Early transpyloric vs gastric feeding in preterm infants: a retrospective cohort study.

BACKGROUND: Neonatal transpyloric feeding (TPF) has not been rigorously studied since the 1980s. Our objective was to evaluate early TPF, defined as TPF initiated within the first week after birth, among preterm infants in the setting of modern neonatal practice. STUDY DESIGN: A retrospective cohort study was conducted between 2013 and 2017 for all extremely low birth weight (ELBW) infants born in a tertiary neonatal intensive care unit where early TPF is a common practice. Infants were excluded if they did not receive enteral feeding within the first week after birth or if they died prior to initiation of enteral feeding. The primary outcome was death or bronchopulmonary dysplasia (BPD). The association between early TPF and the primary outcome was assessed using multivariable logistic regression, with adjustment for gestational age, birth weight, and intubation status. RESULT: The study sample included 368 ELBW infants. Twenty-seven percent received early TPF. Death or BPD occurred in 58% of infants who received early TPF compared with 67% of infants who received gastric feeding, adjusted odds ratio 0.6, 95% confidence interval 0.3-0.9. Growth and adverse gastrointestinal outcomes did not differ between the two groups. CONCLUSION: Early TPF is associated with reduced risk of death or BPD among ELBW infants. Further investigation in the form of a randomized controlled trial is required to confirm a causal association between early TPF and improved clinical outcomes.

Failed umbilical artery catheterization and adverse outcomes in extremely low birth weight infants.

Purpose: To determine whether successful catheterization of the umbilical artery is associated with a reduced risk of death or neurodevelopment impairment among critically ill extremely low birth weight (ELBW) infants. Study design: A retrospective chart review was conducted between 2007 and 2014 at Stanford University for all ELBW infants that required intubation immediately after birth. The primary outcome was death or neurodevelopmental impairment at 18-22 months. We measured the association of successful umbilical artery catheterization with the primary outcome using multivariable logistic regression with adjustment for gestational age. Bayesian analysis was also performed due to small sample size. Results: Eighty-four ELBW infants met inclusion criteria. Successful umbilical artery catheterization occurred in 88% of infants and failed catheterization in 12%. Death or neurodevelopmental impairment occurred in 41% of infants with successful catheterization, compared to 60% of infants with failed catheterization of the umbilical artery, adjusted odds ratio 0.3, 95% confidence interval 0.1-1.3, p = .11. The Bayesian analysis indicated a 92% posterior probability of reduced death or neurodevelopmental impairment with successful catheterization and a 68% posterior probability of reduced death or neurodevelopmental by absolute risk difference of 20% or more, adjusted relative risk 0.74, 95% confidence interval 0.45-1.14. Conclusions: Among critically ill ELBW infants, successful catheterization of the umbilical artery compared to failed catheterization was not statistically significantly associated with the primary outcome. However, the Bayesian analysis indicated a high likelihood of benefit associated with successful umbilical artery catheterization.

Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas.

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.

What factors are related to recurrent preterm birth among underweight women?

OBJECTIVE: Our objective was to identify factors associated with recurrent preterm birth among underweight women. METHODS: Maternally linked hospital and birth certificate records of deliveries in California between 2007 and 2010 were used. Consecutive singleton pregnancies of women with underweight body mass index (BMI <18.5 kg/m2) in the first pregnancy were analyzed. Pregnancies were categorized based on outcome of the first and second birth as: term-term; term-preterm; preterm-term and preterm-preterm. RESULTS: We analyzed 4971 women with underweight BMI in the first pregnancy. Of these, 670 had at least one preterm birth. Among these 670, 86 (21.8%) women experienced a recurrent preterm birth. Odds for first term - second preterm birth were decreased for increases in maternal age (aOR: 0.90, 95%CI: 0.95-0.99) whereas inter-pregnancy interval <6 months was related to both first term - second preterm birth (aOR:1.66, 95%CI: 1.21-2.28) and first preterm birth - second term birth (aOR: 1.43, 95%CI: 1.04-1.96). Factors associated with recurrent preterm birth were: negative or no change in pre-pregnancy weight between pregnancies (aOR: 1.67, 95%CI: 1.07-2.60), inter-pregnancy interval <6 months (aOR: 2.14, 95%CI: 1.29-3.56), and maternal age in the first pregnancy (aOR: 0.93, 95%CI: 0.90-0.97). CONCLUSIONS: Recurrent preterm birth among underweight women was associated with younger age, short inter-pregnancy interval, and negative or no weight change between pregnancies.

RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome.

Germline mutations in RASA1 are associated with capillary malformation-arteriovenous malformation (CM-AVM) syndrome. CM-AVM syndrome is characterized by multi-focal capillary malformations and arteriovenous malformations. Lymphatic anomalies have been proposed as part of the phenotype. Intrafamilial variability has been reported, suggesting modifiers and somatic events. The objective of the study was to identify somatic RASA1 "second hits" from vascular malformations associated with CM-AVM syndrome, and describe phenotypic variability. Participants were examined and phenotyped. Genomic DNA was extracted from peripheral blood on all participants. Whole-exome sequencing was performed on the proband. Using Sanger sequencing, RASA1 exon 8 was PCR-amplified to track the c.1248T>G, p.Tyr416X germline variant through the family. A skin biopsy of a capillary malformation from the proband's mother was also obtained, and next-generation sequencing was performed on DNA from the affected tissue. A familial germline heterozygous novel pathogenic RASA1 variant, c.1248T>G (p.Tyr416X), was identified in the proband and her mother. The proband had capillary malformations, chylothorax, lymphedema, and overgrowth, while her affected mother had only isolated capillary malformations. Sequence analysis of DNA extracted from a skin biopsy of a capillary malformation of the affected mother showed a second RASA1 somatic mutation (c.2245C>T, p.Arg749X). These results and the extreme variable expressivity support the hypothesis that somatic "second hits" are required for the development of vascular anomalies associated with CM-AVM syndrome. In addition, the phenotypes of the affected individuals further clarify that lymphatic manifestations are also part of the phenotypic spectrum of RASA1-related disorders. © 2016 Wiley Periodicals, Inc.

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

Effect of antepartum meconium staining on perinatal and neonatal outcomes among pregnancies with gastroschisis.

OBJECTIVE: To investigate the association between meconium staining and perinatal and neonatal outcomes in pregnancies with gastroschisis. METHODS: Retrospective analysis of infants with prenatally diagnosed gastroschisis born in two academic medical centers between 2008 and 2013. Neonatal outcomes of deliveries with and without meconium staining were compared. Primary outcome was defined as any of the following: neonatal sepsis, prolonged mechanical ventilation, bowel atresia or death. Secondary outcomes were preterm delivery, preterm-premature rupture of membranes (PPROM) and prolonged hospital length of stay. RESULTS: One hundred and eight infants with gastroschisis were included of which 56 (52%) had meconium staining at delivery. Infants with meconium staining had a lower gestational age at delivery (36.3 (±1.4) versus 37.0 (±1.2) weeks, p = 0.007), and a higher rate of PPROM (25% versus 8%, p = 0.03) than infants without meconium. Meconium staining was not significantly associated with the primary composite outcome or with any of its components. After adjustments, meconium staining remained significantly associated with preterm delivery at <36 weeks [odds ratio OR = 4.0, 95% confidence intervals (CI): 1.5-11.4] and PPROM (OR = 3.8, 95%CI: 1.2-14.5). CONCLUSIONS: Among infants with gastroschisis, meconium staining was associated with prematurity and PPROM. No significant increase in other adverse neonatal outcomes was seen among infants with meconium staining, suggesting a limited prognostic value of this finding.

Inflammatory biomarkers and spontaneous preterm birth among obese women.

