Indirect neonatal hyperbilirubinemia in hospitalized neonates on the Thai-Myanmar border: a review of neonatal medical records from 2009 to 2014.

BACKGROUND: Indirect neonatal hyperbilirubinemia (INH) is a common neonatal disorder worldwide which can remain benign if prompt management is available. However there is a higher morbidity and mortality risk in settings with limited access to diagnosis and care. The manuscript describes the characteristics of neonates with INH, the burden of severe INH and identifies factors associated with severity in a resource-constrained setting. METHODS: We conducted a retrospective evaluation of anonymized records of neonates hospitalized on the Thai-Myanmar border. INH was defined according to the National Institute for Health and Care Excellence guidelines as 'moderate' if at least one serum bilirubin (SBR) value exceeded the phototherapy threshold and as 'severe' if above the exchange transfusion threshold. RESULTS: Out of 2980 records reviewed, 1580 (53%) had INH within the first 14 days of life. INH was moderate in 87% (1368/1580) and severe in 13% (212/1580). From 2009 to 2011, the proportion of severe INH decreased from 37 to 15% and the mortality dropped from 10% (8/82) to 2% (7/449) coinciding with the implementation of standardized guidelines and light-emitting diode (LED) phototherapy. Severe INH was associated with: prematurity (< 32 weeks, Adjusted Odds Ratio (AOR) 3.3; 95% CI 1.6-6.6 and 32 to 37 weeks, AOR 2.2; 95% CI 1.6-3.1), Glucose-6-phosphate dehydrogenase deficiency (G6PD) (AOR 2.3; 95% CI 1.6-3.3), potential ABO incompatibility (AOR 1.5; 95% CI 1.0-2.2) and late presentation (AOR 1.8; 95% CI 1.3-2.6). The risk of developing severe INH and INH-related mortality significantly increased with each additional risk factor. CONCLUSION: INH is an important cause of neonatal hospitalization on the Thai-Myanmar border. Risk factors for severity were similar to previous reports from Asia. Implementing standardized guidelines and appropriate treatment was successful in reducing mortality and severity. Accessing to basic neonatal care including SBR testing, LED phototherapy and G6PD screening can contribute to improve neonatal outcomes.

High positive predictive value of Gram stain on catheter-drawn blood samples for the diagnosis of catheter-related bloodstream infection in intensive care neonates.

Catheter-related bloodstream infections (CRBSIs) remain a leading cause of healthcare-associated infections in preterm infants. Rapid and accurate methods for the diagnosis of CRBSIs are needed in order to implement timely and appropriate treatment. A retrospective study was conducted during a 7-year period (2005-2012) in the neonatal intensive care unit of the University Hospital Erasme to assess the value of Gram stain on catheter-drawn blood samples (CDBS) to predict CRBSIs. Both peripheral samples and CDBS were obtained from neonates with clinically suspected CRBSI. Gram stain, automated culture and quantitative cultures on blood agar plates were performed for each sample. The paired quantitative blood culture was used as the standard to define CRBSI. Out of 397 episodes of suspected CRBSIs, 35 were confirmed by a positive ratio of quantitative culture (>5) or a colony count of CDBS culture >100 colony-forming units (CFU)/mL. All but two of the 30 patients who had a CDBS with a positive Gram stain were confirmed as having a CRBSI. Seven patients who had a CDBS with a negative Gram stain were diagnosed as CRBSI. The sensitivity, specificity, positive predictive value and negative predictive value of Gram stain on CDBS were 80, 99.4, 93.3 and 98.1 %, respectively. Gram staining on CDBS is a viable method for rapidly (<1 h) detecting CRBSI without catheter withdrawal.

Gender differences in language and motor-related fibers in a population of healthy preterm neonates at term-equivalent age: a diffusion tensor and probabilistic tractography study.

