Endocan: A biomarker for endothelial dysfunction and inflammation, linking maternal obesity and pediatric obesity in a cohort of preterm neonates.

OBJECTIVES: Numerous animal and epidemiologic studies have demonstrated a positive association between maternal obesity in pregnancy and obesity in offspring. The biologic mechanisms of this association remain under investigation. One proposed mechanism includes fetoplacental endothelial dysfunction secondary to inflammation. Endocan is a relatively new biomarker for endothelial dysfunction and inflammation. Our objectives were to examine (1) the association between maternal obesity and neonatal serum endocan at birth, and (2) the association between neonatal serum endocan at birth and pediatric obesity at 24-36 months of age. STUDY DESIGN: This was a secondary analysis of a prospective cohort of neonates born < 33 weeks gestation. Serum endocan was collected within 48 hours of birth. Serum endocan levels were compared in neonates born to obese mothers vs. those born to non-obese mothers. BMI data were retrospectively collected from cohort neonates between 24 and 36 months of age. RESULTS: The analysis included 120 mother/neonate dyads. Neonates born to obese mothers had higher median serum endocan at birth compared to neonates born to non-obese mothers (299 ng/L [205-586] vs. 251 ng/L [164-339], p = 0.045). In a linear regression modeled on neonatal serum endocan level, maternal obesity had a statistically significant positive association (p = 0.021). Higher mean serum endocan level at birth was associated with pediatric obesity between 24 and 36 months (obese vs. non-obese offspring; 574 ng/L (222) vs. 321 ng/L (166), p = 0.005). CONCLUSIONS: In our cohort of preterm neonates, elevated serum endocan at birth was associated with both maternal obesity and downstream pediatric obesity. More research is needed to understand intergenerational transmission of obesity. A large focus has been on epigenetic modification. Endothelial dysfunction and inflammation may play important roles in these pathways. Effective biomarkers, including endocan, may also serve as intermediate outcomes in future pregnancy research.

Neonatal cord blood eucapnic pH: A potential biomarker predicting the need for transfer to the NICU.

INTRODUCTION: The best biomarker for neonatal metabolic acidosis (NMA) and its related complications is still a matter of debate. Umbilical artery (Ua) cord pH is not sufficiently specific, as is lactatemia, while base deficit is considered to offer no added value. From a physiological point of view, the calculated neonatal eucapnic pH is a more specific marker for neonatal metabolic acidosis and may be a better predictor of birth complications of hypoxic origin, because complications related to asphyxia are always preceded by neonatal depression leading to a transfer to a neonatal intensive care unit (NICU) for close monitoring. OBJECTIVE: This study aimed to test the hypothesis that in a group of neonates with significant acidemia, neonatal eucapnic pH (pH euc-n) predicts NICU admission better than the Ua cord pH does. METHODS: From a cohort of 5,392 infants all born at ≥35 weeks' gestation, we identified a group of 30 cases with Ua cord pH <7.0. We calculated the area under the curve (AUC) for pH euc-n and Ua cord pH using the receiver-operating characteristic (ROC) curve and compared the performance of these biological markers in predicting transfer to the NICU. Cut-off points were determined by selecting the best value of the positive likelihood ratio that maximizes the accuracy of prediction. RESULTS: From the 30 newborns diagnosed with significant acidemia, four infants were transferred to the NICU. No case of neonatal encephalopathy was observed. In these infants, the pH euc-n AUC (0.66) was significantly higher than the Ua cord pH AUC (0.44) (P<0.005), with the best pH euc-n cut-off value at 7.11. CONCLUSION: Despite the study limitations, our results suggest that pH euc-n is a better marker than Ua pH for predicting admission to the NICU in newborns with acidemia at birth. These are preliminary results and further investigations are mandatory in larger population samples to confirm these findings and to determine the optimal cut-off value for pH euc-n for the most accurate prediction of a complicated transition to extrauterine life and, potentially, neonatal hypoxic-ischemic encephalopathy.

The association between AB blood group and neonatal disease.

