Exclusive breastfeeding among women with type 1 and type 2 diabetes mellitus.

OBJECTIVE: To compare exclusive breastfeeding (BF) and BF initiation among 185 women with Type 1 and 212 women with Type 2 pregestational diabetes who intended exclusive or partial BF and delivered at ≥34 weeks of gestation. METHODS: Retrospective cohort study. At discharge, exclusive BF is direct BF or BF complemented with expressed breast milk. BF initiation is defined by exclusive or partial BF. RESULTS: Type 1 and Type 2 groups were similar in prior BF experience (69 vs 67%) but were different in intention to BF exclusively (92 vs 78%) and partially (8 vs 22%). Women in the Type 1 group were younger (median age 30 vs 33y), likely to be primiparous (47 vs 25%), have a lower median BMI (32 vs 36 kg/m2) and deliver by primary cesarean (37 vs 26%). Infants born to Type 1 women were more likely to be admitted to the NICU (44 vs 18%) and to have hypoglycemia (59 vs 41%). At discharge, exclusive BF among Type 1 was higher (34 vs 23%), partial BF was similar (47 vs 46%) while FF (formula feeding) was lower (19 vs 31%) than in the Type 2 group. BF initiation occurred in 81% of Type 1 and 69% of Type 2 women. CONCLUSION: Intention to BF exclusively was higher in Type 1 women compared to Type 2. At discharge, exclusive BF and BF initiation were lower and FF higher in the Type 2 group highlighting the need for different strategies if lactation in this special population is to be improved.

Neonatal Histamine-2 Receptor Antagonist and Proton Pump Inhibitor Treatment at United States Children's Hospitals.

OBJECTIVE: To determine treatment frequency and duration of histamine-2 receptor antagonist (H2RA)/proton pump inhibitor (PPI) use among infants hospitalized within US children's hospital neonatal intensive care units and evaluate diagnoses/demographic factors associated with use. STUDY DESIGN: We retrospectively analyzed a cohort of neonatal intensive care unit infants admitted to 43 US children's hospitals within the Pediatric Health Information System database between January 2006 and March 2013 to determine H2RA/PPI treatment frequency, timing/duration of treatment, factors associated with use, percent of infants remaining on treatment at discharge, and interhospital prescribing variation. We used a modified Poisson regression to calculate the adjusted probability of infants ever receiving H2RAs/PPIs in relation to diagnosis, gestation, and sex. RESULTS: Of the 122 002 infants evaluated, 23.8% (n = 28 989) ever received an H2RA or PPI; 19.0% received H2RAs (n = 23 187), and 10.5% (n = 12 823) received PPIs. Extremely preterm infants and term infants were the most likely to receive H2RA and PPI treatment. Infants with gastroesophageal reflux disease (relative risk [RR] = 3.13) and congenital heart disease (RR = 2.41) had the highest H2RA/PPI treatment probabilities followed by those with an ear, nose, and throat diagnosis (RR = 2.34; P < .05). The majority of treated infants remained treated at discharge. CONCLUSIONS: Despite limited evidence and increasing safety concerns, H2RAs/PPIs are frequently prescribed to extremely preterm neonates and those with congenital anomalies and continued through discharge. Our findings support the need for innovative studies to examine the comparative effectiveness and safety of H2RA/PPIs vs no treatment in these high-risk neonatal populations.

Impact of excessive gestational weight gain on exclusive breastfeeding among women with Type 1 and Type 2 diabetes and obesity.

