CER VI CAL LENGTH AND PHOSP HO RI LA TED
IN SU LIN LI KE GROWTH FAC TOR BIN D ING
PRO TEIN-1 AS THE PRE DIC TORS OF SPON TA NE US
PRE TERM DE LI V ERY IN SYMP TO M A TIC WO MEN
Ha d`i-Le ga Ma ri ja
,
1Da ne va Mar ko va Ana,
1Ste fa no vic Mi lan
2 1Uni ver sity Cli nic of Ob ste t rics & Gy ne co l ogy, Me d i cal Fa c ulty, Ss. Cyril and Met ho di us Uni ver sity, Sko pje, Re pu b lic of Ma c e do nia
2
De part ments of Ob ste t rics & Gy ne co l ogy, Me d i cal Fa c ulty Nis, Re pu b lic of Ser bia
Pri mljen/Re ce i ved 16. 04. 2014. god. Pri hva }en/Ac cep ted 10. 06. 2014. god.
Ab stract: Ob jec ti ve: To as sess the com bi ned use of cer vi cal length and cer vi cal phosp horyla ted in su -lin-li ke growth fac tor bin d ing pro tein-1 (phIGFBP-1) in the pre dic tion of pre term de li v ery in symp to m a tic wo men in next 14 days.
Met h ods: Cer vi cal length was pro spec ti vely me -a su red in 58 con se c u ti ve sin gle ton preg n-an ci es with in tact mem bra nes and re g u lar con trac ti ons at 24–36 we eks, and phIGFBP-1 was as ses sed. De mo grap hic da ta was eva l u a ted(hi s tory of pre vi o us pre term de li v ery,hi s tory of spon ta ne o us abor tion,pa r ity,BMI,ma ter -nal age, Or t ho dox or Mu s lims).
Re sults: Va l u es of all va ri a bles we re eva l u a ted (de -mo grap hic da ta, cer vi cal length and va l u es of phIGFBP-1) alo ne and in com bi na tion with cer vi cal length of £ 15 mm and mo re than 15 mm.
In wo men with cer vi cal length less than 15 mm/ /phIGFPB1 was po s i ti ve in 30 pa ti ents(22 of them de -li v e red in 14 days). In wo men with cer vi cal length less than 15 mm/phIGFBP-1was po s i ti ve in 9 of de li v e red preg nant wo men in 14 days. In wo men with cer vi cal length less than 25 mm/phIGFBP-1was po s i ti ve in 26 pa ti ents (2 of them de li v e red in 14 days). In pa ti ents with cer vi cal length mo re than 25 mm/ph IGFBP-1 was po s i ti ve in 4 pa ti ents (2 of them de li v e red in 14 days). With lo gi s tic re gres sion we con fir med that with OR 0.117 and CI 95% (0.046–0.295) and p < 0.01 odds for pre term birth among pa ti ents with ne g a ti ve phIGFBP-1 is 0.117 lo wer than the odds for pre term birth among pa ti ents with po s i ti ve test re sults. With sa -me test for p = 0.009 (p < 0.01) we con fir -med with OR and CI 95% (0.06 to 0.671) that cer vi cal length less
than 25 mm is good pre dic tor of pre term de li v ery with symp to m a tic pa ti ents.
Pro b a bi l ity for de li v ery in the fol lo w ing 14 days with pa ti ents with po s i ti ve phIGFBP-1and cer vi cal length £ 15 mm is 0.88 or pro b a bi l ity for not de li v e r ing in tho se pa ti ents is 0.12. In 88% pa ti ents with po s i ti ve phIGFBP-1 and cer vi cal length £ 15 mm will de li ver in the fol lo w ing 14 days.
Con clu si ons: In symp to m a tic wo men phIGFBP-1 may sig ni f i cantly im pro ve the risk as ses s ment for pre term de li v ery with cer vi cal length and help to plan sub -se qu ent preg nancy ma n a ge ment.
Key words: Pre term la bor, tran sva gi nal ul tra so -und, pre dic ti ve va lue, sen si ti v ity, spe c i fi es.
IN TRO DUC TION
Pre term de li v ery is the le a d ing ca u se of neo na tal mor ta l ity and mor bi d ity. Con se qu ently, wo men pre -sen t ing with thre a t e ned pre term la bor are of ten tre a ted with ho s pi ta l i za tion and the ad mi n i s tra tion of to -colytics to avoid pre term de li v ery. Ran do m i zed stu d i es on the use of to colytics in thre a t e ned pre term la bor ha ve de m on stra ted a sig ni f i cant pro lon ga tion of preg -nancy by abo ut 7 days but no sig ni f i cant re duc tion in the in ci den ce of pre term de li v ery, pe ri na tal mor bi d ity or mor ta l ity (1, 2).
Only a mi no r ity of the wo men pre sen t ing with thre -a t e ned pre term de li v ery will -ac tu -ally de li ver pre term (3). Gi ven the si de ef fects of to colysis and the costs of ho s pi tal ad mis sion, a pro per and cor rect di ag no sis of im pen d ing pre term de li v ery is cru cial. In the last years,
the re ha ve been at tempts to iden tify, among wo men pre -sen t ing with ute r i ne con trac ti ons, the sub gro up with the hig h est risk of de li v e r ing pre term. The re is a we alth of li t e r a tu re sug ge st ing that cer vi cal length me a su red by ul tra so und and fe tal fi bro nec tin has the po ten tial to im -pro ve the pre dic tion of pre term de li v ery (4, 5, 6).
In or der to in sti tu te mo re ap pro pri a te spe ci fic the r apy, it is im por tant to ha ve adju vant tests to help pre -dic t ing who is most li kely to ha ve a pre ter mde li very. The de tec tion of phIGFBP-1 in cer vi cal se c re tion of wo men pre sen t ing with pre term la bor has been shown to be as so ci a ted with an in cre a sed risk of pre term de li -v ery (7, 8, 9).
