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1.  Population-Based Incidence and Etiology of Community-Acquired Neonatal Bacteremia in Mirzapur, Bangladesh: An Observational Study 
The Journal of infectious diseases  2009;200(6):906-915.
Background
To devise treatment strategies for neonatal infections, the population-level incidence and antibiotic susceptibility of pathogens must be defined.
Methods
Surveillance for suspected neonatal sepsis was conducted in Mirzapur, Bangladesh, from February 2004 through November 2006. Community health workers assessed neonates on postnatal days 0, 2, 5, and 8 and referred sick neonates to a hospital, where blood was collected for culture from neonates with suspected sepsis. We estimated the incidence and pattern of community-acquired neonatal bacteremia and determined the antibiotic susceptibility profile of pathogens.
Results
The incidence rate of community-acquired neonatal bacteremia was 3.0 per 1000 person–neonatal periods. Among the 30 pathogens identified, the most common was Staphylococcus aureus (n = 10); half of all isolates were gram positive. Nine were resistant to ampicillin and gentamicin or to ceftiaxone, and 13 were resistant to cotrimoxazole.
Conclusion
S. aureus was the most common pathogen to cause community-acquired neonatal bacteremia. Nearly 40% of infections were identified on days 0–3, emphasizing the need to address maternal and environmental sources of infection. The combination of parenteral procaine benzyl penicillin and an aminoglycoside is recommended for the first-line treatment of serious community-acquired neonatal infections in rural Bangladesh, which has a moderate level of neonatal mortality. Additional population-based data are needed to further guide national and global strategies.
Trial registration
ClinicalTrials.gov identifier: NCT00198627.
doi:10.1086/605473
PMCID: PMC2841956  PMID: 19671016
2.  Risk Factors for Neonatal Mortality due to Birth Asphyxia in Southern Nepal 
Pediatrics  2008;121(5):e1381-e1390.
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. 23,662 infants were born in study regions between September 2002 - 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 (9.7/1,000 live births) accounted for 30% of neonatal mortality. Antepartum risk factors for birth asphyxia mortality included low paternal education (relative risk [RR]: 1.69; 95% confidence interval [CI]: 1.23 to 2.33), Madeshi ethnicity (RR: 1.94; CI: 1.27 to 2.97) and primiparity (RR: 1.71; CI: 1.16 to 2.53). Facility delivery (RR: 1.89; CI: 1.19 to 3.00), maternal fever (RR: 2.02; CI: 1.26 to 3.23), maternal swelling of the face, hands or feet (RR: 1.40; CI: 1.01 to 1.96), and multiple births (RR: 4.77; CI: 2.78 to 8.20) were significant intrapartum risk factors for birth asphyxia mortality. Premature infants (<37 weeks) were at higher risk (RR: 2.28; CI: 1.69 to 3.09), and the combination of maternal fever and prematurity resulted in a synergistic elevation in risk for birth asphyxia mortality (RR: 7.12; CI: 4.25 to 11.90).
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 further 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.
doi:10.1542/peds.2007-1966
PMCID: PMC2377391  PMID: 18450881
asphyxia neonatorum; risk factors; mortality; neonatal; Nepal
3.  Verbal Autopsy Methods to Ascertain Birth Asphyxia Deaths in a Community-based Setting in Southern Nepal 
Pediatrics  2008;121(5):e1372-e1380.
OBJECTIVES
1) Develop an approach to ascertain birth asphyxia deaths using verbal autopsy data from a community-based setting in Nepal, and 2) explore variations in birth asphyxia mortality fractions using different birth asphyxia case definitions and hierarchal classifications.
PATIENTS AND METHODS
Data were prospectively collected during a cluster-randomized, community-based trial of health interventions on neonatal mortality in Sarlahi, Nepal from 2002-2006. To assign cause of death, four computer-assigned, symptom-based asphyxia case definitions; Nepali physician classification; and our independent review of verbal autopsy open narratives were used. Varying hierarchal classification approaches to assign cause of death were also explored.
RESULTS
Birth asphyxia specific mortality ranged from 26%-54% depending on the computer case definition used. There was poor agreement between computer and physician classification of birth asphyxia (kappa 0.15). By comparing computer, physician, and our independent ascertainment of cause of death, we identified 246 cases of birth asphyxia (32% of neonatal deaths). Allowing for more than one cause of death, 30% and 42% of asphyxia cases also met criteria for prematurity and serious infection, respectively. When a hierarchy was used to assign a single cause of death, the birth asphyxia proportionate mortality was reduced to 12% when identification of deaths due to congenital anomalies, prematurity, and serious infections preceded birth asphyxia.
CONCLUSIONS
Use of varying verbal autopsy definitions and hierarchal approaches to assign cause of death may substantially affect estimates of birth asphyxia-specific mortality and analyses of risk factors. Verbal autopsy methods need to be standardized and validated in order to generate accurate global estimates to direct policy and resource allocation in low-middle income countries.
doi:10.1542/peds.2007-2644
PMCID: PMC2366089  PMID: 18450880
asphyxia; neonatal mortality; newborn; Nepal; verbal autopsy
4.  Etiology of Bacteremia in Young Infants in Six Countries 
Background:
Neonatal illness is a leading cause of death worldwide; sepsis is one of the main contributors. The etiologies of community-acquired neonatal bacteremia in developing countries have not been well characterized.
Methods:
Infants <2 months of age brought with illness to selected health facilities in Bangladesh, Bolivia, Ghana, India, Pakistan and South Africa were evaluated, and blood cultures taken if they were considered ill enough to be admitted to hospital. Organisms were isolated using standard culture techniques.