BACKGROUND: Numerous studies have examined the association between ABO blood groups and adult disease states, but very few have studied the neonatal population. The objective of this study was to determine the relationship between AB blood group and the occurrence of common neonatal disorders such as neutropenia at birth, sepsis, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and patent ductus arteriosus (PDA) compared to all other blood groups. METHODS: We performed a retrospective review on 3,981 infants born at 22 0/7 to 42 6/7 weeks' gestational age and compared the relative risk of neonatal diseases in infants with AB blood group to that of infants with all other blood groups (A, B, and O). RESULTS: When compared to all other blood groups, AB infants demonstrated an increased risk for developing negative clinical outcomes. AB blood group was significantly associated with a 14-89% increased risk of neutropenia at birth, sepsis, RDS, and ROP. Risks for IVH and PDA were not significant. CONCLUSION: We hypothesize that the phenotypic expression of A and B antigens, rather than the antigens themselves, in the AB group may reveal an enhanced susceptibility to injury at the endothelial level resulting in an increased risk for disease development.

The role of fetal inflammatory response syndrome and fetal anemia in nonpreventable term neonatal encephalopathy.

OBJECTIVE: To evaluate asphyxial patterns in term encephalopathic newborns caused by chorioamnionitis or intrapartum blood loss that resulted in cerebral palsy and allegations of obstetrical professional liability. STUDY DESIGN: As an expert witness, JKM identified term newborns with profound neurologic impairment: 18 born in the presence of chorioamnionitis and 14 with significant anemia. RESULT: In both study groups, profound depression with low 10-min Apgars was associated with early-onset seizures (88%), multiorgan failure (94%) and a partial prolonged injury to the cortex and subcortical white matter (94%). A cord arterial pH>7.00 was noted in 68% and deep gray matter injury involving the basal ganglia and thalamus occurred in only 19% of the newborns studied. CONCLUSION: The cord arterial pH and pCO2 values, early-onset seizures and paucity of isolated deep gray matter injury support that significant injury occurred postnatally despite appropriate resuscitation. This unique pattern may refute allegations of obstetrical mismanagement in the intrapartum period.

Factors influencing independent oral feeding in preterm infants.

OBJECTIVE: Determine the mean post-menstrual age when preterm infants attain independent oral feeding skills and whether gestational age, common neonatal morbidities, gender, race, delivery route, or birth year affects this reflex. METHODS: A retrospective chart review of 2700 preterm infants, born before 37 weeks gestational age admitted to a level III NICU between January 1978 and July 2013, to determine the post-menstrual age when independent oral feedings occur. RESULTS: Mean post-menstrual age at achievement of independent oral feeding was 36 + 4/7 weeks ± 14 days. Gestational age under 29 weeks correlated with delayed post-menstrual age at achievement of independent oral feeding at 37 + 3/7 weeks versus 36 + 1/7 weeks for gestational age 29-33 weeks and 36 + 3/7 weeks for late preterm infants (p < 0.0001). Preterm infants with certain morbidities experienced a delay in independent oral feeding: necrotizing enterocolitis at 38 + 6/7 weeks (p < 0.0001), bronchopulmonary dysplasia at 38 + 1/7 weeks (p < 0.0001), severe intraventricular hemorrhage at 37 + 6/7 weeks (p < 0.001). Preterm infants born before the year 2000 achieved independent oral feeding two days later than preterm infants born since the year 2000 (p < 0.0001). Preterm infants delivered vaginally achieved independent oral feeding three days sooner than infants delivered via c-section (p < 0.0001). Female infants orally fed one day sooner than male preterm infants (p = 0.0008). CONCLUSIONS: Preterm infants achieve independent oral feeding at 36 + 4/7 weeks. Factors negatively influencing when the preterm infant will achieve independent oral feeding include gestational age under 29 weeks and major morbidities, whereas vaginal delivery and ongoing advances in neonatal care may accelerate the transition to independent oral feeding.

Acute drop in blood monocyte count differentiates NEC from other causes of feeding intolerance.

