Corrigendum: A randomized synbiotic trial to prevent sepsis among infants in rural India.

This corrects the article DOI: 10.1038/nature23480.

A randomized synbiotic trial to prevent sepsis among infants in rural India.

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Changes in the Gut Microbiota After Early Administration of Oral Synbiotics to Young Infants in India.

OBJECTIVES: The authors examined the changes in the developing gut microbiota of Indian infants enrolled in a colonization study of an oral synbiotic (Lactobacillus plantarum and fructo-oligosaccharides) preparation. METHODS: Frozen stool samples were available from a previously published clinical study of the synbiotic preparation administered daily for 7 days to full-term Indian infants delivered by C-section. 16S rRNA gene sequencing of fecal bacterial community-DNA was done in 11 infants sampled on day 7 and day 60 of life. RESULTS: All infants showed changes in bacterial diversity with age. While Firmicutes and Proteobacteria were predominant in all, Actinobacteria and Bacteroidetes were initially low on day 7. In control infants, we observed a significant increase (P = 0.012) in the proportions of Actinobacteria on day 60. In the treated group, during the 60-day period, there was a 10-fold increase in Bacteroidetes, a somewhat smaller increase in Firmicutes, and a reduction in Proteobacteria. Compared to controls, treated infants were increasingly colonized by different Gram-positive genera including Enterococcus, Lactobacillus, and Bifidobacterium. Relatively less known taxa and some unassigned sequence reads added to enriched diversity observed in the treated group. CONCLUSIONS: There was a high level of bacterial diversity among infants examined in the present study. Synbiotic treatment induced an increase in overall taxa and Gram-positive diversity, especially in the first week of life. Changes in the microbiota during early infancy should be used as a rationale for selecting probiotics in diverse clinical settings.

Role of central endpoint adjudication and challenges in trials on neonatal sepsis-a case of ProSPoNS trial.

Despite progress in reducing the infant mortality in India, the neonatal mortality decline has been slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming to prevent neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention includes probiotic supplementation. This article communicates the decision by the ProSPoNS trial investigators to establish a Central Endpoint Adjudication Committee (CEAC) as an addendum to the protocol published in Trials in 2021 for the purpose of clarifying the primary outcome. In the published protocol, the study hypothesis and primary objective are based on "sepsis," the primary outcome has been specified as sepsis/PSBI, whereas the sample size estimation was performed based on the "physician diagnosed sepsis." To align all the three above, the investigators meeting, held on 17th-18th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that "physician diagnosed sepsis" is the primary study outcome which includes sepsis/PSBI. The CEAC, chaired by an external subject expert and members including trial statistician, a microbiologist, and all site principal investigators will employ four criteria to determine "physician diagnosed sepsis": (1) blood culture status, (2) sepsis screen status, (3) PSBI/non-PSBI signs and symptoms, and (4) the clinical course for each sickness event. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No. 5/7/915/2012 version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. The decision to utilize the guidance of a CEAC is recommended as the gold standard in multicentric complex clinical trials to achieve consistency and accuracy in assessment of outcomes.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.

Newborn-care training and perinatal mortality in developing countries.

BACKGROUND: Of the 3.7 million neonatal deaths and 3.3 million stillbirths each year, 98% occur in developing countries. An evaluation of community-based interventions designed to reduce the number of these deaths is needed. METHODS: With the use of a train-the-trainer model, local instructors trained birth attendants from rural communities in six countries (Argentina, Democratic Republic of Congo, Guatemala, India, Pakistan, and Zambia) in the World Health Organization Essential Newborn Care course (which focuses on routine neonatal care, resuscitation, thermoregulation, breast-feeding, "kangaroo" [skin-to-skin] care, care of the small baby, and common illnesses) and (except in Argentina) in a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (which teaches basic resuscitation in depth). The Essential Newborn Care intervention was assessed among 57,643 infants with the use of a before-and-after design. The Neonatal Resuscitation Program intervention was assessed as a cluster-randomized, controlled trial involving 62,366 infants. The primary outcome was neonatal death in the first 7 days after birth. RESULTS: The 7-day follow-up rate was 99.2%. After birth attendants were trained in the Essential Newborn Care course, there was no significant reduction from baseline in the rate of neonatal death from all causes in the 7 days after birth (relative risk with training, 0.99; 95% confidence interval [CI], 0.81 to 1.22) or in the rate of perinatal death; there was a significant reduction in the rate of stillbirth (relative risk with training, 0.69; 95% CI, 0.54 to 0.88; P=0.003). In clusters of births in which attendants had been randomly assigned to receive training in the Neonatal Resuscitation Program, as compared with control clusters, there was no reduction in the rates of neonatal death in the 7 days after birth, stillbirth, or perinatal death. CONCLUSIONS: The rate of neonatal death in the 7 days after birth did not decrease after the introduction of Essential Newborn Care training of community-based birth attendants, although the rate of stillbirths was reduced. Subsequent training in the Neonatal Resuscitation Program did not significantly reduce the mortality rates. (ClinicalTrials.gov number, NCT00136708.)

Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0-2-month-old low birth weight infants in India-the "ProSPoNS" Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Progress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising. METHODS: A phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites. DISCUSSION: This adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low-middle-income countries. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197 . Registered on 16 May 2019.

Exposure of pregnant women to indoor air pollution: a study from nine low and middle income countries.

OBJECTIVE: We studied exposure to solid fuel and second-hand tobacco smoke among pregnant women in south Asia, Africa and Latin America. DESIGN: Prospective cross-sectional survey. SETTING: Antenatal clinics in Argentina, Brazil, Ecuador, Guatemala, Uruguay, Democratic Republic of Congo, Zambia, India and Pakistan. SAMPLE: A total of 7,961 pregnant women in ten sites in nine countries were interviewed between October 2004 and September 2005. METHODS: A standardized questionnaire on exposure to indoor air pollution (IAP) and second-hand smoke was administered to pregnant women during antenatal care. MAIN OUTCOME MEASURES: Exposure to IAP and second-hand tobacco smoke. RESULTS: South Asian pregnant women commonly reported use of wood (49.1-89.7%), crop residue and animal dung as cooking and heating fuel. African pregnant women reported higher use of charcoal (85.4-93.5%). Latin American pregnant women had greater use of petroleum gas. Among south Asian women, solid fuel use and cooking on an open flame inside the home were common. There was a significant association between solid fuel use and allowing smoking within the home at the Asian sites and in Zambia (p < 0.05). CONCLUSIONS: Pregnant women from low/middle income countries were commonly exposed to IAP secondary to use of solid fuels. Among these populations, exposure to second-hand tobacco smoke was also common. This combination of exposures likely increases the risk of poor pregnancy outcomes among the most vulnerable women. Our study highlights the importance of further research on the combined impact of IAP and second-hand tobacco smoke exposures on adverse maternal and perinatal outcomes.

Tobacco use and secondhand smoke exposure during pregnancy: an investigative survey of women in 9 developing nations.

OBJECTIVES: We examined pregnant women's use of cigarettes and other tobacco products and the exposure of pregnant women and their young children to secondhand smoke (SHS) in 9 nations in Latin America, Asia, and Africa. METHODS: Face-to-face surveys were administered to 7961 pregnant women (more than 700 per site) between October 2004 and September 2005. RESULTS: At all Latin American sites, pregnant women commonly reported that they had ever tried cigarette smoking (range: 78.3% [Uruguay] to 35.0% [Guatemala]). The highest levels of current smoking were found in Uruguay (18.3%), Argentina (10.3%), and Brazil (6.1%). Experimentation with smokeless tobacco occurred in the Democratic Republic of the Congo and India; one third of all respondents in Orissa, India, were current smokeless tobacco users. SHS exposure was common: between 91.6% (Pakistan) and 17.1% (Democratic Republic of the Congo) of pregnant women reported that smoking was permitted in their home. CONCLUSIONS: Pregnant women's tobacco use and SHS exposure are current or emerging problems in several low- and middle-income nations, jeopardizing ongoing efforts to improve maternal and child health.

Long-term colonization of a Lactobacillus plantarum synbiotic preparation in the neonatal gut.

