Souvik Mitra

Chorioamnionitis as a Risk Factor for Retinopathy of Prematurity: A Systematic Review and Meta-Analysis

Background: The role of chorioamnionitis (CA) in the development of retinopathy of prematurity (ROP) has not been well established. Objective: To conduct a systematic review and meta-analysis of the association between CA and ROP in preterm infants. Data Sources: The authors searched MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and PubMed, reviewed reference lists of relevant articles, abstracts and conference proceedings (Society for Pediatric Research, European Society for Paediatric Research 1990-2012), sought results of unpublished trials, and contacted the primary authors of relevant studies. Study Selection: Studies were included if they had a comparison group, examined preterm infants, and reported primary data that could be used to measure the association between exposure to CA and the development of ROP. Data Extraction: Two reviewers independently screened the search results, applied inclusion criteria and assessed methodological quality using the Newcastle-Ottawa Scale. One reviewer extracted data and a second reviewer checked data extraction. Summary relative risks (RRs) were calculated using a random effects model. Data Synthesis: We identified 1,249 potentially relevant studies from the electronic databases. Twenty-seven studies involving 10,590 preterm neonates with 2,562 cases of ROP were included. Taking into account all included studies without adjusting for gestational age (GA), CA was significantly associated with ROP (any stage) [summary RR 1.33 (95% CI 1.14-1.55, I2 = 77%, pheterogeneity < 0.0001)], and a borderline significant association was observed for severe ROP (stage ≥3) [summary RR 1.27 (95% CI 0.99-1.63, I2 = 74%, pheterogeneity < 0.0001)]. There was no publication bias with Beggs test. However, subgroup analysis of studies adjusting for GA showed no significant association on CA with ROP [summary RR 0.98 (95% CI 0.77-1.26, I2 = 0%, pheterogeneity = 0.89)]. Conclusion: Unadjusted analyses showed that CA was significantly associated with ROP (any stage) as well as with severe ROP (stage ≥ 3). However, the association disappeared on analysis of studies adjusting for GA. Hence, CA cannot be definitively considered as a risk factor for ROP, and further studies should adjust for potential confounding factors and report results by stage to clarify the association with severe ROP.

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis

Importance Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA. Objectives To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. Data Sources and Study Selection The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data Extraction and Synthesis Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage. Results In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. Conclusions and Relevance A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. Trial Registration PROSPERO Identifier: CRD42015015797

Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: a protocol for a systematic review and network meta-analysis

Introduction Management of patent ductus arteriosus (PDA) in preterm infants is one of the most controversial topics in neonatal medicine. The availability of different pharmacotherapeutic options often poses a practical challenge to the practising neonatologist as to which one to choose as a therapeutic option. Our objectives are to determine the relative merits of the available pharmacotherapeutic options for the management of PDA. Methods and Analysis We will conduct a systematic review of all randomised controlled trials evaluating the use of intravenous or oral: indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. The primary outcome is failure of closure of the PDA. Secondary outcomes are neonatal mortality, need for surgical closure, duration of ventilator support, chronic lung disease, intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleeding, time to full enteral feeds and oliguria. We will search Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach). Subgroup analysis according to gestational age, birth weight, different doses of interventions, time of administration of the first dose of the intervention, and echocardiographic definition of haemodynamically significant PDA and ROB are planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data are available. Ethics and Dissemination The results will help to reduce the uncertainty about the safety and effectiveness of the interventions, will identify knowledge gaps or will encourage further research for other therapeutic options. Therefore, its results will be disseminated through peer-reviewed publications and conference presentations. On the basis of the nature of its design, no ethics approval is necessary for this study. Trial registration number CRD42015015797.

Target fortification of breast milk: levels of fat, protein or lactose are not related.

Target fortification (TFO) of breast milk has the potential to improve the nutritional outcomes of preterm infants. However, the primary logistic constraint in introducing TFO is analysers that rapidly and accurately analyse macronutrients (fat, protein and lactose). In this prospective observational study, we aim to evaluate whether the levels of fat, protein and carbohydrate could be predicted from one key macronutrient.