Results:
Eight thousand eight hundred and eighty-nine infants were recruited, including 3177 0–6 days of age and 5712 7–59 days of age; 10.7% (947/8889) had a blood culture performed. Of those requiring hospital management, 782 (54%) had blood cultures performed. Probable or definite pathogens were identified in 10.6% including 10.4% of newborns 0–6 days of age (44/424) and 10.9% of infants 7–59 days of age (39/358). Staphylococcus aureus was the most commonly isolated species (36/83, 43.4%) followed by various species of Gram-negative bacilli (39/83, 46.9%; Acinetobacter spp., Escherichia coli and Klebsiella spp. were the most common organisms). Resistance to second and third generation cephalosporins was present in more than half of isolates and 44% of the Gram-negative isolates were gentamicin-resistant. Mortality rates were similar in hospitalized infants with positive (5/71, 7.0%) and negative blood cultures (42/557, 7.5%).
Conclusions:
This large study of young infants aged 0–59 days demonstrated a broad array of Gram-positive and Gram-negative pathogens responsible for community-acquired bacteremia and substantial levels of antimicrobial resistance. The role of S. aureus as a pathogen is unclear and merits further investigation.
doi:10.1097/INF.0000000000000549
PMCID: PMC4272225  PMID: 25389919
Neonatal sepsis; infant; neonate; bacteremia; Staphylococcus aureus
5.  Animal Husbandry Practices in Rural Bangladesh: Potential Risk Factors for Antimicrobial Drug Resistance and Emerging Diseases 
Antimicrobial drug administration to household livestock may put humans and animals at risk for acquisition of antimicrobial drug–resistant pathogens. To describe animal husbandry practices, including animal healthcare-seeking and antimicrobial drug use in rural Bangladesh, we conducted semi-structured in-depth interviews with key informants, including female household members (n = 79), village doctors (n = 10), and pharmaceutical representatives, veterinarians, and government officials (n = 27), and performed observations at animal health clinics (n = 3). Prevalent animal husbandry practices that may put persons at risk for acquisition of pathogens included shared housing and water for animals and humans, antimicrobial drug use for humans and animals, and crowding. Household members reported seeking human and animal healthcare from unlicensed village doctors rather than formal-sector healthcare providers and cited cost and convenience as reasons. Five times more per household was spent on animal than on human healthcare. Strengthening animal and human disease surveillance systems should be continued. Interventions are recommended to provide vulnerable populations with a means of protecting their livelihood and health.
doi:10.4269/ajtmh.12-0713
PMCID: PMC3820344  PMID: 24062478
6.  Determinants and pattern of care seeking for preterm newborns in a rural Bangladeshi cohort 
Background
Despite the increased burden of preterm birth and its complications, the dearth of care seeking data for preterm newborns remains a significant knowledge gap. Among preterm babies in rural Bangladesh, we examined: 1) determinants and patterns of care seeking, and 2) risk analysis for care-seeking from qualified and unqualified providers.
Method
Trained community health workers collected data prospectively from 27,460 mother-liveborn baby pairs, including 6,090 preterm babies, between June 2007 and September 2009. Statistical analyses included binomial and multinomial logistic regressions.
Results
Only one-fifth (19.7%) of preterm newborns were taken to seek either preventive or curative health care. Among care-seeker preterm newborns, preferred providers included homeopathic practitioners (50.0%), and less than a third (30.9%) sought care from qualified providers. Care-seeking from either unqualified or qualified providers was significantly lower for female preterm babies, compared to male babies [Relative Risk Ratio (RRR) for unqualified care: 0.68; 95% Confidence Interval (CI): 0.58, 0.80; RRR for qualified care: 0.52; 95% CI: 0.41, 0.66]. Among preterm babies, care-seeking was significantly higher among caregivers who recognized symptoms of illness [RR: 2.14; 95% CI: 1.93, 2.38] or signs of local infection (RR: 2.53; 95% CI: 2.23, 2.87), had a history of child death [RR: 1.21; 95% CI: 1.07, 1.37], any antenatal care (ANC) visit [RR: 1.41; 95% CI: 1.25, 1.59]. Birth preparedness (RRR: 1.24; 95% CI: 1.09, 1.68) and any ANC visit (RRR: 1.73; 95% CI: 1.50, 2.49) were also associated with increased likelihood of care seeking for preterm babies from qualified providers.
Conclusion
To improve care seeking practices for preterm babies and referral of sick newborns to qualified providers/facilities, we recommend: 1) involving community-preferred health care providers in community-based health education and awareness raising programs; 2) integrating postnatal care seeking messages into antenatal counselling; and 3) further research on care seeking practices for preterm babies.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6963-14-417) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6963-14-417
PMCID: PMC4261985  PMID: 25242278
7.  Incidence of and Risk Factors for Neonatal Respiratory Depression and Encephalopathy in Rural Sarlahi, Nepal 
Pediatrics  2011;128(4):e915-e924.
OBJECTIVES:
To characterize the incidence of, risk factors for, and neonatal morbidity and mortality associated with respiratory depression at birth and neonatal encephalopathy (NE) among term infants in a developing country.
METHODS:
Data were collected prospectively in 2002–2006 during a community-based trial that enrolled 23 662 newborns in rural Nepal and evaluated the impact of umbilical-cord and skin cleansing on neonatal morbidity and mortality rates. Respiratory depression at birth and NE were defined on the basis of symptoms from maternal reports and study-worker observations during home visits.
RESULTS:
Respiratory depression at birth was reported for 19.7% of live births, and 79% of cases involved term infants without congenital anomalies. Among newborns with probable intrapartum-related respiratory depression (N = 3465), 112 (3%) died before their first home visit (presumed severe NE), and 178 (5%) eventually developed symptoms of NE. Overall, 629 term infants developed NE (28.1 cases per 1000 live births); 2% of cases were associated with congenital anomalies, 25% with infections, and 28% with a potential intrapartum event. The incidence of intrapartum-related NE was 13.0 cases per 1000 live births; the neonatal case fatality rate was 46%. Infants with NE more frequently experienced birth complications and were male, of multiple gestation, or born to nulliparous mothers.
