Abstract

Introduction

While infant mortality has decreased in the world, due mainly to a constant decline in post-neonatal mortality, neonatal mortality has become the most important component of infant mortality ¹. In Brazil, prematurity is the leading cause of neonatal death and 70% of the deaths on the first day of life ²2 . Victora CG, Aquino EM, do Carmo Leal M, Monteiro CA, Barros FC, Szwarcwald CL. Maternal and child health in Brazil: progress and challenges. Lancet 2011; 377:1863-76. ^{, 3}3 . Departamento de Análise de Situação de Saúde, Secretaria de Vigilância em Saúde, Ministério da Saúde, organizador. Saúde Brasil 2011: uma análise da situação de saúde e a vigilância da saúde da mulher. v. 1. Brasília: Ministério da Saúde; 2012.. Studies in recent decades have shown an improvement in survival rates of preterm newborns ⁴4 . Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M. Outcomes of infants born at 22 and 23 weeks’ gestation. Pediatrics 2013; 132:62-71. ^{, 5}5 . Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, et al. Every newborn: progress, priorities, and potential beyond survival. Lancet 2014; 384:189-205. ^{, 6}6 . Field DJ, Dorling JS, Manktelow BN, Draper ES. Survival of extremely premature babies in a geographically defined population: prospective cohort study of 1994-9 compared with 2000-5. BMJ 2008; 336:1221-3.. The Brazilian Network for Neonatal Research reported improved survival in extremely preterm newborns and those with very low birth weight (< 1,500g) in the year 2012, compared to the results in 2008. As an example, the survival of newborns in the 400-499g weight range, nearly non-existent in 2008, increased to 7.4% in 2012, and the survival of newborns with birth weight in the 1,250-1,499g range was 94.3% in 2012 ⁷7 . Rede Brasileira de Pesquisas Neonatais. Relatório anual 2013. http://www.redeneonatal.fiocruz.br/images/stories/relatorios/rbpn2013.pdf (acessado em 24/Ago/2014).
http://www.redeneonatal.fiocruz.br/image... .

In addition to its contribution to mortality, prematurity is responsible for the high morbidity in survivors, due to acute and long-term complications, with important physical and intellectual sequelae ⁸8 . Grunewaldt KH, Fjortoft T, Bjuland KJ, Brubakk AM, Eikenes L, Haberg AK, et al. Follow-up at age 10 years in ELBW children – functional outcome, brain morphology and results from motor assessments in infancy. Early Hum Dev 2014; 90:571-8. ^{, 9}9 . Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L, Tammela O, et al. Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996-1997. Pediatrics 2005; 116:1391-400. ^{, 10}10 . Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L, Borawski E. Growth of very low birth weight infants to age 20 years. Pediatrics 2003; 112(1 Pt 1):e30-8.. From the respiratory point of view, due to their immature lungs, premature newborns frequently present respiratory distress syndrome, apnea, and infection, requiring prolonged oxygen therapy and/or ventilatory support.

