Published online May 1, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1381-e1390 (doi:10.1542/peds.2007-1966)
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ARTICLE

Risk Factors for Neonatal Mortality Due to Birth Asphyxia in Southern Nepal: A Prospective, Community-Based Cohort Study

Anne CC. Lee, MD, MPHa, Luke C. Mullany, PhDa, James M. Tielsch, PhDa, Joanne Katz, ScDa, Subarna K. Khatry, MBBSb, Steven C. LeClerq, MPHa,b, Ramesh K. Adhikari, MDc, Shardaram R. Shrestha, MPHb and Gary L. Darmstadt, MD, MSa

a Department of International Health, International Center for Advancing Neonatal Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
b Nepal Nutrition Intervention Project-Sarlahi, Kathmandu, Nepal
c Institute of Medicine, Tribhuvan University, Kathmandu, Nepal


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Our goal was to identify antepartum, intrapartum, and infant risk factors for birth asphyxia mortality in a rural, low-resource, population-based cohort in southern Nepal.

PATIENTS AND METHODS. Data were collected prospectively during a cluster-randomized, community-based trial evaluating the impact of newborn skin and umbilical cord cleansing on neonatal mortality and morbidity in Sarlahi, Nepal. A total of 23662 newborn infants were enrolled between September 2002 and January 2006. Multivariable regression modeling was performed to determine adjusted relative risk estimates of birth asphyxia mortality for antepartum, intrapartum, and infant risk factors.

RESULTS. Birth asphyxia deaths (9.7/1000.0 live births) accounted for 30% of neonatal mortality. Antepartum risk factors for birth asphyxia mortality included low paternal education, Madeshi ethnicity, and primiparity. Facility delivery; maternal fever; maternal swelling of the face, hands, or feet; and multiple births were significant intrapartum risk factors for birth asphyxia mortality. Premature infants (<37 weeks) were at higher risk, and the combination of maternal fever and prematurity resulted in a 7-fold elevation in risk for birth asphyxia mortality compared to term infants of afebrile mothers.

CONCLUSIONS. Maternal infections, prematurity, and multiple births are important risk factors for birth asphyxia mortality in the low-resource, community-based setting. Low socioeconomic status is highly associated with birth asphyxia, and the mechanisms leading to mortality need to be elucidated. The interaction between maternal infections and prematurity may be an important target for future community-based interventions to reduce the global impact of birth asphyxia on neonatal mortality.

Key Words: asphyxia neonatorum • risk factors • mortality • neonatal • Nepal

Abbreviations: RR—relative risk • CI—confidence interval • OR—odds ratio • IL—interleukin

Birth asphyxia is defined by the World Health Organization as "the failure to initiate and sustain breathing at birth."1 Accurate estimates of the proportion of neonatal mortality attributable to birth asphyxia are limited by the lack of a consistent definition for use in community-based settings and the absence of vital registration in communities where the majority of neonatal deaths occur. Hospital-based studies in Nepal2 and South Africa3 estimated that birth asphyxia accounted for 24% and 14% of perinatal mortality, respectively. However, these may substantially underestimate the burden in rural areas, where early deaths, most of which occur at home, are more likely to be underreported.4 In rural regions of the Uttar Pradesh5 and Maharashtra6 states of India, 23% and 25% of neonatal mortality were attributed to birth asphyxia, respectively. Globally, hypoxia of the newborn (birth asphyxia) or the fetus ("fresh stillbirth") is estimated to account for 23% of the 4 million neonatal deaths7 and 26% of the 3.2 million stillbirths each year.8,9 An estimated 1 million children who survive birth asphyxia live with chronic neurodevelopmental morbidities, including cerebral palsy, mental retardation, and learning disabilities.10

Definitions of birth asphyxia designed for use in hospital-based settings require evaluation of umbilical cord pH, Apgar scores, neurologic clinical status, and markers of multisystem organ function11 and are not feasible for community settings.12 Given that the majority of neonatal deaths occur in the home without medical supervision, community-based definitions must rely on data gathered from verbal autopsy methods and use more general symptom- and sign-based algorithms. For example, the National Neonatology Forum of India has defined birth asphyxia as "gasping and ineffective breathing or lack of breathing at 1 minute after birth."13 Such sign-based definitions are not, however, implemented consistently, and varying study-specific definitions may affect estimation of the proportion of neonatal deaths attributed to birth asphyxia.