OBJECTIVE: Necrotizing enterocolitis (NEC) is characterized by macrophage infiltration into affected tissues. Because intestinal macrophages are derived from recruitment and in situ differentiation of blood monocytes in the gut mucosa, we hypothesized that increased recruitment of monocytes to the intestine during NEC reduces the blood monocyte concentration and that this fall in blood monocytes can be a useful biomarker for NEC. STUDY DESIGN: We reviewed medical records of very-low-birth-weight (VLBW) infants treated for NEC and compared them with a matched control group comprised of infants with feeding intolerance but no signs of NEC. Clinical characteristics and absolute monocyte counts (AMCs) were recorded. Diagnostic accuracy of AMC values was tested using receiver-operator characteristics (ROC). RESULT: We compared 69 cases and 257 controls (median 27 weeks, range 26 to 29 in both the groups). In stage II NEC, AMCs decreased from median 1.7 × 10(9) l(-1) (interquartile range (IQR) 0.98 to 2.4) to 0.8 (IQR 0.62 to 2.1); P < 0.05. In stage III NEC, monocyte counts decreased from median 2.1 × 10(9) l(-1) (IQR 0.1.5 to 3.2) to 0.8 (IQR 0.6 to 1.9); P < 0.05. There was no change in AMCs in control infants. ROC of AMC values showed a diagnostic accuracy (area under the curve) of 0.76. In a given infant with feeding intolerance, a drop in AMCs of > 20% indicated NEC with sensitivity of 0.70 (95% confidence interval (CI) 0.57 to 0.81) and specificity of 0.71 (95% CI 0.64 to 0.77). CONCLUSION: We have identified a fall in blood monocyte concentration as a novel biomarker for NEC in VLBW infants.

Adult outcomes of three newborns with a combined weight of 1100 grams.

OBJECTIVE: To present the short- and long-term (20 years) growth and developmental outcomes of four micropremies (birth weight of less than 500 grams). METHOD: Retrospective review of medical records and prospective assessment/interview with patients and their families. RESULTS: One infant was lost at long-term follow-up. The other three showed a quite satisfactory health status and life style in early adulthood. CONCLUSIONS: Despite extreme low birth weight (less than 500 grams) normal outcomes are possible. In the case of micropremies, gestational age appears to be of greater importance than birth weight as well as female gender in the decision-making process regarding initiation of resuscitation.

Decreased survival in necrotizing enterocolitis is significantly associated with neonatal and maternal blood group: the AB isoagglutinin hypothesis.

OBJECTIVE: To determine the effect of neonatal and maternal blood group on the mortality risk from necrotizing enterocolitis (NEC). STUDY DESIGN: Retrospective chart review of all neonates admitted to the neonatal intensive care unit over 24 years. Data on birth date, gestational age, maternal/neonatal blood group, number of transfusions, and survival time (defined as date of birth to date of death/discharge) were collected on those with NEC. RESULT: 276 neonates with Bell stage II-III NEC were analyzed. AB neonates had a significantly higher risk of mortality from NEC compared with other blood groups (HR 2.87; 95% CI 1.40 to 5.89; P=0.003). Multivariate analysis showed AB blood group to be an independent risk factor for mortality from NEC. CONCLUSION: Neonatal and maternal blood groups are significantly associated with a neonate's survival from NEC. The increased mortality of AB neonates may be related to factors such as neonatal blood group antigens and/or transplacental transfer of isoagglutinins.

Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial.

CONTEXT: The practice of administering weekly courses of antenatal corticosteroids to pregnant women at risk of preterm delivery is widespread, but no randomized trial has established the efficacy or safety of this practice. OBJECTIVES: To evaluate the efficacy of weekly administration of antenatal corticosteroids compared with a single course in reducing the incidence of neonatal morbidity and to evaluate potential complications of weekly treatment. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled intention-to-treat trial conducted in 13 academic centers in the United States from February 1996 through April 2000. PARTICIPANTS: A total of 502 pregnant women between 24 and 32 completed weeks' gestation who were at high risk of preterm delivery. INTERVENTION: All patients received a complete single course of antenatal corticosteroids (either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses, or dexamethasone, 6 mg intramuscularly repeated every 12 hours for 4 doses). Participants who had not delivered 1 week after receipt of the single course were randomly assigned to receive either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses every week until 34 weeks' gestation or delivery, whichever came first (n = 256), or a similarly administered placebo (n = 246). MAIN OUTCOME MEASURE: Composite neonatal morbidity (including severe respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, proven sepsis, necrotizing enterocolitis, or perinatal death). RESULTS: Composite morbidity occurred in 22.5% of the weekly-course group vs 28.0% of the single-course group (unadjusted relative risk, 0.80; 95% confidence interval, 0.59-1.10). Neither group assignment nor the number of treatment courses was associated with a reduction in composite morbidity. CONCLUSIONS: Weekly courses of antenatal corticosteroids did not reduce composite neonatal morbidity compared with a single course of treatment. Weekly courses of antenatal corticosteroids should not be routinely prescribed for women at risk of preterm delivery.

