bronchopulmonary dysplasia; predictors/risk factors; chronic lung disease; mechanical ventilation
To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.
This was a prospective pilot RCT of infants 230/7 – 266/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. 161 (44%) infants were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study due to the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.
This pilot RCT was not feasible due to low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.
Extremely preterm infant; hypotension; hydrocortisone; dopamine; informed consent
We sought to determine if a center’s approach to care of premature infants at the youngest gestational ages (22–24 weeks’ gestation) is associated with clinical outcomes among infants of older gestational ages (25–27 weeks’ gestation).
Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks’ gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks’ gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity.
Our study included 3631 infants 22 to 24 weeks’ gestation and 5227 infants 25 to 27 weeks’ gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22- to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants.
This study suggests that physicians’ willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants.
low-birth weight infant; NICUs; treatment; patient outcome assessment
Treatment of Mycoplasma hominis meningitis in infants is limited by a lack of consensus regarding therapy and limited pharmacokinetic data for agents to which M. hominis is susceptible. We report the successful treatment of a premature infant with M. hominis meningitis with doxycycline and moxifloxacin and provide a pharmacokinetic profile of moxifloxacin.
meningitis; moxifloxacin; Mycoplasma hominis; infant; pharmacokinetic
We examined the association between elevated concentrations of 25 blood proteins in blood spots collected on postnatal days 1, 7, and 14 from infants < 28 weeks gestation who survived to 24 months and the risk of two patterns of early lung disease i.e., early and persistent pulmonary dysfunction (EPPD), and normal early pulmonary function followed by pulmonary deterioration (PD). 38% (N=347) of our cohort had PD, and 43% (N=383) had EPPD. On postnatal day 14, elevated concentrations of two proteins (RANTES and VEGF) were associated with reduced risk of PD. Similarly, the risk of EPPD was also reduced if three proteins had elevated concentrations on postnatal day 14 (RANTES, MMP-1, and VEGF). In contrast, the risk of EPPD was increased if on day 14 two proteins had elevated concentrations (IL-8 and ICAM-1). Inflammation might influence the risk of EPPD and PD, or be a consequence of lung damage or therapies to minimize lung dysfunction.
Necrotizing enterocolitis is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood.
To describe the factors associated with mortality in infants with necrotizing enterocolitis and to quantify the degree to which catastrophic presentation contributes to mortality in infants with necrotizing enterocolitis.
We performed a retrospective review of the Pediatrix's Clinical Data Warehouse (1997-2009) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC versus those who died. Associations were tested by bivariate and multivariate analysis.
In a total cohort of 560,227 infants, there were 2661 cases (17%) of surgically treated and 6460 (42%) of medically treated necrotizing enterocolitis; 1505 (16.5%) died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, a need for assisted ventilation on the day of diagnosis of NEC, a need for vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die.
Two thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often required vasopressors and more often were treated with high frequency ventilation at the time of diagnosis compared to patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occur within 7 days was relatively consistent (65-75 percent of the patients who died) across all gestational ages.
Mortality among infants who have necrotizing enterocolitis remains high and infants who die of necrotizing enterocolitis commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness.
Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children.
clinical trial simulation; opportunistic study; pediatrics; pharmacodynamics; pharmacokinetics; pharmacometrics; therapeutics
Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity including neurodevelopmental impairment.
Describe the epidemiology of CoNS infections in the NICU. Determine mortality among infants with definite, probable, or possible CoNS infections.
We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from infants <121 postnatal days.
248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009.
We identified 16,629 infants with 17,624 episodes of CoNS infection: 1734 (10%) definite, 3093 (17%) probable, and 12,797 (73%) possible infections. Infants with lower gestational age and birth weight had a higher incidence of CoNS infection. Controlling for gestational age, birth weight, and 5-minute Apgar score, infants with definite, probable, or possible CoNS infection had lower mortality—OR=0.74 (95% confidence interval; 0.61, 0.89), OR= 0.68 (0.59, 0.79), and OR=0.69 (0.63, 0.76)—compared to infants with negative cultures (P<0.001). No significant difference in overall mortality was found in infants with definite CoNS infection compared to those with probable or possible CoNS infection—OR=0.93 (0.75, 1.16) and OR=0.85 (0.70, 1.03), respectively.
CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants diagnosed with definite, probable, or possible CoNS infection was observed.
nosocomial infection; infant; prematurity; Staphylococcus
Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
bronchopulmonary dysplasia; prematurity; low-birth-weight infant
Lung inflammation contributes to the pathogenesis of bronchopulmonary dysplasia (BPD) and may be accompanied by a systematic inflammatory response. The objective of this study was to investigate the role of systemic inflammation in the development of BPD in a cohort of extremely low gestational age newborns (ELGANs) by examining the relationships between inflammation-associated proteins in neonatal blood samples and pulmonary outcomes. Proteins were measured in blood specimens collected on postnatal days 1–3, 5–8 and 12–15 from 932 ELGANs. Increased risk of BPD was associated with elevated blood concentrations of a variety of pro-inflammatory cytokines, adhesion molecules and proteases. Reduced risk was prominently associated with increased concentrations of one chemokine, RANTES. Elevations of inflammatory proteins associated with BPD risk occurred during the first days following birth, and inflammation intensified thereafter. Therefore, exposures that promote inflammation after the first postnatal days may be more critical in the pathogenesis of BPD. Fetal growth restriction, a known BPD risk factor, was not accompanied by proteins elevations and therefore does not appear to be mediated by systemic inflammation. By contrast, mechanical ventilation altered protein levels and may be associated with systemic inflammation.
To evaluate, in extremely low gestational age newborns (ELGANs), relationships between indicators of early postnatal hypotension and cranial ultrasound indicators of cerebral white matter damage imaged in the nursery and cerebral palsy diagnoses at 24 month follow-up.
The 1041 infants in this prospective study were born at < 28 weeks gestation, were assessed for 3 indicators of hypotension in the first 24 postnatal hours, had at least one set of protocol cranial ultrasound scans, and were evaluated with a structured neurologic exam at 24 months corrected age. Indicators of hypotension included: 1) lowest mean arterial pressure (MAP) in the lowest quartile for gestational age; 2) treatment with a vasopressor; and 3) blood pressure lability, defined as the upper quartile of the difference between each infant’s lowest and highest MAP. Outcomes included indicators of cerebral white matter damage, i.e. moderate/severe ventriculomegaly or an echolucent lesion on cranial ultrasound, and cerebral palsy diagnoses at 24 months gestation. Logistic regression was used to evaluate relationships among hypotension indicators and outcomes, adjusting for potential confounders.
Twenty-one percent of surviving infants had a lowest blood pressure in the lowest quartile for gestational age, 24% were treated with vasopressors, and 24% had labile blood pressure. Among infants with these hypotension indicators, 10% percent developed ventriculomegaly and 7% developed an echolucent lesion. At 24-months follow-up, 6% had developed quadriparesis, 4% diparesis, and 2% hemiparesis. After adjusting for confounders, we found no association between indicators of hypotension, and indicators of cerebral white matter damage or a cerebral palsy diagnosis.
The absence of an association between indicators of hypotension and cerebral white matter damage and or cerebral palsy suggests that early hypotension may not be important in the pathogenesis of brain injury in ELGANs.
hypotension; mean arterial blood pressure; cranial ultrasound; ventriculomegaly; echolucent lesion; cerebral palsy; extremely preterm infants
The purpose of this study is to examine the results of repeat lumbar puncture in infants with initial positive cerebrospinal fluid (CSF) cultures in order to determine the clinical characteristics and outcomes of infants with repeat positive cultures.
Cohort study of infants with an initial positive CSF culture undergoing repeat lumbar puncture between 1997 and 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical group. We compared the clinical outcomes of infants with repeat positive cultures and infants with repeat negative cultures.
We identified 118 infants with repeat CSF cultures. Of these, 26 infants had repeat positive cultures. A higher proportion with repeat positive cultures died compared to those with repeat negative cultures, 6/23 (26%) vs. 6/81 (7%), respectively (p=0.02).
Among infants with a positive CSF culture, a repeat positive CSF culture is common. The presence of a second positive culture is associated with increased mortality.
neonate; newborn; cerebrospinal fluid; infection; mortality
To develop an accurate, proxy-reported bedside measurement tool for assessment of the severity of bronchopulmonary dysplasia (also called chronic lung disease) in preterm infants to supplement providers' current biometric measurements of the disease.
We adapted Patient-Reported Outcomes Measurement Information System (PROMIS) methodology to develop the Proxy-Reported Pulmonary Outcomes Scale (PRPOS). A multidisciplinary group of registered nurses, nurse practitioners, neonatologists, developmental specialists, and feeding specialists at five academic medical centers participated in the PRPOS development, which included five phases: (1) identification of domains, items, and responses; (2) item classification and selection using a modified Delphi process; (3) focus group exploration of items and response options; (4) cognitive interviews on a preliminary scale; and (5) final revision before field testing.
Each phase of the process helped us to identify, classify, review, and revise possible domains, questions, and response options. The final items for field testing include 26 questions or observations that a nurse assesses before, during, and after routine care time and feeding.
We successfully created a prototype scale using modified PROMIS methodology. This process can serve as a model for the development of proxy-reported outcomes scales in other pediatric populations.
