Milk Curd Obstruction in Human Milk-Fed Preterm Infants.

BACKGROUND: Milk curd obstruction as a cause of intestinal obstruction has been known since 1959, but has nearly disappeared. However, in recent years it has experienced a revival in small premature infants. OBJECTIVE: The aim of this study was to evaluate the clinical characteristics of milk curd obstruction (lactobezoar) in preterm infants. METHODS: Data of preterm infants with milk curd obstruction cared for at a large tertiary neonatal intensive care unit between 2012 and 2016 were retrieved from the electronic registry and paper records. RESULTS: A total of 10 infants (2 girls, 8 boys) were identified: the median birth weight was 595 g (range 270-922), gestational age was 24.4 weeks (23.4-27.0), weight-for-gestational age percentile was 16 (0-62), and age at diagnosis was 28 days (16-64). Five infants (50%) were small for gestational age. All neonates had received fortified human milk (added protein 2.0 g/100 mL, range 0-2.8; added calcium 2,400 µmol/100 mL, range 0-6 844; added phosphate 2,400 µmol/100 mL, range 0-5,178). Seven neonates underwent surgery, and 2 infants died. Hyperechoic masses in extended bowel loops, visualised by abdominal ultrasound, and pale/acholic faeces were hallmarks of milk curd obstruction. CONCLUSIONS: In this study, milk curd obstruction occurred exclusively in infants with a birth weight < 1,000 g (2.2%) and < 28 weeks' gestational age (2.4%). Male and small for gestational age infants appeared to be at increased risk. Paying attention to the colour of the faeces of infants at risk might help to diagnose milk curd obstruction at an early stage.

Maternal overweight is not an independent risk factor for increased birth weight, leptin and insulin in newborns of gestational diabetic women: observations from the prospective 'EaCH' cohort study.

BACKGROUND: Both gestational diabetes mellitus (GDM) as well as overweight/obesity during pregnancy are risk factors for detrimental anthropometric and hormonal neonatal outcomes, identified to 'program' adverse health predispositions later on. While overweight/obesity are major determinants of GDM, independent effects on critical birth outcomes remain unclear. Thus, the aim of the present study was to evaluate, in women with GDM, the relative/independent impact of overweight/obesity vs. altered glucose metabolism on newborn parameters. METHODS: The prospective observational 'Early CHARITÉ (EaCH)' cohort study primarily focuses on early developmental origins of unfavorable health outcomes through pre- and/or early postnatal exposure to a 'diabetogenic/adipogenic' environment. It includes 205 mother-child dyads, recruited between 2007 and 2010, from women with treated GDM and delivery at the Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, Germany. Recruitment, therapy, metabolite/hormone analyses, and data evaluation were performed according to standardized guidelines and protocols. This report specifically aimed to identify maternal anthropometric and metabolic determinants of anthropometric and critical hormonal birth outcomes in 'EaCH'. RESULTS: Group comparisons, Spearman's correlations and unadjusted linear regression analyses initially confirmed that increased maternal prepregnancy body-mass-index (BMI) is a significant factor for elevated birth weight, cord-blood insulin and leptin (all P < 0.05). However, consideration of and adjustment for maternal glucose during late pregnancy showed that no maternal anthropometric parameter (weight, BMI, gestational weight gain) remained significant (all n.s.). In contrast, even after adjustment for maternal anthropometrics, third trimester glucose values (fasting and postprandial glucose at 32nd and 36th weeks' gestation, HbA1c in 3rd trimester and at delivery), were clearly positively associated with critical birth outcomes (all P < 0.05). CONCLUSIONS: Neither overweight/obesity nor gestational weight gain appear to be independent determinants of increased birth weight, insulin and leptin. Rather, 3rd trimester glycemia seems to be crucial for respective neonatal outcomes. Thus, gestational care and future research studies should greatly consider late pregnancy glucose in overweight/obese women with or without GDM, for evaluation of critical causes and interventional strategies against 'perinatal programming of diabesity' in the offspring.

Starter formula enriched in prebiotics and probiotics ensures normal growth of infants and promotes gut health: a randomized clinical trial.

This corrects the article DOI: 10.1038/pr.2016.270.

