Validation of visual estimation of neonatal jaundice in low-income and middle-income countries: a multicentre observational cohort study.

OBJECTIVE: Determine the sensitivity and specificity of neonatal jaundice visual estimation by primary healthcare workers (PHWs) and physicians as predictors of hyperbilirubinaemia. DESIGN: Multicentre observational cohort study. SETTING: Hospitals in Chandigarh and Delhi, India; Dhaka, Bangladesh; Durban, South Africa; Kumasi, Ghana; La Paz, Bolivia. PARTICIPANTS: Neonates aged 1-20 days (n=2642) who presented to hospitals for evaluation of acute illness. Infants referred for any reason from another health facility or those needing immediate cardiopulmonary resuscitation were excluded. OUTCOME MEASURES: Infants were evaluated for distribution (head, trunk, distal extremities) and degree (mild, moderate, severe) of jaundice by PHWs and physicians. Serum bilirubin level was determined for infants with jaundice, and analyses of sensitivity and specificity of visual estimations of jaundice used bilirubin thresholds of >260 µmol/L (need for phototherapy) and >340 µmol/L (need for emergency intervention in at-risk and preterm babies). RESULTS: 1241 (47.0%) neonates had jaundice. High sensitivity for detecting neonates with serum bilirubin >340 µmol/L was found for 'any jaundice of the distal extremities (palms or soles) OR deep jaundice of the trunk or head' for both PHWs (89%-100%) and physicians (81%-100%) across study sites; specificity was more variable. 'Any jaundice of the distal extremities' identified by PHWs and physicians had sensitivity of 71%-100% and specificity of 55%-95%, excluding La Paz. For the bilirubin threshold >260 µmol/L, 'any jaundice of the distal extremities OR deep jaundice of the trunk or head' had the highest sensitivity across sites (PHWs: 58%-93%, physicians: 55%-98%). CONCLUSIONS: In settings where serum bilirubin cannot be measured, neonates with any jaundice on the distal extremities should be referred to a hospital for evaluation and management, where delays in serum bilirubin measurement and appropriate treatment are anticipated following referral, the higher sensitivity sign, any jaundice on the distal extremities or deep jaundice of the trunk or head, may be preferred.

Comparison of stool colonization in premature infants by three dose regimes of a probiotic combination: a randomized controlled trial.

OBJECTIVE: To compare stool colonization among premature infants receiving high-dose probiotics versus standard dose. STUDY DESIGN: This blinded, randomized, placebo-controlled trial was conducted in a Level III neonatal unit. Eligibility criteria were gestational age 27-33 weeks, age < 96 hours, tolerating milk ≥ 15 mL/kg/day and availability for follow-up. Gastro-intestinal/life-threatening malformations and necrotizing enterocolitis/sepsis were exclusions. A total of 149 subjects were randomly allocated to groups A through D (received 12-hourly probiotic supplements of 10(10) cells for 21 days, 10(10) cells for 14 days, 10(9) cells for 21 days and placebo, respectively). Key outcome was stool colonization by a probiotic organism at 28 days. RESULTS: Colonization with Lactobacillus and Bifidobacterium was significantly higher in groups A, B, and C versus placebo respectively, but groups A through C did not differ from each other. There were trends toward more colony forming unit (cfu) of Lactobacillus and Bifidobacterium per milliliter of stool in group A versus B and B versus C. Groups A and B and spontaneous preterm labor (SPL) independently predicted high Lactobacillus counts on day 28; groups A, B, and C and SPL predicted high Bifidobacterium counts. CONCLUSION: Proportion of infants colonized with probiotic species was similar with high-dose and standard dose regimes.

Iron status at birth and at 4 weeks in term small-for-gestation infants in comparison with appropriate-for-gestation infants.