In su lin-li ke growth fac tor bin d ing pro tein-1 (IGFBP-1) is a 28-kDa hy dro p ho bic pro tein which is non-glycosyla ted and binds and re g u la tes the fun c tion of in su lin-li ke growth fac tors. Am ni o tic fluid con ta ins lit tle of the phosp horyla ted iso-forms of IGFBP-1, whi le tis su es pro du ce ma inly phosp horyla ted forms (phIGFBP-1). IGFBP-1 le v els in am ni o tic fluid are 100–1000 ti mes hig her than in se rum and are es sen ti ally un de tec t a ble in ot her body flu ids. The phosp horyla ted IGFBP1 isoforms are pre do m i nantly se c re -ted by hu man de ci dual cells. IGFBP-1 and phIGFBP-1 can be dif fe r en ti a ted by the use of spe ci fic mo noc lo nal an ti bo d i es (10). Con se qu ently, the pre s en ce of IGFBP-1 can be used to de tect pre term rup tu re of mem bra nes (PROM) (10), whi le the pre s en ce of phIGFBP1 in cer vi cal se c re ti ons re flects de ci dual ac ti va tion (11). Re -cently, cer vi co va gi nal con cen tra ti ons of phIGFBP-1 ha ve been shown in cor re la tion with the risk of pre term de li v ery (12–24). Dis rup tion to the cho ri o de ci dual in -ter fa ce re sults in el e va ted le v els in cer vi cal se c re ti ons. Po ten ti ally con ta m i na t ing body flu ids with fe tal fi bro nec tin (fFN), such as se men and uri ne, con tain only tra -ce qu an ti ti es of phIGFBP1 (10). A com mer cial bed si de test kit is ava i l a ble to de tect Phosp horyla ted in su -lin-li ke growth fac tor bin d ing pro tein-1 (phIGFBP-1) in cer vi cal se c re ti ons of wo men pre sen t ing with thre a t e ned pre term la bor. The Ac tim Par tus test (Me dix Bi oc he mi ca, Ka u ni a i nen, Fin land) is an im mu noc hro ma to -grap hic dip stick test ba sed on mo noc hro mal an ti bo d i es for phIGFBP-1. The test is si m i lar in prin ci ple to a uri ne preg nancy test and do es not re qu i re tec h ni cal ex per ti -se. The cost per test is ap pro x i ma tely one qu ar ter that of fFN.
Ava i l a ble re se arch sug ge sted that a ne g a ti ve phIGFBP-1 test wo uld ru le out im mi nent de li v ery in ¬90 to 95% of pa ti ents (25–29). The ne g a ti ve pre dic ti ve va lue (NPV) of phIGFBP-1 was the re fo re felt to be com pa ra ble to fFN, al t ho ugh the re was lit tle ev i den ce di rectly com pa -r ing the two tests in the sa me po p u la tion (30).
The pur po se of pre s ent study was to eva l u a te the com bi na tion of cer vi cal length me a su re ment and cer
-vi co va gi nal phIGFBP-1 as pre dic tion fac tor of pre term de li v ery wit hin 14 days in symp to m a tic pa ti ents.
MET H ODS
Po p u la tion study
58 preg nant wo men we re el i gi ble to join the study if they at ten ded the Uni ver sity Cli nic for Gy ne co l ogy and Ob ste t rics, Sko pje and we re ad mit ted to De part -ment of High Risk preg nancy Unit with symp toms of pre term la bor (symp toms of ute r i ne ac ti v ity jud ged by the as ses s ing phy si cian to be in di c a ti ve of pre term la -bor) at 24 to 36 we eks ge s ta tion. They we re re c ru i ted in pe riod of 6 months, from Sep tem ber 2013 till March 2014. They we re with symp toms or com pla ints sug ge -s ti ve of pre term la bor in clu d ing ute r i ne con trac ti on-s, in ter mit tent lo wer ab do m i nal pain and pel vic pres su re. Re c ru i ted pa ti ents had in tact am ni o tic mem bra nes de ter mi ned by spe cu lum ex a m i na ti on and mi n i mal cer vi -cal di la ta tion (£ 3 cm).Wo men we re ex clu ded if they had rup tu red mem bra nes, an te par tum he m o r r ha ge, ac -ti ve la bor, ge s ta -ti o nal hy per ten sion, pre ec lamp sia, ti ple ge s ta tion, a cer vi cal cer cla ge in pla ce and su spec -ted cho ri o am ni o ni tis (de fi ned by fe ver, ab do m i nal pain, le u kocyto sis).
Con sen t ing wo men we re tre a ted ac cor d ing to usual ho s pi tal pro to col, with ad di tion of va gi nal swabs ta ken for phIGFBP-1. Wo men we re asked to empty the ir blad ders and we re pla ced in dor sal lit ho tomy po si tion. An ul tra so und pro be was in ser ted in to the va gi -na, with ul tra so und gel ap plied only be t we en the pro be and the pro be co ver, and not on the ex ter nal sur fa ce of the pro be co ver. The pro be was pla ced in the an te ri or for nix, and the cer vi cal length was me a su red as pre vi o -usly de scri bed (31).
the se con di ti ons we re ex clu ded from the study. Uri ne or se m i nal li q u id did not in ter fe re with the test re sult. All wo men ga ve the ir writ ten in for med con sent, and the study was ap pro ved by the lo cal Et h i cal Com mit tee. The ma n a g ing cli ni cian was awa re of cer vi cal length me a su re ments, but blin ded to phIGFBP-1 re sults.
