Neonatal Jaundice and Breastfeeding Maria Fernanda B. de Almeida and Cecilia Maria Draque NeoReviews 2007;8;e282-e288 DOI: 10.1542/neo.

8-7-e282

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/cgi/content/full/neoreviews;8/7/e282

NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 2000. NeoReviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2007 by the American Academy of Pediatrics. All rights reserved. Online ISSN: 1526-9906.

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Article

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Neonatal Jaundice and Breastfeeding

Maria Fernanda B. de Almeida, MD, FAAP,* Cecilia Maria Draque, MD

Objectives

After completing this article, readers should be able to:

Author Disclosure Drs de Almeida and Draque did not disclose any nancial relationships relevant to this article.

1. Describe the natural history of jaundice in healthy breastfed term neonates in different populations. 2. Explain possible factors associated with breast nonfeeding jaundice. 3. Recognize the clinical course and possible etiologic mechanisms related to breast milk jaundice. 4. Prevent and manage hyperbilirubinemia in breastfed neonates.

Abstract
Neonatal jaundice is related to breastfeeding in three primary clinical situations: exclusively breastfed healthy term newborns during the rst postnatal week, newborns who receive inadequate breastfeeding and have high concentrations of indirect bilirubin during the rst postnatal week (nonfeeding jaundice), and breastfed infants who experience prolonged unconjugated hyperbilirubinemia (breast milk jaundice). Nonfeeding jaundice has been suggested to be related to a signicantly greater weight loss on the third postnatal day compared with the birthweight following delayed initiation of or inadequate breastfeeding. This can be a particular problem among neonates discharged from the hospital within 48 hours, often requiring readmission for treatment of hyperbilirubinemia. Several hypotheses have been proposed for the source of breast milk jaundice, including the presence of a UDP-glucuronosyltransferase inhibitor, beta-glucuronidase, or a yet-unidentied factor in human milk that could inhibit bilirubin excretion and result in hyperbilirubinemia. Careful education about breastfeeding and monitoring of mothers as well as assessment of newborns for the risk of developing severe hyperbilirubinemia can aid in preventing neonatal jaundice. Treatment of hyperbilirubinemia is based on total serum bilirubin concentrations and can range from administration of intravenous uids and supplementation with milk formula to intensive phototherapy and exchange transfusion. Experimental treatments include the use of stannsoporn and betaglucuronidase inhibitors as chemoprevention therapies and minimal aliquots of L-aspartic acid and enzymatically hydrolyzed casein to inhibit beta-glucuronidase.

Introduction
Jaundice is one of the most frequent problems of the neonatal period and corresponds to the clinical expression of hyperbilirubinemia, dened as a serum unconjugated bilirubin concentration of greater than 1.3 to 1.5 mg/dL (22.2 to 25.7 mcmol/L) or conjugated bilirubin concentration of higher than 1.5 mg/dL (22.2 mcmol/L). (1) Indirect hyperbilirubinemia usually reects a neonatal adaptation to bilirubin metabolism and is termed physiologic jaundice. Other times, it results from a pathologic process, with bilirubin reaching high concentrations that can cause brain damage. Since the early 1990s, numerous publications have noted the presence of bilirubin encephalopathy in breastfed patients of at least 35 weeks gestation who are discharged from the hospital before 48 hours. (2)(3)(4)

*Associate Professor, Pediatrics, Division of Neonatal Medicine, Sao Paulo Federal University, Sao Paulo, Brazil. Medical Assistant, Pediatrics, Division of Neonatal Medicine, Sao Paulo Federal University, Sao Paulo, Brazil. e282 NeoReviews Vol.8 No.7 July 2007

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The association between jaundice and maternal milk was recognized 4 decades ago. Since then, several published articles have distinguished three specic situations: Healthy term newborns who are appropriately and exclusively breastfed during the rst postnatal week Inadequate breastfeeding associated with high concentrations of indirect bilirubin during the rst postnatal week, termed breast nonfeeding jaundice Prolonged unconjugated hyperbilirubinemia, termed breast milk jaundice

