THE JOURNAL OF \

Obstetrics and Gynaecology Research

J. Obstet. Gynaecol. Res. Vol. )'* No.5: 780-78 ! "ay #0$

doi:10.1111 !.1""#$0#%&.2011.01'0".(
#

Maternal serum C-reactive protein in early pregnancy and occurrence of preterm premature rupture of membranes and preterm birth
+ida ,oghadda- .anae-/* .ita ,oha-adi/* ,oha-ad 0sghari 1aafarabadf and 2arges 0liyan ,oghada-/
%"&'(&)e*y an' Re+*o',ct&-e Healt. /e+a*t0ent! 1ac,lty o) "e'&cal 2c&ences! Ta*b&at "o'a*es Un&-e*s&ty! Te.*an! an' #Nat&onal3,bl&c Healt. "ana4e0ent 5ente* 6N3"57 an' /e+a*t0ent o) 2tat&st&cs an' E+&'e0&olo4y! 2c.ool o) Healt. an' N,t*&t&on! Tab*&8 Un&-e*s&ty o) "e'&cal 2c&ences! Tab*&8! %*an

Abstract

A&0: 3he ai- of this study 4as to deter-ine the relationship bet4een -aternal seru- 5$reacti6e protein 75R89 le6els in the first 20 4ee:s of pregnancy and later occurrence of preter- pre-ature rupture of -e-branes and preter- birth. "ate*&al an' "et.o's: 0 prospecti6e cohort study that -easured -aternal seru- 5R8 le6els in ##'pregnant 4o-en in the first half of pregnancy 4as perfor-ed in the city of 2oor 7north ;ran9* and included follo4$up of patients up to ti-e of deli6ery. 8reter- pre-ature rupture of -e-branes and preter- birth 4ere defined as the occurrence of -e-branes rupture and birth* respecti6ely before )# 4ee:s of gestation. Res,lts: Of the ##' pregnancies studied* 1< 72."1=9preter- pre-ature rupture of -e-branes and %' 7#.)=9 preter- births 4ere seen. ,edian 5R8 le6els in preter- pre-ature rupture of -e-branes and preter- birth cases 4ere -uch higher than in ter- deli6eries 7# and &.' respecti6ely 6s 2." -g +: &&.&# and &".#&*respec ti6ely 6s 2".)'n-ol +9. 5R8 le6els >" -g + had statistically significant relationships 4ith preter- pre-ature rupture of -e-branes 7OR %.<1*<%= 5; 2.0#$1&.'<9 and preter- birth 7OR '.<%* <%= 5; ".&0$1#.")9.?ith a cut$off le6el of " -g + of 5R8*sensiti6ity* specificity*and li:elihood ratios 7+R@and +R9 for preter- birth 4ere '1* #0* 2.#0* 0.2'=*respecti6ely* and for preter- pre-ature rupture of -e-branes they 4ere #<* &#* 2."1 and 0.)1=* respecti6ely. 5oncl,s&on: It see-s that the infla--atory -ar:er* 5R8* can be used in the early stages of pregnancy to identify 4o-en at ris: of e(periencing preter- pre-ature rupture of -e-branes and preter- birth. Aey 4ords: cohort study* 5$reacti6e protein* pregnancy* preter- birth* preter- pre-ature rupture of -e-branes. $ $ $ P ..

Introduction
8reter- birth 783.9is defined as the presence of uterine contractions of sufficient freDuency and intensity to affect progressi6e efface-ent and cer6i( dilation prior to ter- gestation 7bet4een 20 and )# 4ee:s9 and is an

-ortaliB Co4e6er* the e(act -echanis- of preterbirth is still largely un:no4n* e6en though -uch e6i i-portant factor for infant and ne4born -orbidity and
Recei6ed: January )12011. 0ccepted: October < 2011.

Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

dence has sho4n that chronic infection and infla--a tion can play an i-portant role. So-e researchers ha6e suggested that infections are responsible for )0$%0=

of preter- birthBnd that intrauterine infection -ight be responsible for "0$%0= of preter- deli6eries.8;t has
E

Reprint reDuest to: Fr +ida ,oghadda- .anae-* ,id4ifery and Reproducti6e Cealth Fepart-ent* Faculty of ,edical Sciences* 3arbiat ,odares Gni6ersity* 3ehran 1"11#1)11&*;ran. H-ail: -oghadda-bI-odares.ac.ir

L. ,oghadda- .anae-

et al.

also been clai-ed that -aternal syste-ic infection leads to an increase in infla--atory cyto:ine le6els to pro6o:e production of prostaglandins. 3his process leads to uterine contraction and cer6i( ripening* 4hich finally leads to preter- birth issues. ;ncrease in infla-atory cyto:ines le6els such as interleu:in & and ' in -aternal seru- is probably associated 4ith pre-ature birth issues./ 3here is so-e e6idence that pro6es the theory that bacterial infection in fetal -e-branes -ay lead to chorioa-nionitis* 4hich has a strong relationship 4ith preter- birth and preter- pre-ature rupture of -e-branes.tJ Rupture of -e-branes 7RO,9 is a natural physi ological pheno-enon that occurs before deli6ery* but 4hen it happens before 37 4ee:s of pregnancy it is called preter- pre-ature rupture of -e-branes 788RO,9.' ,any clinical and epide-iological factors are related 4ith 88RO,. So-e of the- include s-o:ing* se(ually trans-itted infections 7S3;s9* -aternal deficiency of 6ita-in 5* pregnancy co-plications.eJ genital tract infectionsJ and infection or infla--ation of chorioanion. 0ll these factors -ay play pri-ary or secondary roles in the pathogenesis of 88RO,.1)K1" ,easuring infla--atory -ar:ers can be a predic ti6e -ethod for detecting 4o-en at high ris: for preter- labor. 5$reacti6e protein 75R89 is a sensiti6e -ar:er for syste-ic infla--ation. It is produced in hepatocytes in response to infection and tissue

Material and Methods

da-age*J
5R8 production is sti-ulated by the release of infla--atory cyto:ines including interleu:in 1 and &* and alpha$tu-or necrotic factor. 0lthough 5R8 e(ists in both acute and chronic infla--atory disorders* it -ay so-eti-es be produced in response to acute phase reactions. 0ccording to pre6ious studiesL increased le6els of seru- 5R8 ha6e a relationship 4ith intrauterine infection.1&K1# 3here are studies at hand on 5R8 le6els as potential -eans for identifying hidden infection in pregnant ?01l1en4ho ha6e e(perienced 83. and 88RO,.1' 3illett et al. 4ere the first to isolate 5R8 in 1<)0 as a substance in the seru- of patients 4ith acute

infla--ation.J
5onsidering the nu-erous co-plications resulting fro- 83.* prediction of 88RO, and 83. can be effec ti6ely useful in reducing -aternal and neonatal -ortal ity and -orbidity. 3hus* 4e perfor-ed this study to e6aluate the role of early pregnancy 5R8 le6els in later de6elop-ent and prediction of 88RO, and 83..

1his 4as a prospecti6e cohort studB5 nducted in three pri6ate Obstetrics and Gynecology 5linics in 2oor 7north ;ran9 fro- February 200' t ,arch 200<. 3he study sa-ple 7a total of 778) co isted of pregnant 4o-en 4ho attended these clinics r prenatal care and ga6e 4ritten consent 7offered by e 3arbiat ,odares Gni6ersity -edical ethics co--i e9 to enter the study after recei6ing sufficient e(plana .ons about the study fro- one of the in6estigators. 3he inclusion criteria 4ere as llo4s: gestational age under 20 4ee:sL singleton pre cyL and no history of diabetes* hypertension* syst -ic disease* or se6ere syste-ic infection in the past ear. Sub!ects 4ho de6eloped se ere syste-ic infections and needed hospitaliMation d ing the course of their pregnancy 4ere e(cluded fro the studyL o6erall there 4ere three such cases 7infec ons 4ith rubella 6irus9. Gestational age 4as deter . ed on the basis of last -enstrual period 7+,89 and . st ultrasound perfor-ed before 20 4ee:s of gestation ;n 4o-en 4ho had irregu lar -enstruation or did no :no4 their +,8* the first ultrasound 4as used ins tea . If there 4as inconsistency in gestational age acDuire fro- +,8 4ith the first ultrasound* the latter 4as nsidered as gestational age. 3he reDuired infor-a on 4ere collected using a Duestionnaire on de- graphic and reproducti6e historyL -edical historyL onsu-ption of supple-ental iron* 6ita-ins* folic aci * and calciu- during preg nancyL and -aternal t acco use 7induding passi6e s-o:ing or li6ing 4i an acti6e s-o:er9. 3here 4as only one easure-ent of 5R8 le6els: upon entry into the study se 5R8 le6els 7high sensiti6ity 5R8: hs 5R89 4ere -e sured by i--unoturbido-etric assay using photo.c analyMer 78ars$0M-oon AitL 8ars 0M-oon 5o-p y* 3ehran* ;ran9. 3;le sensiti6ity of the assay 4as 0.0 -g +. 0ll 5R8 assays 4ere per for-ed in a single ; oratory in 2oor to increase reli ability and -ini-iM 6ariance bet4een the laboratories and different eDuip ent 0s -ost laboratories routinely reported 5R8 assa s as either /positi6e/ or /negati6e/* arrange-ents 4ere ade to ensure that the actual le6els of 5R8 4ere -eas ed and recorded for all sa-ples. 3hen the sub!ects der4ent routine prenatal care up to deli6ery. 0ll de 6eries 4ere perfor-ed in ;-aAho-eini hospital/ 2oor. 3hen the reDuired data on the ti-e of deli6e or rupture of -e-branes 4ere obtained fro- the p .ent files in the sa-e place. 8reter- birth 783s9 and preter- pre-ature rupture of -e-branes 788RO,9 4ere defined respecti6ely as