BACKGROUND AND PURPOSE: Sex differences in white matter structure are controversial. In this MR imaging study, we aimed to investigate possible sex differences in language and motor-related tracts in healthy preterm neonates by using DTI and probabilistic tractography. MATERIALS AND METHODS: Thirty-eight preterm neonates (19 boys and 19 girls, age-matched), healthy at term-equivalent age and at 12 months were included. TBV was measured individually. Probabilistic tractography provided tract volumes, relative tract volumes (volume normalized to TBV), FA, MD, and λ(⊥) in the SLF, in the TRs, and in the CSTs. Data were compared by using independent t tests, and Bonferroni corrections were performed to adjust for multiple comparisons. RESULTS: We showed that healthy preterm boys had larger TBV than girls. However, girls had statistically significantly larger relative tract volumes than boys bilaterally in the parieto-temporal SLF, and in the left CST. Moreover, in the left parieto-temporal SLF, a trend toward lower MD and λ(⊥) was observed in females. CONCLUSIONS: Structural sex differences were found in preterm neonates at term-equivalent age in both sides of the parieto-temporal SLF and in the left CST. Further studies are necessary to investigate whether these structural differences are related to later sex differences in language skills and handedness or to the effect of prematurity.

[First SIBEN clinical consensus: diagnostic and therapeutic approach to patent ductus arteriosus in premature newborns]. / Primer consenso clínico de SIBEN: enfoque diagnóstico y terapéutico del ductus arterioso permeable en recién nacidos pretérmino.

OBJECTIVE: To report the process and results of the first neonatal clinical consensus of the Ibero-American region. DESIGN AND METHODS: Two recognized experts in the field (Clyman and Van Overmeire) and 45 neonatologists from 23 countries were invited for active participation and collaboration. We developed 46 questions of clinical-physiological relevance in all aspects of patent ductus arteriosus (PDA). Guidelines for consensus process, literature search and future preparation of educational material and authorship were developed, reviewed and agreed by all. Participants from different countries were distributed in groups, and assigned to interact and work together to answer 3-5 questions, reviewing all global literature and local factors. Answers and summaries were received, collated and reviewed by 2 coordinators and the 2 experts. Participants and experts met in Granada, Spain for 4.5 h (lectures by experts, presentations by groups, discussion, all literature available). RESULTS: 31 neonatologists from 16 countries agreed to participate. Presentations by each group and general discussion were used to develop a consensus regarding: general management, availability of drugs (indomethacin vs. ibuprofen), costs, indications for echo/surgery, etc. Many steps were learnt by all present in a collaborative forum. CONCLUSIONS: This first consensus group of Ibero-American neonatologists SIBEN led to active and collaborative participation of neonatologists of 16 countries, improved education of all participants and ended with consensus development on clinical approaches to PDA. Furthermore, it provides recommendations for clinical care reached by consensus. Additionally, it will serve as a useful foundation for future SIBEN Consensus on other topics and it could become valuable as a model to decrease disparity in care and improve outcomes in this and other regions.

Clinical pharmacology of non opioid analgesics in neonates.

An integrated approach of neonatal analgesia starts with the systematic evaluation of pain and should be followed by effective interventions, mainly based on the appropriate (i.e. safe and effective) administration of analgesics. In contrast to the more potent opioids, data on the pharmacokinetics and -dynamics of non-opioid analgesics in this specific population are still rare or even lacking. We therefore evaluated various aspects of developmental pharmacology of non-opioid analgesics (paracetamol, ibuprofen, acetylsalicyl acid) in neonates. We first performed a single dose propacetamol study in preterm and term neonates. Based on these preliminary findings, a repeated dose administration scheme was developed and tested and maturational aspects from preterm till teenage were documented. Although non-selective COX-inhibitors might be effective in the treatment of postoperative or inflammatory pain syndromes in neonates, potential efficacy should be balanced against the drugs' safety profile. Neonatal renal clearance strongly depends on glomerular filtration rate (GFR) and GFR itself strongly depends on the vaso-dilatative of prostaglandins on the afferent arterioli. We therefore evaluated the impact of the administration of ibuprofen or acetylsalicylic acid on renal clearance in preterm infants and hereby used amikacin clearance as a surrogate marker. We hereby documented the negative effect of ibuprofen on glomerular filtration rate in preterm infants up to 34 weeks and we were able to show that ibuprofen and acetylsalicylic acid had an equal impact on the glomerular filtration rate.

Ibuprofen and cerebral oxygenation and circulation.

The effect of prophylactic administration of ibuprofen on the cerebral circulation in preterm babies was measured with near infrared spectroscopy. No significant difference in the change in cerebral blood volume, change in cerebral blood flow, or tissue oxygenation index was found between administration of ibuprofen or placebo.

Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life.

