Abstract
Objective
To identify sociodemographic and clinical factors associated with withholding or withdrawing life-sustaining treatment (WWLST) for extremely low gestational age neonates.
Design
Observational study of prospectively collected registry data from 19 National Institute of Child Health and Human Development Neonatal Research Network centers on neonates born at 22–28 weeks’ gestation who died >12 hours through 120 days of age during 2011–2016. Sociodemographic and clinical factors were compared between infants who died following WWLST and without WWLST.
Results
Of 1168 deaths, 67.1% occurred following WWLST. Withdrawal of assisted ventilation (97.4%) was the primary modality. WWLST rates were inversely proportional to gestational age. Life-sustaining treatment was withheld or withdrawn more often for non-Hispanic white infants than for non-Hispanic black (72.7% vs. 60.4%; 95% CI 1.00–1.92) or Hispanic infants (72.7% vs. 67.2%; 95% CI 1.32–3.72). WWLST rates varied across centers (38.6%–92.6%; p<0.001). The center with the highest rate had adjusted odds 4.89 times greater than the average (95% CI 1.18–20.18). The adjusted odds of WWLST were higher for infants with necrotizing enterocolitis (OR 1.77; 95% CI 1.21–2.59) and severe brain injury (OR 1.98; 95% CI 1.44–2.74).
Conclusions
Among infants who died, WWLST rates varied widely across centers and were associated with gestational age, race, ethnicity, necrotizing enterocolitis, and severe brain injury. Further exploration is needed into how race, center, and approaches to care of infants with NEC and severe brain injury influence WWLST.
Keywords: preterm neonates, end-of-life care
Introduction
Most neonatal deaths in the United States (US), Canada and Australia occur after withholding or withdrawing life-sustaining treatment (WWLST).(1–5) For extremely low gestational age neonates (ELGANs), this occurs via shared decision-making between parents and neonatologists.(6–10) Besides gestational age (GA) and birth weight, little is known about factors that contribute to WWLST or how WWLST varies across centers for ELGANs who have life-sustaining treatment initiated in the delivery room. A few small, single-center studies (1, 3, 4) provide limited data on sociodemographic and medical factors associated with treatment limitation for ELGANs. Understanding factors that contribute to WWLST may guide medical professionals on how best to support families of ELGANs during the shared decision-making process.(11) We hypothesized that, among infants who died, WWLST would be influenced by GA, race, ethnicity, socioeconomic factors, center, and medical diagnoses.
The aims of this study were to understand which modalities of life-sustaining treatment were withdrawn or limited, to examine associations between medical and sociodemographic characteristics of ELGANs who underwent WWLST, and to assess center variations in WWLST.
Methods
Study Design
This was a retrospective analysis of data that were prospectively collected in the Eunice Kennedy Schriver National Institute of Child Health and Human Development (NICHD) high-risk preterm infant registry at 19 Neonatal Research Network (NRN) centers. The Institutional Review Board at each center approved the high-risk preterm infant registry. In 3 centers, written or verbal consent was obtained from the parent or guardian, and in the other 22 centers, a consent was waived by the Institutional Review Board on the basis of de-identification of data and minimal risk of harm.
Study Population
We included infants with GA 22 0/7 through 28 6/7-weeks and/or birth weight 401–1,000 grams who were born from April 2011 through December 2016 and who died after 12 postnatal hours through 120 postnatal days. Infants who died within the first 12 postnatal hours were excluded because actions taken to limit initial resuscitation, possibly due to obstetric or neonatal assessment of nonviability, could confound the results.(12) In addition, morbidity data was not available for these infants. Infants who died after 120 postnatal days were excluded due to the incomplete availability of morbidity data between 120 days and death. Infants were classified into two groups: those who died following WWLST and those who died without WWLST.
Data Collection
Data were abstracted from medical charts by trained NRN coordinators.(13) Data included maternal and infant sociodemographic characteristics, pregnancy and delivery information, and infants’ clinical course and morbidities during hospitalization. Race and ethnicity were self-reported by mothers. Specific information from questions about ethics and palliative care were collected for all infants. These questions provided data on (1) whether intubation/ventilation, nutrition/hydration, or medications were withheld or withdrawn with the intent to limit care between 12 postnatal hours through 120 days and (2) which of the three modalities were withdrawn. Assignment to the WWLST group required a “yes” response to at least one of the three modalities.
