A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice Among Breatfed Newborn

7/31/2019 A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice Among Breatfed Newborn

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DOI:10.1542/peds.2004-18072005;116;385-391Pediatrics

Glenn R. Gourley, Zhanhai Li, Bill L. Kreamer and Michael R. KosorokAmong Breastfed Newborns

A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice

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A Controlled, Randomized, Double-Blind Trial of Prophylaxis AgainstJaundice Among Breastfed Newborns

Glenn R. Gourley, MD*; Zhanhai Li, PhD; Bill L. Kreamer, BS; and Michael R. Kosorok, PhD

ABSTRACT. Objectives. Neonatal jaundice is agreater problem for infants fed breast milk, comparedwith formula. This study tested the hypotheses that feed-ing breastfed newborns -glucuronidase inhibitors dur-ing the first week after birth would increase fecal biliru-bin excretion and would reduce jaundice withoutaffecting breastfeeding deleteriously.

Methods. Sixty-four breastfed newborns were ran-domized to 4 groups, ie, control or receiving 6 doses perday (5 mL per dose) of L-aspartic acid, enzymaticallyhydrolyzed casein (EHC), or whey/casein (W/C) for thefirst week. L-Aspartic acid and EHC inhibit -glucuron-

idase. Transcutaneous bilirubin levels (primary out-come) were measured daily (Jaundice Meter [Minolta/AirShields, Hatboro, PA] and Bilicheck [Respironics, Pitts-burgh, PA]). All stools were collected, and fecal bilepigments, including bilirubin diglucuronide, bilirubinmonoglucuronides, and bilirubin, were analyzed withhigh-performance liquid chromatography. Follow-up as-sessments included day 7 body weight, day 6/7 prebreast-feeding/postbreastfeeding weights, maternal ratings, andages at formula introduction and breastfeeding cessation.

Results. The groups were comparable at entry. Over-all, the L-aspartic acid, EHC, and W/C groups had signif-icantly lower transcutaneous bilirubin levels than didthe control group (75.8%, 69.6%, and 69.2%, respectively,

of the control mean, 8.53 mg/dL, at the bilirubin peak onday 4). The L-aspartic acid, EHC, and W/C groups hadsignificantly lower transcutaneous bilirubin levels ondays 3 to 7. Fecal bile pigment excretion was greatest inthe L-aspartic acid group, significantly greater than con-trol values. There were no significant differences in dos-ages, follow-up measurements, and maternal ratings.

Conclusions. Use of minimal aliquots of L-asparticacid and EHC for -glucuronidase inhibition results inincreased fecal bilirubin excretion and less jaundice,without disruption of the breastfeeding experience. De-creased jaundice in the W/C group, which lacked a -glu-curonidase inhibitor, suggests a different mechanism.Pediatrics 2005;116:385391; neonate, jaundice, hyperbil-

irubinemia, breastfeeding, -glucuronidase, bilirubin.

ABBREVIATIONS. EHC, enzymatically hydrolyzed casein; W/C,whey/casein; HPLC, high-performance liquid chromatography;BMG, bilirubin monoglucuronide; BDG, bilirubin diglucuronide;BP, bile pigment; AAP, American Academy of Pediatrics.

Most newborns experience benign hyperbil-irubinemia. Severe elevation of serum bili-rubin levels, however, can result in brain

damage known as kernicterus.1,2 Infants with hyper-bilirubinemia may require bilirubin surveillance,feeding changes, phototherapy, or exchange transfu-sion, and the National Institutes of Health support

development of an investigational drug that inhibitsthe production of bilirubin.3,4