Pre-exchange 5% Albumin Infusion in Low Birth Weight Neonates with Intensive Phototherapy Failure—A Randomized Controlled Trial

OBJECTIVE To evaluate the role of 5% albumin infusion before exchange transfusion in reducing post-exchange unconjugated serum bilirubin (UCB) levels in low birth weight (LBW) neonates with intensive phototherapy failure. METHODS In a placebo-controlled Randomized Controlled Trial, 42 healthy LBW (birth weight between 1000 and 2499 g and gestational age ≥ 32 weeks) neonates were randomly allocated into intervention and control groups. Post-exchange UCB at 6 and 12 h were compared in the two groups along with the duration of post-exchange phototherapy, repeat-exchange requirement, adverse effects of albumin and hospital stay. RESULTS The intervention group (n = 21) with mean birth weight 1619 ± 324 g, gestational age 34.5 ± 1.65 weeks, peak UCB 19 ± 3.85 mg dl(-1), was demographically comparable with the control group (n = 21) (1660 ± 320 g, 34 ± 1.6 weeks, 19.4 ± 3.59 mg dl(-1), respectively). Significant reduction in the post-exchange UCB (10.55 ± 1.53 mg dl(-1) at 6 h; 5.86 ± 1.21 mg dl(-1) at 12 h in albumin group; 15.26 ± 1.78 mg dl(-1) at 6 h; 11.69 ± 1.52 mg dl(-1) at 12 h in control group) and phototherapy duration (23.8 ± 3.2 h vs. 40.3 ± 7.2 h) was observed in the intervention group (p < 0.0001). Repeat exchange requirement was reduced by 86% (RR = 0.14; 95%CI: 0.19-1.06). Mean duration of hospital stay was significantly lower (10.1 ± 5.8 days vs. 12.4 ± 6.6 days) (p = 0.021). No albumin transfusion-related complications were observed.

Dorfman-Chanarin syndrome: A rare neutral lipid storage disease

Dorfman-Chanarin syndrome is a rare neutral lipid storage disorder characterized by ichthyosis, lipid vacuolations in peripheral leucocytes, and multisystem involvement. It is an autosomal recessive disorder caused by mutations in the CGI-58 gene. A total of 42 cases have been reported worldwide till February 2009 out of which 4 have been previously reported from India. We report a case of a 20-month-old male with congenital ichthyosis, organomegaly, and bilateral cryptorchidism. Examination of the peripheral smear revealed lipid vacuoles in the leucocytes consistent with Jordans anomaly, which was confirmed by transmission electron microscopy. Liver biopsy revealed micronodular cirrhosis with macrovesicular steatosis while skin biopsy showed ichthyosis vulgaris. Dorfman-Chanarin syndrome was diagnosed on the basis of clinical and laboratory criteria with certain unreported manifestations. Dietary modifications were instituted and followed up after 1 year with promising results. This emphasizes the importance of neonatal screening for lipid vacuolations in peripheral blood in all cases of congenital ichthyosis.

Granulocyte colony-stimulating factor for preterms with sepsis and neutropenia: A randomized controlled trial

Background: Bacterial sepsis is one of the major causes of mortality in newborn infants. Mortality increases when sepsis is associated with neutropenia. Materials and Methods: We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor on preterm neonates (gestational age (GA) <34 weeks) with sepsis and absolute neutrophil count (ANC) of <1500 cells/mm3. Mortality, duration of Neonatal Intensive Care Unit (NICU) stay, hematological parameters (ANC, platelet count, and total leukocyte count) were compared between the two groups. The GCSF group (n=39) received GCSF intravenously in a single daily dose of 10 μg/kg/day in a 5% dextrose solution over 20-40 min for three consecutive days, while the control group (n=39) received placebo of an equivalent volume of 5% dextrose. Results: Baseline demographic profile among the two groups was comparable. Mortality rate in the GCSF group was significantly lower than in the control group (10% vs. 35%; P<0.05). By day 3 of treatment, ANC in the GCSF group was significantly higher (3521±327) compared to 2094±460 in the control group, with P value being <0.05. Duration of NICU stay also decreased significantly in the GCSF group. Conclusion: The administration of GCSF in preterms with septicemia and neutropenia resulted in lower mortality rates. Further studies are required to confirm our results and establish this adjunctive therapy in neonatal sepsis.

The association of platelets with failed patent ductus arteriosus closure after a primary course of indomethacin or ibuprofen: a systematic review and meta-analysis

