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 thez test for parametric variables and the ttest 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 μmol/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 μmol/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.
Neonatal jaundice remains the most common and, perhaps, the most vexing problem in full-term infants during the immediate postnatal period. Despite the numerous articles published on this subject, many aspects of neonatal hyperbilirubinemia remain unexplained.1–7 In particular, there is an important debate on the role of breastfeeding versus formula feeding in determining the number of infants with significant hyperbilirubinemia as well as influencing the peak serum bilirubin concentration1–7 in the first days of life.
The aim of this study was to investigate the occurrence of significant hyperbilirubinemia in a large unselected population of full-term newborns in a metropolitan area.
A population of 2174 newborn infants with gestational age ≥37 weeks consecutively born in the Department of Obstetrics and Gynecology of the University of Florence Hospital between November 15, 1997 and November 14, 1998 was prospectively studied. Gestational age was determined according to last menstrual period. No participants presented severe asphyxia, infections, abnormal direct serum bilirubin values, malformations, or other pathologic conditions. All infants admitted to the study were in a continuous rooming-in setting, meaning that newborns were in their cots near their mothers' beds.
Mothers had their blood group typed and all newborns had blood group determination and the Coombs' test performed on cord blood. Total bilirubinemia in infants with jaundice was measured by direct spectrophotometry of the serum in a microhematocrit tube (using the Elmed Ginevri bilirubinometer). A bilirubin level >12.9 mg/dL (221 μmol/L) was considered significant. Infants with bilirubin level >12.9 mg/dL (221 μmol/L) at 24 hours of life and with bilirubin level >17 mg/dL (291 μmol/L) in the days that followed were candidates for phototherapy according to the guidelines of the Italian Society of Neonatology.8 Serum bilirubin levels were monitored in infants with jaundice twice daily in subsequent days until a steady decrease was observed. The variables evaluated in this study are the following: type of feeding (breastfeeding, formula feeding, or supplementary feeding); method of delivery (vaginal delivery, cesarean section, or vacuum extractor); weight loss after birth in relationship to type of feeding; and maternal and neonatal risk factors for jaundice development (maternal diabetes and hypertension, neonatal gender, origin and gestational age, positive Coombs' test, blood group systems of A, AB, B, and O [ABO] incompatibility, and the presence of cephalohematoma).
Breastfeeding refers to infants who were exclusively breastfed. The mothers started nursing in the delivery room and breastfed on their infants' demand every 1 to 3 hours (generally 10 minutes on each breast) with no supplementation of water or formula at any time. Pacifiers were forbidden and the number of feedings was between 6 and 12 per day.
Supplementary feeding refers to infants who were breastfed and received additional formula supplements. In our nursery, the attending neonatologist commonly prescribed supplementary formula if birth weight was ≤2500 g or if weight loss after birth was significant (≥4% after 24 hours or ≥8% after 48 hours or ≥10% after 72 hours). No water or glucose water was administered at any time.
Formula feeding refers to infants who were exclusively bottle- fed because their mothers presented some pathologic conditions that represented contraindications to breastfeeding or declined to breastfeed.
Most infants were discharged after 72 hours of life. Newborns who were born by cesarean section, were jaundiced, or presented significant weight loss remained in the hospital longer. The range of length of stay was 83.43 ± 0.53 hours.
Statistical analyses were performed using the z test for parametric variables and the t test for nonparametric variables. A P value <.05 was considered statistically significant. In addition, the multiple logistic regression allows us to estimate the role of the individual characteristics in the development of hyperbilirubinemia; a value of t = 1.96 (P = .05) was chosen as the significant cutoff value. Data concerning serum bilirubin peak distribution in jaundiced newborns were analyzed using a single and a double Gaussian best fit at least squares. Thet test was performed to compare 2 values (high and low) of serum bilirubin peak in breastfed and supplementary-fed infants with those in bottle-fed infants.