The combination of ventilatory support and prolonged oxygen use in the neonatal period, especially in premature newborns with gestational age less than 30 weeks, is related to the appearance of bronchopulmonary dysplasia ¹¹11 . Rebello CM, Mascaretti RS. A “nova” displasia broncopulmonar. Sistema de educação médica continuada a distância. Programa de atualização em neonatologia. http://www.artmedpanamericana.com.br/file.php/1/biblioteca/SEMCAD/PRORN/ciclo%201/rnc1m2-03.pdf (acessado em 24/Ago/2014).
http://www.artmedpanamericana.com.br/fil... ^{, 12}12 . Carvalho CG, Silveira RC, Procianoy RS. Ventilator-induced lung injury in preterm infants. Rev Bras Ter Intensiva 2013; 25:319-26.. Various studies have also found that premature newborns that received mechanical ventilation (MV) during the neonatal period showed greater risk of developing respiratory diseases like asthma and pneumonia in early childhood when compared to those that did not receive MV ¹³13 . Fauroux B, Gouyon JB, Roze JC, Guillermet-Fromentin C, Glorieux I, Adamon L, et al. Respiratory morbidity of preterm infants of less than 33 weeks gestation without bronchopulmonary dysplasia: a 12-month follow-up of the CASTOR study cohort. Epidemiol Infect 2014; 142:1362-74. ^{, 14}14 . Stevens TP, Dylag A, Panthagani I, Pryhuber G, Halterman J. Effect of cumulative oxygen exposure on respiratory symptoms during infancy among VLBW infants without bronchopulmonary dysplasia. Pediatr Pulmonol 2010; 45:371-9. ^{, 15}15 . Friedrich L, Corso AL, Jones MH. Prognóstico pulmonar em prematuros. J Pediatr (Rio J.) 2005; 81(1 Suppl):S79-88. ^{, 16}16 . de Mello RR, Dutra MV, Lopes JM. Morbidade respiratória no primeiro ano de vida de prematuros egressos de uma unidade pública de tratamento intensivo neonatal. J Pediatr (Rio J.) 2004; 80:503-10. ^{, 17}17 . Chalfun G, Mello RR, Dutra MVP, Andreozzi VL, Silva KS. Fatores associados à morbidade respiratória entre 12 e 36 meses de vida de crianças nascidas de muito baixo peso oriundas de uma UTI neonatal pública. Cad Saúde Pública 2009; 25:1399-408.. Neonatal MV was also associated with altered pulmonary function (spirometry) at 8-9 years ¹⁸18 . Kotecha SJ, Watkins WJ, Paranjothy S, Dunstan FD, Henderson AJ, Kotecha S. Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents. Thorax 2012; 67:54-61., as well as increased odds of asthma during childhood and adulthood ¹⁹19 . Gibson AM, Doyle LW. Respiratory outcomes for the tiniest or most immature infants. Semin Fetal Neonatal Med 2014; 19:105-11. ^{, 20}20 . Greenough A. Long-term pulmonary outcome in the preterm infant. Neonatology 2008; 93:324-7. ^{, 21}21 . Kotecha S, Kotecha SJ. Long term respiratory outcomes of perinatal lung disease. Semin Fetal Neonatal Med 2012; 17:65-6..

Although the literature includes studies in countries like the United Kingdom and United States on the mid and long-term consequences of neonatal ventilatory support, there are still few findings on these problems in children from middle and low-income countries. The main objective of the current study was to assess the association between neonatal ventilatory support and respiratory diseases at six years of age in children from the 2004 Pelotas (Rio Grande do Sul State, Brazil) Birth Cohort study.

Methods

Data source

In 2004, a birth cohort study was launched in Pelotas with an estimated population of 340,000. The majority of the residents lived in the urban area (93%), and the city had five maternity hospitals and two neonatal intensive care units (ICU). There were 4,263 live births during the year in mothers that resided in the city, 4,231 of which were included in the study (0.8% losses). Less than 1% of the deliveries occurred outside the hospital.

The newborns were examined at the maternity hospital immediately after birth. The mothers answered a questionnaire after the delivery, with socioeconomic information on the family, prenatal care, and use of healthcare services. Children in the cohort were followed up for a mean (standard deviation) at 3.0 (0.1), 11.9 (0.2), 23.9 (0.4), 49.5 (1.7), and 82.2 (4.0) months of life. The numbers of children identified at these ages (including children that had died and were identified as belonging to the cohort) were 3,985, 3,907, 3,869, 3,799, and 3,722, respectively, with response rates ranging from 90 to 96%. Figure 1 shows the flow chart for the 2004 cohort, highlighting the deaths, refusals, and losses over the course of the study. All follow-up visits were conducted at the homes, except for the last visit, which was held at a clinic especially organized for this purpose. Detailed information on the methodology of the 2004 Pelotas Birth Cohort study has been published elsewhere ²²22 . Santos IS, Barros AJ, Matijasevich A, Zanini R, Chrestani Cesar MA, Camargo-Figuera FA, et al. Cohort profile update: 2004 Pelotas (Brazil) birth cohort study. Body composition, mental health and genetic assessment at 6 years follow-up. Int J Epidemiol 2014; 43:1437-1437a-f..

Outcomes

The study outcomes were chest wheezing in the previous twelve months (between five and six years of age), lifetime history of medical diagnosis of asthma, and episode of pneumonia between hospital discharge after birth and six years of age.