Breastfeeding is the best choice for infant nutri-tion,5,6 and the incidence of breastfeeding initiationin the United States is 70%.7 Breastfed infants,however, have higher serum bilirubin concentrationsthan formula-fed infants,8 and 98% of the infants in aUS kernicterus registry were breastfed.9 One third ofthose in the kernicterus registry lack a diagnosisother than breastfeeding to explain severe hyperbil-irubinemia. In a large retrospective study, breast-feeding was the second highest independent factor(odds ratio: 5.7) associated with serum bilirubin con-

centrations of

25 mg/dL (428 mol/L).10

In 2001,the Joint Commission on Accreditation of HealthcareOrganizations,11 the Centers for Disease Control andPrevention,12 and the American Academy of Pediat-rics (AAP)13 all noted increased reports of ker-nicterus and warned that breastfeeding is an impor-tant risk factor for the development of severehyperbilirubinemia.-Glucuronidase is a factor in neonatal jaundice,

because it potentiates the enterohepatic circulation ofbilirubin by deconjugating intestinal bilirubin conju-gates, producing bilirubin that is better absorbed bythe intestine.14 In utero, this facilitates bilirubin clear-ance via the placenta. After birth, however, the en-terohepatic circulation of bilirubin delays bilirubinclearance.15 Breast milk is rich in -glucuronidase.14

Routine infant formula has negligible -glucuroni-dase, and infants consuming such formula have less

jaundice than breastfed infants.16,17 Casein hydroly-sate formula inhibits -glucuronidase, and infantsconsuming such formula have less jaundice than in-fants receiving routine formula.16,17 The major -glu-curonidase inhibitor in casein hydrolysate is l-aspar-tic acid.18 Inhibition of human milk -glucuronidasehas been shown to decrease intestinal absorption of

bilirubin in a rat model with bile duct and duodenalcatheters.19 The purpose of this study was to test the

From the *Department of Pediatrics, Oregon Health and Science University,

Portland, Oregon; and Department of Biostatistics and Medical Informatics

and Waisman Center, University of Wisconsin, Madison, Wisconsin.

Accepted for publication Nov 23, 2004.

doi:10.1542/peds.2004-1807

No conflict of interest declared.

Address correspondence to Glenn R. Gourley, MD, Oregon Health and

Science University, 707 SW Gaines Rd, Mailcode CDRCP, Portland, OR

97239-2998. E-mail: [email protected]

PEDIATRICS (ISSN 0031 4005). Copyright 2005 by the American Acad-

emy of Pediatrics.

PEDIATRICS Vol. 116 No. 2 August 2005 385

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hypotheses that feeding breastfed newborns -glu-curonidase inhibitors during the first 1 week after

birth would increase fecal bilirubin excretion andwould result in less jaundice without deleteriouslyaffecting breastfeeding.

METHODS

Study Design

This project was approved by human subjects committees at theUniversity of Wisconsin (Madison, WI) and Monroe Hospital(Monroe, WI). Enrollment extended from April 2000 to April 2002,with follow-up monitoring to August 2002. Pregnant women atMonroe Clinic, recruited through posters, contacted Dr Gourley,who obtained written consent. Consented newborns who met thefollowing criteria were enrolled soon after birth: (1) healthy full-term (37 weeks of gestation), (2) white (to avoid racial variables),and (3) exclusive breastfeeding planned. A formal sample sizecalculation was performed, in which a difference of 2 mg/dL wasdetermined to be the effect size that we wished to detect and thatmight be clinically important. The estimated SD for group meantranscutaneous bilirubin levels, based on our preliminary data,was 0.87. With an of 0.05/6 .0083 (Bonferroni adjustment) anda power of 0.85 to 0.95, the estimated group number was 15.Sixty-nine newborns were assigned (randomization table) to 1 of 4groups, ie, breastfeeding only (control, 19 subjects) or breastfeed-ing plus 6 doses per day (5 mL per dose) of 1 of 3 nutritionalingredients, ie, l-aspartic acid (180 mg/5 mL of water) (17 sub-