CONCLUSIONS:
In Sarlahi, the incidence of neonatal respiratory depression and NE, associated neonatal case fatality, and morbidity prevalence are high. Action is required to increase coverage of skilled obstetric/neonatal care in this setting and to evaluate long-term impairments.
doi:10.1542/peds.2010-3590
PMCID: PMC3182846  PMID: 21949140
neonatal encephalopathy; neonatal respiratory depression; birth asphyxia; Nepal; developing country; neurodevelopment; intrapartum
8.  Seasonality of birth outcomes in rural Sarlahi District, Nepal: a population-based prospective cohort 
Background
While seasonality of birth outcomes has been documented in a variety of settings, data from rural South Asia are lacking. We report a descriptive study of the seasonality of prematurity, low birth weight, small for gestational age, neonatal deaths, and stillbirths in the plains of Nepal.
Methods
Using data collected prospectively during a randomized controlled trial of neonatal skin and umbilical cord cleansing with chlorhexidine, we analyzed a cohort of 23,662 babies born between September 2002 and January 2006. Project workers collected data on birth outcomes at the infant’s household. Supplemental data from other studies conducted at the same field site are presented to provide context. 95% confidence intervals were constructed around monthly estimates to examine statistical significance of findings.
Results
Month of birth was associated with higher risk for adverse outcomes (neonatal mortality, low birthweight, preterm, and small for gestational age), even when controlling for maternal characteristics. Infants had 87% (95% CI: 27 – 176%) increased risk of neonatal mortality when born in August, the high point, versus March, the low point.
Conclusion
Seasonality of neonatal deaths, stillbirths, birth weight, gestational age, and small for gestational age were found in Nepal. Maternal factors, meteorological conditions, infectious diseases, and nutritional status may be associated with these adverse birth outcomes. Further research is needed to understand the causal mechanisms that explain the seasonality of adverse birth outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2393-14-310) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2393-14-310
PMCID: PMC4162951  PMID: 25195204
Gestational age; Low birth weight; Intrauterine growth restriction; Neonatal mortality; Season; Preterm birth
9.  Injections during labor and intrapartum-related hypoxic injury and mortality in rural southern Nepal 
Objective
To estimate the association between unmonitored use of injections during labor and intrapartum-related neonatal mortality and morbidity among home births.
Methods
Recently delivered women in Sarlahi, Nepal, reported whether they had received injections during labor. Data on breathing and crying status at birth, time to first breath, respiratory rate, sucking ability, and lethargy were gathered. Neonatal respiratory depression (NRD) and encephalopathy (NE) were compared by injection receipt status using multivariate regression models.
Results
Injections during labor were frequently reported (7108 of 22 352 [31.8%]) and were predominantly given by unqualified village “doctors.” Multivariate analysis (excluding facility births and complicated deliveries) revealed associations with intrapartum-related NRD (relative risk [RR] 2.52; 95% CI, 2.29–2.78) and NE (RR 3.48; 95% CI, 2.46–4.93). The risks of neonatal death associated with intrapartum-related NRD (RR 3.78; 95% CI, 2.53–5.66) or NE (RR 4.47; 95% CI, 2.78–7.19) were also elevated.
Conclusion
Injection during labor was widespread at the community level. This practice was associated with poor outcomes and possibly related to the inappropriate use of uterotonics by unqualified providers. Interventions are required to increase the safety of childbirth in the community and in peripheral health facilities.
Parent trial registered at clinicaltrials.gov (NCT00 109616).
doi:10.1016/j.ijgo.2013.02.013
PMCID: PMC3674195  PMID: 23523332
Home births; Injections; Neonatal encephalopathy; Neonatal mortality; Nepal
10.  Nosocomial Sepsis Risk Score for Preterm Infants in Low-resource Settings 
Journal of Tropical Pediatrics  2009;56(2):82-89.
Sepsis is a leading cause of mortality for neonates in developing countries; however, little research has focused on clinical predictors of nosocomial infection of preterm neonates in the low-resource setting. We sought to validate the only existing feasible score introduced by Singh et al. in 2003 and to create an improved score. In a secondary analysis of daily evaluations of 497 neonates ≤33 weeks gestational age admitted to a tertiary care NICU in Dhaka, Bangladesh, we tested the Singh score and then constructed and internally validated our own bedside predictive score. The Singh score had low sensitivity of 56.6% but good positive predictive value (PPV) of 78.1% in our sample. Our five-sign model requiring at least one clinical sign of infection (apnea, hepatomegaly, jaundice, lethargy and pallor) had an area under the receiver operating characteristic of 0.70, sensitivity of 77.1%, and PPV of 64.9%. Our clinical sepsis score is the first bedside clinical screen exclusively for hospitalized, very premature neonates in a low-resource setting, and warrants external validation.
doi:10.1093/tropej/fmp061
PMCID: PMC3115678  PMID: 19622712
neonate; sepsis; prematurity; very low birth-weight; developing countries; nosocomial
11.  Household surveillance of severe neonatal illness by community health workers in Mirzapur, Bangladesh: coverage and compliance with referral 
Health Policy and Planning  2009;25(2):112-124.
Background Effective and scalable community-based strategies are needed for identification and management of serious neonatal illness.
Methods As part of a community-based, cluster-randomized controlled trial of the impact of a package of maternal-neonatal health care, community health workers (CHWs) were trained to conduct household surveillance and to identify and refer sick newborns according to a clinical algorithm. Assessments of newborns by CHWs at home were linked to hospital-based assessments by physicians, and factors impacting referral, referral compliance and outcome were evaluated.