Study Definitions
Ethnicity was categorized as Hispanic or non-Hispanic. All mothers who reported non-Hispanic ethnicity were then categorized by race. Maternal education and insurance were proxies for socioeconomic level. Previously reported NRN definitions of clinical conditions were used.(13) GA, measured in completed weeks, was determined by obstetrical estimate or neonatal exam. Small for gestational age was defined as birth weight below the 10th percentile based on published sex and GA graphs.(14) Bronchopulmonary dysplasia (BPD) was expressed as a categorical variable (none, mild, moderate, severe) based on the NICHD consensus definition.(15) Proven necrotizing enterocolitis (NEC) was defined as modified Bell’s stage II or greater.(16) Severe intracranial hemorrhage (ICH) was established when hemorrhage within the ventricle(s) with ventriculomegaly and/or intraparenchymal hemorrhage was documented by any cranial ultrasound within 28 days chronological age. Cystic periventricular leukomalacia (PVL) and ventriculomegaly were recorded from the cranial ultrasound closest to 28 days chronological age or 36 weeks postmenstrual age.
Statistical Analysis
Demographic information, clinical factors, and NRN center in infants who died following WWLST were compared to those who died without WWLST. The association between WWLST and demographics, birth characteristics, and morbidities was assessed via chi-square test, Fisher’s exact test, or t-test. A multiple logistic regression model was developed for infants who died to associate the probability of WWLST with certain demographic and clinical features, and adjusted for center variation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were generated from this model that included center, birth weight as a continuous variable, GA groups (3 levels: 22–24, 25–26 and 27–28 weeks), sex, maternal age (greater than or equal to 26 years), maternal education (college degree, high school diploma, or no high school diploma), Medicaid insurance, race/ethnicity (4 categories: non-Hispanic white, non-Hispanic black, Hispanic, other), epinephrine administration in the delivery room, proven NEC, and severe ICH or PVL.
Results
Patient Characteristics
Among infants included in the NRN high-risk preterm infant registry during the study period, 7141 survived beyond 12 hours, and of those, 1171 died between 12 hours and 120 days of life. Of the 1171 infants who died, 3 were excluded due to incomplete data; 784 (67.1%) infants had WWLST prior to death and 384 (32.9%) did not.
Modality of Limitation
Among the 784 infants who died following WWLST, 764 (97.4%) had assisted ventilation withdrawn (alone or with withdrawal of hydration/nutrition or medication), while 20 (2.6%) had hydration/nutrition (18) and/or medication (4), but not ventilation, withheld or withdrawn.
Baseline Characteristics
Demographic factors for infants who died following WWLST and without WWLST are described in Table 1. Rates of WWLST were significantly different (p<0.001) across racial and ethnic groups. White infants had a higher rate of WWLST than either black infants or Hispanic infants.
Table 1:
Socio-demographic Factors and Clinical Characteristics of Infants Who Died Following WWLST and Without WWLST
| Socio-demographic Factors | Deaths Preceded by WWLST (n=784) | Deaths Without WWLST (n=384) | p-valuea |
|---|---|---|---|
| Femaleb - n (%) | 338 (43.1) | 173 (45.1) | 0.53 |
| Male - n (%) | 446 (56.9) | 211 (54.9) | |
| Race / Ethnicity | |||
| white - n (%) | 344 (43.9) | 129 (33.6) | |
| black - n (%) | 300 (38.3) | 197 (51.3) | <0.001 |
| Hispanic - n (%) | 92 (11.7) | 45 (11.7) | |
| other or unknown - n (%) | 48 (6.1) | 13 (3.4) | |
| Maternal age >=26 years - n (%) | 490 (62.6) | 207 (53.9) | 0.004 |
