subclinical hypoxia of infants with intrauterine growth

7212019 Subclinical Hypoxia of Infants With Intrauterine Growth

httpslidepdfcomreaderfullsubclinical-hypoxia-of-infants-with-intrauterine-growth 16

Ouml KIRMEMİŞ M M ALI CAYMAN C KOCA A KARADAĞ N URAS U DİLMEN H KAFALI

795

urk J Med Sci2011 41 (5) 795-800copy UumlBİAKE-mail medscitubitakgovtrdoi103906sag-1007-948

Subclinical hypoxia of infants with intrauterine growthretardation determined by increased serum S100B protein levels

Oumlzlem KIRMEMİŞ1 Mustaa Mansur ALI2 Cuumlneyt AYMAN2 Cemile KOCA3 Ahmet KARADAĞ4

Nurdan URAS5 Uğur DİLMEN5 Hasan KAFALI6

Aim o test the hypothesis that serum S100B levels could be useul in detecting neurological damage in inants with

intrauterine growth retardation (IUGR)Materials and methods Te study group consisted o inants with IUGR and the control group consisted o age-matched healthy inants S100B protein levels were measured afer birth and compared between groups

Results For this study 43 inants with IUGR and 25 inants as a control group were recruited Gender gestational agetype o delivery and maternal age o the groups were statistically insignificant with the exception o the mean birthweights (2120 plusmn 450 g in the IUGR group and 3096 plusmn 570 g in the control group (P lt 0001) respectively) S100B proteinlevels o the IUGR inants (113 plusmn 054) were significantly higher than those o the control group (045 plusmn 013) (P lt0001) IUGR inants treated with antenatal steroids showed lower S100B levels than IUGR inants that did not receiveantenatal steroid treatments (P lt 005) Te study group inants were divided into 2 groups or growth retardation (GR)that was asymmetric (n = 15) and symmetric (n = 28) Te asymmetric and symmetric GR inantsrsquo S100B levels were114 plusmn 047 pgmL and 121 plusmn 034 pgmL respectively and no significant differences were ound between the 2 groupsin terms o S100B levels (P = 032)

Conclusion Te results o this study avor the opinion that there is an existing intrauterine hypoxia causing hypoxicbrain tissue damage in IUGR inants even when ollowed up with modern obstetrical screening protocols Measurementso S100B may be useul in the prediction o outcome in these inants

Key words S100B IUGR intrauterine growth retardation intrauterine hypoxia

İntrauterin buumlyuumlme gerelikli infantların subklinik hipoksilerinin artmış serumS100B protein seviyeleri ile saptanması

Amaccedil Bu prospekti ccedilalışmada intrauterin gelişme geriliği (IUGR) olan inantlarda noumlrolojik hasarı tespit etmedeS100B seviyelerinin aydalı olduğu hipotezi test edildi

Youmlntem ve gereccedil Ccedilalışma grubu İUGR inantlardan ve kontrol grubu benzer yaştaki sağlıklı inantlardan oluşmaktaydıS100B protein seviyeleri doğum sonrası oumllccediluumllduuml ve 2 grup karşılaştırıldı

Bulgular Kırk uumlccedil IUGR ve kontrol grubunda 25 inant ccedilalışmaya alındı Cinsiyet gestasyonel yaş doğum şekli vegrupların maternal yaşı arasında ortalama doğum ağırlığı (sırasıyla IUGR grubunda 2120 plusmn 450 g kontrol grubunda

Original Article

Received 08072010 ndash Accepted 161220101 Department o Pediatrics Faculty o Medicine Fatih University Ankara - URKEY2 Department o Neonatology Faculty o Medicine Fatih University Ankara - URKEY3 Division o Biochemistry Faculty o Medicine Fatih University Ankara - URKEY4 Division o Neonatology Faculty o Medicine İnonuuml University Malatya - URKEY5 Division o Neonatology Dr Zekai ahir Burak Womenrsquos Health Education and Research Hospital Ankara - URKEY6 Division o Womenrsquos Health Faculty o Medicine Fatih University Ankara - URKEY

Correspondence Cuumlneyt TAYMAN Department of Neonatology Faculty of Medicine Fatih University Ankara - TURKEY

