Vitamin D and bronchopulmonary dysplasia in preterm infants.

OBJECTIVE: Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25-hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation. STUDY DESIGN: We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at -80 °C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex. RESULTS: Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml(-1) in preterm infants who subsequently died or developed BPD and 33.8 ng ml(-1) in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml(-1) among survivors without BPD and 64.2 ng ml(-1) among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively). CONCLUSIONS: Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml(-1) by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations.

Perinatal systemic inflammatory responses of growth-restricted preterm newborns.

AIM: To compare the early post-natal pattern of systemic inflammation in growth-restricted infants born before the 28th week of gestation to that of appropriately grown peers. METHODS: We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 post-natal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile. RESULTS: Severely growth-restricted infants (birth weight Z-score <-2) were not at increased risk of systemic inflammation shortly after birth. On post-natal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1ß, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia or duration of ventilation. CONCLUSION: Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by post-natal day 14.

Transitional hypothermia in preterm newborns.

Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants < 1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself. Journal of Perinatology (2007) 27, S45-S47. doi:10.1038/sj.jp.7211842.

Transitional hypothermia in preterm newborns.

Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants <1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself.

Growth-restricted premature infants are at increased risk for low thyroxine.

OBJECTIVE: To evaluate, in extremely premature infants, the relationship between growth restriction and early total thyroxine levels, and to determine how maternal, prenatal, perinatal and neonatal variables influence the relationship. STUDY DESIGN: 719 infants born at four medical centers in Massachusetts, New York and New Jersey between 1991 and 1993 were studied. Entry criteria included: gestational age 23--30 weeks, birth weight 500--1500 g, and a serum thyroxine level obtained in the first week of life. Infants born to mothers with a history of thyroid disease were excluded. Birth weight and total thyroxine level are expressed as z-scores (standard deviation units) to adjust for their relationship to gestational age. RESULTS: In linear regression analysis, there was a 0.18 decrease in the total thyroxine z-score for each 1.0 (1 standard deviation unit) decrease in birth weight z-score (p=0.0001). Adjustment for multiple potential maternal, prenatal, perinatal and neonatal confounders failed to identify a factor or factors that could account for the observed association. CONCLUSIONS: The early total thyroxine level in extremely preterm infants was significantly associated with birth weight z-score. This relationship persisted even after adjustment for maternal, prenatal, perinatal and neonatal confounders suggesting antenatal influences. Of clinical importance, growth-restricted infants are at increased risk for early hypothyroxinemia and, possibly, to its related morbidities.

Antenatal glucocorticoid treatment does not reduce chronic lung disease among surviving preterm infants.

BACKGROUND: Antenatal glucocorticoid treatment (AGT) is associated with a number of postnatal benefits to the preterm infant, including reduced risk of respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis. OBJECTIVE: To evaluate the hypothesis that maternal AGT not only reduces the risk of surfactant deficiency but also reduces the occurrence of chronic lung disease (CLD) among surviving preterm infants. STUDY DESIGN: Case-referent study of 1454 very low birth weight infants born between January 1991 and December 1993 at 4 university medical centers. RESULTS: Rates of AGT varied among the 4 centers (11%-69%), as did rates of CLD (4%-21%), defined as a requirement for supplemental oxygen at 36 weeks' postmenstrual age. CLD rates at each center, however, did not vary with the rate of AGT exposure. In multivariate logistic regression analyses, AGT did not contribute significantly to CLD risk. CONCLUSION: AGT may play a less prominent role in modifying CLD risk than other factors such as biologic immaturity, infection, or neonatal intensive care unit practices, such as mechanical ventilation, continuous positive airway pressure, and surfactant replacement therapy.

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, < 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.

Hypocarbia during the first 24 postnatal hours and white matter echolucencies in newborns < or = 28 weeks gestation.

The purpose of the present study was to test the hypothesis that newborns < or = 28 wk gestation who have a PCO(2) measurement in the lowest gestational age-specific quartile (hypocarbia) on the first day of life are not at increased risk for ultrasonographic white matter echolucency (EL) after adjustment for confounders. The sample consisted of 799 infants < or = 28 wk gestation born during 1991-1993. Forty-eight infants with EL were classified as cases and compared with 751 controls, i.e. those without EL. We performed univariable comparisons, stratified analyses, and multivariable logistic regression. In the univariable analyses, hypocarbia on the first day of life was associated with an increased EL risk. The odds ratios for the hypocarbia-EL relationship were prominently elevated in the strata of infants who did not have other major risk factors for EL (e.g. gestational age 26-28 wk, normothyroxinemia, no characteristics of antenatal infection). In the multivariable analyses, the association diminished after adjustment with a hypocarbia propensity score (odds ratio = 1.7; 95 % confidence interval, 0.8-3.2) or with potential confounders.