jects), enzymatically hydrolyzed casein (EHC) (11.9 g plus 88.1 gof water; 10% protein equivalent solution with 0.5 g of nitrogenper 5 mL) (16 subjects), or whey/casein (W/C) (60/40; 6 g of wheyprotein isolate plus 4 g of sodium caseinate from cow milk plus89 g of water; 10% protein with 0.5 g of protein per 5 mL) (17subjects). The W/C group was included as another type of controlgroup (ie, receiving no -glucuronidase inhibitor) but, unlike thecontrol group, which received nothing but breastfeeding, the W/Cgroup received a small amount of protein that lacked any -glu-curonidase inhibitor. These dosages were determined on the basisof prior studies with formula-fed infants.16,17 Six newborns with-drew (1 in the control group, because of infant illness; 2 in thel-aspartic acid group, because 1 received formula early and 1received formula on the fourth day [therefore, only data beforethis were included in the analysis]; 1 in the EHC group, becausethe mother rejected breastfeeding; and 2 in the W/C group, be-

cause of maternal illness and maternal dislike of W/C odor).Doses, beginning with the second breastfeeding, were adminis-tered when the infant was changing breasts or after breastfeeding,with an oral syringe that was preloaded daily by a study nursewho visited the patient in the hospital and at home, collected data,provided similar breastfeeding education/support to all groups,and reported adverse reactions.

Parents and researchers were blinded to the treatment identity.The code was not broken until study completion. Mead Johnson(Evansville, IN) prepared the code and ingredients (componentsof current infant formulas) and confirmed product sterilitythroughout the study.

Outcome Measures

Data confirming group comparability included gender, gesta-tional age, birth weight, and delivery with forceps, vacuum ex-traction, or cesarean section. Daily transcutaneous jaundice indexvalues and bilirubin levels were measured (forehead) with a Jaun-dice Meter-102 (Minolta/Air Shields, Hatboro, PA; 3 readingswere averaged)20 and a Bilicheck (Respironics, Pittsburgh, PA; 1reading included 5 replicates),21,22 respectively (primary outcomemeasures). Hospital and home jaundice measurements were usu-ally made between the hours of 9 am and 5 pm.

All stools were collected by saving diapers in a freezer andrecording the date and time of stool passage, pooled for each24-hour period after birth, and analyzed for bilirubin diglucu-ronide (BDG), bilirubin monoglucuronide (BMG), bilirubin, total

bile pigments (BPs) (BDG plus BMG plus bilirubin), urobilinoids,and zinc coproporphyrin (a meconium marker) with reverse-phase high-performance liquid chromatography (HPLC), as de-scribed previously,23 with the following modifications. After BPswere extracted into the upper organic layer, this layer was re-

moved and pooled with a triple extraction of the protein interface.This extraction was accomplished by removing the interface, add-ing 0.1 mL of dimethylformamide, sonicating the mixture for 1minute, and centrifuging the mixture (12 400g for 1 minute). Thispooled sample (0.5 mL) was refrigerated (20C for 15 minutes) toprecipitate protein and recentrifuged (12 700g for 5 minutes), theclarified organic extract was transferred to a 0.22-m nylon mi-crofuge filter (MSI, Westboro, MA) and recentrifuged (6370g for 2minutes), and 20 L were analyzed with a Hewlett Packard model1090 HPLC system (Hewlett Packard, Brookfield, WI) with a 20-mm, C18 Bondapak guard column (Waters Associates, Milford,MA). Detection was at 436 nm (bandwidth: 4 nm) minus 554 nm(bandwidth: 22 nm). Because the extinction coefficients for biliru-

bin, BMG, and BDG are nearly identical,24

the standard curve forbilirubin was used to quantify these pigments with a coumarin 6internal standard.

Urobilinoids were determined by oxidizing urobilinogens tourobilins and were measured as 1 group.25 Potassium iodate en-sured complete oxidation; stercobilin and fluorescein served asstandards, with results being expressed in stercobilin equiva-lents.26

Daily fecal output included wet and dry weights, allowingquantitation of total excretion. Parents logged feeding and dosagetimes. Doses received were recorded (all, most, or little). On days6 and 7, parents weighed their infants before and after breastfeed-ing (BLB-12 scale; Tanita Corp, Tokyo, Japan), to determine intake,as frequently as they considered comfortable. Study terminationassessment included a nude weight.

