Neonatal bilirubin production-conjugation imbalance: effect of glucose-6-phosphate dehydrogenase deficiency and borderline prematurity.

OBJECTIVE: To evaluate relations between production and conjugation of bilirubin in the pathophysiology of jaundice in glucose-6-phosophate dehydrogenase (G6PD) deficient neonates. METHODS: Term and borderline premature (35-37 weeks gestational age), healthy, male, G6PD deficient neonates were studied close to the beginning of the 3rd day. Blood carboxyhaemogobin corrected for inspired CO (COHbc; an index of bilirubin production) and serum total conjugated bilirubin (TCB; a reflection of bilirubin conjugation) were measured in simultaneously drawn blood samples by gas chromatography and reverse phase high performance liquid chromatography respectively. A bilirubin production-conjugation index comprising COHbc/TCB was determined; a high index reflects imbalance between the bilirubin production and conjugation processes. COHbc and TCB individually and the production-conjugation index were studied in relation to serum total bilirubin (STB) concentration. RESULTS: Fifty one G6PD deficient neonates were sampled at 51 (8) hours. COHbc values did not correlate with STB (r=0.22, p=0.15). TCB did correlate inversely with STB (r=-0.42, p=0.004), and there was a positive correlation between the production-conjugation index and STB (r=0.45, p=0.002). The production-conjugation index (median (interquartile range)) was higher in the premature (n=8) than term neonates (2.31 (2.12-3.08) v 1.05 (0.53-1.81), p=0.003). This difference was the result of changes in TCB. CONCLUSIONS: The data show that jaundice in G6PD deficient neonates is the result of an imbalance between production and conjugation of bilirubin with a tendency for inefficient bilirubin conjugation over increased haemolysis in its pathogenesis. Borderline premature infants are at special risk of bilirubin production-conjugation imbalance.

Effect of blood transfusions on oxidative stress in preterm infants.

OBJECTIVE: To confirm the increase in non-transferrin bound iron (NTBI) after packed red cell (PRC) transfusion and to evaluate the association with increased oxidative stress in preterm infants. METHOD: Twenty healthy preterm infants (gestational age 28.2 (2.2) weeks; birth weight 1047 (230) g), who required blood transfusion for anaemia of prematurity were prospectively studied. Serum concentrations of NTBI, total hydroperoxides (TH), and protein SH groups, and plasma total radical trapping antioxidant capability (TAC) were measured within three hours before and after PRC transfusion. The infants were transfused with 38.6 (23) ml PRCs over 5.8 (1.0) hours, at a mean age of 43.3 (25.1) days. RESULTS: After PRC transfusion, haemoglobin concentration increased from 9.2 (1.1) to 14.6 (1.5) g/l. Mean plasma NTBI concentration after transfusion was significantly higher (0.43 (0.45) v 2.03 (1.31) micromol/l; p = 0.001), while plasma concentrations of TH (212.3 (42.2) v 214.7 (66.3) Carr units/l) and protein SH groups (317.5 (38.8) v 353.8 (57.4) micromol/), and TAC (256.3 (36.1) v 267.1 (42.4) micromol HClO/ml) remained unchanged. CONCLUSION: For three hours after PRC transfusion, plasma NTBI is significantly increased in preterm infants, but this is not associated with significant changes in oxidative stress.

Prediction of early tolerance to enteral feeding by measurement of superior mesenteric artery blood flow velocity: appropriate- versus small-for-gestational-age preterm infants.

AIM: To evaluate whether serial Doppler measurements of superior mesenteric artery blood flow velocity could predict early tolerance to enteral feeding in preterm infants. METHODS: In a prospective study, 54 healthy preterm neonates were assigned to one of the following groups: neonates with birthweight appropriate for gestational age (group 1), neonates small for gestational age without (group 2) and with prenatal haemodynamic disturbances (group 3). We studied Doppler blood flow velocity and resistance index before and after the first feed. RESULTS: Contrary to patients of group 3, infants in groups 1 and 2 showed a significant increase in blood flow velocity and a significant decrease in resistance index from the preprandial values after the first feed. At each postprandial time, we found significant differences in all velocity and resistance measurements between patients of group 3 and patients of both groups 1 and 2. In all patients, we found that the value of mean velocity measured 30 min after the first feed was the most predictive of early feed tolerance, with 95% sensitivity and 94% specificity when mean velocity >0.38 m/s. CONCLUSION: Small-for-gestational-age preterm infants with prenatal haemodynamic disturbances have an unusual intestinal haemodynamic response to the first feed. In the whole group of preterm infants, the value of mean velocity measured 30 min after the first feed is a good tool for the clinician in predicting early enteral feeding.