OBJECTIVE: To determine body iron stores at birth in term small-for-gestational age (SGA) infants as compared to appropriate-for-gestational age (AGA) infants. METHODS: In this prospective study, mother-infant pairs with gestation of  ≥ 37 weeks and birth weight of at least 1.5 kg were enrolled. Asymmetric SGA infants were taken as cases and term AGA infants as controls. Maternal, cord blood, and infant blood samples at 4 weeks were obtained for measurement of various iron indices - cord serum ferritin, serum ferritin at 4 weeks, and correlation among maternal and neonatal iron indices - Hb, serum iron, ferritin, and total iron binding capacity (TIBC). RESULTS: There were 50 SGA and 50 AGA mother-infant pairs. Cord serum ferritin levels were low in SGA group as compared to AGA [median (IQR): 68 (30,136) vs. 141 (63,259), p = 0.007]. The proportion of infants with 'low' cord ferritin (< 40 µg/l) were more in SGA [p = 0.05]. There was no correlation among various maternal and neonatal cord iron parameters. The serum ferritin levels at 4 weeks were similar in both the groups (p = 0.16). CONCLUSIONS: Term SGA infants have lesser total iron stores as compared to AGA infants at birth. Future studies can be designed to look at long-term neurodevelopmental outcome of the SGA babies with low as well as normal ferritin and also the role of early iron supplementation in term SGA neonates.

Hydration status of exclusively and partially breastfed near-term newborns in the first week of life.

An in-hospital prospective, observational cohort study was conducted to assess the effects of type of feeding (exclusively breastfed [EBF] vs partially breastfed [PBF]) on the hydration status of near-term newborns in the first week of life. A total of 205 babies of 35 to 37 weeks of completed gestation were enrolled (82 in the EBF group and 123 in the PBF group). The overall incidence of significant weight loss (>or=10%) was 18% with no significant difference between EBF and PBF groups (18.3% vs 17.9%, P=.94). The incidence of hypernatremia (serum NA>or=150 meq/L) was 2.4% in the EBF group and 5.7% in the PBF group (P=.32). The factors associated with significant weight loss in the total cohort were having a mother with previous negative breastfeeding experience (adjusted odds ratio [OR]=16.5, 95% confidence interval [CI]=2.1-115.7), exposure to phototherapy (adjusted OR=9.0, 95% CI=2.5-31.8), and cesarean delivery (adjusted OR=6.7, 95% CI=2.3-19.7).

UGT1A1 gene polymorphisms in North Indian neonates presenting with unconjugated hyperbilirubinemia.

Genetic factors are implicated in pathogenesis of neonatal hyperbilirubinemia. In this nested case-control study, we determined 1) frequency of thymine-adenine (TA)n promoter polymorphism and Gly71Arg mutation in uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene in neonates > or =35-wk gestation presenting with bilirubin levels > or =18 mg/dL and controls, 2) interaction among (TA)n promoter polymorphism, glucose-6-phosphate dehydrogenase (G6PD) gene mutations, and peak bilirubin. The number of TA repeats was assessed by PCR-single-strand conformation polymorphism (SSCP) analysis and Gly71Arg mutation by PCR-RFLP. Fifty samples of both mutations were verified with DNA sequencing. One hundred twenty-seven neonates were enrolled (77 hyperbilirubinemics, 50 controls). The incidence of (TA)n polymorphism was higher in babies with hyperbilirubinemia [89.6% vs. 50%, OR 8.63 (95% CI, 3.2-24.1)]. Gly71Arg mutation was not found either in hyperbilirubinemics or controls. A novel polymorphism (Ala72Pro) at codon position 72 of exon 1 was detected in all 50 samples (21 hyperbilirubinemics, 29 controls), which were sequenced. Presence of variant (TA)n promoter (adjusted OR, 10.6; 95% CI, 3.3-34.2), G6PD deficiency (adjusted OR, 20.6; 95% CI, 3.6-117.3), and history of jaundice in sibling requiring phototherapy (adjusted OR, 12.6; 95% CI, 1.1-141.6) were independent risk factors for bilirubin levels > or =18 mg/dL.

Donor blood glucose 6-phosphate dehydrogenase deficiency reduces the efficacy of exchange transfusion in neonatal hyperbilirubinemia.