tJ t-

Harly pregnancy seru- 5R8 in 88RO, and 83.

deli6ery and rupture of -e-branes before )# 4ee:s of pregnancy. 0ll data 4ere recorded and analyMed by S8SS 6ersio 1% 7S8SS ;nc.* 5hicago* ;+* GS09 and S303 6ersion 0 soft4are 7S0S ;nstitute ;nc.* 5ary* 25* GS09. 3o a the data* first the characteristics of pregnancies c cated 4ith 88RO, and 83. 4ere co-pared 4i terdeli6eries* using the ,ann$?hitney G$test. en the relationship bet4een potential ris: factor 4ith the percei6ed outco-es 788RO, and 83.9 4 e assessed using the binary logistic regression -od and the sig nificant factors 4ere -ar:ed. Finally* by: ecei6er oper ating characteristic 7RO59 analysis* an onsidering the opti-al co-bination of sensiti6ity d specificity* 4e deter-ined the best cut$off point 6al es of 5R8 for each outco-e and -easured the relat d li:elihood ratios 7+R9. 3he. -entioned indices 4 e reported together 4ith their <%= confidence inte ;s 75;9. Further* the area under cur6e 70G59 and it <%= 5; 4ere presented as a -easure of outco-e p ediction adeDuacy using 5R8le6el. 5onsidering that the p siti6e predicti6e 6alue of a diagnostic test is -uch . uenced by the pre6alence of a disease in the popul .on $ lo4 pre6alence results in lo4 positi6e predicti 6alues $ and that the pre6alence of both 88RO, an 3. are lo4 in -ost co--unities 7N10=9* 4e calcul ted li:elihood ratios of 5R8 le6els higher than the tained cut$off point le6els in predict ing both 88R and 83.* along 4ith positi6e and negati6e pre cti6e 6alues.J p < 0.0% 4as considered statistically gnificant

Results

~
~

Of ##' pregnant 4o-en in the present study* 1< 72."1=9 de6eloped 88RO,* and %E# 7#.)=9 had 83..

0ll 88RO, cases ended 4ith 83.* and none of thecould be pre6ented fro- leading to 83.. General characteristics of the study sub!ects are su--ariMed in 3able 1. It should be noted that as the distribution of cases a-ong three groups of pregnancy 7terdeli6ery* 88RO, and 83.9 4as uneDual and unbal anced* 4e used nonpara-etric analysis to co-pare different characteristics of 88RO, or 83. cases 4ith ter- deli6eries. 0nd as 88RO, in all cases led to 83.* 4e could not co-pare 88RO, cases 4ith 83. cases. Only 5R8 le6els and gestational age in 88RO, and 83. cases 4ere significantly different fro- those in nor-al pregnancies (P < 0.001 for all four coparisons9. ,edian gestational ages in 88RO, and 83. cases 4ere less than ter- deli6eries 7)% and )&.#1 4ee:s respecti6ely 6s )<.1" 4ee:s9 and -edian 5R8 le6els in 88RO, and 83. 4ere -uch higher than in ter- deli6eries 7# and &.' respecti6ely 6s 2.%& -g +9 7&&.&# and &".#& respecti6ely 6s 2".)' n-ol +9 73able 1). ?e used RO5 analysis to obtain opti-u- cut$off point 6alues for 5R8 in 88RO, and 83.. ;n this analy sis* 5R8 le6els had statistically significant influence on both 88RO, and 83. 7Figs 1*29. 0fter studying the RO5 results and considering the best sensiti6ity and specificity* 4e chose a 5R8 cut$off of 4 -g + 7)'.0<& n-ol +9 for both 88RO, and 83.. 3o assess the influence of potential ris: factors on 88RO, and 83.* 4e used binary logistic regres sion analysis. 8otential ris: factors of 83. entered in the -odel along 4ith 5R8 le6el >" -g + 4ere as follo4s: -other/s e-ploy-ent status* socioecono -ic status 7represented by house o4nership9* age of -other* pri-iparity* positi6e history of abortion and 83.* s-o:ing 7as none of the cases 4ere s-o:ers

