Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines.

Our study describes neonates from low- and middle-income countries with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in high-income countries. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.

MicroRNA Expression in Neonates with Late-onset Sepsis - A Cross-sectional Comparative Study.

BACKGROUND: Neonatal sepsis is a major health concern among neonates with higher morbidity and mortality rate. Studies have recently speculated the importance of differential expression of circulating mature micro-RNAs (miRNAs) which could serve as diagnostic as well as prognostic markers for risk of mortality in neonatal sepsis. This study aimed to analyze the expression pattern and to assess the diagnostic/prognostic value of miRNAs miR-21, miR-29a miR-31, miR-146a, and miR-155 in late-onset neonatal sepsis. METHODS: A cross-sectional comparative study was conducted including 42 healthy controls and 42 neonates with late-onset neonatal sepsis. SYBR green-based miScript RT-PCR assay was used for the expression analysis and the comparative Ct method 2-delta (Ct) method was used for relative quantification of the candidate miRNAs in plasma. Significantly higher expression of miR-21 and miR-155 and lower expression of miR-29a and miR-146a was observed in cases compared to control except miR-31. In subgroups analysis, miR-21(p = .03) showed a significant difference between pre-term and term neonates and miR-31 (p = .01) and miR-155 (p = .03) showed a significant difference between low-birth-weight and normal-birth-weight neonates. miR-146a showed significantly lower expression in the non-survivor group compared to the survivor group (p = .005). A receiver operating characteristic curve (ROC) analysis of miR-21 and miR-29a (0.829 and 0.787 AUC of ROC curves) showed good discrimination for the identification of sepsis from non-sepsis neonates. CONCLUSION: The current study shows evidence of differential expression of miRNAs in neonatal sepsis and this altered expression of candidate miRNAs could be involved in immune dysregulation, thus leading to sepsis-related severity in newborns.

Effect of Therapeutic Hypothermia on the Outcome in Term Neonates with Hypoxic Ischemic Encephalopathy-A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of therapeutic hypothermia on the outcome in term neonates with hypoxic ischemic encephalopathy (HIE). METHODS: A randomized controlled trial was conducted in a tertiary care teaching hospital in south India. Term infants with moderate to severe HIE were randomized to be treated with normothermia or hypothermia. Mortality, neurological abnormality or normal outcome was recorded at hospital discharge or 28 days of age, whichever was earlier, and at 18 months of age. RESULTS: The baseline maternal and neonatal characteristics in the two groups were similar. The 78 infants in the hypothermia group had more normal survivors at discharge (38%) than the 84 infants in the normothermia group (30%), ratio 1.29 (95% confidence interval 0.84-1.99), and at 18 months of age (65% vs. 42%), ratio 1.54 (1.13-2.10). When these results were combined with those of a previous randomized trial in the same neonatal unit, there were significantly more normal survivors with hypothermia compared to normothermia at discharge, ratio 1.49 (1.18-1.88) and at 6-18 months of age, ratio 1.37 (1.17-1.60). CONCLUSION: In term infants with HIE, therapeutic hypothermia reduced mortality and neurological abnormalities, and resulted in more normal survivors. LAY SUMMARY: Babies who do not breathe immediately after they are born are likely to die or have brain damage. Previous studies have suggested that cooling these babies after birth might reduce the number who die or have brain damage. In this resource-limited setting, babies who were cooled were less likely to die or survive with brain damage.

Endotracheal Suction for Nonvigorous Neonates Born through Meconium Stained Amniotic Fluid: A Randomized Controlled Trial.

OBJECTIVE: To assess whether endotracheal suctioning of nonvigorous infants born through meconium stained amniotic fluid (MSAF) reduces the risk and complications of meconium aspiration syndrome (MAS). STUDY DESIGN: Term, nonvigorous babies born through MSAF were randomized to endotracheal suction and no-suction groups (n=61 in each). Risk of MAS, complications of MAS and endotracheal suction, mortality, duration of neonatal intensive care unit stay, and neurodevelopmental outcome at 9 months were assessed. RESULTS: Maternal age, consistency of meconium, mode of delivery, birth weight, sex, and Apgar scores were similar in the groups. In total, 39 (32%) neonates developed MAS and 18 (14.8%) of them died. There were no significant differences in MAS, its severity and complications, mortality, and neurodevelopmental outcome for the 2 groups. One infant had a complication of endotracheal suctioning, which was mild and transient. CONCLUSIONS: The current practice of routine endotracheal suctioning for nonvigorous neonates born through MSAF should be further evaluated. TRIAL REGISTRATION: Clinical Trial Registry of India: CTRI/2013/03/003469.

