Linda J. Van Marter

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.

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.

Risk Factors for Persistent Pulmonary Hypertension of the Newborn

OBJECTIVE. Persistent pulmonary hypertension of the newborn, a clinical syndrome that results from the failure of the normal fetal-to-neonatal circulatory transition, is associated with substantial infant mortality and morbidity. We performed a case-control study to determine possible antenatal and perinatal predictors of persistent pulmonary hypertension of the newborn. METHODS. Between 1998 and 2003, the Slone Epidemiology Center enrolled 377 mothers of infants with persistent pulmonary hypertension of the newborn and 836 mothers of matched control subjects. Within 6 months of delivery, study nurses interviewed participants regarding demographic, medical, and obstetric characteristics. RESULTS. Factors that were independently associated with an elevated risk for persistent pulmonary hypertension of the newborn were infant male gender and black or Asian maternal race compared with white race. High prepregnancy BMI (>27 vs <20) was also associated with persistent pulmonary hypertension of the newborn, as were diabetes and asthma. Compared with infants who were delivered vaginally, the risk for persistent pulmonary hypertension of the newborn was higher for those who were born by cesarean section. Compared with infants who were born within 37 to 41 gestational weeks, the risk was higher for those who were born between 34 and 37 completed weeks and for those born beyond 41 weeks. Compared with infants within the 10th and 90th percentiles of birth weight for gestational age distribution, the risk was higher for infants above the 90th percentile. CONCLUSIONS. Our findings suggest an increased risk for persistent pulmonary hypertension of the newborn associated with cesarean delivery; late preterm or postterm birth; being large for gestational age; and maternal black or Asian race, overweight, diabetes, and asthma. It remains unclear whether some of these factors are direct causes of persistent pulmonary hypertension of the newborn or simply share common causes with it; however, clinicians should be alert to the increased need for monitoring and intervention among pregnancies with these risk factors.

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.

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.

Epidemiology of bronchopulmonary dysplasia

First described more than 40 years ago, bronchopulmonary dysplasia (BPD) remains one of the most serious and vexing challenges in the care of very preterm infants. Affecting approximately one-quarter of infants born <1500g birth weight, BPD is associated with prolonged neonatal intensive care unit hospitalization, greater risk of neonatal and post-neonatal mortality and a host of associated medical and neurodevelopmental sequelae. This seminar focuses on the epidemiology and definition of BPD as well as the current evidence pertaining to a number of potential preventive treatments for BPD: non-invasive respiratory support technologies, inhaled nitric oxide, vitamin A, and caffeine.

Rate of bronchopulmonary dysplasia as a function of neonatal intensive care practices

Some differences among neonatal intensive care units (NICUs) in incidence of bronchopulmonary dysplasia may reflect variations in medical care practices. After adjusting for differences in the inherent risk of bronchopulmonary dysplasia among 223 infants of less than 1751 gm birth weight who were admitted to three Harvard-affiliated NICUs, we used multivariate analysis to explore the extent to which medical care practices during the first days of life varied with the rate of bronchopulmonary dysplasia. In our analyses, variables were grouped by three major hypotheses: oxygen toxicity, barotrauma, and fluid overload. The NICU designated 1 (the one with the highest rate of bronchopulmonary dysplasia) used much higher than expected colloidal volumes during the first 4 days of life; in contrast, in the NICU designated 3 (the one with the lowest rate of bronchopulmonary dysplasia), infants consistently received lower than expected amounts of colloidal solution. Signs of patent ductus arteriosus were also much more frequent than expected during this time at NICU 1; rates were much lower than predicted at NICU 2 and were near predicted values at NICU 3. Maximum inspired oxygen fraction during the first 4 days varied significantly in a direction inconsistent with the oxygen toxicity hypothesis. Maximum arterial oxygen tension was significantly less than expected at the hospital with the lowest rate of bronchopulmonary dysplasia (NICU 3). None of six medical care practices indicating potential for barotrauma varied with NICU expect for positive end-expiratory pressure, which varied in a direction suggesting a protective effect against bronchopulmonary dysplasia. These findings agree best with the hypothesis that differences in hydration during the first days of life account for some of the difference among NICUs in bronchopulmonary dysplasia occurrence.

Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn.

