Peter J. Giannone

Maternal preeclampsia and neonatal outcomes.

Preeclampsia is a multiorgan, heterogeneous disorder of pregnancy associated with significant maternal and neonatal morbidity and mortality. Optimal strategies in the care of the women with preeclampsia have not been fully elucidated, leaving physicians with incomplete data to guide their clinical decision making. Because preeclampsia is a progressive disorder, in some circumstances, delivery is needed to halt the progression to the benefit of the mother and fetus. However, the need for premature delivery has adverse effects on important neonatal outcomes not limited to the most premature infants. Late-preterm infants account for approximately two thirds of all preterm deliveries and are at significant risk for morbidity and mortality. Reviewed is the current literature in the diagnosis and obstetrical management of preeclampsia, the outcomes of late-preterm infants, and potential strategies to optimize fetal outcomes in pregnancies complicated by preeclampsia.

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.

Neonatal abstinence syndrome: transitioning methadone-treated infants from an inpatient to an outpatient setting

Objective:Each year in the US ∼50 000 neonates receive inpatient pharmacotherapy for the treatment of neonatal abstinence syndrome (NAS). The objective of this study is to compare the safety and efficacy of a traditional inpatient only approach with a combined inpatient and outpatient methadone treatment program.Study Design:Retrospective review (2007 to 2009). Infants were born to mothers maintained on methadone in an antenatal substance abuse program. All infants received methadone for NAS treatment as inpatient. Methadone weaning for the traditional group (75 patients) was inpatient, whereas the combined group (46 patients) was outpatient.Result:Infants in the traditional and combined groups were similar in demographics, obstetrical risk factors, birth weight, gestational age (GA) and the incidence of prematurity (34 and 31%). Hospital stay was shorter in the combined than in the traditional group (13 vs 25 days; P<0.01). Although the duration of treatment was longer for infants in the combined group (37 vs 21days, P<0.01), the cumulative methadone dose was similar (3.6 vs 3.1 mg kg−1, P=0.42). Follow-up information (at least 3 months) was available for 80% of infants in the traditional and 100% of infants in the combined group. All infants in the combined group were seen ⩽72 h from hospital discharge. Breastfeeding was more common among infants in the combined group (24 vs 8% P<0.05). Following discharge there were no differences between the two groups in hospital readmissions for NAS. Prematurity (34 to 36 weeks GA) was the only predictor for hospital readmission for NAS in both groups (P=0.02, OR 5). Average hospital cost for each infant in the combined group was

Effects of prenatal lipopolysaccharide exposure on epithelial development and function in newborn rat intestine.

13 817 less than in the traditional group.Conclusion:A combined inpatient and outpatient methadone treatment in the management of NAS decreases hospital stay and substantially reduces cost. Additional studies are needed to evaluate the potential long-term benefits of the combined approach on infants and their families.

Breastfeeding in women with severe preeclampsia.

Background: Maternal infection during pregnancy is associated with several neonatal morbidities, including periventricular leukomalacia and lung maldevelopment and injury. Objective: To test the hypothesis that responses to prenatal maternal exposure to lipopolysaccharide (LPS) alter intestinal epithelial development and function in newborn rats. Design/Methods: Timed-pregnancy female Sprague-Dawley rats were administered either 2 mg LPS or an equal volume of isotonic saline by intraperitoneal injection at E16 and allowed to deliver naturally. Pups were weighed and then killed at days of life (DOL) 0, 3, 7 and 14. Morphometric parameters were measured on standard hematoxylin and eosin-stained sections using ImagePro software. Immunohistochemistry was performed with antibody specific for inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine on distal ileal intestinal samples analyzed at each time point. Optical density was determined and quantified for site-specific regions of intestinal sections. On DOL 14, in vivo mucosal permeability was measured by feeding rats fluorescein isothiocyanate (FITC) via orogastric tube; and then serum FITC was measured. Results: There were no significant differences in pup weights. Mucosal thicknesses were significantly less in the distal ileum from pups born to LPS-exposed dams on DOL 0, 3 and 7 (P < 0.001). On DOL 0, iNOS protein concentrations in the prenatal LPS treatment group were significantly greater than iNOS protein concentrations in the distal villus (P < 0.001), proximal villus/crypts (P < 0.01), submucosa (P < 0.001) and muscularis (P < 0.01) in the distal small intestine of the control group. On DOL 3, 7 and 14, significant differences were observed in iNOS protein concentrations in the distal villus and submucosal regions between groups (P < 0.001). On DOL 0, 3, 7 and 14, 3-nitrotyrosine immunostaining was significantly elevated in the prenatal LPS-exposed pups in the distal villus on (P < 0.001) as well as in the submucosa on DOL 3 (P < 0.001). Serum FITC measurement was significantly greater in prenatal LPS exposure group at DOL 14 (P < 0.001). Conclusions: Maternal exposure to LPS during pregnancy alters intestinal growth and regulation of iNOS in the newborn rat intestine.

LPS-binding protein enables intestinal epithelial restitution despite LPS exposure.

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.

