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1.  Surgery and Neurodevelopmental Outcome of Very Low Birth Weight Infants 
JAMA pediatrics  2014;168(8):746-754.
IMPORTANCE
Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.
OBJECTIVE
To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low birth weight infants.
DESIGN
Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age.
SETTING
22 academic neonatal intensive care units.
PARTICIPANTS
Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible.
EXPOSURES
Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia).
MAIN OUTCOME MEASURES
Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006.
RESULTS
There were 2186 major, 784 minor and 9141 no surgery patients. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% confidence interval 1.08–1.55). For patients who had major surgery compared with those who had no surgery the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% confidence interval 1.24–1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery the adjusted odds ratio for neurodevelopmental impairment was 1.56 (95% confidence interval 1.26–1.93) and the adjusted mean Mental Developmental Index and mean Psychomotor Developmental Index values were lower.
CONCLUSIONS AND RELEVANCE
Major surgery in very low birth weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18–22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.
doi:10.1001/jamapediatrics.2014.307
PMCID: PMC4142429  PMID: 24934607
2.  Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial 
The Journal of pediatrics  2014;165(2):240-249.e4.
Objective
To explore the early childhood pulmonary outcomes of infants who participated in the NICHD SUPPORT Trial, using a factorial design that randomized extremely preterm infants to lower vs. higher oxygen saturation targets and delivery room CPAP vs. intubation/surfactant, found no significant difference in the primary composite outcome of death or BPD.
Study design
The Breathing Outcomes Study, a prospective secondary to SUPPORT, assessed respiratory morbidity at 6 month intervals from hospital discharge to 18–22 months corrected age (CA). Two pre-specified primary outcomes, wheezing more than twice per week during the worst 2 week period and cough longer than 3 days without a cold were compared between each randomized intervention.
Results
One or more interviews were completed for 918 of 922 eligible infants. The incidence of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between study arms of either randomized intervention. Infants randomized to lower vs. higher oxygen saturation targets had similar risks of death or respiratory morbidities (except for croup, treatment with oxygen or diuretics at home). Infants randomized to CPAP vs. intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs. 36.5%, p<0.05), respiratory illnesses diagnosed by a doctor (47.7% vs. 55.2%, p<0.05) and physician or emergency room visits for breathing problems (68.0% vs. 72.9%, p<0.05) by 18–22 months CA.
Conclusion
Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18–22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.
doi:10.1016/j.jpeds.2014.02.054
PMCID: PMC4111960  PMID: 24725582
Bronchopulmonary Dysplasia; Infant, Newborn; Infant, Low Birth Weight; Infant, Extremely Low Birth Weight; Infant, Premature; Infant, Extremely Low Gestational Age; Infant mortality; Respiratory morbidity; Intensive care, neonatal; Hospital Readmission; Oximetry; Randomized controlled trial; Retinopathy of prematurity (ROP); Continuous Positive Airway Pressure; Intubation, endotracheal; Pulmonary surfactants/therapeutic use; Oxygen inhalation therapy/methods; Oxygen administration & dosage; Follow-up studies
3.  Causes and Timing of Death in Extremely Premature Infants from 2000 through 2011 
The New England journal of medicine  2015;372(4):331-340.
BACKGROUND
Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.
METHODS
We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.
RESULTS
The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008–2011 period (P = 0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008–2011 than in 2000–2003 and 2004–2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P = 0.002). Similarly, in 2008–2011, as compared with 2000–2003, there were decreases in deaths attributed to immaturity (P = 0.05) and deaths complicated by infection (P = 0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P = 0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.
CONCLUSIONS
We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis–related deaths increased. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1403489
PMCID: PMC4349362  PMID: 25607427
4.  Developmental Trajectories of Children with Birth Asphyxia through 36 Months of Age in Low/Low-Middle Income Countries 
Early human development  2014;90(7):343-348.
Background
Resuscitation following birth asphyxia reduces mortality, but may be argued to increase risk for neurodevelopmental disability in survivors.
Aims
To test the hypothesis that development of infants who received resuscitation following birth asphyxia is not significantly different through 36 months of age from infants who had healthy births.
Study Design
Prospective observational cohort design comparing infants exposed to birth asphyxia with resuscitation or healthy birth.
Subjects
A random sample of infants with birth asphyxia who received bag-and-mask resuscitation was selected from birth records in selected communities in 3 countries. Exclusion criteria: birth weight < 1500g, severely abnormal neurological examination at 7 days, mother < 15 years, unable to participate, or not expected to remain in the target area. A random sample of healthy-birth infants (no resuscitation, normal neurological exam) was also selected. Eligible = 438, consented = 407, and ≥ 1 valid developmental assessment during first 36 months = 376.
Outcome Measure(s)
Bayley Scales of Infant Development-II Mental (MDI) and Psychomotor (PDI) Development Index.
Results
Trajectories of MDI (p = .069) and PDI (p = .143) over 3 yearly assessments did not differ between children with birth asphyxia and healthy-birth children. Rather there was a trend for birth asphyxia children to improve more than healthy-birth children.
Conclusions
The large majority of infants who are treated with resuscitation and survived birth asphyxia can be expected to evidence normal development at least until age 3. The risk for neurodevelopmental disability should not justify the restriction of effective therapies for birth asphyxia.
doi:10.1016/j.earlhumdev.2014.04.013
PMCID: PMC4097313  PMID: 24815056
Birth asphyxia; resuscitation; low resource countries; developmental outcomes; neurodevelopmental disability
5.  Data quality monitoring and performance metrics of a prospective, population-based observational study of maternal and newborn health in low resource settings 
Reproductive Health  2015;12(Suppl 2):S2.