OBJECTIVES: Acute intravascular hemolysis after exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood has been reported; however, it is not routine to screen donor blood for glucose 6-phosphate dehydrogenase deficiency while performing exchange transfusion. We hypothesized that exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood would lead to a less-than-expected decrease in total serum bilirubin. The objective of this study was to evaluate the effect of exchange transfusion with glucose 6-phosphate dehydrogenase-deficient blood in neonates with idiopathic hyperbilirubinemia on postexchange total serum bilirubin levels, duration of phototherapy, and need for repeat exchange transfusions. METHODS: All neonates who were undergoing exchange transfusion for idiopathic hyperbilirubinemia were enrolled. A sample of donor blood was collected at the time of exchange transfusion for a glucose 6-phosphate dehydrogenase assay. The standard criteria for starting and stopping phototherapy and exchange transfusion were applied. RESULTS: During the 1-year study period, 21 infants underwent exchange with glucose 6-phosphate dehydrogenase-deficient blood, and 114 neonates with similar baseline characteristics underwent exchange transfusion with glucose 6-phosphate dehydrogenase-normal blood. From 6 to 60 hours after exchange transfusion, there was a significantly lesser drop in total serum bilirubin in the recipients of glucose 6-phosphate dehydrogenase-deficient donor blood compared with recipients of glucose 6-phosphate dehydrogenase-normal blood. The mean duration of phototherapy in the postexchange period and number of infants who underwent repeat exchange transfusions were significantly higher in recipients of glucose 6-phosphate dehydrogenase-deficient donor blood in comparison with control subjects. Concurrently, there was a significantly higher drop in hematocrit and rise in plasma hemoglobin in the glucose 6-phosphate dehydrogenase-deficient donor group. CONCLUSIONS: Exchange transfusion with glucose 6-phosphate dehydrogenase-deficient donor blood leads to a lesser drop in postexchange total serum bilirubin. It prolongs the duration of phototherapy and increases the need for repeat exchange transfusions.

Gemfibrozil in late preterm and term neonates with moderate jaundice: a randomized controlled trial.

OBJECTIVE: To determine, if oral Gemfibrozil is effective in decreasing the duration of phototherapy by at least 24 hours in neonates >34 weeks gestation with non-hemolytic jaundice, as compared to placebo. DESIGN: Double blind placebo controlled randomized controlled trial. SETTING: Tertiary care neonatal unit in north India. SUBJECTS: Ninety seven neonates >34 weeks gestation with non-hemolytic jaundice within first 7 days of life requiring phototherapy. INTERVENTION: Two doses of Gemfibrozil (60 mg/kg/dose) or placebo, 12 hours apart. Babies were treated with single surface special blue light phototherapy. Serum total bilirubin (STB) was measured 8 hourly. Phototherapy was stopped if two consecutive STB values were below phototherapy zone. PRIMARY OUTCOME MEASURE: Duration of phototherapy. RESULTS: The median (IQR) duration of phototherapy was 40 (30, 60) hours in Gemfibrozil and 36 (19, 55) hours in the placebo group (P=0.13). The peak STB levels were 16.8 +/- 2.7 mg/dL and 16.3 +/- 2.3 mg/dL in Gemfibrozil and placebo groups, respectively. No side effect of the drug or placebo was noticed. CONCLUSION: Two doses of gemfibrozil (60 mg/kg/dose) given 12 hours apart were not able to reduce the duration of phototherapy, or peak bilirubin level in babies > 34 weeks gestation with non-hemolytic jaundice in the first week of life. Gemfibrozil was not associated with any side effects.

Evaluation of oxidant and antioxidant status in term neonates: a plausible protective role of bilirubin.

In vitro studies have shown unequivocally that bilirubin is an antioxidant. We hypothesized that bilirubin serves a physiological role of an antioxidant in vivo. To investigate the probable protective role of bilirubin in vivo, term babies with clinical jaundice were grouped into four categories-serum total bilirubin (STB) <160 mg/l, 160-200 mg/l, >200 mg/l, and kernicterus. Serum bilirubin, serum albumin, plasma glucose-6-phosphate dehydrogenase (G6PD), lipid peroxidation in blood cells, and reduced glutathione (GSH) content in whole blood were investigated. We also measured superoxide dismutase (SOD) and catalase in hemolysate and total plasma antioxidant capacity (TAC). Lipid peroxidation and antioxidant enzymes were significantly lower in babies with STB <200 mg/l compared to controls. TAC had a positive and MDA had a negative correlation with STB till 200 mg/l. However, TAC had a negative and MDA had a positive correlation with bilirubin >200 mg/l and in babies with bilirubin encephalopathy. Elevated levels of MDA, SOD, and catalase and significantly decreased levels of reduced glutathione and total antioxidant capacity were observed in STB >200 mg/l group. Antioxidant enzymes were also significantly inhibited in bilirubin encephalopathy babies. Post phototherapy, MDA production and antioxidant levels were significantly increased whilst total antioxidant capacity and reduced glutathione were significantly decreased compared to pre-phototherapy values. Exchange transfusion resulted in reduced oxidative stress in subjects with encephalopathy, whereas no significant difference was observed in other babies with STB >200 mg/l. Taken together, the present study propounds that bilirubin acts as a physiological antioxidant till 200 mg/l concentration in full-term normal neonates. It is conjectured that beyond 200 mg/l, it can no longer be considered physiologic. However, the cause of pathological jaundice needs to be identified and treated. The present data documents that phototherapy also induces oxidative stress.