Magnesium Sulfate as an Adjunct to Therapeutic Hypothermia in the Management of Term Infants with Hypoxic-Ischemic Encephalopathy: A Randomized, Parallel-Group, Controlled Trial.

OBJECTIVE: To evaluate whether magnesium sulfate and therapeutic hypothermia in combination decreases mortality and/or major neurodevelopmental disability at 1 y of age among term neonates with hypoxic-ischemic encephalopathy. METHODS: A total of 134 term neonates were randomized to receive intravenous magnesium sulfate at a dose of 250 mg/kg (at 8 mg/kg/min) once daily for 3 d starting within 6 h after birth along with therapeutic hypothermia in the intervention group and therapeutic hypothermia alone in the comparator group. The primary outcome was the composite outcome of mortality and/or major neurodevelopmental disability (Developmental Assessment Scale for Indian Infants score < 70) at 1 y of age. RESULTS: A total of 115 infants were included in the primary analysis. The composite primary outcome occurred in 14 (24%) infants in the intervention group and 19 (33%) infants in the comparator group, and the difference was not statistically significant (p = 0.30; relative risk 0.72; 95% confidence interval 0.40-1.30). The secondary outcomes including neonatal mortality, major neurodevelopmental disability at 1 y of age, neurological status at discharge, level of oxidative stress markers, and adverse effects including hypotension and respiratory depression requiring support were also comparable between the groups. CONCLUSIONS: The combination of magnesium sulfate and therapeutic hypothermia did not improve the composite outcome of neonatal mortality and/or major neurodevelopmental disability at 1 y of age. TRAIL REGISTRATION: Clinical Trials Registry of India (CTRI/2018/06/014594), prospectively registered.

Oral domperidone versus placebo for enhancing exclusive breastfeeding among post-lower segment cesarean section mothers - a double-blind randomized controlled trial.

OBJECTIVE: To assess whether oral domperidone compared to placebo increases the rate of exclusive breastfeeding for 6 months among post-lower segment cesarean section (LSCS) mothers. METHODS: This double-blind Randomized Controlled Trial, conducted in a tertiary care teaching hospital in South India, included 366 post-LSCS mothers with delayed initiation of breastfeeding or with subjective feelings of not having enough milk. They were randomized to two groups - Group A: Standard lactation counseling and oral Domperidone and Group B: Standard lactation counseling and a placebo. The primary outcome was an exclusive breastfeeding rate at 6 months. Exclusive breastfeeding rates at 7 days and 3 months and serial weight gain of an infant were assessed in both groups. RESULTS: Exclusive breastfeeding rate at 7 days was statistically significant in the intervention arm. The exclusive breastfeeding rates at 3 months and 6 months were higher in the domperidone arm compared to placebo but not statistically significant. CONCLUSION: Oral Domperidone along with effective breastfeeding counseling showed an increasing trend of exclusive breastfeeding rate at 7 days and at six months. Appropriate breastfeeding counseling and postnatal lactation support are important in enhancing exclusive breastfeeding. TRIAL REGISTRATION: The study was prospectively registered with CTRI - Reg no. CTRI/2020/06/026237.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Evaluation of T-piece resuscitator in the delivery room management of pre-term neonates with respiratory distress syndrome in resource-limited settings: A pre-post intervention study.

The aim of our study was to evaluate the impact of the T-piece resuscitator in the delivery room management of pre-term neonates in a resource-limited setting. We compared the incidence rates of delivery room intubation, surfactant replacement therapy, pulmonary air leak syndrome, and pre-term very low birth weight infant mortality, before and after T-piece use. Bi-monthly neonatal resuscitation training sessions were conducted for healthcare providers during the study period. We emphasized hands-on experience with the T-piece resuscitator and delivery room early respiratory care practices during the post-intervention epoch. Our pre- and post-intervention data recorded statistically significant decline in delivery room intubations, a 32% decrease in surfactant replacement therapy, and a 57% decrease in air leaks in pre-term neonates. However, the use of T-piece resuscitator did not have a statistically significant effect on pre-term very low birth weight infant mortality.