Background
To describe quantitative data quality monitoring and performance metrics adopted by the Global Network’s (GN) Maternal Newborn Health Registry (MNHR), a maternal and perinatal population-based registry (MPPBR) based in low and middle income countries (LMICs).
Methods
Ongoing prospective, population-based data on all pregnancy outcomes within defined geographical locations participating in the GN have been collected since 2008. Data quality metrics were defined and are implemented at the cluster, site and the central level to ensure data quality. Quantitative performance metrics are described for data collected between 2010 and 2013.
Results
Delivery outcome rates over 95% illustrate that all sites are successful in following patients from pregnancy through delivery. Examples of specific performance metric reports illustrate how both the metrics and reporting process are used to identify cluster-level and site-level quality issues and illustrate how those metrics track over time. Other summary reports (e.g. the increasing proportion of measured birth weight compared to estimated and missing birth weight) illustrate how a site has improved quality over time.
Conclusion
High quality MPPBRs such as the MNHR provide key information on pregnancy outcomes to local and international health officials where civil registration systems are lacking. The MNHR has measures in place to monitor data collection procedures and improve the quality of data collected. Sites have increasingly achieved acceptable values of performance metrics over time, indicating improvements in data quality, but the quality control program must continue to evolve to optimize the use of the MNHR to assess the impact of community interventions in research protocols in pregnancy and perinatal health.
Trial registration number
NCT01073475
doi:10.1186/1742-4755-12-S2-S2
PMCID: PMC4464020  PMID: 26062714
data monitoring; data quality; maternal health; newborn health; perinatal registry; metrics; low-income countries
6.  Lost to follow-up among pregnant women in a multi-site community based maternal and newborn health registry: a prospective study 
Reproductive Health  2015;12(Suppl 2):S4.
Background
It is important when conducting epidemiologic studies to closely monitor lost to follow up (LTFU) rates. A high LTFU rate may lead to incomplete study results which in turn can introduce bias to the trial or study, threatening the validity of the findings. There is scarce information on LTFU in prospective community-based perinatal epidemiological studies. This paper reports the rates of LTFU, describes socio-demographic characteristics, and pregnancy/delivery outcomes of mothers LTFU in a large community-based pregnancy registry study.
Methods
Data were from a prospective, population-based observational study of the Global Network for Women's and Children's Health Research Maternal Newborn Health Registry (MNHR). This is a multi-centre, international study in which pregnant women were enrolled in mid-pregnancy, followed through parturition and 42 days post-delivery. Risk for LTFU was calculated within a 95%CI.
Results
A total of 282,626 subjects were enrolled in this study, of which 4,893 were lost to follow-up. Overall, there was a 1.7% LTFU to follow up rate. Factors associated with a higher LTFU included mothers who did not know their last menstrual period (RR 2.2, 95% CI 1.1, 4.4), maternal age of < 20 years (RR 1.2, 95% CI 1.1, 1.3), women with no formal education (RR 1.2, 95% CI 1.1, 1.4), and attending a government clinic for antenatal care (RR 2.0, 95% CI 1.4, 2.8). Post-natal factors associated with a higher LTFU rate included a newborn with feeding problems (RR 1.6, 94% CI 1.2, 2.2).
Conclusions
The LTFU rate in this community-based registry was low (1.7%). Maternal age, maternal level of education, pregnancy status at enrollment and using a government facility for ANC are factors associated with being LTFU. Strategies to ensure representation and high retention in community studies are important to informing progress toward public health goals.
Trial registration
Registration at the Clinicaltrials.gov (ID# NCT01073475).
doi:10.1186/1742-4755-12-S2-S4
PMCID: PMC4464022  PMID: 26062899
Community based registry; maternal and newborn registry; lost to follow up rate; maternal socio demographic characteristics; pregnancy outcomes
7.  Stillbirth rates in low-middle income countries 2010 - 2013: a population-based, multi-country study from the Global Network 
Reproductive Health  2015;12(Suppl 2):S7.
Background
Stillbirth rates remain nearly ten times higher in low-middle income countries (LMIC) than high income countries. In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented characteristics or care for mothers with stillbirths. Non-macerated stillbirths, those occurring around delivery, are generally considered preventable with appropriate obstetric care.
Methods
We undertook a prospective, population-based observational study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). Staff collected demographic and health care characteristics with outcomes obtained at delivery.
Results
From 2010 through 2013, 269,614 enrolled women had 272,089 births, including 7,865 stillbirths. The overall stillbirth rate was 28.9/1000 births, ranging from 13.6/1000 births in Argentina to 56.5/1000 births in Pakistan. Stillbirth rates were stable or declined in 6 of the 7 sites from 2010-2013, only increasing in Pakistan. Less educated, older and women with less access to antenatal care were at increased risk of stillbirth. Furthermore, women not delivered by a skilled attendant were more likely to have a stillbirth (RR 2.8, 95% CI 2.2, 3.5). Compared to live births, stillbirths were more likely to be preterm (RR 12.4, 95% CI 11.2, 13.6). Infants with major congenital anomalies were at increased risk of stillbirth (RR 9.1, 95% CI 7.3, 11.4), as were multiple gestations (RR 2.8, 95% CI 2.4, 3.2) and breech (RR 3.0, 95% CI 2.6, 3.5). Altogether, 67.4% of the stillbirths were non-macerated. 7.6% of women with stillbirths had cesarean sections, with obstructed labor the primary indication (36.9%).
