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).

Scrub typhus due to vertical transmission in a neonate: rare presentation of a common tropical infection.

Vertical transmission as a route of infection has been well reported in many viral infections. Scrub typhus is a zoonotic disease transmitted by ticks which has had a resurgence in recent times in several tropical countries. It affects all age groups including neonates. Reports of neonates affected with scrub typhus are few, and vertical transmission is rare. We report a case, where a newborn was symptomatic with signs of infection within the first 72 hours of life and Orientia tsutsugamushi, the causative organism was confirmed by PCR in both mother and baby.

Procalcitonin for Detecting Culture-Positive Sepsis in Neonates: A Prospective, Multicenter Study.

INTRODUCTION: It is unclear if serum procalcitonin (PCT) estimated at sepsis suspicion can help detect culture-positive sepsis in neonates. We evaluated the diagnostic performance of PCT in culture-positive sepsis in neonates. METHODS: This was a prospective study (February 2016 to September 2020) conducted in four level-3 units in India. We enrolled neonates suspected of sepsis in the first 28 days of life. Neonates with birth weight <750 g, asphyxia, shock, and major malformations were excluded. Blood for PCT assay was drawn along with the blood culture at the time of suspicion of sepsis and before antibiotic initiation. The investigators labeled the neonates as having culture-positive sepsis or "no sepsis" based on the culture reports and clinical course. PCT assay was performed by electrochemiluminescence immunoassay, and the clinicians were masked to the PCT levels while assigning the label of sepsis. Primary outcomes were the sensitivity, specificity, and likelihood ratios to identify culture-positive sepsis. RESULTS: The mean birth weight (SD) and median gestation (IQR) were 2,113 (727) g and 36 (32-38) weeks, respectively. Of the 1,204 neonates with eligible cultures, 155 (12.9%) had culture-positive sepsis. Most (79.4%) were culture-positive within 72 h of birth. The sensitivity, specificity, and positive and negative likelihood ratios at 2 ng/mL PCT threshold were 52.3% (95% confidence interval: 44.1-60.3), 64.5% (60.7-68.1), 1.47 (1.23-1.76), and 0.74 (0.62-0.88), respectively. Adding PCT to assessing neonates with 12.9% pretest probability of sepsis generated posttest probabilities of 18% and 10% for positive and negative test results, respectively. CONCLUSION: Serum PCT did not reliably identify culture-positive sepsis in neonates.

Transfusion reactions in neonates and pediatrics: How and why are they different?

Neonates and children are physically as well as physiologically different from adults. They are immunologically vulnerable, and the effects of transfusion can be longstanding, including with respect to their development. The transfusion reactions in children differ from those in adults in the type of reactions, incidence, and severity. The incidence is more than that in adults for the common type of reactions noted in children. Transfusion reactions are most commonly associated with platelets, followed by plasma and red blood cell transfusions in children. Febrile, allergic, and hypotensive reactions or volume overload are the common types in children. Standardizing pediatric adverse transfusion reaction definitions and criteria are necessary to improve studies and reports. Several modifications are needed to be adapted for transfusing blood products in neonates and children to evade the reactions as much as possible and make transfusion safer in this vulnerable population. This article provides a brief articulation of the transfusion reactions in neonatal and pediatric populations describing how they are different from adults.

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.

Assessment of Antenatal and Postnatal Prognostic Indicators in the Outcome of Neonatal Congenital Diaphragmatic Hernia: A Prospective Observational Study.