Risk factors for birth asphyxia in hospital-based settings in developing countries have been categorized into antepartum, intrapartum, and infant or postnatal characteristics (Table 1). Hospital-based and home-based risk factors for birth asphyxia may be similar, but such data are entirely lacking.


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  		TABLE 1 Antepartum, Intrapartum, and Infant Risk Factors for Birth Asphyxia Reported Previously From Hospital-Based Studies

 
In this study, we identify risk factors for birth asphyxia among newborns of rural Sarlahi district, Nepal, from data collected prospectively within the context of a large, community-based trial of the impact of chlorhexidine cleansing of newborn skin and umbilical cord on neonatal morbidity and mortality.14,15


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 CONCLUSIONS
 REFERENCES
 
Data Collection
The data for this study were collected from 2002 to 2006 by the Nepal Nutrition Intervention Project, Sarlahi, Kathmandu, Nepal. Study procedures have been reported in detail previously.14,15 Briefly, pregnant women were identified during midpregnancy, the study was explained, and oral consent was obtained. All of the women received albendazole (400 mg), iron-folic acid, and vitamin A supplementation, as well as health education on prenatal nutrition, infant thermal care, and hygienic umbilical cord care. Data were recorded on socioeconomic status, household structure, and maternal reproductive history.

Newborns were randomly assigned within clusters (n = 413 sectors, identified based on the population that 1 local female worker could service, ~40–50 households) in a factorial design to 1 of 2 full-body skin cleansing regimens (0.25% chlorhexidine or placebo)15 and subsequently, within each of these 2 groups, to 1 of 3 cord cleaning regimens (umbilical stump cleansing with 4% chlorhexidine, cleansing with soap and water, or dry cord care).14 A comparative phase from September 2002 to March 2005 was followed by a second period during which all of the infants received the beneficial chlorhexidine cleansing interventions, on recommendation of the trial's Data Safety and Monitoring Board.

Data regarding maternal report of morbidity before, during, and after childbirth were collected. Newborns were visited ≤11 times (days 1–4, 6, 8, 10, 12, 14, 21, and 28) by study area coordinators and assessed for vital status and symptoms and signs of morbidity. Gestational age was estimated from 2 maternal reports (at the time of pregnancy registration and at first assessment after delivery) of time since last menstrual period. Verbal autopsies were conducted soon after a neonatal death (median time: 2.0 days; 75% within 1 week, 90% within 3 weeks of death) by supervisory workers who were trained in verbal autopsy techniques and had 3 to 12 years of experience in conducting verbal autopsies in this setting. The verbal autopsy questionnaire was based on the World Health Organization standard verbal autopsy form16 with minor modifications.17

Case Definition of Birth Asphyxia
The selection of birth asphyxia cases is described in detail in the accompanying paper.15 In brief, four verbal autopsy-based definitions (ie, algorithms) of birth asphyxia were identified in the literature and are reported in 3 publications: the World Health Organization Standard Verbal Autopsy Methods (definitions 3 and 4),16 Baqui et al,5 and the Nepal Newborn Washing Study.15 The algorithms contained varying combinations of clinical symptoms, including timing of death, crying at birth, breathing at birth, presence of convulsions, and sucking at birth, and are shown in Fig 1. Each of the 4 algorithms was applied to the 759 neonatal deaths to determine whether the death was attributable to birth asphyxia.


Figure 1
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  		FIGURE 1 Assignment of birth asphyxia (BA) as cause of neonatal death. a Algorithm 1 (World Health Organization definition 316): infant was not able to cry after birth and either not able to breathe after birth or not able to suckle normally after birth; algorithm 2 (World Health Organization definition 416): infant was not able to cry after birth and either had convulsions/spasms or was not able to suckle normally after birth; algorithm 3 (Baqui et al5): infant died in the first 7 days of life and was not able to cry at birth, not able to breathe at birth, or unable to suckle normally at birth; algorithm 4 (Newborn Washing Study15): infant died in the first 7 days of life, was not able to cry at birth, and was not able to breathe at birth, unable to suckle normally at birth, or had convulsions. b A local Nepali physician (Drs Adhikari or Khatry) reviewed the verbal autopsy interview and open verbatim histories to assign cause of death. c Investigators (Drs Lee, Darmstadt, and Mullany) reviewed the open verbatim histories to verify cause of death. d Application of standard CHERG19 hierarchy without removal of preterm births.