The aim of this study was to assess the effects of intravenous co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin during the first days of life in preterm infants. The pharmacokinetics of amikacin were retrospectively calculated in a cohort of 73 neonates (gestational age <31 weeks) who received either ibuprofen-lysine or placebo following inclusion in the multicentre ibuprofen prophylaxis study. Assuming a one-compartment model with instantaneous input and first-order output, there was no significant difference in the median distribution volume (0.63 vs. 0.59 liters/kg), but the median serum half-life (16.4 vs. 12.4 h) of amikacin was significantly longer (p <0.02), and the clearance (0.36 vs. 0.6 ml/kg/min; p <0.005) of amikacin was significantly lower in infants who received ibuprofen-lysine. We conclude that the time interval between consecutive amikacin administrations should be prolonged, if ibuprofen-lysine is co-administered.

QTc interval prolongation and QTc dispersion in children and adolescents with type 1 diabetes.

OBJECTIVES: To evaluate whether QT interval, QT interval corrected for heart rate (QTc), and QTc dispersion changes are already present in children and adolescents with diabetes. STUDY DESIGN: QT interval, QTc, and QTc dispersion were measured on a 12-lead surface electrocardiogram in 60 children and adolescents with stable type 1 diabetes and in 63 sex- and age-matched control subjects. Differences were evaluated by using the Kolmogorov-Smirnov Z test. The number of patients with QTc > 440 ms was compared in the two groups. The possible influence of age, sex, diabetes duration, and glycosylated hemoglobin (HbA(1c)) was examined by using Spearman correlation analysis. RESULTS: Diabetic children had significantly longer QTc intervals and a significantly larger QTc dispersion. The number of individuals with a QTc >440 ms was significantly higher in the diabetic group (14/60) than in the control group (2/63). The effect of age on R-R interval and QTc dispersion in healthy children was less pronounced in children with diabetes. HbA(1C) values did not significantly correlate with any of the parameters. CONCLUSIONS: QTc prolongation and a larger QTc dispersion are already present in a significant proportion of children and adolescents with diabetes.

Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus.

OBJECTIVE: Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. METHODS: Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC. RESULTS: A total of 27 premature infants were included (gestational age, 28.6 +/- 1.9 weeks; birth weight, 1250 +/- 460 g; values are mean +/- standard deviation). Ibuprofen pharmacokinetics followed a 2-compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vd(c)) (0.244 versus 0.171 L/kg; P =.03) and area under the plasma concentration-time curve (524 versus 447 mg. h/L; P =.01). The decrease in Vd(c) was most pronounced in patients with a closing ductus. Total body clearance and plasma half-life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment. CONCLUSION: Ibuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus.

Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome.

OBJECTIVE: To compare efficacy and side effects of early versus late indomethacin treatment for patent ductus arteriosus (PDA) in premature infants. METHODS: One hundred twenty-seven neonates receiving ventilatory assistance (gestational age: 26-31 weeks) with PDA confirmed by echocardiography were randomly assigned in a prospective multicenter trial to either early (day 3, n = 64) or late (day 7, n = 63) intravenous indomethacin treatment (3 x 0.2 mg/kg every 12 hours). Treatment history and side effects were registered. RESULTS: The PDA closure rate was higher in the early treatment group at both 6 (73% vs 44%, P =.0008) and 9 days of age (91% vs 78%, P =.047). However, there was no significant difference in PDA ligation. Urine output was significantly lower (P <.0001), serum creatinine level was higher (P =.016), and more indomethacin courses were administered in the early treatment group (70 vs 26). Respiratory support, number of deaths, and intraventricular hemorrhages were similar in both groups. However, on the whole, major adverse events (death, necrotizing enterocolitis, and/or localized perforation, extension of hemorrhage, or cystic leukomalacia) occurred more frequently in the early treatment group (P =.017). CONCLUSION: Early indomethacin treatment improves PDA closure but is associated with increased renal side effects and more severe complications and has no respiratory advantage over late indomethacin administration in ventilated, surfactant-treated, preterm infants <32 weeks' gestational age.

A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus.