Starter formula enriched in prebiotics and probiotics ensures normal growth of infants and promotes gut health: a randomized clinical trial.

BACKGROUND: Prebiotics and probiotics exert beneficial effects by modulating gut microbiota and immune system. This study evaluates efficacy and safety of an infant formula containing bovine milk-derived oligosaccharides and Bifidobacterium animalis ssp lactis (B. lactis) (CNCM I-3446) on incidence of diarrhea and febrile infections during the first year of life (primary outcome). METHODS: Full-term infants receiving Test or Control (without bovine milk-derived oligosaccharide and B. lactis) formulae were enrolled in a multicenter, randomized, controlled, and double-blind trial with a reference breastfeeding group. . RESULTS: 413 infants were assigned between Test (n = 206) and Control (n = 207) formula. There was no significant difference for diarrhea and febrile infections incidence between groups at 6 (odds ratio (95% confidence interval) = 0.56 (0.26-1.15), P = 0.096) and 12 mo (odds ratio = 0.66 (0.38-1.14), P = 0.119). Test formula was well tolerated, anthropometrics parameters were not significantly different between groups and aligned with WHO growth standards up to 12 mo. Data from test group showed that gut microbiota pattern, fecal IgA and stool pH were brought to be closer to those of breastfed infants. CONCLUSION: An infant formula enriched with bovine milk-derived oligosaccharide and B. lactis supports normal infant growth, is well tolerated and improves intestinal health markers. No differences in diarrhea and febrile infection incidence were found in the population studied.

Effect of vitamin A supplementation on the urinary retinol excretion in very low birth weight infants.

UNLABELLED: Despite high-dose vitamin A supplementation of very low birth weight infants (VLBW, <1500 g), their vitamin A status does not improve substantially. Unknown is the impact of urinary retinol excretion on the serum retinol concentration in these infants. Therefore, the effect of high-dose vitamin A supplementation on the urinary vitamin A excretion in VLBW infants was investigated. Sixty-three VLBW infants were treated with vitamin A (5000 IU intramuscular, 3 times/week for 4 weeks); 38 untreated infants were classified as control group. On days 3 and 28 of life, retinol, retinol-binding protein 4 (RBP4), glomerular filtration rate, proteinuria, and Tamm-Horsfall protein were quantified in urine. On day 3 of life, substantial retinol and RBP4 losses were found in both groups, which significantly decreased until day 28. Notwithstanding, the retinol excretion was higher (P < 0.01) under vitamin A supplementation as compared to infants of the control group. On day 28 of life, the urinary retinol concentrations were predictive for serum retinol concentrations in the vitamin A treated (P < 0.01), but not in the control group (P = 0.570). CONCLUSION: High urinary retinol excretion may limit the vitamin A supplementation efficacy in VLBW infants. Advanced age and thus postnatal kidney maturation seems to be an important contributor in the prevention of urinary retinol losses.

The relative dose response test based on retinol-binding protein 4 is not suitable to assess vitamin A status in very low birth weight infants.

BACKGROUND: The relative dose response (RDR) test, which quantifies the increase in serum retinol after vitamin A administration, is a qualitative measure of liver vitamin A stores. Particularly in preterm infants, the feasibility of the RDR test involving blood is critically dependent on small sample volumes. OBJECTIVES: This study aimed to assess whether the RDR calculated with retinol-binding protein 4 (RBP4) might be a substitute for the classical retinol-based RDR test for assessing vitamin A status in very preterm infants. METHODS: This study included preterm infants with a birth weight below 1,500 g (n = 63, median birth weight 985 g, median gestational age 27.4 weeks) who were treated with 5,000 IU retinyl palmitate intramuscularly 3 times a week for 4 weeks. On day 3 (first vitamin A injection) and day 28 of life (last vitamin A injection), the RDR was calculated and compared using serum retinol and RBP4 concentrations. RESULTS: The concentrations of retinol (p < 0.001) and RBP4 (p < 0.01) increased significantly from day 3 to day 28. On day 3, the median (IQR) retinol-RDR was 27% (8.4-42.5) and the median RBP4-RDR was 8.4% (-3.4 to 27.9), compared to 7.5% (-10.6 to 20.8) and -0.61% (-19.7 to 15.3) on day 28. The results for retinol-RDR and RBP4-RDR revealed no significant correlation. The agreement between retinol-RDR and RBP4-RDR was poor (day 3: Cohen's κ = 0.12; day 28: Cohen's κ = 0.18). CONCLUSION: The RDR test based on circulating RBP4 is unlikely to reflect the hepatic vitamin A status in preterm infants.

