Evidence-Based Guidelines for Acute Stabilization and Management of Neonates with Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn, or PPHN, represents a challenging condition associated with high morbidity and mortality. Management is complicated by complex pathophysiology and limited neonatal specific evidence-based literature, leading to a lack of universal contemporary clinical guidelines for the care of these patients. To address this need and to provide consistent high-quality clinical care for this challenging population in our neonatal intensive care unit, we sought to develop a comprehensive clinical guideline for the acute stabilization and management of neonates with PPHN. Utilizing cross-disciplinary expertise and incorporating an extensive literature search to guide best practice, we present an approachable, pragmatic, and clinically relevant guide for the bedside management of acute PPHN. KEY POINTS: · PPHN is associated with several unique diagnoses; the associated pathophysiology is different for each unique diagnosis.. · PPHN is a challenging, dynamic, and labile process for which optimal care requires frequent reassessment.. · Key management goals are adequate tissue oxygen delivery, avoiding harm..

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.

Cellular strain amplifies LPS-induced stress signaling in immature enterocytes: potential implications for preterm infant NCPAP.

BACKGROUND: Recent clinical observations of increased necrotizing enterocolitis (NEC) incidence in some nasal continuous positive airway pressure (NCPAP) patients raise concerns about whether the related abdominal distension is benign or contributes to NEC. We tested the hypothesis that mechanical strain causes an exaggerated enterocyte inflammatory response and decreased enterocyte growth and proliferation in the absence and presence of lipopolysaccharide (LPS). METHODS: First we used a confluent enterocyte (IEC-6) monolayer to investigate effects of strain on inflammatory cytokine production and Toll-like receptor 4 (TLR-4) gene expression. Then we used a low seeding density to measure cell growth and proliferation. Ten percent mechanical strain was applied. RESULTS: Significant increases in interleukin (IL)-8 and in IL-6 were observed after 8 and 24 h of cellular strain, respectively, and maintained throughout the study. TLR-4 expression was increased at 48 h. Mechanical strain led to slower proliferation and division whereas LPS alone had minimal effects. The responses of LPS and strain were supra-additive, suggesting synergistic cellular effects. CONCLUSION: We speculate intestinal distension associated with the use of NCPAP, especially in the presence of abnormal gut colonization, may result in increased inflammatory cytokine production and be a contributing factor to neonatal intestinal morbidities.

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.

Poly(ADP-ribose) polymerase-1: a novel therapeutic target in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of infancy, afflicting 11% of infants born 22-28 wk GA. Both inflammation and oxidation may be involved in NEC pathogenesis through reactive nitrogen species production, protein oxidation, and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme activated to facilitate DNA repair using nicotinamide adenine dinucleotide (NAD+) as a substrate. However, in the presence of severe oxidative stress and DNA damage, PARP-1 overactivation may ensue, depleting cells of NAD+ and ATP, killing them by metabolic catastrophe. Here, we tested the hypothesis that NO dysregulation in intestinal epithelial cells during NEC leads to marked PARP-1 expression and that administration of a PARP-1 inhibitor (nicotinamide) attenuates intestinal injury in a newborn rat model of NEC. In this model, 56% of control pups developed NEC (any stage) versus 14% of pups receiving nicotinamide. Forty-four percent of control pups developed high-grade NEC (grades 3-4), whereas only 7% of pups receiving nicotinamide developed high-grade NEC. Nicotinamide treatment protects pups against intestinal injury incurred in the newborn rat NEC model. We speculate that PARP-1 overactivation in NEC may drive mucosal cell death in this disease and that PARP-1 may be a novel therapeutic target in NEC.

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.

Use of polyethylene bags in extremely low birth weight infant resuscitation for the prevention of hypothermia.