E-mail ctayman22gmailcom



S100B protein in intrauterine growth retardation

796

Introduction

Placental insuffi ciency with a consequent

reduction in etal nutritive and oxygen supply is oneo the most important causes o intrauterine growthrestriction (IUGR) and etal hypoxia which is one othe main causes o perinatal mortality and morbidity(12) Episodes o acute and chronic etal hypoxiacan result in brain lesions which may leave long-term neurological sequelae such as auditory and visual impairment mental retardation and seizuredisorders Moreover minimal brain alterationssuch as a reduction in learning capabilities dyslexiaand attention-deficithyperactivity disorder could

originate rom the prenatal andor perinatal exposureto hypoxia (2-4) Nowadays the managemento IUGR includes the combination o serialmorphological ultrasound examinations to assessetal growth and amniotic 1047298uid quantity combinedwith unctional testing such as a biophysical profileetal heart rate testing and Doppler examinationso etal hemodynamics (5) Unortunately even ihypoxia is detected none o the presently availabletests can define the amount o hypoxia that the

etus can endure without developing hypoxic brainlesions or the length o duration Only the answersto these questions would enable the definition o theoptimal timing o delivery in the case o chronic etalhypoxia and prevention o perinatal brain damageAlthough in this situation the delay o the deliverymight cause the prolongation o etal exposure tohypoxia which could affect brain development andcause brain damage early delivery carries the risko prematurity and associated risk o neurologicaldisorders Additionally IUGR inants may show

hyperre1047298exia hypore1047298exia jitteriness andor

hypertonicity in their early lie In most situationsneurological examinations o IUGR inants areuneventul and there is no evidence or the prediction

o long-term neurological disorders in these babies(346) Tereore the ability to monitor high-risketuses in the perinatal period by use o biochemicalindexes could be particularly useul in detectingcases at risk o adverse neurological outcomes andin determining the timing o insults that damagethe central nervous system as early as possible withrespect to uture measures o prevention

S100B is an acidic calcium-binding proteinthat is released by brain tissue and is known to

be highly specific to the nervous system (7) It isthought to play a dual role in the regulation o cellunction being beneficial to cells at low doses butdetrimental at high doses Te protein appears to bemost abundant in glial cells although its presencein neuronal subpopulations has also been reportedTese findings have answered the question about theputative role o S100B in brain injury (8) Tereoreincreased S100B concentrations in biological 1047298uids(eg cerebrospinal 1047298uid blood urine and amniotic

1047298uid) o adults inants and etuses afer cell injury inthe nervous system have supported the use o S100Bas a biochemical marker o brain damage (7) It wasound that this protein is increased in demyelinatingbrain diseases phenylketonuria and especiallyin hypoxic-ischemic brain damage (HI) (79)S100B in the blood was measured hypothesizingthat during active brain injury the protein couldbe released rom the damaged tissue and part oit could spread into the systemic circulation alsoas a result o the hemodynamic rearrangement o

the blood-brain barrier In this regard increased

3096 plusmn 570 g (P lt 0001)) haricinde istatistiksel arklılık yoktu S100B protein seviyleri IUGR inantlarda (113 plusmn 054)kontrol grubundan (045 plusmn 013) anlamlı derecede daha yuumlksek bulundu (P lt 0001) S100B seviyelerinin antenatalsteroid tedavisi alan IUGR inantlarda antenatal steroit tedavisi almayan İUGR inantlara goumlre daha duumlşuumlk duumlzeydeolduğu goumlsterildi (P lt 005) Ccedilalışma grubundaki inantlar asimetrik (n = 15) ve simetrik (n = 28) gelişme geriliği olmakuumlzere 2 gruba ayrıldılar Asimetrik ve simetrik gelişme geriliği olan inantların S100B seviyeleri sırasıyla 114 plusmn 047pgmL ve 121 plusmn 034 pgmL idi İki grup arasında S100B seviyesi bakımından anlamlı arklılık bulunmadı (P = 032)

Sonuccedil Bu ccedilalışmanın sonuccedilları modern obstetrik metodlarla takip edilse de İUGR inantlarda hipoksik beyin hasarınaneden olan intrauterin hipoksi varlığı duumlşuumlncesini desteklemektedir Bu proteinin oumllccediluumllmesi bu inantların akibetlerinitahmin etmede yaralı olabilir