Growth of very low birth weight infants after increased amino acid and protein administration.

AIM: To assess the impact of a high enteral protein nutrition strategy in human milk-fed very low birth weight (VLBW) infants (<1500 g) on growth during the first 5 weeks of life. DESIGN: Weight, length and head circumference of VLBW infants were recorded after introduction of a high protein strategy. RESULTS: Forty-three infants (median/interquartile range) of gestational age 27+6 weeks (26+0/29+6), birth weight 984 g (675/1130) were included. Parenteral nutrition was administered for 16 (14/18) days and the nutritional intakes achieved target values 4.3 g/kg/day protein (4.0/4.4); 128 kcal/kg/day energy (119/131). Human milk was fortified with 0.5-2.3 g/kg/day protein powder in addition to a fortifier. Near-intrauterine growth was observed: Weight gain from days 8-35: 17.6 g/kg/day (14.9/20.5); head growth from day 1-35: 0.70 cm/week (0.50/0.80); length growth from day 1-35: 1.0 cm/week (0.8/1.2). The total protein intake was shown to have a significant impact on infant's weight gain up to the 35th day of life. CONCLUSION: High protein nutrition enables similar to fetal growth weight gain and head growth of VLBW infants during the first 5 weeks of life. These data support recently published ESPGHAN recommendations.

Vascular Endothelial Growth Factor (VEGF) and soluble VEGF receptor 1 (sFlt-1) levels in early and mature human milk from mothers of preterm versus term infants.

BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors regulate angiogenesis (formation of blood vessels). The soluble VEGF receptor 1 (sFlt-1) binds VEGF as a potent antagonist. OBJECTIVE: The objective of this study was to compare VEGF and sFlt-1 levels in milk from mothers of preterm (n = 50) versus term (n = 49) infants in a longitudinal study. METHODS: Milk samples were collected on days 3 and 28 of lactation. Vascular endothelial growth factor and sFlt-1 were quantified by sandwich-type enzyme-linked immunosorbent assay. RESULTS: Vascular endothelial growth factor and sFlt-1 were found in high concentrations in early milk (lactation day 3) from mothers of preterm and term infants and were lower in mature milk (lactation day 28). On day 3, median VEGF concentration was lower in preterm than in term milk (37.1 vs 53.9 ng/mL, P < .01). Otherwise, VEGF (day 28) and sFlt-1 (days 3 and 28) did not differ in preterm versus term milk. CONCLUSIONS: It was shown for the first time that sFlt-1 is present in human milk. Early human milk contains high concentrations of VEGF and sFlt-1, which decrease over the course of lactation.

Leptin determination in colostrum and early human milk from mothers of preterm and term infants.

BACKGROUND: Leptin is involved in the regulation of food intake and energy expenditure and is therefore important for growth and brain development. Analytical methods used for leptin measurement in human milk differ widely in the literature and yield varying results. AIMS: To compare different preparation methods for the analysis of leptin in human milk and to investigate the leptin levels in colostrum and mature human milk from mothers of preterm or term infants. METHODS: Mothers delivering a preterm (n=37) or a term infant (n=40) were recruited for a prospective study and were ask to collect breast milk on the 3rd and 28th day of lactation. Leptin, protein and fat concentrations were analysed. Clinical data of mother and child were recorded prospectively. RESULTS: Skim milk was most appropriate for leptin analysis. Human milk leptin concentrations did not differ between preterm and term human milk. In term milk, leptin concentration on day 28 was lower than on day 3 (p<0.05). Milk leptin levels on the 3rd and 28th day were positively correlated with mothers' body mass index, but not with fat content in milk. CONCLUSION: Skim milk was the most stabile preparation for leptin analysis. Preterm and term human milk contain leptin in equal concentrations. Human milk leptin depends on mothers' body mass index.