Af ter col lec tion of the cer vi cal sam ple, a tran sva -gi nal ul tra so und me a su re ment was per for med us ing 6.5 MHz tran sva gi nal pro be ac cor d ing to the Fe tal Me d i ci ne Fo un da tion Cri te ria (32). The mean of three me a su re ments was used. A di g i tal ex a m i na ti on of the cer vix was then per for med and cer vi cal sta tus do c u men ted ac cor d ing to the mo d i fied Bis hop sco re. A 30mi n u te car di o to co gram was per for med and ute r i ne con -trac ti ons re cor ded. Uri ne anal y sis was per for med in all ca ses to ex clu de uri nary tract in fec tion.To colysis with be ta mim me tics was used ac cor d ing to cli n i cal pro to -cols and ste ro ids we re ad mi n i s tra ted as ap pro pri a te.
Out co me va ri a ble was oc cur ren ce of pre term de li v -ery wit hin 14 days from the day of ho s pi tal ad mis sion.
Sta ti s ti cal anal y sis
IBM SPSS Sta ti s tics 20 was used for anal y sis. Test for lo gi s tic re gres sion (bi nary) and re ce i ver op e r a -t ing cha r ac -te r i s -tic cur ves (ROC) we re used, p-va l u es &l-t; 0.05 we re con si d e red as sig ni f i cant.
RE SULTS
The main de mo grap hic cha r ac te r i s tics of the study po p u la tion are shown in Ta ble 1. Mean ma ter nal age was 30.12. Mean ge s ta ti o nal age was 31.55 at re c ru it -ment. Mean he ight was 164.34. Mean we ight was 74.05. Mean BMI was 27.54. From 58 wo men, with hi -s tory of pre vi o u-s pre term de li v ery we re 10. We al -so eva l u a ted num ber of pre vi o us spon ta ne o us abor tion, pa r ity and smo k ing, Mu s lims or Or t ho dox at pa ti ents with thre a t e ned pre term la bor.
Va l u es of all va ri a bles which we re eva l u a ted, de mo -grap hic da ta, cer vi cal length and va l u es of phIGFBP-1 alo ne and in com bi na tion with cer vi cal length of £ 15 mm and mo re than 15 mm, are shown in Ta ble 2. phIGFPB1 was po s i ti ve in 30 pa ti ents (22 of them de li -v e red in 14 days). In wo men with cer -vi cal length less than 15 mm phIGFBP-1 was po s i ti ve with 9 of de li v e red preg nant wo men in 14 days. In wo men with cer vi cal length less than 25 mm phIGFBP was po s i ti ve with 26 pa ti ents (20 of them de li v e red in 14 days). In pa ti ents with cer vi cal length mo re than 25 mm phIGFBP-1 was po s i ti ve with 4 pa ti ents (2 of them de li v e red in 14 days).
With lo gi s tic re gres sion we con fir med that with OR 0.117 and CI 95% (0.046–0.295) and p < 0.01 odds for pre term birth among pa ti ents with ne g a ti ve phIGFBP1 is smal ler (0.117) than the odds for pre -term birth among pa ti ents with po s i ti ve test re sults. With sa me test (p < 0.01), we con fir med OR = 14.722 and CI 95 % (5.273 to 41.104)that cer vi cal length less than 25 mm is good pre dic tor of pre term de li v ery with symp to m a tic pa ti ents.
With sta ti s ti cal anal y sis we find pre dic ti ve for mu la for pre dic tion of pre term de li v ery in the fol lo w ing 14 days by com bi na tion of cer vi cal length and phIGFBP-1. For mu la for pre dic tion if de li v ery in next 14 days by cer vi cal length < 15 mm and po s i ti ve phIGFBP1 is cal cu la -ted li ke:
In (odds of pre term birth) = 0.186 + 0.829 x (ac -tim par tus) + 1.437 x (cer vi cal length < 15 mm) = 2.08
P (pre term birth) = 1/(1 + e–(ln(odds of pre term birth)) = 1/(1 + e–2,08) =1/1 + 0.1249 = 1/1.1249 = 0.88.
(e — ba sis of the na t u ral lo g a rithm (ln = lo ge), e
= 2718281828459… = 2.718)
It me ans that pro b a bi l ity for de li v ery in the fol lo -w ing 14 days -with pa ti ents -with po s i ti ve phIGFBP-1 and cer vi cal length £ 15 mm is 0.88 or pro b a bi l ity for not de li v e r ing with that pa ti ents is 0.12.In 88% pa ti ents with po s i ti ve phIGFBP-1 and cer vi cal length £ 15 mm will de li ver in the fol lo w ing 14 days.
Mean ± SD (ran ge)
Ma ter nal age (years) 30.12 ± 4.82 (20–40)
Ge s ta tion age at ex a m i na ti on 31.55 ± 3.95 (22–36)
BMI 27.54 ± 4.93 (18.7–43.8)
n (%)
Pa r ity
Nu li pa ro us 13 (22.41)
Mul ti pa ro us 45 (77.59)
Pre vi o us pre term de li v ery 10 (17.24)
Smo ker 11 (18.96)
Ta ble 1. De mo grap hic cha r ac te r i s tics of study po p u la tion (n = 58)
Ta ble 2. Pre v a len ce and ra te of cer vi cal length, phIGFBP-1 at study en try and de li v ery ac cor d ing
the out co me (n = 58)
N %
Cer vi cal length £ 15 14 24.1
Cer vi cal length 15–25 23 39.6
Cer vi cal length > 25 21 36.2
phIGFBP-1 (+) 30 51.7
De li v ery in < 7 days 24 41.6
De li v ery in 7–14 days 11 18.9
For mu la for pre dic tion of de li v ery in the fol lo w -ing 14 days by com bi na tion of cer vi cal length < 25 mm and po s i ti ve phIGFBP-1:
In (odds of pre term birth) = – 0.754 + 0.593 x (acim par tus) + 1.399 x (cer vi cal length < 25 mm) = 1.238
P (pre term birth) = 1/(1+e–(ln(odds of pre term birth)) = 1/(1+e–1.238) = 0.775
It me ans that pro b a bi l ity for de li v ery in the fol lo -w ing 14 days -with pa ti ents -with po s i ti ve phIGFBP-1 and cer vi cal length < 25 mm is 0.76 or pro b a bi l ity for not de li v e r ing with that pa ti ents is 0.24. Thus, 76% of the pa ti ents with po s i ti ve phIGFBP-1 and cer vi cal length < 25 mm will de li ver in the fol lo w ing 14 days.