Conclusions
Stillbirth rates were high, but with reductions in most sites during the study period. Disadvantaged women, those with less antenatal care and those delivered without a skilled birth attendant were at increased risk of delivering a stillbirth. More than two-thirds of all stillbirths were non-macerated, suggesting potentially preventable stillbirth. Additionally, 8% of women with stillbirths were delivered by cesarean section. The relatively high rate of cesarean section among those with stillbirths suggested that this care was too late or not of quality to prevent the stillbirth; however, further research is needed to evaluate the quality of obstetric care, including cesarean section, on stillbirth in these low resource settings.
Study registration
Clinicaltrials.gov (ID# NCT01073475)
doi:10.1186/1742-4755-12-S2-S7
PMCID: PMC4464024  PMID: 26063292
Stillbirth; low-middle income countries; obstetric care
8.  Adverse maternal and perinatal outcomes in adolescent pregnancies: The Global Network’s Maternal Newborn Health Registry study 
Reproductive Health  2015;12(Suppl 2):S8.
Background
Adolescent girls between 15 and 19 years give birth to around 16 million babies each year, around 11% of births worldwide. We sought to determine whether adolescent mothers are at higher risk of maternal and perinatal adverse outcomes compared with mothers aged 20–24 years in a prospective, population-based observational study of newborn outcomes in low resource settings.
Methods
We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in six low-middle income countries (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). The study population for this analysis was restricted to women aged 24 years or less, who gave birth to infants of at least 20 weeks’ gestation and 500g or more. We compared adverse pregnancy maternal and perinatal outcomes among pregnant adolescents 15-19 years, <15 years, and adults 20-24 years.
Results
A total of 269,273 women were enrolled from January 2010 to December 2013. Of all pregnancies 11.9% (32,097/269,273) were in adolescents 15-19 years, while 0.14% (370/269,273) occurred among girls <15 years. Pregnancy among adolescents 15-19 years ranged from 2% in Pakistan to 26% in Argentina, and adolescent pregnancies <15 year were only observed in sub-Saharan Africa and Latin America. Compared to adults, adolescents did not show increased risk of maternal adverse outcomes. Risks of preterm birth and LBW were significantly higher among both early and older adolescents, with the highest risks observed in the <15 years group. Neonatal and perinatal mortality followed a similar trend in sub-Saharan Africa and Latin America, with the highest risk in early adolescents, although the differences in this age group were not significant. However, in South Asia the risks of neonatal and perinatal death were not different among adolescents 15-19 years compared to adults.
Conclusions
This study suggests that pregnancy among adolescents is not associated with worse maternal outcomes, but is associated with worse perinatal outcomes, particularly in younger adolescents. However, this may not be the case in regions like South Asia where there are decreasing rates of adolescent pregnancies, concentrated among older adolescents. The increased risks observed among adolescents seems more likely to be associated with biological immaturity, than with socio-economic factors, inadequate antenatal or delivery care.
Trial registration number
NCT01073475
doi:10.1186/1742-4755-12-S2-S8
PMCID: PMC4464033  PMID: 26063350
adolescent pregnancy
9.  Risk factors for maternal death and trends in maternal mortality in low- and middle-income countries: a prospective longitudinal cohort analysis 
Reproductive Health  2015;12(Suppl 2):S5.
Background
Because large, prospective, population-based data sets describing maternal outcomes are typically not available in low- and middle-income countries, it is difficult to monitor maternal mortality rates over time and to identify factors associated with maternal mortality. Early identification of risk factors is essential to develop comprehensive intervention strategies preventing pregnancy-related complications. Our objective was to describe maternal mortality rates in a large, multi-country dataset and to determine maternal, pregnancy-related, delivery and postpartum characteristics that are associated with maternal mortality.
Methods
We collected data describing all pregnancies from 2010 to 2013 among women enrolled in the multi-national Global Network for Women’s and Children’s Health Research Maternal and Neonatal Health Registry (MNHR). We reported the proportion of mothers who died per pregnancy and the maternal mortality ratio (MMR). Generalized linear models were used to evaluate the relationship of potential medical and social factors and maternal mortality and to develop point and interval estimates of relative risk associated with these factors. Generalized estimating equations were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals.
Results
We recorded 277,736 pregnancies and 402 maternal deaths for an MMR of 153/100,000 live births. We observed an improvement in the total MMR from 166 in 2010 to 126 in 2013. The MMR in Latin American sites (91) was lower than the MMR in Asian (178) and African sites (125). When adjusted for study site and the other variables, no formal education (RR 3.2 [1.5, 6.9]), primary education only (RR 3.4 [1.6, 7.5]), secondary education only (RR 2.5 [1.1, 5.7]), lack of antenatal care (RR 1.8 [1.2, 2.5]), caesarean section delivery (RR 1.9 [1.3, 2.8]), hemorrhage (RR 3.3 [2.2, 5.1]), and hypertensive disorders (RR 7.4 [5.2, 10.4]) were associated with higher risks of death.
Conclusions
The MNHR identified preventable causes of maternal mortality in diverse settings in low- and middle-income countries. The MNHR can be used to monitor public health strategies and determine their association with reducing maternal mortality.
Trial Registration
clinicaltrials.gov NCT01073475
doi:10.1186/1742-4755-12-S2-S5
PMCID: PMC4464034  PMID: 26062992
10.  Maternal and newborn outcomes in Pakistan compared to other low and middle income countries in the Global Network’s Maternal Newborn Health Registry: an active, community-based, pregnancy surveillance mechanism 
Reproductive Health  2015;12(Suppl 2):S15.