OBJECTIVE: To identify associations between second-trimester serum inflammatory biomarkers and preterm birth among obese women. METHODS: In this nested case-control study, we compared 65 serum inflammatory biomarkers in obese women whose pregnancies resulted in early spontaneous preterm birth (<32 weeks gestation, n = 34) to obese women whose pregnancies resulted in term birth (n = 34). These women were selected from a larger population-based California cohort. Random forest and classification and regression tree techniques were employed to identify biomarkers of importance, and adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Random forest and classification and regression tree techniques found that soluble vascular endothelial growth factor receptor-3 (sVEGFR3), soluble interleukin-2 receptor alpha-chain (sIL-2RA) and soluble tumor necrosis factor receptor-1 (sTNFR1) were related to preterm birth. Using multivariable logistic regression to compare preterm cases and term controls, decreased serum levels of sVEGFR3 and increased serum levels of sIL-2RA and sTNFR1 were associated with increased risk of preterm birth among obese women, aOR = 3.2 (95% CI: 1.0-9.9), aOR = 2.8 (95% CI: 0.9-9.0), and aOR = 4.1 (95% CI: 1.2-14.1), respectively. CONCLUSIONS: In this pilot study, we identified three serum biomarkers indicative of inflammation to be associated with spontaneous preterm birth among obese women: sVEGFR3, sIL-2RA and sTNFR1.

Heme oxygenase-1 promoter polymorphisms and risk of spina bifida.

BACKGROUND: Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs. METHODS: This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 non-malformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared. RESULTS: For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity. CONCLUSION: Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study.

SUNDROP: six years of screening for retinopathy of prematurity with telemedicine.

OBJECTIVE: To report the 6-year results of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) initiative in the context of telemedicine screening initiatives for retinopathy of prematurity (ROP). DESIGN: A retrospective analysis. PARTICIPANTS: Premature newborns requiring ROP screening at 6 neonatal intensive care units from December 1, 2005, to November 30, 2011. METHODS: Infants were evaluated via remote retinal photography by an ROP specialist. A total of 608 preterm infants meeting ROP examination criteria were screened with the RetCam II/III (Clarity Medical Systems, Pleasanton, Calif.). Primary outcomes were treatment-warranted ROP (TW-ROP) and adverse anatomical events. RESULTS: During the 6 years, 1216 total eyes were screened during 2169 examinations, generating 26 970 retinal images, an average of 3.56 examinations and 44.28 images per patient. Twenty-two (3.6%) of the infants screened met criteria for TW-ROP. Compared with bedside binocular ophthalmoscopy, remote interpretation of RetCam II/III images had a sensitivity of 100%, specificity of 99.8%, positive predicative value of 95.5%, and negative predicative value of 100% for the detection of TW-ROP. No adverse anatomical outcomes were observed for any enrolled patient. CONCLUSIONS: The 6-year results for the SUNDROP telemedicine initiative were highly favourable with respect to diagnostic accuracy. Telemedicine appears to be a safe, reliable, and cost-effective complement to the efforts of ROP specialists, capable of increasing patient access to screening and focusing the resources of the current ophthalmic community on infants with potentially vision-threatening disease.

A randomized clinical trial of therapeutic hypothermia mode during transport for neonatal encephalopathy.

OBJECTIVE: To determine if temperature regulation is improved during neonatal transport using a servo-regulated cooling device when compared with standard practice. STUDY DESIGN: We performed a multicenter, randomized, nonmasked clinical trial in newborns with neonatal encephalopathy cooled during transport to 9 neonatal intensive care units in California. Newborns who met institutional criteria for therapeutic hypothermia were randomly assigned to receive cooling according to usual center practices vs device servo-regulated cooling. The primary outcome was the percentage of temperatures in target range (33°-34°C) during transport. Secondary outcomes included percentage of newborns reaching target temperature any time during transport, time to target temperature, and percentage of newborns in target range 1 hour after cooling initiation. RESULTS: One hundred newborns were enrolled: 49 to control arm and 51 to device arm. Baseline demographics did not differ with the exception of cord pH. For each subject, the percentage of temperatures in the target range was calculated. Infants cooled using the device had a higher percentage of temperatures in target range compared with control infants (median 73% [IQR 17-88] vs 0% [IQR 0-52], P < .001). More subjects reached target temperature during transport using the servo-regulated device (80% vs 49%, P <.001), and in a shorter time period (44 ± 31 minutes vs 63 ± 37 minutes, P = .04). Device-cooled infants reached target temperature by 1 hour with greater frequency than control infants (71% vs 20%, P < .001). CONCLUSIONS: Cooling using a servo-regulated device provides more predictable temperature management during neonatal transport than does usual care for outborn newborns with neonatal encephalopathy.