Abstract Objective: To conduct a meta-analysis of the association of platelet counts and pharmacotherapeutic failure in preterms with a patent ductus arteriosus (PDA). Methods: MEDLINE, Embase, Science Citation Index, abstracts and conference proceedings were searched, and principal authors contacted. Included studies reported indomethacin or ibuprofen use for PDA closure, compared a group which failed treatment versus a group which did not and reported the association between platelet counts and indomethacin or ibuprofen failure. Two reviewers independently screened results and assessed methodological quality using the Newcastle-Ottawa Scale. Results are expressed as mean difference in platelet counts and summary odds ratios (OR) using a random effects model. Results: 1105 relevant studies were identified; eight involving 1087 preterms were included. Platelet counts were significantly lower in infants who failed pharmacotherapy (Meandifference:–30.88 × 109/L; 95% CI:–45.69 × 109,–16.07 × 109/L; I2 = 24%; pheterogeneity = 0.24). Similar results were obtained based on either pharmacotherapeutic agent. Treatment failure was also significantly associated with pre-treatment thrombocytopenia (summary OR:1.75; 95% CI:1.23–2.49, I2 = 36%, pheterogeneity = 0.20). Conclusions: Platelet counts are significantly lower in preterms who fail primary treatment for PDA. Pre-treatment thrombocytopenia is associated with higher odds of failure. Further cohort studies reporting platelet counts in prostaglandin inhibitor failure are needed for meta-analyses to firmly establish or refute a stronger association.

Indomethacin dose-interruption and maternal chorioamnionitis are risk factors for indomethacin treatment failure in preterm infants with patent ductus arteriosus

Background: Indomethacin has been used as the primary pharmacotherapeutic agent for the closure of patent ductus arteriosus (PDA) in preterm infants. However, it is commonly observed that infants often respond differently to indomethacin treatment with some requiring multiple courses of the drug and subsequently surgical ligation. Objectives: To explore common variables that could be associated with failure of a primary course of indomethacin for PDA in preterm infants.Methods: We examined 83 preterm infants who received intravenous indomethacin for PDA treatment from 2010 to 2013. We identified those who failed primary pharmacotherapy and required subsequent courses or surgical ligation. A number of perinatal/neonatal variables in the infants with and without primary indomethacin failure were compared initially for univariate analysis. Following the univariate analysis, those variables which had a significant difference between the two groups were selected to carry out logistic regression analysis to find out independent risk factors for indomethacin failure. Results: Of 77 infants analyzed, 36 (46.7%) had a primary indomethacin failure and nine infants (11.7%) underwent surgical ligation. Univariate analysis revealed that infants with primary indomethacin failure were significantly more preterm, were more likely to be males, did not receive a complete course of antenatal corticosteroids, their mothers had clinical chorioamnionitis and indomethacin dose interruption was documented during clinical care. The multivariate logistic regression analysis showed that dose interruption (odds ratio [OR]: 27.14; 95% confidence interval [CI]: 5.94, 124.07) and clinical chorioamnionitis (OR: 7.80; 95% CI: 1.73, 35.00) were independent risk factors for indomethacin failure. Conclusion: Indomethacin dose interruption and clinical chorioamnionitis appear to be independent risk factors for primary indomethacin failure in preterm infants.

Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age: A Systematic Review and Meta-Analysis

Objectives To compare the respiratory syncytial virus (RSV)‐related hospitalization rate, hospital length of stay (LOS), and need for assisted ventilation in children aged <2 years with Down syndrome and those without Down syndrome. Study design MEDLINE, Embase, and CINAHL databases were searched from inception up to December 2017. Studies that provided data on RSV‐related hospitalization in children aged <2 years with Down syndrome and those without Down syndrome were included. Data were independently extracted in pairs by 2 reviewers and synthesized with random‐effects meta‐analysis. Results In 10 studies including a total of 1 748 209 children, 12.6% of the children with Down syndrome (491 of 3882) were hospitalized with RSV infection. The presence of Down syndrome was associated with a significantly higher risk of RSV‐related hospitalization (relative risk [RR], 6.06; 95% CI, 4.93‐7.45; I2 = 65%; Grading of Recommendations, Assessment, Development and Evaluation [GRADE], moderate). RSV‐related LOS (mean difference, 2.11 days; 95% CI, 1.47‐2.75 days; I2 = 0%; GRADE, low), and the need for assisted ventilation (RR, 5.82; 95% CI, 1.81‐18.69; I2 = 84%; GRADE, low). Children with Down syndrome without congenital heart disease (RR, 6.31; 95% CI, 4.83‐8.23; GRADE, moderate) also had a significantly higher risk of RSV‐related hospitalization. The risk of RSV‐related hospitalization remained significant in the subgroup of children aged <1 year (RR, 6.25; 95% CI, 4.71‐8.28; GRADE, high). Conclusion RSV‐related hospitalization, hospital LOS, and the need for assisted ventilation are significantly higher in children with Down syndrome aged <2 years compared with those without Down syndrome. The results should prompt reconsideration of the need for routine RSV prophylaxis in children with Down syndrome up to 2 years of age.