BACKGROUND: Pregestational diabetes, obesity and gestational weight gain (GWG) are associated with adverse perinatal outcomes, however, the influence of excessive GWG on lactation at discharge is less known. Our aim is to evaluate the impact of excessive GWG using the LifeCycle project guidelines on exclusive breastfeeding (EBF) and any BF rates at discharge among 171 women with Type 1 and 294 Type 2 diabetes and obesity who intended to BF. METHODS AND FINDINGS: Retrospective cohort study. Obesity was defined by BMI (kg/m2) as grade 1 (30-34.9), grade 2 (35-39.9) or grade 3 (≥40). GWG was categorized as adequate, inadequate or excessive according to the 2019 LifeCycle Project guidelines. Women with Type 1 were younger (30 vs 33y), primiparous (51 vs 32%), delivered earlier (37 vs 38w) than women with Type 2 andwere different in grade 1 (40 vs 26%), grade 3 obesity (19 vs 49%) and median GWG (15 vs 11kg). Of all 465 women with Type 1 and Type 2 combined, 365 (78%) who had excessive GWG and 100 (22%) who had non-excessive GWG showed similar EBF (27 vs 25%) and any BF (72 vs 72%) rates. Regression analysis showed that after adjusting for potential confounders excessive GWG was not a predictor of EBF or any BF at discharge. CONCLUSION: Type 1 and Type 2 diabetes, obesity and excessive GWG are associated with low EBF, however, excessive GWG is not an independent predictor of low EBF or any BF at discharge.

Nitric oxide suppression of cellular proliferation depends on cationic amino acid transporter activity in cytokine-stimulated pulmonary endothelial cells.

Inducible nitric oxide (NO) synthase (iNOS) is a stress response protein upregulated in inflammatory conditions, and NO may suppress cellular proliferation. We hypothesized that preventing L-arginine (L-arg) uptake in endothelial cells would prevent lipopolysaccharide/tumor necrosis factor-α (LPS/TNF)-induced, NO-mediated suppression of cellular proliferation. Bovine pulmonary arterial endothelial cells (bPAEC) were treated with LPS/TNF or vehicle (control), and either 10 mM L-leucine [L-leu; a competitive inhibitor of L-arg uptake by the cationic amino acid transporter (CAT)] or its vehicle. In parallel experiments, iNOS or arginase II were overexpressed in bPAEC using an adenoviral vector (AdiNOS or AdArgII, respectively). LPS/TNF treatment increased the expression of iNOS, arginase II, CAT-1, and CAT-2 mRNA in bPAEC, resulting in greater NO and urea production than in control bPAEC, which was prevented by L-leu. LPS/TNF treatment resulted in fewer viable cells than in controls, and LPS/TNF-stimulated bPAEC treated with L-leu had more viable cells than LPS/TNF treatment alone. LPS/TNF treatment resulted in cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase expression, which was attenuated by L-leu. AdiNOS reduced viable cell number, and treatment of AdiNOS transfected bPAEC with L-leu preserved cell number. AdArgII increased viable cell number, and treatment of AdArgII transfected bPAEC with L-leu prevented the increase in cell number. These data demonstrate that iNOS expression in pulmonary endothelial cells leads to decreased cellular proliferation, which can be attenuated by preventing cellular L-arg uptake. We speculate that CAT activity may represent a novel therapeutic target in inflammatory lung diseases characterized by NO overproduction.

Probiotics and prebiotics for the prevention of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) continues to be a major cause of morbidity and mortality in premature infants. Although the pathogenesis of NEC remains unclear, abnormal bacterial colonization has been postulated as playing a central role. Various factors impact bacterial colonization following delivery. Compared to term infants, the bacterial colonization pattern in prematurely born infants is markedly different, with a greater predilection for colonization with pathogenic bacteria. Probiotic and prebiotic administration offers the opportunity to manipulate the intestinal bacterial environment, favoring the growth of commensal bacteria. Experimental data from animal studies and data from human trials suggest that probiotics decrease the incidence of NEC. These preliminary studies support the need for a large, randomized, controlled trial to further investigate the role of probiotics in the prevention of NEC.

Inhaled nitric oxide decreases leukocyte trafficking in the neonatal mouse lung during exposure to >95% oxygen.