Redox status in very-low birth-weight newborns.

Inborn metabolic diseases, such as disorders in pyruvate metabolism, in gluconeogenesis or in the respiratory chain, may present with lactic acidosis in newborn infants. A simple tool to screen for the efficacy of mitochondrial oxidation reduction activity is the detection of the redox status through simultaneous measurements of plasma lactate, pyruvate and ketone bodies, which are strongly influenced by feeding and stress. We present the redox status values of 55 very-low birth-weight infants under different nutritional conditions. We were able to demonstrate that the redox status values are not dependent on the type of nutrition (oral feeding or continuous enteral nutrition). Instead we observed a strong difference between newborns with intrauterine growth retardation and newborns with appropriate growth. Newborns with intrauterine growth retardation show lower preprandial values of glucose and ketone bodies than newborns with appropriate weight, but higher levels of lactate and pyruvate; nevertheless the lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios are normal. The results of the redox status study could suggest the reduced activity of gluconeogenesis and, probably, of beta-oxidation in very-low birth-weight newborns with intrauterine growth retardation.

Perfluorocarbons attenuate oxidative lung damage.

The aim of this study was to investigate the effect of tidal liquid ventilation (TLV) compared to conventional mechanical ventilation (CMV) on oxidative lung damage in the setting of acute respiratory distress syndrome (ARDS). After repeated lung lavages, 10 minipigs were treated with CMV or TLV for 4 hr before the animals were sacrificed. Samples for blood gas analysis and bronchial aspirate samples were withdrawn before the induction of lung injury, and at 10 min, 2 hr, and 4 hr after the beginning of ventilatory support. To assess lung oxidative damage, total hydroperoxide (TH) and advanced oxidation protein product (AOPP) concentrations were measured in bronchial aspirate samples. After 2 and 4 hr of ventilatory support, partial oxygen tension (PaO(2)) and base excess (BE) were significantly higher in the TLV group than in the CMV group, while PaCO(2) was slightly higher, but with no statistical significance. In the CMV group, the AOPP level was significantly higher at 4 hr than at baseline. TH and AOPP bronchial aspirate concentrations were higher in the CMV group than in the TLV group at 2 and 4 hr of ventilation. We conclude that animals treated with TLV showed lower oxidative lung damage compared to animals treated with CMV.

Prolonged hyperinsulinemic hypoglycemia in a small for date preterm.

Hyperinsulinism is an important cause of hypoglycemia in early infancy. Many forms of hyperinsulinemic hypoglycemia are described: transient, prolonged, persistent. Transient forms are well recognized in infants of diabetic mother; prolonged forms are responsible for the hypoglycemia in small-for-date (SGA) infants and asphyxiated newborns. Persistent hyperinsulinemic hypoglycemia occurs in a group of congenital disorders associated with an abnormality of beta-cell regulation throughout the pancreas. Accurate diagnosis and treatment are essential in all various forms of hyperinsulinism also because newborns are at high risk of permanent brain damage. We report a case of prolonged hyperinsulinemic hypoglycemia in a SGA preterm, immediately treated with a high dose of glucose and glucocorticoid and then with diazoxide. Hypoglycemia was continued until 2 months of age when it resolved spontaneously and completely.

Plasma bilirubin level and oxidative stress in preterm infants.

OBJECTIVE: To assess the hypothesis that changes in plasma total bilirubin levels (Btot) can influence the antioxidant system and oxidative stress in preterm infants. METHODS: Twenty two healthy preterm infants who presented with visible non-haemolytic hyperbilirubinaemia were studied at the mean (SD) age of 3.7 (1.5) days. Btot, plasma total hydroperoxide concentration (TH), plasma protein SH group concentration, and total antioxidant capacity of the plasma (TAC) were measured at study entry and after 24 hours. RESULTS: Btot did not correlate with TH, TAC, or protein SH group concentration, but a significant correlation was found between TH and TAC, TH and protein SH groups, and TAC and protein SH groups, both at study entry and after 24 hours. CONCLUSION: The decrease in plasma bilirubin was contemporary with an increase in plasma antioxidant capacity and decrease in oxidative stress in preterm infants. This may be the result of the pro-oxidant effect of haem oxygenase, mediated by iron release, which may outcompete the antioxidant properties of bilirubin.