Anahtar soumlzcuumlkler S100B IUGR intrauterin gelişme geriliği intrauterin hipoksi




797

concentrations o S100B were detected 48-72 hbeore any clinical laboratory or ultrasonographicsigns o intraventricular hemorrhage in pretermnewborns and o hypoxic ischemic encephalopathy(HIE) in ull-term newborns (8) Currently there areew studies about S100B in the serum o inants withIUGR that are under risk o perinatal brain damage(10-12)

In the present study we aimed to investigatethe serum S100B levels in inants with IUGRto provide early prediction o possible negativeneurodevelopmental outcomes or both early andlater lie in this particular population

Materials and methodsTe study was perormed at 2 different tertiary

reerral centers or obstetrics and neonatal intensivecare units rom February to July o 2007 We studied43 women with singleton pregnancies complicatedby IUGR between the 30th and 42nd weeks ogestation Inormed consent was obtained romboth hospitalsrsquo ethics committees and the parentsGestational age was determined by clinical dataand by a first trimester ultrasound scan IUGR was

defined by the presence o ultrasonographic signs(biparietal diameter below the 10th percentile andabdominal circumerence below the 5th percentile)according to the nomograms o Campbell andToms (713) A drop in the percentile o etal sizeswas recorded between the first scan afer reerral andthe final scan beore delivery Fetal growth restrictionwas confirmed by a birth weight below the 10thpercentile in all o the etuses Te ponderal indexwas calculated or each o the GR inants Aferwardsinants were divided into 2 groups related to theponderal index asymmetric GR inants (lt50 oponderal index) and symmetric GR inants (gt50o ponderal index) (14) Te control group consistedo 25 normal etuses matched or gestational age atsampling (range 30-42 weeks o gestation) and birthweights between the 10th and 90th percentiles

All women in both the study and the controlgroups gave birth either vaginally or by electivecesarean section based on obstetric indications Atdelivery the umbilical cord was clamped beore any

signs o breathing were seen and blood was drawn

rom the umbilical vein or the standard assessments(blood cell count alanine aminotranserase aspartateaminotranserase blood urea creatinine glucoseelectrolytes interleukin-6 and C-reactive protein)

Inants that ulfilled all o the ollowing criteriawere admitted to the study no maternal illness nosigns o etal distress a pH greater than 72 in cordblood or venous blood and Apgar scores above 7at 1 and 5 min Exclusion criteria were multiplepregnancies and maternal alcohol or cocaineaddiction inants with any malormation cardiacor renal diseases hemolytic disease or intrauterineinections

Peripheral venous blood samples or S100B

measurement were obtained rom a peripheral vein12 h afer birth and centriuged immediately at 5000g or 10 min and the sera were stored at ndash80 degC untilconcentration analyses were perormed All serumsamples or S100B were o good quality withouthemolysis Te S100B serum levels were determinedby ully automatic electrochemoluminometricimmunoassay (Elecsys S100reg Roche DiagnosticsPenzberg Germany) with a measurement range o0005-39 ngL

A neurological examination was perormed atthe same time as the blood sampling and duringhospital discharge Neonatal neurological conditionswere classified as normal or abnormal An inantwas considered to be abnormal when one or more othe ollowing neurological syndromes were presenthypo- or hyperkinesias hyper- or hypotonicitydystonia hemisyndrome apathy syndrome orhyperexcitability syndrome

Statistical analysis

For evaluation o the distribution o S100Bmeasurement results histogram and Kolmogorov-Smirnov tests were applied Studentrsquos t-test was usedor statistical evaluation o continuous variablesRelationships between S100B protein levels and birthweight birth length maternal age and gestationalage were evaluated with Pearsonrsquos correlationanalysis Te gender o the inants type o birthand type o anesthesia were compared to each otherusing the chi-square test Data were analyzed withSPSS version 130 (SPSS Inc Chicago USA) with

significance defined as P lt 005




798

Results

Te findings o the study are summarized inthe able Te study group consisted o 43 inantsand the control group o 25 inants No significant

