Nemeth et al., Hyperbilirubinemia after antepartum dexamethasone 35

J. Perinat. Med.9(1981)35

Hyperbflirubinemia and urinary D-glucaric acid excretion in prematureinfants following antepartum dexamethasone treatment

I. Nemeth, T. Szeleczki, D. Boda

Department of Pediatrics, Medical University, Szeged, Hungary

l IntroductionContrary to the numerous reports on the pro-mising results with antepartum glucocorticoidtreatment of respiratory distress syndrome (RDS)[2-4, 13, 17, 20], little Information is availableon the risks of this form of therapy to the prem-ature infant [2, 19]. Hyperbilirubinaemia withconsequent jaundice is known to be by far themost common and potentially harmful abnorm-ality associated with several neonatal pathologicalconditions (prematurity, RDS, acidosis, hypoxia,hypothermia, etc.) [16]. There are only veiy fewand conflicting data regarding the correlation be-tween prenatal glucocorticoid treatment and neo-natal hyperbilirubinaemia. No significant increasein the serum bilirubin levels of newborn infantswas found following antepartum maternal admini-stration of betamethasone [13], By contrast, pred-nisolon sodium succinate, when given to mothers,proved capable of aggravating hyperbilirubin-aemia in their premature infants [23], The possibleinfluence on the neonatal serum bilirubin concen-tration of maternal treatment with dexamethasone,another glucocorticoid used to prevent RDS [20],has not yet been studied.The present study was, therefore, undertaken toevaluate the effect of maternally administereddexamethasone on the serum bilirubin levels ofpremature infants. Since the hepatic microsomalenzyme glucuronyl transferase (UDPGT), which isimmature in the newborn infant [1,8,24], plays akey role in the metabolism of both bilirubin andglucocorticoids [7], it was also of some interest to

Curriculum vitaeILONA NfeMETH studiedmedicine at the Universityof Pecst Hungary from1963 to 1969. She received ;postgraduate training in ·biochemistry and pharma- \cology at the Szeged Uni- }versity of Medical Sciencesand became specialist in :clinical chemistry in 1972. \Since 1973 she has beenworking at the Department 'of Pediatrics of the sameuniversity äs Scientific Investigator. Her main researchinterest is clinical pharmacology of the perinatal periodand childhood, including therapeutic and adverse effectsof new pharmaceutical agents äs well äs monitoring druglevels in pediatric patients.

provide additional data by studying the influenceof prenatal dexamethasone treatment on the urin-ary D-glucaric acid excretion of infants bom pre-maturely.

2 Patients and methodsPremature infants of similar gestational age, birthweight, APGAR scores, CLEMENTS' test (Tab. I),severity of RDS and therapy (antibiotics, theo-phylline, phototherapy) were included in the study.Gases with maternal diabetes, hypothyroidism,oxytocin infusion during labour and evidence ofblood group (ABO and Rh) incompatibility wereexcluded from this study äs were those who suf-fered excess bruising or bleeding due to abnormaldelivery.

033-5577/81/0009-0003S02.00© by Walter de Gruyter & Co. · Berlin · New York

36 Nemeth et al., Hyperbilirubinemia after antepartum dexamethasone

Tab. L Parameters of control and dexamethasone-treated premature infants at birth.1 Mean values ± S.E.2 10 mg i.m. dexamethasone was given to the mother at least 24 hours before delivery. · i

Gestational age[weeks] l

Controls 3 1.9 ±0.7

n- 18

Dexametha- 31.8 ± 0.9sone-treatedinfants2 n= 16

Birth weight[gm]1

2010 ± 110

n= 18

2003 ±134

n= 16

APGAR score CLEMENTS' test1min 5min + ++ +++ ++++<5 >5 <5 >5

2 1 0 1 U 2 4 2 1 2

n=12 n = l l

2 10 1 11 2 2 3 1 4

n=12 n-12

16 premature infants received antenatal glucocorti-coid therapy; 10 mg dexamethasone (Oradexon®-\N. V. ORGANON, Oss, Holland) was given intra-muscularly to the mothers 24 hours before de-livery. 18 pre-term infants with similar parametersbut without dexamethasone treatment served äscontrols. The indication for the antepartumsteroid administration was based upon gestationalage and biparietal cranial diameter. Serum levels ofunconjugated (indirect) bilirubin was measuredover the first 7 days of Hfe by the method ofJENDRASSIK et al. [6].In order to assess the activity of the hepaticmicrosomal enzyme UDPGT, urine was collectedfor periods of 24 hours during the first week oflife, and the excretion of D-glucaric acid (juM/kg/24 hours) was determined by the method ofMARSH [15] äs modified by SIMMONS et al. [18].Statistical analysis of the results was carried outusing Student's "t" test äs well äs 2 test withYates correction.