Sepsis-induced alteration in T-cell Ca(2+) signaling in neonatal rats.

Sepsis-induced suppression in T-cell proliferation follows deranged Ca(2+) signaling in adult rats. In preliminary studies, we observed suppression in T-cell proliferation in septic neonatal rats as well. In this study, we assessed splenic T-cell cytosolic Ca(2+) concentration, [Ca(2+)](i), as its elevation plays an important role in T-cell proliferation. Also, we investigated the role of PGE(2) in sepsis-related changes in T-cell [Ca(2+)](i) in animals pretreated with cyclooxygenase-1 (COX-1) inhibitor (resveratrol) and cyclooxygenase-2 (COX-2) inhibitor (NS-398). Sepsis was induced in 15-day-old rat pups by intraperitoneal implantation of fecal pellets containing Escherichia coli and Bacteroides fragilis. The sham group consisted of pups implanted with sterile fecal pellets. Septic and sham pups were sacrificed 24 h after implantation and their spleens were removed. The spleens from sham and septic pups, along with spleens from unoperated control pups, were processed for single cell suspensions, and T cells were isolated using nylon wool columns. Fura-2 fluorophotometry was employed for the measurement of [Ca(2+)](i) (in nM units) in T cells stimulated with concanavalin A (ConA). Our results show that ConA-mediated T-cell [Ca(2+)](i) response is significantly suppressed in septic neonatal rats. Pretreatment of pups with COX-2, but not COX-1 inhibitor, prevented the decrease in the [Ca(2+)](i) response. These findings suggest that PGE(2) might induce the attenuation in T-cell Ca(2+) signaling during sepsis in neonatal rats.

Neonatal-perinatal risk factors for the development of persistent pulmonary hypertension of the newborn in preterm newborns.

There is a long-held belief that preterm newborns lack sufficient arteriolar musculature to maintain a prolonged elevated pulmonary vascular resistance (PVR) after birth. Net ductal flow is thought to be minimal, with the developing pulmonary circulation incapable of significant vasoconstriction. We identified retrospectively 15 premature newborns over a 10-year period weighing < or = 1500 g and with a gestational age of < or = 30 weeks with documented persistent pulmonary hypertension of the newborn (PPHN) in the first 24 hours after birth. We matched 36 newborns of similar weight and gestation with no clinical evidence of shunting. The control group weaned to an FiO2 < or = 0.50 by 12 hours after birth. Despite similar gestational ages, the PPHN group (n = 15) had significantly higher birth weights than the control group (n = 36). The duration of ruptured membranes, maternal tobacco use, and use of antenatal steroids were significantly higher in the PPHN group. We speculate that these three factors might act in a synergistic relationship with which to accelerate pulmonary vascular smooth muscle development in premature newborns.

Prophylactic treatment of endotoxic shock with monophosphoryl lipid A in newborn rats.

