Variations in medical practice of retinopathy of prematurity among 8 Asian countries from an international survey.

Advances in perinatal care have led to the increased survival of preterm infants with subsequent neonatal morbidities, such as retinopathy of prematurity (ROP). This study aims to compare the differences of neonatal healthcare systems, resources, and clinical practice concerning ROP in Asia with review of current literature. An on-line survey at the institutional level was sent to the directors of 336 neonatal intensive care units (NICU) in 8 collaborating national neonatal networks through the Asian Neonatal Network Collaboration (AsianNeo). ROP screening was performed in infants born at < 34 weeks in Indonesia and Japan. In South Korea, Malaysia, and Taiwan, most screened for ROP in infants born at < 32 weeks. In all networks, majority of NICUs conducted ROP screening to infants with birth weight < 1500 g. In most NICU's in-hospital ophthalmologists performed indirect ophthalmoscopy and some were supplemented with digital imaging. Both laser photocoagulation and anti-vascular endothelial growth factor injection are performed for treatment and, vitreous surgeries are conducted less frequently in all countries. Despite limited information collected by the survey, this first study to compare ROP practices implemented in eight Asian countries through AsianNeo will enable an understanding of the differences and facilitate quality improvement by sharing better practices.

Perinatal Hemolytic Disorders and Identification Using End Tidal Breath Carbon Monoxide.

Hemolytic disorders can cause severe morbidity or can be life-threatening. Before the recent development of practical and inexpensive testing for hemolysis by quantifying carbon monoxide in end-tidal breath, some hemolytic disorders in perinatal patients were not detected until severely problematic hyperbilirubinemia and/or anemia occurred. Here we review studies aimed at establishing the normal reference intervals for end tidal breath carbon monoxide (ETCO) in various perinatal populations. We also review reports, and new theories, about using this methodology to diagnose and quantify hemolytic disorders in term and premature neonates, anemic pregnant women, and fetuses in utero. The purposes of making these measurements are to; (1) identify patients who have hemolytic disorders, (2) characterize the severity of the hemolysis in each hemolytic patient, and (3) predict and prevent co-morbidities, thereby improving outcomes.

How Does Human Milk Protect Against Necrotizing Enterocolitis (NEC)? Targeted Validation and Time-Course Analysis of 35 Gene Responses as NEC-Signature in Fetal Intestinal Epithelial Cells.

Breastfeeding reduces the risk of necrotizing enterocolitis (NEC), one of the most common causes of morbidity and mortality in preterm infants. However, the molecular substrates by which human milk (HM) offers protection against NEC are not well known. Using fetal intestinal epithelial cells treated with known NEC aggravators, namely lipopolysaccharide (LPS) and platelet-activating factor (PAF), we mapped the time-course of changes in targeted expression analysis of 35 NEC-associated genes, so-called the NEC signature. We found, first, that HM treatment fully rescued LPS/PAF-induced fetal intestinal cell death at 12 and 24 h (n = 5). Differential gene expression and bioinformatics revealed that HM did not mitigate inflammatory and cell death signals, but instead promoted cell proliferation and stress response pathways to mitigate LPS/PAF-induced inflammatory cell death. From this, epidermal growth factor (EGF) synthesis emerged as the central player in rescue of the fetal intestinal cell death. Functional validation was supported by reversal of the cellular rescue by HM following EGF knockdown by small interfering RNA. In conclusion, this study suggests that HM might offer protection against NEC through enhancing intestinal EGF production to rescue the inflammatory cell death. Future studies are warranted to verify these HM molecular protective effects in NEC models in vivo. The findings reported herein also support future research avenues to discover new therapeutics to boost intrinsic EGF production in the injured intestinal tissues in neonates with NEC, for example, by bioactive components in human milk, natural compounds, or small molecules.

Reference intervals for end-tidal carbon monoxide of preterm neonates.