BACKGROUND: Indomethacin is the conventional treatment for hemodynamically important patent ductus arteriosus in preterm infants. However, its use is associated with various side effects. In a prospective study, we compared ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants. METHODS: We studied 148 infants (gestational age, 24 to 32 weeks) who had the respiratory distress syndrome and an echocardiographically confirmed, hemodynamically important patent ductus arteriosus. The infants were randomly assigned at five neonatal intensive care centers to receive three intravenous doses of either indomethacin (0.2 mg per kilogram of body weight, given at 12-hour intervals) or ibuprofen (a first dose of 10 mg per kilogram, followed at 24-hour intervals by two doses of 5 mq per kilogram each), starting on the third day of life. The rate of ductal closure, the need for additional treatment, side effects, complications, and the infants' clinical course were recorded. RESULTS: The rate of ductal closure was similar with the two treatments: ductal closure occurred in 49 of 74 infants given indomethacin (66 percent), and in 52 of 74 given ibuprofen (70 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.17; P=0.41). The numbers of infants who needed a second pharmacologic treatment or surgical ductal ligation did not differ significantly between the two groups. Oliguria occurred in 5 infants treated with ibuprofen and in 14 treated with indomethacin (P=0.03). There were no significant differences with respect to other side effects or complications. CONCLUSIONS: Ibuprofen therapy on the third day of life is as efficacious as indomethacin for the treatment of patent ductus arteriosus in preterm infants with the respiratory distress syndrome and is significantly less likely to induce oliguria.

The addition of indomethacin to betamimetics for tocolysis: any benefit for the neonate?

OBJECTIVE: To study the influence on the neonate of indomethacin administered to the mother as an additional tocolytic. STUDY DESIGN: The neonatal outcome in 76 closely matched low birth weight infants was compared retrospectively: those whose mothers received indomethacin together with betamimetics formed the study group, those whose mothers received only betamimetics formed the control group. RESULTS: There was an increased incidence of respiratory distress syndrome (RDS) in the study group (97% versus 45%; P<0.001), an increased need for surfactant use (68% versus 26%; P<0.001) and increased ventilatory support, and an increased incidence of bronchopulmonary dysplasia (BPD) (47% versus 24%; P=0.03). Gestation could not be prolonged significantly by the addition of indomethacin. CONCLUSION: Indomethacin as an additional tocolytic agent was associated with an increased incidence of RDS, surfactant use and BPD but did not significantly prolong gestation.

Treatment of patent ductus arteriosus with ibuprofen.

AIM: To evaluate the efficiency and side effects of ibuprofen for the early treatment of patent ductus arteriosus (PDA) and compare it with indomethacin. METHODS: Forty preterm infants with gestational ages of less than 33 weeks, with respiratory distress syndrome (RDS) and echocardiographically confirmed PDA, were randomly assigned at days 2 to 3 of life to receive either intravenous indomethacin 3 x 0.2 mg/kg at 12 hour intervals or intravenous ibuprofen 1 x 10 mg/kg, followed by 5 mg/kg 24 and 48 hours later. RESULTS: PDA closed in 15 of 20 patients from the indomethacin group (75%) and in 16 of 20 (80%) from the ibuprofen group. Seven patients (three indomethacin, four ibuprofen) required a second treatment with indomethacin and in five (three in the indomethacin group and two in the ibuprofen group) the duct was ultimately ligated. Ibuprofen patients had a better urinary output and showed no increase in serum creatinine concentrations compared with the indomethacin group. Ibuprofen was not associated with any other side effect. CONCLUSIONS: Ibuprofen treatment seems to be as efficient as indomethacin in closing PDA on the third day of life in preterm infants with respiratory distress syndrome and seems to have fewer renal side effects.

Aspirin versus indomethacin treatment of patent ductus arteriosus in preterm infants with respiratory distress syndrome.

Indomethacin (Indo) is commonly used for treatment of patent ductus arteriosus (PDA) but has renal failure as a main side effect. Aspirin (ASA) is an alternative, but there are no controlled trials on its efficacy. We randomly assigned 75 premature infants suffering from respiratory distress syndrome (RDS) (mean gestational age: 29.6 +/- 2.5 wk, mean birth weight: 1295 +/- 464 g) (+/- SD) and on artificial ventilation at the start of the study (mean: 3.4 d of life), to either Indo (3 x 0.2 mg/kg/12 h) or ASA (4 x 15 mg/kg/6 h). PDA and degree of shunting were evaluated by echocardio-Doppler; side effects were carefully recorded. PDA closed in 35/38 patients from the Indo group (92%) and in 16/37 patients from the ASA group (43%) (p < 0.0001). Nineteen patients needed further treatment with Indo or surgery (17 in the ASA group and 2 in the Indo group). The only side effect observed was a decrease of uresis in the Indo group during 4 d post treatment (p < 0.01). Closing of PDA was positively correlated with gestational age, but not with time of starting Indo/ASA or grade of shunting. We conclude that ASA is not as effective in closing PDA as Indo, but has no adverse effect on uresis.