Utility of Low Dose Vasopressin for Persistent Pulmonary Hypertension of Newborn with Catecholamine Refractory Shock.

OBJECTIVE: To evaluate the effect of low dose vasopressin on the hemodynamics of neonates with persistent pulmonary hypertension and catecholamine refractory shock. METHODS: This retrospective study was conducted in a level III NICU of a tertiary care teaching hospital, south India. Eighteen neonates with hypoxemic respiratory failure due to persistent pulmonary hypertension of newborn with catecholamine refractory shock were studied. Neonates were managed for hypotension with conventional inotropic support with the additional use of low dose vasopressin (LDV). Effect of vasopressin on oxygenation index (OI), blood pressure, duration of inotropic usage and survival was evaluated. RESULTS: Mean OI was 38.2 ± 4.9, and mean blood pressure was 30.7 ± 5.3 mmHg before the start of vasopressin. Initiation of LDV (0.0003 ± 0.0001 IU/kg/min) for a median duration 36.4 ± 17.9 h was followed by a reduction in OI (p < 0.001), control of hypotension (p < 0.001), reduction in lactic acidosis (p < 0.001) and decline in inotropic support. CONCLUSIONS: In resource-restricted settings, LDV may be useful as a rescue therapy for persistent pulmonary hypertension of newborn with catecholamine refractory shock.

Comparison of efficacy of oral paracetamol versus ibuprofen for PDA closure in preterms - a prospective randomized clinical trial.

Background: Currently nonselective cyclooxygenase (COX) inhibitors, ibuprofen and indomethacin, are approved drugs for closure of patent ductus arteriosus but have potential toxicities. There are reports of the effectiveness of paracetamol in ductal closure. However, there is paucity of data comparing paracetamol to ibuprofen or indomethacin in relation to the efficacy and safety profile.Methods: This randomized clinical trial was done in our tertiary care neonatal unit from October 2014 to January 2016 after clearance from ethical committee. It was registered with clinical trial registry of India (CTRI/2016/09/007261) and drug controller general of India (CT/Drugs/56/2014). Preterm neonates with clinical suspicion of hemodynamically significant PDA after echo confirmation were included in the study. Randomization was done by stratified randomization through sealed opaque envelopes. A sample size of 150 was estimated with an expected difference in success of closure as 20% between the treatment groups at level of 5% significance and 80% power. The echocardiography was done 24 hours after completion of treatment by a cardiologist blinded to treatment.Results: The baseline parameters were comparable between two groups. One hundred and forty-six babies had hs-PDA, out of which 110 babies were randomized. No significant difference was found between the two groups with respect to PDA closure (RR 0.97, 95%CI 0.78-1.20, p = 1), mortality or cardio-respiratory morbidity. The babies who received ibuprofen had a higher occurrence of acute kidney injury (RR 0.33, 95%CI 0.13-0.85, p = 0.024).Conclusions: Paracetamol is as effective as ibuprofen for PDA closure in preterm neonates. Ibuprofen used for PDA closure in preterms poses an increased risk for acute kidney injury compared to paracetamol.

Does fortification of pasteurized donor human milk increase the incidence of necrotizing enterocolitis among preterm neonates? A randomized controlled trial.

Objective: To compare the effect of fortified pasteurized donor human milk (PDHM) versus unfortified PDHM on the incidence of necrotizing enterocolitis (NEC) and immediate outcome among preterm neonates. Methods: This randomized controlled trial (RCT) conducted in a tertiary care teaching hospital, south India included 80 healthy preterm neonates randomized to two groups (Group A and B). Neonates in Group A and B were fed with fortified PDHM and unfortified PDHM, respectively. Neonates in both groups were managed uniformly as per standard NICU protocol. The primary outcome was the incidence of NEC and the secondary outcomes included severity of NEC, incidence of sepsis, mortality, duration of hospital stay, number of days to reach full enteral feeds and weight gain. Neonates were followed up for 28 days or discharge whichever was earlier. Results: The baseline maternal and neonatal characteristics in both groups were comparable. There was no increase in incidence of NEC in fortified PDHM group compared to unfortified PDHM group (2.5 versus 7.5%, p = .31). Severity of NEC, incidence of sepsis, mortality, duration of hospital stay, number of days to reach full enteral feeds and weight gain were also similar in both groups. Conclusions: Standard fortification of PDHM does not increase the incidence of NEC among preterm neonates.