BACKGROUND: Probiotic, prebiotic, and synbiotic (a combination of pro- and prebiotic) supplements increasingly are being used to prevent and treat a variety of health conditions. Although colonization is considered a key element in the success of such treatments, few clinical studies have addressed colonizing ability. Studies are even more limited in neonates and infants, who may benefit most from such treatment. The present study was conducted to determine the colonizing ability, tolerance, and impact on the stool flora of 7 days of administration of a synbiotic supplement to a neonatal cohort, in preparation for a larger hospital-based trial. PATIENTS AND METHODS: In this randomized, double-masked, controlled trial, healthy inborn newborns >35 weeks of gestational age and >1800 g birth weight were randomized between 1 and 3 days after birth to receive an oral synbiotic preparation (Lactobacillus plantarum and fructooligosaccharides) or a dextrose saline placebo. Two babies were treated with the synbiotic preparation for every 1 baby treated with the placebo. Duration of therapy was 7 days. Comprehensive stool cultures were done at baseline and on days 3, 7, 14, 21, and 28. RESULTS: Nineteen infants received the active study supplement and 12 infants received the placebo for 7 days. L plantarum was cultured from the stools of 84% of the treated infants after 3 days of treatment, and from 95% of infants on day 28 after birth. Of the infants, 100%, 94%, 88%, 56%, and 32% remained colonized at months 2, 3, 4, 5, and 6, respectively. In both groups, the total mean number of species and the mean log colony counts increased over time. The number of bacterial species was significantly higher on days 21 and 28 in the synbiotic preparation group compared with placebo (P = 0.002 and 0.03, respectively). There was a linear increase in the mean log gram-negative colony counts in the placebo group during the 4-week period that was significantly higher than that in the Lactobacillus group on days 14, 21, and 28 (P < 0.001 for each). In contrast, the supplement group had significantly higher gram-positive colony counts on days 14 (P = 0.002) and 28 (P = 0.04). Only 1 infant in the placebo group was colonized with L fermentum during the first 28 days of life. No difference was found in the percent increase in weight between baseline and day 7, but on day 28 and months 2, 3, and 6, the percent increase from baseline was higher in the probiotic-treated group (P

The global network: a prospective study of stillbirths in developing countries.

OBJECTIVE: Our goal was to determine stillbirth rates in a multisite population-based study in community settings in the developing world. STUDY DESIGN: Outcomes of all community deliveries in 5 resource-poor countries (Democratic Republic of Congo, Guatemala, India, Zambia, and Pakistan) and in 1 mid-level country (Argentina) were evaluated prospectively over an 18-month period. Births of > 1000 g with no signs of life were defined as stillbirth. RESULTS: Outcomes of 60,324 deliveries were included. Stillbirth rates ranged from 34 per 1000 in Pakistan to 9 per 1000 births in Argentina. Increased stillbirth rates were associated significantly with lower skilled providers, out-of-hospital births, and low cesarean section rates. Maceration was present in 17.2% of stillbirths. CONCLUSION: The stillbirth rates among births of > or = 1000 g in these developing countries were substantially higher than reported stillbirth rates in developed countries (3-5/1000 births). Because most developed countries define stillbirth as > or = 20 weeks of gestation or > or = 500 g and because almost one-half of all stillbirths are < 1000 g, the developing/developed country difference is actually larger than apparent from this study. Maceration was uncommon, which indicates that most of the deaths probably occurred during labor. The low rates of physician attendance, hospital delivery, and cesarean section deliveries suggest that stillbirth rates could be reduced by access to higher quality institutional deliveries.

Challenges in Implementation of the ANISA Protocol at the Odisha Site in India.

BACKGROUND: The Aetiology of Neonatal Infection in South Asia (ANISA) study is being carried out at 5 sites across Bangladesh, India and Pakistan, generating in-depth information on etiologic agents in the community setting. Pregnancies are identified, births are registered and young infants are followed up to 59 days old with regular assessments for possible serious bacterial infection following a generic protocol. Specimens are collected from suspected cases. This article describes the challenges in implementing the generic ANISA protocol and modifications made to accommodate the Odisha site, India. CHALLENGES: Primary challenges in implementing the protocol are the large geographic area, with a population of over 350,000, to be covered; assessing young infants at home and arranging timely transport of sick young infants to study hospitals for physician confirmation of illness; and specimen collection and treatment. A large workforce is deployed in a 3-tier system in the field, while clinical, microbiology, laboratory and data management teams collaborate dynamically. Mobile phones with text message capability, integration with the Odisha State government's health system, involvement of local communities and strict monitoring at different levels have been critical in addressing these challenges. CONCLUSION: This article describes the challenges and modalities adopted to collect complex and accurate data on etiology, timing of disease and associated factors for community-acquired neonatal infections. Attention to local culture and customs, training and employing community level workers and supervisors, involving existing government machinery, using technology (cell phones), and uninterrupted systematic monitoring are critical for implementing such complex protocols that aim to collect population-based data to drive policy.

Extended-spectrum beta-lactamase-producing Gram-negative bacteria causing neonatal sepsis in India in rural and urban settings.