The variable “chest wheezing in the last twelve months” was defined according to the ISAAC questionnaire (International Study of Allergy and Asthma in Childhood) ²³23 . Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998; 351:1225-32. ^{, 24}24 . Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995; 8:483-91., collected at the six-year follow-up with the following question: “did <child’s name> have chest wheezing in the last twelve months?” For medical diagnosis of asthma, the mother or person accompanying the child at the six-year follow-up was asked: “did a doctor ever say that <child’s name> had asthma?” Pneumonia as the outcome variable was assessed at each follow-up, with the following question: “has <child’s name> ever had pontada or pneumonia?” For this outcome, the term “pontada” (a local lay term) was considered synonymous with “pneumonia”.

Principal exposure

The principal exposure variable was neonatal ventilatory support, as recorded on the hospital patient chart. Ventilatory support was defined as the use of nasal continuous positive airway pressure (NCPAP) and/or MV for more than three hours from the moment of hospitalization at birth up to 28 days of life. This variable was categorized as “use of NCPAP alone”, “NCPAP plus MV or MV alone”, and “no ventilatory support”.

Potential confounding variables

• Maternal variables

  1. Socioeconomic and demographic characteristics

     Family income in the month prior to the child’s birth was recorded in Reais and standardized in multiples of the prevailing minimum wage. Maternal schooling (complete years of formal education), marital status, parity, and maternal skin color (classified according to the interviewer’s observation) were recorded at the time of delivery.

  2. Characteristics of the index pregnancy

     Mothers were asked when the last prenatal visit had occurred. Smoking during the pregnancy was based on the woman’s own report, and smoking was defined as at least one cigarette per day during any trimester of the pregnancy. Mothers were asked if they had had a urinary tract infection during the pregnancy. Prenatal steroid use was also investigated. Type of delivery was classified as vaginal (induced or not) or cesarean.

• Infant’s variables

  1. Information collected at birth

     Gestational age of the newborns was assessed by date of last menstruation recorded on the mother’s prenatal card or reported by her (in this order of priority); when the date was unknown or inconsistent, it was assessed by ultrasound prior to 20 weeks of gestation; and when the mother did not have an ultrasound report, the Dubowitz method was used, performed in the majority of the newborns.

     Birth weight was measured with an electronic pediatric scale, accurate to 10g. Information was recorded on twin births, sex, and five-minute Apgar score, performed by the pediatrician or other health professional attending the newborn.

Statistical analysis

The descriptive analyses included calculation of frequency distributions for outcomes and categorical exposures. Dichotomous outcomes were related to categorical exposure variables using contingency tables, and prevalence ratios with respective 95% confidence intervals (95%CI) were estimated. Statistical tests were based on the chi-square test.

The multivariate analyses used Poisson regression with robust variance, with results expressed as prevalence ratios (PR) and their respective 95%CI. The multivariate analysis only included potential confounding factors for the association between neonatal ventilatory support and each of the three target outcomes. Confounding variables were defined as those that presented an association with the principal exposure and the outcome (for example, chest wheezing) with p-value < 0.20 and without participating in the causal chain between the exposure and outcome. We analyzed which exposure variables might act as confounding factors for each of the target associations. All the analyses used Stata 12.1 (Stata Corp., College Station, USA).

Ethical issues

The protocols for all the follow-up visits in the 2004 Pelotas Birth Cohort study were approved by the Ethics Research Committee at the School of Medicine, Federal University of Pelotas. The protocol for the current study was also approved by the Ethics Research Committees at the School of Medicine and the respective committees at the São Francisco de Paula University Hospital (Catholic University of Pelotas) and the Academic Hospital (Federal University of Pelotas).

Results

Of the 4,231 children participating in the 2004 Pelotas Birth Cohort study, 254 (6%) were admitted at birth to neonatal ICU, and of these, 121 (47.6 %) required ventilatory support at birth. Of the 254 children admitted to the neonatal ICU, 37 (14.6%) died during the neonatal period, 8 (3.1%) in the post-neonatal period, and 4 (1.6%) between one and six years of age. Of the children not admitted to the neonatal ICU at birth, 10 (0.3%) died during the neonatal period, 22 (0.6%) in the post-neonatal period, and 14 (0.3%) between one and six years of age. The current study analyzed 3,624 children (85.7% of the original cohort) with information available on the study outcomes.