By lo gi s tic re gres sion we eva l u a ted pre dic tion of de li v ery in next 14 days by hi s tory of pre vi o us pre term de li v ery, p is not sig ni f i cant (p = 0.2) and mo del is wor -k ing with 62% ac cu racy, so hi s tory of pre vi o us pre term de li v ery is not a good pre dic tor of pre term de li v ery in the fol lo w ing 14 days. We al so eva l u a ted hi s tory of
pre vi o us spon ta ne o us abor tion, pa r ity, smo k ing, BMI, va g i nal ph and no ne of them se p a ra tely is a good pre -dic tor for de li v ery in next 14 days (p is not sig ni f i cant). The ad di tion of a po s i ti ve phIGFBP-1 to cer vi cal length
£15 or 25 mm im pro ve ac cu racy of the pre dic ti ve va -lue of iso la ted cer vi cal length.
ROC cur ves of Ac tim par tus test per for man ce as in di vi d ual pre dic tor in pre term de li v ery is shown in Fi -g u re 1. ROC cur ves for us in-g cer vi cal len-gth to pre dict de li v ery in the fol lo w ing 14 days sho wed a cer vi cal length of £25 mm and Ac tim par tus as gi v ing an area un der the cur ve (AUC) of 0.667(0.517 – 0.817, p < 0.05) (Fi g u re 3). ROC cur ves we re sig ni f i cant for cer vi cal length £ 25 mm in pre dic tion of de li v ery in next 14 days. ROC cur ves for us ing po s i ti ve Ac tim par tu sto pre dict de li v ery in the fol lo w ing 14 days sho wed a po s -i t-i ve Ac t-im par tu sas g-i v -ing an area un der cur ve (AUC)
Fi g u re 1. ROC cur ve of Ac tim par tus test per for man ce as in di vi d ual pre dic tor in pre term de li v ery
Fi g u re 2. ROC cur ves for the per for man ce of com bi na ti ons of Ac tim par tus test and length of cer vix CL £ 15 mm as pre dic tors of pre term birth
Fi g u re 3. ROC cur ves for the per for man ce of com bi na ti ons of Ac tim par tus test and length of cer vix CL < 25 mmas pre dic tors of pre term birth
Fi g u re 4. ROC cur ves for the per for man ce of com bi na ti ons ofAc tim par tus test, Ac tim par tus test
of 0.624 (0.474 – 0.773, p > 0.05). ROC cur ves we re not sig ni f i cant for po s i ti ve phIGFBP alo ne as a pre dic -tor for de li v ery in next 14 days. ROC cur ves for us ing cer vi cal length £ 15 mm and £ 25 mm in com bi na tion of po s i ti ve Ac tim par tus sho wed them as gi v ing an area un der cur ve (AUC) of 0.683 (0.545 – 0.821, p < 0.05) and 0.698 (0.554 – 0.843, p, 0.05) (Fi g u re 4). So, both com bi na tion of cer vi cal length £ 15 mm and cer vi cal length £ 25 mm with po s i ti ve Ac tim par tus are good pre dic tion mo del of de li v ery in next 14 days (Fi g u re 4). ROC cur ves for ot her va ri a bles which we re eva l u a ted for pre dic tion of de li v ery in the fol lo w ing 14 days (hi s tory of pre term de li v ery, hi s tory of spon ta ne o us abor -tion, pa r ity, BMI, ph of va gi na, Or t ho dox or Mu s lims) sho wed that area un der cur ve (AUC) are be t we en 0.5 to 0.6 and p > 0.05. They are not good pre dic tors for de li v ery in next 14 days (Fi g u re 5). In the Fi g u re 6 are shown all eva l u a ted pre dic tors in ROC cur ve.
DI S CUS SION
De spi te ad van ces in ob ste t ric ca re, pre term de li v -ery re ma ins a ma jor ca u se of neo na tal mor bi d ity and mor ta l ity. With wo men pre sen t ing an acu te risk of pre -term de li v ery, to colysis, ste ro ids and in ute ro tran s fer to a cen ter with neo na tal in ten si ve ca re are re c om men ded (33). This in vol ves un ne c es sary tre at ment and com plex ma n a ge ment in a re l e vant num ber of symp to m a tic wo -men who even tu ally will not de li ver pre term. The re fo re, the re is a need for as ses s ment to ols to re li ably iden tify ca ses who are at hig h est risk of early de li v ery, and tho se who are not and can avoid tre at ment. Cer vi cal length me a su re ment by tran sva gi nal ul tra so und and as ses s ment of fi bro nec tin in cer vi cal se c re tion are the most ex ten si vely stu d ied prog no s tic fac tors in ca ses of thre a t e -ned pre term de li v ery (34). Cer vi co va gi nal fi bro nec tin is es ti ma ted to ha ve a po s i ti ve and ne g a ti ve li ke li hood ra tio of 4.10 and 0.35, re spec ti vely, in the pre dic tion of de li v ery wit hin 7–10 days, whi le the sa me va l u es for a cer -vi cal length me a su re ment of 15 mm are 8.61 and 0.03 (34). Ho w e ver, gi ven the cli n i cal sig ni f i can ce of the risk of a fal se ne g a ti ve di ag no sis, i.e. the risk of not ap pro pri a tely tre a t ing a preg nancy which is go ing to de li ver wit hin a few days, the re ha ve been va r i o us at tempts to com bi ne cer vi cal length and fi bro nec tin as ses s ment in a sin -gle or two-step test, with di s cor dant re sults (4, 35–40). phIGFBP1 ap pe ars to ha ve a si m i lar ac cu racy to fi bro -nec tin, with a po s i ti ve and ne g a ti ve li ke li hood ra tio of 3.29 and 0.20, re spec ti vely, in the pre dic tion of de li v ery wit hin 7 days, a po s i ti ve and ne g a ti ve li ke li hood ra tio of 2.53 and 0.32, re spec ti vely, in the pre dic tion of de li v ery wit hin 48 ho urs (34). As well as fi bro nec tin, phIGFBP-1 is com mer ci ally ava i l a ble as a bedsi de test, and is ap -pro x i ma tely 50% che a per.