Effect of blood transfusions on cerebral haemodynamics in preterm infants.

AIM: To assess the possible cerebral haemodynamic changes occurring in preterm infants after blood transfusions. METHODS: Preterm infants who had undergone blood transfusions were prospectively studied using both near infrared spectroscopy and cerebral Doppler ultrasonography. RESULTS: Fourteen infants (mean gestational age 29.6 wk, SD 2.6; mean birthweight 1,430g, SD 332) were studied at the mean age of 29 (SD 14) d. A significant increase in oxygenated haemoglobin (O2Hb), deoxygenated haemoglobin (HHb), mixed cerebral oxygen saturation (SmO2) and change in cerebral blood volume occurred after transfusion. Between ultrasound parameters, we found a decrease in diastolic velocity and an increase in resistance index. CONCLUSION: Blood transfusions improve cerebral oxygen supply and induce a decrease in cerebral blood volume, probably due to an increase in cerebral vessel resistance.

Haemodynamic changes in the brain after vaginal delivery and caesarean section in healthy term infants.

OBJECTIVE: To investigate whether the mode of delivery may affect neonatal cerebral haemodynamics during the first hour of life. DESIGN: Prospective study. SAMPLE: Healthy infants with gestational age > or =37 weeks and birthweight appropriate for gestational age, born after uncomplicated pregnancy by vaginal delivery or elective caesarean section, two to five hours after the delivery. METHODS: Near infra-red spectroscopy was used to measure changes of oxygenated haemoglobin, deoxygenated haemoglobin, oxidized-reduced cytochrome aa3, and mean cerebral oxygen saturation (mixed cerebral oxygen saturation = oxygenated haemoglobin/total haemoglobin). Changes in cerebral blood volume were calculated. RESULTS: Near infra-red spectroscopy data did not show significant differences between infants born by vaginal delivery or by caesarean section. There was a significant decrease of oxygenated haemoglobin and change of cerebral blood volume values at 120 and 180 minutes in both the groups, while deoxygenated haemoglobin and oxidized-reduced cytochrome aa3 were unchanged. CONCLUSIONS: A decrease of cerebral blood volume occurs after birth and this occurs both in infants born by vaginal delivery and by caesarean section.

Pharmacokinetics of oxatomide in preterm infants.

The pharmacokinetics and tolerability of oxatomide oral suspension were investigated in preterm infants to evaluate the feasibility of planning a further study to assess its antiinflammatory effects and its effectiveness in preventing chronic lung disease (CLD). Following the administration of oxatomide 1 mg/kg, the peak plasma concentration (Cmax), the elimination half-life (t1/2), the volume of distribution (Vd), and the area under the curve (AUC) 0-36 h were measured and the following results were obtained: 42.2 +/- 15 ng/ml at 2 h after oxatomide administration, 41.4 +/- 2.0 h, 37.4 +/- 4.2 l/kg, and 468 +/- 52 ng/ml/h, respectively. Our study, therefore, demonstrated that a dose of 1 mg/kg/day oxatomide was effective in reaching therapeutic plasma levels in preterm infants without inducing adverse effects.

Role of ultrasound evaluation of nuchal translucency in prenatal diagnosis.