Results Seventy-three per cent (7310/10 006) of live-born neonates enrolled in the study were assessed by CHWs at least once; 54% were assessed within 2 days of birth, but only 15% were attended at delivery. Among assessments for which referral was recommended, compliance was verified in 54% (495/919). Referrals recommended to young neonates 0–6 days old were 30% less likely to be complied with compared to older neonates. Compliance was positively associated with having very severe disease and selected clinical signs, including respiratory rate ≥70/minute; weak, abnormal or absent cry; lethargic or less than normal movement; and feeding problem. Among 239 neonates who died, only 38% were assessed by a CHW before death.
Conclusions Despite rigorous programmatic effort, reaching neonates within the first 2 days after birth remained a challenge, and parental compliance with referral recommendation was limited, particularly among young neonates. To optimize potential impact, community postnatal surveillance must be coupled with skilled attendance at delivery, and/or a worker skilled in recognition of neonatal illness must be placed in close proximity to the community to allow for rapid case management to avert early deaths.
doi:10.1093/heapol/czp048
PMCID: PMC2912547  PMID: 19917652
Community health worker; neonatal illness; referral; surveillance; care seeking
12.  Incidence and risk factors of preterm birth in a rural Bangladeshi cohort 
BMC Pediatrics  2014;14:112.
Background
Globally, about 15 million neonates are born preterm and about 85% of global preterm birth occurs in Asia and Africa regions. We aimed to estimate the incidence and risk factors for preterm birth in a rural Bangladeshi cohort.
Methods
Between June 2007 and September 2009, community health workers prospectively collected data from 32,126 mother-live-born baby pairs on household socio-demographic status, pregnancy history, antenatal care seeking and newborn gestational age determined by recall of date of last menstrual period.
Results
Among all live births, 22.3% were delivered prior to 37 weeks of gestation (i.e. preterm); of which 12.3% were born at 35–36 weeks of gestation (late preterm), 7.1% were born at 32–34 weeks (moderate preterm), and 2.9% were born at 28–31 weeks of gestation (very preterm). Overall, the majority of preterm births (55.1%) were late preterm. Risk of preterm birth was lower among women with primary or higher level of education (RR: 0.92; 95% CI: 0.88, 0.97), women who sought antenatal care at least once during the index pregnancy (RR: 0.86; 95% CI: 0.83, 0.90), and women who had completed all birth preparedness steps (RR: 0.32; 95% CI: 0.30, 0.34). In contrast, risk of preterm birth was higher among women with a history of child death (RR: 1.05; 95% CI: 1.01, 1.10), who had mid-upper arm circumference (MUAC) ≤250 mm, indicative of under nutrition (for women having MUAC <214 mm the risk was higher; RR: 1.26; 95% CI: 1.17, 1.35), who reported an antenatal complication (RR: 1.32; 95% CI: 1.14, 1.53), and who received iron-folic acid supplementation for 2–6 months during the index pregnancy (RR: 1.33; 95% CI: 1.24, 1.44).
Conclusions
In resource poor settings with high burden of preterm birth, alike Bangladesh, preterm birth risk could be reduced by close monitoring and/or frequent follow-up of women with history of child death and antenatal complications, by encouraging women to seek antenatal care from qualified providers, to adopt birth preparedness planning and to maintain good nutritional status. Additional research is needed to further explore the associations of antenatal iron supplementation and maternal nutritional status on preterm birth.
doi:10.1186/1471-2431-14-112
PMCID: PMC4021459  PMID: 24758701
Preterm birth; Risk factors; Bangladesh; Community-based program
13.  Impact of Clean Delivery-kit use on Newborn Umbilical Cord and Maternal Puerperal Infections in Egypt 
This cross-sectional cohort study explored the impact of the use of clean delivery-kit (CDK) on morbidity due to newborn umbilical cord and maternal puerperal infections. Kits were distributed from primary-care facilities, and birth attendants received training on kit-use. A nurse visited 334 women during the first week postpartum to administer a structured questionnaire and conduct a physical examination of the neonate and the mother. Results of bivariate analysis showed that neonates of mothers who used a CDK were less likely to develop cord infection (p=0.025), and mothers who used a CDK were less likely to develop puerperal sepsis (p=0.024). Results of multiple logistic regression analysis showed an independent association between decreased cord infection and kit-use [odds ratio (OR)=0.42, 95% confidence interval (CI) 0.18–0.97, p=0.041)]. Mothers who used a CDK also had considerably lower rates of puerperal infection (OR=0.11, 95% CI 0.01–1.06), although the statistical strength of the association was of borderline significance (p=0.057). The use of CDK was associated with reductions in umbilical cord and puerperal infections.
PMCID: PMC2928112  PMID: 20099758
Cohort studies; Cross-sectional studies; Delivery-kit; Evaluation studies; Impact studies; Morbidity; Sepsis; Umbilical cord infections; Egypt
14.  Simplified Dosing of Gentamicin for Treatment of Sepsis in Bangladeshi Neonates 
Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24- or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed <2,000 g (n=23), 10 mg every 24 hours if the infant weighed 2,000–2,249 g (n=12), or 13.5 mg every 24 hours if the infant weighed 2,500–3,000 g (n=24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean±standard deviation peak concentration of gentamicin was 12.3±3.7 µg/mL in infants weighing <2,000 g, 9.6±3.1 µg/mL in infants 2,000–2,249 g, and 10.0±3.4 µg/mL in infants 2,500–3,000 g. Initial peak concentration of gentamicin was >12 µg/mL in 28.8% and initial trough concentration was >2 µg/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis.
