To assess the association between systemic levels of inflammation-associated proteins and severe retinopathy of prematurity (ROP) in extremely preterm infants.
We collected whole blood on filter ...paper on postnatal days 1, 7, 14, 21, and 28 from 1205 infants born before the 28th week of gestation, and measured the concentrations of 27 inflammation-associated, angiogenic, and neurotrophic proteins. We calculated odds ratios with 95% confidence intervals for the association between top quartile concentrations of each protein and prethreshold ROP.
During the first three weeks after birth, high concentrations of VEGF-R1, myeloperoxidase (MPO), IL-8, intercellular adhesion molecule (ICAM)-1, matrix metalloproteinase 9, erythropoietin, TNF-α, and basic fibroblast growth factor were associated with an increased risk for prethreshold ROP. On day 28, high levels of serum amyloid A, MPO, IL-6, TNF-α, TNF-R1/-R2, IL-8, and ICAM-1 were associated with an increased risk. Top quartile concentrations of the proinflammatory cytokines TNF-α and IL-6 were associated with increased risks of ROP when levels of neuroprotective proteins and growth factors, including BDNF, insulin-like growth factor 1, IGFBP-1, VEGFR-1 and -2, ANG-1 and PlGF, were not in the top quartile. In contrast, high concentrations of NT-4 and BDNF appeared protective only in infants without elevated inflammatory mediators.
Systemic inflammation during the first postnatal month was associated with an increased risk of prethreshold ROP. Elevated concentrations of growth factors, angiogenic proteins, and neurotrophins appeared to modulate this risk, and were capable of reducing the risk even in the absence of systemic inflammation.
Improvement in survival of extremely premature infants over the past several decades has resulted in an increase in the number of infants with chronic lung disease (CLD). Historical neonatal ...exposures associated with CLD now less frequently precede the disease. There is now increasing interest in exposures and events before delivery that predict CLD. The objective of this study was to identify current prenatal predictors of CLD.
We collected data about prenatal, placental, and neonatal characteristics of 1241 newborns who were delivered before completion of the 28th week of gestation. Associations between prenatal factors, microbiologic and histologic characteristics of the placenta, and selected neonatal characteristics and CLD risk were first evaluated in univariate analyses. Subsequent multivariate analyses investigated the contribution of prenatal factors, particularly fetal growth restriction (FGR), to CLD risk.
Among the prenatal factors, birth weight z scores, used as a marker of FGR, provided the most information about CLD risk. Indicators of placental inflammation and infection were not associated with increased risk of CLD. Within nearly all strata of prenatal, placental, and neonatal variables, growth-restricted infants were at increased CLD risk, compared with infants who were not growth-restricted. FGR was the only maternal or prenatal characteristic that was highly predictive of CLD after adjustment for other risk factors.
FGR is independently associated with the risk of CLD. Thus, factors that control fetal somatic growth may have a significant impact on vulnerability to lung injury and in this way increase CLD risk.
Pulmonary disease among infants of <28 weeks' gestation (extremely low gestational age newborns) often has the following pattern: the infant starts out with little need for supplemental oxygen and ...ventilatory support in the first postnatal week but then has pulmonary deterioration in the second postnatal week, with an increased need for supplemental oxygen and respiratory support. We evaluated the antecedents and correlates of patterns of early lung disease, with particular emphasis on pulmonary deterioration, in a large cohort study (the Extremely Low Gestational Age Newborn ELGAN study).
We examined data collected prospectively on 1340 infants born between 2002 and 2004 at 23 to 27 completed weeks of gestation and who survived to 14 days. Pulmonary deterioration was defined as receipt of fraction of inspired oxygen < 0.23 on any day between days 3 and 7 and receipt of fraction of inspired oxygen > or = 0.25 on day 14.
