A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials

Objective To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother– neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at !24 weeks’ GA. Results Among 17,912 mother–neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at \u3c31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately

Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network.

OBJECTIVE: This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA). METHODS: Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS: Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at CONCLUSION: Although the majority of infants with GAs of \u3eor=24 weeks survive, high rates of morbidity among survivors continue to be observed

Systemic responses of preterm newborns with presumed or documented bacteraemia

AIM: To compare the frequency of elevated concentrations of inflammation-related proteins in the blood of infants born before the 28th week of gestation who had documented bacteraemia and those who had presumed (antibiotic-treated but culture-negative) bacteraemia to those who had neither. METHODS: The subjects of this study are the 868 infants born at 14 institutions for whom information about protein measurements on at least two of the three protocol days (days 1, 7, and 14) was available and who did not have Bell stage 3 necrotizing enterocolitis or isolated bowel perforation, which were strongly associated with bacteraemia in this sample. RESULTS: Newborns with presumed early (week 1) bacteraemia had elevated concentrations of only a few inflammation-related proteins, while those who had presumed late (weeks 2-4) bacteraemia did not have any elevations. In contrast, newborns who had documented early bacteraemia had a moderately strong signal, while those who had documented late bacteraemia had a stronger signal with more protein concentrations elevated on two separate occasions a week apart. CONCLUSIONS: Culture-confirmed early and late bacteraemia are accompanied/followed by systemic inflammatory responses not seen with presumed early and late bacteraemia

Factors associated with treatment for hypotension in extremely low gestational age newborns during the first postnatal week

OBJECTIVE: The goals were to identify the blood pressures of extremely low gestational age newborns that prompt intervention, to identify other infant characteristics associated with receipt of therapies intended to increase blood pressure, and to assess the interinstitutional variability in the use of these therapies. METHODS: The cohort included 1507 extremely low gestational age newborns born at 23 weeks to 27 weeks of gestation, at 14 institutions, between March 2002 and August 2004; 1387 survived the first postnatal week. Blood pressures were measured as clinically indicated. Interventions were grouped as any treatment (ie, vasopressor and/or fluid boluses of \u3e10 mL/kg) and vasopressor treatment, and logistic regression analyses were performed. RESULTS: At each gestational age, the lowest mean arterial pressures in treated and untreated infants tended to increase with advancing postnatal age. Infants who received any therapy tended to have lower mean arterial pressures than infants who did not, but uniform thresholds for treatment were not apparent. The proportion of infants receiving any treatment decreased with increasing gestational age from 93% at 23 weeks to 73% at 27 weeks. Treatment nearly always began during the first 24 hours of life. Lower gestational age, lower birth weight, male gender, and higher Score for Neonatal Acute Physiology-II values were associated with any treatment and vasopressor treatment. Institutions varied greatly in their tendency to offer any treatment and vasopressor treatment. Neither the lowest mean arterial pressure on the day of treatment nor other characteristics of the infants accounted for center differences in treatment. CONCLUSIONS: Blood pressure in extremely premature infants not treated for hypotension increased directly with both increasing gestational age and postnatal age. The decision to provide treatment was associated more strongly with the center where care was provided than with infant attributes

A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials

Objective  To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design  A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother–neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ≥24 weeks\u27 GA. Results  Among 17,912 mother–neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions  Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately

Psychiatric Symptoms: Prevalence, Co-occurrence, and Functioning Among Extremely Low Gestational Age Newborns at Age 10 Years

OBJECTIVE: To evaluate the percentage of children born extremely preterm (EP) who screen positive for \u3e /=1 DSM-IV psychiatric disorders, the co-occurrence of and sex-related differences in these classifications, and the functional correlates of psychiatric symptoms. METHODS: The Extremely Low Gestational Age Newborn (ELGAN) Study is a prospective cohort follow-up of children born \u3c 28 weeks\u27 gestation. For 871 10-year-old children, parents completed the Child Symptom Inventory-4 (CSI-4), a child educational/medical history questionnaire, and the Pediatric Quality of Life Inventory (PedsQL). RESULTS: At age 10 years, ELGANs were more likely to screen positive for a number of psychiatric disorders when compared with normative expectations on the CSI-4, with a few sex-related differences. Fifteen percent of participants screened positive for 1 disorder, 7% for 2, 3% for 3, and 4% for \u3e /=4 psychiatric disorders. Compared with children who did not screen positive for psychiatric disorders, children who screened positive for \u3e /=3 psychiatric disorders were approximately twice as likely to have repeated a grade, have an individualized educational program, have an individual school aide, and to require special remediation classes. Children who screened positive for any psychiatric disorder were 4 times more likely to use 1 or more psychotropic medication, and those who screened positive for \u3e /=2 psychiatric disorders had lower PedsQL scores. CONCLUSION: Among 10-year-old children born EP, rates of psychiatric symptoms exceeded normative expectation, and children who screened positive for more than 1 psychiatric disorder were at increased risk of having multiple functional impairments