3 ResultsThe serum bilirubin levels increased considerablyin dexamethasone-treated premature infantsthroughout the first week of life (Tab. II). In addi-tion, on days 3 to 4 of the postnatal period, the in-cidence of serum bilirubins over 15 mg/100 ml(256.56 /1) (the value thought to be the upperlimit of the usual ränge in pre-term neonates [5])was three times greater in the steroid-treated thanin the control group (2 out of 17 controls vs. 7 outof 15treated;p<0.05).

On the other hand the difference between theD-glucaric acid excretion of infants with dexa-methasone therapy and that of the untreated con-trols did not reach the level of statistical signi-ficance over the first 7 days of life. It was con-spicuous, however, that the urinary excretion ofD-glucaric acid showed some tendency to decreasein the dexamethasone-treated group of infants onthe third and fourth postnatal days when thehighest serum bilirubin concentrations weremeasured (Tab. II).

4 DiscussionThe evidence presented in this paper suggests thatdexamethasone may increase the serum level ofunconjugated bilirubin in premature infants overthe first 7 days of life. Apart from the antepartummaternal administration of dexamethasone and thesubsequent elevation of serum bilirubin concentra-tion the two groups of infants involved in ourstudy were similar in every respect. It thus seemsvery likely that the observed phenomenon reflectsa cause and effect relationship. In theory, hepaticuptake, transfer, conjugation and excretion ofbilirubin may all be diminished by a drug in-ducing hyperbilirubinaemia. In neonates the hep-atic concentration of and Z proteins is low anddexamethasone, similarly to other drugs [12], maycompete with bilirubin for binding to these pro-teins, thereby decreasing the uptake and transportof bilirubin in the liver. The limiting factor in thehepatic conjugation of bilirubin is the adequacyand availability of the microsomal enzyme, UDPGT

J. Perinat. Med. l (1981)

Nemeth et al., Hyperbilirubinemia aftcr antepartum dexamethasone 37

Tab. II. Serum bilirubin concentrations and urinary D-glucaric acid excretion in premature infants over the first 7 daysof life following antepartum administration of dexamethasone to the mother.1 Mean values ± S. E.2 see footnote in Tab. L

Serum bilirubin concentrationMM/l [mg/1 00 ml]1

Age [days]

Controls

Dexametha-sone-treatedinfants2

1-2

139.8 ± 10.6[8.18 ± 0.62]

n=17

187.0 t 12.9[10.93 ±0.75]

n =15

3-4

199.9 ±[11.69 ±

n =

238.8 ±[ 13.96 t

n =

11.40.66]17

10.60.62]15

6-7

153.5[8.98

n

188.8[11.04

n

± 11.3± 0.66]= 16

± 11.4± 0.67]= 14

D-glucaric acid excretionMM/kg/24 hrs1

1-2

0.22 ±n =

0.27 ±n =

0.0517

0.0915

3-4

0.20 ±n =

0.15 ±n =

0.0317

0.0312

6-7

0.20 ±n =

0.18 ±n =

0.0516

0.0311

Statistical p < 0.01 p < 0.02 p < 0.05 N.S. N.S. N.S.

[9, 10]. Deficiency of this enzyme is considered tobe the principal factor underlying the developmentof the "physiologic" neonatal hyperbilirubinaemiaboth in full-term and in premature infants [l, 24].Thus the major cause of the aggravation of the al-ready existing hyperbilirubinaemia in the dexa-methasone-treated preterm infants involved in ourstudy could be a simidtaneous and competitivebinding of bilirubin and dexamethasone to UDPGTleading to a decrease in the glucuronidation ofbilirubin and elevation of serum bilirubin levels.D-glucaric acid excretion, which reflects the act-ivity of hepatic microsomal enzymes has beenfound to increase in full-term infants during thefirst week of life [21, 22], whereas no consider-able change and low basal excretion were foundin the same period in the control premature in-fants included in our present study. The observeddifference is presumably related to the knownmaturational delay in the hepatic microsomßlenzyme Systems of pre-term infants. The clear-ance of bilirubin administered intravenously doesnot change in premature infants, but increasesprogressively in full-term infants in the first weekof life [11].Recent reports on the functional heterogeneity ofthe enzyme UDPGT have revealed that transferase

activities toward different Substrates (Group 1:e.g. 2-aminophenol; Group 2: e.g. bilirubin, chlor-amphenicol) develop at different periods and ratesand respond differentially to a wide ränge ofStimuli, including antepartum dexamethasonetreatment [27].Glucocorticoids, when administered antenatally,stimulate transferase activity in Group l ('steroidgroup'), but have negligible effect on those inGroup 2 ('non-steroid group') [14,25]Conversely,phenobarbital was found to stimulate significantlyGroup 2 transferase activities under conditions inwhich Group l activities remained unaffected[26]. It appears likely that our observation regard-ing the most pronounced glucaric acid excretion ofdexamethasone-treated premature infants on theIst and 2nd postnatal days can, at least in pari, beattributed to some increase in Group l trans-ferase activities.In the light of the results presented, more detailedclinical and experimental analysis of the effects ofglucocorticoids on bilirubin metabolism of pre-term infants and investigations into the drug pro-phylaxis of steroid-induced hyperbilirubinaemiawould be well worth while.