Context: Despite advances in neonatal intensive care, surgical methods, and anesthesia, congenital diaphragmatic hernia (CDH) is still associated with significant mortality. Predicting which babies will have poorer outcomes is essential to identify the high-risk babies and to give targeted care and accurate prognosis to the parents, especially in a resource crunch set-up. Aims: The aim of this study is to evaluate the antenatal and postnatal prognostic factors in neonatal CDH that can be used to predict the outcome. Settings and Design: This was a prospective observational study in a tertiary care center. Subjects and Methods: Neonates presented with CDH within 28 days of life were included in the study. Bilateral disease, recurrent diseases, and babies operated outside were excluded from the study. The data were collected prospectively, and babies were followed until discharge or death. Statistical Analysis Used: Data were expressed in mean with standard deviation or median with range based on normality. All the data were analyzed using the SPSS software version 25. Results: Thirty babies with neonatal CDH were studied. There were three right-sided cases. The male-to-female ratio was 2.3:1, and 93% of babies were antenatally diagnosed. Seventeen out of the 30 babies underwent surgery. Nine (52.9%) underwent laparotomy, and 8 (47%) underwent thoracoscopic repair. Overall mortality was 53.3%, and operative mortality was 17.6%. Demographic characteristics were comparable between expired versus survived babies. The significant predictors of outcome identified were - Persistent pulmonary hypertension (PPHN), mesh repair, high-frequency oscillatory ventilation (HFOV), use of inotropes, 5-min APGAR, ventilator index (VI), and HCO3 levels. Conclusions: We conclude that the prognostic indicators associated with poor prognosis are low 5-min APGAR, high VI, low HCO3 levels in venous blood gas analysis, mesh repair, HFOV, inotropes usage, and PPHN. None of the antenatal factors studied showed any statistical significance. Further prospective studies with a larger sample size are recommended to confirm the findings.

Short-term Outcome and Predictors of Survival Among Neonates with Moderate or Severe Hypoxic Ischemic Encephalopathy: Data From the Indian Neonatal Collaborative.

BACKGROUND: Among term and late preterm infants, hypoxic ischemic encephalopathy (HIE) is an important cause of mortality, and neurologic morbidity among survivors. OBJECTIVE: The primary objective was to study the incidence of survival to discharge among late preterm and term infants with moderate or severe HIE. Secondary objectives were to explore variation in the management of HIE across participating sites and to identify the predictors of survival. SETTING: Indian Neonatal Collaborative (INNC), a network of 28 neonatal units in India. STUDY DESIGN: Retrospective cohort. PARTICIPANTS: Late preterm (34-36 weeks) and term (37-42 weeks) infants with moderate to severe HIE from 2018-2019. OUTCOME: The primary outcome was survival to discharge (including discharged home and transfer to other hospital). A multivariate logistic regression model was constructed to identify the predictors of survival. RESULTS: Of 352 infants with moderate or severe HIE, 59% received therapeutic hypothermia. Survival to discharge among infants with moderate or severe HIE was 82%. Severe HIE (aOR 0.04; 95% CI 0.02-0.10), persistent pulmonary hypertension (PPHN) (aOR 0.22; 95% CI 0.08-0.61) and requirement of epinephrine during resuscitation (aOR 0.21; 95% CI 0.05-0.84) were independently associated with decreased odds of survival to discharge. CONCLUSION: Survival to discharge among infants with moderate or severe HIE was 82%. Severe HIE, requirement of epinephrine during resuscitation and PPHN decreased the odds of survival.

Maternal and perinatal outcomes of pregnant women with tetralogy of Fallot: a tertiary center experience from south-India.

BACKGROUND: Women with tetralogy of Fallot especially uncorrected are at increased risk of adverse maternal and perinatal outcomes. METHOD: We reviewed the maternal complications and pregnancy outcomes of women with tetralogy of Fallot (ToF), having corrected or uncorrected lesion during the period from 2011 to 2019 attending a south-Indian tertiary care center. Data regarding demographics, clinical course, and medications received and echocardiographic diagnosis regarding ToF, labor and delivery details, and postpartum follow-up was collected from the records. For each case, four women matched for age (±2 years), without a diagnosis of heart disease, were included as controls. We compared the outcomes in pregnant women with ToF and controls as well between those who have undergone repair with those without repair and also with the controls. RESULTS: There were 27 pregnancies in 19 patients with ToF, including eight pregnancies in seven women with uncorrected lesions. There was no maternal death or occurrence of infective endocarditis. Women with uncorrected lesion had significantly higher rates of fetal growth restriction (37.5% vs 6.7%), preterm birth (50% vs. 13.3%) resulting in lower birth weight (1907.5 g vs. 2607.3 g)) compared to those with a corrected lesion. Women with corrected lesion had similar outcomes to the controls (p > .5). CONCLUSION: Women with uncorrected ToF are at increased risk of perinatal complications compared to those with corrected lesion and require care under a multidisciplinary team, with an individualized plan for delivery to optimize the outcomes.