Antenatal antecedents of a small head circumference at age 24-months post-term equivalent in a sample of infants born before the 28th post-menstrual week

BACKGROUND: Little is known about the antecedents of microcephaly in early childhood among children born at extremely low gestational age. AIM: To identify some of the antecedents of microcephaly at age two years among children born before the 28th week of gestation. STUDY DESIGN: Observational cohort study. SUBJECTS: 1004 infants born before the 28th week of gestation. OUTCOME MEASURES: Head circumference Z-scores of \u3c-2 and \u3eor=-2, \u3c-1. RESULTS: Risk of microcephaly and a less severely restricted head circumference decreased monotonically with increasing gestational age. After adjusting for gestational age and other potential confounders, the risk of microcephaly at age 2 years was increased if microcephaly was present at birth [odds ratio: 8.8 ((95% confidence interval: 3.7, 21)], alpha hemolytic Streptococci were recovered from the placenta parenchyma [2.9 (1.2, 6.9)], the child was a boy [2.8 (1.6, 4.9)], and the child\u27s mother was not married [2.5 (1.5, 4.3)]. Antecedents associated not with microcephaly, but with a less extreme reduction in head circumference were recovery of Propionibacterium sp from the placenta parenchyma [2.9 (1.5, 5.5)], tobacco exposure [2.0 (1.4, 3.0)], and increased syncytial knots in the placenta [2.0 (1.2, 3.2)]. CONCLUSIONS: Although microcephaly at birth predicts a small head circumference at 2 years among children born much before term, pregnancy and maternal characteristics provide supplemental information about the risk of a small head circumference years later. Two findings appear to be novel. Tobacco exposure during pregnancy, and organisms recovered from the placenta predict reduced head circumference at age two years

Mediators of fetal inflammation in extremely low gestational age newborns

To establish levels of mediators of inflammation in cord blood and postnatal serum from extremely low gestational age newborns (ELGANs, \u3c or =28 weeks), we measured sixteen markers of inflammation by recycling immunoaffinity chromatography in 15 ELGANs who had serum sampled at days 2-5. Median levels of IL-1, IL-6, IL-8, IL-11, IL-13, TNF-alpha, G-CSF, M-CSF, GM-CSF, MIP-1alpha, and RANTES were considerably higher than published values of these inflammatory mediators from term newborns. In three of eight ELGANS who had serial measurements taken, levels of IL-1, IL-6, IL-8, IL-11, TNF-alpha, G-CSF, and MIP-1alpha declined from initially very high levels to reach an apparent baseline towards the end of the first postnatal week. In these same three infants, GM-CSF and TGF-beta1 levels increased continuously during the first week. In the other five ELGANs, no consistent changes were observed. We speculate, that in some ELGANs, a fetal systemic inflammatory response is characterized by an antenatal wave of pro-inflammatory cytokines, followed by a second, postnatal wave of anti-inflammatory cytokines. Large epidemiologic studies are needed to clarify relationships among inflammation markers and their expression in the fetal and neonatal circulation over time. Such studies would also add to our understanding of the possible role of inflammatory mediators in the pathophysiology of the major complications of extreme prematurity

Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age

INTRODUCTION: Few studies have examined the relationship between birth plurality and neurocognitive function among children born extremely preterm. STUDY DESIGN: We compared rates of Z-scores \u3c /=-2 on 18 tests of neurocognitive function and academic achievement at age 10 years in 245 children arising from twin pregnancies, 55 from triplet pregnancies, and 6 from a septuplet pregnancy to that of 568 singletons, all of whom were born before the 28th week of gestation. RESULTS: In total, 874 children were evaluated at the age of 10 years. After adjusting for confounders, children of multifetal pregnancies performed significantly better on one of six subtests of executive function than their singleton peers. Performance was similar on all other assessments of intelligence, language, academic achievement, processing speed, visual perception, and fine motor skills. CONCLUSION: We found no evidence that children born of multifetal pregnancies had worse scores than their singleton peers on assessments of neurocognitive and academic function