OBJECTIVE: To compare the clinical responses of extremely low birth weight (ELBW) infants resuscitated in polyethylene bags with ELBW infants who were resuscitated using traditional temperature control measures. STUDY DESIGN: Retrospective cohort investigation of 70 ELBW infants who were resuscitated using polyethylene bags (study) and 70 ELBW infants (control) resuscitated without polyethylene bags matched by birth weight, gestational age and gender. RESULTS: Infants in the study and control groups were comparable demographically and in obstetric risk factors. Study and control infants were similar in birth weight, gestational age and low 5-minute Apgar score. Axillary temperature on admission to the neonatal intensive care unit (NICU) and at 1 hour was greater in the study group as compared with controls. The incidence of grade III-IV intraventricular hemorrhage and periventricular leukomalacia (PVL) combined was decreased in the study group as compared with controls. Other neonatal comorbidities were not different. CONCLUSION: Resuscitation of ELBW infants in polyethylene bags led to higher skin temperature on admission to the NICU and at 1 hour of life. These infants were less likely to develop grade 3-4 PVL than infants resuscitated using traditional temperature control measures. No deleterious clinical effects were observed in infants resuscitated using polyethylene bags.

Prenatal lipopolysaccharide increases postnatal intestinal injury in a rat model of necrotizing enterocolitis.

BACKGROUND: An increased incidence of necrotizing enterocolitis (NEC) has been noted in infants who are born to mothers with chorioamnionitis. HYPOTHESIS: Our objective was to test the hypothesis that newborn rat pups born to mothers exposed to prenatal lipopolysaccharide during pregnancy would be more susceptible to intestinal injury in a rat model of NEC and that the increased intestinal injury is mediated by dysregulation of inducible nitric oxide synthase. METHODS: Time-dated pregnant Sprague-Dawley dams were given an intraperitoneal injection of either 2 mg/kg of lipopolysaccharide or vehicle. Rat pups from each group of dams were delivered at term and placed in a rat NEC model. A subset of pups was given either vehicle or aminoguanidine. Intestines were harvested and graded for degree of intestinal injury. RESULTS: Maternal prenatal lipopolysaccharide exposure increased the frequency and severity of intestinal injury in the neonatal rat NEC model. Treatment with aminoguanidine significantly decreased plasma nitric oxide levels. Additionally, aminoguanidine significantly decreased intestinal injury. CONCLUSIONS: Intestinal injury observed may be mediated via nitric oxide synthase dysregulation.

The neonatal intestinal vasculature: contributing factors to necrotizing enterocolitis.

Based on the demonstration of coagulation necrosis, it is clear that intestinal ischemia plays a role in the pathogenesis of necrotizing enterocolitis (NEC). Intestinal vascular resistance is determined by a dynamic balance between vasoconstrictive and vasodilatory inputs. In the newborn, this balance heavily favors vasodilation secondary to the copious production of endothelium-derived nitric oxide (NO), a circumstance which serves to ensure adequate blood flow and thus oxygen delivery to the rapidly growing intestine. Endothelial cell injury could shift this balance in favor of endothelin (ET)-1-mediated vasoconstriction, leading to intestinal ischemia and tissue injury. Evidence obtained from animal models and from human tissue collected from infants with NEC implicates NO and ET-1 dysregulation in the pathogenesis of NEC. Strategies focused on maintaining the delicate balance favoring vasodilation in the newborn intestinal circulation may prove to be useful in the prevention and treatment of NEC.

Necrotizing enterocolitis in neonates with congenital heart disease.

Both necrotizing enterocolitis (NEC) and congenital heart disease (CHD) are causes of significant morbidity and mortality in the neonatal population. While two distinct disease processes, NEC and CHD are inter-related as the incidence of NEC is greater in neonates with CHD than the normal newborn population. It is likely that circulatory perturbations, especially those seen in infants with left ventricular outflow tract lesions and single ventricle physiology, the stress of cardiac surgery and cardiopulmonary bypass, and the underlying baseline elevation of circulating endotoxin and proinflammatory cytokines all play a role in the pathogenesis of NEC in this uniquely susceptible population. The neurodevelopmental impairment in infants requiring surgery for NEC and in infants with complex congenital heart disease is alarming and requires further investigation. As medical and surgical advances allow for the palliation and correction of complex lesions at an earlier gestational age and lower birth weight, the already high risk of NEC in this population is likely to increase. This will require more aggressive study of the etiology of NEC in patients with CHD and the development of preventative therapies in order to decrease the impressive morbidity and mortality associated with the combination of these disease processes. In this article, we review the pathogenesis of NEC and CHD including associated mortality and morbidities and discuss possible mechanisms linking these two disease states.