OBJECTIVES: We constructed reference intervals for end-tidal carbon monoxide (ETCOc) levels of neonates 28 0/7 to 34 6/7 weeks gestation in order to assess hemolytic rate. STUDY DESIGN: This is a prospective four-NICU study in Bangkok, Thailand, and Utah, USA. RESULTS: Of 226 attempted measurements, 92% were successful. Values from day 1 through 28 were charted and upper (>95th percentile) reference interval limits calculated. During the entire 28 days, the ETCOc upper reference intervals from babies in Bangkok were higher than those in Utah (p < 0.01). No differences were found due to sex, or earliest vs. latest gestation at birth (both p > 0.1). Similar to term neonates, preterm neonates in Bangkok and Utah had higher ETCOc values during the first 48 h after birth than thereafter (p < 0.01). CONCLUSIONS: Using this methodology, and the reference interval chart, the hemolytic rate of preterm infants ≥28 weeks can be assessed.

HMP-S7 Is a Novel Anti-Leukemic Peptide Discovered from Human Milk.

Chemotherapy in childhood leukemia is associated with late morbidity in leukemic survivors, while certain patient subsets are relatively resistant to standard chemotherapy. It is therefore important to identify new agents with sensitivity and selectivity towards leukemic cells, while having less systemic toxicity. Peptide-based therapeutics has gained a great deal of attention during the last few years. Here, we used an integrative workflow combining mass spectrometric peptide library construction, in silico anticancer peptide screening, and in vitro leukemic cell studies to discover a novel anti-leukemic peptide having 3+ charges and an alpha helical structure, namely HMP-S7, from human breast milk. HMP-S7 showed cytotoxic activity against four distinct leukemic cell lines in a dose-dependent manner but had no effect on solid malignancies or representative normal cells. HMP-S7 induced leukemic cell death by penetrating the plasma membrane to enter the cytoplasm and cause the leakage of lactate dehydrogenase, thus acting in a membranolytic manner. Importantly, HMP-S7 exhibited anti-leukemic effects against patient-derived leukemic cells ex vivo. In conclusion, HMP-S7 is a selective anti-leukemic peptide with promise, which requires further validation in preclinical and clinical studies.

Fetal Intestinal Cell Growth as a Measure of the Comparative Biofunctionality of Human Milk and Infant Formulas: An In Vitro Study.

BACKGROUND: Infant formulas are produced to resemble human milk (HM) and to provide adequate energy and appropriate nutritional components for suitability of infant growth and development, some of which are customized for specific medical conditions. However, it has remained unclear whether formulas contain any biofunctionality equivalent to HM, particularly fetal intestinal cell growth promotion. OBJECTIVE: To evaluate the biofunctionality in HM and various formulas by using an in vitro fetal intestinal cell growth assay. MATERIALS AND METHODS: Nine specimens of HM collected from 9 milk donors and 16 formulas consisting of 5 regular formulas (RFs), 2 preterm formulas (PFs), 2 partial hydrolysate formulas (PHFs), 3 extensive hydrolysate formulas (EHFs), 2 amino acid formulas (AAFs), and 2 soy protein formulas (SPFs) were included. Fetal intestinal cell growth assay was performed in six replicates per milk specimen. Biofunctionality of HM digest (HMD) derived from in vitro tryptic digestion of HM was also examined. Statistical analysis was performed by ANOVA with post-hoc Tukey's Honestly Significant Difference test. RESULTS: The fetal intestinal cell growth-promoting activity of HM and formula groups were sorted from the highest as follows: HM, 192.8% ± 16.7%; AAF, 153.5% ± 17.8%; EHF, 149.4% ± 12.5%; RF, 123.5% ± 14.2%; PHF, 111.2% ± 17.9%; PF, 110.3% ± 8.2%; and SPF, 109.3% ± 17.3%. Statistical analysis showed that growth promotion of HM was significantly higher than that of all examined formulas (p < 0.0001). Among formulas, EHF and AAF showed greater growth-promoting activity than the others (p < 0.0001). HM and HMD had a comparable growth-promoting effect on fetal intestinal cells (198.5% ± 27.9% versus 191.2% ± 17.9%, p = 0.724), supporting the potential impact of HM biofunctionality under physiologic gastrointestinal digestion. CONCLUSIONS: Our data suggested that formulas are not equivalent to HM in respect of fetal intestinal cell growth biofunctionality. Despite having less activity than HM, EHF and AAF exhibited considerable levels of growth-promoting effect that may have clinical implications, especially when HM is unavailable.