The characteristics of the study group are shown in Table 1. During their hospital stay, 528 infants (24.3% of the 2174 studied) were recognized to be clinically jaundiced and required bilirubin determination, of whom there were 43% on the second day of life and 46% on the third day of life. Among these, only 112 (5.1%) had total serum bilirubin (TSB) >12.9 mg/dL or >221 μmol/L (significant hyperbilirubinemia). A serum bilirubin peak >12.9 mg/dL occurred more frequently on the third and fourth days of life. A statistically significant positive correlation was found between TSB >12.9 mg/dL (221 μmol/L) and supplementary feeding (P < .001), delivery by vacuum extractor (P < .001), perinatal complications (cephalohematoma, positive Coombs' test, and ABO incompatibility; P < .001), and Asian origin (P < .001). Breastfeeding showed a negative correlation with TSB >12.9 mg/dL (P< .001) (Table 2). Newborns with TSB >12.9 mg/dL (221 μmol/L) underwent a greater weight loss after 72 hours of life than did the overall studied population (8.0% vs 6.4%;P < .001; Table 3). Infants given mixed feeding lost more weight than did breastfed and formula-fed newborns. The additional multiple logistic regression analysis shows a positive, statistically significant correlation between TSB >12.9 and supplementary feeding, delivery by vacuum extractor, ABO incompatibility, and weight loss percentage after birth. A negative, statistically significant correlation was observed between TSB >12.9 and cesarean section (Table 4). In this type of analysis, neonatal characteristics, just as the appearance of cephalohematoma, a positive Coombs' test, and Asian origin, have not proved to be statistically significant: probably, the number of infants with these disorders are too few to have sufficient statistical power. Best Gaussian fitting of our data suggests that 2 subpopulations are present among breastfed and supplementary-fed infants with jaundice of unknown origin: a subpopulation with a low serum bilirubin peak and a subpopulation with a high serum bilirubin peak. In bottle-fed newborns, only 1 population seems present. The subgroups of breastfed and supplementary-fed infants have a higher second serum bilirubin peak compared with bottle-fed newborns (14.4 ± 2.9 mg/dL, 14.1 ± 3.1 mg/dL vs 11.0 ± 4.5 mg/dL; P < .05; data are shown in Fig 1).
This epidemiologic study investigated the effects of different variables on nonphysiologic hyperbilirubinemia in a large cohort of full-term newborn infants in the first week of life. Several authors have reported an increase in the frequency of readily visible jaundice in the last 25 years, probably secondary to breastfeeding encouragement in the same period.2,3 In our study, the incidence of clinically evident jaundice resulted similar to the National Collaborative Perinatal Project conducted from 1959 to 1966 (24.3% vs 26.3%)8; at that time, only 22% to 23% of mothers in the United States were breastfeeding their infants. Because 73.4% of our infants were breastfed, our findings seem to suggest that the frequency of infants with clinically evident jaundice is not related to the type of feeding in our study population.
During the first week of life, the incidence of nonphysiologic hyperbilirubinemia (TSB >10–12.9 mg/dL or 171–221 μmol/L) in full-term newborns was reported in different studies to be between 4.8% and 15.5%1,3,5: in our study population the incidence of significant hyperbilirubinemia is low (5.15%).
Our findings confirm the strong association between neonatal jaundice and known risk factors such as a positive Coombs' test and ABO incompatibility; a policy of watchful anticipation justifies repetitive serum bilirubin determinations if indicated. It is not surprising that a known cause of hyperbilirubinemia was not found in 65/112 of our infants (58%) in agreement with previous investigations (55%–56%).1,3 The controversy in literature regarding hyperbilirubinemia of unknown origin is whether breastfeeding increases the incidence of jaundice in the first days of life. Numerous authors1–4,10,12 have reported a striking association between breastfeeding and significant hyperbilirubinemia, but other reports5,11 have not substantiated this observation. Our data show that a TSB >12.9 mg/dL (221 μmol/L) is significantly associated with supplementary feeding and weight loss after birth, whereas breastfeeding is not correlated with hyperbilirubinemia in the first days of life: breastfed infants represent only 38.4% of infants with a bilirubin level >12.9 mg/dL (221 μmol/L). One possible explanation is that in our hospital, full-term newborn infants start breastfeeding in the delivery room, they are in a rooming-in setting, and are breastfed on demand. Infants receive supplementary feeding only when adequate breastfeeding has failed. In fact, breastfed infants, compared with newborns given supplementary feeding, had lower weight loss after birth than did the overall studied population. Moreover, jaundice was first evident in 42% of infants on the second day and in 55% on the third day when the percentage of infants with a maximum weight loss was 52% and 45%, respectively. Multiple regression logistic analysis shows a statistically positive correlation between TSB >12.9 mg/dL (221 μmol/L) and weight loss percentage after birth. These data confirm that the development of neonatal jaundice is not associated with breastfeeding per se but rather with increased weight loss after birth subsequent to fasting, suggesting the important role of caloric intake in the regulation of serum bilirubin. In fact, Osborn et al2 as well as Maisels et al4 found that jaundiced infants did lose more weight than control infants. A relationship between fasting and hyperbilirubinemia has been previously reported both in adults and animals.13,14 The effect of caloric restriction on serum bilirubin was first noted by Gilbert