All infants were exclusively breastfed except for study doses.

Parents completed a long-term follow-up questionnaire after thestudy, including age of first nonstudy supplementation, age ofbreastfeeding cessation, and impression of study (excellent, good,satisfactory, poor, and very poor). Several subjects were unreach-able for long-term follow-up assessment (2 of 18 in the controlgroup, 4 of 16 in the l-aspartic acid group, 1 of 15 in the EHCgroup, and 2 of 15 in the W/C group).

Statistical Methods

Group characteristics and follow-up information were com-pared with analyses of variance and 2 tests for continuous anddiscrete variables, respectively. Jaundice was assessed daily withthe Bilicheck and Jaundice Meter, and the time of measurementwas recorded. Because the units of measurement differed, a re-gression equation was developed to estimate transcutaneous bil-irubin levels from jaundice indices on the basis of all data (Bili-check data, Jaundice Meter data, and time). The averagetranscutaneous bilirubin level from both meters for each subjecton each day was used to represent the transcutaneous bilirubinlevel.

Repeated measures of transcutaneous bilirubin levels, fecal BPs[normalized as log(measurements 1)], and dosages amonggroups were compared with a generalized estimating equation27

with an independence working correlation and an identity linkadjusting for time to a third-order polynomial. Models were eval-uated by examining predicted versus residual values, and 2 ex-treme outliers were dropped from 501 bilirubin measurements.When there were significant overall model effects (P .05), pairedgroup comparisons were made and results were considered sig-nificant at P .0083 (0.05/6; Bonferroni adjustment).28,29 Pairedcomparisons were made each day, and results were consideredsignificant at P .0083 (Bonferroni adjustment).28,29 Our methods

were detailed previously.17

RESULTS

There were no significant differences in gender,birth weight, vacuum extraction rate, and cesareansection rate and no forceps deliveries (Table 1). Al-though they were statistically significant, the gesta-tional age differences were not clinically significant.

Figure 1 presents transcutaneous bilirubin levels.The l-aspartic acid, EHC, and W/C groups hadlower levels than did the control group from day 3 today 7. Paired group comparisons revealed that thel-aspartic acid, EHC, and W/C groups had signifi-

386 NEONATAL JAUNDICE PROPHYLAXIS



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cantly lower levels than did the control group (P .0066, P .001, and P .001, respectively); dailycomparisons showed that the l-aspartic acid, EHC,and W/C groups had levels similar to those of thecontrol group from day 0 to day 2 but significantlylower levels from day 3 to day 6 or 7. At the bilirubinpeak (day 4), treatment group levels were 75.8%,

69.6%, and 69.2% of control values (control mean:8.53 mg/dL) for the l-aspartic acid, EHC, and W/Cgroups, respectively.

Figure 2 presents fecal total BP data. Overall fecalBP excretion was significantly higher than controlvalues in the l-aspartic acid (P .001) and W/C (P .0014) groups; the l-aspartic acid group excreted

Fig 1. Transcutaneous bilirubin levels (in milligrams per deciliter or micromolar) as a function of age among 4 groups of breastfed infantsduring the first week after birth. Infants were given l-aspartic acid (Lasp), EHC, W/C, or nothing (control). Average SEs are shown asvertical lines (0.21, 0.19, 0.25, and 0.27 mg/dL for the control, l-aspartic acid, EHC, and W/C groups, respectively).

Fig 2. Fecal total BPs (BDG plus BMG plus bilirubin) as a function of age among 4 groups of breastfed infants during the first week afterbirth. Infants were given l-aspartic acid (Lasp), EHC, W/C, or nothing (control). Average SEs are shown as vertical lines (739, 547, 478,and 428 nmol/day for the control, l-aspartic acid, EHC, and W/C groups, respectively).

