DOI: 10.1542/peds.2007-3723 2009;123;327Pediatrics

Sanjiv B. Amin, Diane Prinzing and Gary MyersHyperbilirubinemia and Language Delay in Premature Infants

  

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ARTICLE

Hyperbilirubinemia and Language Delay inPremature InfantsSanjiv B. Amin, MD, MS, Diane Prinzing, AAS, Gary Myers, MD

Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject

To our knowledge, no studies have evaluated the role of severity and duration of hyper-bilirubinemia on language development in premature infants.

What This Study Adds

Although this is a negative study, the rationale of conducting this retrospective study maychange the perception of a disease process, specifically how hyperbilirubinemiamay affectlanguage development. Second, we recommend future research on the subject by consid-ering better biochemical measures such as unbound bilirubin as a predictor.

ABSTRACT

OBJECTIVE.Our goal was to evaluate whether language delay at 3 years in prematureinfants is associated with previous exposure to hyperbilirubinemia during the first 2weeks after birth.

PATIENTS AND METHODS.We performed a retrospective case-control study of infants ad-mitted to the NICU between January and October 2003. Inclusion criteria includeda birth weight of �1500 g and follow-up to age 3 years. Exclusion criteria includedgenetic disorders and hearing loss or recurrent ear infections. Peak total serumbilirubin levels during the first 2 weeks and duration of hyperbilirubinemia (dayswith total serum bilirubin level at �8 mg/dL) were determined. Infants with lan-guage delay and who were receiving speech therapy by 3 years were identifiedthrough developmental clinic charts and a tracking program and compared withinfants who had normal language development.

RESULTS.A total of 125 infants with birth weight of �1500 g were admitted to the NICUbetween January and October 2003. Fifteen infants died, and 110 were dischargedfrom the hospital. A total of 102 (93%) of 110 infants had follow-up to the age of 3years. Four infants were excluded (1 genetic disorder, 3 delayed hearing loss orrecurrent ear infections). Twenty-four infants had a language delay and receivedspeech therapy, whereas 74 infants had normal language development. There wasno significant difference in peak total serum bilirubin level and duration of hyper-bilirubinemia between the 2 groups. On logistic regression, only bronchopulmonarydysplasia was associated with language delay.

CONCLUSIONS.Hyperbilirubinemia, defined as peak total serum bilirubin level or dura-tion of elevated bilirubin in days, is not associated with language delay in prematureinfants. However, this issue deserves investigation, because other measures of bili-rubin, such as unbound bilirubin, may be associated with language delay. Pediatrics2009;123:327–331

PREMATURE INFANTS ARE at increased risk of developmental language disorders.1–3 The reasons for this are not wellunderstood, but auditory development is known to be intricately related to language development.4–9 Auditory

sensory deprivation during a critical period of development has been demonstrated to lead to central auditoryprocessing and language problems.10–12 Studies in neonates and children have associated auditory dysfunction asevaluated by auditory brainstem evoked response with developmental language disorders.13–15

The auditory neural system is known to be sensitive to bilirubin-induced neurotoxicity.16 Several large observa-tional studies have been conducted to evaluate the association between neurodevelopmental outcomes and hyper-bilirubinemia in premature infants.17–20 The only significant and consistent association demonstrated has beenbetween hyperbilirubinemia and hearing deficits.17,19 These observational studies did not specifically evaluatelanguage development in association with hyperbilirubinemia. Recently, hyperbilirubinemia has been associatedwith auditory dysfunction as evaluated by auditory brainstem evoked responses in premature infants.21 Despiteknowledge about the effect of hyperbilirubinemia on the auditory system and the intricate developmental relation-ship known to exist between auditory and language development, there is limited information available in the

www.pediatrics.org/cgi/doi/10.1542/peds.2007-3723

doi:10.1542/peds.2007-3723

This work was presented at the annualmeeting of the Pediatric AcademicSocieties; May 5–8, 2007; Toronto, Ontario,Canada