PMCID: PMC2928089  PMID: 19902799
Aminoglycoside; Antibiotics; Gentamicin; Infection; Newborns; Observational studies; Pharmacokinetics; Prospective studies; Sepsis; Bangladesh
15.  Determining Gestational Age in a Low-resource Setting: Validity of Last Menstrual Period 
The validity of three methods (last menstrual period [LPM], Ballard and Dubowitz scores) for assessment of gestational age for premature infants in a low-resource setting was assessed, using antenatal ultrasound as the gold standard. It was hypothesized that LMP and other methods would perform similarly in determining postnatal gestational age. Concordance analysis was applied to data on 355 neonates of <33 weeks gestational age enrolled in a topical skin-therapy trial in a tertiary-care children's hospital in Bangladesh. The concordance coefficient for LMP, Ballard, and Dubowitz was 0.878, 0.914, and 0.886 respectively. LMP and Ballard underestimated gestational age by one day (±11) and 2.9 days (±7.8) respectively while Dubowitz overestimated gestational age by 3.9 days (±7.1) compared to ultrasound finding. LMP in a low-resource setting was a more reliable measure of gestational age than previously thought for estimation of postnatal gestational age of preterm infants. Ballard and Dubowitz scores are slightly more reliable but require more technical skills to perform. Additional prospective trials are warranted to examine LMP against antenatal ultrasound for primary assessment of neonatal gestational age in other low-resource settings.
PMCID: PMC2761790  PMID: 19507748
Gestational age; Last menstrual period; Neonatal health; Obstetrics; Bangladesh
16.  Delivering interventions to reduce the global burden of stillbirths: improving service supply and community demand 
BMC Pregnancy and Childbirth  2009;9(Suppl 1):S7.
Background
Although a number of antenatal and intrapartum interventions have shown some evidence of impact on stillbirth incidence, much confusion surrounds ideal strategies for delivering these interventions within health systems, particularly in low-/middle-income countries where 98% of the world's stillbirths occur. Improving the uptake of quality antenatal and intrapartum care is critical for evidence-based interventions to generate an impact at the population level. This concluding paper of a series of papers reviewing the evidence for stillbirth interventions examines the evidence for community and health systems approaches to improve uptake and quality of antenatal and intrapartum care, and synthesises programme and policy recommendations for how best to deliver evidence-based interventions at community and facility levels, across the continuum of care, to reduce stillbirths.
Methods
We systematically searched PubMed and the Cochrane Library for abstracts pertaining to community-based and health-systems strategies to increase uptake and quality of antenatal and intrapartum care services. We also sought abstracts which reported impact on stillbirths or perinatal mortality. Searches used multiple combinations of broad and specific search terms and prioritised rigorous randomised controlled trials and meta-analyses where available. Wherever eligible randomised controlled trials were identified after a Cochrane review had been published, we conducted new meta-analyses based on the original Cochrane criteria.
Results
In low-resource settings, cost, distance and the time needed to access care are major barriers for effective uptake of antenatal and particularly intrapartum services. A number of innovative strategies to surmount cost, distance, and time barriers to accessing care were identified and evaluated; of these, community financial incentives, loan/insurance schemes, and maternity waiting homes seem promising, but few studies have reported or evaluated the impact of the wide-scale implementation of these strategies on stillbirth rates. Strategies to improve quality of care by upgrading the skills of community cadres have shown demonstrable impact on perinatal mortality, particularly in conjunction with health systems strengthening and facilitation of referrals. Neonatal resuscitation training for physicians and other health workers shows potential to prevent many neonatal deaths currently misclassified as stillbirths. Perinatal audit systems, which aim to improve quality of care by identifying deficiencies in care, are a quality improvement measure that shows some evidence of benefit for changes in clinical practice that prevent stillbirths, and are strongly recommended wherever practical, whether as hospital case review or as confidential enquiry at district or national level.
Conclusion
Delivering interventions to reduce the global burden of stillbirths requires action at all levels of the health system. Packages of interventions should be tailored to local conditions, including local levels and causes of stillbirth, accessibility of care and health system resources and provider skill. Antenatal care can potentially serve as a platform to deliver interventions to improve maternal nutrition, promote behaviour change to reduce harmful exposures and risk of infections, screen for and treat risk factors, and encourage skilled attendance at birth. Following the example of high-income countries, improving intrapartum monitoring for fetal distress and access to Caesarean section in low-/middle-income countries appears to be key to reducing intrapartum stillbirth. In remote or low-resource settings, families and communities can be galvanised to demand and seek quality care through financial incentives and health promotion efforts of local cadres of health workers, though these interventions often require simultaneous health systems strengthening. Perinatal audit can aid in the development of better standards of care, improving quality in health systems. Effective strategies to prevent stillbirth are known; gaps remain in the data, the evidence and perhaps most significantly, the political will to implement these strategies at scale.
doi:10.1186/1471-2393-9-S1-S7
PMCID: PMC2679413  PMID: 19426470
17.  Reducing stillbirths: interventions during labour 
BMC Pregnancy and Childbirth  2009;9(Suppl 1):S6.
Background
Approximately one million stillbirths occur annually during labour; most of these stillbirths occur in low and middle-income countries and are associated with absent, inadequate, or delayed obstetric care. The low proportion of intrapartum stillbirths in high-income countries suggests that intrapartum stillbirths are largely preventable with quality intrapartum care, including prompt recognition and management of intrapartum complications. The evidence for impact of intrapartum interventions on stillbirth and perinatal mortality outcomes has not yet been systematically examined.
Methods
We undertook a systematic review of the published literature, searching PubMed and the Cochrane Library, of trials and reviews (N = 230) that reported stillbirth or perinatal mortality outcomes for eight interventions delivered during labour. Where eligible randomised controlled trials had been published after the most recent Cochrane review on any given intervention, we incorporated these new trial findings into a new meta-analysis with the Cochrane included studies.