Healthy Breastfed Term Newborns and Jaundice in the First Postnatal Week
Studies related to the progress of bilirubinemia in healthy breastfed newborns show differences in the average and maximum values of serum unconjugated bilirubin or total serum bilirubin (TSB), depending on the population. In England, in a cross-section study of 312 breastfed neonates, the mean TSB on the sixth postnatal day was 8 mg/dL (136.8 mcmol/L). (5) In a study of 176 Canadian breastfed neonates, TSB was measured on the rst, second, third, and fth days after birth, and the mean concentration was 8.8 mg/dL (150.5 mcmol/L); the time point at which bilirubin peaks were attained was not reported. (6) In Nigeria, 56 term, appropriate-forgestational-age and healthy neonates, most of whom were breastfed, were assessed daily for 12 days, and TSB concentrations of 8 mg/dL (136.8 mcmol/L) were identied on the fth postnatal day. (7) The mean values of 8 mg/dL (136.8 mcmol/L) were measured on the third and fourth days after birth in 1,087 Israeli neonates, 78% of whom were totally or partially breastfed. (1) Fifty healthy breastfed term Japanese newborns had mean values of 12 mg/dL (205.2 mcmol/L) between the third and seventh postnatal days. (8) These babies had a mutant UDP-glucuronosyltransferase gene associated with the bilirubin conjugation deciency. (9) Studies conducted in Turkey showed a mean bilirubin value of 12 mg/dL (205.2 mcmol/L) in term predominantly breastfed neonates on the fth day after birth, and this result was attributed to ethnic and geographic characteristics of that region. (10) In the United States, Maisels and Kring, (11) when studying the natural history of bilirubinemia during the rst 96 hours after birth in 2,966 newborns whose gestational ages were at least 35 weeks (70% exclusively breastfed), reported a progressive increase in transcutaneous bilirubin (TcB), on average up to 8 mg/dL (136.8 mcmol/L), and a 95th percentile of 13 mg/dL

(222.3 mcmol/L). They emphasized that the peak was not reached until 96 hours after birth. Healthy term Italian newborns who initiated breastfeeding in the delivery room, remained in continuous rooming-in with their mothers, fed on demand 10 to 12 times a day, and received no supplementation of water or dextrose water, showed a maximum weight loss of approximately 4.2% relative to the birthweight, which is similar to the weight loss in infants fed a milk formula. (12) Indirect bilirubin values greater than 12.9 mg/dL (220.6 mcmol/L) were reported in 4.6% of those who received maternal milk and 3.5% of those fed milk formula. (12) In Brazil, the population is highly miscegenated, especially with descendents of Europeans and Africans, and 96% of the mothers breastfeed their babies at maternity hospitals. A cohort study of 223 healthy, term, exclusively breastfed neonates (46% white, 34% mulatto, and 20% black), who were followed during the rst 12 postnatal days, documented a TcB 50th percentile value of 5.6 mg/dL (95.8 mcmol/L) between the third and fth postnatal days, which decreased to 3 mg/dL (51.3 mcmol/L) 12 days after birth. (13) The 95th percentile corresponded to 12 mg/dL (205.2 mcmol/L) between the third and fth postnatal days and to 8.5 mg/dL (145.4 mcmol/L) on the 12th postnatal day. The 223 neonates were born between 37 and 41 weeks gestation and were appropriate for gestational age, 74% were born vaginally, and 66% initiated breastfeeding in the delivery room. All infants remained in continuous rooming-in with their mothers, fed on demand, and had a maximum weight loss of 4.7% (SD 2%) relative to the birthweight between the second and third days after birth. They were discharged from the hospital when 48 to 72 hours old and recovered their birthweights, on average, on the fth postnatal day. (14) Investigations have shown that appropriate maternal milk administration accelerates intestinal transit time and facilitates the elimination of meconium, with a reduction in the enterohepatic circulation of bilirubin and decrease in indirect bilirubin concentrations. Additionally, early breastfeeding frequently provides sufcient uid and energy intake and decreases physiologic weight loss and time to recover birthweight. (15) Mean bilirubin concentrations and time of peak concentrations vary in different populations of term predominantly breastfed newborns. It is possible that new mutations in UDP-glucuronosyltransferase may explain the higher degrees of bilirubinemia in breastfed infants of different ethnic groups. (16)
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Breast Nonfeeding Jaundice