After excluding the 95 children that died during the first 6 years of follow-up of the 2004 Pelotas Birth Cohort, the 3,624 children included in the current study were compared to the 512 children for whom the study outcomes were not available (387 losses, 27 refusals, and 98 children with incomplete information). Loss of information for the study outcomes was more frequent in children of mothers with more previous children (Table 1).

Of the 3,624 children included in the study, 3,553 (98%) did not receive ventilatory support at birth, 32 (0.9%) received only NCPAP, and 39 (1.1%) received NCPAP and MV or MV alone. In all, 22.4% (n = 812) had presented chest wheezing in the previous 12 months (between 5 and 6 years of age), 18.8% (n = 680) had already received a medical diagnosis of asthma, and 20.8% (n = 752) had a history of pneumonia between hospital discharge after birth and six years of age. Figure 2 depicts the association between use of neonatal ventilatory support and frequency of the target outcomes up to six years of age. Children that required NCPAP and MV or MV alone presented the highest frequencies of pneumonia following hospital charge after birth, chest wheezing between five and six years of age, and medical diagnosis of asthma (41%, 43.6%, and 48.7%, respectively).

Table 2 shows the distribution of the outcomes pneumonia, chest wheezing, and asthma according to maternal characteristics. Children of poorer families and of mothers with less schooling and black or brown skin color, multiparous mothers, and those with a history of urinary tract infection during the index pregnancy had higher prevalence rates of pneumonia and asthma. Children of mothers less than 20 years of age had higher prevalence rates of pneumonia and chest wheezing. Children of mothers that smoked during the index pregnancy showed higher frequency of pneumonia, chest wheezing, and medical diagnosis of asthma. No differences were observed in pneumonia, chest wheezing, or asthma based on type of delivery or prenatal steroid use. As for the children’s characteristics (Table 3), boys showed higher prevalence rates for chest wheezing and asthma when compared to girls. Pneumonia and asthma were the most frequent diseases in preterm or low birth weight children.

Table 4 shows the crude and adjusted association between neonatal ventilatory support and each of the study outcomes. In the crude analysis, newborns exposure to ventilatory support at birth (NCPAP with MV or MV alone) showed a twofold prevalence of pneumonia and chest wheezing and a nearly threefold prevalence of medical diagnosis of asthma, when compared to those who had not used neonatal ventilatory support. After adjusting for potential confounding variables, the association between ventilatory support and medical diagnosis of asthma remained virtually unchanged in relation to the crude model, and the associations between ventilatory support and pneumonia and wheezing lost significance.

Discussion

The current study was conducted in a cohort of 4,231 newborns, of which 6% were admitted to a neonatal ICU at birth, and of these, nearly half required some form of ventilatory support during their hospital stay. The use of ventilatory support (NCPAP and MV or MV alone) was associated with higher prevalence of medical diagnosis of asthma assessed at six years de life, even after adjusting for a series of maternal and child variables.

Prevalence of preterm births has increased in many countries, even in high-income nations ²⁵25 . Lawn JE, Gravett MG, Nunes TM, Rubens CE, Stanton C, Group GR. Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data. BMC Pregnancy Childbirth 2010; 10 Suppl 1:S1.. A report published in 2012 by the World Health Organization (WHO) estimated that more than 10% of all births in the world are premature. The report also identified Brazil as the tenth leading country in the world in absolute number of preterm births ¹1 . UN Children’s Fund/World Health Organization. Countdown to 2015 maternal, newborn & child survival. Building a future for women and children: the 2012 report. Washington DC: World Health Organization; 2012.. This high prevalence of prematurity has important social and economic repercussions in both the short and long term. Neonatology faces numerous challenges in the acute treatment of diseases in premature newborns and in the prevention of long-term sequelae. Ideally, prematurity would be prevented at any cost, but few measures have been associated with significant population-based reductions in preterm births ²⁶26 . Barros FC, Bhutta ZA, Batra M, Hansen TN, Victora CG, Rubens CE, et al. Global report on preterm birth and stillbirth (3 of 7): evidence for effectiveness of interventions. BMC Pregnancy Childbirth 2010; 10 Suppl 1:S3..