Considerable effort has been devoted to the development of strategies to reduce the incidence of chronic lung disease, including use of medications, nutritional therapies, and respiratory care practices. Unfortunately, most of these strategies have not been successful. To date, the only two treatments developed specifically to prevent CLD whose efficacy is supported by evidence from randomized, controlled trials are the parenteral administration of vitamin A and corticosteroids. Two other therapies, the use of caffeine for the treatment of apnea of prematurity and aggressive phototherapy for the treatment of hyperbilirubinemia were evaluated for the improvement of other outcomes and found to reduce CLD. Cohort studies suggest that the use of CPAP as a strategy for avoiding mechanical ventilation might also be beneficial. Other therapies reduce lung injury in animal models but do not appear to reduce CLD in humans. The benefits of the efficacious therapies have been modest, with an absolute risk reduction in the 7–11% range. Further preventive strategies are needed to reduce the burden of this disease. However, each will need to be tested in randomized, controlled trials, and the expectations of new therapies should be modest reductions of the incidence of the disease.
chronic lung disease; bronchopulmonary dysplasia; prevention; prophylaxis; vitamin A; corticosteroids; caffeine
Patent ductus arteriosus (PDA) is a common diagnosis among extremely premature infants, especially in those with lung disease. Treatments are often used to close the PDA. Despite nearly three decades of research, the question of whether the benefits of treatments to prevent ductal patency or promote closure outweigh the risks of these treatments remains unanswered. The authors rarely use treatments designed to close the PDA. This article reviews three considerations in support of this restrained approach: rates of spontaneous closure of the ductus arteriosus; adverse effect of persistent ductal patency; and benefits and risks of treatments for closure.
patent ductus arteriosus; indomethacin; ibuprofen; ductal ligation
Improvement in survival of extremely premature infants over the past several decades has resulted in an increase in the number 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 antenatal predictors of CLD.
Patients and Methods
We collected data about antenatal, placental and neonatal characteristics of 1241 newborns delivered before completion of the 28th week of gestation who were enrolled in a 14-center, observational study conducted during the years 2002-2004. Associations between antenatal 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 antenatal factors, particularly fetal growth restriction (FGR), to CLD risk.
Among the antenatal factors, birth weight Z-score, 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 antenatal, 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 antenatal 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. Future investigations should focus on the impact of FGR on growth factors that modulate lung growth.
chronic lung disease; bronchopulmonary dysplasia; prematurity; preterm infant
Extremely low gestational age newborns (ELGANs) are at increased risk of chronic lung disease (CLD) and of developmental delay. Some studies have suggested that CLD contributes to developmental delay.
Patients and Methods
We examined data collected prospectively on 915 infants born before the 28th week of gestation in 2002–2004 who were assessed at 24 months of age with the Bayley Scales of Infant Development-2nd Edition or the Vineland Adaptive Behavior Scales. We excluded infants who were not able to walk independently (Gross Motor Function Classification System score < 1) and, therefore, more likely to have functionally important fine motor impairments. We defined CLD as receipt of oxygen at 36 weeks' postmenstrual age and classified infants as either not receiving mechanical ventilation (MV) (CLD without MV) or receiving MV (CLD with MV).
Forty-nine percent of ELGANs had CLD; of these, 14% were receiving MV at 36 weeks' postmenstrual age. ELGANs without CLD had the lowest risk of a Mental Developmental Index (MDI) or a Psychomotor Developmental Index (PDI) of <55, followed by ELGANs with CLD not receiving MV, and ELGANs with CLD receiving MV (9%, 12%, and 18% for the MDI and 7%, 10%, and 20% for the PDI, respectively). In time-oriented multivariate models, the risk of an MDI of <55 was associated with the following variables: gestational age of <25 weeks; single mother; late bacteremia; pneumothorax; and necrotizing enterocolitis. The risk of a PDI of <55 was associated with variables such as single mother, a complete course of antenatal corticosteroids, early and persistent pulmonary dysfunction, pulmonary deterioration during the second postnatal week, pneumothorax, and pulmonary interstitial emphysema. CLD, without or with MV, was not associated with the risk of either a low MDI or a low PDI. However, CLD with MV approached, but did not achieve, nominal statistical significance (odds ratio: 1.9 [95% confidence interval: 0.97–3.9]) for the association with a PDI of <55.
Among children without severe gross motor delays, risk factors for CLD account for the association between CLD and developmental delay. Once those factors are considered in time-oriented risk models, CLD does not seem to increase the risk of either a low MDI or a low PDI. However, severe CLD might increase the risk of a low PDI.
lung disease; prematurity; preterm infant; neurodevelopmental outcome
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).
Patients and Methods
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 ≥ 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.
lung disease; prematurity; preterm infant
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.
The cohort included 1507 extremely low gestational age newborns born at 23 weeks to
276/7 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.
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.
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.
premature infant; blood pressure; hypotension