3able 1 5haracteristics of study sub!ects in three groups of pregnancy 3er- deli6ery ,edian 7<%=5;9 n = #21 7<2.#=9 0ge 7years9 5R8 7-g +9
5R8 7runol +9

88RO,

8reter- birth ,edian 7<%=5;9

n=57 (7.3%)

WBC

BMI (kg/rn') Gestational age 74ee:s9 Gra6id 8re6ious abortions

2& 72%$2&9 2.%& 72."$2.#9 2".)' 722.'&$2%.#19 2%.'0 72%.2#$2&.29 )<.1" 7)<.1"$)<.2'9 '"&0 7')00$'&00 2 71$29 0.00 70$09

2' 72)$))9 #.00O 7".%%$'.<9 &&.&#O 7").))$'".#&9 2".00 72)$2&.&'9 )%.00O 7)"$)%.#19 '<00 7#"00$<&&1.1'9 2 71$)9 0.00 70$19

2& 72)$2'9 &.'0O 7%."1$#."9 &".#&O 7%1.%2$#0."'9 2&.10 72".)#$2#.")9 )&.#1O 7)&.2'$)&.#19 <200 7#<1).<2$<%").0"9 2 71$29 0.00 70$09

/Significant difference 4ith nor-al pregnancy up based on ,ann$?hitney G$test 78 < O.OS9. .,;* body -ass inde(L 5;* confidence inte * !P" 5$reacti6e proteinL 88RO,* preter- pre-ature rupture of -e-branesL ?.5*4hite blood cells.

782

2012 3he 0uthors

1.0

0.'

1.0

1 -

Specificity cei6er Dperating 5haracteristic7RO59cur6e of 5$reacti6e protein le6els 7-g +9 and pre-ature rupture of -e-branes.

7OR: '.<%* <%= 5;: ".&0$1#.")9 had statistically signifi cant relation 4ith 83.* -eaning that 83. occurrence 4as nearly nine ti-es -ore co--on in 4o-en 4ith early pregnancy seru- 5R8 le6els higher than " -g +* in co-parison to those 4ith lo4er le6els of 5R8 73able 29. For 88RO,* the ris: factors 4hich 4ere studied along 4ith 5R8 le6el >" -g + included -other/s e-ploy-ent* age of -other* pri-iparity* and passi6e s-o:ing. In this logistic regression analysis* 5R8 le6els >" -g + 7OR %.<1* <%= 5; 2.0#$1&.'<9 and passi6e s-o:ing 7OR 0.)2* <%= a 0.12$0.''9 had a statistically significant relationship 4ith 88RO,L early pregnancy 5R8 le6els higher than " -g + 4ere acco-panied by nearly si( ti-es -ore occurrence of 88RO, 73able )9. .y obser6ing the sensiti6ities and specificities obtained 4ith the cut$off le6el of 5R8 at " -g + 73able "9* 4e -ay conclude that '1= of -others 4ho finally de6eloped 83. and #<= of 4ho- 4ere de6el oping 88RO,* had 5R8 le6els in a higher range than " -g + in their fist half of pregnancy* and that #0= and &#= of -others respecti6ely 4ho did not de6elop 83,* or 88RO,* had early pregnancy 5R8 le6els in a lo4er range than " -g +. 8ositi6e predicti6e 6alues of this le6el of 5R8 in predicting 83. and 88RO, 4ere respecti6ely 1#= and &=* but negati6e predicti6e 6alues 4ere <'= and <<=* 4hich 4ere re-ar:able* indicating that if early pregnancy 5R8 le6els 4ere lo4er than " -g +* then there 4as little chance of later occurrence of both 83. and 88RO, 73able "9. 0lternati6ely* the +R@for 83. and 88RO, sho4ed that a positi6e test is 2.# and 2."1 ti-es -ore li:ely to be found in the presence of 83. and 88RO,* rather than their absence* respecti6ely* 4hich 4as 6ery re-ar:able in defining the predicti6e po4er of 5R8 le6els for 83. and 88RO, occurrence. 0nd the +R for 83. and 88RO, indicated that a negati6e test is respecti6ely 0.2' and 0.)1 ti-es -ore li:ely to be found in the presence of 83. and 88RO,* rather than their absence.