Ebstein's anomaly during pregnancy: experience from a tertiary care centre - a case series and review of literature.

Pregnancy complicated with uncorrected Ebstein's anomaly is uncommon and may pose a serious threat to maternal and foetal life in the clinical setting of altered hemodynamics of pregnancy. Data of eight pregnancies in four women with Ebstein's anomaly who delivered in a tertiary care institute was analysed. Among the four women, one had associated atrial septal defect, one had pulmonary hypertension and three had right bundle branch block. There were two miscarriages and six successful pregnancies resulting in live births. Three of the pregnancies were delivered by caesarean section. There was one pregnancy complicated by severe preeclampsia, no preterm births or maternal cardiac complications. There was one neonate with congenital ostium secundum atrial septal defect. All patients were managed by a multidisciplinary team involving Obstetrician, Cardiologist, Anaesthesiologist and Neonatologist.IMPACT STATEMENTWhat is already known on this subject? Ebstein's anomaly is a rare congenital anomaly with apical displacement of the septal tricuspid leaflet in association with leaflet dysplasia. It may cause varied presentation in pregnancy depending on the severity of the lesion.What do the results of this study add? Ebstein's anomaly may become symptomatic for the first-time during pregnancy. Patients with NYHA class II symptoms and no cyanosis generally tolerate pregnancy well. Miscarriages and intrauterine growth restriction may occur in the presence of this condition. Vaginal delivery is advised and caesarean is done only for obstetric indications.What are the implications of these findings for clinical practise and/or future research? The management of pregnancy with uncorrected Ebstein's anomaly is highly challenging especially in a low resource setting and requires tertiary centre care. Multidisciplinary team involvement can help to improve the outcomes in such pregnancies.

Biliary Atresia Screening in India-Strategies and Challenges in Implementation.

OBJECTIVE: To assess the utilization of SCC implemented in southern India and the effect on SCC utilization of face-to-face verbal education versus video-based content delivery. METHODS: The study included newborns with postnatal age of less than 2 wk at discharge. Mothers were administered SCCs and provided standardized verbal or video health education based on the time-period of enrollment. Home based monitoring of stool color and return of SCC on postnatal day 21 was advised. Telephone surveys were conducted to identify SCC use among families that did not return the SCC by post. RESULTS: Of the 2254 newborns enrolled, 1130 were in the verbal-counseling group and 1124 in the video-counseling group. No newborns with pale stools and biliary atresia were identified. SCC return rates were 3.8% and 2.8%. Comparing the verbal and video-counseling groups, there were no differences in the conservative (81.8% vs. 81.5%) and optimistic estimates (97.1% vs. 97.3%) of SCC utilization rates. Mothers with better educational status had higher optimistic estimates of SCC utilization. CONCLUSIONS: The use of a validated SCC in Tamil with standardized information delivery leads to good utilization rates in southern India, with video content delivery being as effective as face-to-face verbal content delivery. SCC return by post is not a feasible mode of identification of card use. TRIAL REGISTRATION: The study is registered under Clinical Trials Registry - India (CTRI/2018/01/011285).

Management dilemmas in pineoblastoma recurrence diagnosed during pregnancy.

Pineoblastoma is an extremely rare intracranial neoplasm, with increased risk of craniospinal metastasis. There is only one case reported in the literature who presented during pregnancy. Described here is a woman who presented at five months of gestation with recurrence of pineoblastoma, who had previously defaulted adjuvant therapy following surgical decompression. The challenges in the diagnosis and treatment of pineoblastoma and its effects on pregnancy are also discussed.

A Hospital Based Cross Sectional Study of Midline Cutaneous Lesions in Neonates and its Association with Spinal Dysraphism Detected Using Ultrasound.