Mortality due to gram-negative septic shock remains high despite advances in medical care. Induction of endotoxin tolerance might be a new treatment strategy to prevent septic shock in the newborn. The present study was performed to show that an injection in pregnant rats of monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS), induces tolerance to Salmonella enteritidis LPS and tumor necrosis factor alpha (TNF-alpha) in their offspring. MPL at a dose of 2 mg/kg was injected into pregnant rats on the 19th day of gestation. Their 0-day-old offspring later received an intraperitoneal injection of S. enteritidis LPS or TNF-alpha. Newborn rats of MPL-treated dams exhibited a higher survival rate, absence of lactacidemia and lower plasma TNF-alpha concentration in response to S. enteritidis LPS when compared to the newborn rats of saline-treated dams. Newborn rats of MPL-treated dams were more tolerant to TNF-alpha than those of saline-treated dams. MPL injection into pregnant rats did not increase plasma endotoxin concentration in the fetuses, suggesting no placental passage took place, but it did increase plasma TNF-alpha concentration. We concluded that an injection of MPL into pregnant rats induced tolerance to LPS in their offspring, which might be due to TNF-alpha-induced TNF-alpha tolerance.

Perinatal myocardial infarction in a newborn with a structurally normal heart.

Myocardial infarction in a newborn infant in the absence of congenital heart disease and anomalous coronary artery anatomy is extremely rare. We report a case of a newborn with a structurally normal heart who presented shortly after birth with congestive heart failure and cardiovascular collapse suggestive of a hypoplastic left ventricle or critical aortic stenosis. This newborn had a massive myocardial infarction caused by thromboembolic occlusion of the left main coronary artery. Clinical, laboratory, and autopsy data suggest the event occurred in utero.

Placental pathologic conditions in anticardiolipin antibody positive women whose infants had congenital heart defects.

Anticardiolipin antibodies (ACLA) are present in 10% of women with recurrent pregnancy loss. Other associations with ACLA are arterial and venous thrombosis, cerebral infarction, pulmonary hypertension, preterm delivery, and fetal growth retardation. A previous prospective study of infants of mothers with positive ACLA identified an increased incidence of congenital heart disease in this population. As a follow-up, the placentas of the initial 40 ACLA-positive patients were studied to determine whether there was an increased incidence of infarct or thrombosis compared with that in control subjects matched for maternal age and gestational age within the same 2-year period. The age of ACLA-positive mothers was 30 +/- 5 years versus 29 +/- 5 years in the ACLA-negative mothers. Gestational age was 37 +/- 2 weeks in both groups; placental weight was 553 +/- 169 gm in the ACLA-positive group versus 593 +/- 117 gm in the ACLA-negative group. The birth weight was 2972 +/- 709 gm in infants of ACLA-positive mothers and 2920 +/- 674 gm in infants of ACLA-negative mothers. There was no statistically significant difference between the two groups in gestational age, maternal disease, placental histologic findings, placental weight, type of delivery, or type of ACLA. Twenty-seven ACLA-positive women were receiving prednisone. Chi square analysis showed the ACLA-positive mothers to have more spontaneous abortions (p = 0.02) and to have more children with congenital heart disease (5 ventricular septal defects and 2 atrial septal defects) (p = 0.006). In summary, infants born with congenital heart defects in women positive for ACLA did not have significant placental pathologic conditions when compared with control infants.

The ethics of caring for conjoined twins. The Lakeberg twins.

In June 1993, conjoined twin Amy and Angela Lakeberg became the focus of national attention. They shared a complex six-chambered heart and one liver; only one could survive separation surgery; and even her chances were slim. The medical challenge was great and the ethical challenges were even greater.

Severe rhinorrhea and respiratory distress in a neonate exposed to fluphenazine hydrochloride prenatally.

OBJECTIVE: To report a case of respiratory distress with severe rhinorrhea in a newborn exposed prenatally to fluphenazine hydrochloride. CASE SUMMARY: The safety of phenothiazines during pregnancy and the effect on the fetus and newborn are not well known. We describe a newborn who had severe rhinorrhea, vomiting, and respiratory distress after being exposed in utero to fluphenazine hydrochloride. Sepsis, choanal atresia, and congenital syphilis were excluded as causative factors for rhinorrhea. The rhinorrhea and upper airway obstruction responded to treatment with pseudoephedrine. CONCLUSIONS: Severe rhinorrhea, vomiting, and respiratory distress that occurred in this infant have not been reported previously following prenatal fluphenazine hydrochloride exposure. Awareness of this problem would be helpful to clinicians and should be considered in the differential diagnosis of rhinorrhea in newborns.