 
Assignment of cause of death to birth asphyxia was based on an assessment of the level of concordance of the 4 algorithms, as well as further local physician ascertainment of cause of death in Nepal (Drs Adhikari and Khatry) and study investigator review of the open narrative accounts of death (Drs Lee, Darmstadt, and Mullany) (Fig 1).18 All of the neonatal deaths meeting 3 or 4 of the definitions (n = 230) were assigned as birth asphyxia deaths. For those meeting ≤2 definitions, an additional 16 infants were identified as birth asphyxia deaths, bringing the total to 246 (32%) of the 759 total neonatal deaths.

Because computer-algorithmic approaches to verbal autopsy data often result in multiple potential causes of death, a standard hierarchal approach was applied19 to identify and exclude deaths potentially attributable to neonatal tetanus or congenital malformations (confirmed through direct physician [Drs Adhikari and Khatry] assessment in Nepal and additional review by the study investigators [Drs Lee, Darmstadt, and Mullany], of the open narrative portion of the verbal autopsy provided by caretakers in the household) 230 (30%) of the 759 neonatal deaths were finally attributed to birth asphyxia. Premature infants were not excluded, given the overlapping clinical symptoms between premature and asphyxiated infants. Of the 230 birth asphyxia deaths, 70 infants (30%) also met verbal autopsy criteria for prematurity (defined as "being born early").

Statistical Analysis
The clinical characteristics of newborns in the study were analyzed with simple descriptive statistics and compared among birth asphyxia deaths, alternate causes of death, and surviving infants, using {chi}2 tests for categorical data and analysis of variance for continuous data. Risk factors for birth asphyxia mortality were grouped into antepartum, intrapartum, and postnatal or infant variables. Certain intrapartum risk factors were assessed by maternal self-report of symptoms in the 7 days before childbirth: (1) "high fever" indicative of potential maternal infection; (2) "bleeding from the vagina" for antepartum hemorrhage; (3) "swelling of the hands, face, or feet" and "convulsions" for potential preeclampsia or eclampsia; (4) "hours the labor pains lasted" for determining length of labor (prolonged labor defined as >24 hours in primiparous and >12 hours in multiparous mothers)20; (5) "hours before delivery the water broke" for establishing length of rupture of membranes (prolonged rupture of membranes defined as >24 hours); and (6) "color of the water" for assessing meconium staining. For each potential risk factor, the relative risk (RR) for birth asphyxia death was calculated in bivariate analysis by using log binomial regression. Risk factors that were associated with birth asphyxia death with a P value of <.05 were considered for testing in the multivariate models.

Multivariate models were first generated separately for antepartum, intrapartum, and infant variables. Risk factors identified in the bivariate analyses were further evaluated in the multivariate models if they were associated with mortality after adjustments and/or substantially confounded the relationship between birth asphyxia mortality and other risk factors. Exceptions were maintained and variables were included that have been established as important risk factors in previous studies; for example, the antepartum variables maternal age20,21 and literacy22 (defined as the ability to read and write a simple letter). The multivariate model, which focused on intrapartum risk factors, included only those that temporally preceded the asphyxial event. For example, we excluded actions including resuscitative measures, assisted delivery, injections, and cesarean section that may have been undertaken as a result of labor complications potentially related to birth asphyxia. The intrapartum model included all of the significant (P < .05) covariates meeting this criterion, given that each was a well-established risk factor for asphyxia in hospital-based studies. The postnatal or infant model included all of the significant covariates without substantial missing data.

More comprehensive models combining antepartum, intrapartum, and infant variables were also developed. Interaction was tested between prematurity and specific intrapartum risk factors (maternal fever, swelling, vaginal bleeding, and prolonged rupture of membranes). Stratified analysis was performed for premature versus term infants. The treatment effects of chlorhexidine skin and umbilical cord cleansing were explored both by intention to treat as well as actual treatment received.

In all of the models, SEs were adjusted for nonindependence of events for mothers contributing >1 child to the cohort. Colinearity was inspected and, in the case of substantial between-variable correlation, only the most significant variable was added to the model. Stata 9.0 (Stat Corp, College Station, TX) was used to conduct all of the analyses.

