http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1031740

ORIGINAL ARTICLE

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Death or survival with major morbidity in VLBW infants born at Brazilian neonatal research network centers Ruth Guinsburg1, Maria Fernanda Branco de Almeida1, Junia Sampel de Castro1, Rita C. Silveira2, Jamil Pedro de Siqueira Caldas3, Humberto Holmer Fiori4, Maryne´a Silva do Vale5, Vaˆnia Olivetti Steffen Abdallah6, Laura Emilia Monteiro Bige´lli Cardoso7, Navantino Alves Filho8, Maria Elisabeth Moreira9, Ana Lucia Acquesta10, Lı´gia S. Lopes Ferrari11, Maria Regina Bentlin12, Paulyne Stadler Venzon13, Walusa Assad Gonc¸alves Ferri14, Jucille do Amaral Meneses15, Edna Maria De Albuquerque Diniz16, Dulce Maria Toledo Zanardi17, Cristina Nunes Dos Santos18, Jose´ Luiz Bandeira Duarte19, and Maria Albertina Santiago Rego20 1

Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil, 2Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil, 3Hospital da Mulher Prof. Jose´ Aristodemo Pinotti, Centro de Atenc¸a˜o Integral a` Sau´de da Mulher, Universidade Estadual de Campinas, Campinas, Sa˜o Paulo, SP, Brazil, 4Department of Pediatrics, Pontifı´cia Universidade Cato´lica do Rio Grande do Sul, Porto Alegre, RS, Brazil, 5Hospital Universita´rio da Universidade Federal do Maranha˜o, Sa˜o Luı´s, MA, Brazil, 6Hospital de Clı´nicas, Faculdade de Medicina, Universidade Federal de Uberlaˆndia, Uberlaˆndia, MG, Brazil, 7Hospital das Clı´nicas, Faculdade de Medicina, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil, 8Faculdade de Cieˆncias Me´dicas de Minas Gerais, Belo Horizonte, MG, Brazil, 9Instituto Fernandes Figueira da Fundac¸a˜o Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brazil, 10Hospital Geral de Pirajussara, Sa˜o Paulo, SP, Brazil, 11Hospital Universita´rio da Universidade Estadual de Londrina, Londrina, PR, Brazil, 12Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brazil, 13 Department of Pediatrics, Universidade Federal do Parana´, Curitiba, PR, Brazil, 14Faculdade de Medicina de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Sa˜o Paulo, SP, Brazil, 15Instituto de Medicina Integral Prof Fernando Figueira, Recife, PE, Brazil, 16Hospital Universita´rio da Faculdade de Medicina, Universidade de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil, 17Hospital Estadual Sumare´, Sumare´, SP, Brazil, 18Hospital Estadual de Diadema, Diadema, Sa˜o Paulo, SP, Brazil, 19Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil, and 20Hospital das Clı´nicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil Abstract

Keywords

Objective: To analyze unfavorable outcomes at hospital discharge of preterm infants born at Brazilian public university centers. Methods: Prospective cohort of 2646 inborn infants with gestational age 23–33 weeks and birth weight 400–1499 g, without malformations, born at 20 centers in 2012–2013. Unfavorable outcome was defined as in-hospital death or survival at hospital discharge with 1 major morbidities: bronchopulmonary dysplasia (BPD) at 36 corrected weeks, intraventricular hemorrhage (IVH) grades 3–4, periventricular leukomalacia (PVL) or surgically treated retinopathy of prematurity (ROP). Results: Among 2646 infants, 1390 (53%) either died or survived with major morbidities: 793 (30%) died; 497 (19%) had BPD; 358 (13%) had IVH 3–4 or PVL; and 84 (3%) had ROP. Logistic regression adjusted by center showed association of unfavorable outcome with: antenatal steroids (OR 0.70; 95%CI 0.55–0.88), C-section (0.72; 0.58–0.90), gestational age 530 (4.00; 3.16– 5.07), being male (1.44; 1.19–1.75), small for gestational age (2.19; 1.72–2.78), 5th-min Apgar57 (3.89; 2.88–5.26), temperature at NICU admission 536.0  C (1.42; 1.15–1.76), respiratory distress syndrome (3.87; 2.99–5.01), proven late sepsis (1.33; 1.05–1.69), necrotizing enterocolitis (3.10; 2.09–4.60) and patent ductus arteriosus (1.69; 1.37–2.09). Conclusions: More than half of the VLBW infants born at public university level 3 Brazilian hospitals either die or survive with major morbidities.