Evaluation of Fetal Intestinal Cell Growth and Antimicrobial Biofunctionalities of Donor Human Milk After Preparative Processes.

BACKGROUND: Donor human milk is considered the next best nutrition following mother's own milk to prevent neonatal infection and necrotizing enterocolitis in preterm infants who are admitted at neonatal intensive care unit. However, donor milk biofunctionalities after preparative processes have rarely been documented. OBJECTIVE: To evaluate biofunctionalities preserved in donor milk after preparative processes by cell-based assays. MATERIALS AND METHODS: Ten pools of donor milk were produced from 40 independent specimens. After preparative processes, including bacterial elimination methods (holder pasteurization and cold-sterilization microfiltration) and storage conditions (-20°C freezing storage and lyophilization) with varied duration of storage (0, 3, and 6, months), donor milk biofunctionalities were examined by fetal intestinal cell growth and antimicrobial assays. RESULTS: At baseline, raw donor milk exhibited 193.1% ± 12.3% of fetal intestinal cell growth and 42.4% ± 11.8% of antimicrobial activities against Escherichia coli. After bacteria eliminating processes, growth promoting activity was better preserved in pasteurized donor milk than microfiltrated donor milk (169.5% ± 14.3% versus 146.0% ± 11.8%, respectively; p < 0.005), whereas antimicrobial activity showed no difference between groups (38.3% ± 14.1% versus 53.7% ± 17.3%, respectively; p = 0.499). The pasteurized donor milk was further examined for the effects of storage conditions at 3 and 6 months. Freezing storage, but not lyophilization, could preserve higher growth-promoting activity during 6 months of storage (163.0% ± 9.4% versus 72.8% ± 6.2%, respectively; p < 0.005). Nonetheless, antimicrobial activity was lost at 6 months, regardless of the storage methods. CONCLUSIONS: This study revealed that fetal intestinal cell growth and antimicrobial assays could be applied to measure donor milk biofunctionalities and support the utilization of donor milk within 3 months after preparative processes.

Health-care professionals' approach in feeding term small-for-gestational age infants and its potential implications to later growth outcomes.

AIM: To understand feeding practices, nutrition management and postnatal growth monitoring of term small-for-gestational age (tSGA) infants in Southeast Asia. METHODS: Anonymous questionnaires to assess practices on feeding, nutrition management and post-natal growth monitoring of tSGA infants were distributed among health-care professionals (HCPs) participating in regional/local perinatology symposia in Malaysia, Thailand and Singapore. RESULTS: Three hundred seventy-seven respondents from Malaysia (37%), Thailand (27%), Singapore (18%) and other Asian countries (19%) participated in the survey. Respondents were neonatologists (35%), paediatricians (25%) and other HCPs (40%) including nurses and midwives. Exclusive human milk feeding was reported the most preferred feeding option for tSGA infants, followed by fortified human milk feeding (60% and 20%, respectively). This was consistent among the different countries. The perceived nutrient requirements of tSGA infants varied between countries. Most respondents from Malaysia and Singapore reported requirements to be similar to preterm infants, while the majority from Thailand reported that it was less than those of preterm infants. The World Health Organization Growth Chart of 2006 and Fenton Growth Charts of 2013 were the most frequently used charts for growth monitoring in the hospital and after discharge. CONCLUSIONS: Nutrition management and perceived nutrient requirements for tSGA infants among practising HCPs in Southeast Asia showed considerable variation. The impetus to form standardised and evidence based feeding regimens is important as adequate nutritional management and growth monitoring particularly in this population of infants will have long term impact on population health.