0.0

0.2

0.4

0.6

0.'

1.0

1 - Specificity

Figure 2 Recei6erOperating 5haracteristic7RO59cur6e analysis of 5$reacti6e protein le6els 7-g +9 and preterrn birth. the-sel6es* 4e used the passi6e s-o:ing ter- 4hich is the presence of an acti6e s-o:er in the sa-e house as the study sub!ect9. Of all the factors studied in logistic regression analysis* only 5R8 le6el >" -g +

Discussion
3he -ain purpose of t#i$ study 4as to e(a-ine the association bet4een seru- 5R8 le6els and the ris: of 83. and 88RO,. ?e also tried to deter-ine the cut off 6alues that 4ould -a:e 5R8 a useful predictor of 83. and 88RO,.

2012 3he 0uthors Journal of Obstetrics and Gynaecology Research 2012Japan Society of Obstetrics and Gynecology

#')

3able 2 +ogisticregression analysisof potential ris: factors of preter- labor Hffecti6efactor 5R8 >" -g + 7)'.0<&n-ol +9 ,aternale-ploy-ent +o4 socioecono-icstatus 0ge 7years9 8ri-iparity Cistory of abortion Cistory of preter- labor 8assi6es-o:ing
5R8*e$reacti6e protein.

Odds ratio 7OR9 '.<%% 0.<") 1.2"0 0.<&& 0.#&0 1.0<) 2.#0" 0.&)0

<%=5; +o4er Gpper ".&02 0.)%" 0.&)< 0.<1) 0.)## 0.&<# 0.##0 0.)1# 1#."2% 2.%1) 2."0% 1.0 1.% 1. % .%02 1.2%)

3able ) +ogisticregressionanalysisofpotential ris: f ctors of pre-ature rupture of -e-branes Hffecti6efactor 5R8 >" -g + 7)'.0<&n-ol +9 ,aternale-ploy-ent 0ge 8ri-iparity 8assi6es-o:ing
5R8*5$reacti6e protein.

Odds ratio 7OR9

<%=5; Gpper 1&.'<% 2.0#0 0.21% %.0%' 0.<"" 1.10< ).#%' 0."&% 0.11& 0.''0

8$6alue 0.001 0.<%' 0.%'1 0.&00 0.02#

3able " Results of recei6er operating characteristic O59 analysis and opti-u- cut$offs for 5$reacti6eprotein 75R89in pre-ature rupture of -e-branes 78RO,9and . eter- labor 5R8 0G5 7<%=5;9 le6el 7-g +9 8reter- " labor 8RO, " 0.'1270.#%'$0.'&%9 0.#'%70.&'&$0.''"9 Specificity 88P 7<%=5;9 7<%=5;9 28P 7<%=5;9 +R@7<%=5;9 +R$ 7<%=5;9

#0 7&&$#)9 1# 71)$2)9 <' 7<&$<<9 &# 7&"$#09 &= 7"$<9

2.#072.2&$).1&9 0.2'70.1&$0."#9

<< 7<'$1009 2."1 71.'#$).109 0.)170.1)$0.#%9

%&'" area under

the cur6eL 0* confidence/ er6alL +R@*positi6e li:elihood ratioL +R$*negati6e li:elihood ratioL 28Q* negati6e predicti6e 6alueL 88Q*positi6e predicti6e 6alue.