and Hershi15 in 1906. Later on, Barrett16 and Felsher et al17 showed that fasting causes a significant elevation of unconjugated bilirubin. Bloomer et al,13 by injecting bilirubin H3 into normal adult volunteers and in patients with Gilbert's syndrome, demonstrated that the decrease in clearance was the result of reduced hepatic ability to extract bilirubin from the blood. Moreover, in the Cooperative National Institute of Child Health and Human Development phototherapy, Wu et al18 found that infants receiving <90 calories/kg/24 hours had significantly higher peaks in bilirubin concentrations than did those fed >90 calories/kg/24 hours, and phototherapy was much less effective when caloric and fluid intake was low. In contrast, measurements of pulmonary excretion of carbon monoxide (an index of bilirubin production) showed no effect of caloric deprivation on bilirubin production.19 A recent article by Gärtner et al20 investigated the effect of fasting in rats using a technique that enables the assessment of the hepatic handling of unconjugated bilirubin independent of nonhepatic factors. This study clearly documents that enhanced enterohepatic circulation of bilirubin, not altered intrinsic hepatic transport, is a major factor in the pathogenesis of fasting-induced hyperbilirubinemia. In our study, best Gaussian fitting of data concerning serum bilirubin peak distribution in breastfed newborns shows that there is a subpopulation with a high serum bilirubin peak, which is not present in bottle-fed infants. However, this subpopulation seems to be very large among infants with mixed feeding who were the infants with the higher weight loss (Fig 1). It is worthwhile to underline that the occurrence of a decreased incidence of significant jaundice in breastfed infants is related to the first days of life (early jaundice). The incidence of late jaundice, whose onset generally occurs on the fourth day and lasts ∼9 weeks having a peak at 5 to 15 days, was not studied in our population.
It is well known that genetic and environmental factors influence neonatal jaundice. According to previous data in literature, the method of delivery also influences serum bilirubin concentration2,10,21 and this report found that cesarean sections preserve newborn infants by the development of neonatal hyperbilirubinemia. There are some possible explanations. The infants born by emergency cesarean section are stressed before birth and, therefore, induce conjugating enzymes before delivery. Moreover, Osborn et al2 have suggested a probable association between delivery by cesarean section and method of feeding. In their hospital, because women who underwent cesarean section breastfed infrequently during the newborn's first 48 hours of life, these infants, unlike other breastfed infants, were supplemented with formula until nursing was well established. Nevertheless, our setting after cesarean section provides for supplementation with formula only at the mother's request or if weight loss after birth is significant. Yamauchi and Yamanouchi21 demonstrated that from day 1 to day 7 of life, transcutaneous bilirubin measurement in infants born by cesarean section was significantly lower than those of infants born vaginally, likely because of less placental transfusion in infants born by cesarean section. In addition, a strong association was found between significant hyperbilirubinemia in the first week and delivery by means of vacuum extractor; this is probably because of the development of hemorrhaging consequent to this method of delivery as has been observed in the past,22 but currently it is not widely recognized. Ethnic differences in the incidence of neonatal jaundice are significant9,23 and the present investigation confirms that race plays an important role in determining neonatal hyperbilirubinemia; 15.6% of Asian newborn infants compared with 5.1% of the total population (91.8% European newborns) showed a TSB >12.9 mg/dL (221 μmol/L; P < .001). Recently, Akaba et al24 suggested that the high incidence of neonatal hyperbilirubinemia in Japanese, Korean, and Chinese populations is associated with high frequency of the Gly71Arg mutation (missense mutation) of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Our data on the effect of gestational age do not agree with those found by others authors,4,11,25,26 but our population was composed of newborn infants with ≥39 weeks of gestational age (73%). Even if other variables also play a role in hyperbilirubinemia of full-term infants, breastfeeding failure and the lack of breastfeeding are major factors in the pathogenesis of neonatal jaundice.
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 in the first days of life, but rather to the higher bilirubin level in a very small subpopulation of infants with jaundice. These infants, when starved and/or dehydrated, could probably be at high risk of bilirubin encephalopathy, especially after discharge from the hospital when careful follow-up is lacking. Among other well-known conditions favoring neonatal jaundice, it must be emphasized that infants born by vacuum extraction are at risk of exaggerated neonatal jaundice.
We thank Dr Alessandro Ambrosi of the University of Padova for the multiple logistic regression analysis and Kathryn Rakich for her editorial assistance. We also thank Dr M. Jeffrey Maisels of William Beaumont Hospital (Royal Oak, MI) and Dr Vinod K. Buthani of Pennsylvania Hospital (Philadelphia, PA) for reviewing the manuscript and for their suggestions.
- Received November 1, 1999.
- Accepted November 15, 2000.
Reprint requests to (F.F.R.) Section of Neonatology, Careggi University Hospital, Viale Morgagni 85, 50134, Florence, Italy. E-mail:
- ABO =
- blood group systems of A, AB, B, and O •
- TBS =
- total serum bilirubin
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- Copyright © 2001 American Academy of Pediatrics