Bronchopulmonary dysplasia, intraventricular hemorrhage, neonatal mortality, periventricular leukomalacia, preterm newborn infant, retinopathy of prematurity, very low birth weight newborn infant

Introduction The survival of preterm infants reflects the quality of antenatal care, assistance during labor and birth and neonatal Address for correspondence: Ruth Guinsburg, Escola Paulista de Medicina, Universidade Federal de Sa˜o Paulo, R. Vicente Felix 77 apt 09, Sa˜o Paulo, SP, Brazil, CEP 01410-020. Tel: (55-11) 99635-4250. E-mail: [email protected]

History Received 23 January 2015 Revised 18 February 2015 Accepted 17 March 2015 Published online 2 April 2015

care. According to the 2012 ‘‘Born Too Soon: The Global Action Report on Preterm Birth’’ of the World Health Organization, Brazil is ranked 10th among the countries with the highest number of preterm live births and 16th in deaths due to complications of prematurity [1]. The data from 2012 indicate that approximately 3 million babies are born in Brazil each year, 350 000 of whom are born with less than 37 weeks of gestation. Among these, 45 000 are born at a

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gestational age of 32 weeks or less, and 40 000 are very low birth weight (VLBW) infants [2]. VLBW preterm infants are prone to present severe clinical complications during hospitalization immediately after birth, including systemic infections, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL) and retinopathy of prematurity (ROP). These morbidities expose patients to a greater number of diagnostic and therapeutic interventions and are associated with adverse long-term neurodevelopmental outcomes, such as cerebral palsy, cognitive delay, hearing loss and blindness [3,4]. Therefore, mortality or survival with major morbidities is an indicator of the quality of perinatal care. According to a 2009 report from the Vermont Oxford Network, 12.4% of the 43 566 infants with a BW of 500– 1500 g born at 669 North American units died before hospital discharge, and the survivor morbidities were distributed as follows: 26.3% had BPD; 6.1% had IVH grades III or IV (IVH III/IV); 2.7% had PVL; and 6.8% had ROP stages III to V [5]. In its 2012 report, the European network EuroNeoNet reported a 10% frequency of in-hospital deaths among 5765 VLBW infants admitted to 38 neonatal units in 11 countries. The incidence of major morbidities in these infants was 12% for BPD, 7% for severe IVH, 1% for PVL and 1% for severe ROP [6]. In a 2008 Swiss population study, with a sample of 842 infants born in nine neonatal units at a gestational age of 23–31 weeks and a BW of 400–1500 g, in-hospital deaths occurred in 13%, and BPD and/or IVH III/IV and/or PVL and/ or ROP occurred in 28% of the survivors [7]. In a 2008 study from Japan, among 3806 VLBW births at 78 centers, the inhospital mortality rate was 8.7%, and the incidence of major morbidities was 14.3% for BPD, 4.1% for IVH III/IV, 3.3% for PVL and 12.5% for surgically treated ROP [8]. The data from 8234 preterm infants born at a gestational age of 24–31 weeks and a BW of 500–1500 g in 15 units of the South American Neocosur Network of Argentina, Chile, Paraguay, Peru and Uruguay between 2001 and 2011 were published in 2014 and revealed an in-hospital mortality rate of 25.8%. Furthermore, the incidence of major morbidities among the live births was of 25% for BPD, 7% for IVH III/IV, 5% for PVL, 31% for any degree of ROP and 10.9% for NEC. Among the 6060 survivors, 53% exhibited one of the above conditions [9]. In Brazil, there are few data on the survival of VLBW preterm infants with major morbidities. In this context, the objective of the present study was to determine the in-hospital mortality or survival with major morbidities of VLBW preterm infants born at units of the Brazilian Neonatal Research Network (RBPN, for its acronym in Portuguese).

Methods The present work involves a prospective cohort of preterm infants born at 20 university hospitals that assist public patients from the Brazilian Unified Health System, located in 15 municipalities across seven Brazilian states. All the patients born between January 2012 and December 2013 with 230/7 and 336/7 weeks of gestational age, birth weight between 400 and 1499 g and no congenital malformation, were included.