| Maternal education | |||
| college degree - n (%) | 140 (17.9) | 53 (13.8) | |
| high school (HS) diploma - n (%) | 288 (36.7) | 170 (44.3) | 0.030 |
| no HS diploma / Unknown - n (%) | 356 (45.4) | 161 (41.9) | |
| Medicaid – n (%) | 427 (54.5) | 243 (63.4) | 0.004 |
| Clinical characteristics | |||
| Birth weight [grams] - mean (standard deviation) | 656.2 (145.3) | 645.6 (148.7) | 0.25 |
| Gestational age [weeksc] - mean (standard deviation) | 24.4 (1.5) | 24.6 (1.6) | 0.011 |
| Gestational age groups [weeksc] | |||
| 22-24 - n (%) | 458 (58.4) | 194 (50.5) | |
| 25-26 - n (%) | 251 (32.0) | 136 (35.4) | 0.014 |
| 27-28 - n (%) | 75 (9.6) | 54 (14.1) | |
| Small for gestational age [Kramerd] – n (%) | 154 (19.6) | 104 (27.2) | 0.004 |
| Respiratory | |||
| Moderate or severe bronchopulmonary dysplasia (BPD)e - n (%) | 37 (4.7) | 14 (3.6) | 0.40 |
| Pulmonary hemorrhage - n (%) | 141 (18.0) | 110 (28.6) | <0.001 |
| Ventilation days - median (25-75th percentile) | 9 (3 - 21) | 8 (3 - 16) | 0.21 |
| Days on oxygen - median (25-75th percentile) | 9 (3 -24) | 9 (3 - 20) | 0.45 |
| Steroids for BPDe - n (%) | 90 (11.9) | 40 (10.6) | 0.54 |
| Infection | |||
| Early onset sepsis (<=72 hours) - n (%) | 41 (5.2) | 18 (4.7) | 0.69 |
| Late onset sepsis (>72 hours) - n (%) | 201 (25.8) | 110 (28.9) | 0.26 |
| Gastrointestinal | |||
| Spontaneous gastrointestinal Perforation - n (%) | 53 (6.8) | 25 (6.5) | 0.88 |
| Proven necrotizing enterocolitis (NEC) - n (%) | 164 (20.9) | 55 (14.3) | 0.007 |
| Neurologyf | |||
| Intracranial hemorrhage (ICH) grade 3/4 - n (%) | 285 (36.4) | 89 (23.2) | <0.001 |
| Periventricular leukomalacia (PVL) - n (%) | 48 (6.1) | 5 (1.3) | <0.001 |
| Ventriculomegaly -n (%) | 275 (35.1) | 89 (23.2) | <0.001 |
| ICH or PVL | 295 (37.6) | 90 (23.4) | <0.001 |
| ICH, PVL or ventriculomegaly - n (%) | 317 (40.4) | 98 (25.5) | <0.001 |
| Ophthalmology | |||
| Retinopathy of prematurity (ROP) – n (%) | 37 (4.7) | 14 (3.6) | 0.40 |
| Other | |||
| Syndromes and malformations - n (%) | 41 (5.2) | 19 (4.9) | 0.83 |
| Delivery Room Epinephrine – n (%) | 48 (6.1) | 28 (7.3) | 0.44 |
| Major surgery n (%) | 199 (25.4) | 86 (22.9) | 0.26 |
| Age at death [days] - mean (standard deviation) | 19.7 (23.8) | 18.5 (22.8) | 0.41 |
| Age at death [days] - median (25th & 75th percentiles) | 10 (3 - 26.5) | 10 (4 - 22.5) | 0.73 |
p-values are chi-square, t-test or Wilcoxon as appropriate; p-values are truncated according to level of significance.
Includes 1 neonate with sex recorded as ambiguous
Gestational Age is measure in completed weeks
Kramer MS, Platt RW, Wen SW, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001;108:E35.
Respiratory definitions: BPD = bronchopulmonary dysplasia, moderate or severe, by NRN consensus definition. Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants. American Journal of Respiratory and Critical Care Medicine, 183, 1715–1722. Steroids for BPD = infant received a dose or course of systemic steroids to prevent or treat BPD or chronic lung disease.
Neurologic definitions: ICH = intracranial hemorrhage, Grade III or IV; PVL = cystic periventricular leukomalacia; measured on either of the cranial ultrasounds closest to 28 days and 36 weeks of life.
Rates of WWLST prior to death varied greatly across centers, ranging from 38.6% to 92.6% with an average rate of 67.1% (Figure 1). Overall, the differences among centers were statistically significant (p<0.001). Racial distribution of WWLST differed by center, ranging from 10.4% to 72.7% for white infants, 3.3% to 78.1% for black infants, 1.7% to 56.3% for Hispanic infants, and 0.6% to 25.9% for other infants. However, these differences were not assessed statistically due to the small number of WWLST infants in specific racial groups at some centers.