BACKGROUND: Nuchal translucency (NT) is the ultrasonographic pattern of the accumulation of subcutaneous fluid (> or = 3 mm) behind the fetal neck. The measurement of NT thickness by ultrasound examination at 11-14 weeks of gestation has been associated with maternal age and to be an effective screening tool for trisomy 21; with an invasive method rate of 5%, about 75% of trisomical pregnancies can be identified. With the association of some biochemical markers like maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) to ultrasonography at 11-14 weeks, it is possible to identify about 90% of chromosomal abnormalities. An increase of NT also allows us to identify most other chromosomal abnormalities, a large number of major cardiac defects, skeletal dysplasias, and genetic syndromes. In monochorial twins the discordance in the measurement of NT represents an early sign of twin-to-twin transfusion syndrome (TTTS). METHODS: The objective of our study was to assess the detection of fetal structural defects with an ultrasound scan at 11-14 weeks of gestation. We submitted 3,157 pregnant women to a routine ultrasound examination at 11-14 weeks. The patients were then submitted to ultrasound scan in the second or third trimester of pregnancy. An isolated increased NT thickness was not considered an abnormality, but these patients, nonetheless, were submitted to an early echocardiographic evaluation. Fetal structural abnormalities were classified as major or minor and of early or late onset. RESULTS: A detection rate of 4.3% (135 cases) of abnormalities was found and 22.6% of these (30 cases) were diagnosed by ultrasound scan at 11-14 weeks, including seven cardiac defects associated with increased NT. The antenatal ultrasound detection rate was 73.5%, and 33.2% were diagnosed in the first trimester assessment. A rate of 76.8% of the major defects were diagnosed by the prenatal scan and 35.8% by the scan at 11-14 weeks. Fetal structural defects with the ultrasonography at 11-14 weeks were diagnosed in about 24.3% of the cases, therefore, a second trimester abnormality is important in routine antenatal care to increase the prenatal assessment of fetal anomalies. CONCLUSIONS: As for the introduction of every new technique in routine clinical practice, the operators who perform the ultrasound scan at 11-14 weeks should be submitted to adequate training and to strict quality control.

Paralytic ileus in a mechanically ventilated preterm infant treated with fentanyl.

The administration of fentanyl for sedation of ventilated newborns can induce several side-effects such as hypertension, respiratory muscle rigidity and, as shown in this report, decreased gastrointestinal motility. We report a case of paralytic ileus in a ventilated preterm infant who was given fentanyl in the first 24 hours of life. To our knowledge, the association of paralytic ileus with fentanyl has not been reported previously in full-term or preterm infants. This study indicates that early recognition is required to shorten the delay in diagnosis.

Randomised controlled trial of the effect of cisapride on the pyloric muscle in preterm infants.

UNLABELLED: In this study we determined the effects of cisapride on the pyloric muscle in preterm infants. To perform a randomised, double blind, placebo controlled study, two groups each of 16 preterm newborns were given either cisapride (0.2 mg/kg every 8 h) or a placebo for at least 7 days. Infants were studied first on the day when treatment with cisapride or placebo was to be initiated (time 0), and then after 3 (time 1) and 7 days (time 2). In each group, the following parameters were studied by ultrasonography: cross-sectional diameter of the entire pylorus, muscle thickness, and length of the pyloric canal. Also, the mean daily total gastric aspirate volume was studied for the entire week of the study. At time 0, we observed no significant differences between the two groups with respect to diameter, muscle thickness and length of the pyloric muscle. At time 1 and time 2, both diameter and muscle thickness were significantly greater in the cisapride group than in the placebo group. Furthermore, the length of the pyloric canal was significantly greater in the cisapride group than in placebo group at time 2, though not so at time 1. For the entire week of the study, we found a significantly larger mean daily total gastric aspirate volume in the group of infants treated with cisapride compared to the placebo treated group. CONCLUSION: Cisapride significantly affects all of the main measurements of the pyloric muscle and causes a significantly larger amount of daily total gastric aspirate volume. Its use to promote feeding intolerance in preterm newborns cannot be recommended.

Influence of maternal magnesium sulphate and ritodrine treatment on cerebral blood flow velocity of the preterm newborn.

BACKGROUND: To evaluate the effect of antenatal tocolytic administration of magnesium sulphate and ritodrine on the cerebral blood flow velocity and on the cerebral vascular resistance of preterm newborns in the first hours of life. METHODS: Cerebral blood flow velocity, resistance index and relative vascular resistance were studied in 27 preterm infants (<34 weeks gestation) with antenatal exposure to maternal magnesium sulphate treatment and in 27 preterm infants (<34 weeks gestation) with antenatal exposure to maternal ritodrine treatment. Both antenatal magnesium sulphate or ritodrine were used for tocolysis. Cerebral blood flow was measured, using Doppler ultrasonography, in the anterior cerebral artery, in the left middle cerebral artery and in the right middle cerebral artery. RESULTS: We did not find any significant difference in the blood flow velocity, resistance index or relative vascular resistance in the three cerebral arteries between the two treatment groups. CONCLUSIONS: Our study shows that maternal antenatal administration of magnesium sulphate to delay preterm delivery, compared to antenatal administration of ritodrine, does not induce any significant differences either in cerebral blood flow velocity or in cerebral vascular resistance of preterm infants in the first hours of life.