Results
We found a paucity of studies reporting statistically significant evidence of impact on perinatal mortality, especially on stillbirths. Available evidence suggests that operative delivery, especially Caesarean section, contributes to decreased stillbirth rates. Induction of labour rather than expectant management in post-term pregnancies showed strong evidence of impact, though there was not enough evidence to suggest superior safety for the fetus of any given drug or drugs for induction of labour. Planned Caesarean section for term breech presentation has been shown in a large randomised trial to reduce stillbirths, but the feasibility and consequences of implementing this intervention routinely in low-/middle-income countries add caveats to recommending its use. Magnesium sulphate for pre-eclampsia and eclampsia is effective in preventing eclamptic seizures, but studies have not demonstrated impact on perinatal mortality. There was limited evidence of impact for maternal hyperoxygenation, and concerns remain about maternal safety. Transcervical amnioinfusion for meconium staining appears promising for low/middle income-country application according to the findings of many small studies, but a large randomised trial of the intervention had no significant impact on perinatal mortality, suggesting that further studies are needed.
Conclusion
Although the global appeal to prioritise access to emergency obstetric care, especially vacuum extraction and Caesarean section, rests largely on observational and population-based data, these interventions are clearly life-saving in many cases of fetal compromise. Safe, comprehensive essential and emergency obstetric care is particularly needed, and can make the greatest impact on stillbirth rates, in low-resource settings. Other advanced interventions such as amnioinfusion and hyperoxygenation may reduce perinatal mortality, but concerns about safety and effectiveness require further study before they can be routinely included in programs.
doi:10.1186/1471-2393-9-S1-S6
PMCID: PMC2679412  PMID: 19426469
18.  Reducing stillbirths: screening and monitoring during pregnancy and labour 
BMC Pregnancy and Childbirth  2009;9(Suppl 1):S5.
Background
Screening and monitoring in pregnancy are strategies used by healthcare providers to identify high-risk pregnancies so that they can provide more targeted and appropriate treatment and follow-up care, and to monitor fetal well-being in both low- and high-risk pregnancies. The use of many of these techniques is controversial and their ability to detect fetal compromise often unknown. Theoretically, appropriate management of maternal and fetal risk factors and complications that are detected in pregnancy and labour could prevent a large proportion of the world's 3.2 million estimated annual stillbirths, as well as minimise maternal and neonatal morbidity and mortality.
Methods
The fourth in a series of papers assessing the evidence base for prevention of stillbirths, this paper reviews available published evidence for the impact of 14 screening and monitoring interventions in pregnancy on stillbirth, including identification and management of high-risk pregnancies, advanced monitoring techniques, and monitoring of labour. Using broad and specific strategies to search PubMed and the Cochrane Library, we identified 221 relevant reviews and studies testing screening and monitoring interventions during the antenatal and intrapartum periods and reporting stillbirth or perinatal mortality as an outcome.
Results
We found a dearth of rigorous evidence of direct impact of any of these screening procedures and interventions on stillbirth incidence. Observational studies testing some interventions, including fetal movement monitoring and Doppler monitoring, showed some evidence of impact on stillbirths in selected high-risk populations, but require larger rigourous trials to confirm impact. Other interventions, such as amniotic fluid assessment for oligohydramnios, appear predictive of stillbirth risk, but studies are lacking which assess the impact on perinatal mortality of subsequent intervention based on test findings. Few rigorous studies of cardiotocography have reported stillbirth outcomes, but steep declines in stillbirth rates have been observed in high-income settings such as the U.S., where cardiotocography is used in conjunction with Caesarean section for fetal distress.
Conclusion
There are numerous research gaps and large, adequately controlled trials are still needed for most of the interventions we considered. The impact of monitoring interventions on stillbirth relies on use of effective and timely intervention should problems be detected. Numerous studies indicated that positive tests were associated with increased perinatal mortality, but while some tests had good sensitivity in detecting distress, false-positive rates were high for most tests, and questions remain about optimal timing, frequency, and implications of testing. Few studies included assessments of impact of subsequent intervention needed before recommending particular monitoring strategies as a means to decrease stillbirth incidence. In high-income countries such as the US, observational evidence suggests that widespread use of cardiotocography with Caesarean section for fetal distress has led to significant declines in stillbirth rates. Efforts to increase availability of Caesarean section in low-/middle-income countries should be coupled with intrapartum monitoring technologies where resources and provider skills permit.
doi:10.1186/1471-2393-9-S1-S5
PMCID: PMC2679411  PMID: 19426468
19.  Reducing stillbirths: prevention and management of medical disorders and infections during pregnancy 
BMC Pregnancy and Childbirth  2009;9(Suppl 1):S4.
Background
An estimated two-thirds of the world's 3.2 million stillbirths occur antenatally, prior to labour, and are often overlooked in policy and programs. Poorly recognised, untreated or inadequately treated maternal infections such as syphilis and malaria, and maternal conditions including hypertensive disorders, are known risk factors for stillbirth.
Methods
We undertook a systematic review of the evidence for 16 antenatal interventions with the potential to prevent stillbirths. We searched a range of sources including PubMed and the Cochrane Library. For interventions with prior Cochrane reviews, we conducted additional meta-analyses including eligible newer randomised controlled trials following the Cochrane protocol. We focused on interventions deliverable at the community level in low-/middle-income countries, where the burden of stillbirths is greatest.
Results
Few of the studies we included reported stillbirth as an outcome; most that did were underpowered to assess this outcome. While Cochrane reviews or meta-analyses were available for many interventions, few focused on stillbirth or perinatal mortality as outcomes, and evidence was frequently conflicting. Several interventions showed clear evidence of impact on stillbirths, including heparin therapy for certain maternal indications; syphilis screening and treatment; and insecticide-treated bed nets for prevention of malaria. Other interventions, such as management of obstetric intrahepatic cholestasis, maternal anti-helminthic treatment, and intermittent preventive treatment of malaria, showed promising impact on stillbirth rates but require confirmatory studies. Several interventions reduced known risk factors for stillbirth (e.g., anti-hypertensive drugs for chronic hypertension), yet failed to show statistically significant impact on stillbirth or perinatal mortality rates. Periodontal disease emerged as a clear risk factor for stillbirth but no interventions have reduced stillbirth rates.