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

OBJECTIVE: We 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). DESIGN: Single-center, prospective, randomized, controlled trial. SETTING: Newborn intensive care unit of a tertiary care teaching hospital. PATIENTS: We studied infants with a gestational age of > or =34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (PaO2 < or =100 mm Hg on FIO2 = 1.0), despite optimal medical management Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded. INTERVENTIONS: The 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 RESULTS: Primary 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. CONCLUSIONS: Among 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.

Antecedents of clinically significant pulmonary hemorrhage among newborn infants.

OBJECTIVE: To evaluate risk factor profiles associated with clinically significant pulmonary hemorrhage (PH) in preterm (PT) and term infants. STUDY DESIGN: Case-control study of all infants with PH cared for in three Harvard-affiliated neonatal intensive care units between 1987 and 1994. RESULTS: A total of 50 cases of PH occurred in PT infants (gestational age (GA) of < or = 34 weeks), and 26 cases occurred in near-term/full-term (NT/FT) infants (GA of > 34 weeks). The median age at the time of PH was 46 hours among PT infants compared with 6 hours among NT/FT infants. For PT infants, four factors best predicted PH: a GA of between 24 and 26 weeks and antenatal glucocorticoid treatment reduced the risk (odds ratios (ORs) of 0.7 and 0.3, respectively), whereas requirement for resuscitation with positive pressure ventilation and thrombocytopenia were associated with increased risk (ORs of 4.3 and 4.0, respectively). Among the NT/FT infants, the model included three variables: meconium aspiration (OR 4.9), requirement for resuscitation with positive pressure ventilation (OR 2.9), and hypotension (OR 3.5). CONCLUSION: Antecedent factors and timing of PH differ between PT and NT/FT infants, suggesting that the mechanisms contributing to PH are influenced by developmental maturity as well as perinatal and neonatal medical conditions and interventions.

Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network.

OBJECTIVE: To explore the hypothesis that variation in respiratory management among newborn intensive care units (NICUs) explains differences in chronic lung disease (CLD) rates. DESIGN: Case-cohort study. SETTING: NICUs at 1 medical center in New York (Babies' and Children's Hospital [Babies']) and 2 in Boston (Beth Israel Hospital and Brigham and Women's Hospital [Boston]). STUDY POPULATION: Four hundred fifty-two infants born at 500 to 1500 g birth weight between January 1991 and December 1993, who were enrolled in an epidemiologic study of neonatal intracranial white matter disorders. CASE DEFINITION: Supplemental oxygen required at 36 weeks' postmenstrual age. RESULTS: The prevalence rates of CLD differed substantially between the centers: 4% at Babies' and 22% at the 2 Boston hospitals, despite similar mortality rates. Initial respiratory management at Boston was more likely than at Babies' to include mechanical ventilation (75% vs 29%) and surfactant treatment (45% vs 10%). Case and control infants at Babies' were more likely than were those at Boston to have higher partial pressure of carbon dioxide and lower pH values on arterial blood gases. However, measures of oxygenation and ventilator settings among case and control infants were similar at the 2 medical centers in time-oriented logistic regression analyses. In multivariate logistic regression analyses, the initiation of mechanical ventilation was associated with increased risk of CLD: after adjusting for other potential confounding factors, the odds ratios for mechanical ventilation were 13.4 on day of birth, 9.6 on days 1 to 3, and 6.3 on days 4 to 7. Among ventilated infants, CLD risk was elevated for maximum peak inspiratory pressure >25 and maximum fraction of inspired oxygen = 1.0 on the day of birth, lowest peak inspiratory pressure >20 and maximum partial pressure of carbon dioxide >50 on days 1 to 3, and lowest white blood count <8 K on days 4 to 7. Even after adjusting for white blood count <8 K and the 4 respiratory care variables, infants in Boston continued to be at increased risk of CLD, compared with premature infants at Babies' Hospital. CONCLUSION: In multivariate analyses, a number of specific measures of respiratory care practice during the first postnatal week were associated with the risk of a very low birth weight infant developing CLD. However, after adjusting for baseline risk, most of the increased risk of CLD among very low birth weight infants hospitalized at 2 Boston NICUs, compared with those at Babies' Hospital, was explained simply by the initiation of mechanical ventilation.

Pulmonary hypertension associated with nonketotic hyperglycinaemia.