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At each center, two to three neonatologists entered maternal and neonatal information into an electronic online database of the RBPN. Gestational age, in completed weeks, was determined by the date of the last menstrual period, followed by the first-trimester ultrasound and, if both were unavailable, by a physical exam of the newborn. Smallfor-gestational-age (SGA) was defined according to Olsen et al [10]. Hypothermia at admission to the neonatal intensive care unit (NICU) was determined by an axillary temperature below 36.0  C [11]. The SNAPPE-II (Score for Neonatal Acute Physiology and Perinatal Extension) severity score was calculated within the first 12 h of life [12]. The primary outcome was the occurrence of in-hospital death or the presence of BPD, IVH III/IV, PVL and/or surgically treated ROP. Death or survival with one or more of the above morbidities was considered an unfavorable neonatal outcome. BPD was determined as the requirement for inspired oxygen at a fraction above 0.21 at a corrected GA of 36 weeks [13]. IVH was diagnosed by cranial ultrasound or by necropsy and was classified according to Papille et al. [14], being severe IVH those with degrees III or IV. PVL was diagnosed by the presence of intraparenchymal white matter cystic lesions observed via a cranial ultrasound performed during hospitalization [15]. ROP was evaluated by indirect ophthalmoscopy at all the centers and was classified according to the International Committee for the Classification of Retinopathy of Prematurity [16]. Patients who required surgical intervention were included in the analysis. Patients were classified according to the presence or not of an unfavorable outcome, and both groups were then compared by descriptive statistics with chi-square for qualitative data and t-test for numerical variables. Independent factors associated with an unfavorable outcome for the study population were determined by backwards stepwise multiple logistic regression analysis, including all the maternal, delivery and neonatal morbidity variables that had a p value 50.20 in the univariate analysis [17]. The independent variables were removed one by one from the model according to their adjusted significance by Wald test. Fitness of the model was tested by Hosmer-Lemeshow test. The SPSS software (IBM SPSS Statistics for Windows, Version 21.0. IBM Corp., Armonk, NY) was used. The research project was approved by the coordinators of each of the 20 RBPN units and by the Research Ethics Committee of Instituto Fernandes Figueira – Fundac¸a˜o Oswaldo Cruz, Rio de Janeiro, Brazil, the leading center for database evaluation in the network.

Results During the study, 3629 VLBW preterm infants were born in the 20 RBPN units, of which 2818 met the inclusion criteria. No information was available for 228 (8%) of the patients regarding a cranial ultrasound or indirect ophthalmoscopy. Therefore, unfavorable outcomes were analyzed for a total of 2646 patients, of whom 793 (30%) died, 497 (19%) had BPD, 277 (10%) had severe IVH, 160 (6%) presented with PVL and 84 (3%) developed ROP that required surgery, totaling 1390 (53%) cases with an unfavorable outcome. Among the 1853 survivors at hospital discharge, 456 (29%) had BPD, while 153 (8%) had severe IVH and 120 (6%) had

Outcome of VLBW infants born at Brazilian neonatal network centers

DOI: 10.3109/14767058.2015.1031740

Table 1. Maternal characteristics of the 2646 infants classified according to the presence or absence of unfavorable outcome (in-hospital death, bronchopulmonary dysplasia at 36 corrected weeks, intraventricular hemorrhage grades 3–4, periventricular leukomalacia or surgically treated retinopathy of prematurity).

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Unfavorable outcome

Maternal age 520 years Maternal age 435 years Schooling 58 years Prenatal care Multiple gestation Hypertension Diabetes Chorioamnionitis Abruptio or previa Antenatal corticosteroids Cesarean section Gestational age (weeks) Gestational age 530 weeks

Present n ¼ 1390

Absent n ¼ 1256

p value

254 (18%) 166 (51%) 366 (27%) 1238 (89%) 253 (18%) 457 (33%) 74 (5%) 238 (17%) 159 (12%) 940 (68%) 799 (58%) 27.4 ± 2 1136 (82%)

228 (18%) 1224 (53%) 303 (25%) 1155 (92%) 272 (22%) 529 (42%) 86 (7%) 134 (11%) 95 (8%) 1023 (82%) 870 (69%) 29.9 ± 2 587 (47%)

0.936 0.575 0.127 0.011 0.026 50.001 0.102 50.001 0.001 50.001 50.001 50.001 50.001

Abruptio or previa, abruptio placentae or placenta previa.