Fetal akinesia caused by a novel actin filament aggregate myopathy skeletal muscle actin gene (ACTA1) mutation.

We report a female newborn, diagnosed with fetal akinesia in utero, who died one hour after birth. Post-mortem muscle biopsy demonstrated actin-filament myopathy based on immunolabelling for sarcomeric actin, and large areas of filaments, without rod formation, ultrastructurally. Analysis of DNA extracted from the muscle disclosed a novel de novo heterozygous c.44G>A, GGC>GAC, 'p.Gly15Asp' mutation in the ACTA1 gene. Analysis of the location of the mutated amino-acid in the actin molecule suggests the mutation most likely causes abnormal nucleotide binding, and consequent pathological actin polymerization. This case emphasizes the association of fetal akinesia with actin-filament myopathy.

Trace elements and antioxidant enzymes in extremely low birthweight infants.

Oxygen radicals are believed to contribute to typical diseases of prematurity, such as bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC). Our aim was to investigate whether these disorders are associated with disturbances in antioxidant enzyme activities and with low trace elements, which are co-factors of antioxidant enzymes. 209 infants with birthweight less than 1000g were enrolled into a European multicentre randomised erythropoietin (rhEPO) trial; 155 developed one or more of the above mentioned diseases. We analysed Zn, Cu, Fe, Se in plasma and red blood cells (RBCs), superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in RBCs on the 3rd and 68th day of life. Zn, Fe, Se in plasma, and Se in RBCs decreased (p<0.01), and Zn in RBC (p<0.001), CuZn-SOD (p<0.01) and CAT increased (p<0.05), whereas GSH-Px remained unchanged. No differences were observed between the rhEPO and control groups. Antioxidant enzyme activities did not correlate with gestational age. In infants with BPD, IVH, ROP, or NEC, CuZn-SOD and CAT (p<0.05) were higher at day 68 than in infants without these diseases. CuZn-SOD and GSH-Px at 3 days and CuZn-SOD at 68 days correlated positively (p<0.05) with the duration of oxygen treatment. In conclusion, in ELBW infants, trace element concentrations decreased over the first 10 weeks of life. Lower trace element concentrations, did not affect the activities of CuZn-SOD, GSH-Px, and CAT. Typical diseases of prematurity were not associated with decreased antioxidant enzyme activities.

Urinary vitamin A excretion in very low birth weight infants.

Vitamin A (VA) deficiency in very low birth weight (VLBW) infants is associated with an increased risk for disorders related to kidney and lung maturation and function. VA losses through increased urinary retinol (ROH) excretion might contribute to this deficiency risk. The mechanism accounting for ROH loss in the urine has not yet been clarified. The aim of this study was to assess the excretion of ROH, retinol-binding protein 4 (RBP4) and transthyretin (TTR) in urine from VLBW infants in comparison with that in term infants in relation to kidney function. Urine specimens were collected from 15 VLBW infants (birth weight < 1,500 g) as well as from 20 term infants during the first 2 days after birth. ROH in urine was detectable in 14 of the 15 VLBW infants at a median concentration of 234 nmol/g creatinine. In the group of term infants, 17 of the 20 excreted ROH, but at an approximately five-times lower concentration (P < 0.001). Excretion of RBP4 and TTR was also much higher in VLBW infants (both P< 0.001). The urinary ROH excretion in VLBW infants may be related to the impaired tubular handling of its carrier proteins RBP4 and TTR. Thus, ROH excretion might contribute to an increased risk of VA deficiency, especially in VLBW infants.

Low Apgar score without acidosis may indicate neuromuscular disorder.