Figure 1:
WWLST Among Infants Who Died by Clinical Center
Number above each bar is the percent value for each respective center.
Clinical Characteristics
Infants born at lower GAs had a higher rate of WWLST (70.2% for infants born at 22 to 24 weeks) than those born at higher GAs (58.1% for infants born at 27 to 28 weeks).
The age at death did not differ between infants who died following or without WWLST (Table 1). WWLST was significantly associated with proven NEC (p=0.007), severe ICH or cystic PVL (p<0.001), and severe ICH, cystic PVL, or ventriculomegaly (p<0.001) (Table 1). WWLST was less likely for small for gestational age infants (p=0.004) and infants with pulmonary hemorrhage (p<0.001). Infants who died with and without WWLST had similar rates of late morbidities and late therapies such as moderate or severe BPD (p=0.40), similar days of ventilation (p=0.21), and similar rates of postnatal steroid therapy (p=0.54).
Logistic Regression Model of WWLST
Race and ethnicity associations were analyzed in a logistic regression model of WWLST (Table 2). White infants who died had significantly higher likelihood of WWLST than either black or Hispanic infants (adjusted OR: white vs. black 1.39, 95% CI 1.00–1.92; white vs. Hispanic (2.22, 95% CI 1.32–3.72) who died. Black infants trended towards higher rates of WWLST prior to death than Hispanic infants, but this difference was not statistically significant (adjusted OR 1.59; 95% CI 0.96–2.64). Significant center differences in WWLST remained even after adjustment in the logistic regression model. In the center with the highest odds of WWLST, infants who died had almost 5 times greater adjusted odds of WWLST than infants who died at all centers (adjusted OR 4.89, 95% CI 1.18–20.18). In the center with the lowest odds of WWLST, infants who died had 0.4 lower odds of WWLST compared to all other centers (95% CI 0.24–0.68). In our model, GA remained a significant predictor of WWLST, with infants born at 22–24 weeks GA more likely to die after WWLST (adjusted OR 2.13, 95% CI 1.33–3.40) than infants born at 27–28 weeks. Proven NEC (adjusted OR 1.77, 95% CI 1.21–2.59) and severe ICH or cystic PVL (adjusted OR 1.98, 95% CI 1.44–2.74) also remained highly associated with WWLST.
Table 2:
Logistic Regression Model Describing the Association Between Clinical Factors and WWLST.
| Model Parametera | Adjusted Odds Ratio (95% CI) |
|---|---|
| Center with Highest Oddsb Center with Lowest Oddsb |
4.89 (1.18 - 20.18) 0.40 (0.24 - 0.68) |
| Birth weight (100 gram increase) | 1.06 (0.95 - 1.18) |
| Gestational age | |
| 22-24 vs. 27-28 weeks | 2.13 (1.33 - 3.40) |
| 25-26 vs. 27-28 weeks | 1.55 (0.99 - 2.43) |
| Male | 1.05 (0.80 - 1.38) |
| Maternal age >=26 years | 1.25 (0.93 - 1.67) |
| Maternal education: high school diploma | 1.07 (0.79 - 1.46) |
| Insurance: not Medicaid | 1.10 (0.81 - 1.48) |
| Maternal race | |
| white vs. black | 1.39 (1.00 - 1.92) |
| white vs. Hispanic | 2.22 (1.32 - 3.72) |
| white vs. other | 1.08 (0.54 - 2.18) |
| black vs. Hispanic | 1.59 (0.96 - 2.64) |
| No delivery room epinephrine | 1.43 (0.83 - 2.46) |
| Proven NEC | 1.77 (1.21 - 2.59) |
| ICH grade 3/4 or PVL vs no ICH grade 3/4 and no PVL | 1.98 (1.44 - 2.74) |
This table includes all parameters used in the estimation of the multiple logistic regression model.
Odds Ratios for an individual center are calculated vs.
Discussion
This study describes categories of therapies withdrawn from infants who died following WWLST. It also reports characteristics associated with higher rates of WWLST (race, ethnicity, center, and specific morbidities). This study focuses on medical care options that occur for ELGANs who were resuscitated and survived the immediate postnatal period. We limited analysis to ELGANs who died after 12 hours of age to exclude infants with prenatal and delivery room decisions to withhold initial therapy. WWLST occurred in more than two-thirds of ELGANs who died and was inversely related to GA at birth. These findings are consistent with previously published single-center US and multicenter Canadian, European, and Australian studies.(1–5, 17, 18)
The WWLST analysis from this multicenter study provides new information, including: 1) modality of therapeutic care withheld or withdrawn, 2) variations across different racial and ethnic populations, 3) center differences, 4) an association of WWLST with a small group of morbidities, and 5) the concomitant lack of association with other morbidities.