Fi g u re 5. ROC cur ves for the per for man ce of ot her va ri a bles te sted for abi l ity of pre dic tion of pre term la bor
Fi g u re 6. ROC cur ves for the per for man ce of all va ri a bles te sted for abi l ity of pre dic tion
So me re cent stu d i es eva l u a ted a com bi na tion of cer vi cal length and phIGFBP1 in the pre dic tion of pre -term de li v ery in symp to m a tic wo men. Ero glu et al. (20) as ses sed 51 ca ses be t we en 24 and 35 we eks of ge s ta tion. The se au t hors re por ted an in cre a se in spe c i fi c ity and po -s i ti ve pre dic ti ve va lue by com bi n ing phIGFBP-1 with cer vi cal length. Ho w e ver, the sen si ti v ity re por ted for phIGFBP1 alo ne (> 80%) was si m i lar to that de scri bed by the sa me and ot her gro ups (15, 16), but ap pre ci -a bly hig her th-an wh-at w-as re por ted by ot h ers (8, 21) and fo und in our se ri es. This va ri a bi l ity may be ex pla i -ned by the small ab so lu te num ber of events in each study, as well by dif fe r en ces in ca se se lec tion cri te ria. Pa ter no s ter et al. (23) stu d ied 210 wo men with a sin gle ton preg nancy with do c u men ted ute r i ne con trac ti -ons and in tact mem bra nes be t we en 24 and 34 we eks’ ge s ta tion. They fo und that a cer vi cal length of d < 26 mm and a po s i ti ve phIGFBP-1 ha ve an odds ra tio of 16 and 9 for pre term de li v ery be fo re 37 we eks, re spec ti -vely. Rah ko nen et al. (24) ex a m i ned 246 symp to m a tic wo men be t we en 22 and 34 we eks of ge s ta tion, among which 10 (4.1%) de li v e red be fo re 34 we eks. They fo und that a short cer vix (< 25 mm), a po s i ti ve phIGFBP-1 test, and a com bi na tion of both we re as so ci a ted with pre term de li v ery £ 34 we eks or wit hin 14 days (p < 0.01). The ne g a ti ve pre dic ti ve va l u es for de li v ery £ 34 we eks we re 97.4, 97.6, and 97.1, re spec ti vely, and wit -hin 14 days 98.7, 99.0, and 98.3, re spec ti vely.
Our study con cen tra ted on the most cli n i cally re l e vant forms of pre term de li v ery, i.e. tho se de li v e r i es ta k ing pla ce wit hin 14 days from pre sen ta tion. We con -fir med that the ma jo r ity of preg nant wo men pre sen t ing with thre a t e ned pre term la bor po ten ti ally un der go es un ne c es sary tre at ment very few will de li v ery wit hin 14 days (only 36). PhIGFBP1alo ne is not a good pre dic -tor for de li v e r ing in next 14 days but com bi na tion of cer vi cal length (£ 15 mm, £ 25 mm) with phIGFBP-1 is a good pre dic tor. It me ans that pro b a bi l ity for de li v -ery in the fol lo w ing 14 days in pa ti ents with po s i ti ve phIGFBP-1 and cer vi cal length #15 mm is 0.88 or pro -b a -bi l ity for not de li v e r ing in tho se pa ti ents is 0.12. In 88% pa ti ents with po s i ti ve phIGFBP-1 and cer vi cal length £ 15 mm will de li ver in the fol lo wing14 days. At ten tion was paid to avoid any bi as in phIGFBP1 re sults re la ted to the sam pling met h o d o l ogy. The cer vi -cal rat her than va g i nal ap pro ach was cho sen, as it was li kely to pro vi de mo re ro bust re sults as re cently de m on stra ted (36). No ul tra so und gel was used on the pro -be co ver for the tran sva gi nal ul tra so und ex a m i na ti on,
and all di g i tal cer vi cal ex a m i na ti ons we re per for med af ter sam pling for phIGFBP-1, as the ir ef fect on te st ing re sults is un cle ar. Va g i nal ble e d ing, which may gi ve fal se po s i ti ve re sults, was a cri te rion for pa ti ent ex clu -si on (36).
At ten tion was paid to avoid any bi as in phIGFBP-1 re sults re la ted to the sam pling met h o d o l ogy. The cer vi -cal rat her than va g i nal ap pro ach was cho sen, as it was li kely to pro vi de mo re ro bust re sults as re cently de m on stra ted (24). No ul tra so und gel was used on the pro -be co ver for the tran sva gi nal ul tra so und ex a m i na ti on, and all di g i tal cer vi cal ex a m i na ti ons we re per for med af ter sam pling for phIGFBP-1, as the ir ef fect on te st ing re sults is un cle ar. Va g i nal ble e d ing, which may gi ve fal se po s i ti ve re sults, was a cri te rion for pa ti ent ex clu -si on (24).
In this study, the ma n a g ing cli ni cian was awa re of cer vi cal length me a su re ments, but blin ded to phIGFBP-1 re sults. This is li kely to ha ve af fec ted the de ci sion to use cor ti co ste ro ids and to colysis, and con se qu ently ha -ve in flu en ced the fi nal in ci den ce of pre term de li v ery with the dif fe r ent sub gro ups.