Numerous studies showed evidence of higher bilirubin concentrations in breastfed infants compared with infants fed milk formulas during the rst postnatal week. A review of 12 studies comprising 8,252 patients evaluated up to the fth postnatal day showed that 13% of breastfed patients had bilirubin values of 12 mg/dL (205.2 mcmol/L) or greater compared with only 4% of those fed formula. (17) Additionally, analysis of six of the studies showed bilirubin concentrations of 15 mg/dL (256.5 mcmol/L) or more in 2% of breastfed and 0.3% of formula-fed newborns. However, neither the review nor the original articles reported the time when maternal breastfeeding began, the frequency of feedings, or the presence of supplementation with water. Other studies showed similar results and proposed the possibility of the association resulting from a signicantly greater weight loss on the third postnatal day compared with the birthweight (between 5% and 8% in breastfed neonates and between 3% and 4% in those fed milk formulas). (5)(6)(18)(19)(20) This more pronounced bilirubinemia has been described as breast nonfeeding jaundice (21) because the probable explanation for its occurrence is a greater weight loss resulting from delayed initiation of breastfeeding, insufcient frequency and ingestion of maternal milk, and the administration of water before or in addition to maternal feeding. These may be signicant factors for the increased bilirubin in the enterohepatic circulation and resulting greater hepatocyte overload of bilirubin. (22) Corroborating this theory, de Carvalho and associates (15) showed that newborns breastfed more than eight times a day during the rst three days after birth had lower bilirubin values (6.5 mg/dL [111.2 mcmol/L] versus 9.3 mg/dL [159 mcmol/L]) than those fed less frequently. They also demonstrated that breastfed neonates had a smaller weight of evacuations compared with those who received formula (58 g versus 82 g), excreted less bilirubin (15.7 mg versus 23.8 mg), and had more serum bilirubin (9.5 mg/dL [152.5 mcmol/L] versus 6.8 mg/dL [116.3 mcmol/L]) on the third day after birth. The supplementation of water and dextrose water did not change the incidence of hyperbilirubinemia. Other authors even showed an increase in plasma bilirubin in infants breastfed and supplemented with water or glucose. (23)(24) More recently, special attention has been directed toward late preterm infants (gestational age between 340/7 and 366/7 weeks) born vaginally and breastfed, who are discharged from the hospital within 48 hours. This group has a 2.2-fold greater risk of being readmitted
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compared with term newborns who are breastfed, and jaundice is the primary cause for hospital readmission. (25) Such infants have difculty in sucking that, in association with impaired hepatic bilirubin conjugation, favors hyperbilirubinemia. The meconium that accumulates in the intestines during fetal life contains a large quantity of bilirubin, and delayed meconium elimination is associated with hyperbilirubinemia. Corchia and colleagues (26) found concentrations of bilirubin twice as high in breastfed neonates who eliminated meconium for the rst time 8 hours after birth compared with patients who eliminated meconium before this age. Tudehope and associates (27) noted an increased frequency of evacuations on the second and third days after birth in infants who had lower concentrations of bilirubin, regardless of the type of diet. Another hypothesis suggested that the presence of pronounced jaundice associated with maternal breastfeeding is related to the increased quantity of betaglucuronidase in the milk. (28) However, other authors have not shown a correlation between the concentrations of beta-glucuronidase in milk and bilirubinemia during the rst days after birth. (29) Studies with exhaled carbon monoxide determinations did not show increased bilirubin synthesis or an association between a decient ingestion of calories and greater synthesis of bilirubin in breastfed patients compared with those fed formula. (30) Moreover, there is no evidence that inappropriate breastfeeding interferes with bilirubin uptake or conjugation. (31) Over the last few years, breast nonfeeding jaundice has been associated with early hospital discharge (ie, before 48 hours after birth). Since the 1990s, there has been a worldwide tendency to shorten the hospital stay. Hence, the risk of readmission for hyperbilirubinemia has increased, accounting for 65% of newborns readmitted. (32) Most of those who needed rehospitalization were exclusively breastfed, and problems with feeding and dehydration were the primary causes of hyperbilirubinemia. (33) The shortened hospital stay can limit the mothers ability to assimilate and process the information she receives on breastfeeding and care for her baby, leading to inappropriate feeding. (34) One important aspect related to breastfeeding and delivery route is worth mentioning. There are reports that cesarean sections have a negative inuence on the start and duration of breastfeeding, and consequently, on weight loss during the rst postnatal days. (35)(36) The association between early hospital discharge and maternal breastfeeding also appears to be contributing to the reappearance of bilirubin encephalopathy in the