OBJECTIVE: We hypothesized that in term infants low Apgar score with normal umbilical artery pH (UApH) indicates prenatal damage to the neuromuscular system. STUDY DESIGN: Retrospective database search of 42,117 liveborn infants born 1993-2005. Medical record analysis of 3104 term infants with cardiorespiratory maladaptation referred for special neonatal care. Focus on infants with UApH >7.00 and 5-min Apgar <6 (group A, n=74), UApH <7.00 and 5-min Apgar >5 (group B, n=49), and UApH <7.00 and 5-min Apgar <6 (group C, n=14). RESULTS: Incidence of 5-min Apgar score <6 was 0.50% in term infants. Mean (SD) UApH was 7.262 (0.075, P=0.075); incidence of UApH <7.00 was 0.30% in term infants. Nucleated red blood cells were elevated without differences in all three groups. Parental consanguinity was present in 39 of the 137 maladapted infants. In groups A/B/C, 10/18/2 infants were small for gestational age (P=0.002 for A vs B) and in 16/1/0 neuromuscular anomalies were identified (P=0.004 for A vs B). Eight of the 17 anomalies had been suspected prenatally. Logistic regression proved neuromuscular disorder the only independent variable discriminating between groups A and B. CONCLUSIONS: Neuromuscular problems are the cause rather than the result of maladaptation. For unexplained low Apgar score, especially without acidosis, meticulous examination of the infant including brain imaging and EEG is justified.

Outbreaks in neonatal intensive care units - they are not like others.

BACKGROUND: Outbreaks of health care-associated infections in neonatal intensive care units (NICUs) are frequent and have received more attention in medical literature than outbreaks from other types of intensive care units (ICUs). The objective of this systematic review was to identify differences between outbreaks of health care-associated infections in NICUs and other ICUs as reported to date in the medical literature. METHODS: Screening the outbreak database (http://www.outbreak-database.com), a systematic comparison of outbreaks was performed with the following categories: causing pathogen, type of infection, sources identified, and measures taken to stop the outbreak. RESULTS: Two hundred and seventy-six outbreaks were reported from NICUs and 453 from other ICU types. Enterobacteriaceae were significantly more often responsible for NICU outbreaks, whereas nonfermenting bacteria are more frequently identified in other ICU types. On average, 23.9 patients and 1.8 health care workers were involved in NICU outbreaks. Average mortality in NICU outbreak was 6.4% (1.5 newborns on average). In 48.6% of NICU outbreaks the authors were unable to identify the sources compared with 38.0% in other ICU outbreaks. The most important infection control measures were significantly more often implemented in NICUs than in other ICUs. CONCLUSIONS: Systematic outbreak analysis is essential for gaining insights into the control of NICU outbreaks.

Insulin-like growth factors and binding proteins in early milk from mothers of preterm and term infants.

Breast-fed preterm infants often show a better outcome, partly ascribed to the benefit of insulin-like growth factors (IGFs) and their binding proteins (IGFBP). We compared IGF-I, IGF-II, IGFBP-2 and IGFBP-3 levels, measured by radioimmunoassays in milk samples from 30 mothers of preterm (<31 weeks) and from 19 mothers of term (>37 weeks) infants at days 7 and 21 postpartum. Proteolysis of IGFBP-2 within mother's milk and digestion of (125)I-IGF-II and (125)I-IGFBP-2 by gastric juice from neonates were assessed by electrophoretic techniques. Mean concentrations did not differ between preterm and term milk: IGF-I (2.8 +/- 0.2 vs. 2.3 +/- 0.1 ng/ml), IGF-II (12.0 +/- 0.4 vs. 12.2 +/- 0.5 ng/ml), IGFBP-3 (100.0 +/- 5.1 vs. 80.0 +/- 5.8 ng/ml), but did so for IGFBP-2 (3,144 +/- 172 vs. 2,428 +/- 188 ng/ml, p < 0.02). Immunoblots revealed 42% (p < 0.05) more IGFBP-2 fragments of 14 and 25 kDa in preterm milk. Incubation with gastric juice caused cleavage of (125)I-IGFBP-2 and partial cleavage of (125)I-IGF-II. Mutual complexation protected IGF-II and IGFBP-2 from cleavage, suggesting that both are likely to arrive in the bowel in an intact form to exert promotive effects. The results provide further evidence that IGFBP-2 and IGF-II in breast milk are relevant factors for the early development of preterm infants.

Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants.