The study was approved by the Nepal Health Research Council (Katmandu, Nepal) and Johns Hopkins Bloomberg School of Public Health Committee on Human Research.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
CONCLUSIONS
 REFERENCES
 
Subject Characteristics
Between September 2002 and January 2006, there were 23662 live births and 759 neonatal deaths in the study area. The overall characteristics of the study population have been described previously.15 The majority (20295 of 22364 [91%]) of infants were born in the nuclear family home, maiti (maternal home), or outdoors. The overall prevalence of low birth weight was 29.8% (6784 of 22762; 95% confidence interval [CI]: 29.2–30.4). Verbal autopsies were completed on 750 (99%) of 759 neonatal deaths.

The incidence of birth asphyxia was 9.7 deaths (n = 230) per 1000 live births (95% CI: 8.5–10.9; proportionate mortality: 30.3%). Asphyxiated infants were of lower birth weight and gestational age (mean: 2.22 kg and 37.1 weeks, respectively) than the surviving infants (mean: 2.71 kg and 39.3 weeks, respectively) and died at an earlier age than those dying from other causes (median: 0.46 vs 2.96 days; Table 2). Asphyxiated infants had delayed onset of breathing, poor movement and color, and an increased frequency of convulsions. The median age at death because of birth asphyxia was 11 hours; 158 (69%) and 228 (99%) of such deaths occurred within the first 1 and 7 days of life, respectively.


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  		TABLE 2 Characteristics of Asphyxiated Infants, Nonbirth Asphyxia Deaths, and Surviving Infants

 
Bivariate Analysis
Antepartum Risk Factors
Infants of mothers aged 20 to 29 years old were at lower risk for birth asphyxia mortality compared with infants of young mothers (<20 years; Table 3). Birth asphyxia risk decreased significantly with increasing maternal education (RR: 0.57; 95% CI: 0.40–0.83), maternal literacy (RR: 0.54; 95% CI: 0.37–0.77), paternal education (>10 years; RR: 0.44; 95% CI: 0.29–0.68), and paternal literacy (RR: 0.52; 95% CI: 0.40–0.69). Newborns of Madeshi ethnicity ("people from the plains") had a 2.51 times (95% CI: 1.71–3.68) increased risk versus those of Pahadi ethnicity ("people from the hills"). Infants of primiparous women carried a higher risk for birth asphyxia mortality (RR: 1.74; 95% CI: 1.33–2.28), whereas history of a previous child death did not significantly predict birth asphyxia mortality (RR: 0.99; 95% CI: 0.70–1.40).


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  		TABLE 3 Bivariate Analysis of Antepartum Risk Factors for Birth Asphyxia Mortality

 
Intrapartum Risk Factors
Although the majority of births in this region took place at home, the deliveries that took place "on the way to clinic" (RR: 2.43; 95% CI: 1.09–5.43) and in medical facilities (RR: 1.85; 95% CI: 1.27–2.68) were associated with a higher risk of birth asphyxia mortality (Table 4). Of maternal symptoms self-reported within 7 days before childbirth, fever (RR: 3.30; 95% CI: 2.15–5.07); vaginal bleeding (RR: 2.00; 95% CI: 1.23–3.27); swelling of the hands, face, or feet (RR: 1.78; 95% CI: 1.33–2.37); convulsions (RR: 4.74; 95% CI: 1.80–12.46); prolonged labor (RR: 1.31; 95% CI: 1.00–1.73); and prolonged rupture of membranes (RR: 1.83; 95% CI: 1.22–2.76) were significantly associated with increased risk for birth asphyxia mortality. Multiple births (twin or triplet) were strongly related to birth asphyxia mortality (RR: 5.73; 95% CI: 3.38–9.72).


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  		TABLE 4 Bivariate Analysis of Intrapartum and Infant Risk Factors for Birth Asphyxia Mortality

 
Infants with "green" (presumably meconium-stained) amniotic fluid had a nonsignificant greater risk of birth asphyxia (RR: 1.32; 95% CI: 0.19–2.16); however, the sample size was small, and precision of the estimate was low. "Red" amniotic fluid carried a 1.58 (95% CI: 1.15–2.16) times increased risk; however, this was clinically difficult to distinguish from vaginal bleeding and was, therefore, not included in the final multivariate models.