CON CLU SION
Fi nally, te st ing the va lue of the com bi na tion of phIGFBP1 and cer vi cal length al low us to find pre dic -tion mo del ba sed on lo gi s tic re gres sion anal y sis. Again, our study po p u la tion was too small to al low such an ap -pro ach. Ho w e ver, the com bi ned use of phIGFBP-1 and cer vi cal length with symp to m a tic wo men might ha ve the po ten tial for de c re a s ing the fal se po s i ti ve di ag no ses of im pen d ing pre term de li v ery, al lo w ing the re fo re to re du ce the bi o lo g i cal and eco no mic costs of in ap pro -pri a te tre at ment.
Ot her de mo grap hic da ta (hi s tory of pre vi o us pre -term de li v ery, hi s tory of spon ta ne o us abor tion, pa r ity, BMI, Or t ho dox or Mu s lims, va g i nal Ph) are not good pre dic tors for de li v ery in the fol lo w ing 14 days.
Ab bre vi a ti ons
phIGFBP-1 — phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein-1
BMI — Body mass in dex
OR — Odds ra tio
CI — Con fi den ce in ter val
PROM — Pre ma tu re rup tu re of mem bra nes
Sa `e tak
DU @I NA CER VIK SA I phIGFBP-1 (PHOSP HO RI LA TED IN SU LIN LI KE
GROWTH FAC TOR BIN D ING PRO TEIN-1) KAO PRE DIK TO RI SPON TA NOG
PRE VRE ME NOG PO RO \A JA KOD SIMP TO MAT SKIH @E NA
Ha d`i-Le ga Ma ri ja,1 Da ne va Mar ko va Ana,1 Ste fa no vic Mi lan21
Uni ver sity Cli nic of Ob ste t rics & Gy ne co l ogy, Me d i cal Fa c ulty, Ss. Cyril and Met ho di us Uni ver sity, Sko pje, Re pu b lic of Ma c e do nia
2
De part ments of Ob ste t rics & Gy ne co l ogy, Me d i cal Fa c ulty Nis, Re pu b lic of Ser bia
Cilj: pro ce ni ti kom bi no va nu upo tre bu du `i ne cer vik sa i phIGFBP1 kao pre dik to ra spon ta nog pre vre me nog po ro |a ja kod simp to mat skih `e na u to ku na red -nih 14 da na.
Me to do lo gi ja: du `i na cer vik sa i phIGFBP-1 su pro spek tiv no me re ni kod 58 uza stop nih jed no plod nih trud no }a 24–36 ne de lje, sa in takt nim plo do vim ovoj ni ca ma i re gu lar nim kon trak ci ja ma. Eva lu i ra ni su de mo graf ski po da ci (isto ri ja pret hod nih pre vre me nih po ro -|a ja, pa ri tet, BMI, go di ne sta ro sti maj ke, ve ro i spo vest) i iz vr {e na od go va ra ju }a sta ti sti~ ka ana li za.
Re zul ta ti: eva lu i ra ne su vred no sti svih va ri ja bli (de -mo graf ski po da ci, du `i na gr li }a i vred no sti phIGFBP-1), po je di na~ no i u od no su na du `i nu cer vik sa £ 15 mm i vi {e od 15 mm.
Kod `e na sa du `i nom cer vik sa ma njom od 15 mm/phIGFPB-1 je bio po zi ti van kod 30 pa ci jent ki nja
(njih 22 su se po ro di le za 14 da na). Lo gi sti~ kom re gre -si jom po tvr di li smo da sa OR 0.117 i CI 95% (0.046 – 0.295) i p < 0.01, {an sa za pre vrem ni po ro |aj me |u pa -ci jent ki nja ma sa ne ga tiv nim phIGFBP-1 je 0.117 ni `a ne go {an sa za pre vrem ni pro |aj me |u pa ci jent ki nja ma sa po zi tiv nim re zul ta tom. Istim te stom za p = 0.009 (p < 0.01) po tvr di li smo sa OR i CI 95% (0.06 to 0.671) da je du `i na gr li }a ma nja od 15 mm do bar pre dik tor za pre vre me ni po ro |aj kod simp to mat skih `e na. 88% pa -ci jent ki nja sa po zi tiv nim phIGFBP-1 i cer vi kal nom du `i nom £ 15 mm }e se po ro di ti u na red nih 14 da na.
Za klju ~ak: Kod simp to mat skih `e na, phIGFBP-1 i du `i na cer vik sa, mo gu zna ~aj no po bolj {a ti pro ce nu ri zi ka za pre vre me ni po ro |aj i po mo }i u da ljem pla ni -ra nju tret ma na trud no }e.
Klju~ ne re ~i: pre vre me ni po ro |aj, tran sva gi nal ni ul tra zvuk, du `i na cer vik sa, phIGFBP-1.
RE F E R EN CES
1. Ta nir HM, Se ner T, Yil diz Z. Cer vi cal phosp horyla ted in su lin-li ke grow thfac tor bin d ing pro tein-1 for the pre dic tion of pre term de li v ery insympto ma tic ca ses with in tact mem bra nes. J Ob stet Gyna e col Res. 2009; 35(1): 66–72.
2. King J F, Grant A, Ke ir se M, Chal mers I. Be ta-mi me tics in pre term la bo ur: an over vi ew of the ran do m i zed con trol led tri -als. Br J Ob stet Gyna e col. 1988; 95: 211–22.
3. McPhe e ters ML, Mil ler WC, Hart mann KE et al. The ep i de mi o l ogy of thre a t e ned pre term la bor: a pro spec ti ve co hort study. Am J Ob stet Gyne col. 2005; 192(4): 1325–9.
4. Go mez R, Ro me ro R, Me di na L et al.Cer vi co va gi nal fi bro nec tin im pro ves the pre dic tion of pre term de li v ery ba sed on so no -grap hic cer vi cal length in pa ti ents with pre term ute r i ne con trac ti ons and in tact mem bra nes. Am J Ob stet Gyne col. 2005; 192(2): 350–9.