differences between the 2 groups were ound in termso gender gestational age at delivery type o deliveryantenatal glucocorticoid treatment and maternalage with the exception o birth weight Te birthweights o the 2 groups were 2120 plusmn 450 g in theIUGR group and 3096 plusmn 570 g in the control group(P lt 0001) respectively Tere were no significantdifferences in the laboratory parameters (red bloodcell count alanine aminotranserase aspartateaminotranserase blood urea creatinine glucose

electrolytes (sodium potassium and calcium)interleukin-6 and C-reactive protein) between theIUGR and control groups upon admission to theneonatal intensive care unit (P gt 0005) Te studyand the control group were ound to be similarwith respect to neurological examinations In bothgroups none o the inants showed neurologicalabnormalities at the time o discharge rom thehospital and no overt neurological syndromes wereobserved during recovery Isolated and transientsymptoms including hypertoniahypotonia

dystonia and hyperexcitability were shown in 15o the IUGR inants and in 11 o the control inantsMean etal S100B levels in the IUGR group (113 plusmn054 pgmL) were significantly higher (P lt 0001)than those in the control group (04 plusmn 013 pgmL) Tere was a weak and low correlation betweengestational age and S100B protein levels (r = 024 P= 012) and a weak and low correlation between birthweight and S100B protein levels (r = ndash02 P = 0006)When the IUGR etuses were grouped according toantenatal steroid treatment status o neurologicalexamination type o delivery and type o anesthesiaduring delivery those groups were ound to be similarwith respect to these parameters except or thepresence o antenatal steroid treatment IUGR inants

treated with antenatal steroids showed lower S100Blevels than those without antenatal steroid treatment(P lt 005) Te study group inants were divided into2 groups asymmetric GR and symmetric GR Teasymmetric GR group consisted o 15 neonates andthe symmetric SGA group consisted o 28 neonatesTe asymmetric and symmetric GR inantsrsquo S100Blevels were 114 plusmn 047 pgmL and 121 plusmn 034 pgmL respectively and no significant differences wereound between the 2 groups in terms o S100B levels(P = 032)

able Characteristics o the study population and comparison o intrauterine growth retardation(IUGR) and control groups

IUGR(n = 43)

CONTROL(n = 25)

P

Maternal age (mean plusmn SD years) 284 plusmn 40 288 plusmn 45 07

Gestational age at delivery (mean plusmn SD weeks) 377 plusmn 28 380 plusmn 25 06

Gender (maleemale) 2221 1411 07

Birth weight (mean plusmn SD g) 2120 plusmn 450 3096 plusmn 570 lt0001

Maternal glucocorticoid treatment (N) 1125 520 05

ype o delivery (cesareanvaginal) 2617 1312 05

ype o anesthesia during delivery (generalregional) 2320 1510 06

Neurological examination (normalabnormal) 2815 1411 09

S100B protein (pgmL) 113 plusmn 054 045 plusmn 013 lt0001






800

that investigated the effects of a single course of

antenatal betamethasone on S100B concentrations

in preterm rats in which a clinically equivalent dose

and half of this dose was used (19) Te authors

found that the hippocampal S100B content wasreduced by a clinically equivalent dose of 12 mg

twice but not by half of this dose Interestingly the

effect of betamethasone on brain cell proliferation

also showed a dose-dependent pattern as

investigated in the same hippocampal homogenates

Te authors speculated that lowering the dose of

antenatal steroids may be less detrimental for brain

maturation

Conclusion

Te results o this study and previous studieswarrant consideration and avor the opinion thatthere is an existing intrauterine hypoxia causing

hypoxic brain tissue damage in IUGR inants evenwhen ollowed up with modern obstetrical screeningprotocols Te major goals o modern obstetricscreening procedures are the identification o growth-restricted etuses among the small-or-gestational-age etuses Early detection o etal hypoxia in high-risk pregnancies and timely termination o high-riskpregnancies will prevent the development o hypoxicbrain injury

References

1 Rosenberg A Te IUGR newborn Semin Perinatol 2008 32219-24

2 Salihagić-Kadić A Medić M Jugović D Kos M Latin VKusan Jukić M et al Fetal cerebrovascular response to chronichypoxia - implications or the prevention o brain damage JMatern Fetal Neonatal Med 2006 19 387-96

3 Itakura A Kurauchi O Morikawa S Matsuzawa K MizutaniS omoda Y Neonatal EEG findings soon afer birth in theintrauterine growth retarded inant Nippon Sanka FujinkaGakkai Zasshi 1995 47 109-14