One fifth (20%) of the infants had consistently low fraction of inspired oxygen, approximately two fifths (38%) had pulmonary deterioration, and the remaining approximately two fifths (43%) had consistently high fraction of inspired oxygen (early and persistent lung dysfunction). Compared with infants who had consistently low fraction of inspired oxygen, infants who experienced pulmonary deterioration had lower gestational ages and lower birth weights, had higher scores for neonatal acute physiology, and received more intensive modes of respiratory support. Gender, multifetal pregnancy, cesarean delivery, antenatal steroids, chorioamnionitis, and funisitis were not associated with pulmonary deterioration. The incidence of chronic lung disease, defined as oxygen therapy at 36 weeks' postmenstrual age, was 17% in the consistently low fraction of inspired oxygen group, 51% in the pulmonary deterioration group, and 67% in the early and persistent pulmonary dysfunction group. The incidence of death in these 3 groups before 36 weeks' postmenstrual age was 1%, 3%, and 5%, respectively.
Nearly 40% of extremely low gestational age newborns experience pulmonary deterioration in the first 2 postnatal weeks, and half of these infants develop chronic lung disease. Indicators of developmental immaturity and illness severity were associated with both pulmonary deterioration and chronic lung disease. Studying the antecedents of pulmonary deterioration might provide new insights about chronic lung disease pathogenesis.
Objective To evaluate whether concentrations of inflammation-related proteins are elevated in the blood of preterm newborns who develop cerebral white matter damage. Study design We measured 25 ...proteins in blood collected on days 1, 7, and 14 from 939 infants born before the 28th week of gestation. Brain ultrasound scans were read by at least two sonologists, who agreed on the presence or absence of lesions. A protein concentration was considered elevated if it was in the highest quartile for gestational age and the day on which the specimen was collected. Results In time-oriented models, elevated concentrations of vascular endothelial growth factor receptor 1, serum amyloid A, and macrophage inflammatory protein 1β on day 1 and interleukin-8 on day 7 were associated with increased risk of ventriculomegaly. Elevated concentrations of macrophage inflammatory protein 1β on day 1 and intercellular adhesion molecule 1 on day 7 were associated with increased risk of an echolucent lesion. Infants with elevated concentrations of inflammation-related proteins on two separate days were at significantly increased risk for ventriculomegaly, but at only modestly increased risk for an echolucent lesion. Conclusions Concentrations of inflammation-related proteins in the circulation in the first days after preterm birth provide information about the risk of sonographic white matter damage. The inflammatory process might begin in utero.
Objective The objective of the study was to quantify and identify aerobic and anaerobic bacteria as well as Mycoplasma and Ureaplasma in the chorionic parenchyma. Study Design A sample of the ...chorionic parenchyma from neonates delivered between 23-27 completed weeks was cultured and tested by polymerase chain reaction (PCR) methods using universal bacterial primers for the presence of bacteria and mycoplasmas. Results The culture positive rate was higher for vaginal deliveries (333/489; 68%) than for cesarean sections (363/876; 41%). Thirty percent of all culture-positive samples had only aerobic bacteria, 21% of the samples had only anaerobic bacteria, and 9% of the samples had only Mycoplasma/Ureaplasma. The mean concentration of Mycoplasma/Ureaplasma (4.00 ± 1.11 log10 CFU/g) was significantly higher ( P < .001) than the total count of either aerobes (3.24 ± 1.12 log10 CFU/g) or anaerobes (2.89 ± 0.99 log10 CFU/g). Staphylococcus sp. and Corynebacterium sp. as well as organisms associated with bacterial vaginosis were the most frequently recovered. A PCR product was not detected from either randomly selected or known culture-positive samples. Conclusion Approximately half of second-trimester placentas harbor organisms within the chorionic plate. The chorion parenchyma appears to harbor constituents that prevent the identification of bacterial deoxyribonucleic acid by PCR methods.
Objective To examine the predictive validity of the Modified Checklist for Autism in Toddlers (M-CHAT) administered at age 24 months for autism spectrum disorder (ASD) diagnosed at 10 years of age in ...a US cohort of 827 extremely low gestational age newborns (ELGANs) followed from birth. Study design We examined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the M-CHAT in predicting an ASD diagnosis at age 10 years based on gold standard diagnostic instruments. We then assessed how these predictive parameters were affected by sensorimotor and cognitive impairments, socioeconomic status (SES), and emotional/behavioral dysregulation at age 2 years. Results Using standard criteria, the M-CHAT had a sensitivity of 52%, a specificity of 84%, a PPV of 20%, and an NPV of 96%. False-positive and false-negative rates were high among children with hearing and vision impairments. High false-positive rates also were associated with lower SES, motor and cognitive impairments, and emotional/behavioral dysregulation at age 2 years. Conclusions Among extremely preterm children with ASD, almost one-half were not correctly screened by the M-CHAT at age 2 years. Sensorimotor and cognitive impairments, SES, and emotional/behavioral dysregulation contributed significantly to M-CHAT misclassifications. Clinicians are advised to consider these factors when screening very preterm toddlers for ASD.