Conclusion
Evidence for some newly recognised risk factors for stillbirth, including periodontal disease, suggests the need for large, appropriately designed randomised trials to test whether intervention can minimise these risks and prevent stillbirths. Existing evidence strongly supports infection control measures, including syphilis screening and treatment and malaria prophylaxis in endemic areas, for preventing antepartum stillbirths. These interventions should be incorporated into antenatal care programs based on attributable risks and burden of disease.
doi:10.1186/1471-2393-9-S1-S4
PMCID: PMC2679410  PMID: 19426467
20.  Reducing stillbirths: behavioural and nutritional interventions before and during pregnancy 
BMC Pregnancy and Childbirth  2009;9(Suppl 1):S3.
Background
The vast majority of global stillbirths occur in low- and middle-income countries, and in many settings, the majority of stillbirths occur antenatally, prior to the onset of labour. Poor nutritional status, lack of antenatal care and a number of behaviours increase women's risk of stillbirth in many resource-poor settings. Interventions to reduce these risks could reduce the resulting burden of stillbirths, but the evidence for the impact of such interventions has not yet been comprehensively evaluated.
Methods
This second paper of a systematic review of interventions that could plausibly impact stillbirth rates covers 12 different interventions relating to behavioural and socially mediated risk factors, including exposures to harmful practices and substances, antenatal care utilisation and quality, and maternal nutrition before and during pregnancy. The search strategy reviewed indexed medical journals on PubMed and the Cochrane Library. If any eligible randomised controlled trials were identified that were published after the most recent Cochrane review, they were added to generate new meta-analyses. Interventions covered in this paper have a focus on low- and middle-income countries, both because of the large burden of stillbirths and because of the high prevalence of risk factors including maternal malnutrition and harmful environmental exposures. The reviews and studies belonging to these interventions were graded and conclusions derived about the evidence of benefit of these interventions.
Results
From a programmatic perspective, none of the interventions achieved clear evidence of benefit. Evidence for some socially mediated risk factors were identified, such as exposure to indoor air pollution and birth spacing, but still require the development of appropriate interventions. There is a need for additional studies on culturally appropriate behavioural interventions and clinical trials to increase smoking cessation and reduce exposure to smokeless tobacco. Balanced protein-energy supplementation was associated with reduced stillbirth rates, but larger well-designed trials are required to confirm findings. Peri-conceptional folic acid supplementation significantly reduces neural tube defects, yet no significant associated reductions in stillbirth rates have been documented. Evidence for other nutritional interventions including multiple micronutrient and Vitamin A supplementation is weak, suggesting the need for further research to assess potential of nutritional interventions to reduce stillbirths.
Conclusion
Antenatal care is widely used in low- and middle-income countries, and provides a natural facility-based contact through which to provide or educate about many of the interventions we reviewed. The impact of broader socially mediated behaviors, such as fertility decision-making, access to antenatal care, and maternal diet and exposures like tobacco and indoor air pollution during pregnancy, are poorly understood, and further research and appropriate interventions are needed to test the association of these behaviours with stillbirth outcomes. For most nutritional interventions, larger randomised controlled trials are needed which report stillbirths disaggregated from composite perinatal mortality. Many antepartum stillbirths are potentially preventable in low- and middle-income countries, particularly through dietary and environmental improvement, and through improving the quality of antenatal care – particularly including diagnosis and management of high-risk pregnancies – that pregnant women receive.
doi:10.1186/1471-2393-9-S1-S3
PMCID: PMC2679409  PMID: 19426466
21.  3.2 million stillbirths: epidemiology and overview of the evidence review 
BMC Pregnancy and Childbirth  2009;9(Suppl 1):S2.
More than 3.2 million stillbirths occur globally each year, yet stillbirths are largely invisible in global data tracking, policy dialogue and programme implementation. This mismatch of burden to action is due to a number of factors that keep stillbirths hidden, notably a lack of data and a lack of consensus on priority interventions, but also to social taboos that reduce the visibility of stillbirths and the associated family mourning. Whilst there are estimates of the numbers of stillbirths, to date there has been no systematic global analysis of the causes of stillbirths. The multiple classifications systems in use are often complex and are primarily focused on high-income countries. We review available data and propose a programmatic classification that is feasible and comparable across settings. We undertook a comprehensive global review of available information on stillbirths in order to 1) identify studies that evaluated risk factors and interventions to reduce stillbirths, 2) evaluate the level of evidence for interventions, 3) place the available evidence for interventions in a health systems context to guide programme implementation, and 4) elucidate key implementation, monitoring, and research gaps. This first paper in the series outlines issues in stillbirth data availability and quality, the global epidemiology of stillbirths, and describes the methodology and framework used for the review of interventions and strategies.
doi:10.1186/1471-2393-9-S1-S2
PMCID: PMC2679408  PMID: 19426465
22.  Gender Differences in Perception and Care-seeking for Illness of Newborns in Rural Uttar Pradesh, India 
Although gender-based health disparities are prevalent in India, very little data are available on care-seeking patterns for newborns. In total, 255 mothers were prospectively interviewed about their perceptions and action surrounding the health of their newborns in rural Uttar Pradesh, India. Perception of illness was significantly lower in incidence (adjusted odds ratio=0.56, 95% confidence interval 0.33-0.94) among households with female versus male newborns. While the overall use of healthcare providers was similar across gender, the average expenditure for healthcare during the neonatal period was nearly four-fold higher in households with males (Rs 243.3±537.2) compared to females (Rs 65.7±100.7) (p=0.07). Households with female newborns used cheaper public care providers whereas those with males preferred to use private unqualified providers perceived to deliver more satisfactory care. These results suggest that, during the neonatal period, care-seeking for girls is neglected compared to boys, laying a foundation for programmes and further research to address gender differences in neonatal health in India.