4 Leitner Y Fattal-Valevski A Geva R Eshel R oledano-Alhade H Rotstein M et al Neurodevelopmental outcome ochildren with intrauterine growth retardation a longitudinal10-year prospective study J Child Neurol 2007 22 580-87

5 Tornton JG Hornbuckle J Vail A Spiegelhalter DJ LeveneM Inant wellbeing at 2 years o age in the Growth RestrictionIntervention rial (GRI) multicentred randomised controlledtrial Lancet 2004 364 513-20

6 Ferrari F Cioni G Einspieler C Roversi MF Bos AF PaolicelliPB et al Cramped synchronized general movements inpreterm inants as an early marker or cerebral palsy ArchPediatr Adolesc Med 2002 156 460-7

7 Florio P Marinoni E Di Iorio R Bashir M Ciotti S Sacchi Ret al Urinary S100B protein concentrations are increased inintrauterine growth-retarded newborns Pediatrics 2006 118747-54

8 Gazzolo D Abella R Marinoni E Di Iorio R Li Volti GGalvano F et al New markers o neonatal neurology J MaternFetal Neonatal Med 2009 22 57-61

9 Michetti F Gazzolo D S100B protein in biological 1047298uids a toolor perinatal medicine Clin Chem 2002 48 2097-104

10 Gazzolo D Marinoni E Di Iorio R Lituania M Marras MBruschettini M et al High maternal blood S100B concentrationsin pregnancies complicated by intrauterine growth restriction

and intraventricular hemorrhage Clin Chem 2006 52 819-26

11 Gazzolo D Visser GH Lituania M Sarli R BruschettiniM Michetti F et al S100B protein cord blood levels anddevelopment o etal behavioral states a study in normal andsmall-or-dates etuses J Matern Fetal Neonatal Med 2002 11378-84

12 Gazzolo D Marinoni E di Iorio R Lituania M BruschettiniPL Michetti F Circulating S100beta protein is increased inintrauterine growth-retarded etuses Pediatr Res 2002 51215-9

13 Campbell S Toms A Ultrasound measurement o the etal

head to abdomen circumerence ratio in the assessment ogrowth retardation Br J Obstet Gynaecol 1977 84 165-74

14 Landmann E Reiss I Misselwitz B Gortner L Ponderal indexor discrimination between symmetric and asymmetric growthrestriction percentiles or neonates rom 30 weeks to 43 weekso gestation J Matern Fetal Neonatal Med 2006 19 157-60

15 Rothermundt M Peters M Prehn JH Arolt V S100B in braindamage and neurodegeneration Microsc Res ech 2003 60614-32

16 Giussani DA Takor AS Frulio R Gazzolo D Acute hypoxiaincreases S100beta protein in association with blood 1047298owredistribution away rom peripheral circulations in etal sheep

Pediatr Res 2003 55 1-717 skitishvili E Komoto Y emma-Asano K Hayashi S

Kinugasa Y subouchi H et al S100B protein expression in theamnion and amniotic 1047298uid in pregnancies complicated by pre-eclampsia Mol Hum Reprod 2006 12 755-61

18 Gazzolo D Di Iorio R Marinoni E Masetti P Serra GGiovannini L et al S100B protein is increased in asphyxiatedterm inants developing intraventricular hemorrhage CritCare Med 2002 30 1356-60

19 Miller SL Chai M Loose J Castillo-Meleacutendez M WalkerDW Jenkin G et al Te effects o maternal betamethasoneadministration on the intrauterine growth-restricted etus