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United States. The voluntary notication of 90 cases between 1992 and 2001 showed that among the 61 patients readmitted during the rst postnatal week, all were being breastfed and had been discharged from the hospital, on average, at 18 hours after birth. (2) In one third of the cases, no cause was found to explain the hyperbilirubinemia, and a weight loss of more than 10% and 15% relative to the birthweight was common in 26% and 13%, respectively, of the newborns. (2) The number of notied cases of bilirubin encephalopathy, kernicterus, or both increased to 125 by January 2003, with 50% of affected infants discharged from the hospital between 24 and 28 hours after birth, 7.5% at less than 24 hours of age, and almost all being breastfed. (3) In fact, in one case-control study, Newman and associates (37) detected exclusive breastfeeding at birth discharge as one of the most important risk factors (odds ratio 5.7; 95% condence interval 2.1 to 15.5) associated with bilirubin concentrations of more than 25 mg/dL (427.5 mcmol/ L). In clinical practice, inappropriate breastfeeding may be suspected if there is a delay in the elimination of meconium, fewer than three evacuations per day, presence of meconial feces on the third or fourth postnatal day, decreased urinary ow, or weight loss greater than 5% to 7% on the third day after birth. (21)

Breast Milk Jaundice

Breast milk jaundice becomes more apparent after the rst postnatal week and persists from 2 to 3 weeks and for up to 3 months. Some 2% to 4% of all breastfed infants have bilirubin concentrations greater than 10 mg/dL (171 mcmol/L) at 3 weeks of age. (21)After that, bilirubinemia declines slowly, although values may remain elevated for 2 to 3 months. The neonates are healthy and vigorous and progress with appropriate weight gain and normal gastrointestinal elimination. Furthermore, they have no disease that could be responsible for indirect hyperbilirubinemia. Most infants have maximal indirect bilirubin concentrations of less than 20 mg/dL (342 mcmol/L). The rst cases of breast milk jaundice were described in newborns who had high concentrations of bilirubin during the third and fourth postnatal days that persisted for weeks. At this moment, however, is unclear how these two types of hyperbilirubinemia are related. (38) In 1963, a progesterone metabolite (pregnane-3alpha-20-beta-diol), an in vitro UDP-glucuronosyltransferase inhibitor, was isolated in the milk of mothers whose babies had breast milk jaundice. In 1972, it was postulated that increased concentrations of nonsteried

fatty acids in breast milk were responsible for inhibiting UDP-glucuronosyltransferase activity in vitro. At the same time, other studies identied an increased or abnormal activity of serum-lipoprotein lipase and bile saltstimulated lipase by bile salts in milk as a cause for increased free fatty acids. No current evidence shows if pregnanediol or free fatty acids inhibit hepatic conjugation of bilirubin in vivo or play an etiologic role in breast milk jaundice. (21) Another hypothesis considers the presence of high concentrations of beta-glucuronidase in maternal milk. In 21-day-old neonates, the activity of this enzyme was higher in the feces of breastfed patients, primarily in those who had breast milk jaundice, compared with those who were formula-fed. (28) However, a later study did not nd any difference in beta-glucuronidase activity between the milk ingested by jaundiced and nonjaundiced patients during the second, third, and fourth postnatal weeks. (39) Still another theory suggests that the serum elevation of bile acids or the modications of taurine and glycine conjugated bile acids might be related to jaundice caused by maternal milk, even though the signicance of these ndings remains unclear. At present, the possibility of a yet-unidentied factor in human milk that would increase the intestinal absorption of bilirubin and explain the delayed onset of jaundice is considered because of its appearance after the transition of colostrum to more mature milk. (21) In addition, many other factors related to the control of UDP-glucuronosyltransferase activity and compounds potentially passed by human milk (eg, metal ions, steroids, or nucleotides) possibly could inhibit bilirubin excretion and result in hyperbilirubinemia. (38) There is no evidence that increased bilirubin production is responsible for breast milk jaundice, and decient hepatic uptake of bilirubin has not been studied in relation to the condition. (21) Recently, Japanese researchers studied 17 healthy breastfed newborns who had bilirubin concentrations greater than 10 mg/dL (171 mcmol/L) between the third and fourth postnatal weeks and showed a mutation of the UDP-glucuronosyltransferase (UGT1A1) gene similar to that detected in patients who have Gilbert syndrome. (9)(40) It is speculated that one or more of the components of human milk previously discussed could trigger jaundice in neonates who have this mutation.