Extended-spectrum ß-lactamase (ESBL)-producing Gram-negative bacilli (GNB) are of increasing clinical concern in all age groups worldwide. Whilst sepsis continues to be the leading cause of morbidity and mortality in Indian neonates in the community, identification of microbiological attributes in this population is lacking. This population-based study enrolled 1738 infants with a diagnosis of clinical sepsis at four participating centres in India. Each study site conducted Bactec blood culture, identified bacterial species by API test and stored isolates at -70 °C. From 252 GNB isolates, 155 (113 Klebsiella species, 21 Escherichia coli and 21 other) were subjected to drug susceptibility testing, ESBL phenotyping and testing for clonal relatedness of ESBL strains by PFGE. The results demonstrated that Klebsiella species and E. coli are the most common GNB causes of neonatal sepsis in India, and over one-third are ESBL producers in both community and hospital settings. ESBL-producing strains exhibited frequent co-resistance to aminoglycosides and ciprofloxacin, but remained susceptible to imipenem. PFGE analysis revealed extensive genetic diversity within the ESBL-producing isolates, showing multiple profiles (total of 23). Over 40% of all ESBL-producing isolates formed three pulsed-field profiles (PFP I-III), with PFP-II being the largest cluster (>20% of all ESBL-producing isolates), sharing strains from two distant locations. Identification of a common clone at two geographically distant centres indicated that predominant clones with increased virulence may exist, even in the absence of any clear outbreak. The presence of ESBL-producing strains in community infants with no prior history of hospitalization or antibiotic use dictates heightened vigilance and further studies on the ecology of these organisms.

High mortality rates for very low birth weight infants in developing countries despite training.

OBJECTIVE: The goal was to determine the effect of training in newborn care and resuscitation on 7-day (early) neonatal mortality rates for very low birth weight (VLBW) infants. The study was designed to test the hypothesis that these training programs would reduce neonatal mortality rates for VLBW infants. METHODS: Local instructors trained birth attendants from 96 rural communities in 6 developing countries in protocol and data collection, the World Health Organization Essential Newborn Care (ENC) course, and a modified version of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP), by using a train-the-trainer model. To test the impact of ENC training, data on infants of 500 to 1499 g were collected by using a before/after, active baseline, controlled study design. A cluster-randomized, controlled trial design was used to test the impact of the NRP. RESULTS: A total of 1096 VLBW (500-1499 g) infants were enrolled, and 98.5% of live-born infants were monitored to 7 days. All-cause, 7-day neonatal mortality, stillbirth, and perinatal mortality rates were not affected by ENC or NRP training. CONCLUSIONS: Neither ENC nor NRP training of birth attendants decreased 7-day neonatal, stillbirth, or perinatal mortality rates for VLBW infants born at home or at first-level facilities. Encouragement of delivery in a facility where a higher level of care is available may be preferable when delivery of a VLBW infant is expected.

Clinical manifestations and predictors of severe malaria in Indian children.

OBJECTIVE: Although the greatest morbidity and mortality attributable to malaria occurs among children in Africa, up to one third of the world's malaria burden is borne by non-African countries, where levels of endemicity are lower. Because there are few published criteria for managing life-threatening malaria in children in these countries, we conducted a study of major syndromes and predictors of death among critically ill Indian children to identify factors that could be used to improve the approach to their treatment. METHODS: A prospective study was conducted at the pediatric ward of SCB Medical College in eastern India (Orissa). Baseline demographic data were collected on all of the patients with confirmed slide-positive falciparum malaria. Patients satisfying any 1 of the 2000 World Health Organization criteria for severe malaria were included in the analysis. Prevalence of and mortality as a result of major symptoms were calculated followed by multiple regression modeling to identify major predictors of death. RESULTS: Of 1682 confirmed cases of malaria during a 32-month period, 374 subjects met the World Health Organization criteria for severe malaria. The case fatality rate was 12% in this series. Multiple regression analysis identified respiratory distress, coma, multiple organ dysfunctions, and hyperparasitemia as major predictors of death. Anemia and jaundice did not emerge as important markers of mortality. Many patients presented with multiple major complications, and the mortality rate was consistently high when >1 major predictor was present in a patient. CONCLUSIONS: Clinical features in Indian children differed from those reported in most studies that involved an African population. Multiple organ dysfunctions emerged as an important presenting feature and a new predictor of death in childhood malaria.