TABLE 1. Characteristics of the Study Groups

Control(n 18)

l-Aspartic Acid(n 16)

EHC(n 15)

W/C(n 15)

P

Gender, % male 67 69 67 53 .80Gestational age, wk,

mean SD39.8 1.1 40.3 0.7 39.1 1.5 39.4 1.1 .013

Birth weight, kg,mean SD

3.614 0.483 3.618 0.502 3.671 0.274 3.697 0.454 .94

Vacuum extraction, n 0 0 0 1 .35Cesarean section, n 0 1 0 1 .53

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more fecal BP than did the control group on days 4 to6, and the W/C group excreted more BP than did thecontrol group on days 2 to 4. BP fecal excretion didnot differ significantly between the l-aspartic acidand EHC groups.

We also performed analyses of fecal excretion ofBDG, BMG, and bilirubin. Overall BDG fecal excre-tion was significantly greater than control values inthe EHC (P .0025) and W/C (P .0053) groups.Daily comparisons showed that the EHC group ex-creted more fecal BDG than did the control group ondays 3 to 5 and the W/C group excreted more BDGthan did the control group on days 2 to 4. Paireddaily comparisons showed that the 3 treatmentgroups did not differ from each other in BDG excre-tion. Overall fecal BMG excretion was significantlygreater than control values in all treatment groups (P .001 for all), and the l-aspartic acid and EHCgroups did not differ significantly in BMG excretionfrom the W/C group. The l-aspartic acid and EHCgroups excreted more fecal BMG than did the controlgroup on days 2 to 6, and the W/C group excretedmore BMG than did the control group on days 2 to 4.Paired daily comparisons showed that the l-aspartic

acid group excreted more BMG than did the W/Cgroup on days 5 to 6. Overall fecal bilirubin excretionwas significantly higher than control values in thel-aspartic acid (P .001) and W/C (P .0022)groups. The l-aspartic acid group excreted more fe-cal bilirubin than did the control group on days 4 to6, and the W/C group excreted more bilirubin thandid the control group on days 2 to 4. Fecal BP excre-tion resembled bilirubin excretion because the mag-nitudes of BDG and BMG fecal excretion were only0.13% and 21% that of bilirubin, respectively.BDG, BMG, and bilirubin fecal excretion did notdiffer significantly between the l-aspartic acid and

EHC groups. Dosages received among the treatmentgroups showed no significant differences in numberof doses per day (P .42), number of feedings perday (P .74), total dosage volume per day (P .80),or percentage of theoretical cumulative dose re-ceived (P .99).

Follow-up information showed no significant dif-ferences in day 7 weight, number of day 6/7weighed feedings, weight of day 6/7 milk and treat-ment, weighed day 6/7 milk, age at first formulafeeding, breastfeeding cessation age, and mothersrating of at least good (Table 2). There were no

significant differences among the groups in meco-nium clearance, as determined with fecal zinc cop-roporphyrin measurements (P .59), or in fecal uro-

bilinoid levels (P .43). There were no knownadverse events or side effects. None of the infantsdemonstrated excessive weight loss (ie, 10%).

DISCUSSION

Our results showed that breastfed newborns givenl-aspartic acid, EHC, or W/C during the first week

had significantly lower transcutaneous bilirubin lev-els than did control subjects. We hypothesized thatfeeding -glucuronidase inhibitors (l-aspartic acidor EHC) would inhibit -glucuronidase present inthe intestine. -Glucuronidase (-G) hydrolyzes glu-curonic acid from bilirubin conjugates, convertingBDG to BMG and BMG to bilirubin as illustrated.