Background
Despite global improvements in maternal and newborn health (MNH), maternal, fetal and newborn mortality rates in Pakistan remain stagnant. Using data from the Global Network’s Maternal Newborn Health Registry (MNHR) the objective of this study is to compare the rates of maternal mortality, stillbirth and newborn mortality and levels of putative risk factors between the Pakistani site and those in other countries.
Methods
Using data collected through a multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in communities in discrete geographical areas in seven sites across six countries including Pakistan, India, Kenya, Zambia, Guatemala and Argentina from 2010 to 2013, the study compared MNH outcomes and risk factors. The MNHR captures more than 60,000 deliveries annually across all sites with over 10,000 of them in Thatta, Pakistan.
Results
The Pakistan site had a maternal mortality ratio almost three times that of the other sites (313/100,000 vs 116/100,000). Stillbirth (56.5 vs 22.9/1000 births), neonatal mortality (50.0 vs 20.7/1000 livebirths) and perinatal mortality rates (95.2/1000 vs 39.0/1000 births) in Thatta, Pakistan were more than twice those of the other sites. The Pakistani site is the only one in the Global Network where maternal mortality increased (from 231/100,000 to 353/100,000) over the study period and fetal and neonatal outcomes remained stagnant. The Pakistan site lags behind other sites in maternal education, high parity, and appropriate antenatal and postnatal care. However, facility delivery and skilled birth attendance rates were less prominently different between the Pakistani site and other sites, with the exception of India. The difference in the fetal and neonatal outcomes between the Pakistani site and the other sites was most pronounced amongst normal birth weight babies.
Conclusions
The increase in maternal mortality and the stagnation of fetal and neonatal outcomes from 2010 to 2013 indicates that current levels of antenatal and newborn care interventions in Thatta, Pakistan are insufficient to protect against poor maternal and neonatal outcomes. Delivery care in the Pakistani site, while appearing quantitatively equivalent to the care in sites in Africa, is less effective in saving the lives of women and their newborns. By the metrics available from this study, the quality of obstetric and neonatal care in the site in Pakistan is poor.
Trial registration
The study is registered at clinicaltrials.gov [NCT01073475].
doi:10.1186/1742-4755-12-S2-S15
PMCID: PMC4464035  PMID: 26062610
Pakistan; maternal mortality; stillbirth; neonatal mortality
11.  A prospective observational description of frequency and timing of antenatal care attendance and coverage of selected interventions from sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia 
Reproductive Health  2015;12(Suppl 2):S12.
Background
The Global Network for Women’s and Children’s Health Research is one of the largest international networks for testing and generating evidence-based recommendations for improvement of maternal-child health in resource-limited settings. Since 2009, Global Network sites in six low and middle-income countries have collected information on antenatal care practices, which are important as indicators of care and have implications for programs to improve maternal and child health. We sought to: (1) describe the quantity of antenatal care attendance over a four-year period; and (2) explore the quality of coverage for selected preventative, screening, and birth preparedness components.
Methods
The Maternal Newborn Health Registry (MNHR) is a prospective, population-based birth and pregnancy outcomes registry in Global Network sites, including: Argentina, Guatemala, India (Belgaum and Nagpur), Kenya, Pakistan, and Zambia. MNHR data from these sites were prospectively collected from January 1, 2010 – December 31, 2013 and analyzed for indicators related to quantity and patterns of ANC and coverage of key elements of recommended focused antenatal care. Descriptive statistics were generated overall by global region (Africa, Asia, and Latin America), and for each individual site.
Results
Overall, 96% of women reported at least one antenatal care visit. Indian sites demonstrated the highest percentage of women who initiated antenatal care during the first trimester. Women from the Latin American and Indian sites reported the highest number of at least 4 visits. Overall, 88% of women received tetanus toxoid. Only about half of all women reported having been screened for syphilis (49%) or anemia (50%). Rates of HIV testing were above 95% in the Argentina, African, and Indian sites. The Pakistan site demonstrated relatively high rates for birth preparation, but for most other preventative and screening interventions, posted lower coverage rates as compared to other Global Network sites.
Conclusions
Results from our large, prospective, population-based observational study contribute important insight into regional and site-specific patterns for antenatal care access and coverage. Our findings indicate a quality and coverage gap in antenatal care services, particularly in regards to syphilis and hemoglobin screening. We have identified site-specific gaps in access to, and delivery of, antenatal care services that can be targeted for improvement in future research and implementation efforts.
Trial registration
Registration at Clinicaltrials.gov (ID# NCT01073475)
doi:10.1186/1742-4755-12-S2-S12
PMCID: PMC4464209  PMID: 26063483
Maternal-newborn health; birth registry; antenatal care; Africa; Asia; Latin America; focused antenatal care; quality of care
12.  Rates and determinants of early initiation of breastfeeding and exclusive breast feeding at 42 days postnatal in six low and middle-income countries: A prospective cohort study 
Reproductive Health  2015;12(Suppl 2):S10.
Background
Early initiation of breastfeeding after birth and exclusive breastfeeding through six months of age confers many health benefits for infants; both are crucial high impact, low-cost interventions. However, determining accurate global rates of these crucial activities has been challenging. We use population-based data to describe: (1) rates of early initiation of breastfeeding (defined as within 1 hour of birth) and of exclusive breastfeeding at 42 days post-partum; and (2) factors associated with failure to initiate early breastfeeding and exclusive breastfeeding at 42 days post-partum.