Probiotics and Prebiotics for the Prevention of Necrotizing Enterocolitis

Objectives: Intestinal epithelial restitution is the first part in the process of mucosal repair after injury in the intestine. Integrity of the intestinal mucosal barrier is important as a first line of defense against bacteria and endotoxin. Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in extremely-low-birth-weight infants, but its mechanisms are not well defined. Abnormal bacterial colonization, immature barrier function, innate immunity activation, and inflammation likely play a role. Lipopolysaccharide (LPS)-binding protein (LBP) is secreted by enterocytes in response to inflammatory stimuli and has concentration-dependent effects. At basal concentrations, LBP stimulates the inflammatory response by presenting LPS to its receptor; however, at high concentrations, LBP is able to neutralize LPS and prevent an exaggerated inflammatory response. We sought to determine how LBP would affect wound healing in an in vitro model of intestinal cell restitution and protect against intestinal injury in a rodent model of NEC. Methods: Immature intestinal epithelial cells (IEC-6) were seeded in poly-L-lysine–coated 8-chamber slides and grown to confluence. A 500-&mgr;m wound was created using a cell scraper mounted on the microscope to achieve uniform wounding. Media was replaced with media containing LPS ± LBP. Slide wells were imaged after 0, 8, and 24 hours and then fixed. Cellular restitution was evaluated via digital images captured on an inverted microscope and wound closure was determined by automated analysis. Toll-like receptor 4 (TLR4) was determined by reverse transcriptase-polymerase chain reaction after RNA isolation from wounded cells 24 hours after treatment. Results: LPS alone attenuated wound healing in immature intestinal epithelium. This attenuation is reversed by 24 hours with increasing concentrations of LBP so that wound healing is equivalent to control (P < 0.001). TLR4 was increased with LPS alone but levels returned to that of control after addition of LBP in the higher concentrations. LBP had no effect on the development of intestinal injury when given during our rodent model of NEC. Abnormal bacterial colonization and activation of innate immunity by LPS are likely involved in the pathogenesis of NEC. The attenuation of wound healing was reversed when LBP was added to LPS but only in the higher concentrations. At these same concentrations of LBP, TLR4 was decreased to that of control. Conclusions: These results indicate that LBP may be a novel therapeutic strategy to facilitate wound healing after the acute phase of NEC and other forms of intestinal injury.

Indomethacin prophylaxis or expectant treatment of patent ductus arteriosus in extremely low birth weight infants

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.

Timing of umbilical cord clamping among infants born at 22 through 27 weeks’ gestation

Background:Indomethacin prophylaxis or expectant treatment are common strategies for the prevention or management of symptomatic patent ductus arteriosus (sPDA).Objective:To compare the clinical responses of extremely low birth weight (ELBW) infants to indomethacin prophylaxis with hat of other infants who were managed expectantly by being treated with indomethacin or surgically only after an sPDA was detected.Methods:Retrospective cohort investigation of 167 ELBW infants who received indomethacin prophylaxis (study) and 167 ELBW infants (control) treated expectantly who were matched by year of birth (1999 to 2006), birth weight, gestational age (GA) and gender.Results:Mothers of the two groups of infants were comparable demographically and on the history of preterm labor, pre-eclampsia, antepartum steroids and cesarean delivery. Study and control infants were similar in birth weight, GA, low 5 min Apgar scores, surfactant administration, the need for arterial blood pressure control, bronchopulmonary dysplasia and neonatal mortality. Necrotizing enterocolitis, spontaneous intestinal perforations, intraventricular hemorrhage grade III to IV, periventricular leukomalacia and stage 3 to 5 retinopathy of prematurity occurred also with similar frequency in both groups of infants. In the indomethacin prophylaxis group, 29% of the infants developed sPDA, and of them 38% responded to indomethacin treatment. In the expectantly treated group, 37% developed sPDA, and of them 59% responded to indomethacin treatment. Overall, surgical ligation rate for sPDA was similar between both groups of patients.Conclusion:In our experience, indomethacin prophylaxis does not show any advantages over expectant early treatment on the management of sPDA in ELBW infants. Although no deleterious effects were observed, prophylaxis exposed a significant number of infants who may have never developed sPDA, to potential indomethacin-related complications.

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

Objective:To investigate the safety, feasibility and efficacy of delayed cord clamping (DCC) compared with immediate cord clamping (ICC) at delivery among infants born at 22 to 27 weeks’ gestation.Study Design:This was a pilot, randomized, controlled trial in which women in labor with singleton pregnancies at 22 to 27 weeks’ gestation were randomly assigned to ICC (cord clamped at 5 to 10 s) or DCC (30 to 45 s).Results:Forty mother–infant pairs were randomized. Infants in the ICC and DCC groups had mean gestational ages (GA) of 24.6 and 24.4 weeks, respectively. No differences were observed between the groups across all available safety measures, although infants in the DCC group had higher admission temperatures than infants in the ICC group (97.4 vs 96.2 °F, P=0.04). During the first 24 h of life, blood pressures were lower in the ICC group than in the DCC group (P<0.05), despite a threefold greater incidence of treatment for hypotension (45% vs 12%, P<0.01). Infants in the ICC group had increased numbers of red blood transfusions (in first 28 days of life) than infants in DCC group (4.1±3.9 vs 2.8±2.2, P=0.04).Conclusion:Among infants born at an average GA of 24 weeks’, DCC appears safe, logistically feasible, and offers hematological and circulatory advantages compared with ICC. A more comprehensive appraisal of this practice is needed.