Endothelial nitric oxide synthase in human intestine resected for necrotizing enterocolitis.

OBJECTIVE: To determine the expression and function of endothelial nitric oxide synthase (eNOS) in submucosal arterioles harvested from human intestine resected for necrotizing enterocolitis (NEC) or congenital bowel disease. STUDY DESIGN: eNOS expression was determined by using immunohistochemistry. The arteriolar diameter was measured in vitro at pressures of 10 to 40 mm Hg and also in response to the eNOS agonist acetylcholine (ACh), the exogenous nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine, and the smooth muscle relaxant papaverine. Arteriolar release of NO in response to ACh was determined with a Sievers NOAnalyzer. Hemodynamics were also determined at flow rates of 50 and 100 microL/min. RESULTS: eNOS was present in microvessels from both groups, but NEC arterioles failed to demonstrate physiological evidence of eNOS function: they constricted in response to pressure, failed to dilate or generate NO in response to ACh, and failed to dilate in response to flow. However, they dilated in response to exogenous NO and papaverine, indicating functional vascular smooth muscle and vasodilator reserve. CONCLUSION: eNOS-derived NO, a vasodilator in the newborn intestine, did not contribute to vasoregulation in arterioles harvested from intestine resected for NEC. These vessels were constricted; lack of eNOS-derived NO may contribute to this vasoconstriction.

Breastfeeding initiation among macrosomic infants born to obese nondiabetic mothers.

BACKGROUND: Women who are overweight or obese are at risk for maternal and neonatal medical complications, including macrosomia (birth weight ≥4,000 g), that may contribute to breastfeeding initiation failure. This study examined factors associated with breastfeeding initiation among obese women without diabetes who delivered macrosomic infants. STUDY DESIGN AND METHODS: A retrospective chart review was conducted from 2008 to 2011. Based on prepregnancy body mass index (in kg/m(2)), women were classified as normal (18-24.9), overweight (25-29.9), obese (30-34.9), very obese (35-39.9), and extremely obese (≥40). Intention to breastfeed was ascertained prenatally, and breastfeeding initiation was defined if at discharge ≥50% of the infant feedings were breastmilk. RESULTS: Twenty-nine percent of the population was overweight, 23% obese, 14% very obese, and 12% extremely obese. Intention to breastfeed was similar among normal-weight, overweight, obese, and very obese women but was significantly lower for those who were extremely obese (p<0.05). Breastfeeding initiation was 75% for normal-weight, 72% for overweight, 71% for obese, 66% for very obese, and 53% for extremely obese women (p<0.05). Among women who intended to breastfeed, breastfeeding initiation was uniformly high: 94% for normal-weight, 93% for overweight, 95% for obese, 92% for very obese, and 87% for extremely obese women. CONCLUSIONS: Intention to breastfeed as well as breastfeeding initiation was significantly lower for extremely obese women. Lack of intention to breastfeed declared during the antepartum period by extremely obese women highlights a need as well as an opportunity for intervention.

Necrotizing enterocolitis: preventative strategies.

Necrotizing enterocolitis (NEC) remains a major cause of morbidity and mortality in premature infants. Although the pathogenesis of NEC is unclear, prevention strategies have been developed based on clinical observations and epidemiologic and experimental data. Most current strategies have centered on feeding practices (eg, institution of feeds, advancement of feeds, composition of feeds, and standardization of feeding practices). Emerging strategies include amino acid supplementation, the use of platelet-activating factor(PAF) antagonists or PAF-acetylhydrolase administration, polyunsaturated fatty acid administration, epidermal growth factor administration, and the use of pre- and probiotics.

Newborn intestinal circulation. Physiology and pathophysiology.

The physiologic characteristics of the newborn intestinal circulation are unique when compared with the adult condition. Most important, intestinal vascular resistance across newborn intestine is exceptionally low and this transient reduction is mediated by an increased constitutive and stimulated production of NO. The low vascular resistance characteristic of newborn intestine alters the capacity of this vasculature to respond to systemic circulatory perturbations, such as hypotension and arterial hypoxemia. The essential role of endothelial production of NO in maintaining newborn intestinal hemodynamics might be important in the pathogenesis of NEC, because endothelial dysfunction would limit, or possibly eliminate, NO production, leading to substantial intestinal ischemia.