If -glucuronidase is inhibited, then there should berelative preservation of conjugates on the left side ofthis equation. The fate of bilirubin is more compli-cated, however, because bilirubin is more easily ab-sorbed from the intestine than are bilirubin conju-gates30,31 and because intestinal bacteria can convert

bilirubin and its conjugates to urobilinoids, a familyof reduction-oxidation products.32 If bilirubin is notabsorbed or converted to urobilinoids, then it is ex-

creted in feces. The EHC group excreted significantlymore fecal BDG and BMG than did the controlgroup. The l-aspartic acid group also excreted sig-nificantly more BMG than did the control group.Interestingly, the W/C group also excreted moreBDG and BMG than did the control group. BecauseW/C lacks -glucuronidase inhibitors, some othermechanism must underlie this observation. One pos-sibility is increased binding of bilirubin conjugates

by components of the W/C supplement in the intes-tinal lumen. Overall, however, fecal excretion of bil-irubin glucuronides was minor, compared with total

TABLE 2. Follow-up Information Regarding Breastfeeding and Study Rating (Mean SD) in 4 Groups of Breastfed Infants

Control l-Aspartic Acid EHC W/C P

Short-term study findings n 18 n 16 n 15 n 15Weight on day 7, kg 3.63 0.42 3.51 0.47 3.54 0.35 3.62 0.45 .86No. of weighed feedings on days 6 and 7 10.4 3.9 8.5 3.4 9.3 4.5 10.2 3.4 .49Average weight of milk and supplement on

days 6 and 7, g (per feed)64.29 17.10 55.34 21.08 49.85 20.88 56.51 19.36 .23

Average weight of milk on days 6 and 7, g(per feed)

64.29 17.10 52.15 20.97 46.65 21.00 53.50 18.97 .084

Long-term follow-up findings n 16 n 12 n 14 n 13Age at first supplementation, wk 21.4 19.8 21.2 16.4 24.8 29.8 19.2 17.5 .93Age at breastfeeding cessation, wk 25.4 18.7 25.4 15.8 43.1 36.1 26.5 17.2 .21Rating of at least good, % 100 100 100 85 .082

Infants received supplements of l-aspartic acid, EHC, W/C, or nothing (control).

BDG BMG

Bilirubin

Intestinal absorption

Conversion (urobilinoids)

Fecal excretion




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fecal bilirubin excretion (predominantly unconju-gated). This underscores the importance of -glucu-ronidase, because little unconjugated bilirubin is ex-creted into bile. Bilirubin excretion was significantlyhigher in the l-aspartic acid group, compared withthe control group, consistent with inhibition of -glu-curonidase in the l-aspartic acid group.

Important events occur at the time of birth regard-ing bilirubin metabolism. Bilirubin glucuronides arepresent in fetal bile by 22 weeks of gestation andincrease in concentration with the maturation of he-patic bilirubin glucuronosyltransferase.33 In the in-testinal lumen, bilirubin glucuronides can undergohydrolysis by -glucuronidase, producing bilirubinthat is more easily reabsorbed into the circula-tion.30,31 In the fetus, this mechanism facilitates pla-cental clearance of bilirubin. After birth, however,this enterohepatic bilirubin circulation delays clear-ance and prolongs jaundice. Although bilirubin glu-curonosyltransferase does not plateau at adult levelsuntil 14 weeks of age,34 the small but statisticallysignificant gestational age differences among ourgroups cannot explain the findings in this study,

because only the l-aspartic acid group had a mean

gestational age greater than that of the control group.An important consideration is any effect on breast-

feeding. The AAP promotes breastfeeding as the bestinfant nutrition5,6 and recommends against supple-ments (eg, water, glucose-water solution, or formula)unless a medical indication exists.6 The AAP ClinicalPractice Guideline regarding neonatal hyperbiliru-

binemia recommends against routine supplementa-tion of nondehydrated breastfed infants with wateror dextrose-water solution, noting that this does notprevent hyperbilirubinemia. It also lists exclusive

breastfeeding as a major risk factor for the develop-ment of severe hyperbilirubinemia and exclusive