Clinical experience with ceftriaxone treatment in the neonate.

The safety of ceftriaxone has been evaluated in 80 neonates who were treated empirically for suspected infection with either ceftriaxone and ampicillin (group A, age 0-72 h) or ceftriaxone and vancomycin (group B, age greater than 72 h). Within 48 h after birth 2 group A patients died from sepsis (Haemophilus influenzae, Streptococcus pneumoniae, 1 case each); 1 group B patient died from sepsis (Pseudomonas aeruginosa). All bacterial isolates from group A patients were susceptible to ceftriaxone, but in 4 of the 8 group B patients with positive cultures a change in antibiotic therapy was required. Eosinophilia, thrombocytosis and an increase in serum alkaline phosphatases were observed in a limited number of patients during and after discontinuation of treatment. Direct hyperbilirubinemia ( > 2 mg/dl) occurred in 2 cases during treatment. Gallbladder sludge was sonographically diagnosed in 6 patients, but disappeared within 2 weeks after detection. One neonate had exanthema. Nurses rated ease of administration as very good. Ceftriaxone appears to be an interesting alternative in the empiric antibiotic treatment in the early neonatal period.

A pseudoepidemic of adenoviruses in a neonatal care unit.

A number of stool samples from a neonatal intensive care unit reacted in a latex agglutination test (LAT) for adenoviruses. However, the majority of these babies had no symptoms. Virus particles were not visualized by electron microscopy, whereas the results of ELISAs and stool cultures in appropriate cell lines remained negative. The episode was interpreted as a pseudoepidemic. The LAT for adenoviruses is not suited for the examination of stools from very young babies.

Neonatal outcome after very prolonged and premature rupture of membranes.

Very premature and prolonged rupture of the membranes (VPPROM) for at least 5 days is associated with an increased incidence of perinatal infection and lung hypoplasia. There is, however, limited information about outcome of premature neonates born after VPPROM uncomplicated by oligohydramnios. The present study compared the outcome, in three categories of neonates born before 34 weeks gestation: group I, VPPROM without oligohydramnios (n = 28); group II, VPPROM with oligohydramnios (n = 14); and group III, the comparison group without VPPROM (n = 39). Mortality in group I (2 of 28) was similar to that in group III (6 of 39) and was lower than that in group II (5 of 14). Lung hypoplasia and limb deformities were not more frequent in group I than in group III (2 of 28 and 0 of 28 versus 3 of 39 and 1 of 39, respectively) but occurred more frequently only in group II (5 of 14 and 4 of 14). All deaths in groups I and II were accounted for by lung hypoplasia. There was no difference between the groups for asphyxia, (respiratory distress syndrome, air leaks, bronchopulmonary dysplasia, or intracranial bleeding. Neonatal infection was more frequent in group I (4 of 14, 28.6%) and group II (7 of 28, 25%) when compared with group III (2 of 39, 5%). Within groups I and II rupture of the membranes was not more prolonged in the neonates with infection (median, 9.7 days) compared with the neonates without infection (median, 9.6 days). In conclusion, when VPPROM is not complicated by oligohydramnios, mortality, lung hypoplasia, and limb deformities are not more frequent than in control neonates of similar gestational age. As shown by others, the present data support the fact that VPPROM is associated with an increased risk of perinatal infection, but this is not responsible for the poor outcome.

Syndromic association of cleft palate, bilateral choanal atresia, curly hair, and congenital hypothyroidism.

We describe a patient with the unusual association of cleft palate, bilateral choanal atresia, curly hair, and congenital hypothyroidism. This association has been reported before in two brothers and may represent a new syndrome.

The use of intravenously administered immunoglobulins in the prevention of severe infection in very low birth weight neonates.

In a randomized prospective study in 116 selected neonates with very low birth weight, the effect of standard doses of intravenously administered immunoglobulins (IVIG) on the occurrence of severe infections was studied. No difference in infection rate or severity of infection could be observed between the treated neonates and the control group. The lack of effect could not be explained by an insufficient increase in the IgG serum levels, or inversely, by high immunosuppressive IgG levels. It is concluded that in very low birth weight neonates the administration of IVIG, under the conditions used in this investigation, does not protect against severe infection.