A. S. M. Nawshad Uddin Ahmed

Effect of Skin Barrier Therapy on Neonatal Mortality Rates in Preterm Infants in Bangladesh: A Randomized, Controlled, Clinical Trial

OBJECTIVE. Skin barrier therapy during the neonatal period, when the skin barrier is most highly compromised and the risk of death is greatest, has been shown to have a number of potential benefits, including reduced risk of nosocomial sepsis. Topical application of emollients that augment skin barrier function was evaluated as a strategy for improving survival rates among hospitalized preterm infants in Bangladesh. METHODS. A prospective, randomized, controlled, clinical trial was conducted in the special care nursery at Dhaka Shishu (Children) Hospital, the largest tertiary care childrens hospital in Bangladesh. Preterm infants (gestational age: ≤33 weeks; N = 497) received daily topical applications of sunflower seed oil or Aquaphor ointment. Neonatal mortality rates were compared in an intent-to-treat analysis with a control group that did not receive emollient therapy. RESULTS. Treatment with sunflower seed oil resulted in a statistically significant 26% reduction in mortality rates, compared with infants not receiving topical emollient therapy. Aquaphor therapy also significantly reduced mortality rates, by 32%. CONCLUSIONS. Topical therapy with skin barrier-enhancing emollients improved survival rates among preterm hospitalized infants in Bangladesh. This study provides strong evidence for the implementation of topical therapy for high-risk preterm neonates in developing countries.

Evaluation of a Cluster-Randomized Controlled Trial of a Package of Community-Based Maternal and Newborn Interventions in Mirzapur, Bangladesh

Background To evaluate a delivery strategy for newborn interventions in rural Bangladesh. Methods A cluster-randomized controlled trial was conducted in Mirzapur, Bangladesh. Twelve unions were randomized to intervention or comparison arm. All women of reproductive age were eligible to participate. In the intervention arm, community health workers identified pregnant women; made two antenatal home visits to promote birth and newborn care preparedness; made four postnatal home visits to negotiate preventive care practices and to assess newborns for illness; and referred sick neonates to a hospital and facilitated compliance. Primary outcome measures were antenatal and immediate newborn care behaviours, knowledge of danger signs, care seeking for neonatal complications, and neonatal mortality. Findings A total of 4616 and 5241 live births were recorded from 9987 and 11153 participants in the intervention and comparison arm, respectively. High coverage of antenatal (91% visited twice) and postnatal (69% visited on days 0 or 1) home visitations was achieved. Indicators of care practices and knowledge of maternal and neonatal danger signs improved. Adjusted mortality hazard ratio in the intervention arm, compared to the comparison arm, was 1.02 (95% CI: 0.80–1.30) at baseline and 0.87 (95% CI: 0.68–1.12) at endline. Primary causes of death were birth asphyxia (49%) and prematurity (26%). No adverse events associated with interventions were reported. Conclusion Lack of evidence for mortality impact despite high program coverage and quality assurance of implementation, and improvements in targeted newborn care practices suggests the intervention did not adequately address risk factors for mortality. The level and cause-structure of neonatal mortality in the local population must be considered in developing interventions. Programs must ensure skilled care during childbirth, including management of birth asphyxia and prematurity, and curative postnatal care during the first two days of life, in addition to essential newborn care and infection prevention and management. Trial Registration Clinicaltrials.gov NCT00198627

Infection control practices reduce nosocomial infections and mortality in preterm infants in Bangladesh

OBJECTIVE:The skin is a potential source for invasive infections in neonates from developing countries such as Bangladesh, where the level of environmental contamination is exceedingly high. A randomized controlled trial was conducted from 1998 to 2003 in the Special Care Nursery of a tertiary hospital in Bangladesh to test the effectiveness of topical emollient therapy in enhancing the skin barrier of preterm neonates less than 33 weeks of gestational age. In the initial months of the study, the infection and mortality rates were noted to be unacceptably high. Therefore, an infection control program was introduced early in the trial to reduce the rate of nosocomial infections.STUDY DESIGN:After a comprehensive review of neonatal care practices and equipment to identify sources of nosocomial infections, a simple but comprehensive infection control program was introduced that emphasized education of staff and caregivers about measures to decrease risk of contamination, particularly hand-washing, proper disposal of infectious waste, and strict asepsis during procedures, as well as prudent use of antibiotics.RESULTS:Infection control efforts resulted in declines in episodes of suspected sepsis (47%), cases of culture-proven (61%) sepsis, patients with a clinical diagnosis of sepsis (79%), and deaths with clinical (82%) or culture-proven sepsis (50%).CONCLUSION:The infection control program was shown to be a simple, low-cost, low-technology intervention to reduce substantially the incidence of septicemia and mortality in the nursery.

Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial

BACKGROUND Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. METHODS We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. FINDINGS Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). INTERPRETATION Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable.

Effect of Topical Emollient Treatment of Preterm Neonates in Bangladesh on Invasion of Pathogens Into the Bloodstream

Topical emollient therapy may reduce the incidence of serious infections and mortality of preterm infants in developing countries. We tested whether emollient therapy reduced the burden of pathogens on skin and/or prevented bacterial translocation. Neonates <33 wk gestational age were randomized to treatment with sunflower seed oil (SSO) or Aquaphor or the untreated control group. Skin condition score and skin cultures were obtained at enrollment and on d 3, 7, and weekly thereafter, and blood cultures were obtained for episodes of suspected nosocomial sepsis. For analysis, blood cultures were paired with skin cultures obtained 0–3 d before the blood culture. Skin condition scores at 3 d were better in patients treated with either emollient compared with untreated controls; however, skin flora was similar across the groups. The SSO group showed a 72% elevated odds of having a false-positive (FP) skin culture associated with a negative blood culture (i.e. skin flora blocked from entry into blood) compared with the control group. Topical therapy with SSO reduced the passage of pathogens from the skin surface into the bloodstream of preterm infants.

Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa

Background: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0–59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. Methods: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. Conclusion: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing.

Neurodevelopmental Sequelae in Pneumococcal Meningitis Cases in Bangladesh: A Comprehensive Follow-up Study

BACKGROUND Evaluation of the long-term impact of pneumococcal meningitis on surviving children and their families is critical to fully comprehending the burden of pneumococcal disease and to facilitating an evidence-based decision for the introduction of pneumococcal vaccine. This study was an investigation of the short- and long-term impacts of pneumococcal meningitis among Bangladeshi children. METHODS Case patients with pneumococcal meningitis who were hospitalized between January 2006 and March 2007 were subjected to short-term follow-up within 30-40 days of discharge. Case patients discharged prior to January 2005 were selected for long-term follow-up at 6-24 months after the date of discharge. Both cohorts were enrolled from Dhaka Shishu Hospital, a pediatric hospital in Bangladesh. Healthy children matched for age, sex, socioeconomic status, and area of residence were recruited from the community as control subjects. During follow-up visits, case patients and control subjects were assessed for their physical and neurodevelopmental status by use of a standardized protocol. The impact of pneumococcal meningitis on siblings and the family as a whole was assessed by means of qualitative interviews. RESULTS Neurodevelopmental assessments of the short-term follow-up cohort (n=51) revealed hearing, vision, mental, and psychomotor deficits in 33%, 8%, 41%, and 49% of the case patients, respectively. These deficits were 18%, 4%, 41%, and 35% in the long-term follow-up cohort (n=51), respectively. Such deficits were seen in only 2% of the control subjects, none of whom had vision or hearing deficits. CONCLUSIONS In addition to the risk of death, pneumococcal meningitis in children causes severe disabilities among survivors, as well as disruption of the life of other siblings and family members. This study demonstrated that high rates of sequelae are associated with pneumococcal meningitis. Neurodevelopmental assessment during follow-up of patients with meningitis is critical to our understanding of the burden of the adverse consequences of pneumococcal disease. These data, along with the fact of poor access to health care, provide a compelling argument in favor of the introduction of pneumococcal vaccine, specifically in a setting where access to health care is poor and disabled children remain incapacitated because of a lack of resources and facilities.