Table 2. Neonatal characteristics of the 2646 infants classified according to the presence or absence of unfavorable outcome (in-hospital death, bronchopulmonary dysplasia at 36 corrected weeks, intraventricular hemorrhage grades 3–4, periventricular leukomalacia or surgically treated retinopathy of prematurity). Unfavorable outcome

Birth weight (g) Birth weight 51000 g Male Small for gestational age 5th-minute Apgar 0–6 Hypothermia at NICU admission SNAPPE II Hypoglycemia Respiratory distress syndrome Air leaks PDA with surgical closure Early sepsis with positive BC Late sepsis with positive BC Necrotizing enterocolitis

Present n ¼ 1390

Absent n ¼ 1256

p value

867 ± 257 982 (71%) 742 (53%) 459 (33%) 430 (31%) 868 (68%) 38 ± 24 346 (26%) 1184 (90%) 136 (10%) 115 (9%) 56 (4%) 369 (28%) 149 (11%)

1156 ± 211 297 (24%) 558 (44%) 423 (34%) 72 (6%) 732 (59%) 15 ± 14 200 (16%) 748 (60%) 15 (1%) 17 (1%) 20 (2%) 230 (18%) 56 (5%)

50.001 50.001 50.001 0.720 50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001 50.001

SNAPPE II, Score for Neonatal Acute Physiology, Perinatal Extension, Version II; PDA, persistent ductus arteriosus; BC, blood culture.

PVL; 84 (5%) presented with ROP that required surgical intervention. The frequency of unfavorable outcome at hospital discharge varied from 40 to 79% among the 20 RBPN centers, with a mean value of 53%. When patients were classified according to gestational age [18], unfavorable outcome was present in 80% of the 1005 extremely preterm (528 weeks); in 39% of the 1342 very preterm (28–31 weeks); and in 20% of the 299 moderate preterm infants (32–33 weeks). The comparison between groups classified according to the presence or absence of an unfavorable outcome regarding maternal characteristics and neonatal morbidity are listed in Tables 1 and 2, respectively.

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The results from the logistic regression analysis adjusted by center and multiple gestations are expressed as odds ratios (ORs) and 95% confidence intervals (95%CIs). Protective factors with respect to an unfavorable outcome were the exposure to antenatal steroids (OR 0.70; 95%CI 0.55–0.88) and cesarean delivery (0.72; 0.58–0.90). The following factors were associated with a higher risk for an unfavorable outcome: GA 530 weeks (4.00; 3.16–5.07), male sex (1.44; 1.19–1.75), being small for gestational age (2.19; 1.72–2.78); a 5-min Apgar score of 0–6 (3.89; 2.88–5.26), a temperature at admission to the NICU 536.0  C (1.42; 1.15–1.76), the occurrence of respiratory distress syndrome (RDS) (3.87; 2.99–5.01), proven late sepsis (1.33; 1.05–1.69), NEC (3.10; 2.09–4.60) and patent ductus arteriosus (PDA) with the need for surgical ligation (1.69; 1.37–2.09).

Discussion In the 20 RBPN units, 3629 VLBW preterm infants were born between 2012 and 2013, accounting for 4.8% of all VLBW Brazilian live births [2], of whom 2646 (71%) had a gestational age of 23–33 weeks, a birth weight of 400 g or more, an absence of malformations and known studied outcomes. Among the latter, 30% died in the hospital, and 53%died or survived with one or more of the following morbidities: BPD, severe IVH, PVL and/or surgically treated ROP. Biological variables and factors regarding perinatal care were associated with the analyzed outcome, with an emphasis on the exposure to antenatal corticoids, the type of delivery, vitality at birth and cardiorespiratory and infectious diseases after birth. When comparing the in-hospital mortality rate of this cohort of VLBW preterm infants from Brazil with the international data, the mortality rate appears to be three times higher than that described in reports from European and North American neonatal networks and from populational studies from Switzerland and Japan, which varied within 9– 13% of all VLBW preterm between 2008 and 2012 [5–8]. The data on 8234 VLBW live births from South America for the years 2001 to 2011 are similar to those from Brazil, with 26% in-hospital deaths [9]. In addition to the observed high mortality rate, the incidence of major morbidities in infants born at the RBPN centers was higher than in Japan, Europe and Switzerland [6–8], except for BPD, as follows: 9% versus 12–15% for BPD, 10% versus 4–7% for severe IVH, 6% versus 1–3% for LPV and 3% versus 2–3% for severe and/or surgically treated ROP. If considering only the survivors, the frequency of morbidities in the VLBW preterm infants at hospital discharge evaluated in this study was also higher than what has been described in the North American Vermont Oxford Network centers (29% versus 26% for BPD, 8% versus 6% for severe IVH, 6% versus 3% for PVL), and the frequency of surgically treated ROP in the RBPN database was 5% versus 7% ROP grade III in North America [5]. Notably, the outcomes analyzed in the cohort of Brazilian preterm infants with a birth weight of 400–1499 g and a gestational age of 23 to 33 weeks are similar to those described 10 years ago by the American Neonatal Research Network for extremely preterm infants. In this study of 13 085 neonates with a gestational age of 22–31 weeks born between 1998 and 2005, 3732 (29%)