BACKGROUND: Spinal dysraphism occurs due to incomplete fusion of the midline mesenchymal, bony, or neural elements of the spine. The defects in the spinal cord can be associated with skin lesion since both have same embryonic origin. AIMS AND OBJECTIVES: This study was conducted to determine the association of midline and paramedian cutaneous lesions with spinal dysraphism by using spinal ultrasonography. MATERIALS AND METHODS: Two thousand apparently healthy neonates were screened in the postnatal ward of a tertiary care center in South India. Those neonates with cutaneous lesions in the midline and paramedian region were screened for evidence of spinal dysraphism by using spinal ultrasonography. RESULTS: Among 2000 neonates, 120 (6%) had at least one cutaneous lesion, of which 114 (5.7%) were in the midline and 6 (0.3%) were on the paramedian region of dorsal and ventral aspect of the body. Among these neonates, two cases had more than one skin lesions. The most common cutaneous lesion observed was typical dimple (82, 68%) followed by hypertrichosis (12, 10%). Ultrasonography revealed spinal anomaly in six (5%) of them. The cutaneous lesions associated with spinal dysraphism were obvious midline swelling, dermal sinus, and multiple skin lesions. CONCLUSION: Congenital midline and paramedian skin lesions may be the marker of spinal dysraphism. In the presence of such cutaneous lesions, only 5% of them had associated spinal anomaly in our study.

Does oropharyngeal administration of colostrum reduce morbidity and mortality in very preterm infants? A randomised parallel-group controlled trial.

AIM: To evaluate whether a strategy of oropharyngeal administration of colostrum reduces morbidity and mortality in very preterm infants. METHODS: A total of 260 neonates with gestational age 26-31 weeks at birth were randomised between August 2017 and August 2018 to receive 0.2 mL of human milk or placebo respectively via the oropharyngeal route, beginning within 24 h after birth, and continued every 3 h until oral feeds were initiated. The primary outcome was a composite of death, late-onset sepsis (LOS) or necrotising enterocolitis (NEC) in the neonatal period. RESULTS: A total of 260 infants (mean gestational age 29.5 weeks, and mean birthweight 1201.7 g) were included in the primary analysis. The composite primary outcome occurred in 43 (33.6%) infants in the colostrum group and 38 infants (29.7%) in the placebo group, and the difference was not statistically significant (P = 0.50). Secondary outcomes including the incidence of death, NEC, LOS, probable sepsis, intraventricular haemorrhage, ventilator-associated pneumonia, retinopathy of prematurity, bronchopulmonary dysplasia, time to full feeds, time to regain birthweight, duration of hospital stay and survival to 6 months without major neurosensory impairment were also comparable between the two groups. CONCLUSION: A strategy of oropharyngeal administration of colostrum in very preterm and extremely preterm neonates did not decrease the composite primary outcome of death, LOS or NEC. This finding is consistent with most published literature in the area.

Short Term Outcome and Predictors of Mortality Among Very Low Birth Weight Infants - A Descriptive Study.

OBJECTIVE: To assess the short term outcome and predictors of mortality among very low birth weight (VLBW) neonates. METHODS: This descriptive study from a tertiary care teaching institute in south India included 239 VLBW neonates who were uniformly managed as per unit's protocol and followed up till discharge or death, whichever was earlier. Univariate analysis and logistic regression analysis were done to determine the predictors of mortality. Two logistic regression models were developed and to evaluate their discriminative performance, area under the receiver operating characteristic curves were calculated. RESULTS: Mean gestational age and mean birth weight of neonates were 31.4 ± 3 wk and 1191 ± 245 g respectively. Among the 239 infants, 49 (20.5%) expired and 190 (70.5%) survived. Mortality among extremely low birth weight (ELBW) and extreme preterm infants were 69.3% and 73.3% respectively. Univariate analysis showed multiple perinatal factors and neonatal morbidities were associated with mortality. On adjusted multivariate logistic regression, birth weight < 1000 g (OR 9.27), severe grade of intraventricular hemorrhage (IVH) (OR 29.2), hyperglycemia (OR 7.8) and respiratory distress syndrome (RDS) requiring surfactant therapy (OR 6.2) were the significant predictors of mortality. Both logistic regression models developed showed good prediction of mortality. CONCLUSIONS: VLBW mortality rate is 20% in the population studied. Birth weight < 1000 g, severe grade of IVH, hyperglycemia, and RDS requiring surfactant therapy were the significant predictors of mortality among VLBW neonates. Both prediction models developed showed good prediction of mortality.