Infant Factors
A substantial proportion of birth weight information was missing on the birth asphyxia cases (179 of 230 [78%]), because death occurred before the first visit by study staff (median time to visit for birth weight measurement: 19 hours). The risk for birth asphyxia mortality was 11.88-fold (95% CI: 6.09–23.14) higher in the lowest weight category of <2 kg as compared with the 2.5- to 2.9-kg weight category (Table 4). However, because of the considerable differential missing data for birth asphyxia cases, birth weight was not included in the final multivariate model. Prematurity carried a substantially higher risk of birth asphyxia mortality, with gestational age 34 to 37 weeks increasing the risk by a factor of 1.61 (95% CI: 1.13–2.27) and gestational age <34 weeks increasing risk by a factor of 14.33 (95% CI: 10.31–19.91). In contrast to hospital-based studies,20 postterm infants were not at greater risk for birth asphyxia.

There was no significant treatment effect on birth asphyxia mortality for infants who received either the full-body skin cleansing (chlorhexidine versus placebo wipes; RR: 0.87; 95% CI: 0.57–1.31) or umbilical cord cleansing treatments (chlorhexidine versus dry cord care; RR: 0.85; 95% CI: 0.40–1.82). A large proportion of the infants allocated to treatment who died from birth asphyxia did not live long enough to receive either skin cleansing (135 of 230 [59%]) or umbilical cord cleansing (179 of 230 [78%]). Because there was not a significant difference in the risk of birth asphyxia mortality between the infants who actually received the skin cleansing with chlorhexidine versus placebo or among infants in the chlorhexidine cord cleansing group or soap-and-water cleansing group versus placebo, treatment allocation was not included in the multivariate models.

Multivariate Analysis
Antepartum Risk Factors
Maternal and paternal literacy, education, and occupation were correlated socioeconomic covariates; paternal education was the most significant risk factor, associated with a 41% lower birth asphyxia risk (any versus none; adjusted RR: 0.59; 95% CI: 0.43–0.81, final model; Table 5). Maternal literacy was the strongest maternal socioeconomic indicator and, thus, retained in the antepartum model to control for maternal socioeconomic status, although it was not significant after adjustment (RR: 0.79; 95% CI: 0.50–1.25). Ethnicity (RR: 1.94; 95% CI: 1.27–2.97) remained significant after controlling for the other socioeconomic indicators.


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  		TABLE 5 Multivariate Models of Antepartum, Intrapartum, and Infant Risk Factors for Birth Asphyxia Mortality

 
Parity confounded the relationship between maternal age and birth asphyxia mortality. Although maternal age was not significantly associated with birth asphyxia in the final model (Table 5), the risk was difficult to disassociate from parity, because age and parity were strongly correlated at low maternal age. Given the recent findings of prematurity and low birth weight mediating the risk of neonatal mortality in adolescent mothers (V Sharma, written communication, 2007), this relationship was further explored and found applicable to birth asphyxia deaths. Among adolescent mothers <16 years old, the unadjusted excess risk for birth asphyxia mortality was 88% (reference: 20–24 years; RR: 1.88; 95% CI: 0.83–4.25). After adjusting for antepartum and intrapartum risk factors (including parity and excluding prematurity), the excess risk was reduced to 22% (RR: 1.22; 95% CI: 0.51–2.95). Prematurity further attenuated the birth asphyxia risk attributed to adolescent maternal age by an additional 7% (RR: 1.15; 95% CI: 0.49–2.74). The relationship of birth weight was not explored given the differential missing data for birth asphyxia deaths.

Intrapartum Risk Factors
The increased risk for birth asphyxia mortality associated with facility-based births remained significant after controlling for intrapartum complications and socioeconomic and infant factors (RR: 1.89; 95% CI: 1.19–3.00; Table 5). Maternal fever carried a higher risk for birth asphyxia mortality (RR: 2.02; 95% CI: 1.26–3.23; model 3), and the effect was significantly modified by prematurity (term RR: 0.84, 95% CI: 0.31–2.28, final model; premature RR: 3.11, 95% CI: 1.78–5.46). Maternal swelling (RR: 1.40; 95% CI: 1.01–1.96) was associated with elevated asphyxia risk, whereas prolonged rupture of membranes and vaginal bleeding resulted in a 28% and 62% nonsignificant increased risk after controlling for the remaining covariates. The risk of prolonged labor was attenuated after adding intrapartum covariates to the model. Prolonged labor may act as an intermediate variable, mediating the effects of other factors, such as primiparity and multiple birth,23 and was, therefore, not included in the multivariate models.