5. Ka gan KO, To M, Tsoi E, Ni co la i des KH. Pre term birth: the va lue of so no grap hic me a su re ment of cer vi cal length. BJOG. 2006; 113 (Suppl 3): S52–6.
6. Smith V, De va ne D, Be gley CM, Clar ke M, Hig gins S. A sys te m a tic re vi ew and qu a l ity as ses s ment of sys te m a tic re vi ews of fe tal fi bro nec tin and tran sva gi nal length for pre dic t ing pre term birth. Eur J Ob stet Gyne col Re prod Biol. 2007; Aug 133(2): 134–42. 7. Al tin kaya O, Gun gor T, Ozat M, Da ni sman N, Mol la -mah mu to glu L.Cer vi cal phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein-1 in pre dic tion of pre term de li v ery. Arch Gyne col Ob stet. 2009; 279(3): 279–83.
8. Kek ki M, Kur ki T, Kark ka i nen T, Hi i le smaa V, Pa a vo -nen J, Ru ta -nen EM. In su lin-li ke growth fac tor-bin d ing pro tein-1 in cer vi cal se c re tion as a pre dic tor of pre term de li v ery. Ac ta Ob -stet Gyne col Scand. 2001; 80(6): 546–51.
9. Lem bet A, Ero glu D, Er gin T et al. New ra pid bed-si de test to pre dict pre term de li v ery: phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein1 in cer vi cal se c re ti ons. Ac ta Ob -stet Gyne col Scand. 2002;81(8):706-12.
10. Ba lic D, La ti fa gic A, Hu dic I. In su linli ke growth fac torbin d ing pro tein1(IGFBP1) in cer vi cal se c re ti ons as a pre -dic tor of pre term de li v ery. J Ma tern Fe tal Neo na tal Med. 2008; 21(5): 297–300.
11. Aben ha im HA, Mo rin L, Be nja min A. Do es ava i l a bi l -ity of fe tal fi bro nec tin te sting in the ma n a ge ment of thre a t e ned pre term la bo ur af fect the u ti li za tion of ho s pi tal re so ur ces? J Ob -stet Gyna e col Can. 2005; 27(7): 689–94.
12. Aben ha im HA, Mo rin L, Be nja min A. Do es ava i l a bi l -ity of fe tal fi bro nec tin te sting in the ma n a ge ment of thre a t e ned pre term la bo ur af fect the u ti li za tion of ho s pi tal re so ur ces? J Ob -stet Gyna e col Can. 2005; 27(7): 689–94.
13. Kek ki M, Kur ki T, Kark ka i nen T, Hi i le smaa V, Pa a vo -nen J, Ru ta -nen EM. In su lin-li ke growth fac tor-bin d ing pro tein-1 in cer vi cal se c re tion as a pre dic tor of pre term de li v ery. Ac ta Ob -stet Gyne col Scand. 2001; 80(6): 546–51.
14. Kur ki nen-Raty M, Ru o ko nen A, Vu o pa la S, et al. Com bi na tion of cer vi cal in ter le u kin-6 and -8, phosp horyla ted in su lin-li ke growth fac tor-bin d ing pro tein-1 and tran sva gi nal cer vi cal ul tra so no graphy in as ses s ment of the risk of pre term birth. BJOG. 2001;108 (8): 875–81.
Cor re spon den ce to/Autor za ko re spon den ci ju
Ma ri ja Ha d`i-Le ga, MD
De part ment of Ob ste t rics and Gy ne co l ogy Sta te Uni ver sity Ho s pi tal of Sko pje
Stre et Vod njan ska; num ber 17, 100 Sko pje, Ma c e do nia ma ri ja had zi le gaªya hoo.com; mo bi le ++ 389 78 485 580 Ana Da ne va Mar ko va, MD
De part ment of Ob ste t rics and Gy ne co l ogy Sta te Uni ver sity Ho s pi tal of Sko pje
Stre et Vod njan ska; num ber 17, 100 Sko pje, Ma c e do nia ana da ne vaªya hoo.com: mo bi le ++389 70 714 71 Mi lan Sre fa no vic, Phd, MD
De part ment of Ob ste t rics and Gy ne co l ogy Sta te Uni ver sity Ho s pi tal of Nis
mi la9ªopen.te le kom.rs
16. Kwek K, Khi C, Ting HS, Yeo GS. Eva l u a tion of a bed si de test for phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein-1 in pre term la bo ur. Ann Acad Med Sin ga po re. 2004; 33(6): 780–3.
17. Aker can F, Ka zan di M, Sen dag F, et al. Va lue of cer vi cal phosp horyla ted in su lin li ke growth fac tor bin d ing pro tein-1 in the pre dic tion of pre term la bor. J Re prod Med. 2004; 49 (5): 368–72.
18. Eli zur SE, Yinon Y, Ep stein GS, Se id man DS, Schiff E, Si van E. In su linli ke growth fac tor bin d ing pro tein1 de tec tion in pre term la bor: eva l u a tion of a bed si de test. Am J Pe ri na -tol. 2005; 22(6): 305–9.
19. Bit tar RE, da Fon se ca EB, de Car val ho MH, Mar ti nel li S, Zu ga ib M. Pre dic t ing pre term de li v ery in asymp to m a tic pa ti -ents with pri or pre term de li v ery by me a su re ment of cer vi cal length and phosp horyla ted in su lin-li ke growth fac tor-bin d ing pro tein-1. Ul tra so und Ob stet Gyne col. 2007; 29(5): 562–7.
20. Ero glu D, Yanik F, Ok tem M, Zeyne lo glu HB, Ku scu E. Pre dic tion of pre term de li v ery among wo men with thre a t e ned pre term la bor. Gyne col Ob stet In vest. 2007; 64(2): 109–16.