Endocrinology 2006 148 1288-95




796

Introduction

Placental insuffi ciency with a consequent

reduction in etal nutritive and oxygen supply is oneo the most important causes o intrauterine growthrestriction (IUGR) and etal hypoxia which is one othe main causes o perinatal mortality and morbidity(12) Episodes o acute and chronic etal hypoxiacan result in brain lesions which may leave long-term neurological sequelae such as auditory and visual impairment mental retardation and seizuredisorders Moreover minimal brain alterationssuch as a reduction in learning capabilities dyslexiaand attention-deficithyperactivity disorder could

originate rom the prenatal andor perinatal exposureto hypoxia (2-4) Nowadays the managemento IUGR includes the combination o serialmorphological ultrasound examinations to assessetal growth and amniotic 1047298uid quantity combinedwith unctional testing such as a biophysical profileetal heart rate testing and Doppler examinationso etal hemodynamics (5) Unortunately even ihypoxia is detected none o the presently availabletests can define the amount o hypoxia that the

etus can endure without developing hypoxic brainlesions or the length o duration Only the answersto these questions would enable the definition o theoptimal timing o delivery in the case o chronic etalhypoxia and prevention o perinatal brain damageAlthough in this situation the delay o the deliverymight cause the prolongation o etal exposure tohypoxia which could affect brain development andcause brain damage early delivery carries the risko prematurity and associated risk o neurologicaldisorders Additionally IUGR inants may show

hyperre1047298exia hypore1047298exia jitteriness andor

hypertonicity in their early lie In most situationsneurological examinations o IUGR inants areuneventul and there is no evidence or the prediction

o long-term neurological disorders in these babies(346) Tereore the ability to monitor high-risketuses in the perinatal period by use o biochemicalindexes could be particularly useul in detectingcases at risk o adverse neurological outcomes andin determining the timing o insults that damagethe central nervous system as early as possible withrespect to uture measures o prevention

S100B is an acidic calcium-binding proteinthat is released by brain tissue and is known to

be highly specific to the nervous system (7) It isthought to play a dual role in the regulation o cellunction being beneficial to cells at low doses butdetrimental at high doses Te protein appears to bemost abundant in glial cells although its presencein neuronal subpopulations has also been reportedTese findings have answered the question about theputative role o S100B in brain injury (8) Tereoreincreased S100B concentrations in biological 1047298uids(eg cerebrospinal 1047298uid blood urine and amniotic

1047298uid) o adults inants and etuses afer cell injury inthe nervous system have supported the use o S100Bas a biochemical marker o brain damage (7) It wasound that this protein is increased in demyelinatingbrain diseases phenylketonuria and especiallyin hypoxic-ischemic brain damage (HI) (79)S100B in the blood was measured hypothesizingthat during active brain injury the protein couldbe released rom the damaged tissue and part oit could spread into the systemic circulation alsoas a result o the hemodynamic rearrangement o

the blood-brain barrier In this regard increased

3096 plusmn 570 g (P lt 0001)) haricinde istatistiksel arklılık yoktu S100B protein seviyleri IUGR inantlarda (113 plusmn 054)kontrol grubundan (045 plusmn 013) anlamlı derecede daha yuumlksek bulundu (P lt 0001) S100B seviyelerinin antenatalsteroid tedavisi alan IUGR inantlarda antenatal steroit tedavisi almayan İUGR inantlara goumlre daha duumlşuumlk duumlzeydeolduğu goumlsterildi (P lt 005) Ccedilalışma grubundaki inantlar asimetrik (n = 15) ve simetrik (n = 28) gelişme geriliği olmakuumlzere 2 gruba ayrıldılar Asimetrik ve simetrik gelişme geriliği olan inantların S100B seviyeleri sırasıyla 114 plusmn 047pgmL ve 121 plusmn 034 pgmL idi İki grup arasında S100B seviyesi bakımından anlamlı arklılık bulunmadı (P = 032)

Sonuccedil Bu ccedilalışmanın sonuccedilları modern obstetrik metodlarla takip edilse de İUGR inantlarda hipoksik beyin hasarınaneden olan intrauterin hipoksi varlığı duumlşuumlncesini desteklemektedir Bu proteinin oumllccediluumllmesi bu inantların akibetlerinitahmin etmede yaralı olabilir

Anahtar soumlzcuumlkler S100B IUGR intrauterin gelişme geriliği intrauterin hipoksi




797



















798

Results







IUGR(n = 43)

CONTROL(n = 25)

P















800












maturation

Conclusion



References



























797



















798

Results







IUGR(n = 43)

CONTROL(n = 25)

P















800












maturation

Conclusion



References



























798

Results







IUGR(n = 43)

CONTROL(n = 25)

P















800












maturation

Conclusion



References





























800












maturation

Conclusion



References
























subclinical hypoxia of infants with intrauterine growth

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