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died during the neonatal period, with frequencies of morbidities among survivors of 27% for BPD, 6% for severe IVH and 5% for PVL [19]. Of note, there was a large variation regarding the incidence of an unfavorable outcome according to the birth center, with percentages ranging from 40 to 79%. This variation between centers regarding the mortality and morbidity of VLBW neonates has been reported in several studies [20–23]. Such differences can be explained both by the characteristics of the population of each unit and their inherent risks, and, more importantly, by the set of diagnostic and therapeutic interventions performed in each center, the effects of which cannot be evaluated separately [23]. Such interventions comprise obstetric care in the antenatal phase and during delivery and neonatal care immediately after birth and in the NICU. Among the reasons for a better performance with respect to neonatal outcomes in a given center, compared to other centers of the same network with an equivalent quality of data collection, is the presence of a group of health care professionals interested in improving the prognosis of preterm infants at the verge of viability who implement this organized set of interventions, with results that extend to more mature patients [24]. Among the factors associated with an unfavorable outcome for the cohort of preterm infants analyzed in the present study, four groups of variables stand out, namely, those associated with obstetric care (the absence of exposure to antenatal corticoids, vaginal delivery), those related to biological variables (prematurity less than 30 weeks, restricted intrauterine growth, male sex), those associated with assistance at birth (5-min Apgar score of 0–6, hypothermia at the time of admission to the NICU) and those related to intensive care (RDS, PDA, late sepsis, NEC). These results point to areas for quality improvement in perinatal care, specifically increasing the use of antenatal corticoids, stabilizing the newborn at birth, focusing on the prevention of hypothermia in the delivery room and training NICU health care professionals, with respect to respiratory care, hemodynamic monitoring and, most importantly, the prevention of hospital-acquired infections. Antenatal corticosteroids are among the interventions with proven efficacy in reducing complications of prematurity and neonatal mortality [25]. In the present study, at least one dose of the medication had been administered to 82% of the patients who exhibited no major morbidity at hospital discharge and to only 68% of those with an unfavorable outcome. A study from the American Neonatal Research Network with data obtained between 2002 and 2008 from 8858 births with birthweight between 401 and 1000 g reports that antenatal corticoids were used in 62% of births with a gestational age between 22 and 24 weeks and in 87% of those with a GA between 25 and 27 weeks [24]. As for perinatal asphyxia, the presence of this complication is known to be associated with high mortality in preterm infants. A study of the American Neonatal Research Network of 125 542 live births with 22–31 weeks of gestational age found an 8% incidence of infants with a 5th-min Apgar score below 4, showing that resuscitation is frequently necessary in this population [26]. At the same time, the need for advanced resuscitation practices in the delivery room is associated with high mortality and an increased frequency of morbidity in