bottle-feeding as a factor associated with decreasedrisk of significant jaundice.2 In the management ofjaundiced breastfed infants, the AAP notes that tem-porary interruption of breastfeeding, with the sub-stitution of formula, can reduce bilirubin levels; ifsupplemental fluid is needed, then the best fluid touse is a milk-based formula, because it inhibits theenterohepatic circulation of bilirubin and shouldhelp lower serum bilirubin levels. Our data showedthat feeding of l-aspartic acid, EHC, or W/C involumes of up to 30 mL per day had no deleteriouseffect on weight gain, milk intake per feeding, age atsubsequent first supplementation, or duration of

breastfeeding. Mothers approved the feedings, with100% rating their study experience as good or excel-lent in the control, l-aspartic acid, and EHC groups.Estimated energy intake attributable to study nutri-ents was negligible (50 J/day, 13.8 J/kg of birthweight per day). Our experience was similar to thatof Nicoll et al,35 who showed that 38.6 mL of 5%dextrose per 1 kg of birth weight per day had nodeleterious effect on breastfeeding, and our studyused much less.

As judged by the age at first supplementation andthe age at breastfeeding cessation, this study in-cluded many highly motivated, breastfeeding moth-ers. However, mothers could benefit from this ap-

proach independent of breastfeeding duration,because the approach was limited to the first week oflife. The interventions were simple and well toler-ated, as verified by the high ratings parents gave thestudy after completion. As indicated in Table 2,mothers rated this study very highly, and it is un-likely they would do so if these interventions wereproblematic. Therefore, we think that such interven-tions can be quite acceptable to both mothers andpediatricians, as part of a breastfeeding support/education program.

The 2004 AAP hyperbilirubinemia guidelines2 in-clude a nomogram developed by Bhutani et al36 toclassify serum bilirubin concentrations into 4 differ-ent risk zones. Seventeen of our subjects were in arisk zone above the low-risk zone within the first 48hours after birth (6 in the control group, 5 in thel-aspartic acid group, 1 in the EHC group, and 5 inthe W/C group). The decline times (in hours) from arisk zone above the low-risk zone within the first 48hours to a low-risk zone after 48 hours were com-pared among the 4 groups for these 17 subjects.There were no significant differences in decline times

between the 2 groups that received no -glucuroni-

dase inhibitor (control: mean SD: 49.00 34.01hours; median: 31.00 hours; W/C: mean SD: 48.90 5.70 hours; median: 49.58 hours; P .41). Therewere also no significant differences in decline times

between the 2 groups that received a -glucuroni-dase inhibitor (l-aspartic acid: mean SD: 25.23 16.84 hours; median: 14.67 hours; EHC: mean SD:23.58 0 hours; median: 23.58 hours; P 1.0). Thecombined inhibitor groups had a significantlyshorter decline time than the combined no-inhibitorgroups (inhibitor: mean SD: 24.96 15.08 hours;median: 19.13 hours; no-inhibitor: mean SD: 48.95 24.32 hours; median: 45.33 hours; P .039, Wil-

coxon test) (Fig 3). Only 1 subject in our entire studywas in the highest (95th percentile) risk zone (age:22.7 hours). That subject was in the EHC group, andthe risk decreased to the next-to-lowest risk zone(4075th percentile) at 46.3 hours and to the lowestrisk zone at 74.9 hours. It would be of interest toevaluate the effect of -glucuronidase inhibitors onlarger numbers of infants in high-risk zones.

Although 64 infants were recruited into the study,when the infants were randomized into 4 groupseach group became rather small. Nevertheless, ourstudy showed significant differences clearly. Becausethis was a controlled, randomized, double-blind

trial, we have confidence in its real clinical signifi-cance. However, future studies with larger samplesizes are warranted. Our treatment groups had peak

bilirubin levels 25% to 30% lower than control val-ues, and those that received the -glucuronidase in-hibitor did decrease to lower risk zones faster thanthe groups that did not receive the -glucuronidaseinhibitor. Whether this would be helpful for infantswith higher bilirubin levels is not addressed withthese data. However, if infants with bilirubin levelsin the high-risk zone decreased their levels by 25% to30%, this certainly could be helpful.