Randomized controlled trial of compact fluorescent lamp versus standard phototherapy for the treatment of neonatal hyperbilirubinemia.

BACKGROUND: Special blue tube lights of standard length are used in most neonatal units to deliver phototherapy. Of late, special blue compact fluorescent lamp phototherapy equipments have been introduced in India, which are claimed to be better than standard tube lights. AIM: To compare special blue compact fluorescent lamp (CFL) phototherapy with special blue standard-length tube lights (STL). METHODS: This randomized, controlled trial was conducted in a level III NICU. Neonates, otherwise healthy, of gestation greater than 34 weeks with hyperbilirubinemia requiring phototherapy, were included. Rh iso-immunized babies, those who underwent prior exchange transfusion and whose parents declined to consent were excluded. By stratified block randomization, babies were allocated to receive phototherapy by CFL or STL. CFL and STL were both special blue lights with irradiance maintained above 15 microWatts/nm/cm2. Total serum bilirubin (TSB) was measured 12 hourly till phototherapy was stopped or an exchange transfusion was done. Temperature and clinical and laboratory parameters of dehydration were recorded 12 hourly till 72 hrs. Nursing staff answered an objectivized proforma about the disadvantageous effects on nurses. RESULTS: Fifty babies were enrolled in each group. Baseline characteristics, causes of jaundice, hemolysis, baseline TSB and irradiance were similar in both groups. Mean duration of phototherapy (P = 0.98) was similar in both groups. Kaplan-Meier analysis of phototherapy duration showed no difference in the survival curves of the 2 groups (P = 0.6). Axillary temperature was similar in both groups and no baby was dehydrated. Nursing staff reported no significant differences between CFL and STL visavis glare hurting the eyes, giddiness and headache. CONCLUSIONS: CFL phototherapy has no superiority over STL phototherapy in terms of efficacy and adverse effects on the neonate and effects on nursing staff.

A randomized controlled trial of fluid supplementation in term neonates with severe hyperbilirubinemia.

OBJECTIVE: To evaluate the effectiveness of fluid supplementation in decreasing the rate of exchange transfusion and the duration of phototherapy in term neonates with severe nonhemolytic hyperbilirubinemia. STUDY DESIGN: This was a randomized controlled trial conducted in a tertiary care referral unit in northern India. Seventy-four term neonates with severe nonhemolytic hyperbilirubinemia (total serum bilirubin > 18 mg/dL [308 micromol/L] to < 25 mg/dL [427 micromol/L]). The subjects were randomized to an "extra fluids" group (intravenous fluid supplementation for 8 hours and oral supplementation for the duration of phototherapy; n = 37) or a control group (n = 37). RESULTS: At inclusion, 54 infants (73%) had high serum osmolality, including 28 (75%) in the extra fluids group and 26 (70%) in the control group. The proportion of infants who underwent exchange transfusion was lower in the extra fluids group than in the control group: 6 (16%) versus 20 (54%)(P = .001; relative risk = 0.30; 95% confidence interval = 0.14 to 0.66). The duration of phototherapy was also shorter in the extra fluids group: 52 +/- 18 hours versus 73 +/- 31 hours (P = .004). CONCLUSION: Fluid supplementation in term neonates presenting with severe hyperbilirubinemia decreased the rate of exchange transfusion and duration of phototherapy.

A randomized, triple-blind, placebo-controlled trial of prophylactic oral phenobarbital to reduce the need for phototherapy in G6PD-deficient neonates.