Prevention and Management

An effective educational program to warrant success and satisfaction for the mother who breastfeeds may aid in preventing breast nonfeeding jaundice. The volume of
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milk produced is related intimately to the time of onset, frequency of feeding, complete emptying of the breast, and ability of the neonate to suckle effectively. Initiating breastfeeding during the rst hour after birth, followed by at least 10 to 12 times per day during the rst postnatal week, with no supplementation of water or other liquids, via an appropriate technique that assures an effective transfer of milk to the newborn can minimize weight loss to less than 7% and maintain low bilirubin concentrations. (8)(12)(15)(41) Continuous contact of the mother with the child in the presence of a staff prepared to instruct about breastfeeding in delivery room, rooming-in, and later during follow-up at the patients home enables progression with no major difculties in most cases. The American Academy of Pediatrics recommends that pediatricians encourage mothers to breastfeed at least 8 to 12 times a day during the rst days. Breastfeeding needs to be evaluated in the rst 24 to 48 hours after birth and again during follow-up at 48 to 72 hours after hospital discharge. Routine supplementation with water or dextrose water for breastfed neonates is not advised. (42)(43) Additionally, every newborn needs to be assessed for the risk of developing severe hyperbilirubinemia through clinical risk factors or a predischarge measurement of bilirubin using TSB or TcB interpreted according to the infants age in hours. (43)(44) For most infants who have TSB values less than 15 mg/dL (256.5 mcmol/L), noninvasive TcB measurement devices can provide a valid estimate of the TSB. (43)(45) In the presence of any TSB value higher than 12.9 mg/dL (220.6 mcmol/L), regardless of the infants age, the clinician must be sure that the neonate does not have hemolytic disease (maternal and infant ABO and Rh type, direct Coombs test, hematocrit or hemoglobin, examination of erythrocyte morphology, and glucose-6-phosphate-dehydrogenase value), hypothyroidism, galactosemia, or any other pathologic condition. Therefore, conjugated bilirubin concentrations also must be determined. Intravenous uids should be administered to children readmitted during the rst week after birth due to breast nonfeeding jaundice with dehydration (43) to increase the excretion of bilirubin photoproducts in urine and bile. In these cases, efforts should be directed toward making feeding more effective; sometimes, breastfeeding may need to be supplemented with milk formula to increase caloric intake. It is possible to interrupt breastfeeding temporarily and introduce formula. (46) TSB concentrations of 25 mg/dL (427.5 mcmol/L) or more in any breastfed newborn whose gestational age
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is 35 weeks or more is considered a medical emergency, and the infant should be readmitted immediately for intensive phototherapy, breastfeeding or formula feeding every 2 to 3 hours, and repeat TSB measurement within 2 to 3 hours. If the infant is sick (dehydration) or at 35 to 37 weeks gestation with a TSB of 20 mg/dL (342 mcmol/L) or more, intensive phototherapy should be started immediately and the TSB measurement repeated within 3 to 4 hours. In this situation, providing intensive phototherapy (irradiance 30 mcW/cm2 per nanometer or higher delivered to as much of the infant s surface area as possible) is crucial; waiting for potential positive effects of uncontrolled phototherapy can be dangerous. (47) If the TSB concentration is lower than 20 mg/dL (342 mcmol/L) during phototherapy, the measurements should be repeated in 4 to 6 hours. Phototherapy may be discontinued when the TSB is lower than 14 mg/dL (239.4 mcmol/L). (43) Exchange transfusion may be considered in the following situations: TSB of 19 mg/dL (324.9 mcmol/L) or more in babies between 35 and 37 weeks gestation who have risk factors; TSB of 22 mg/dL (376.2 mcmol/L) or more in newborns of 35 and 37 weeks gestation who do not have risk factors or 38 weeks gestation or more who have risk factors; and TSB of 25 mg/dL (427.5 mcmol/L) or more in infants of 38 weeks gestation or more who do not have risk factors. (43) Finally, the use of stannsoporn (tin mesoporphyrin) and beta-glucuronidase inhibitors as chemoprevention therapies in breastfed newborns is worth mentioning. An open, randomized study from Argentina documented the efcacy of stannsoporn, a synthetic heme analog that is a competitive inhibitor of heme oxygenase, in controlling hyperbilirubinemia in healthy term breastfed newborns in whom TSBs between 15 and 18 mg/dL (256.5 and 307.8 mcmol/L) were reached between 48 and 96 hours. (48) The 80 stannsoporn-treated newborns (4.5 mg/kg subcutaneous) did not need phototherapy compared with 19 (22%) of the 86 newborns in the control group in whom phototherapy was initiated at a TSB of 19.5 mg/dL (333.5 mcmol/L). In addition, the use of stannsoporn resulted in fewer plasma bilirubin measurements and a shorter duration of hospitalization. (49) The long-term safety of this agent, however, is not well understood and should be determined before its widespread or prophylactic use in neonates with hyperbilirubinemia can be recommended. (49) A recent blind, randomized study involving the administration of minimal aliquots of L-aspartic acid and enzymatically hydrolyzed casein (5 mL per dose and 6