In this study white infants had a higher rate of WWLST than black or Hispanic infants. This retrospective study could not address the potential reasons for racial and ethnic differences. However, other studies have speculated that values, religious beliefs, and cultural attitudes of both families and healthcare professionals may play a role in these racial and ethnic differences.(17, 19–27) We speculate that trust of medical professionals, communication barriers, and contextual factors such as access to care may also contribute to the differences.(28) Three previous studies have reported racial differences in WWLST for neonates.(29–31) Similar racial disparities have been demonstrated in palliative and end-of-life care for adult and pediatric populations in the US.(32–36)
Varying attitudes of neonatal healthcare professionals can also influence disparities in decisions concerning WWLST. A recent NRN study and another in a pediatric intensive care population described lower rates of discussion about WWLST with black families than white families.(31, 33, 37, 38) Our study examined WWLST occurrence, not discussion. Another study in a pediatric end-of-life care setting reported factors, including physician racial bias, racial similarity, trust, and communication effectiveness, that influenced the relationship between patient and physician and the use of hospice.(35) European and US studies have demonstrated that physician cultural and religious differences, values, and nationally based attitudes about WWLST influence rates of WWLST in neonatal intensive care units.(17, 19–26, 39) Additional research regarding families’ and health professionals’ beliefs, values, and attitudes toward neurodevelopmental disability and chronic medical disorders could illuminate the influence of these biases on neonatal treatment decisions.
The likelihood of WWLST for infants differs widely by NRN center, which is consistent with results from three other multicenter studies.(2, 38, 40) These studies reported variations in the rate of early resuscitation and discussion regarding WWLST by center, and identified a physician’s willingness to propose WWLST and, possibly, the type of conversations between neonatologists and parents as factors contributing to center discrepancies in WWLST. The distribution of WWLST by race across centers in the study varied, though the study was not set up to evaluate these differences. This warrants further examination of the potential interaction between race and center.
The wide variation in WWLST by center prompts questions that require additional investigation. Possible causes of center differences include institutional policy, geographic region, and families’ and neonatologists’ differences in race and ethnicity, religion and spirituality, and culture. Other potential etiologies include local incidences of specific morbidities, medical team experience with difficult discussions, medical team sociodemographic characteristics, availability of palliative care and ethics consultation, and medical team attitudes regarding quality of life, disability, and end-of-life care. Deeper exploration of these center differences may provide important insights into center variations that could affect treatment recommendations and decision-making for ELGANs.
The diagnoses associated with WWLST provide insight into the medical factors prioritized at the time of the WWLST decision. The association between WWLST and neonatal morbidity was limited to only severe ICH, cystic PVL, ventriculomegaly, and proven NEC. These disorders predispose to severe neurodevelopmental delay, short bowel syndrome and/or death. Healthcare professionals and families may worry about the infant’s suffering or perceive quality of life with such disabilities to be poor and eligible for consideration of WWLST. Only pulmonary hemorrhage, which usually causes death acutely, and low weight for gestational age were associated with dying without WWLST. Imminent death may not provide time for a decision regarding WWLST. These results support our expectation that the potential for severe adverse neurodevelopmental outcomes, severe disability, or death increased the likelihood of WWLST.
Importantly, no other morbidities, including BPD, days of ventilation, or postnatal steroid therapy were associated with WWLST. We speculate that neonatologists and parents may perceive infants with severe chronic lung disease to have a better quality of life than those with short bowel syndrome or severe cognitive disability. Alternatively, WWLST may have occurred after 120 days in infants with BPD. Finally, neonatologists and families may find WWLST more difficult after bonding with the infant for many months. Further investigation of these factors is warranted.
The strengths of this study are the large number of participants, the prospective data collection using established definitions, and the inclusion of infants from multiple centers. This study provides unique information by restricting the analysis to the most immature infants, including those near the limit of viability, and investigating center variations, sociodemographic factors, and medical diagnoses associated with WWLST.