OBJECTIVE: Decreased conjugation is probably more important than hemolysis for causing jaundice in G6PD-deficient neonates. The role of enzyme inducers, like phenobarbital, in G6PD deficiency is unclear. This randomized controlled trial was performed to evaluate Phenobarbital's role in reducing the need for phototherapy among G6PD-deficient neonates. STUDY DESIGN: This stratified, randomized, triple-blinded, placebo-controlled trial was conducted in a level III NICU. Consecutive babies with gestation >/=34 weeks and birth weight >/=1800 g were screened from cord blood. G6PD-deficient neonates, who were otherwise healthy, were enrolled. Rh isoimmunization, maternal Phenobarbital use and lack of parental consent were exclusion criteria. Subjects were randomly allocated to receive 5 mg/kg day of oral phenobarbital/ placebo for first 3 days. They were monitored daily for total serum bilirubin (TSB) until declining TSB was documented twice. The primary outcome was requirement for phototherapy and secondary outcomes were duration of phototherapy, need for exchange transfusion, peak TSB and adverse effects. Sample size of 56 could detect a decline in phototherapy requirement from 40 to 5% with 80% power and 5% error. RESULTS: Of 2370 babies screened, 63 were G6PD-deficient. Of them, 56 eligible babies were allocated to phenobarbital (n=27) or placebo (n=29). The mean age of administration of the first dose was 18.55+/-7.3 h. In total, 44% in phenobarbital group and 41% in placebo group required phototherapy (p=1.0). There was no significant difference in exchange transfusion rates (18.5 vs 10%, p=0.46). No baby had adverse reactions. CONCLUSION: Prophylactic oral phenobarbital does not decrease the need for phototherapy or exchange transfusions in G6PD-deficient neonates.

Subgaleal hematoma and seven exchange transfusions.

A 3 kg baby was delivered by cesarean section after prolonged labor. He had massive subgaleal hematoma. He developed anemia requiring packed cell transfusions and hyperbilirubinemia requiring a total of seven exchange transfusions and highly intensive phototherapy. There were no adverse complications of the hyperbilirubinemia or the exchange transfusion.

Intravenous immunoglobulins in rhesus hemolytic disease.

OBJECTIVE: To evaluate the role of intravenous immunoglobulins in Rh hemolytic disease of newborn. METHODS: The study included all DCT positive Rh isoimmunized babies admitted in the unit from August 2000 to February 2001. Intravenous immunoglobulins in the dose of 500 mg/kg on day 1 and day 2 of life in addition to the standard therapy. Babies who received IVIG were compared with those who did not receive IVIG for the peak bilirubin levels, duration of phototherapy, number of exchange transfusions, discharge PCV and the need for blood transfusions for late anemia till 1 months of age. RESULTS: A total of 34 babies were eligible for the study. 8 babies received IVIG and 26 babies only standard treatment. The mean maximum bilirubin levels were significantly lower in the IVIG group compared to the group who received NO IVIG (16.52 +/- 2.96 Vs 22.72 +/- 8.84, p=0.004). Five babies in the IVIG group (62.5%) and 23 babies in the NO IVIG group required exchange transfusions (88.5%, p=0.014). 12 of the 26 babies in the NO IVIG group required multiple exchange transfusions while none of the babies in IVIG group required more one exchange transfusion (p=0.03). The mean duration of phototherapy was 165 +/- 109 hours in the IVIG group as against 119 +/- 56 hours in the NO IVIG group (p=0.29). Blood transfusion for anemia was more common in the IVIG group (37.5% Vs 11.5% p=0.126) though the packed cell volumes at discharge were similar in both the groups (39.5 +/- 11 Vs 40 +/- 5.1, P=0.92). CONCLUSION: Intravenous immunoglobulins is effective in decreasing the maximum bilirubin levels and the need for repeated exchange transfusions in Rh hemolytic disease of newborn. There is however an increased need for blood transfusions for late anemia in the babies treated with IVIG.

Phenobarbitone prophylaxis for neonatal jaundice in babies with birth weight 1000-1499 grams.

Management of neonatal jaundice is simple but in sick, very low birth weight babies poses additional hemodynamic insult. Role of prophylactic postnatal phenobarbitone (two different dosage regimens) was evaluated prospectively on occurrence of neonatal jaundice and the need for therapy in 150 babies with birth weight 1000-1499 grams. Phenobarbitone in the dose of 10mg/kg given within 6 hours of life followed by 5mg/kg/day till day 5 of life intravenously significantly decreased the need for exchange transfusion and duration of phototherapy in babies with birth weight of 1000-1499 grams. This dosage schedule was better than dose of 5mg/kg for 5 days in significantly reducing the duration of phototherapy