The anatomical and physiological formation of the lungs during the prenatal and postnatal periods depends on a complex network of factors that regulate the airways’ vascular development and differentiation ²⁷27 . Ranganathan S. Lung development, lung growth and the future of respiratory medicine. Eur Respir J 2010; 36:716-7. ^{, 28}28 . Burri PH. Structural aspects of postnatal lung development – alveolar formation and growth. Biol Neonate 2006; 89:313-22. ^{, 29}29 . Askin DF, Diehl-Jones W. Pathogenesis and prevention of chronic lung disease in the neonate. Crit Care Nurs Clin North Am 2009; 21:11-25. ^{, 30}30 . Turner BS, Bradshaw W, Brandon D. Neonatal lung remodeling: structural, inflammatory, and ventilator-induced injury. J Perinat Neonatal Nurs 2005; 19:362-76.. This process of bronchoalveolar and vascular maturation of the lungs can be altered at any moment, leading to chronic complications that begin in the neonatal period (neonatal chronic pulmonary disease) or later in the life cycle. Some known factors in the development of these problems are prematurity, use of supplementary oxygen, ventilatory support, infection, late implementation of enteral nutrition, and patent ductus arteriosus ¹²12 . Carvalho CG, Silveira RC, Procianoy RS. Ventilator-induced lung injury in preterm infants. Rev Bras Ter Intensiva 2013; 25:319-26. ^{, 31}31 . Abman SH. Bronchopulmonary dysplasia. New York: Informa Healthcare USA Inc.; 2010..

The use of MV in the neonatal period can cause alterations in the airways, especially through barotrauma and volutrauma, atelectrauma, and biotrauma. MV also induces the release of pro and anti-inflammatory mediators (IL-1, IL-6, IL-10, and TNF-α), injuring the pulmonary epithelial and endothelial cells, which can lead to alveolar edema and morphological alteration of the bronchoalveolar structure. These lesions produced in an early period of life can be irreversible, even after pulmonary maturation and airway remodeling in later stages ³⁰30 . Turner BS, Bradshaw W, Brandon D. Neonatal lung remodeling: structural, inflammatory, and ventilator-induced injury. J Perinat Neonatal Nurs 2005; 19:362-76. ^{, 31}31 . Abman SH. Bronchopulmonary dysplasia. New York: Informa Healthcare USA Inc.; 2010. ^{, 32}32 . Nardelli LM, Garcia C, Pássaro CP, Rocco PR. Entendendo os mecanismos determinantes da lesão pulmonar induzida pela ventilação mecânica. Rev Bras Ter Intensiva 2007; 19:469-74..

