Identifying the Newborns at Risk for Developing Significant ...

ORIGINAL ARTICLEJ. Arab Neonatal Forum 2005; 2:81-85Identifying the Newborns at Risk for Developing SignificantHyperbilirubinemia by Measuring Cord Bilirubin LevelsRostami N 1 , Mehrabi Y 2Department of Pediatrics, Taleghani Hospital, Shaheed Beheshti University of Medical Sciences , Tehran,Iran; 2 Department of Health and Community Medicine, Shaheed Beheshti University of Medical Sciences,Tehran, Iran.__________________________________________________________________________________________AbstractBackground: Jaundice is mostly benign, but because of the potential of bilirubin toxicity, neonates should bemonitored carefully for developing severe hyperbilirubinemia. The need to recognize infants who are at risk forsignificant jaundice is apparent in the era of routine early discharge. The aim of this prospective study is toidentify healthy newborns at risk for developing significant hyperbilirubinemia by measuring bilirubin level incord blood. Methods: Umbilical cord serum bilirubin concentration was analyzed in 643 full term infants withbirth weight ≥ 2500 grams and an Apgar score ≥ 7, born at Mahdieh Hospital, Tehran, Iran. Infants with signs ofecchymosis, cephalohematoma, septicemia, and/or premature rupture of membrane were excluded from thestudy. Serum bilirubin level was obtained at day three of age and total bilirubin ≥ 239µmol/l (14 mg/dl) wasdefined as significant hyperbilirubinemia. Data were analyzed using t-test, chi-square, and Receiver OperatingCharacteristics (ROC) curve. Results: Mean and standard deviation of cord bilirubin level was 34.2 ± 15.9µmol/l (2.00 ± 0.93 mg/dl). There was a statistically significant relation between use of oxytocin and subsequentsignificant hyperbilirubinemia (p < 0.04). 92.4% of neonates with cord bilirubin levels below 51.3 µmol/l (3mg/dL) did not develop significant hyperbilirubinemia. A cord serum bilirubin level above 51.3 µmol/l is not auseful predictor of neonatal jaundice. Conclusion: Cord serum bilirubin levels cannot identify newborns withsubsequent significant hyperbilirubinemia. Early discharged neonates need close follow-up and use of any otherstrategies to identify newborns at high risk of jaundice.Keywords: Hyperbilirubinemia, cord bilirubin, neonates.IntroductionHyperbilirubinemia is a common problem during theneonatal period and is the most common reason forreadmission after early hospital discharge. It can be aphysiologic condition or a severe disease with braindamage. 1-4 Hyperbilirubinemia is quite common innewborns; it affects nearly 70% of term and 80% ofpreterm neonates during the first week of life 5 . Theimportant risk factors most frequently associated withsever hyperbilirubinemia are breast feeding,gestational age below 38 weeks, significant jaundicein a previous sibling, and jaundice noted beforedischarge 6 .Early newborn discharge began as a consumerinitiatedmovement and as an alternative to homedelivery in the 1980’s. Reports of recent experienceswith early discharge show both problems and successwith this policy. 7 A short hospital stay, for less than48 hours after birth, resulted in an increase inneonatal readmission for hyperbilirubinemia. TheAmerican Academy of Pediatrics (AAP) recommendsthat newborns discharged within 48 hours shouldDr. Nahid Rostami, Department of Pediatrics,Neonatology Division, Taleghani Hospital,Shaheed Beheshti University of Medical Sciences,Evin, Tehran, 19857, Iran, E-mail:Rostami@sbmu.ac.ir , neonatal_sbmu@yahoo.com ,Phone: +98 21 2240 3583, Fax: +98 21 4417 0550have a follow up visit after 2-3 days to detectsignificant jaundice and other problems. 8 Bilirubintoxicity remains a significant problem despite recentadvances in the care of jaundiced neonates. 9Kernicterus, though infrequent, is the cause of 10%of mortalities and at least 70% of long-termmorbidities among newborns. 