PMCID: PMC2761808  PMID: 19248649
Healthcare-seeking behaviour; Equity; Gender; Health expenditure; Healthcare-use; Neonatal health; Perceptions; Rural health; India
23.  Using verbal autopsy to measure causes of death: the comparative performance of existing methods 
BMC Medicine  2014;12:5.
Background
Monitoring progress with disease and injury reduction in many populations will require widespread use of verbal autopsy (VA). Multiple methods have been developed for assigning cause of death from a VA but their application is restricted by uncertainty about their reliability.
Methods
We investigated the validity of five automated VA methods for assigning cause of death: InterVA-4, Random Forest (RF), Simplified Symptom Pattern (SSP), Tariff method (Tariff), and King-Lu (KL), in addition to physician review of VA forms (PCVA), based on 12,535 cases from diverse populations for which the true cause of death had been reliably established. For adults, children, neonates and stillbirths, performance was assessed separately for individuals using sensitivity, specificity, Kappa, and chance-corrected concordance (CCC) and for populations using cause specific mortality fraction (CSMF) accuracy, with and without additional diagnostic information from prior contact with health services. A total of 500 train-test splits were used to ensure that results are robust to variation in the underlying cause of death distribution.
Results
Three automated diagnostic methods, Tariff, SSP, and RF, but not InterVA-4, performed better than physician review in all age groups, study sites, and for the majority of causes of death studied. For adults, CSMF accuracy ranged from 0.764 to 0.770, compared with 0.680 for PCVA and 0.625 for InterVA; CCC varied from 49.2% to 54.1%, compared with 42.2% for PCVA, and 23.8% for InterVA. For children, CSMF accuracy was 0.783 for Tariff, 0.678 for PCVA, and 0.520 for InterVA; CCC was 52.5% for Tariff, 44.5% for PCVA, and 30.3% for InterVA. For neonates, CSMF accuracy was 0.817 for Tariff, 0.719 for PCVA, and 0.629 for InterVA; CCC varied from 47.3% to 50.3% for the three automated methods, 29.3% for PCVA, and 19.4% for InterVA. The method with the highest sensitivity for a specific cause varied by cause.
Conclusions
Physician review of verbal autopsy questionnaires is less accurate than automated methods in determining both individual and population causes of death. Overall, Tariff performs as well or better than other methods and should be widely applied in routine mortality surveillance systems with poor cause of death certification practices.
doi:10.1186/1741-7015-12-5
PMCID: PMC3891983  PMID: 24405531
Verbal autopsy; VA; Validation; Cause of death; Symptom pattern; Random forests; InterVA; King-Lu; Tariff
24.  Extended-interval Dosing of Gentamicin for Treatment of Neonatal Sepsis in Developed and Developing Countries 
Serious bacterial infections are the single most important cause of neonatal mortality in developing countries. Case-fatality rates for neonatal sepsis in developing countries are high, partly because of inadequate administration of necessary antibiotics. For the treatment of neonatal sepsis in resource-poor, high-mortality settings in developing countries where most neonatal deaths occur, simplified treatment regimens are needed. Recommended therapy for neonatal sepsis includes gentamicin, a parenteral aminoglycoside antibiotic, which has excellent activity against gram-negative bacteria, in combination with an antimicrobial with potent gram-positive activity. Traditionally, gentamicin has been administered 2–3 times daily. However, recent evidence suggests that extended-interval (i.e. ≥24 hours) dosing may be applicable to neonates. This review examines the available data from randomized and non-randomized studies of extended-interval dosing of gentamicin in neonates from both developed and developing countries. Available data on the use of gentamicin among neonates suggest that extended dosing intervals and higher doses (>4 mg/kg) confer a favourable pharmacokinetic profile, the potential for enhanced clinical efficacy and decreased toxicity at reduced cost. In conclusion, the following simplified weight-based dosing regimen for the treatment of serious neonatal infections in developing countries is recommended: 13.5 mg (absolute dose) every 24 hours for neonates of ≥2,500 g, 10 mg every 24 hours for neonates of 2,000–2,499 g, and 10 mg every 48 hours for neonates of <2,000 g.
PMCID: PMC2740664  PMID: 18686550
Developing countries; Drug therapy; Gentamicin; Infant, Newborn; Pharmacokinetics; Review literature; Sepsis
25.  Practices of Rural Egyptian Birth Attendants During the Antenatal, Intrapartum and Early Neonatal Periods 
Neonatal deaths account for almost two-thirds of infant mortality worldwide; most deaths are preventable. Two-thirds of neonatal deaths occur during the first week of life, usually at home. While previous Egyptian studies have identified provider practices contributing to maternal mortality, none has focused on neonatal care. A survey of reported practices of birth attendants was administered. Chi-square tests were used for measuring the statistical significance of inter-regional differences. In total, 217 recently-delivered mothers in rural areas of three governorates were interviewed about antenatal, intrapartum and postnatal care they received. This study identified antenatal advice of birth attendants to mothers about neonatal care and routine intrapartum and postpartum practices. While mothers usually received antenatal care from physicians, traditional birth attendants (dayas) conducted most deliveries. Advice was rare, except for breastfeeding. Routine practices included hand-washing by attendants, sterile cord-cutting, prompt wrapping of newborns, and postnatal home visits. Suboptimal practices included lack of disinfection of delivery instruments, unhygienic cord care, lack of weighing of newborns, and lack of administration of eye prophylaxis or vitamin K. One-third of complicated deliveries occurred at home, commonly attended by relatives, and the umbilical cord was frequently pulled to hasten delivery of the placenta. In facilities, mothers reported frequent use of forceps, and asphyxiated neonates were often hung upside-down during resuscitation. Consequently, high rates of birth injuries were reported. Priority areas for behaviour change and future research to improve neonatal health outcomes were identified, specific to type of provider (physician, nurse, or daya) and regional variations in practices.
PMCID: PMC2740680  PMID: 18637526
Home care; Community; Daya; Delivery; Newborn; Traditional birth attendant; Egypt

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