Nonketotic hyperglycinaemia (NKH) is an autosomal recessive disorder characterized by defective glycine degradation by the mitochondrial glycine cleavage system. The clinical features include lethargy, hypotonia, apnoea, seizures and severe psychomotor retardation, all attributed to the accumulation of glycine in the nervous system. Pulmonary hypertension (PHN) has not been reported in NKH. We describe four patients with NKH who had PHN in addition to the characteristic manifestations of NKH. This newly recognized association might provide additional insight into the underlying pathophysiology of PHN.

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants. Developmental Epidemiology Network Investigators.

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 x g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; fetoplacental 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 > or =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.

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 mother's hospital charts were reviewed. Infants were classified according to mother's 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.

Hypothyroxinemia of prematurity and the risk of cerebral white matter damage.

OBJECTIVE: Infants 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. STUDY DESIGN: We 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 mother's 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). RESULTS: After 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. CONCLUSION: Our 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.

Inhaled nitric oxide does not affect adenosine 5'-diphosphate-dependent platelet activation in infants with persistent pulmonary hypertension of the newborn.

OBJECTIVE: To investigate the effect of inhaled nitric oxide (NO) treatment in newborns with persistent pulmonary hypertension on adenosine 5'-diphosphate (ADP)-dependent platelet activation. METHODS: After parental informed consent, infants with persistent pulmonary hypertension of the newborn were randomly assigned to receive conventional treatment (control group) or treatment with 40 parts per million of inhaled NO. Platelet activation was measured at time of entry and 30 minutes later by surface expression of P-selectin in response to increasing concentrations of the agonist ADP (0, 2, 5, 10, and 20 microM) using fluorescence-activated flow cytometry. RESULTS: We examined 11 infants in the inhaled NO group and 13 in the control group. P-selectin expression, quantified as mean fluorescence, was not significantly different in the two groups of patients at baseline. Median percent change from baseline fluorescence was assessed using the Wilcoxon matched-pairs signed-rank test. At 30 minutes after enrollment there were no statistically significant changes from baseline fluorescence in either group of patients and at all ADP concentrations. CONCLUSION: Thirty minutes of exposure to 40 ppm of inhaled NO does not inhibit ADP-dependent platelet activation as measured by surface expression of P-selectin in infants with persistent pulmonary hypertension of the newborn.

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.

Maternal receipt of magnesium sulfate does not seem to reduce the risk of neonatal white matter damage.

OBJECTIVE: To investigate whether in utero exposure to magnesium sulfate is associated with a lower incidence of cranial ultrasonographic abnormalities that predict cerebral palsy in infants who weigh less than 1501 g at birth. DESIGN: For a prospective study of the antecedents of cranial ultrasonographic abnormalities, we enrolled infants who weighed 500 to 1500 g when born at five institutions. Data were collected by interview of the mothers and review of medical records. Protocol cranial ultrasonograms were obtained as close as possible to postnatal days 1, 7, and 21. Abnormality on cranial ultrasound scans was determined by a consensus committee of three sonologists. RESULTS: Of the 1518 infants for whom we knew whether the mothers received magnesium sulfate, the first protocol cranial ultrasound scan was available for 1409 infants, the second for 1274 infants, and the third for 1050 infants. Forty-five percent of infants were exposed to magnesium sulfate before delivery. The major correlates of magnesium sulfate exposure were receipt of antenatal corticosteroids and a diagnosis of preeclampsia and/or pregnancy-induced hypertension. Maternal magnesium receipt was not associated with a reduced incidence of hypoechoic or hyperechoic images of white matter parenchyma, intraventricular hemorrhage, or ventriculomegaly, even when the sample was stratified by each of six potential confounders. When adjustment was made for gestational age, a measure of birth weight for gestational age, antenatal corticosteroid exposure, preeclampsia and pregnancy-induced hypertension, route of delivery, and the occurrence of any labor, the risk ratios for each cranial ultrasonographic abnormality associated with magnesium sulfate exposure hovered close to 1. CONCLUSION: Maternal receipt of magnesium sulfate does not seem to be associated with an appreciably reduced risk of cranial ultrasonographically defined neonatal white matter damage, intraventricular hemorrhage, or ventriculomegaly.

Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the effect of inhaled nitric oxide (NO) on clinical outcome in newborns with persistent pulmonary hypertension (PPHN). DESIGN: A prospective, randomized trial of patients referred to a level 3 nursery in a single large center. Clinicians were not masked to group assignment. Crossover of patients from control to NO treatment was not permitted. METHODS: We randomized 49 mechanically ventilated newborns, transferred to our center with clinical and echocardiographic evidence of severe PPHN (arterial oxygen tension [PaO2] <100; fractional inspired oxygen = 1) to treatment with or without NO. Patients with gestational age <34 weeks or with congenital heart disease or diaphragmatic hernia were excluded. High-frequency oscillatory ventilation was used but not allowed concomitantly with NO. Primary outcome variables were oxygenation, mortality, and use of extracorporeal membrane oxygenation (ECMO). RESULTS: Meconium aspiration syndrome and isolated PPHN were the most common diagnoses (32/49) and were distributed equally between groups. The median age at the time of entry into the study was similar between groups, 25 hours for control patients and 18 hours for NO patients. Median baseline oxygenation index (OI) was similar in 23 control (OI = 29) and 26 NO (OI = 30) patients. Mortality (8%), use of ECMO (33%), median days on mechanical ventilation (9 days), and duration of supplemental oxygen (13 days) were not different between treatment groups. PaO2, oxygen saturation, and OI improved in the NO group compared with baseline and to control patients at 15 minutes. The median percent change in OI (-31%) in the NO group was significantly different from baseline and from the control group. The difference in oxygenation between treatment groups was still apparent 12 hours after baseline. Before cannulation for ECMO, oxygenation was better in the NO group compared with control patients. Among patients who were placed on ECMO, the median time from baseline to ECMO cannulation was 2.4 hours (range, 1 to 12 hours) among control patients and 3.3 hours (range, 2 to 68 hours) for those randomized to receive NO. There was a tendency to observe fewer adverse neurologic events (seizure and intracranial hemorrhage) in the NO group (4/26 vs 8/23). One child with alveolar capillary dysplasia confirmed by postmortem examination could not be weaned from 80 parts per million of NO and transiently developed methemoglobinemia (peak methemoglobin level = 17%). No other side effects were observed. CONCLUSIONS: Although mortality and ECMO use were similar for both treatment groups using this study size and design, sustained improvement in oxygenation with NO and better oxygenation at initiation of ECMO may have important clinical benefits. We speculate that modification of treatment to include specific lung expansion strategies with NO treatment and recognition that early improvement of oxygenation may be sustained with NO may lead to reduced use of ECMO in NO treated patients compared with controls.

Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy.

OBJECTIVE: Prenatal causation of persistent pulmonary hypertension of the newborn (PPHB) is suggested by a specific pattern of pulmonary vascular remodeling observed immediately after birth in some infants with fatal PPHN. The goal of this study was to determine whether PPHN is associated with fetal exposure to: (1) tobacco and marijuana smoking (ie, contributors to fetal hypoxemia), (2) consumption of aspirin and other nonsteroidal antiinflammatory drugs (ie, inhibitors of prostaglandin synthesis), and (3) cocaine use (ie, a contributor to vasospasm). DESIGN: Case-control interview study. SETTING: Two Harvard-affiliated newborn intensive care units. PARTICIPANTS: Mothers of case infants who had PPHN or who met criteria for the referent group. INTERVENTIONS: During July 1985 through April 1989, we interviewed mothers of 103 infants with PPHN and 298 control infants. Because of potential selection bias that might result from recruiting only inborn control infants even though two-thirds of cases were outborn, separate analyses compared the 103 total and 35 inborn infants with PPHN with the 298 inborn control infants. Multivariate analyses were used to adjust for potential confounding factors, including maternal education and Medicaid health insurance (ie, two markers of socioeconomic status), other antenatal factors found to be associated with PPHN (ie, maternal urinary tract infection and diabetes mellitus), and the infant's sex. MAIN OUTCOME MEASURES: Self-reported use or consumption of tobacco, marijuana, cocaine, aspirin, and other nonsteroidal antiinflammatory drugs during pregnancy. RESULTS: The adjusted odds ratios (and 95% confidence intervals) for maternal pregnancy exposures to the factors of principal interest among the total study population were: aspirin, 4.9 (1.6-15.3); and nonsteroidal antiinflammatory drugs, 6.2 (1.8-21.8); for the inborn group they were aspirin, 9.6 (2.4-39.0); and nonsteroidal antiinflammatory drugs, 17.5 (4.3-71.6). Although the association between tobacco smoking during pregnancy and PPHN was elevated in univariate analyses, with odds ratios (and 95% confidence intervals) of 2.0 (1.2-3.4) and 1.3 (0.6-3.3) for total and inborn populations, respectively, the relationship was not significant after adjustment for all other factors in the final logistic regression model. Acknowledged illicit drug use was too infrequent (3.2%) to evaluate. CONCLUSION: Maternal consumption of nonsteroidal antiinflammatory drugs and aspirin during pregnancy or the reasons these drugs were ingested seem to contribute to an increased risk of PPHN.