KeyWordshyperbilirubinemia, premature infants,language

AbbreviationsTSB—total serum bilirubinNCCTP—Neonatal Continuity CareTracking ProgramPDA—patent ductus arteriosusIVH—intraventricular hemorrhagePVL—periventricular leukomalaciaBPD—bronchopulmonary dysplasiaNEC—necrotizing enterocolitisCI—confidence interval

Accepted for publication Apr 22, 2008

Address correspondence to Sanjiv B. Amin,MD, MS, University of Rochester School ofMedicine and Dentistry, Department ofPediatrics, PO Box 651, 601 Elmwood Ave,Rochester, NY 14642. E-mail: sanjiv_amin@urmc.rochester.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005;Online, 1098-4275). Copyright © 2009 by theAmerican Academy of Pediatrics

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literature regarding the effect of indirect hyperbiliru-binemia on language development in premature in-fants.22 We hypothesized that premature infants withlanguage delay identified during the first 3 years ofpostnatal life have a higher peak total serum bilirubin(TSB) level and/or a longer duration of hyperbiliru-binemia during the first 2 postnatal weeks comparedwith premature infants with normal language develop-ment. Our objective was to determine whether a lan-guage delay at 3 years of age in premature infants isassociated with the severity or duration of hyperbiliru-binemia during the first 2 postnatal weeks of life.

METHODS

Study DesignA retrospective case-control study was designed to de-termine whether the severity or duration of hyperbiliru-binemia during the first 2 weeks of postnatal life wasrelated to a language delay at 3 years of age in prematureinfants. We compared premature infants with a birthweight �1500 g who received speech therapy by 3 yearsold with those who did not. Speech therapy was used asa surrogate measure of language delay and its absence asurrogate measure of normal language development.The study was approved by the institutional researchreview board.

Subject PopulationAll premature infants �1500 g admitted to the NICU atthe Golisano Children’s Hospital at Strong between Jan-uary and October 2003 and who had neurodevelopmen-tal follow-up at 3 years old were eligible. We excludedthose with a major congenital malformation, delayedhearing loss (normal newborn hearing screen but diag-nosed to have hearing loss at a later period), or recurrentear infections (�3/year during first 3 years).

Language Evaluation and Speech TherapyThe NICU at the Golisano Children’s Hospital at Strongoffers a neurodevelopmental clinic for high risk gradu-ates. Families of premature infants with birth weight�1500 g are advised on discharge to follow-up in theneurodevelopmental clinic during the first few years. Inthe neurodevelopmental clinic, the infants are evaluatedby a neurologist, psychologist and a neonatologist. In-fants with suspected or confirmed speech and languagedelay, based on the assessment by the psychologist onthe speech and language domain of the Bayley InfantNeurodevelopmental Screener, are referred to the EarlyIntervention Program for additional evaluation andtherapy. Infants may also be referred to the Early Inter-vention Program by their primary care physician. Mostprimary care physicians use the Denver DevelopmentalScreening Test II in their clinic. Infants are then evalu-ated by the speech pathologist involved with the EarlyIntervention Program by using one of the standardizedlanguage assessment tools approved by the New YorkState Early Intervention Program. The standardized toolsused are either the Preschool Language Scale (fourthedition) or Parent Receptive Expressive Emergent Lan-

guage test (third edition). If an infant shows a 33% delayin speech acquisition based on this evaluation, then theinfant is determined to have speech and language delayand is offered speech therapy for a minimum of 6months.

After the second year evaluation in the neurodevel-opmental clinic, each child is followed through the Neo-natal Continuity Care Tracking Program (NCCTP) from 3to 10 years of age. This involves sending a survey ques-tionnaire to parents and primary care physician of eachsubject on developmental milestones achieved, intervalmedical illness, interval hospitalization, interval surgicaloperations, current medications, and type of therapy forany developmental issues the child is currently receivingor has received.

Study GroupsWe identified infants who had follow-up data at 3 yearsof age through the NCCTP. Among these infants, thosewho had received speech therapy were identified andconstituted the Case group. Those infants with normallanguage development who did not receive speech ther-apy constituted the Control group.