Cow milk protein allergy presenting as feeding intolerance and eosinophilia: case reports of three preterm neonates.

Three preterm infants with cow milk protein allergy (CMPA) presented with feeding intolerance, sepsis-like episodes and persistent moderate-to-severe eosinophilia. After eliminating cow milk, the clinical symptoms improved significantly. CMPA can cause common manifestations in sick preterm infants such as feeding intolerance and eosinophilia.

Cow milk protein allergy presenting as feeding intolerance and eosinophilia: case reports of three preterm neonates.

Three preterm infants with cow milk protein allergy (CMPA) presented with feeding intolerance, sepsis-like episodes and persistent moderate-to-severe eosinophilia. After eliminating cow milk, the clinical symptoms improved significantly. CMPA can cause common manifestations in sick preterm infants such as feeding intolerance and eosinophilia.

Current information and Asian perspectives on long-chain polyunsaturated fatty acids in pregnancy, lactation, and infancy: systematic review and practice recommendations from an early nutrition academy workshop.

The Early Nutrition Academy supported a systematic review of human studies on the roles of pre- and postnatal long-chain polyunsaturated fatty acids (LC-PUFA) published from 2008 to 2013 and an expert workshop that reviewed the information and developed recommendations, considering particularly Asian populations. An increased supply of n-3 LC-PUFA during pregnancy reduces the risk of preterm birth before 34 weeks of gestation. Pregnant women should achieve an additional supply ≥200 mg docosahexaenic acid (DHA)/day, usually achieving a total intake ≥300 mg DHA/day. Higher intakes (600-800 mg DHA/day) may provide greater protection against early preterm birth. Some studies indicate beneficial effects of pre- and postnatal DHA supply on child neurodevelopment and allergy risk. Breast-feeding is the best choice for infants. Breast-feeding women should get ≥200 mg DHA/day to achieve a human milk DHA content of ∼0.3% fatty acids. Infant formula for term infants should contain DHA and arachidonic acid (AA) to provide 100 mg DHA/day and 140 mg AA/day. A supply of 100 mg DHA/day should continue during the second half of infancy. We do not provide quantitative advice on AA levels in follow-on formula fed after the introduction of complimentary feeding due to a lack of sufficient data and considerable variation in the AA amounts provided by complimentary foods. Reasonable intakes for very-low-birth weight infants are 18-60 mg/kg/day DHA and 18-45 mg/kg/day AA, while higher intakes (55-60 mg/kg/day DHA, ∼1% fatty acids; 35-45 mg/kg/day AA, ∼0.6-0.75%) appear preferable. Research on the requirements and effects of LC-PUFA during pregnancy, lactation, and early childhood should continue. © 2014 S. Karger AG, Basel.

Intestinal mucosal defense system, Part 1. Consensus recommendations for immunonutrients.

When microbial communities colonize in the developing intestinal tract after birth, microorganisms interact with specific apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inflammatory cytokines, thus providing protection from pathogen-induced mucosal damage. Multiple immune modulatory factors in human milk and innate humoral factors also control inflammatory responses, providing additional protective effects. Our understanding of the role of the luminal microbial communities or microbiota is growing rapidly as novel technologies provide new insights into their taxonomy, function during early development, and impact on life-long health. Multiple studies have evaluated the effects of the specific nutrients, glutamine, arginine, nucleotides, polyunsaturated fatty acids, and lactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to modulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is yet known to design specific clinical care practices that support a healthy microbiota.

Intestinal mucosal defense system, Part 2. Probiotics and prebiotics.