Chronic lung injury in the neonate is termed bronchopulmonary dysplasia (BPD). These patients generally require supplemental oxygen therapy, and hyperoxia has been implicated in the pathogenesis of BPD. The concomitant use of oxygen and inhaled NO (iNO) may result in the generation of reactive nitrogen species or may have an anti-inflammatory effect in the neonatal lung. We tested the hypothesis that exposure to >95% O2 in neonatal mice would increase trafficking of leukocytes into the lung and that the addition of iNO to >95% O2 would decrease this leukocyte trafficking. Hyperoxia resulted in fewer alveoli, increased presence of neutrophils and macrophages, and decreased number of mast cells within the lung parenchyma. Adding iNO to hyperoxia prevented the hyperoxia-induced changes and resulted in the numbers of alveoli, neutrophils, macrophages, and mast cells approximating those found in controls (room air exposure). Intercellular adhesion molecule (ICAM) and monocyte chemotactic protein-1 (MCP-1), two factors responsible for leukocyte recruitment, were up-regulated by hyperoxic exposure, but the addition of iNO to the hyperoxic exposure prevented the hyperoxia-induced up-regulation of ICAM and MCP-1. These data demonstrate that iNO alters the hyperoxia-induced recruitment of leukocytes into the lung.

Inhaled nitric oxide prevents 3-nitrotyrosine formation in the lungs of neonatal mice exposed to >95% oxygen.

Inhaled nitric oxide is being evaluated as a preventative therapy for patients at risk for bronchopulmonary dysplasia (BPD). Nitric oxide (NO), in the presence of superoxide, forms peroxynitrite, which reacts with tyrosine residues on proteins to form 3-nitrotyrosine (3-NT). However, NO can also act as an antioxidant and was recently found to improve the oxidative balance in preterm infants. Thus, we tested the hypothesis that the addition of a therapeutically relevant concentration (10 ppm) of NO to a hyperoxic exposure would lead to decreased 3-NT formation in the lung. FVB mouse pups were exposed to either room air (21% O(2)) or >95% O(2) with or without 10 ppm NO within 24 h of birth. In the first set of studies, body weights and survival were monitored for 7 days, and exposure to >95% O(2) resulted in impaired weight gain and near 100% mortality by 7 days. However, the mortality occurred earlier in pups exposed to >95% O(2) + NO than in pups exposed to >95% O(2) alone. In a second set of studies, lungs were harvested at 72 h. Immunohistochemistry of the lungs at 72 h revealed that the addition of NO decreased alveolar, bronchial, and vascular 3-NT staining in pups exposed to both room air and hyperoxia. The lung nitrite levels were higher in animals exposed to >95% oxygen + NO than in animals exposed to >95% oxygen alone. The protein levels of myeloperoxidase, monocyte chemotactic protein-1, and intracellular adhesion molecule-1 were assessed after 72 h of exposure and found to be greatest in the lungs of pups exposed to >95% O(2). This hyperoxia-induced protein expression was significantly attenuated by the addition of 10 ppm NO. We propose that in the presence of >95% O(2), peroxynitrite formation results in protein nitration; however, adding excess NO to the >95% O(2) exposure prevents 3-NT formation by NO reacting with peroxynitrite to produce nitrite and NO(2). We speculate that the decreased protein nitration observed with the addition of NO may be a potential mechanism limiting hyperoxic lung injury.

A trial comparing continuous positive airway pressure (CPAP) devices in preterm infants.

OBJECTIVE: To test the hypothesis that infants born <30 weeks' gestation supported by Seattle-PAP will have lower rates of continuous positive airway pressure (CPAP) failure than infants supported with conventional, Fisher&Paykel-CPAP (FP-CPAP). STUDY DESIGN: Randomized trial (3/2017-01/2019) at 5 NICUs. The primary outcome was CPAP failure; subgroup analyses (gestational age, receipt antenatal corticosteroids) were performed. RESULTS: A total of 232 infants were randomized. Infants in the Seattle-PAP and FP-CPAP groups had mean gestational ages of 27.0 and 27.2 weeks, respectively. We observed no differences in rates of treatment failure between Seattle-PAP (40/112, 35.7%) and FP-CPAP (38/120, 31.7%; risk difference, 4.1%; 95% CI, -8.1-16.2; P = 0.51). Subgroup analysis indicated no differences in rates of CPAP failure. We observed no differences between the two groups in frequencies of adverse events or duration of respiratory support. CONCLUSIONS: Among infants born <30 weeks' gestation, rates of CPAP failure did not differ between Seattle-PAP and FP-CPAP.