OBJECTIVE: A prospective observational study to investigate hematologic alterations during the first 3 months of life in HIV-exposed uninfected infants subjected to antiretroviral medication before and after birth. METHODS: Two hundred twenty-one consecutive uninfected infants born to HIV-positive mothers on antiretroviral medication during pregnancy were included. Perinatal transmission prophylaxis comprised zidovudine (ZDV) administered intravenously intrapartum and 10 days after birth. Blood counts and differentials were determined at birth and at 2, 4, 6, and 12 weeks of age, and hematologic toxicity was graded according to pediatric toxicity scales. Data were analyzed according to the kind of prenatal medication (ZDV alone or with another nucleoside reverse transcriptase inhibitor [NRTI] vs. highly active antiretroviral therapy [HAART]). RESULTS: Median hemoglobin was significantly lower in HAART-exposed newborns from birth (P = 0.004) until day 28. During follow-up, 119 (53.8%) infants had anemia grade 2 or higher on at least 1 occasion; 16 (7.2%) received red blood cell transfusion at 23 (range: 1-56) days of age. Neutropenia grade 2 or higher occurred in 106 (48.0%) infants at least once; 8 infants had staphylococcal infections, and 2 infections were severe. After adjustment for possible confounders (prematurity, birth weight, ethnicity, gender, duration of maternal antiretroviral therapy, maternal Centers for Disease Control and Prevention stage, and maternal illicit drug use), HAART exposure was the only independent risk factor for anemia (odds ratio [OR] = 2.22, 95% confidence interval [CI]: 1.06 to 4.64; P = 0.034) and neutropenia (OR = 2.15, CI: 1.02 to 4.55; P = 0.045). CONCLUSIONS: Antiretroviral transmission prophylaxis is associated with significant anemia and neutropenia in HIV-uninfected infants during the first 3 months of life. Anemia was more profound in HAART-exposed infants.

Nutrition of very low birth weight infants fed human milk with or without supplemental trace elements: a randomized controlled trial.

BACKGROUND: Very low birth weight infants (<1500 g) have high nutritional needs. Deficiencies of minerals, trace elements (especially zinc) may develop as a result of rapid growth, low body stores and low content of these substances in human milk We hypothesized that fortification of human milk might prevent deficiencies. METHODS: Prospective, randomized trial to evaluate mineral, trace element, thyroid status and growth of infants fed human milk fortified with different amounts of calcium, phosphorus and protein, with (BMF) or without (FM 85) trace elements. Sixty-two infants, 1000 to 1499 g birth weight, were randomized. Minerals and trace elements in serum, red blood cells and human milk and alkaline phosphatase activity, TSH, T4 and FT4 in serum were measured once until the fifth day and at 3 and 6 weeks of life. Clinical course and anthropometric measurements were recorded. RESULTS: Intake of zinc, copper, manganese, calcium, phosphorus and magnesium was higher in the BMF group (P < 0.001). Serum zinc concentrations <0.49 mg/L occurred in 12% of the FM 85 group and 7% of the BMF group at 6 weeks (not significant). Median alkaline phosphatase activity was 436/379 IU/L in the FM 85/BMF group at 6 weeks (P < 0.01). The FM 85 group showed a higher weight gain (P < 0.05), possibly because of higher caloric (P < 0.01) and protein intake (P < 0.05) at 3 weeks. CONCLUSIONS: Zinc deficiency was rare. Elevated intake of calcium, phosphorus and zinc was associated with lower serum alkaline phosphatase activity but did not influence serum zinc concentration.

Hyperphenylalaninemia in a premature infant with heterozygosity for phenylketonuria.

Hyperphenylalaninemia in preterm neonates with heterozygosity for phenylketonuria has previously not been described. We report on a very low birth weight infant, born at a gestational age of 27+5 weeks with a birth weight of 1080 g. Due to a positive family history prenatal diagnosis for phenylketonuria was performed, revealing heterozygosity for classic phenylketonuria. Yet the girl showed hyperphenylalaninemia with a maximum serum phenylalanine concentration of 515 micromol/l on the eighth day of life. Phenylalanine-restrictive parenteral and enteral nutrition was kept from the eighth until the 41st day of life. At term serum phenylalanine concentrations had normalized. We hypothesize that heterozygosity for phenylketonuria may be a risk factor for hyperphenylalaninemia in preterm born infants. Prematurity and the resulting immaturity of liver function with the genetically determined reduced activity of phenylalanine hydroxylase might have caused hyperphenylalaninemia in this girl.