It was the hope of this study that breastfed infantscould have the best of both worlds, ie, the advan-

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tages of exclusive breastfeeding plus the decreasedrisk of severe hyperbilirubinemia associated with ex-clusive formula feeding. The results show that sig-nificant reductions in transcutaneous bilirubin levelscan be achieved, with no negative effect on breast-feeding, through administration of small dailyamounts of selected key ingredients of currentlyavailable infant formula. In the l-aspartic acid andEHC groups, the effect probably results from -glu-curonidase inhibition and increased fecal excretionof bilirubin. Lower transcutaneous bilirubin levels inthe W/C group suggest a different mechanism.These results require confirmation with additionalresearch involving larger numbers of subjects.

ACKNOWLEDGMENTS

This work was supported in part by grants from Mead JohnsonNutritionals, the University of Wisconsin Technology and Inno-vation Fund, and the University of Wisconsin Department ofPediatrics and Medical School.

Sincere thanks go to the following nurses: Mona Borgman,Sarah Goebel, Gynel Hagemann, Carmen McDonald, and DebWolff. Thanks also go to Deb Kundert and Pat Berra. We aregreatly indebted to Dr Bruce Duemler, his co-workers, and thestaff of the Monroe Hospital and Clinic (Monroe, WI), who em-

braced and supported this study enthusiastically, and to Dr JohnD. Bancroft. Thanks go to Scott Kerr, Respironics, for providingBilicheck devices. This manuscript is dedicated to the memory ofDr Gerard B. Odell.

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Fig 3. Decline times from a risk zone above the low-risk zone within the first 48 hours to the low-risk zone after 48 hours. The boxesrepresent the 25th and 75th percentiles, the white lines represent the medians, and the whiskers mark the ranges of data.




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THE RELOSTHE NOMADIC, OVERSCHEDULED, AND INCREASINGLYISOLATED AFFLUENT: ONE WAY THE GLOBAL ECONOMY IS

RESHAPING CLASS IN AMERICA

Others complain of stress and anomie. They have traded a home in one placefor a job that could be anyplace. Relo children do not know a hometown; theirparents do not know where their funerals will be. There is little in the way ofsmall-town ties or big-city amenitiesgrandparents and cousins, longtime neigh-

bors, vibrant boulevards, homegrown shopsthat let roots sink in deep. . . . Its asif theyre being molded by their companies, said Tina Davis, a top Alpharetta reloagent for the Coldwell Banker real estate firm. Most of the people will tell you howlong theyll be here. Its usually two to four years. . . . Just how many relos thereare is hard to determine. The tide rolls with corporate fortunes and the globaleconomy, and relos are not singled out in census statistics. But in a survey from

March 2002 to March 2003, the Census Bureau said that about three million peoplemoved to another county, state or country because employers had transferred orrecruited them. . . . Converging on these towns, relos have segregated themselves,less by the old barriers of race, religion and national origin than by age, familystatus, education and, especially, income. Families with incomes of $100,000 headfor subdivisions built entirely of $300,000 houses; those earning $200,000 trade upto subdivisions of $500,000 houses. Isolated, segmented and stratified, these fam-ilies are cut off from the single, the gay and the gray and, except for those tendingthem, anyone from lower classes.

Kilborn PT. New York Times. June 1, 2005

Noted by JFL, MD

ARTICLES 391



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DOI:10.1542/peds.2004-18072005;116;385-391Pediatrics

Glenn R. Gourley, Zhanhai Li, Bill L. Kreamer and Michael R. KosorokAmong Breastfed Newborns

A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice

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A Controlled, Randomized, Double-Blind Trial of Prophylaxis Against Jaundice Among Breatfed Newborn

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