Breast-feeding initiation in women with pregestational diabetes mellitus.

OBJECTIVE: To examine feeding practices and factors associated with breast-feeding initiation (BFI) in women with pregestational diabetes mellitus (PGDM) and their infants. METHODS: In all, 392 PGDM (135 late preterm and 257 term) pregnancies were studied. Infant feeding preference was ascertained on admission. RESULTS: After birth, 166 (42%) of the infants received well-baby care, whereas 226 (58%) were admitted to the newborn intensive care unit (NICU). Hypoglycemia (blood glucose <40 mg/dL), which occurred in 128 (33%) of all infants, did not influence BFI. Of 257 women who intended to BF, 55% initiated BF. Also, 5% of 105 women who intended to feed formula and 13% of the 30 undecided later initiated BF. CONCLUSIONS: The BFI rate for women with PGDM is remarkably low even among those who intended to BF. Factors associated with BFI failure in this population were primiparity, African American race, lower education, smoking, lack of intention to BF, and NICU admission.

Delivery room triage of large for gestational age infants of diabetic mothers.

OBJECTIVE: To review our 4-year experience (2008-2011) with delivery room triage of large for gestational age infants of diabetic mothers. DESIGN/METHODS: Retrospective cohort investigation of 311 large for gestational age infants of diabetic mothers (White's Class A1 (77), A2 (87), B (77), and C-R (70)). RESULTS: Of 311 women, 31% delivered at 34-36 weeks gestational age and 69% at term. While 70% were delivered by cesarean, 30% were vaginal deliveries. A total of 160 asymptomatic infants were triaged from the delivery room to the well baby nursery. Of these, 55 (34%) developed hypoglycemia. In 43 cases, the hypoglycemia was corrected by early feedings; in the remaining 12, intravenous dextrose treatment was required. A total of 151 infants were triaged from the delivery room to the neonatal intensive care unit. Admission diagnoses included respiratory distress (51%), prevention of hypoglycemia (27%), prematurity (21%), and asphyxia (1%). Hypoglycemia affected 66 (44%) of all neonatal intensive care unit infants. CONCLUSION: Safe triage of asymptomatic large for gestational age infants of diabetic mothers from the delivery room to well baby nursery can be accomplished in the majority of cases. Those infants in need of specialized care can be accurately identified and effectively treated in the neonatal intensive care unit setting.

Deliberate practice improves pediatric residents' skills and team behaviors during simulated neonatal resuscitation.

OBJECTIVE: To evaluate the skills and team behavior of pediatric residents during resuscitation with a high-fidelity mannequin before and after a deliberate practice intervention. METHODS: Each month residents participate in two 90-minute videorecorded sessions (2-3 weeks apart) in an "off-site" delivery room during their neonatal ICU rotation. Teams responded to a scenario that required 5 skills (positive pressure ventilation, chest compressions, endotracheal intubation, umbilical vein catheterization, and epinephrine administration). Skills were scored for technique and timeliness and team behaviors for communication, management, and leadership. A 2-hour focused intervention was given between sessions. RESULTS: In all, 33 residents (11 teams) completed the sessions. Gaps in procedural skills noted during the first session were corrected. Timeliness for completion of skills remained below expectations. Improvements in team behaviors were noted. CONCLUSIONS: Deliberate practice improved procedural skills and team performance. Lack of improvement in timeliness suggests that a different educational paradigm is required.

Early feeding and neonatal hypoglycemia in infants of diabetic mothers.