Evaluating the efficacy of Seattle-PAP for the respiratory support of premature neonates: study protocol for a randomized controlled trial.

BACKGROUND: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging regarding the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher & Paykel CPAP or FP-CPAP). METHODS/DESIGN: We designed a multicenter, non-blinded, randomized controlled trial that will enroll 230 premature infants (220/7 to 296/7 weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short- and long-term respiratory morbidity and cost-effectiveness. DISCUSSION: This trial will assess whether Seattle-PAP is more efficacious and cost-effective than FP-CPAP in real-world practice among premature neonates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03085329 . Registered on 21 March 2017.

Neonatal Contrast Sensitivity and Visual Acuity: Basic Psychophysics.

PURPOSE: This research was prospectively designed to determine whether a 0.083 cycles per degree (cy/deg) (20/7200) square-wave stimulus is a good choice for clinical measurement of newborn infants' contrast sensitivity and whether the contrast sensitivity function (CSF) of the newborn infant is band-pass. The results were retrospectively analyzed to determine whether the method of constant stimuli (MCS) and the descending method of limits (dLIM) yielded similar results. METHODS: In across-subjects experimental designs, a pilot experiment used MCS (N = 47 visual acuity; N = 38 contrast sensitivity at 0.083 cy/deg), and a main experiment used dLIM (N = 22 visual acuity; N = 22 contrast sensitivity at 0.083 cy/deg; N = 21 at 0.301 cy/deg) to measure visual function in healthy newborn infants. Three candidate CSFs estimated maximum neonatal contrast sensitivity. MCS and dLIM psychometric functions were compared while taking the stimulus presentation protocols into account. RESULTS: The band-pass CSF fit the data best, with a peak sensitivity near 0.31 at 0.22 cy/deg. However, the 0.083 cy/deg square-wave stimulus underestimated the best performance of newborn infants by less than 0.15 log10 units. MCS and dLIM data agreed well when the stimulus presentation contingencies were taken into account. CONCLUSIONS: Newborn contrast sensitivity is well measured using a 0.083 cy/deg square-wave target, regardless of which CSF shape is correct. MCS and dLIM yield wholly comparable results, with no evidence to suggest effects of other factors such as infant inattention or examiner impatience. TRANSLATIONAL RELEVANCE: These measurements open the way for clinical behavioral measurement of infant visual acuity and contrast sensitivity in the neonatal period.

The contrast sensitivity of the newborn human infant.

PURPOSE: To measure the binocular contrast sensitivity (CS) of newborn infants using a fixation-and-following card procedure. METHODS: The CS of 119 healthy newborn infants was measured using stimuli printed on cards under the descending method of limits (93 infants) and randomized/masked designs (26 infants). One experienced and one novice adult observer tested the infants using vertical square-wave gratings (0.06 and 0.10 cyc/deg; 20/10,000 and 20/6000 nominal Snellen equivalent); the experienced observer also tested using horizontal gratings (0.10 cyc/deg) and using the Method of Constant Stimuli while being kept unaware of the stimulus values. RESULTS: The CS of the newborn infant was 2.0 (contrast threshold = 0.497; 95% confidence interval: 0.475-0.524) for vertically oriented gratings and 1.74 (threshold = 0.575; 95% confidence interval: 0.523-0.633) for horizontally oriented gratings (P < 0.0006). The standard deviation of infant CS was comparable to that obtained by others on adults using the Pelli-Robson chart. The two observers showed similar practice effects. Randomization of stimulus order and masking of the adult observer had no effect on CS. CONCLUSIONS: The CS of individual newborn human infants can be measured using a fixation-and-following card procedure.