Fetal inflammatory response syndrome (FIRS) and outcome of preterm neonates - a prospective analytical study.

OBJECTIVES: To estimate the incidence of fetal inflammatory response syndrome (FIRS) in preterm neonates and correlate it with immediate and one-year neurodevelopmental outcome. MATERIALS AND METHODS: This prospective observational analytical study, in preterm neonates with gestational age between 26 and 34 weeks was conducted from May 2014 to December 2015 in a tertiary care hospital in South India. FIRS was defined as the presence of either elevated levels of interleukin-6 (IL-6) in cord blood ≥11 pg/ml and/or the placental histopathology showing evidence of fetal inflammatory response. One hundred and twenty neonates were recruited. During delivery 2 ml cord blood for interleukin-6 and placenta were collected and stored appropriately. Based on presence/absence of FIRS (IL-6 in cord blood ≥11 pg/ml and or features of placental fetal inflammation), neonates were grouped into two groups. The neonatal and maternal characteristics between two groups were compared. The short-term outcome parameters during NICU stay and neurodevelopmental outcome at one year of corrected age was compared between groups. RESULTS: Among the 120 infants studied, 19 expired. Out of 101 babies discharged, 87 were followed up till corrected 1 year of age. On examination of placenta and cord blood, 50 neonates had evidence of FIRS (41.6%). So there were 50 neonates in FIRS and 70 in NO-FIRS group. The mean gestational age, birth weight, and gender distribution were comparable between the two groups. Mortality [OR: 2.44 (CI: 1.14-5.26)] and early hypotension [OR: 2.13 (CI: 1.1-4.2)] were significantly higher in the FIRS group. The neurodevelopmental assessment at corrected age of 1 year showed that infants with FIRS had lower mean motor developmental quotient by developmental assessment scale for Indian infants (DASII) [87.6 ± 9.15 versus 93.07 ± 9.3, p < .04]. CONCLUSIONS: FIRS has a significant role on survival and neurodevelopmental outcome of preterm infants.

Two Randomized Trials of the Effect of the Russian Strain of Bacillus Calmette-Guérin Alone or With Oral Polio Vaccine on Neonatal Mortality in Infants Weighing <2000 g in India.

BACKGROUND: In randomized trials in Guinea-Bissau, the Danish strain of Bacillus Calmette-Guérin (BCG) reduces neonatal mortality, primarily by reducing deaths from pneumonia and sepsis. Because World Health Organization-prequalified BCG-Denmark was not available in India, we conducted 2 randomized trials to test whether BCG-Russia alone or with oral polio vaccine (OPV) has similar effects to BCG-Denmark. METHODS: We randomized neonates weighing <2000 g to a control group that was not vaccinated before 28 days of age or to receive either BCG-Russia alone (first trial) or BCG-Russia with OPV (second trial) soon after birth. We performed intention-to-treat analysis using Cox hazards models with age as the underlying time and adjusted for weight, sex and inborn versus outborn status. RESULTS: Administration of BCG-Russia alone had no effect on neonatal mortality (to 28 days of age): 15.6% of 1537 infants died in the BCG-Russia group and 16.1% of 1535 died in the control group; the adjusted hazard ratio was 0.95 [95% confidence interval (CI): 0.80-1.13]. Administration of BCG-Russia with OPV also had no effect on neonatal mortality: 18.0% of 1103 infants died in the BCG-OPV group and 17.6% of 1104 died in the control group; the adjusted hazard ratio was 1.01 (95% CI: 0.83-1.23). The adjusted hazard ratio for the 2 trials combined was 0.98 (95% CI: 0.85-1.11). CONCLUSIONS: BCG-Russia with or without OPV had no effect on neonatal mortality. It is important to determine which strains of BCG have the greatest specific effects (on tuberculosis) and nonspecific effects (on infections other than tuberculosis) in high-mortality regions.