Methods
Prospectively collected data from women and their live-born infants enrolled in the Global Network’s Maternal and Newborn Health Registry between January 1, 2010-December 31, 2013 included women-infant dyads in 106 geographic areas (clusters) at 7 research sites in 6 countries (Kenya, Zambia, India [2 sites], Pakistan, Argentina and Guatemala). Rates and risk factors for failure to initiate early breastfeeding were investigated for the entire cohort and rates and risk factors for failure to maintain exclusive breastfeeding was assessed in a sub-sample studied at 42 days post-partum.
Result
A total of 255,495 live-born women-infant dyads were included in the study. Rates and determinants for the exclusive breastfeeding sub-study at 42 days post-partum were assessed from among a sub-sample of 105,563 subjects. Although there was heterogeneity by site, and early initiation of breastfeeding after delivery was high, the Pakistan site had the lowest rates of early initiation of breastfeeding. The Pakistan site also had the highest rate of lack of exclusive breastfeeding at 42 days post-partum. Across all regions, factors associated with failure to initiate early breastfeeding included nulliparity, caesarean section, low birth weight, resuscitation with bag and mask, and failure to place baby on the mother’s chest after delivery. Factors associated with failure to achieve exclusive breastfeeding at 42 days varied across the sites. The only factor significant in all sites was multiple gestation.
Conclusions
In this large, prospective, population-based, observational study, rates of both early initiation of breastfeeding and exclusive breastfeeding at 42 days post-partum were high, except in Pakistan. Factors associated with these key breastfeeding indicators should assist with more effective strategies to scale-up these crucial public health interventions.
Trial registration
Registration at the Clinicaltrials.gov website (ID# NCT01073475).
doi:10.1186/1742-4755-12-S2-S10
PMCID: PMC4464210  PMID: 26063291
Early initiation of breastfeeding; exclusive breastfeeding; neonatal mortality; global health; newborn
13.  The Global Network Maternal Newborn Health Registry: a multi-national, community-based registry of pregnancy outcomes 
Reproductive Health  2015;12(Suppl 2):S1.
Background
The Global Network for Women's and Children's Health Research (Global Network) supports and conducts clinical trials in resource-limited countries by pairing foreign and U.S. investigators, with the goal of evaluating low-cost, sustainable interventions to improve the health of women and children. Accurate reporting of births, stillbirths, neonatal deaths, maternal mortality, and measures of obstetric and neonatal care is critical to efforts to discover strategies for improving pregnancy outcomes in resource-limited settings. Because most of the sites in the Global Network have weak registration within their health care systems, the Global Network developed the Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies at the Global Network sites to provide precise data on health outcomes and measures of care.
Methods
Pregnant women are enrolled in the MNHR if they reside in or receive healthcare in designated groups of communities within sites in the Global Network. For each woman, demographic, health characteristics and major outcomes of pregnancy are recorded. Data are recorded at enrollment, the time of delivery and at 42 days postpartum.
Results
From 2010 through 2013 Global Network sites were located in Argentina, Guatemala, Belgaum and Nagpur, India, Pakistan, Kenya, and Zambia. During this period, 283,496 pregnant women were enrolled in the MNHR; this number represented 98.8% of all eligible women. Delivery data were collected for 98.8% of women and 42-day follow-up data for 98.4% of those enrolled. In this supplement, there are a series of manuscripts that use data gathered through the MNHR to report outcomes of these pregnancies.
Conclusions
Developing public policy and improving public health in countries with poor perinatal outcomes is, in part, dependent upon understanding the outcome of every pregnancy. Because the worst pregnancy outcomes typically occur in countries with limited health registration systems and vital records, alternative registration systems may prove to be highly valuable in providing data. The MNHR, an international, multicenter, population-based registry, assesses pregnancy outcomes over time in support of efforts to develop improved perinatal healthcare in resource-limited areas.
Study Registration: The Maternal Newborn Health Registry is registered at Clinicaltrials.gov (ID# NCT01073475).
doi:10.1186/1742-4755-12-S2-S1
PMCID: PMC4464212  PMID: 26063166
registry; perinatal mortality; neonatal mortality; stillbirth; maternal mortality
14.  A prospective population-based study of maternal, fetal, and neonatal outcomes in the setting of prolonged labor, obstructed labor and failure to progress in low- and middle-income countries 
Reproductive Health  2015;12(Suppl 2):S9.
Background
This population-based study sought to quantify maternal, fetal, and neonatal morbidity and mortality in low- and middle-income countries associated with obstructed labor, prolonged labor and failure to progress (OL/PL/FTP).
Methods
A prospective, population-based observational study of pregnancy outcomes was performed at seven sites in Argentina, Guatemala, India (2 sites, Belgaum and Nagpur), Kenya, Pakistan and Zambia. Women were enrolled in pregnancy and delivery and 6-week follow-up obtained to evaluate rates of OL/PL/FTP and outcomes resulting from OL/PL/FTP, including: maternal and delivery characteristics, maternal and neonatal morbidity and mortality and stillbirth.