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survivors [27]. In the present study, the persistence of a 5-min Apgar score below 7 increased the chances of an unfavorable outcome by four for the analyzed cohort. Regarding hypothermia at admission to the NICU, a study from the RBPN [28] of 1764 births with 23–33 weeks of gestational age showed that hypothermia contributed independently to early neonatal mortality, increasing the risk by 64%. In the present study, these findings are extended because the presence of an axillary temperature536.0  C at admission increased the chances of in-hospital death or survival with a major morbidity by 42% in VLBW preterm infants. The presence of RDS, PDA, late sepsis and NEC as factors strongly associated with an unfavorable outcome for preterm infants in the present study indicates the existence of failures in the implementation of quality improvements based on better practices in the evaluated units. The training initiatives in neonatal care have been shown to improve short-term clinical care and to have an impact on middle- and long-term outcomes [29]. In past years, the foundation of RBPN has allowed for the comparison of outcomes between the diverse Brazilian centers that are part of the network and for the identification of units with better indicators in any given area. The practices associated with these good indicators are investigated in these centers with the goal of serving as an example for the implementation of improvements in the remaining units. That is, there has been an effort to qualify RBPN services to reduce the incidence of the above complications and their impact on neonatal outcomes. However, one must take into account that the organizational efficiency in implementing these initiatives can take several years [30]. There are some limitations to the present study, especially regarding the short-term outcome, i.e. up to hospital discharge, which does not allow for the extrapolation of the data to predict childhood neurodevelopment. Further, the short period of the study of only 2 years does not allow for evaluating the development over the years. Nevertheless, this is the first Brazilian multicenter study that reports data on in-hospital death or survival with major morbidities of VLBW preterm infants born in public hospital units and are national training centers for neonatologists. Of note, the analyzed cohort corresponds to 4.8% of all VLBW births in Brazil, for which data were collected in a prospective and systematic manner, with rigorous definitions of each event and data continuously entered into the electronic database, which was checked for consistency and independently verified by an internal committee. In conclusion, more than half of the VLBW preterm infants born in public university centers at a gestational age GA of 23–33 weeks died or were discharged with severe pulmonary, neurological or ophthalmological complications. The occurrence of unfavorable outcome was inversely proportional to gestational age, reaching 80% of the extremely preterm infants. After evaluating the factors associated with an unfavorable outcome, it is of paramount importance to act by extending the use antenatal corticosteroids from an obstetric perspective. From the neonatal point of view, assistance in the delivery room with effective resuscitation and the minimization of hypothermia are fundamental, as are the ventilatory assistance of newborn infants and the prevention of hospital-acquired infections. Studies focusing on

DOI: 10.3109/14767058.2015.1031740

Outcome of VLBW infants born at Brazilian neonatal network centers

quality improvement strategies for obstetric and neonatal care in the Brazilian context would help to overcome this unfavorable picture.

Acknowledgements We thank Olga Bomfim, MD, Cynthia Magluta, MD, PhD, and Francisco E. Martinez, MD, PhD, for helping with the administration of Brazilian Network on Neonatal Research.

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Declaration of interest BRAZILIAN NETWORK ON NEONATAL RESEARCH (Rede Brasileira de Pesquisas Neonatais RBPN). Health Ministry of Brazil (Ministe´rio da Sau´de do Brasil (MS/ VIGISUS 1755/2000; MS/FNS 274; FIOCRUZ/PDTSP) funded this study. The authors declare no conflicts of interest. Ruth Guinsburg and Maria Fernanda Branco de Almeida conceptualized and designed the study, carried out all study’s analyses, drafted the initial article, reviewed and revised the article, and approved the final article as submitted. Ana Lucia Acquesta, Cristina Nunes Dos Santos, Dulce Maria Toledo Zanardi, Edna Maria De Albuquerque Diniz, Humberto Holmer Fiori, Jamil Pedro de Siqueira Caldas, Jose´ Luiz Bandeira Duarte, Jucille do Amaral Meneses, Junia Sampel de Castro, Laura Emilia Monteiro Bige´lli Cardoso, Lı´gia S. Lopes Ferrari, Maria Albertina Santiago Rego, Maria Elisabeth Moreira, Maria Regina Bentlin, Maryne´a Silva do Vale, Navantino Alves Filho, Paulyne Stadler Venzon, Rita C. Silveira, Vaˆnia Olivetti Steffen Abdallah, and Walusa Assad Gonc¸alves Ferri: helped to design and plan the study, coordinated and supervised data collection at each site, critically reviewed the article, and approved the final article as submitted.

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Death or survival with major morbidity in VLBW infants born at Brazilian neonatal research network centers.

To analyze unfavorable outcomes at hospital discharge of preterm infants born at Brazilian public university centers...
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