Exposure VariablesInformation on TSB levels during the first 2 postnatalweeks for each individual subject was obtained from theClinical Information System. TSB levels were measuredby using the Diazo method. Peak TSB and duration indays of total serum bilirubin �8 mg/dL during the first 2postnatal weeks was determined for each subject. Dataon demographics and covariates were extracted fromneonatal charts by investigators blinded to language out-come. Patent ductus arteriosus (PDA) was reported bythe pediatric cardiologist based on echocardiographyfindings. Intraventricular hemorrhage (IVH) grading onhead ultrasound findings was based on Papille’s classifi-cation and was reported by the pediatric radiologist.Periventricular leukomalacia (PVL) was defined and re-ported by the pediatric radiologist based on head ultra-sound findings of echo lucent cysts in the white matter.Head ultrasounds were routinely performed during thefirst postnatal week, at the end of second postnatalweek, and at 6 to 8 weeks after birth. Bronchopulmo-nary dysplasia (BPD) was defined based on oxygen re-quirement at 36 weeks’ postmenstrual age. Necrotizingenterocolitis (NEC) was defined based on radiographfindings of pneumatosis and/or free air in the perito-neum as reported by the pediatric radiologist. Clinicalsepsis was defined as a clinical condition associated withthe use of intravenous antibiotics for �5 days.

Statistical AnalysesStudent’s t test was used to analyze continuous vari-ables by using Stata (Stata Corporation, College Sta-tion, TX). A �2 or Fisher’s exact test as appropriate wasused to analyze nominal variables. Stratified analyseswith homogeneity tests were used to evaluate forpossible effect modifiers. Bivariate analyses were per-formed to evaluate the association between each clin-

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ical variable (covariates) and language outcome. Sim-ilarly, bivariate analyses were performed to evaluatethe association between covariates and exposure vari-ables (duration of hyperbilirubinemia and peak TSBlevels). All tests were 2-sided, and a P � .05 wasconsidered statistically significant.

Covariates with a significant association (P � .2) tolanguage outcome or exposure variables were consid-ered as possible confounders and included in modelbuilding. Log likelihood ratio test was performed to eval-uate the regression model using backward selectionmethod. Covariates that did not make significant contri-bution to the model (P � .2) as evaluated by the loglikelihood ratio test were removed from the model. Thefinal model was evaluated for a fitness using HosmerLemeshow test. A logistic regression analysis was per-formed using final model to control for potential con-founding factors.

RESULTSA total of 125 infants with birth weight �1500 g wereadmitted to the NICU of Golisano Children’s Hospitalfrom January to October 2003. Among them, 15 infantsdied and 110 infants were discharged from the hospital.There were 102 (93%) infants who had follow-up until3 years old. Four infants were excluded (1 genetic dis-order, 3 with delayed hearing loss or recurrent ear in-fections). Of the remaining 98 infants, 74 identified ashaving normal language were compared with 24 infantswith a language delay.

The demographics of the study subjects are shownin Table 1. There was no significant difference in gesta-tional age, birth weight, gender, race, maternal educa-tion, in utero exposure to illicit drugs, rate of cesareansection delivery, and 5-minute Apgar �3 between in-fants in the 2 groups. The clinical characteristics of studysubjects are shown in Table 2. There were no significantdifferences in the occurrence of respiratory distress syn-drome, PDA, severe IVH, PVL, type of enteral feeding,and clinical sepsis between infants with normal languagedevelopment and infants with language delay. Therewas a significant association between BPD at 36 weeks’

postmenstrual age and language delay, and there was atrend for significant association between NEC and lan-guage delay. There was no significant difference in peakTSB or duration of hyperbilirubinemia between infantswith normal language development and infants withlanguage delay (Table 2).