Results
Between 2010 and 2013, 266,723 of 267,270 records (99.8%) included data on OL/PL/FTP with an overall rate of 110.4/1000 deliveries that ranged from 41.6 in Zambia to 200.1 in Pakistan. OL/PL/FTP was more common in women aged <20, nulliparous women, more educated women, women with infants >3500g, and women with a BMI >25 (RR 1.4, 95% CI 1.3 – 1.5), with the suggestion of OL/PL/FTP being less common in preterm deliveries. Protective characteristics included parity of ≥3, having an infant <1500g, and having a BMI <18. Women with OL/PL/FTP were more likely to die within 42 days (RR 1.9, 95% CI 1.4 – 2.4), be infected (RR 1.8, 95% CI 1.5 – 2.2), and have hemorrhage antepartum (RR 2.8, 95% CI 2.1 – 3.7) or postpartum (RR 2.4, 95% CI 1.8 – 3.3). They were also more likely to have a stillbirth (RR 1.6, 95% CI 1.3 – 1.9), a neonatal demise at < 28 days (RR 1.9, 95% CI 1.6 – 2.1), or a neonatal infection (RR 1.2, 95% CI 1.1 – 1.3). As compared to operative vaginal delivery and cesarean section (CS), women experiencing OL/PL/FTP who gave birth vaginally were more likely to become infected, to have an infected neonate, to hemorrhage in the antepartum and postpartum period, and to die, have a stillbirth, or have a neonatal demise. Women with OL/PL/FTP were far more likely to deliver in a facility and be attended by a physician or other skilled provider than women without this diagnosis.
Conclusions
Women with OL/PL/FTP in the communities studied were more likely to be primiparous, younger than age 20, overweight, and of higher education, with an infant with birthweight of >3500g. Women with this diagnosis were more likely to experience a maternal, fetal, or neonatal death, antepartum and postpartum hemorrhage, and maternal and neonatal infection. They were also more likely to deliver in a facility with a skilled provider. CS may decrease the risk of poor outcomes (as in the case of antepartum hemorrhage), but unassisted vaginal delivery exacerbates all of the maternal, fetal, and neonatal outcomes evaluated in the setting of OL/PL/FTP.
doi:10.1186/1742-4755-12-S2-S9
PMCID: PMC4464213  PMID: 26063492
obstructed labor; maternal mortality; maternal morbidity; neonatal mortality; neonatal morbidity; stillbirth; sub-Saharan Africa
15.  Neonatal mortality and coverage of essential newborn interventions 2010 - 2013: a prospective, population-based study from low-middle income countries 
Reproductive Health  2015;12(Suppl 2):S6.
Background
Approximately 3 million neonatal deaths occur each year worldwide. Simple interventions have been tested and found to be effective in reducing the neonatal mortality. In order to effectively implement public health interventions, it is important to know the rates of neonatal mortality and understand the contributing risk factors. Hence, this prospective, population-based, observational study was carried out to inform these needs.
Methods
The Global Network’s Maternal Newborn Health Registry was initiated in the seven sites in 2008. Registry administrators (RAs) attempt to identify and enroll all eligible women by 20 weeks gestation and collect basic health data, and outcomes after delivery and at 6 weeks post-partum. All study data were collected, reviewed, and edited by staff at each study site. The study was reviewed and approved by each sites’ ethics review committee.
Results
Overall, the 7-day neonatal mortality rate (NMR) was 20.6 per 1000 live births and the 28-day NMR was 25.7 per 1000 live births. Higher neonatal mortality was associated with maternal age > 35 and <20 years relative to women 20-35 years of age. Preterm births were at increased risk of both early and 28-day neonatal mortality (RR 8.1, 95% CI 7.5-8.8 and 7.5, 95% CI 6.9-8.1) compared to term as were those with low birth weight (<2500g). Neonatal resuscitation rates were 4.8% for hospital deliveries compared to 0.9% for home births. In the hospital, 26.5% of deliveries were by cesarean section with an overall cesarean section rate of 12.5%. Neonatal mortality rates were highest in the Pakistan site and lowest in Argentina.
Conclusions
Using prospectively collected data with high follow up rates (99%), we documented characteristics associated with neonatal mortality. Low birth weight and prematurity are among the strongest predictors of neonatal mortality. Other risk factors for neonatal deaths included male gender, multiple gestation and major congenital anomalies. Breech presentation/transverse lie, and no antenatal care were also significant risk factors for neonatal death. Coverage of interventions varied by setting of delivery, with the overall population rate of most evidence-based interventions low. This study informs about risk factors for neonatal mortality which can serve to design strategies/interventions to reduce risk of neonatal mortality.
Trial registration
The trial is registered at clinicaltrials.gov. ClinicalTrial.gov Trial Registration: NCT01073475
doi:10.1186/1742-4755-12-S2-S6
PMCID: PMC4464215  PMID: 26063125
neonatal mortality; newborn care; risk factors
16.  Postpartum contraceptive use and unmet need for family planning in five low-income countries 
Reproductive Health  2015;12(Suppl 2):S11.
Background
During the post-partum period, most women wish to delay or prevent future pregnancies. Despite this, the unmet need for family planning up to a year after delivery is higher than at any other time. This study aims to assess fertility intention, contraceptive usage and unmet need for family planning amongst women who are six weeks postpartum, as well as to identify those at greatest risk of having an unmet need for family planning during this period.
Methods
Using the NICHD Global Network for Women’s and Children’s Health Research’s multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in 100 rural geographic clusters in 5 countries (India, Pakistan, Zambia, Kenya and Guatemala), we assessed fertility intention and contraceptive usage at day 42 post-partum.