The limitations include lack of data about infants who had life-sustaining treatment initiated in the delivery room, but who died in the first 12 hours of life. Infants who died after 120 days were excluded because we did not collect late morbidity data on these infants, possibly affecting data regarding WWLST due to late-occurring morbidities such as BPD. Although prospectively collected, data were limited by medical documentation omissions. We do not have adequate data to make statistical conclusions about the possibly complex inter-relationship between center and race within the context of the multiple logistic regression. Complete information about institutional policies important for decisions to forgo life-sustaining treatment at the various centers was not available; nor was information available regarding palliative care and comfort measures that were provided. Data about the likelihood of death prior to WWLST were not collected. Information concerning shared decision-making processes and/or palliative care team involvement was not available.
Conclusions
This study describes an association between WWLST prior to death and race/ethnicity, hospital center, GA, NEC, and severe ICH, and cystic PVL. These results provide healthcare professionals and others insight into factors influencing WWLST and may aid healthcare professionals counseling families making difficult decisions. This study also raises questions about how race and center differences, including approaches to care of infants with NEC and severe brain injury, influence WWLST. Future research into race/ethnicity, culture, institutional policy, geographic location, disease characteristics, parental involvement in decision making, and characteristics of the healthcare professional discussant is needed to better understand differences in WWLST for these high-risk, ELGANs with the potential for death, severe neurodevelopmental disability, or long-term medical disorders.
What is already known on this topic:
Extremely low gestational age neonates contribute disproportionately to neonatal mortality. Most studies of withholding or withdrawing life-sustaining treatment for infants focused on its incidence and its relationship to gestational age or physicians’ socio-demographic factors. Withholding or withdrawing life-sustaining treatment is inversely related to gestational age in very low birth weight infants and religiosity of physicians.
What this study adds:
We present infants’ socio-demographic and clinical factors associated with withholding or withdrawing life-sustaining treatment for a cohort of extremely low gestational age infants. Specifically, the socio-demographic factors of white race and hospital center were associated with withholding or withdrawing life-sustaining treatment. Necrotizing colitis, intraventricular hemorrhage and/or periventricular leukomalacia were clinical factors associated with withholding or withdrawing life-sustaining treatment.
Acknowledgements
The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network’s Generic Database Study. NICHD staff provided input into the study design, conduct, analysis, and manuscript drafting; NCATS cooperative agreements provided infrastructure support to the NRN. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data collected at participating sites of the NICHD Neonatal Research Network were transmitted to RTI International, the data-coordinating center (DCC) for the network, which stored, managed and analyzed the data included in this study. On behalf of the NRN, Dr. Abhik Das (DCC Principal Investigator) and Mr. John Langer (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
We are indebted to our medical and nursing colleagues and the infants and their parents whose data we collected and analyzed as part of this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chair: Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University (2011–present).
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Abbot R. Laptook, MD; Martin Keszler, MD; Angelita M. Hensman, MS RNC-NIC; Elisa Vieira, RN BSN; Emilee Little, RN BSN.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364) – Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Anna Marie Hibbs, MD; Nancy S. Newman, BA RN.
Children–s Mercy Hospital, University of Missouri Kansas City School of Medicine (U10 HD68284) – William E. Truog, MD; Eugenia K. Pallotto, MD MSCE; Cheri Gauldin, RN BS CCRC; Anne Holmes RN MSN MBA-HCM CCRC; Kathy Johnson RN, CCRC.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, UL1 TR1425) – Kurt Schibler, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC.
Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (U10 HD40492, UL1 TR1117) – Ronald N. Goldberg, MD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Joanne Finkle, RN JD; Matthew M. Laughon, MD MPH; Carl L. Bose, MD; Janice Bernhardt, MS RN; Gennie Bose, RN.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, UL1 TR454) – David P. Carlton, MD; Ellen C. Hale, RN BS CCRC; Yvonne Loggins, RN; Diane I. Bottcher, RN MSN.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Rosemary D. Higgins, MD; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, UL1 TR1108) – Gregory M. Sokol, MD; Leslie Dawn Wilson, BSN CCRC; Dianne E. Herron, RN CCRC; Susan Gunn, NNP CCRC; Lucy Smiley CCRC.
McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, and Memorial Hermann Southwest (UG1 HD87229, U10 HD21373) – Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Julie Arldt-McAlister, RN BSN; Katrina Burson, RN BSN; Allison G. Dempsey, PhD; Patricia W. Evans, MD; M. Layne Lillie, RN BSN; Karen Martin, RN; Sara C. Martin, RN; Georgia E. McDavid, RN; Shawna Rodgers, RN; M. Layne Lillie, RN, BSN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT (ASCP).
Nationwide Children’s Hospital and the Ohio State University Medical Center (U10 HD68278) – Leif D. Nelin, MD; Sudarshan R. Jadcherla, MD; Pablo J. Sánchez, MD; Christine A. Fortney, PhD RN; Ruth Seabrook, MD; Patricia Luzader, RN; Nehal A. Parikh, MD.
RTI International (U10 HD36790) – Dennis Wallace, PhD; Marie G. Gantz, PhD; Jeanette O’Donnell Auman, BS; Margaret Crawford, BS; Carolyn M. Petrie Huitema, MS; Kristin M. Zaterka-Baxter, RN BSN.
Stanford University and Lucile Packard Children’s Hospital (U10 HD27880, UL1 TR1085) – Krisa P. Van Meurs, MD; David K. Stevenson, MD; M. Bethany Ball, BS CCRC; Melinda S. Proud, RCP.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216) – Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN.
University of California - Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (U10 HD68270) – Uday Devaskar, MD; Meena Garg, MD; Teresa Chanlaw, MPH; Rachel Geller, RN BSN.
University of Iowa and Mercy Medical Center (U10 HD53109, UL1 TR442) – Dan L. Ellsbury, MD; Tarah T. Colaizy, MD MPH; Jane E. Brumbaugh, MD; Karen J. Johnson, RN BSN; Jacky R. Walker, RN; Donia B. Campbell, RNC-NIC.
University of New Mexico Health Sciences Center (U10 HD53089, UL1 TR1449) – Kristi L. Watterberg, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Sandra Sundquist Beauman, MSN RNC-NIC.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (U10 HD68244) – David Munson, MD; Barbara Schmidt, MD MSc; Sara B. DeMauro, MD MSCE; Aasma S. Chaudhary, BS RRT; Soraya Abbasi, MD; Toni Mancini, RN BSN CCRC.
University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (U10 HD68263, UL1 TR42) – Carl T. D’Angio, MD; Ronnie Guillet, MD PhD; Satyan Lakshminrusimha, MD; Rosemary L. Jensen; Linda Reubens, RN CCRC; Anne Marie Reynolds, MD MPH; Ann Marie Scorsone, MS CCRC; Ashley Williams, MSEd; Karen Wynn, RN; Deanna Maffett, RN; Diane Prinzing; Julianne Hunn, BS; Stephanie Guilford, BS; Mary Rowan, RN; ; Michael Sacilowski, MAT CCRC Holly I.M. Wadkins, MA.
University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689) – Myra Wyckoff, MD; Pablo J. Sánchez, MD; Luc P. Brion, MD; Diana M. Vasil, MSN BSN; Lijun Chen, PhD RN; Alicia Guzman; Lizette E. Lee, RN.
Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385) – Rebecca Bara, RN BSN; John Barks MD; Mary Christensen RT, Stephanie Wiggins MS, Diane White RT
Funding: The National Institutes of Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (UG1 HD27904, UG1 HD21364, UG1 HD68284, UG1 HD27853, UG1 HD40492, UG1 HD27851, UG1 HD27856, UG1 HD87229, UG1 HD21373, UG1 HD68278, UG1 HD36790, UG1 HD27880, UG1 HD34216, UG1 HD68270, UG1 HD53109, UG1 HD53089, UG1 HD68244, UG1 HD68263, UG1 HD40689, UG1 HD21385) and the National Center for Advancing Translational Sciences (UL1 TR1425, UL1 TR1117, UL1 TR454, UL1 TR1108, UL1 TR1085, UL1 TR442, UL1 TR1449, UL1 TR42) provided grant support for the Neonatal Research Network. Although the National Institute of Child Health and Human Development staff did have input into the study design, conduct, analysis, and manuscript drafting, the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funded by the National Institutes of Health.
Footnotes
Conflict of Interest: The authors declare they have no conflict of interest regarding the publication of this article.
Clinical Trial Registration: ClinicalTrials.gov ID Generic Database: NCT00063063
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