Infant Risk Factors
Gestational age was modeled as a continuous, categorical, and dichotomous variable in initial univariate analysis; however, the choice of scale did not significantly affect the coefficients of the other covariates in the development of the multivariate model. Given that a range of uncertainty exists for gestational age estimation by last menstrual period,24 gestational age was categorized as dichotomous, premature (<37 weeks' gestation) versus term (≥37 weeks), in the final multivariate model. Prematurity was associated with a 2.28-fold (95% CI: 1.69–3.09) higher birth asphyxia risk after adjustment for the other covariates (Table 4). Subanalysis restricting the cohort to term infants yielded similar effects and associations of risk factors as the entire cohort.

Interaction
Maternal fever significantly modified the effect of prematurity on birth asphyxia mortality (exponentiated interaction term coefficient: 3.70; 95% CI: 1.18–11.60; P = .02). Among infants exposed to maternal fever, prematurity resulted in 8.44-fold (95% CI: 2.82–25.29) increased risk for birth asphyxia death, whereas among infants of mothers without intrapartum fever, prematurity was associated with a 2.28 times (95% CI: 1.69–3.09) higher risk for birth asphyxia mortality. The risk of asphyxia was 7.12-fold (95% CI: 4.25–11.90) higher in preterm infants exposed to maternal fever versus term infants of afebrile mothers.

DISCUSSION
In this study, we identify risk factors for birth asphyxia mortality in a large population-based cohort of births in a rural, low-resource region with high rates of home birth and neonatal mortality. Inferences from these data may potentially be made to other high-mortality regions of the developing world where the majority of neonatal deaths occur.

Socioeconomic status, measured by a range of variables, including parental education and ethnicity, was significantly associated with increased risk of birth asphyxia mortality. The associations remained after adjustment for preestablished intrapartum risk factors. These socioeconomic factors may increase asphyxia risk by influencing maternal nutritional status, care seeking, and access to health care services during the antenatal and intrapartum periods. Furthermore, ethnicity may influence maternal height, which may, in turn, affect birth asphyxia risk.20 Maternal height was not measured in this study, however.

Young maternal age has been linked with increased rates of neonatal mortality25,26; however, maternal age is difficult to disassociate from parity in young adolescents. Recent studies have shown an increased risk of prematurity among young nulliparous adolescents,27,28 suggesting that prematurity and low birth weight may mediate the effect of young maternal age on neonatal mortality25 (V Sharma, written communication, 2007). In this analysis, the excess risk of birth asphyxia mortality among adolescent mothers was attenuated after controlling for antepartum and intrapartum risk factors (including parity and prematurity).

Antepartum hemorrhage, maternal fever, preeclampsia, eclampsia, prolonged rupture of membranes, and obstructed labor have been associated with increased risk of birth asphyxia in multiple hospital-based studies.29–33 In this study, among self-reported clinical symptoms reflecting these disease processes, maternal fever (indicative of infection) and swelling of the face, hands, and/or feet (indicative of preeclampsia) were significant predictors of birth asphyxia death after controlling for other factors. As opposed to previous studies,20,21 we chose to adjust for the other intrapartum risk factors to obtain estimates of the independent association of each risk factor. The subsequent nonsignificance of the adjusted relative risk of convulsions, vaginal bleeding, and prolonged rupture of membranes may be because of the low numbers of women with these symptoms, as well as the self-reported and nonspecific nature of data elicited by household surveys compared with hospital-based diagnoses, which may be verified by clinical observation or laboratory testing.

In resource-limited and rural settings such as Sarlahi, where home birth is customary and cost and transportation may deter care seeking during childbirth,34 it is plausible that only the more complicated childbirths seek higher-level medical care. This is reflected in our study by the association of deliveries on the way to clinic and in hospital facilities with significantly increased risk of birth asphyxia mortality, even after controlling for other intrapartum factors. These findings highlight the need to evaluate the training of local birth attendants and hospital facilities in the recognition and management of clinical birth asphyxia in this setting.