5R8 le6els in the first half of pregnancy in pregnant 4o-en 4ith later de6elop-ent of 88RO, or 83. 4ere -ar:edly higher than those 4ith nor-al preg nancies* and there 4ere significant relations bet4een 5R8 le6els and 83.* 88RO,. 3he results of the present study are si-ilar to the findings by C6ilso- et al. in 2002 1 4ho -easured and co-pared 5R8 le6els in '" 4o-en 4ith 83. and "00 -others 4ith ter- deli6ery and found significant dif ferences bet4een the t4o groups 7i.e. increased 5R8 le6els in early pregnancy ob6iously increased the ris: of 83.9. 16

Our results are also consistent 4ith those reported by 8itiphat et al. in 200# 2 4ho found that in the first half of pregnancy* 5R8 4as higher in 4o-en 4ho later had 83. before )" 4ee:s co-pared to those 4ith terdeli6ery or deli6ery at )"$)# 4ee:s. Our findings also confir- the report by ?illia-s et al. in 200& 3 4ho found that in the first half of preg nancy* 5R8 le6els 4ere significantly higher in 4o-en 4ith later 83. occurrence. Our results contrasted those reported by GheMMi et al. in 2002 " 4ho found no association bet4een -ater nal seru- 5R8 concentrations and the ris: of 83.

2012 3he 0uthors Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

7)"$)& 4ee:s9 or 6ery pre-ature deli6ery 7before )" 4ee:s9. 0lso there 4as no rele6ance bet4een a-ni otic fluid 5R8 and -aternal seru- 5R8 concentrations* but all 4o-en 4ith deli6ery before )" or )# 4ee:s had a-niotic fluid 5R8 concentrations higher than those 4ith nor-al ter- deli6ery. +ou:o6aara et al. in 2002() reported that there 4as no

Ac no!ledgments
3his study 4as perfor-ed as the thesis pro!ect in an ,Sc degree in -id4ifery and funded by the Faculty of ,edical Sciences* 3arbiat ,odares Gni6ersity* 3ehran* ;ran. ?e o4e special than:s to the 2oor 5ity +aboratory personnel* 4ithout 4hose assistance the study could not be perfor-ed.

difference bet4een seru- 5R8 le6els in 4o-en 4ith 88RO, and those 4ith ter- deli6ery* 4hich does not -atch our findings. Cyun Qoon et al! in 1<<&2& studied the relationship bet4een seru- 5R8 le6els* and the nu-ber of 4hite blood cells in seru- and a-niotic fluid 4ith 88RO,. 3hey found that 4o-en 4ith positi6e culture and sy-pto-s of chorioa-nionitis had significantly higher le6els of 5R8*and a higher nu-ber of 4hite blood cells in seru- and a-niotic fluid than 4o-en 4ithout such sy-pto-s. 3he best predictor of positi6e a-niotic fluid culture 4as a-niotic fluid 4hite blood cell count In general* the results obtained so far through -any studies suggest a strong relationship bet4een 5R8 le6els in pregnancy and occurrence of 83. and 88RO,. In addition* the present study* considering the obtained OR* indicates that there is a strong rele6ance bet4een 5R8 le6els and the occurrence of 88RO, or 83.*but the e(act -echanis- of these relations re-ain un:no4n to us* and for that* 4e suggest further studies 4ith 5R8 le6els and placental pathology* or a-niotic fluid -ar:ers. Our research also suggests that 4o-en 4ho ha6e high 5R8 le6els in the first half of pregnancy should be follo4ed up closely 4ith regard to 83H and 88RO,* although 4e do not :no4 the e(act -echanis- of early pregnancy seru- 5R8 in resulting 83H or 88RO,*but 4e can still control cases 4ith high 5R8 le6els for other ris: factors of these conseDuences and eli-inate the- if possible. 0 possible li-itation in the present study is that it 4as conducted in a s-all to4n in the north of ;ran* so its results can not be generaliMed to all of the ;ranian population* but as the sub!ects 4ere a rando- sa-ple of pregnant 4o-en in that city and their socioeco no-ic factors 4ere not -uch different fro- other patients in other clinics* 4e could generaliMe the results to the total city population. Co4e6er* as there are still so-e contro6ersies about the role of infla--atory -ar:ers* such as 5R8* in causing 83H or 88RO,* further studies 74ith different sets of sub!ects and larger sa-ples9 are necessary before the association bet4een 5R8 and 83H and 88RO, can be established definitely and proper predicti6e 6alues be obtained.

Disclosure
2one declared.

References
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