Previous studies showed an association between use of neonatal ventilatory support and mid and long-term respiratory consequences. Kotecha et al. ¹⁸18 . Kotecha SJ, Watkins WJ, Paranjothy S, Dunstan FD, Henderson AJ, Kotecha S. Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents. Thorax 2012; 67:54-61. studied 13,961 newborns from the ALSPAC birth cohort (Avon Longitudinal Study of Parents and Children) in the United Kingdom. The authors reported that MV was associated with altered pulmonary function at 8-9 years of age. Vrijlandt et al. ³³33 . Vrijlandt EJ, Gerritsen J, Boezen HM, Duiverman EJ; Dutch POPS-19 Collaborative Study Group. Gender differences in respiratory symptoms in 19-year-old adults born preterm. Respir Res 2005; 6:117. studied 690 children in the Netherlands that were born premature in 1983, evaluating them subsequently, in 2002. They found that children born with gestational age less than 32 weeks and/or birth weight less than 1,500g and that received ventilatory support for more than 28 days showed fivefold odds of dyspnea at 19 years of age when compared to children that received ventilatory support for less than 28 days. Konefal et al. ³⁴34 . Konefal H, Czeszynska Maria B, Sardesai S, Durand M, Miazgowski T. Pulmonary function in school-aged children with mild to moderate infant respiratory distress syndrome requiring nasal continuous positive airway pressure. Ginekol Pol 2010; 81:768-73., in a prospective study with 50 newborns that received neonatal NCPAP, found a higher incidence of laryngitis in the first six years and a higher incidence of bronchitis and pneumonia in the first two years of life, but without altered pulmonary function, when compared to newborns that had not received NCPAP. In the current study, the use of NCPAP alone in the neonatal period was not associated with increased prevalence of pneumonia, wheezing, or diagnosis of asthma in any of the models analyzed. Grischkan et al. ³⁵35 . Grischkan J, Storfer-Isser A, Rosen CL, Larkin EK, Kirchner HL, South A, et al. Variation in childhood asthma among former preterm infants. J Pediatr 2004; 144:321-6., in a birth cohort in the United States with 241 premature newborns, found that those exposed to MV in the neonatal period showed higher odds of asthma between eight and eleven years of age, when compared to those who had not required this type of ventilatory support. Along the same line as the Grischkan et al. study, the children in the 2004 Pelotas Birth Cohort showed higher prevalence of asthma among children that required neonatal MV. However, the effect sizes in the current study were not as high. This could be due to a greater sampling variation in the Grischkan et al. study, secondary to a small sample size, as evidenced by this study’s wide 95%CI. Meanwhile, the current study included information on all the newborns, whether preterm or not, with more conservative measures of association than those reported in studies that only included high-risk children.

The current study’s main strengths are that it was a population-based longitudinal study with a high follow-up rate and data collected prospectively, minimizing recall bias and allowing the identification of temporal relations in the associations, which had received little previous research attention in middle or low-income countries. The study’s main limitation relates to the lack of information on the fraction of inspired oxygen (FiO₂), besides the lack of data on duration and parameters for the ventilatory support administered to the children. Such information would allow studying dose-response relations, strengthening the causal mechanism in the associations. Another limitation is the way the study outcomes were collected. Data collection on the outcome “chest wheezing” used a questionnaire completed by the parents, potentially introducing information bias. Parents may have referred to other noises as “wheezing”, such as those caused by nasal obstruction. Since our study did not ask about lung auscultation by a physician or prescription of bronchodilators, it could be affected by overestimating the true number of children with wheezing. This outcome (which includes a 12-month recall) could also be affected by recall bias, if the child presented some “wheezing” with little or no clinical repercussions and the parents had forgotten the problem, which would underestimate the frequency of wheezing in the children. Another methodological problem could be present in the outcome “pontada or pneumonia” reported by the mother, since there was no information to allow only physician-diagnosed pneumonias in the outcome. This problem could be a source of information bias in our study and contribute to overestimation of the true frequency of pneumonia in children in the cohort. Finally, another limitation is the presence of approximately 14% losses over the course of six years in the study. Although the children lost to follow-up were similar in nearly all their characteristics to the children with information available on the target outcomes, selection bias cannot be ruled out.

The current study’s findings highlight the respiratory complications in the medium run from neonatal ventilatory support. Bronchial hyper-reactivity/asthma is a chronic illness, and depending on the severity it can lead to important restrictions on patients’ lives and high costs for the family and society ³⁶36 . Wang LY, Zhong Y, Wheeler L. Direct and indirect costs of asthma in school-age children. Prev Chronic Dis 2005; 2:A11. ^{, 37}37 . Fletcher JM, Green JC, Neidell MJ. Long term effects of childhood asthma on adult health. J Health Econ 2010; 29:377-87.. The increase in prematurity in Brazil, leading to a greater need for specialized care, indicates the need for adequate services for newborns and the implementation of neonatal protocols that minimize the risks of complications and sequelae from treatments in the long term.

Acknowledgments

The authors wish to thank the families of the participants in the 2004 Pelotas (Brazil) Birth Cohort study. The six-year follow-up of the 2004 Pelotas Birth Cohort was funded by the Wellcome Trust, CNPq, and FAPERGS. Previous phases of the study were funded by PRONEX/CNPq, the Brazilian Ministry of Health, World Health Organization, and Children’s Pastoral Commission.

References

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