The strongest risk factors for birth asphyxia mortality in this study were the combined, synergistic effects of maternal fever, as a sign of serious infection, and prematurity. In a previous study in the same area, the risk of 6-month mortality was 29.6 times higher in infants with symptoms of birth asphyxia, prematurity, and neonatal sepsis as opposed to those with only sepsis (odds ratio [OR]: 3.1), asphyxia (OR: 4.5), or prematurity (OR: 3.4).35 In Gadchiroli,36 the case fatality for preterm infants with sepsis was 51.9% versus prematurity (11.1%) or sepsis (0%) alone, whereas the case fatality for asphyxiated premature infants was 66.7% versus birth asphyxia alone (25%). The synergy between birth asphyxia, infection, and prematurity may be explained by a common inflammatory pathway of neonatal brain injury involving cytokines and chemokines, which stems from hypoxic-ischemic insult (interleukin [IL]-6, IL-1β, intercellular adhesion molecule, and IL-8),37–40 exposure to maternal intrauterine infection (IL-6),41 and prematurity (IL-6, tumor necrosis factor-{alpha}, and prostaglandin E).42 Furthermore, premature infants are more vulnerable to cytokine-induced damage because of the immaturity of their blood-brain barrier. Taken altogether, our findings highlight the importance of integrated maternal-neonatal care, including community-based recognition and treatment of maternal infections during pregnancy to reduce not only prematurity but also birth asphyxia mortality.

The lack of a standard community-based definition of birth asphyxia is a limitation to our study. To address this, we explored several verbal autopsy definitions of birth asphyxia and developed specific methods to most accurately identify birth asphyxia cases. These methods are described in detail elsewhere.18 However, given that almost all of the deaths occurred without medical supervision, our case definitions of birth asphyxia were not validated by physiologic measurements or physician examination. Other limitations include potential reporting bias of maternal and/or infant symptoms and recall bias in the verbal autopsy interviews. Recall periods ranging up to 12 months are considered acceptable,43 and in this study, 75% of interviews were conducted within 1 week of the infant's death, limiting recall bias.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 CONCLUSIONS
REFERENCES
 
The high rate of birth asphyxia mortality in Sarlahi emphasizes the urgent need to develop and evaluate strategies for the identification and management of birth asphyxia in home, community, and peripheral health facility settings. Standardized community-based definitions of birth asphyxia need to be developed.12 Furthermore, our data highlight the critical interrelationship between maternal infections and prematurity as comorbid risk factors for birth asphyxia mortality, thus calling for increased attention to the early recognition and management of these factors in community-based maternal and child health programs.


   ACKNOWLEDGMENTS
 
This study was conducted by the Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, under grants from the National Institutes of Health, Bethesda, MD (HD 44004, HD 38753, and R03 HD 49406); the Bill and Melinda Gates Foundation, Seattle, WA (810–2054); and cooperative agreements between Johns Hopkins University and the Office of Health and Nutrition, US Agency for International Development, Washington, DC (HRN-A-00-97-00015-00, GHS-A-00-03-000019-00). Commodity support was provided by Procter and Gamble Company, Cincinnati, OH.


   FOOTNOTES
 
Accepted Aug 31, 2007.

Address correspondence to Gary L. Darmstadt, MD, MS, Department of International Health E-8153, International Center for Advancing Neonatal Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe St, Baltimore, MD 21205. E-mail: gdarmsta{at}jhsph.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00109616).

Financial supporters and the commodity supplier played no role in the design, conduct, management, analysis, or interpretation of the results or in the preparation, review, or approval of this article.

Drs Darmstadt, Mullany, Katz, and Tielsch made primary contributions to the design, conduct, analysis, interpretation, and writing of this article. As corresponding author, Dr Darmstadt had full access to all the data in the study and had final responsibility for the decision to submit for publication. Dr Khatry, Mr LeClerq, and Mr Shrestha contributed to the field conduct and quality control of the trial. Drs Adhikari and Khatry participated in review of the verbal autopsies. Dr Lee was the primary author and conducted the analysis for this study. All of the authors reviewed and approved the article.


What's Known on This Subject

Birth asphyxia accounts for an estimated 23% of global neonatal mortality. Antepartum and intrapartum risk factors for birth asphyxia have been described in hospital-based settings; however, data from community-based settings, where most neonatal deaths occur, are limited.

 

What This Study Adds

Risk factors for birth asphyxia mortality at the community-level include parental education, ethnicity, parity, delivery place, maternal fever, maternal swelling, multiple birth, male gender, and prematurity. Intrapartum fever and preterm delivery may synergistically increase the risk of birth asphyxia mortality.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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A. C. Lee, G. L. Darmstadt, S. K. Khatry, S. C. LeClerq, S. R. Shrestha, and P. Christian
Maternal-Fetal Disproportion and Birth Asphyxia in Rural Sarlahi, Nepal
Arch Pediatr Adolesc Med, July 1, 2009; 163(7): 616 - 623.
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