Respiratory severity score on day of life 30 is predictive of mortality and the length of mechanical ventilation in premature infants with protracted ventilation.

OBJECTIVE: We tested the hypothesis that Respiratory Severity Score (RSS) on day of life 30 is predictive of mortality and length of mechanical ventilation in premature infants on prolonged mechanical ventilation. METHODS: A retrospective chart review was performed using the Nationwide Children's Hospital medical record and Vermont-Oxford Network databases. The primary outcome variable was survival to hospital discharge and the secondary outcome was length of mechanical ventilation after day of life 30. RESULTS: We identified 199 neonates admitted to Nationwide Children's Hospital between 2004 and 2007 with birth weight less than 1,500 g that received prolonged mechanical ventilation in the first 30 days of their life. A total of 184 infants were included in the analysis, excluding 14 patients with congenital anomalies and one infant with incomplete data. RSS on day of life 30 was significantly greater in the group of infants that died compared to those that survived (P = 0.003, 95% CI = [0.08, 0.40]). Further analysis demonstrated that the maximum difference in mortality was obtained with a threshold RSS of 6. Of the 109 patients who had RSS less than 6 on day of life 30, mortality rate was 4.6% (5/109) while those greater than or equal to 6 had a mortality rate of 21.3% (16/75). Both Kaplan-Meier survival curves comparing mortality and length of mechanical ventilation in infants with RSS < 6 versus those with RSS ≥ 6 demonstrated strong associations between RSS on day of life 30 and survival (P = 0.002) and length of ventilation after day of life 30 (P < 0.001). CONCLUSION: RSS ≥ 6 on day of life 30 is associated with higher mortality and longer period of mechanical ventilation in premature infants requiring mechanical ventilation through 30 days of life.

Utilization of inhaled corticosteroids for infants with bronchopulmonary dysplasia.

OBJECTIVE: To determine demographic and clinical variables associated with inhaled corticosteroid administration and to evaluate between-hospital variation in inhaled steroid use for infants with bronchopulmonary dysplasia (BPD). DESIGN: Retrospective Cohort Study. SETTING: Neonatal units of 35 US children's hospitals; as recorded in the Pediatric Health Information System (PHIS) database. PATIENTS: 1429 infants with evolving BPD at 28 days who were born at <29 weeks gestation with birth weight <1500 grams, admitted within the first 7 postnatal days, and discharged between January 2007-June 2011. RESULTS: Inhaled steroids were prescribed to 25% (n = 352) of the cohort with use steadily increasing during the first two months of hospitalization. The most frequently prescribed steroid was beclomethasone (n = 194, 14%), followed by budesonide (n = 125, 9%), and then fluticasone (n = 90, 6%). Birth gestation <24 weeks, birth weight 500-999 grams, and prolonged ventilation all increased the adjusted odds of ever receiving inhaled corticosteroids (p<0.05). Wide variations between hospitals in the frequency of infants ever receiving inhaled steroids (range: 0-60%) and the specific drug prescribed were noted. This variation persisted, even after controlling for observed confounders. CONCLUSIONS: Inhaled corticosteroid administration to infants with BPD is common in neonatal units within U.S. Children's hospitals. However, its utilization varies markedly between centers from no treatment at some institutions to the majority of infants with BPD being treated at others. This supports the need for further research to identify the benefits and potential risks of inhaled steroid usage in infants with BPD.

Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia.