Routine Skin Cultures in Predicting Sepsis Pathogens among Hospitalized Preterm Neonates in Bangladesh

Background: Few studies from developing countries have examined sensitivity, specificity, positive and negative predictive values of routine surface cultures. Objectives: The purpose of the study was to determine sensitivity, specificity, and positive predictive value (PPV) of skin cultures among preterm neonates admitted to Dhaka Shishu Hospital, Bangladesh. Methods: The study was nested within a prospective, randomized, controlled trial of emollient treatment in Dhaka Shishu Hospital, Bangladesh. A total of 497 preterm infants <33 weeks gestational age and <72 h of chronological age were enrolled, and the sensitivity, specificity, and PPV of skin cultures were analyzed among 3,765 blood-skin culture pairs, wherein the skin culture was obtained within 13 days before the blood culture. Results: Overall sensitivity, specificity, and PPV were 16, 38, and 5%, respectively. PPV during Klebsiella pneumoniae outbreaks was about 9%, and the inguinal site had the highest PPV (6%) among the three skin sites. Acinetobacter spp.- and K. pneumoniae-specific PPVs were 28 and 23%, respectively. PPV was <2% for Candida spp., Enterobacter spp., and Salmonella spp. Conclusion: Routine skin culture is inefficient in predicting the pathogen responsible for sepsis among premature neonates, even in a developing country setting, where the burden of bacterial infection is relatively high. Skin cultures are also of limited utility during K. pneumoniae outbreaks, and are not recommended.

Safety and Efficacy of Simplified Antibiotic Regimens for Outpatient Treatment of Serious Infection in Neonates and Young Infants 0-59 Days of Age in Bangladesh Design of a Randomized Controlled Trial

Background: Because access to care is limited in settings with high mortality, exclusive reliance on the current recommendation of 7–10 days of parenteral antibiotic treatment is a barrier to provision of adequate treatment of newborn infections. Methods: We are conducting a trial to determine if simplified antibiotic regimens with fewer injections are as efficacious as the standard course of parenteral antibiotics for empiric treatment of young infants with clinical signs suggestive of severe infection in 4 urban hospitals and in a rural surveillance site in Bangladesh. The reference regimen of intramuscular procaine-benzyl penicillin and gentamicin given once daily for 7 days is being compared with (1) intramuscular gentamicin once daily and oral amoxicillin twice daily for 7 days and (2) intramuscular penicillin and gentamicin once daily for 2 days followed by oral amoxicillin twice daily for additional 5 days. All regimens are provided in the infant’s home. The primary outcome is treatment failure (death or lack of clinical improvement) within 7 days of enrolment. The sample size is 750 evaluable infants enrolled per treatment group, and results will be reported at the end of 2013. Discussion: The trial builds upon previous studies of community case management of clinical severe infections in young infants conducted by our research team in Bangladesh. The approach although effective was not widely accepted in part because of feasibility concerns about the large number of injections. The proposed research that includes fewer doses of parenteral antibiotics if shown efficacious will address this concern.

Validation of a clinical algorithm to identify neonates with severe illness during routine household visits in rural Bangladesh

Background To validate a clinical algorithm for community health workers (CHWs) during routine household surveillance for neonatal illness in rural Bangladesh. Methods Surveillance was conducted in the intervention arm of a trial of newborn interventions. CHWs assessed 7587 neonates on postnatal days 0, 2, 5 and 8 and identified neonates with very severe disease (VSD) using an 11-sign algorithm. A nested prospective study was conducted to validate the algorithm (n=395). Physicians evaluated neonates to determine whether newborns with VSD needed referral. The authors calculated algorithm sensitivity and specificity in identifying (1) neonates needing referral and (2) mortality during the first 10 days of life. Results The 11-sign algorithm had sensitivity of 50.0% (95% CI 24.7% to 75.3%) and specificity of 98.4% (96.6% to 99.4%) for identifying neonates needing referral-level care. A simplified 6-sign algorithm had sensitivity of 81.3% (54.4% to 96.0%) and specificity of 96.0% (93.6% to 97.8%) for identifying referral need and sensitivity of 58.0% (45.5% to 69.8%) and specificity of 93.2% (92.5% to 93.7%) for screening mortality. Compared to our 6-sign algorithm, the Young Infant Study 7-sign (YIS7) algorithm with minor modifications had similar sensitivity and specificity. Conclusion Community-based surveillance for neonatal illness by CHWs using a simple 6-sign clinical algorithm is a promising strategy to effectively identify neonates at risk of mortality and needing referral to hospital. The YIS7 algorithm was also validated with high sensitivity and specificity at community level, and is recommended for routine household surveillance for newborn illness. ClinicalTrials.gov no. NCT00198627.