Results
We gathered data on 36,687 women in the post-partum period. Less than 5% of these women wished to have another pregnancy within the year. Despite this, rates of modern contraceptive usage varied widely and unmet need ranged from 25% to 96%. Even amongst users of modern contraceptives, the uptake of the most effective long-acting reversible contraceptives (intrauterine devices) was low. Women of age less than 20 years, parity of two or less, limited education and those who deliver at home were at highest risk for having unmet need.
Conclusions
Six weeks postpartum, almost all women wish to delay or prevent a future pregnancy. Even in sites where early contraceptive adoption is common, there is substantial unmet need for family planning. This is consistently highest amongst women below the age of 20 years. Interventions aimed at increasing the adoption of effective contraceptive methods are urgently needed in the majority of sites in order to reduce unmet need and to improve both maternal and infant outcomes, especially amongst young women.
Study registration
Clinicaltrials.gov (ID# NCT01073475)
doi:10.1186/1742-4755-12-S2-S11
PMCID: PMC4464604  PMID: 26063346
Contraception; low-middle income countries; obstetric care; family planning
17.  Developmental Outcomes of Very Preterm Infants with Tracheostomies 
The Journal of pediatrics  2014;164(6):1303-1310.e2.
Objectives
To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.
Study design
Retrospective cohort study from 16 centers of the NICHD Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N=8,683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI, a composite of one or more of: developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed impact of timing, by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.
Results
Tracheostomies were associated with all neonatal morbidities examined, and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without [odds ratio (OR) adjusted for center 7.0 (95%CI, 5.2-9.5)]. After adjustment for potential confounders, odds of death or NDI remained higher [OR 3.3 (95%CI, 2.4-4.6)], but odds of death alone were lower [OR 0.4 (95%CI, 0.3-0.7)], among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life [adjusted OR 0.5 (95%CI, 0.3-0.9)].
Conclusions
Tracheostomy in preterm infants is associated with adverse developmental outcomes, and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.
doi:10.1016/j.jpeds.2013.12.014
PMCID: PMC4035374  PMID: 24472229
newborn; very low birth weight infant; neurodevelopmental impairment; tracheotomy; bronchopulmonary dysplasia; prematurity
18.  Theory-driven process evaluation of a complementary feeding trial in four countries 
Health Education Research  2014;29(2):297-305.
We conducted a theory-driven process evaluation of a cluster randomized controlled trial comparing two types of complementary feeding (meat versus fortified cereal) on infant growth in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo. We examined process evaluation indicators for the entire study cohort (N = 1236) using chi-square tests to examine differences between treatment groups. We administered exit interviews to 219 caregivers and 45 intervention staff to explore why caregivers may or may not have performed suggested infant feeding behaviors. Multivariate regression analysis was used to determine the relationship between caregiver scores and infant linear growth velocity. As message recall increased, irrespective of treatment group, linear growth velocity increased when controlling for other factors (P < 0.05), emphasizing the importance of study messages. Our detailed process evaluation revealed few differences between treatment groups, giving us confidence that the main trial’s lack of effect to reverse the progression of stunting cannot be explained by differences between groups or inconsistencies in protocol implementation. These findings add to an emerging body of literature suggesting limited impact on stunting of interventions initiated during the period of complementary feeding in impoverished environments. The early onset and steady progression support the provision of earlier and comprehensive interventions.
doi:10.1093/her/cyt115
PMCID: PMC3959202  PMID: 24399265
19.  Genetic Variants Associated With Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants 
Purpose.
To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants.
Methods.
Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis.
Results.
Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 × 10−5) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P = 2.9 × 10−7).
Conclusions.
Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.
Two variants in the gene encoding brain-derived neurotrophic factor were significantly associated with severe ROP in the largest candidate gene study of extremely low birth weight US infants.
doi:10.1167/iovs.14-14841
PMCID: PMC4188045  PMID: 25118269
retinopathy of prematurity; extremely low birth weight; brain-derived neurotrophic factor; genetic associations; neurovascular
20.  Training traditional birth attendants on the WHO Essential Newborn Care reduces perinatal mortality 
Objectives
To evaluate the impact of birth attendant training using the World Health Organization Essential Newborn Care (ENC) course among traditional birth attendants, with a particular emphasis on the effect of acquisition of skills on perinatal outcomes.
Design
Population-based, prospective, interventional pre-post design study.
Setting
11 rural clusters in Chimaltenango, Guatemala.
Population
Health care providers.
Methods
This study analyzed the effect of training and implementation of the ENC health care provider training course between September 2005 and December 2006.
Outcome measures
The primary outcome measure was the rate of death from all causes in the first seven days after birth in fetuses/infants ≥1500g. Secondary outcome measures were overall rate of stillbirth, rate of perinatal death, which included stillbirths plus neonatal deaths in the first seven days in fetuses/infants ≥1500g.
Results
Perinatal mortality decreased from 39.5/1000 pre-ENC to 26.4 post-ENC (RR 0.72; 95%CI 0.54–0.97). This reduction was attributable almost entirely to a decrease in the stillbirth rate of 21.4/1000 pre-Essential Newborn Care to 7.9/1000 post-ENC (RR 0.40; 95%CI 0.25–0.64). Seven-day neonatal mortality did not decrease (18.3/1000 to 18.6/1000; RR 1.05; 95%CI 0.70–1.57).
Conclusion
Essential Newborn Care training reduced stillbirths in a population-based controlled study with deliveries conducted almost exclusively by traditional birth attendants. Scale-up of this intervention in other settings might help assess reproducibility and sustainability.
doi:10.1111/j.1600-0412.2012.01374.x
PMCID: PMC4362515  PMID: 22324644
Developing countries; newborn care; perinatal mortality; stillbirths; traditional birth attendants
21.  Incidence and Impact of CMV Infection in Very Low Birth Weight Infants 
Pediatrics  2014;133(3):e609-e615.