OBJECTIVES: To determine (1) between-hospital variation in diuretic use for infants with bronchopulmonary dysplasia (BPD), including hospital-specific treatment frequency, treatment duration, and percentage of infants receiving short (≤5 consecutive days) versus longer (>5 days) courses, and to determine (2) demographic and clinical variables associated with diuretic administration. METHODS: A retrospective cohort study was conducted with the use of the Pediatric Health Information System to determine between-hospital variation in diuretic utilization patterns (primary outcome) and variables associated with diuretic use among <29-week-gestation infants with evolving BPD at age 28 days who were discharged between January 2007 and June 2011. RESULTS: During the 54-month study period, 1429 infants within 35 hospitals met the inclusion criteria for BPD at age 28 days, with 1222 (86%) receiving diuretic therapy for a median of 9 days (25th-75th percentile: 2-33 days). Short courses were administered to 1203 (83%) infants, and 570 (40%) infants received treatment for >5 consecutive days. Furosemide was the most widely prescribed diuretic (1218 infants; 85%), although chlorothiazide had the longest median duration of use (21 days; 25th-75th percentile: 8-46 days). The range of infants receiving a diuretic course of >5 days duration varied by hospital from 4% to 86%, with wide between-hospital variation even after adjustment for confounding variables. CONCLUSIONS: The frequency of diuretic administration to infants with BPD at US children's hospitals, as well as the specific diuretic regimen used, varies markedly by institution. Safety and effectiveness research of long-term diuretic therapy for BPD patients is needed to develop evidence-based recommendations.

Practice Variance, Prevalence, and Economic Burden of Premature Infants Diagnosed With GERD.

OBJECTIVE: To determine the practice variance, prevalence, and economic burden of clinically diagnosed gastroesophageal reflux disease (GERD) in preterm infants. METHODS: Applying a retrospective cohort study design, we analyzed data from 18 567 preterm infants of 22 to 36 weeks' gestation and >400 g birth weight from the NICUs of 33 freestanding children's hospitals in the United States. GERD prevalence, comorbidities, and demographic factors were examined for their association with average length of stay (LOS) and hospitalization cost. RESULTS: Overall, 10.3% of infants received a diagnosis of GERD (95% confidence interval [CI]: 9.8-10.7). There was a 13-fold variation in GERD rates across hospitals (P < .001). GERD diagnosis was significantly (P < .05) associated with bronchopulmonary dysplasia and necrotizing enterocolitis, as well as congenital anomalies and decreased birth weight. GERD diagnosis was associated with $70 489 (95% CI: 62 184-78 794) additional costs per discharge and 29.9 additional days in LOS (95% CI: 27.3-32.5). CONCLUSIONS: One in 10 of these premature NICU infants were diagnosed with GERD, which is associated with substantially increased LOS and elevated costs. Better diagnostic and management strategies are needed to evaluate reflux-type symptoms in this vulnerable NICU population.

Hospital variation in nitric oxide use for premature infants.

OBJECTIVE: To describe inter-center hospital variation in inhaled nitric oxide (iNO) administration to infants born prior to 34 weeks' gestation at US children's hospitals. METHODS: This was a retrospective cohort study using the Pediatric Health Information System to determine the frequency, age at first administration, and length of iNO use among 22 699 consecutive first admissions of unique <34 weeks' gestation infants admitted to 37 children's hospitals from January 1, 2007, through December 31, 2010. RESULTS: A total of 1644 (7.2%) infants received iNO during their hospitalization, with substantial variation in iNO use between hospitals (range across hospitals: 0.5%-26.2%; P < .001). The age at which iNO was started varied by hospital (mean: 20.0 days; range: 6.0-65.1 days, P < .001), as did the duration of therapy (mean: 13.1 days; range: 1.0-31.1 days; P < .001). Preterm infants who received iNO were less likely to survive (36.3% mortality vs 8.3%; odds ratio: 6.27; P < .001). The association between the use of iNO and mortality persists in propensity score-adjusted analyses controlling for demographic factors and diagnoses associated with the use of iNO (odds ratio: 3.79; P < .0001). CONCLUSIONS: iNO practice patterns in preterm infants varied widely among institutions. Infants who received iNO were less likely to survive, suggesting that iNO is used in infants already at high risk of death. Adherence to National Institutes of Health consensus guidelines may decrease variation in iNO use.