The interplay between microorganisms and the intestine of newborn infants is associated with diverse functional and clinical outcomes that result from the specific interactions among microbial communities, their products, and the unique characteristics of the gastrointestinal tract. Multiple mechanisms of action for infant formula ingredients with probiotic activity appear to exist. These mechanisms are thought to protect the host not only from intestinal diseases but also from systemic infection. However, questions about the safety of probiotics for preterm infants remain unanswered, particularly with regard to sepsis, immunomodulatory effects, and microbial resistance. Few well-designed studies have been conducted to evaluate the effects of probiotic, prebiotic, and synbiotic ingredients on relevant clinical outcomes in preterm infants. Although existing data are encouraging, there is insufficient evidence to recommend the routine use of these ingredients in all preterm infants.

Nonketotic hyperglycinemia in two siblings with neonatal seizures.

Seizures are a common problem in neonates. Differential diagnoses include infection, trauma, hypoxia and congenital metabolic disorders. Among these, congenital metabolic disorder is less familiar to general pediatricians. We report two patients with nonketotic hyperglycinemia (NKH), a rare and lethal congenital metabolic disease. Transient hyperammonemia and transient hypouricemia, uncommon features found in NKH, were detected in one patient. High doses of sodium benzoate and dextromethorphan failed to modify the clinical course. Neuropathology denoted characteristic diffuse vacuolization and changes in reactive and gliotic astrocytes. The clinical course, biochemical findings, diagnostic approaches and diagnostic tests are discussed in detail. Recent modalities of treatment are reviewed. Because of its rarity and rapidly progressive course, it maybe underdiagnosed resulting in death before being recognized. Awareness of the possibility of congenital metabolic disorder in early neonatal catastrophe will increase the diagnostic rate.

The use of recombinant activated factor VII to control bleeding in a preterm infant undergoing exploratory laparotomy.

The case of a preterm infant weighing 1120 g who successfully received recombinant activated factor VII (rFVIIa) without complication for control of a life-threatening bleeding event resulting from a ruptured umbilical artery is reported. After performing an exploratory laparotomy at 27 hours of age, hemorrhage from the surgical wound and various sites persisted. By 63 hours of age, the infant had received a total of 192 mL (171 mL/kg) of packed red blood cells, 115 mL (103 mL/kg) of fresh frozen plasma, 8 mL of cryoprecipitate, and 75 mL (67 mL/kg) of platelet concentrate without stabilization. Hemorrhage ceased after 2 doses of 40 microg/kg/dose recombinant activated factor VII given at 63 and 70 hours of age, with subsequent stabilization of the hematocrit and without need for additional transfusion therapy.

Oral erythromycin for treatment of feeding intolerance in preterm infants: a preliminary report.

UNLABELLED: Feeding intolerance is a common problem in preterm infants resulting in a prolonged hyperalimentation which is associated with an increased risk of serious and sometimes even life threatening complications, including cholestasis jaundice, liver impairment, nutritional deficiency, biochemical rickets and catheter-related septicaemia. Erythromycin, a commonly used macrolide antibiotic, has been reported as having potent prokinetic properties and enhancing gastrointestinal motor activity. The authors, therefore, conducted a preliminary study of oral erythromycin for the treatment of feeding intolerance in preterm infants to evaluate the safety and efficacy of this drug. AIM: To evaluate the safety and efficacy of oral erythromycin as a prokinetic agent in promoting enteral feeding in preterm infants with feeding intolerance. METHOD: Preterm infants, gestational age (GA) < or = 36 wk, who met the feeding intolerance criteria, were enrolled in the study. Inclusion criteria included infants who received enteral feeding less than half of full feeding or less than 75 ml/kg/day by day 14 post-natal age or gastric residual > or = 50 per cent of a given amount of feeding, more than 2 consecutive feeds by day 7 post-natal age. All patients received oral erythromycin ethylsuccinate 12 mg/kg every six hours for 2 days, then 3 mg/kg every six hours for 5 days. The times taken to establish full enteral feeding after the drug treatment and time to stop hyperalimentation were recorded. Potential adverse effects of erythromycin were assessed. Response to treatment was defined as decreased gastric residual < 30 per cent of a similar amount of the previous feed and was able to continue to full feeding. RESULTS: Ten preterm infants were enrolled in this study with a mean GA of 30.8 weeks (26-35), mean birth weight of 1,489 g (range 900-2,560 g) and mean age at entry of 9.2 days (range 7-12 days). Nine of 10 infants responded to treatment within 24 hours. The average time to establish full enteral feeding after the drug treatment was 6.6 days (range 4-10 days). None of the infants developed adverse effects such as vomiting, diarrhea, or pyloric stenosis. CONCLUSION: The preliminary data indicates that oral erythromycin is effective and safe in facilitating enteral feeding in preterm infants with feeding intolerance. Infants can achieve full feeding within a week after treatment, and this may shorten the course of hyperalimentaiton. Further randomized controlled trials are warranted.