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doses per day) to inhibit beta-glucuronidase during the rst week after birth in healthy term breastfed newborns resulted in increased fecal bilirubin excretion and lower TcB values without disruption of the breastfeeding experience. (50) The authors emphasized that these results require conrmation with additional research involving a larger number of patients.

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entity. JAMA. 1986;255:3270 3274

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45. Bhutani VK Gourley GR, Adler S, et al. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics. 2000;106:19 46. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in the breast-fed newborn: a controlled trial of four interventions. Pediatrics. 1993;91:470 473 47. Martinez JC, Garcia HO, Otheguy L, et al. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics. 1999; 103:15 48. Dennery PA. Metalloporphyrins for the treatment of neonatal jaundice. Curr Opin Pediatr. 2005;17:167169 49. Martinez JC. Argentinian perspective of the 2004 AAP hyperbilirubinemia guidelines. NeoReviews. 2006;7:e4 e6. Available at: http://neoreviews.aappublications.org/cgi/content/full/7/1/e4 50. Gourley GR, Li Z, Kreamer BL, Kosorok MR. A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics. 2005;116:385391

NeoReviews Quiz
1. Several studies have reported serial serum bilirubin concentrations after birth in neonates of different geographic and racial backgrounds. This information is important in determining the optimal time for testing for bilirubin after discharge of newborns from hospital nurseries. Of the following, among neonates of at least 35 weeks of gestational age, the peak serum bilirubin concentration in most populations occurs by: A. B. C. D. E. 24 hours after birth. 48 hours after birth. 72 hours after birth. 96 hours after birth. 120 hours after birth.

2. A 7-day-old term newborn of a 16-year-old primiparous woman is seen in the emergency department for jaundice. The serum total bilirubin concentration is 28.0 mg/dL (478.8 mcmol/L) with a conjugated fraction of 0.8 mg/dL (13.7 mcmol/L). The mother reports that her breast milk yield has been inadequate. The infants bodyweight shows an 18% loss from birthweight. Laboratory data reveal no evidence of hemolysis. Of the following, the most likely cause of breast nonfeeding jaundice in this infant is: A. B. C. D. E. Delay in meconium elimination. Increase in beta-glucuronidase in mothers milk. Increase in bilirubin synthesis. Interference with bilirubin conjugation. Interference with bilirubin uptake.

3. A 3-week-old term newborn of a 28-year-old primiparous woman has a serum total bilirubin concentration of 18 mg/dL (307.8 mcmol/L) with a conjugated fraction of 0.8 mg/dL (13.7 mcmol/L). The infant has been fed human milk exclusively. Physical examination reveals a healthy-appearing infant who has no evidence of dehydration. Laboratory data reveal no evidence of hemolysis. Of the following, the rst factor in human milk attributed to the development of breast milk jaundice in such an infant is: A. B. C. D. E. Beta-glucuronidase. Glycine and taurine conjugated bile acids. Nonesteried free fatty acids. Nucleotides. Progesterone metabolite pregnanediol.

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Neonatal Jaundice and Breastfeeding Maria Fernanda B. de Almeida and Cecilia Maria Draque NeoReviews 2007;8;e282-e288 DOI: 10.1542/neo.8-7-e282

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