Summaiy

Dexamethasone (10 mg i.m.) administered to mothers 24'hours before delivery for the prevention of respiratoryJ. Perina t. Med. l (1981)

distress syndrome caused a considerable elevation of theserum level of unconjugated bilirubin in premature infants

38 Nemeth et aL, Hyperbilirubinemia after antepartum dexamethasone

throughout the first week of life. On days 3 to 4 the in-cidence of infants with bilirubin levels exceeding 256.56

/1 (15 mg/100 ml) was found to increase (7/15 vs 2/17).The urinary excretion of D-glucaric acid, which reflectsthe activity of the hepatic microsomal enzyme Systems,proved to be low in pre-term infants over the fkst 7 daysof life, and it was not enhanced significantly by antenataldexamethasone therapy.

In the light of the results presented, more detailedclinical and experimental analysis of the effects of gluco-corticoids on bilirubin metabo^ism of pre-term infants andinvestigation intothe drug prophylaxis of steroid-inducedhyperbilirubinaemia are suggested.

Keywords: Antepartum dexamethasone treatment, D-glucaric acid excretion, hyperbilirubinaemia, premature infant.

Zusammenfassung

Hyperbilirubinämie und Ausscheidung von D-Glucarsäureim Urin bei Frühgeborenen nach antepartaler Dexametha-sonbehandlungDie Applikation von Dexamethason (10 mg i.m.) 24 Stun-den vor der Geburt zur Verhütung eines Atemnotsyndromshat einen beträchtlichen Anstieg des unkonjugierten Bili-rubins im Serum der frühgeborenen Kinder während derersten Lebenswoche zur Folge. Erhöhte Bilirubinspiegel(> 256.56 /l = 15 mg/100 ml) am 3. bzw. 4. Lebenstagwaren signifikant häufiger (7 von 15 Frühgeborenen beiDexamethasontherapie versus 2 von 17 ohne Behandlung).An der D-Glucarsäureausscheidung im Harn läßt sich die

Aktivität des mflcrosomalen Enzymapparates der Leberabmessen, welche bei frühgeborenen Kindern während derersten 7 Lebenstage reduziert zu sein scheint. Die ante-natale Dexamethasontherapie fuhrt nicht zu einger Stei-gerung der Aktivität.Wir meinen, daß unsere Ergebnisse detailliertere klinischeund experimentelle Untersuchungen zur Wirkung vonGlukokortikoiden auf den Büirubinstoffwechsel beiFrühgeborenen erforderlich machen und daß Forschungenauf dem Gebiet der medikamentösen Prophylaxe vonsteroidinduzierten Hyperbilirubinämien einsetzen sollten.

Schlüsselwörter: Antepartale Dexamethasontherapie, D-Glucarsäureausscheidung, Frühgeborenes, Hyperbilirubinämie.

Resume

Hyperbilirubinemie excretion urinaire d'acide D-glucari-que chez les enfants prematures apres traitement ante-partal a la dexamethasoneL'administration de dexamethasone (a raison de 10 mg.i.m.) a la mere 24 heures avant l'accouchement afin deprevenir le syndrome de detresse respiratoire provoqueune elevation considerable du taux serique de bilirubinelibre chez les enfants prematures pendant la premieresemaine de vie. Les jours 3 "et 4 a note une augmen-tation de Fincidence des enfants avec des taux de bili-rubine depassant 256.56 mM/1 (15 mg/100 ml), (7/15contre 2/17).

L'excretion urinaire d'acide D-glucarique, refletantl'activite des systemes enzymatiques mlcrosomaux hepa-tiques, etait basse chez les prematures pendant les pre-miers^ 7 jours de vie et n'etait pas significativement aug-mentee par l'administration antenatale de dexametha-sone.A la lumiere des resultats presentes il semble necessaired'obtenir d'avantage d'analyses cliniques et experimen-tales detaillees sur les effets des glucocorticoides sur lemetabolisme de la bilkubine chez les prematures et derecherches sur la prophylaxie medicamenteuse de Fhyper-bilirubinemie provoque par les steroides.

Mots-cles: Excretion d'acide D-glucarique, hyperbilirubinemie, premature, traitement antepartal a la dexamethasone.

Acknowledgement: The authors wish to thank MARIA FOGAS for her valuable help in carrying out laboratory ex-aminations.This work was supported by Research Grant No. 4-24-0503-03-l/B frim the Scientific ResearchCouncil, Ministry of Health and the Division of Clinical Pharmacology, State Office of TechnicalDevelopment, Budapest, Hungary.

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Received December 11, 1979. Revised May 20, 1980.Accepted August 8,1980.

Ilona Nemeth, M.D.Department of PediatricsMedical UniversitySzeged P.O. Box: 471H-6701 Hungary

J. Perinat. Med. l (1981)