Objective To test the hypothesis that children born preterm are more likely to screen positive on the M-CHAT for an autism spectrum disorder. Study design We compared the M-CHAT positive rate of ...those with cerebral palsy, cognitive impairment, and vision and hearing impairments to those without such deficits. Results Relative to children who could walk, the odds for screening positive on the M-CHAT were increased 23-fold for those unable to sit or stand independently and more than 7-fold for those requiring assistance to walk. Compared with children without a diagnosis of cerebral palsy, those with quadriparesis were 13 times more likely to screen positive, and those with hemiparesis were 4 times more likely to screen positive. Children with major vision or hearing impairments were 8 times more likely to screen positive than those without such impairments. Relative to those with a Mental Development Index (MDI) of >70, the odds for screening positive were increased 13-fold for those with an MDI of <55 and more than 4-fold for those with an MDI of 55 to 69. Conclusions Major motor, cognitive, visual, and hearing impairments appear to account for more than half of the positive M-CHAT screens in extremely low gestational age newborns. Even after those with such impairments were eliminated, 10% of children—nearly double the expected rate—screened positive.
Despite reductions in mortality and morbidity among children born extremely preterm, they remain at high risk of neurocognitive deficits, with up to 40% having significant cognitive deficits at ...school age. We assessed the rate of neurocognitive impairment in a contemporary US cohort of 873 children aged 10 years who were born <28 weeks' gestation.
The families of 889 of 966 (92%) children enrolled from 2002 to 2004 at 14 sites in 5 states returned at age 10 years for a comprehensive assessment of IQ, language, attention, executive function, processing speed, visual perception, visual-motor function, and academic achievement.
A total of 873 children were assessed with well-validated tests of cognitive and academic function. Distributions of test scores were consistently and markedly shifted below normative expectation, with one-third to two-thirds of children performing >1 SD below age expectation. The most extreme downward shifts were on measures of executive control and processing speed. Multivariate analyses, adjusted for socioeconomic status, growth restriction, and other potential confounders, revealed that the risk of poor outcome was highest at the lowest gestational age across all 18 measures.
More than half of our extremely preterm cohort exhibited moderate or severe neurocognitive deficits at age 10 years, with the most extensive impairments found among those born at the lowest gestational age. Children born extremely preterm continue to be at significant risk of persistent impairments in neurocognitive function and academic achievement, underscoring the need for monitoring and remediating such outcomes beginning in early childhood.
Objective To evaluate neurodevelopment after necrotizing enterocolitis (NEC) and late bacteremia, alone and together. Study design Sample included 1155 infants born at 23 to 27 weeks' gestation. NEC ...was classified by the modified Bell's staging criteria and grouped as medical NEC or surgical NEC. Late bacteremia was defined as a positive blood culture result after the first postnatal week. Neurodevelopment was assessed at 24 months corrected age. Multivariable models estimated the risk of developmental dysfunction and microcephaly associated with medical or surgical NEC with and without late bacteremia. Results Children who had surgical NEC unaccompanied by late bacteremia were at increased risk of psychomotor developmental indexes <70 (OR = 2.7 1.2, 6.4), and children who had both surgical NEC and late bacteremia were at increased risk of diparetic cerebral palsy (OR = 8.4 1.9, 39) and microcephaly (OR = 9.3 2.2, 40). In contrast, children who had medical NEC with or without late bacteremia were not at increased risk of any developmental dysfunction. Conclusion The risk of neurodevelopmental dysfunction and microcephaly is increased in children who had surgical NEC, especially if they also had late bacteremia. These observations support the hypothesis that bowel injury might initiate systemic inflammation potentially affecting the developing brain.
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