OBJECTIVES: To examine the effects of early formula feeding or breast-feeding on hypoglycemia in infants born to 303 A1-A2 and 88 Class B-RF diabetics. METHODS: Infants with hypoglycemia (blood glucose < 40 mg/dL) were breast-fed or formula-fed, and those with recurrences were given intravenous dextrose. RESULTS: Of 293 infants admitted to the well-baby nursery, 87 (30%) had hypoglycemia, corrected by early feeding in 75 (86%), while 12 (14%) required intravenous dextrose. In all, 98 infants were admitted to the newborn intensive care unit for respiratory distress (40%), prematurity (33%) or prevention of hypoglycemia (27%). Although all newborn intensive care unit patients received intravenous dextrose, 22 (22%) had hypoglycemia. Of 109 hypoglycemia episodes, 89 (82%) were single low occurrences. At discharge, 56% of well-baby nursery and 43% of newborn intensive care unit infants initiated breast-feeding. CONCLUSIONS: Hypoglycemia among infants of diabetic mothers can be corrected by early breast-feeding or formula feeding.

Pediatrics residents' preparedness for neonatal resuscitation assessed using high-fidelity simulation.

BACKGROUND: Pediatrics residents are expected to demonstrate preparedness for neonatal resuscitation, yet research has shown gaps in residents' readiness to perform this skill. OBJECTIVE: To evaluate procedural skills and team performance of pediatrics residents during neonatal resuscitation (NR) using a high-fidelity mannequin, and to assess residents' confidence in their NR skills before and after training. METHODS: Two teams of residents (all had completed NR program training) participated in 2 separate, 90-minute sessions (2 to 3 weeks apart) in an off-site delivery room during their neonatal intensive care rotation. Residents' confidence in assisting and leading NR was surveyed before each session. Teams participated in a scenario (adapted from the NR program), which required 5 skills (positive pressure ventilation, chest compressions, endotracheal intubation, umbilical vein catheterization, and epinephrine administration). Video recording was used for debriefing and scoring. Skills were scored for technique and timeliness, and team behaviors were scored for communication, management, and leadership. RESULTS: Twenty-six residents (11 teams) completed 2 paired sessions. Self-confidence scores increased between the 2 sessions but were not correlated with performance. Gaps in procedural skill performance were observed, and timeliness for most skills did not meet expectations. Significant improvement in team communication was noted. CONCLUSIONS: Important gaps in procedural skill performance, particularly timeliness, were detected by NR simulation training; residents' improvements in self-confidence did not reflect gains in actual performance. Their relative unpreparedness for NR (despite prior certification) highlights the need for deliberate practice and specific team training before and during neonatal intensive care delivery room rotations.

Breastfeeding in women with severe preeclampsia.

BACKGROUND: In the United States, breastfeeding initiation is reported for 75% of all live births; however, little information is available for mothers affected by severe preeclampsia (SP) who because of magnesium sulfate treatment are separated from their infants in the immediate postpartum period. This study examined feeding practices and factors associated with breastfeeding initiation in 281 women with SP and their 200 late-preterm and 81 term infants. SUBJECTS AND METHODS: SP was diagnosed according to established clinical and laboratory criteria. Infant feeding preference was ascertained on admission to labor and delivery. Variables known to influence breastfeeding initiation, including maternal age, smoking, obesity, and racial and educational characteristics, were assessed. RESULTS: All mothers received magnesium sulfate for 24 hours following delivery. Of 281 infants, 54% were admitted to the neonatal intensive care unit (NICU). All mothers and infants survived. On admission, 149 women intended to breastfeed, 73 intended to feed formula, and 59 were undecided. Four of 73 women who did not wish to breastfeed and 27 of 59 originally undecided later initiated breastfeeding. At discharge, 144 (51%) of all these mothers had successfully initiated breastfeeding. Factors associated with breastfeeding initiation failure included African American race, younger age, lower education, multiparity, smoking, and obesity. Of 149 women who intended to breastfeed, 76% were successful, and logistic regression analysis showed that intention to breastfeed was the most significant predictor of breastfeeding initiation. During the first 24 hours postpartum, 78% of infants receiving well-baby care, and 4% of those admitted to the NICU visited with their mother once. Among women who intended to breastfeed, successful breastfeeding initiation involved 85% of infants receiving routine well-baby care and 69% of those admitted to the NICU. CONCLUSIONS: In spite of the challenges created by SP, including early maternal separation, breastfeeding initiation is possible. The strongest predictor for breastfeeding success remains the intention to breastfeed, whereas race, lower level of education, and obesity are associated with breastfeeding initiation failure.