Elizabeth N. Allred

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 ×g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; feto-placental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n= 537), or after a longer interval (n= 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born ≥1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8;p= 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9;p= 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

Pregnancy Disorders That Lead to Delivery Before the 28th Week of Gestation: An Epidemiologic Approach to Classification

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.

Nutritional Practices and Growth Velocity in the First Month of Life in Extremely Premature Infants

OBJECTIVES: The goals of this study were to describe nutritional practices in the first month of life for a large cohort of extremely low gestational age newborns and to determine the impact of these nutritional practices on growth velocity (GV) over the same period. METHODS: The sample included 1187 infants born at 23 to 27 weeks of gestation, at 14 institutions, between 2002 and 2004. Inclusion criteria included survival until day 28 and weight information for days 7 and 28. GV, expressed as grams per kilogram per day, was calculated for the interval between days 7 and 28. Nutritional practices during the first week and on days 14, 21, and 28 were compared with current nutritional guidelines in the literature. Multivariable logistic regression models estimated the contribution of limited nutrition to limited GV. RESULTS: Protein and fat delivery approximated current nutritional recommendations, whereas carbohydrate and total energy intake delivery did not. Despite this, GV of our study infants exceeded the current guideline of 15 g/kg per day. Nevertheless, we found extrauterine growth restriction (ie, weight for gestational age below the 10th centile) in 75% of the infants at 28 days, compared with only 18% at birth. A GV of 20 to 30 g/kg per day was associated with infants maintaining or exceeding their birth weight z score, with rates in the upper range for the gestationally youngest infants. Early (day 7) nutritional practices were positively associated with GV measured between days 7 and 28. CONCLUSION: The early provision of nutrients is an important determinant of postnatal growth. Extrauterine growth restriction remains high in extremely premature infants even when they achieve a GV rate within current guidelines.

Fetal Growth Restriction and Chronic Lung Disease Among Infants Born Before the 28th Week of Gestation

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Microbiologic and histologic characteristics of the extremely preterm infant's placenta predict white matter damage and later cerebral palsy. the ELGAN study.

Inflammatory phenomena seem to contribute to the occurrence of perinatal cerebral white matter damage and CP. The stimulus that initiates the inflammation remains obscure. One thousand two hundred forty-six infants born before the 28th postmenstrual week had a protocol ultrasound scan of the brain read concordantly by two independent sonologists. Eight hundred ninety-nine of the children had a neurologic examination at approximately 24-mo postterm equivalent. The placenta of each child had been biopsied under sterile conditions and later cultured. Histologic slides of the placenta were examined specifically for this study. Recovery of a single microorganism predicted an echolucent lesion, whereas polymicrobial cultures and recovery of skin flora predicted both ventriculomegaly and an echolucent lesion. Diparetic CP was predicted by recovery of a single microorganism, multiple organisms, and skin flora. Histologic inflammation predicted ventriculomegaly and diparetic CP. The risk of ventriculomegaly associated with organism recovery was heightened when accompanied by histologic inflammation, but the risk of diparetic CP was not. Low-virulence microorganisms isolated from the placenta, including common skin microflora, predict ultrasound lesions of the brain and diparetic CP in the very preterm infant. Organism recovery does not seem to be needed for placenta inflammation to predict diparetic CP.

Neurodevelopment of Extremely Preterm Infants who had Necrotizing Enterocolitis with or without Late Bacteremia

OBJECTIVEnTo evaluate neurodevelopment after necrotizing enterocolitis (NEC) and late bacteremia, alone and together.nnnSTUDY DESIGNnSample included 1155 infants born at 23 to 27 weeks gestation. NEC was classified by the modified Bells 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.nnnRESULTSnChildren 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.nnnCONCLUSIONnThe 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.

Hydration during the first days of life and the risk of bronchopulmonary dysplasia in low birth weight infants

We conducted a case-control study of antecedents of bronchopulmonary dysplasia (BPD) in 223 infants enrolled in a prospective, randomized clinical trial of phenobarbital prophylaxis for intracranial hemorrhage. The trial took place at three Boston neonatal intensive care units between June 1981 and April 1984. The 76 babies with BPD had radiographic evidence of the condition and required oxygen therapy for 28 days or more. All 147 control babies survived until day 28 of life without meeting either of these criteria for BPD. Compared with control infants, those with BPD received greater quantities of total, crystalloid, and colloid fluids per kilogram per day in the first 4 days of life. In addition, infants with BPD generally had a net weight gain in the first 4 days of life in contrast to the normal pattern of weight loss seen in control infants. Finally, the infants with BPD were more likely to be given a clinical diagnosis of patent ductus arteriosus and to have received furosemide on days 3 and 4 of life. From these observations we infer that early postnatal phenomena such as excessive fluid therapy may be important in the pathogenesis of BPD.

Hypothyroxinemia of prematurity and the risk of cerebral white matter damage

OBJECTIVEnInfants with hypothyroxinemia of prematurity (HOP) are at increased risk for neurodevelopmental dysfunction. Infants born near the end of the middle trimester are also at increased risk for an echolucency (EL) in the cerebral white matter, which reflects white matter damage and is the cranial ultrasound abnormality that best predicts neurodevelopmental dysfunction. We postulated that some of the increased risk of neurodevelopmental problems associated with HOP reflects an increased risk of EL.nnnSTUDY DESIGNnWe studied 1414 infants weighing 500 to 1500 g who were born at 4 medical centers between 1991 and 1993. The infants had thyroxine blood levels measured during the first weeks of life, at least 1 of 3 cranial ultrasound scans performed at specified postnatal intervals, and their own and their mothers hospital charts reviewed. Infants were classified by whether or not their first thyroxine level placed them in the lowest quartile among all infants in this sample (ie, <67.8 nmol/L, our definition of HOP, equivalent to <5.3 micrograms/dL).nnnRESULTSnAfter adjusting for such potential confounders as low gestational age and measures of illness severity, infants with HOP had twice the risk of EL as their peers with higher thyroxine levels.nnnCONCLUSIONnOur findings are consistent with the hypothesis that a normal blood thyroxine level protects infants born near the end of the middle trimester against the risk of cerebral white matter damage.

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 >10 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.

Detection of bacteria in placental tissues obtained from extremely low gestational age neonates.

OBJECTIVEnThe objective of the study was to quantify and identify aerobic and anaerobic bacteria as well as Mycoplasma and Ureaplasma in the chorionic parenchyma.nnnSTUDY DESIGNnA 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.nnnRESULTSnThe 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.nnnCONCLUSIONnApproximately 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.