21. Pa ter no s ter DM, Mu re san D, Vi tu lo A, et al. Cer vi cal phIGFBP1 in the eva l u a tion of the risk of pre term de li v ery. Ac -ta Ob stet Gyne col Scand. 2007; 86(2): 151–5.
22. Ting HS, Chin PS, Yeo GSH, Kwek K. Com pa r i son of bed si de test kits for pre dic tion of pre term de li v ery: phosp horyla -ted in su lin-li ke growth fac tor bin d ing pro tein-1 (pIGFBP-1) test and fe tal fi bro nec tin test. Ann Acad Med Sin ga po re. 2007; 36(6): 399–402.
23. Pa ter no s ter D, Ri bo ni F, Vi tu lo A, et al. Phosp horyla ted in su linli ke growth fac tor bin d ing pro tein1 in cer vi cal se c -re ti ons and so no grap hic cer vi cal length in the p-re dic tion of spon ta ne o us pre term de li v ery. Ul tra so und Ob stet Gyne col. 2009; 34(4): 437–40.
24. Rah ko nen L, Un ki la-Kal lio L, Nu u ti la M, Sa i nio S, et al. Cer vi cal length me a su re ment and cer vi cal phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein-1 te st ing in pre dic tion of pre term birth in pa ti ents re por t ing ute r i ne con trac ti ons. Ac ta Ob stet Gyne col Scand. 2009; 88(8): 901–8.
25. Gold ben berg RL. The ma n a ge ment of pre term la -bor. Ob stet Gyne col. 2002;100(5 Pt 1): 1020–37.
26. Aker can F, Ka zan di M, Sen dag F, et al. Va lue of cer vi cal phosp horyla ted in su lin li ke growth fac tor bin d ing pro tein-1 in the pre dic tion of pre term la bor. J Re prod Med. 2004; 49 (5): 368–72.
27. Eli zur SE, Yinon Y, Ep stein GS, Se id man DS, SchiV E, Si van E. In su linli ke growth fac tor bin d ing pro tein1 de tec tion in pre term la bor: eva l u a tion of a bed si de test. Am J Pe ri na -tol. 2005; 22(6): 305–9.
28. Kwek K, Khi C, Ting HS, Yeo GS. Eva l u a tion of a bed si de test for phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein-1 in pre term la bo ur.Ann Acad Med Sin ga po re. 2004; 33: 780–3.
29. Lem bet A, Ero glu D, Er gin T, et al. New ra pid bed-si de test to pre dict pre term de li v ery: phosp horyla ted in su lin-li ke growth fac tor bin d ing pro tein1 in cer vi cal se c re ti ons. Ac ta Ob -stetGyne col Scand. 2002; 81(8): 706–12.
30. Ting H-S, Chin PS, Yeo G, Kwek K. Com pa r i son of bed si de test kits for pre dic tion of pre term de li v ery: phosp horyla -ted in su lin-li ke growth fac tor bin d ing pro tein-1 (pIGFBP-1) test and fe tal fi bro nec tin test. Ann Acad Med Sin ga po re. 2007; 36 (6): 399–402.
31. So nek J, Shel lha as C. Cer vi cal so no graphy: a re vi -ew. Ul tra so und Ob stet Gyne col. 1998; 11(1): 71–8.
32. Pa ter no s ter DM, Mu re san D, Vi tu lo A, et al. Cer vi cal phIGFBP1 in the eva l u a tion of the risk ofpre term de li v ery. Ac -ta Ob stet Gyne col Scand. 2007;86(2):151–5.
33. Iams JD, Ro me ro R, Cul ha ne JF, Gol den berg RL. Pri -mary, se c on d ary, and ter ti ary in ter ven ti ons to re du ce the mor bi d ity and mor ta l ity of pre term birth. Lan cet. 2008; 371(9607): 164–75.
34. Ho n est H, For bes CA, Du ree KH, et al. Scre e n ing to pre vent spon ta ne o us pre term birth: sys te m a tic re vi ews of ac cu racy and ef fec ti ve ness li t e r a tu re with eco no mic mo d el ling. He -alth Tec hno lAs sess. 2009; 13(43): 1–627.
35. Schmitz T, Ma il lard F, Bes sardBac qu a ert S,et al. Se lec ti ve use of fe tal fi bro nec tin de tec tion af ter cer vi cal lengthme -a su re ment to pre dict spon t-a ne o us pre term de li v ery in wo men wit hpre term la bor. Am J Ob stet Gyne col. 2006; 194(1): 138–43. 36. Eli zur SE, Yinon Y, Ep stein GS, Se id man DS, Schiff E, Si van E.In su lin-li ke growth fac tor bin d ing pro tein-1 de tec tion in pre term la bor:eva l u a tion of a bed si de test. Am J Pe ri na tol. 2005; 22(6): 305–9.
37. Ro zen berg P, Gof fi net F, Ma la gri da L, et al. Eva l u a t ing the risk of pre term de li v ery: a com pa r i son of fe tal fi bro nec tin and tran sva gi na lul tra so no grap hic me a su re ment of cer vi cal length. Am J Ob stet Gyne col. 1997; 176(1): 196–9.
38. Hincz P, Wilczynski J, Ko zar zew ski M, Sza flik K. Twostep test: the com bi ned use of fe tal fi bro nec tin and so no grap hic ex a m i na ti on of the ute r i ne cer vix for pre dic tion of pre -term de li v ery in symp to m a tic pa ti ents. Ac ta Ob stet Gyne col Scand. 2002; 81(1): 58–63.
39. Tsoi E, Ak mal S, Ge erts L, Jef fery B, Ni co la i des KH. So no grap hic me a su re ment of cer vi cal length and fe tal fi bro nec tin te st ing in thre a t e ned pre term la bor. Ul tra so und Ob stet Gyne -col. 2006; 27(4): 368–72.