Vitamin A status in premature infants.

BACKGROUND: Premature infants are at risk of vitamin A deficiency due to inadequate transplacental transport, inadequate storage and increased tissue utilization. Previous studies reported a significant decrease in serum vitamin A levels in premature infants at birth compared to those of full term infants. OBJECTIVE: To determine serial changes of plasma vitamin A status during the first month of life in 19 healthy, very low birth weight premature infants. METHOD: Subjects were fed with premature infant formula and received multivitamin supplementation. Plasma vitamin A concentrations were measured at 7, 14, and 30 days of age. RESULTS: Plasma vitamin A levels at 7,14 and 30 days of age were 24.63 +/- 6.08, 30.97 +/- 5.26 and 30.68 +/- 7.14 microg/dl, respectively. Plasma vitamin A levels at age 7 days were significantly lower than those at 14 and 30 days of life (p < 0.001). Three infants out of 19 (16%) had low plasma vitamin A (<20 microg/dl) at 7 days. At 14 and 30 days of age, all infants had normal plasma vitamin A levels. CONCLUSION: The results suggested that healthy premature infants were prone to subclinical vitamin A deficiency during the first week of life which could be treated by adequate enteral feeding and routine multivitamin supplementation. A high dose of vitamin A supplementation was not necessary in healthy premature infants.

Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital.

BACKGROUND: Ibuprofen given intravenously to premature newborn infants is a proven treatment for patent ductus arteriosus (PDA). The efficacy of ibuprofen is comparable to indomethacin in many clinical trials with fewer renal side effects. However, the intravenous form of ibuprofen is not available in Thailand, whereas, the oral suspension form is widely used for antipyretic treatment in children. Therefore, the authors investigated the possibilities of using oral ibuprofen for the treatment of PDA in premature newborn infants. OBJECTIVE: To assess whether oral ibuprofen at 10 mg/kg/dose daily for 3 days was as effective as indomethacin to treat symptomatic PDA in premature infants and to compare the side effects of oral ibuprofen to indomethacin. SUBJECTS AND METHOD: Eighteen premature infants with gestational ages less than 34 weeks born at Ramathibodi Hospital who developed symptomatic PDA were randomly assigned to receive three doses of either indomethacin (oral or intravenous administration 0.2 mg/kg/dose for three doses given at 12 hourly intervals or oral ibuprofen (10 mg/kg/dose for three doses given at 24 hourly intervals). The rates of ductal closure, infants' clinical courses, side effects and complications were recorded. RESULTS: Birth weight, gestational age, gender, age onset and number of infants who had respiratory distress syndrome were similar in both groups, PDA was closed in 7 of 9 infants given ibuprofen (78%) and in 8 of 9 infants given indomethacin (89%) (p > 0.05). The mean plasma concentration of ibuprofen was 28.05 microg/ml at 1 hour after the third dose. Neonates in the ibuprofen group had more urine output. However, the increment of serum BUN and creatinine were not significantly different in both groups. There were no significant differences in duration of ventilator support as well as number of patients with bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis and death in both groups. CONCLUSION: Oral ibuprofen therapy is as effective as indomethacin for the treatment of PDA in premature infants and seems to have fewer renal side effects.