Transcutaneous bilirubin measurement: a multicenter evaluation of a new device.

OBJECTIVES: The early discharge of neonates from hospitals makes transcutaneous measurement of total bilirubin concentration a useful tool to monitor neonatal jaundice. The objectives of this study were to determine whether 1) transcutaneous bilirubin (TcB) measurement, as performed using BiliCheck (BC), correlates with total serum bilirubin (TSB) levels, measured with standard laboratory methods and with high-pressure liquid chromatography (HPLC-B); 2) infant race, gestational age, postnatal age, or body weight interferes with the measurement of TcB levels in newborn infants; 3) the variability of the TcB measurement is comparable to the variability of TSB measurements; and 4) TcB measurements obtained from the forehead (BCF) and sternum (BCS) generate comparable results. STUDY DESIGN: Newborn infants who were <28 days and >30 weeks' gestational age and who underwent tests for TSB as part of their normal care in 6 different European hospitals were studied. A total of 210 infants were enrolled in the study, 35 at each site. Near simultaneous (within +/- 30 minutes) blood collection for TSB and BCF and BCS measurements were performed. TSB levels were determined by the serum bilirubin method in use at each site, and all HPLC-B determinations were made at the same, independent laboratory. RESULTS: The study group consisted of 140 white, 31 Asian, 14 Hispanic, 9 African, and another 16 newborns of different races. The correlation coefficient (r) between BCF and HPLC-B was 0.890 (95% confidence interval = 0.858-0.915). BCF and BCS generated similar results (r value = 0.890 for BCF and 0.881 for BCS), even if BCS slightly overestimated (mean error = -0.04 mg/dL) and BCF slightly underestimated (mean error = 0.96 mg/dL) in comparison with HPLC-B. Analysis of covariance demonstrated that BC accuracy was independent of race, birth weight, gestational age, and postnatal age of the newborn. Receiver operating characteristic curves were evaluated for BCF and TSB, each compared with HPLC-B. With the use of a cutoff point for HPLC-B of 13 mg/dL (222 micromol/L) and a cutoff of 11 mg/dL on the BCF and TSB, similar sensitivity/specificity (93%/73% for BCF, 95%/76% for TSB) were observed. The use of a cutoff point for HPLC-B of 17 mg/dL (290 micromol/L) and 14 mg/dL (240 micromol/L) for BCF and TSB also produced similar sensitivity/specificity (90%/87% for the BC and 87%/83% for TSB). CONCLUSIONS: Because the correlation coefficient for HPLC-B and BCF is very similar to that found for HPLC-B and laboratory TSB, BC could be used not only as a screening device but also as a reliable substitute of TSB determination. At higher levels of TSB, in which phototherapy and/or exchange transfusion might be considered, BC performed slightly better than the laboratory. The accuracy and precision of the TcB measurement in this study was observed to be comparable to the standard of care laboratory test.

Liquid ventilation in an infant with persistent interstitial pulmonary emphysema.

We present the case of a full term infant affected by diffuse persistent interstitial pulmonary emphysema (PIPE), who was treated with partial liquid ventilation (PLV) after the failure of conventional management. PIPE is a lethal chronic lung disease of unclear pathogenesis. Clinical history, radiological and histological findings confirmed the diagnosis in our patient. PLV applied for 48 hours resulted in a significant improvement in the infant's respiratory function and was not associated with adverse effects. We concluded that PLV could be effective in prolonging the survival of infants with PIPE; its application represents an effective form of respiratory support in infants with chronic lung disease.

Prevention of bilirubin encephalopathy.

Prevention of bilirubin encephalopathy is based on the detection of infants at risk of developing a significant hyperbilirubinemia. This task can be accomplished by performing a simple umbilical cord blood test, such as blood group, Rh, Coombs' test and glucose-6-phosphate dehydrogenase, in order to detect hemolytic diseases. In preterm infants, the prevention of hyperbilirubinemia with phototherapy is a relatively simple task, since these infants are cared for in hospital. Early hospital discharge of full-term neonates represents a major concern. The management of neonatal jaundice requires that therapy begins when total serum bilirubin levels are significantly below the levels at which kernicterus is considered an immediate threat. Unfortunately, determination of serum bilirubin is a painful procedure, and is not very accurate since there is a high variability in laboratory measurements. The accuracy and precision of a new transcutaneous bilirubin measurement, comparable to the standard of care laboratory test, makes the daily evaluation of transcutaneous bilirubin measurement a useful tool in distinguishing physiological from nonphysiological hyperbilirubinemia, and determining the bilirubin increment in the first days of life. Full-term neonates who lose a significant amount of weight are especially at risk of significant hyperbilirubinemia and must be treated with ad libitum feeding and intensive phototherapy.