Stratified analyses with homogeneity tests revealedno effect modifiers for the association between hyperbi-lirubinemia and language delay. Gestational age, birthweight, BPD, PDA, NEC, and clinical sepsis were identi-fied as possible confounders for the evaluation of anyassociation between hyperbilirubinemia and languagedelay and were included in the full regression model.The final regression model was determined by usingbackward selection method and log likelihood ratio test.The final regression model for the evaluation of an as-sociation between hyperbilirubinemia and language de-velopment included BPD. The Hosmer Lemeshow testsuggested that there was no difference in the expectedfrequencies and observed frequencies and that the finalregression model was a good fit (P � .60). BPD wasassociated with language delay in premature infants (ad-justed odds ratio: 7.3 [95% confidence interval (CI):2.5–22]). Neither peak TSB (adjusted odds ratio: 0.96[95% CI: 0.7–1.3]) nor duration of hyperbilirubinemia(adjusted odds ratio: 1.03 [95% CI: 0.8–1.3]) was asso-ciated with language delay in premature infants with birthweight of �1500 g after controlling for confounders.

DISCUSSIONWe found no relationship between peak TSB or totaldays of bilirubin above 8 mg/dL during the first 2 weeksof life and language development defined as receivingspeech therapy during the first 3 years of life. Thesefindings do not support the hypothesis that there is arelationship between the severity or duration of neona-tal hyperbilirubinemia and language development inpremature infants with birth weight of �1500 g. Webelieve this is the first study to evaluate the role ofseverity and duration of hyperbilirubinemia on languagedevelopment in premature infants.

Language delay is one of the most common develop-mental problems among premature infants, but its

TABLE 1 Demographic Characteristics of Study Population

Normal Language(n � 74)

Language Delay(n � 24)

Pa

Gestational age, mean � SD, wk 29.4� 2.2 28.4� 2.5 .08Birth weight, mean � SD, g 1132� 219 1022� 283 .09Small for gestational age, % 31 25 .6Gender, male/female) 38/36 15/9 .3Race, % white 61 66 .8Maternal education more thancollege, %

67 69 .9

In utero exposure to illicit drugs,%

7 8 .8

Antenatal steroid exposure, % 88 87 .9Mode of delivery, % cesareansection

63 50 .21

Apgar score � 3 at 5 min, % 5 13 .21a Mean � SD were analyzed by using x2 test, and proportions were analyzed by using �2 test.

TABLE 2 Clinical Characteristics of Study Population

NormalLanguage(n � 74)

LanguageDelay

(n � 24)

Pa

Respiratory distress syndrome, % 90 91 .9PDA, % 15 29 .1Grade III/IV IVH, % 4 0 .6PVL, % 2 0 1.0BPD at 36 wk, % 13 54 .001Breast milk feeding during NICU stay, % 44 35 .4NEC with pneumatosis or perforation, % 4 17 .05Clinical sepsis, % 35 52 .1Peak TSB during first 2 wk, mean � SD, mg/dL 9.9� 1.8 9.4� 2.1 .3Days with TSB � 8 mg/dL during first 2 wk(duration of hyperbilirubinemia), mean � SD

3� 2.7 2.7� 2.5 .6

a Mean � SD were analyzed by using x2 test, and proportions were analyzed by using �2 test.

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causes have not been determined.1–3,23,24 Hearing is es-sential to language development, and there is evidencethat peripheral auditory dysfunction or auditory sensorydeprivation during the critical period of developmentmay affect central auditory function and later languagedevelopment.10–12,25 Children with hearing loss and/orauditory neuropathy may demonstrate language prob-lems depending on the timing, degree, and duration ofassociated auditory dysfunction or auditory sensory de-privation.26–29 Auditory neuropathy is characterized bynormal outer hair cell function but abnormal auditorybrainstem evoked responses. Earlier identification andmanagement of these hearing problems has been shownto improve auditory processing and language develop-ment supporting the fact that these hearing disordersaffect language development.26,30,31

