch. RESULTS: Infants exposed to any antenatal corticosteroids had a lower rate of death (2193/9670 [22.7%]) compared to infants without exposure (540/1302 [41.5%]) (adjusted relative risk, 0.71; 95% confidence interval, 0.65-0.76; P < .0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death (654/2520 [26.0%]) compared to infants without exposure (540/1302 [41.5%]); (adjusted relative risk, 0.77; 95% confidence interval, 0.70-0.85; P < .0001). In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23-27 weeks' gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks' gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure. CONCLUSION: Among infants 22-28 weeks' gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ.

Efficacy of pharmacologic closure of patent ductus arteriosus in small-for-gestational-age extremely preterm infants.

BACKGROUND: Optimal management of the patent ductus arteriosus (PDA) in preterm infants remains controversial. Therefore, studies identifying infants who are most likely to benefit from PDA treatment are needed. AIM: We sought to examine if significant intrauterine growth restriction, defined by birth weight z-score, reduces the efficacy of PDA closure with indomethacin or ibuprofen and thereby increases the need for surgical closure of PDA after pharmacologic treatment. STUDY DESIGN, SUBJECTS, AND OUTCOME MEASURES: We studied infants 23-28weeks' gestation born 2006-2013 at NICHD Neonatal Research Network centers. We examined the responses to PDA treatment with indomethacin and/or ibuprofen and whether the PDA was subsequently closed surgically. Logistic regression generated adjusted odds ratios (ORs) for the associations between the z-score groups (<-2, -2 to -0.5, and >-0.5) and PDA surgery following pharmacologic treatment. RESULTS: 5606 infants were diagnosed with PDA; 3587 (64.0%) received indomethacin or ibuprofen or both, and 909 (25.3%) underwent PDA surgery. Mothers of infants with PDA non-closure were less likely to have hypertension (19% vs. 28%). Infants with non-closure were more likely to be female (53% vs. 49%), have lower gestational age and birth weight and to develop sepsis (42% vs. 31%). Compared to infants with z-score>-0.5, PDA surgery was increased among infants with z-score -2 to -0.5 (OR=1.23; 95% CI 1.02-1.47) but not among infants with z-score<-2. CONCLUSION: Infants with birth weight z-score -2 to -0.5 are more likely than normally grown infants to require PDA surgery following pharmacologic treatment.

Neonatal sepsis.

Neonatal sepsis is the cause of substantial morbidity and mortality. Precise estimates of neonatal sepsis burden vary by setting. Differing estimates of disease burden have been reported from high-income countries compared with reports from low-income and middle-income countries. The clinical manifestations range from subclinical infection to severe manifestations of focal or systemic disease. The source of the pathogen might be attributed to an in-utero infection, acquisition from maternal flora, or postnatal acquisition from the hospital or community. The timing of exposure, inoculum size, immune status of the infant, and virulence of the causative agent influence the clinical expression of neonatal sepsis. Immunological immaturity of the neonate might result in an impaired response to infectious agents. This is especially evident in premature infants whose prolonged stays in hospital and need for invasive procedures place them at increased risk for hospital-acquired infections. Clinically, there is often little difference between sepsis that is caused by an identified pathogen and sepsis that is caused by an unknown pathogen. Culture-independent diagnostics, the use of sepsis prediction scores, judicious antimicrobial use, and the development of preventive measures including maternal vaccines are ongoing efforts designed to reduce the burden of neonatal sepsis.

Neonatal outcomes of moderately preterm infants compared to extremely preterm infants.

BackgroundExtremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the United States; yet these infants are the focus of most published research. Moderately preterm neonates (MPT, 29-336/7 weeks) are an understudied group of high-risk infants.MethodsTo determine the neonatal outcomes of MPT infants across the gestational age spectrum, and to compare these with EPT infants. A prospective observational cohort was formed in 18 level 3-4 neonatal intensive care units (NICUs) in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT infants admitted to NICUs and all EPT infants born at sites between January 2012 and November 2013. Antenatal characteristics and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses.ResultsMPT infants experienced morbidities similar to, although at lower rates than, those of EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. Central Nervous System injury occurred, including intraventricular hemorrhage. Most MPT infants required respiratory support, but sequelae such as bronchopulmonary dysplasia were rare. The primary contributors to hospitalization beyond 36 weeks' gestation were inability to achieve adequate oral intake and persistent apnea.ConclusionsMPT infants experience morbidity and prolonged hospitalization. Such morbidity deserves focused research to improve therapeutic and prevention strategies.