10 Recent increases inearly hospital discharges, coupled with a rise inbreast feeding rates, has led to a rise in the rate ofpreventable kernicterus resulting from undetectedhyperbilirubinemia. If extreme hyperbilirubinemiacan be prevented, then almost all cases of kernicterusare avoidable too. Asian and Middle Eastern infantsgenerally have higher total serum bilirubin (TSB)levels, and they are more often breast-fed. Therefore,it is essential to identify infants at high risk fordeveloping pathologic jaundice in these regions.In recent years many efforts have been made toidentify infants likely to develop neonatal jaundice.Reliable strategies can reduce hospital stay fornormal babies and identify significanthyperbilirubinemia that may happen in the future.Universal follow-up within 1 to 2 days of earlydischarge, umbilical cord bilirubin concentration atbirth, routine pre-discharge serum bilirubin andtranscutaneous bilirubin measurement, as well as theuniversal clinical assessment for risk factors ofdeveloping jaundice are various strategies to predictsignificant hyperbilirubinemia.81

Cord bilirubin level and risk for hyperbilirubinemiaIn Iran, due to cultural issues, it is difficult to provideand monitor compliance of a follow-up program forevery infant who is discharged. Therefore, it isimpossible to use hour-specific bilirubin percentile topredict subsequent jaundice. The present study wasconducted to evaluate the ability of cord bilirubinlevel in identifying healthy term infants at risk ofhyperbilirubinemia.Materials and MethodsThe total annual numbers of births in the hospital, inTehran, and in Iran are approximately 5,000, 178,100and 1,171,573 (based on the 2003 report of theStatistical Center of Iran) respectively. According toprevious studies about 18% of infants had TSB of 14and above. Assuming 3% error and 95% confidence,the sample size was worked out as 630 infants.Systematic random sampling was used to select thesubjects. Over a period of 6 months 740 motherswere approached of whom 97 refused to participatein the study. The population of this study thereforeincluded 643 (343 females and 300 males) healthyfull term newborns delivered at Mahdieh Hospital,Tehran, Iran. All infants had gestational age of > 37weeks (based on New Ballard Score), and birthweight ≥ 2500 grams. Also there were no signs ofcephalohematoma, prolonged rupture of membrane(more than 24 hours), septicemia and significantillness with a fifth minute Apgar score ≥7.Frequency1008060402001471013Total Bilirubin (3rd day)Figure 1: Histogram of 3 rd day total serum bilirubinconcentrationSensitivity1.00.75.50161922The umbilical cord bilirubin level at birth and TSBlevels in all infants on day 3 of life were measured.Informed consent was also obtained from all theparents. Blood group and G6PD activity tests wereperformed routinely in all cases. All infants werevisited daily by a pediatrician and were dischargedafter 72 hours. Bilirubin levels were obtained if thenewborn was clinically diagnosed as being jaundicedbefore 72 hours. Significant hyperbilirubinemia wasdefined at TSB level of ≥ 239 µmol/l (14 mg/dl) onday 3 of life. The infants were investigated andsupervised if they were clinically jaundiced on thefirst day of life, if TSB was ≥ 205 µmol/l (12mg/dl)on day 2, and TSB ≥ 239 µmol/l (14 mg/dl) on day 3.Maternal and neonatal data were also collected. Datawere analyzed using descriptive statistics, chi-square,and t-tests. Sensitivity, specificity, and positive andnegative predictive values of different cut-points ofthe cord total bilirubin were obtained. ReceiverOperating Characteristics (ROC) curve analysis wascarried out to evaluate the usefulness of cordbilirubin level for identifying neonates at risk.ResultsA total of 643 newborns were enrolled. Baselinecharacteristics of infants and their mothers are shownin Table 1. All infants were exclusively breast-fed.Significant hyperbilirubinemia was detected in 11.8%of infants. Figure 1 shows the distribution of serumbilirubin concentration on the third day..250.000.00.25.501 - SpecificityFigure 2: Receiver Operating Characteristics (ROC) curveof cord bilirubin for predicting 3 rd day bilirubin(≥14). Area under curve = 0.563 (95% CI:0.490, 0.636).Bilirubin level more than 239 µmol/l (14 mg/dl) wereobserved in 16.9% of infants whose mothers hadreceived oxytocin during delivery, and in 10.6 % ofinfants whose mothers had not received it (p < 0.04).Significant hyperbilirubinemia was detected in 14.3%of G6PD deficient infants as against 11.8% of nonenzymedeficient infants, the difference not beingsignificant. The incidence of ABO incompatibilitywas 12%, and 15.6 % of these infants had pathologicjaundice. The incidence of Rh incompatibility was6.2% and significant hyperbilirubinemia developed in10% of infants in this group. In infants with ABO andRh incompatibilities, third day total bilirubin levelwas not significantly different from other babies ofthe studied group (table 2). Significanthyperbilirubinemia developed in 13.4% of boys and10.6% of girls..751.0082