ObjectiveWe previously reported improved oxygenation, but no change, in rates of extracorporeal membrane oxygenation (ECMO) use or death among infants with persistent pulmonary hypertension of the newborn who received inhaled nitric oxide (NO) with conventional ventilation, irrespective of lung disease. The goal of our study was to determine whether treatment with inhaled NO improves oxygenation and clinical outcomes in infants with persistent pulmonary hypertension of the newborn and associated lung disease who are ventilated with high-frequency oscillatory ventilation (HFOV). DesignSingle-center, prospective, randomized, controlled trial. SettingNewborn intensive care unit of a tertiary care teaching hospital. PatientsWe studied infants with a gestational age of ≥34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (Pao2 ≤100 mm Hg on Fio2 = 1.0), despite optimal medical management. Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded. InterventionsThe treatment group received inhaled NO, whereas the control group did not. Adjunct therapies and ECMO criteria were the same in the two groups of patients. Investigators and clinicians were not masked as to treatment assignment, and no crossover of patients was permitted. Measurements and Main ResultsPrimary outcome variables were mortality and use of ECMO. Secondary outcomes included change in oxygenation and duration of mechanical ventilatory support and supplemental oxygen therapy. Forty-two patients were enrolled. Baseline oxygenation and clinical characteristics were similar in the two groups of patients. Infants in the inhaled NO group (n = 21) had improved measures of oxygenation at 15 mins and 1 hr after enrollment compared with infants in the control group (n = 20). Fewer infants in the inhaled NO group compared with the control group were treated with ECMO (14% vs. 55%, respectively;p = .007). Mortality did not differ with treatment assignment. ConclusionsAmong infants ventilated by HFOV, those receiving inhaled NO had a reduced need for ECMO. We speculate that HFOV enhances the effectiveness of inhaled NO treatment in infants with persistent pulmonary hypertension of the newborn and associated lung disease.

Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5'-monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension.

OBJECTIVE To examine the role of endogenous nitric oxide (NO) and endothelin-1 (ET-1) in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) and to determine whether inhaled NO, currently under investigation as a new therapy for PPHN, affects plasma concentrations of these vasoactive mediators. METHODS Circulating ET-1 and cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay in 15 healthy term newborn infants and 46 newborn infants with PPHN enrolled in a randomized, controlled trial of inhaled NO. These concentrations were followed up longitudinally and compared between the NO and the conventionally treated group. RESULTS Concentrations of ET-1 were significantly higher and cGMP concentrations significantly lower in infants with PPHN compared with healthy newborn infants (median ET-1, 28 vs 11 pmol/L; p = 0.0001; median cGMP, 35 vs 61 pmol/ml; p = 0.0001, respectively). ET-1 concentrations showed an upward trend at 1 and 24 hours of treatment and a subsequent decline at recovery in both subgroups of patients, with the most pronounced decrease in the NO group. cGMP concentrations increased significantly only in the NO group, with a peak at 1 hour of treatment (median, 61 pmol/ml). As the dose of NO decreased, cGMP concentrations declined. In contrast, conventionally treated infants manifested no change in cGMP concentrations from baseline until recovery, when a significant decrease was noted (median decrease of 13 pmol/ml; p = 0.002). We did not find a significant difference between ET-1 and cGMP concentrations in infants who required extracorporeal membrane oxygenation compared with those who did not. CONCLUSIONS PPHN is associated with increased ET-1 and decreased cGMP plasma concentrations, which may contribute to the pathogenesis of the disease. Inhaled NO appears to modulate these mediators during the disease process, suggesting an interaction between ET-1 and NO in vivo.

Antenatal corticosteroids and cranial ultrasonographic abnormalities.

OBJECTIVE This study was undertaken to determine whether very-low-birth-weight infants whose mothers received a course of antenatal corticosteroids were at decreased risk for 3 cranial ultrasonographic entities that predict neurodevelopmental dysfunction. STUDY DESIGN This retrospective cohort study evaluated 1604 infants weighing 500 to 1500 g who underwent >/=1 of 3 cranial ultrasonographic scans required by design at specified postnatal intervals and whose own and mothers hospital charts were reviewed. Infants were classified according to mothers course of antenatal corticosteroids (none, partial, or complete). RESULTS In the total sample the risks of intraventricular hemorrhage and of an echolucent image in the cerebral white matter were only modestly (and not statistically significantly) reduced after a full course of antenatal corticosteroids, whereas antenatal corticosteroids appeared to significantly reduce the risk of ventriculomegaly after even a partial course. Antenatal corticosteroids appeared to halve the risk of ventriculomegaly and echolucent image among the gestationally youngest infants and those with intraventricular hemorrhage, hypothyroxinemia, or vasculitis of the umbilical cord or chorionic plate of the placenta. CONCLUSION These observations are consistent with the hypothesis that antenatal corticosteroids protect very-low-birth-weight infants, especially those who are most vulnerable, against the risk of cranial ultrasonographic abnormalities.