The auditory system is thought to be most sensitiveneural system to bilirubin-induced toxicity.16,32 Previ-ous studies have associated hyperbilirubinemia withsensori-neural hearing loss and auditory neuropathyin neonates.16,17,19,33 Several studies have also reportedreversible auditory dysfunction at the peripheral andbrainstem level secondary to indirect hyperbiliru-binemia, a condition extremely common during the firstpostnatal week in neonates.16,21,34,35 Bilirubin-inducedauditory toxicity may depend on the degree and dura-tion of indirect hyperbilirubinemia.16,35–37 The corollaryof this evidence is that there exists a possibility thatindirect hyperbilirubinemia in neonates, depending onthe duration and severity of hyperbilirubinemia, mayaffect later language development through its effect onthe auditory nervous system.

Premature infants are at higher risk of bilirubin-in-duced neurotoxicity than term infants.16 Moderate hy-perbilirubinemia has been shown to cause auditory dys-function in premature infants.16,21 The consequences ofthese auditory changes on later development in prema-ture infants are not known. There is some evidence thatsuggests that auditory dysfunction may be associatedwith later language development.13–15 Despite supportingevidence and strong biological plausibility, the lack ofassociation between hyperbilirubinemia and languagedevelopment is intriguing and perplexing. One plausibleexplanation for this lack of association can be based onthe free (or unbound) bilirubin theory. Current litera-ture suggests that the unbound bilirubin level might bea better predictor than TSB of acoustic delay in nervoussystem.16,21,38 We have previously shown that auditorychanges as evaluated by auditory brainstem evoked re-sponse are more associated with unbound bilirubin thanTSB.21

Our findings of no significant association betweenhyperbilirubinemia and language development are con-sistent with the findings reported by Ogunet al.22 Theyalso reported that there was no association betweensevere hyperbilirubinemia and language outcomes.22

However, our study differs from theirs. Their study in-volved term infants with severe hyperbilirubinemia,whereas we studied premature infants with any degreeof hyperbilirubinemia. We also evaluated the role ofduration of hyperbilirubinemia. The little available data

suggest that duration of hyperbilirubinemia may also bea determining factor for bilirubin-induced auditory dys-function.36,37 However, when duration of hyperbiliru-binemia was defined as the number of days with TSBlevels of �8 mg/dL during the first 2 weeks of life, it wasnot associated with language delay.

Our findings of 25% incidence of language delayamong premature infants with birth weight at �1500 gare consistent with the reported incidence of languagedelay in the literature.2,39 Our finding of BPD as a riskfactor for language delay is also consistent with otherreports.40 BPD has also been associated with auditorydysfunction in premature infants.41

The major limitation of our study is its retrospectivenature and associated information bias. We used infor-mation provided by the primary care physician and orthe family along with medical information availablefrom the developmental clinic charts to categorize theoutcomes. Second, there were different standardizedlanguage evaluation tools used by the speech patholo-gists to determine which children needed speech ther-apy. We were not able to specify the characteristics ofthe children’s speech and language delay, specifically thereceptive and expressive components. We may haveused an inadequate measure of bilirubin exposure be-cause more recent evidence favors the use of unboundbilirubin as a biochemical measure.21,38,42,43

The study also has several strengths. There was anexcellent follow-up rate of 93%. The incidence of lan-guage delay in our cohort was similar to that reported inthe literature. We found the same association with BPDas reported in the literature. In summary, we found noassociation between peak TSB or total duration of ele-vated bilirubin in premature infants and their languagedevelopment. Despite these findings, we believe the as-sociation of unbound bilirubin with language delay de-serves thorough investigation.

ACKNOWLEDGMENTSThis study was partially supported by National Institutesof Health grant K-23 DC 006229-03.

We are grateful to the neonatologists, developmentalpsychologist, and speech therapist who were involved inthe developmental follow-up evaluation and care ofstudy subjects.

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DOI: 10.1542/peds.2007-3723 2009;123;327Pediatrics

Sanjiv B. Amin, Diane Prinzing and Gary MyersHyperbilirubinemia and Language Delay in Premature Infants

  

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