J. Arab Neonatal Forum 2005; 2:81-85There were no significant relations between type ofdelivery, sex, birth weight, history of jaundice inother siblings, instrumental delivery, parity, maternalage and pathologic jaundice on 3rd day. As shown inthe ROC curve (Figure 2) the cord bilirubin level isnot an appropriate index for identifying high riskneonates. Sensitivity, specificity, positive andnegative predictive values of cord bilirubin level forprediction of pathologic jaundice are shown in Table3.DiscussionThere is a concern about an increasing incidence ofkernicterus in healthy term neonates, andhyperbilirubinemia is one of the most commonreasons for readmission of newborns especially in theMiddle East and Asia. The need for early detection ofhyperbilirubinemia in newborns discharged earlyfrom the hospital is therefore important. Knowledgeof infants at risk of developing jaundice allowssimple bilirubin reducing methods to be implementedbefore bilirubin levels reach critical levels. Earlyhospital discharge policy in developing countriessuch as Iran, along with limited follow up facilities,and inadequate communication between physiciansand parents, necessitate a prognostic test to predictand prevent a potential problem before it occurred.In this study, we assessed the ability of cord bilirubinlevel to be a tool for screening for the risk ofsubsequent significant neonatal jaundice.The present study shows that 92.4% of infants withcord bilirubin level below 3 mg/dl would notpotentially develop significant hyperbilirubinemia.There are conflicting reports of the predictability ofcord blood bilirubin of later hyperbilirubinemia.Rosenfeld 11 showed that infants with cord bilirubinlevels less than 34 µmol/l have only 4 percent chanceof developing hyperbilirubinemia and 1.4 percentchance of needing phototherapy. However, infantswith cord bilirubin > 34µmol/l would have 25 percentchance of developing subsequent hyperbilirubinemia.Knudsen 12 showed if cord bilirubin was below 20.5µmol/l, 2.9% of infants developed jaundiced asopposed to 85% if cord bilirubin was above 43µmol/l. Furthermore, 57% of jaundiced infants withcord bilirubin above 43µmol/l required phototherapy.In another retrospective study, Jacobson et al. 13compared cord bilirubin levels of 87 neonates whoreceived standard phototherapy for neonatal jaundicewith the cord bilirubin levels of 95 neonates withoutneonatal jaundice. There were no significantdifferences in the cord bilirubin levels between thetwo groups leading to the conclusion that cordbilirubin levels could not predict significanthyperbilirubinemia. Simpson et al 5 reported that cordbilirubin levels above 43µmol/l can predictdevelopment of pathologic jaundice (TSB > 222µmol/l) with sensitivity and specificity of 71% and96% respectively, while Carbonell et al 14 showedumbilical cord bilirubin with cut-off point of 38µmol/l was not a useful predictor of neonataljaundice.Table 1- Characteristics data of enrolled infants and their mothersCharacteristics3 rd day serum bilirubin< 14 ≥ 14 TotalNumber (%) 567 (88.2) 76 (11.8) 643Birth weight (mean ± sd) 3158 ± 515 3134 ± 456 3155 ± 508Cord bilirubin (mean ± sd)Total (µmol/l) 34 ± 16 37.4 ± 17 14 ± 16Direct (µmol/l) 4.6 ± 6 4.1 ± 3.2 4.4 ± 6Age of mother (mean ± sd ; yrs) 26.0 ± 5.7 26.6 ± 3.2 26.1 ± 5.8Parity (mean ± sd) 1.6 ± 1.5 1.4 ± 1.7 1.5 ± 1.5Table 2. Occurrence of significant hyperbilirubinemia in different groupsVariablesPercentage of significant hyperbilirubinemiaYesNoABO incompatibilty * 15.6 11.3Rh incompatibility ** 10.0 11.9G6PD deficiency 14.3 11.8History of jaundice in siblings 23.8 11.6Intranatal administration of oxytocin 16.9 † 10.6Neonatal sexBoys 13.4Girls 10.6*Mother’s blood group O, neonate’s blood group A or B , **Mother’s Rh- and neonate’s Rh+ † P< 0.04, ‡ Caesarian section83