The role of blood transfusions and iron intake on retinopathy of prematurity.

BACKGROUND: The role of blood transfusions and iron intake in the pathogenesis or retinopathy of prematurity (ROP) is controversial. AIM: To evaluate the influence of packed red cell (PRC) transfusions and iron intake on ROP incidence. STUDY DESIGN: Prospective observational study. SUBJECTS: Forty-five preterm infants with birthweight <1250 g were studied. After ophthalmological study, they were divided into group A (n=24) that included newborns without ROP, and group B (n=21) that included newborns with ROP. RESULTS: Logistic regression analysis demonstrated that gestational age (OR 0.61; 95% C.I. 0.41-0.90), transfusion volume during the first week (OR 1.16; 95% C.I. 1.03-1.3) and during the first 2 months of life (OR 2.93; 95% C.I. 1.52-5.62), and iron intake during the first week of life (OR 1.15; C.I. 1.01-1.32) and during the first 2 months of life (OR 2.93; 95% C.I. 1.52-5.62) were associated with the development of ROP. CONCLUSION: Our study showed that gestational age, blood transfusion volume and iron load by transfusions are associated with the risk of occurrence of ROP in infants with a birthweight of less than 1250 g.

Is breastfeeding really favoring early neonatal jaundice?

OBJECTIVE: The purpose of this study was to evaluate the development of significant hyperbilirubinemia in a large unselected newborn population in a metropolitan area with particular attention to the relationship between type of feeding and incidence of neonatal jaundice in the first week of life. STUDY DESIGN: A population of 2174 infants with gestational age >/=37 weeks was prospectively investigated during the first days of life. Total serum bilirubin determinations were performed on infants with jaundice. The following variables were studied: type of feeding, method of delivery, weight loss after birth in relationship to the type of feeding, and maternal and neonatal risk factors for jaundice. Statistical analyses were performed using the z test for parametric variables and the t test for nonparametric variables. In addition, the multiple logistic regression allows for the estimation of the role of the individual characteristics in the development of hyperbilirubinemia. Data concerning serum bilirubin peak distribution in jaundiced newborns were analyzed using a single and a double Gaussian best fit at least squares. The t test was performed to compare 2 values (high and low) of the serum bilirubin peak in breastfed and supplementary-fed infants with those in bottle-fed infants. RESULTS: The maximal serum bilirubin concentration exceeded 12.9 mg/dL (221 micromol/L) in 112 infants (5.1%). The study demonstrated a statistically significant positive correlation between patients with a total serum bilirubin concentration >12.9 mg/dL (221 micromol/L) and supplementary feeding; oppositely, breastfed neonates did not present a higher frequency of significant hyperbilirubinemia in the first days of life. However, best Gaussian fitting of our data suggests that a small subpopulation of breastfed infants have a higher serum bilirubin peak than do bottle-fed infants. Newborns with significant hyperbilirubinemia underwent a greater weight loss after birth compared with the overall studied population, and infants given mixed feeding lost more weight than breastfed and formula-fed newborns, indicating that formula has been administered in neonates who had a weight loss beyond a predetermined percentage of birth weight. Significant hyperbilirubinemia was also strongly associated with delivery by vacuum extractor, some perinatal complications (cephalohematoma, positive Coombs' test, and blood group systems of A, AB, B, and O [ABO] incompatibility) and Asian origin. Multiple logistic regression analysis shows that supplementary feeding, weight loss percentage, ABO incompatibility, and vacuum extraction significantly increase the risk of jaundice, while only cesarean section decreases the risk. CONCLUSION: The present study confirms the important role of fasting in the pathogenesis of neonatal hyperbilirubinemia, although breastfeeding per se does not seem related to the increased frequency of neonatal jaundice but to the higher bilirubin level in a very small subpopulation of infants with jaundice. In fact, in the breastfed infants, there is a small subpopulation with higher serum bilirubin levels. These infants, when starved and/or dehydrated, could probably be at high risk of bilirubin encephalopathy.