Association between Use of Prophylactic Indomethacin and the Risk for Bronchopulmonary Dysplasia in Extremely Preterm Infants.

OBJECTIVE: To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. STUDY DESIGN: Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401-1000 g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Prespecified subgroup analyses were performed. RESULTS: Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus after the first day of life was less common among 2587 infants who received prophylactic indomethacin compared with 5244 who did not (21.0% vs 36.1%, P < .001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72-1.10), death (OR 0.80, 95% CI 0.64-1.01), or death or BPD (OR 0.87, 95% CI 0.71-1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a patent ductus arteriosus after the first day of life. CONCLUSIONS: Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Association of Neurodevelopmental Outcomes and Neonatal Morbidities of Extremely Premature Infants With Differential Exposure to Antenatal Steroids.

Importance: Many premature infants are born without exposure to antenatal steroids (ANS) or with incomplete courses. This study evaluates the dose-dependent effect of ANS on rates of neonatal morbidities and early childhood neurodevelopmental outcomes of extremely premature infants. Objective: To compare rates of neonatal morbidities and 18- to 22-month neurodevelopmental outcomes of extremely premature infants exposed to no ANS or partial or complete courses of ANS. Design, Setting, and Participants: In this observational cohort study, participants were extremely premature infants (birth weight range, 401-1000 g; gestational age, 22-27 weeks) who were born at participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 2006 and December 2011. Data were analyzed between October 2013 and May 2016. Main Outcomes and Measures: Rates of death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined as the presence of any of the following: moderate to severe cerebral palsy, a cognitive score less than 85 on the Bayley Scales of Infant and Toddler Development III, blindness, or deafness. Results: There were 848 infants in the no ANS group, 1581 in the partial ANS group, and 3692 in the complete ANS group; the mean (SD) birth weights were 725 (169), 760 (173), and 753 (170) g, respectively, and the mean (SD) gestational ages were 24.5 (1.4), 24.9 (2), and 25.1 (1.1) weeks. Of 6121 eligible infants, 4284 (70.0%) survived to 18- to 22-month follow-up, and data were available for 3892 of 4284 infants (90.8%). Among the no, partial, and complete ANS groups, there were significant differences in the rates of mortality (43.1%, 29.6%, and 25.2%, respectively), severe intracranial hemorrhage among survivors (23.3%, 19.1%, and 11.7%), death or necrotizing enterocolitis (48.1%, 37.1%, and 32.5%), and death or bronchopulmonary dysplasia (74.9%, 68.9%, and 65.5%). Additionally, death or neurodevelopmental impairment occurred in 68.1%, 54.4%, and 48.1% of patients in the no, partial, and complete ANS groups, respectively. Logistic regression analysis revealed that complete (odds ratio, 0.63; 95% CI, 0.53-0.76) and partial (odds ratio, 0.77; 95% CI, 0.63-0.95) ANS courses were associated with lower rates of death or neurodevelopmental impairment compared with the no ANS group. The reduction in the rate of death or neurodevelopmental impairment associated with exposure to a complete ANS course may be mediated through a reduction in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia in the neonatal period. Conclusions and Relevance: Antenatal steroid exposure was associated with a dose-dependent protective effect against death or neurodevelopmental impairment in extremely preterm infants. The effect was partly mediated by ANS-associated reductions in rates of severe intracranial hemorrhage and/or cystic periventricular leukomalacia. These results support prompt administration of ANS, with the goal of a complete course prior to delivery.

Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants.

OBJECTIVE: To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. STUDY DESIGN: We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. RESULTS: The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. CONCLUSIONS: Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.

IMPORTANCE: Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality. OBJECTIVE: To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers. DESIGN, SETTING, PARTICIPANTS: Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012. EXPOSURES: Extremely preterm birth. MAIN OUTCOMES AND MEASURES: Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex. RESULTS: Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063063.