Cord bilirubin level and risk for hyperbilirubinemiaTable 3: Sensitivity, specificity, positive and negative predictive values of cord bilirubin level for prediction of 3rd daysignificant hyperbilirubinemiaCord bilirubincut-off pointsSensitivity SpecificityPositivepredictive value1 93.4 4.1 11.5 82.11.5 85.5 20.3 12.6 91.32 59.2 48.1 13.3 89.82.5 25 84.1 17.4 89.33 18.4 92.4 24.6 89.43.5 13.2 95.9 30.3 89.24 7.9 97.7 31.6 88.8Negativepredictive valueBernalda and Segre 15 reported that bilirubin levels incord blood were significantly higher in newborns thathad required phototherapy. The presence of ABOblood group incompatibility was a significantvariable in relation to the need for phototherapy. Themost useful cutoff point for unconjugated bilirubin incord blood was 34 µmol/l. They declared that 53% ofnewborns who had greater bilirubin levels in cordblood would reach levels requiring phototherapy bythe third day of life.Riskin et al 16 stated that the trained human eye canstill discriminate between the jaundiced and nonjaundicednewborn, and clinical impression ofjaundice remains a reliable primary screening tool forsignificant neonatal hyperbilirubinemia. Percentilecharts of serum bilirubin levels at different postnatalages in near-term and term infants have beenproduced. 17 An hour specific TSB, before hospitaldischarge, can predict newborns at high,intermediate, or low risk for developing clinicallysignificant hyperbilirubinemia (defined as TSB > 95 thpercentile for age in hours). Agarwal et al 18 showedthat TSB level of 103 µmol/l at 24 ± 6 hours of lifepredicts absence of subsequent hyperbilirubinemiawith high probability.A model based on several factors can be used topredict neonatal jaundice and shows a sensitivity of81% and specificity of 82.9%, a false positive rate of80.2% and a false negative rate of 1.1%. Individualrisk assessment could be made based on day one totalserum bilirubin. Later, Sarici et al 20 concluded anearly six-hour serum bilirubin measurement wasuseful in predicting the development of significanthyperbilirubinemia in newborns with ABOincompatibility. The American Academy ofPediatrics (AAP) produced a clinical practiceguideline for the management of hyperbilirubinemiain healthy term newborns. 6 The AAPrecommendation requires that every infant beassessed for the risk of developing severehyperbilirubinemia and all nurseries to establish aprotocol for assessing this risk before discharge fromthe hospital. The AAP recommends two clinicaloptions used individually or in combination for thesystematic assessment of risk: pre-dischargemeasurement of the bilirubin level using TSB ortranscutaneous bilirubin level (TcB), and/orassessment of clinical risk factors. Whether either orboth options are used, appropriate follow-up afterdischarge is essential. TSB can be obtained at thetime of the routine metabolic screen. Some authorshave suggested that a TSB measurement should bepart of the routine screening of all newborns. Aninfant whose pre discharge TSB is in the low-riskzone is at very low risk of developing severhyperbilirubinemia. The incidence of ABOincompatibility in the present study was 12% whichis consistent with results from other studies. 20In the present study oxytocin was used in 39.4% ofmothers and 16.9% of their babies had pathologicjaundice. There was a significant relationshipbetween usage of oxytocin and pathologic jaundice(p < 0.04). The incidence of pathologichyperbilirubinemia was 11.8% in this study. Theseresults are in good agreement with those of otherinvestigators like Alpay 21 who reported that 12.5% ofnewborns had significant jaundice after 72 hours oflife, and Agarwal et al. who showed thathyperbilirubinemia occurred in 10.3% of infants.In the present study, our infants were followed up forup to the third day of life. Infants without significantclinical jaundice were not followed subsequently.Therefore, infants who might have developed latejaundice could have been missed. G6PD deficiency ismore common in the Middle East 6 but in the presentstudy G6PD deficiency was only 2.2%.ConclusionIt can be concluded that, cord bilirubin levels can notidentify newborn infants who are at risk fordeveloping significant hyperbilirubinemia. However,cord bilirubin level below 3 mg/dl identified thoseinfants who are not high risk to develop pathologicjaundice.In Iran due to economical factors, early hospitaldischarge is a routine practice. TSB measurement inhealthy term newborns is not an option because84