BACKGROUND AND OBJECTIVES:
Congenital cytomegalovirus (CMV) is the leading cause of nongenetic deafness in children in the United States and can cause neurodevelopmental impairment in term infants. Limited data exist regarding congenital CMV infections in preterm infants. We aimed to determine the incidence and association with outcomes of congenital CMV in very low birth weight (VLBW) preterm infants.
METHODS:
VLBW infants born in 1993 to 2008 and admitted to the University of Alabama in Birmingham Regional Neonatal ICU were screened on admission for congenital CMV. CMV status and clinical outcomes were identified by using internal patient databases and hospital-based medical records. The primary outcome was death. Secondary outcomes included evidence of neurologic injury in the form of abnormal cranial ultrasound findings, sensorineural hearing loss, or abnormal motor development. Multivariate analysis was performed.
RESULTS:
Eighteen of 4594 VLBW infants had congenital CMV (0.39%; 95% confidence interval, 0.25%–0.62%). An additional 16 infants (0.35%; 95% confidence interval, 0.21%–0.57%) were identified who acquired CMV postnatally. Congenital CMV was not associated with death. Compared with controls, congenitally infected VLBW infants were more likely to have hearing loss at initial screening (67% vs 9%, P < .0001) and confirmed at follow-up (83% vs 2.1%, P < .0001). Congenital CMV was also associated with abnormal neuroimaging (72% vs 25%, P < .0001) and adverse developmental motor outcomes (43% vs 9%, P = .02). Acquired CMV was not associated with any adverse outcomes.
CONCLUSIONS:
Congenital CMV in VLBW infants is associated with high rates of neurologic injury and hearing loss but not death.
doi:10.1542/peds.2013-2217
PMCID: PMC3934333  PMID: 24488749
cytomegalovirus; very low birth weight; sensorineural hearing loss; neurodevelopmental impairment
22.  Neonatal death in Low-Middle Income Countries: A Global Network Study 
American journal of perinatology  2012;29(8):649-656.
Objective
To determine population-based neonatal mortality rates in low and middle income countries and to examine gestational age, birth-weight and timing of death to assess the potentially preventable neonatal deaths.
Methods
A prospective observational study was conducted in communities in five low-income countries (Kenya, Zambia, Guatemala, India, and Pakistan) and one mid-income country (Argentina). Over a two-year period, all pregnant women in the study communities were enrolled by trained study staff and their infants followed to 28 days of age.
Results
Between October 2009 and March 2011, 153,728 babies were delivered and followed through day 28. Neonatal death rates ranged from 41 per 1000 births in Pakistan to 8 per 1000 in Argentina. 54% of the neonatal deaths were >37 weeks and 46% weighed 2500 grams or more. Half the deaths occurred within 24 hours of delivery.
Conclusions
In our population-based low and middle income country registries, the majority of neonatal deaths occurred in babies >37 weeks gestation and almost half weighed at least 2500 grams. Most deaths occurred shortly after birth. With access to better medical care and hospitalization, especially in the intrapartum and early neonatal period, many of these neonatal deaths might be prevented.
doi:10.1055/s-0032-1314885
PMCID: PMC4337792  PMID: 22644832
Neonatal mortality; low-income countries; preterm birth
23.  Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy 
JAMA  2014;312(24):2629-2639.
IMPORTANCE
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
OBJECTIVE
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
DESIGN, SETTING, AND PARTICIPANTS
Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
INTERVENTIONS
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
MAIN OUTCOMES AND MEASURES
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
RESULTS
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
CONCLUSIONS AND RELEVANCE
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
doi:10.1001/jama.2014.16058
PMCID: PMC4335311  PMID: 25536254
24.  Inhaled Nitric Oxide Usage in Preterm Infants in the NICHD Neonatal Research Network: Inter-site Variation and Propensity Evaluation 
Background
The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, an NIH consensus development conference cautioned against use of iNO in preterm infants.
Objective
1) To determine prevalence and variability in use of iNO in the NICHD Neonatal Research Network (NRN) before and after the consensus conference and 2) separately, to examine associations between iNO use and severe BPD or death.
Design/Methods
The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008–2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.
Results
A total of 4,885 infants were assessed between 2008–2011; 128 (2.6%) received iNO before Day 7, 140 (2.9%) between Day 7 and 28 and 47 (1.0%) at >28 days. Center-specific iNO use during 2008–2010 ranged from 21.9% to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6% to 1.6% (p<0.001) in 2011. Use of iNO started between Day 7 and Day 14 was more prevalent among younger infants with more severe courses in Week 1 and associated with increased risk of severe BPD or death (OR 2.24;95% CI 1.23–4.07).
Conclusions
The variability and total use of iNO decreased in 2011 compared to 2008–2010. iNO administration started at ≥Day 7 was associated with more severe outcomes compared to infants without iNO exposure.
doi:10.1038/jp.2014.105
PMCID: PMC4323079  PMID: 24901452
Inhaled nitric oxide; bronchopulmonary dysplasia; extremely premature infant
25.  Death or Neurodevelopmental Impairment at 18 To 22 Months in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2013;164(1):34-39.e2.
Objective
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Methods
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Results
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
Conclusion
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
doi:10.1016/j.jpeds.2013.07.027
PMCID: PMC4120744  PMID: 23992673
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up

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