Cervical insulinlike growth factor binding protein1 (igfbp1) to predict spontaneous onset of labor and induction to delivery interval in postterm pregnancy

Cervical insulin-like growth factor binding protein-1(IGFBP-1) to predict spontaneous onset of labor andinduction to delivery interval in post-term pregnancy OGL1,2, EIRIK SKOGVOLL3,4 & RUNA HEIMSTAD2,5 1Department of Gynecology and Obstetrics, Levanger Hospital, Health Trust Nord-Trøndelag, 2Department of Obstetrics,3Anaesthesiology and Emergency Medicine, St. Olav University Hospital Trondheim, 4Institute of Cancer research andMolecular Medicine, Faculty of Medicine, and 5Institute of Laboratory Medicine, Children's and Women's Health, NorwegianUniversity of Science and Technology (NTNU), Trondheim, Norway Key words
IGFBP-1, post-term, induction of labor, cervicallength, Bishop score Objective. To evaluate whether insulin-like growth factor binding protein-1 (IGFBP-1) assessed in cervical secretion can predict successful induction and spontaneous onset of labor in post-term pregnancy, compared to ultrasound measurement of Malin Andrea Elisabeth D ¨ogl, NSykehuset cervical length and Bishop score. Design. Cohort study, originating from a ran- Levanger, Kirkegate 2, 7600 Levanger.
domized controlled trial. Setting. Obstetric department of a university and tertiary referral hospital, Norway. Population. Five hundred and eight post-term womenwho had been randomized to induction of labor or expectant management 1 week Conflict of interest
The authors have stated explicitly that there
beyond estimated day of delivery (289 [±2] days of gestation). Methods. Time to are no conflicts of interest in connection with delivery was related to presence of IGFBP-1 in cervical secretion, Bishop score and this article.
ultrasound measurement of cervical length recorded at inclusion. Main outcomemeasures. Spontaneous onset of labor and delivery within 3 days in the expectant Received: 5 May 2010 management, and delivery within 24 hours of induction in the induction group. Test Accepted: 26 September 2010 characteristics (sensitivity, specificity and negative and positive values and likeli- hood ratios) for IGFBP-1, Bishop score and cervical length were calculated. Logisticregression and Cox regression were used to account for parity and body mass in-dex. Results. With expectant management, IGFBP-1 predicted spontaneous laboronset and delivery within 72 hours with low sensitivity and high specificity (0.45and 0.80, respectively), as did Bishop score (0.24, 0.92). Cervical length was moresensitive (0.67, 0.58). IGFBP-1 predicted successful induction within 24 hours withlow sensitivity and high specificity (0.30, 0.85), such as Bishop score (0.06, 1.00)and cervical length (0.45, 0.76). Parity enhanced successful induction. Conclusion.
IGFBP-1 predicts both spontaneous labor onset and successful induction in post-term pregnancy. Bishop score and cervical length performed equally well.
of perinatal death (4). Clinical tools for prediction of time to delivery or the induction-to-delivery interval would in- Contradictory opinions exist regarding management of the deed be helpful in weighing the benefits and risks of different uncomplicated post-term pregnancy. It is a matter of debate whether to follow the development expectantly with serial A bedside test for phosphorylated isoforms of insulin- antenatal surveillance or to induce labor. Induction may in- like growth factor binding protein-1 (IGFBP-1) has been crease operative vaginal delivery rates, cesarean delivery rates suggested to predict success of labor induction (5).
and the incidence of excessive uterine activity with abnormal Phosphorylated isoforms of IGFBP-1, different from those fetal heart rate patterns (1–3). A Cochrane review recom- found in amniotic fluid, are produced by decidual cells and mends that induction of labor should be offered to low-risk are presented in the cervical secretion of women with intact women at 41 completed weeks, and thereby reduce the risk fetal membranes. When the cervix matures, the decidua and  2010 The AuthorsActa Obstetricia et Gynecologica Scandinavica c  2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 57–62
IGFBP-1 and post-term pregnancy M. D ¨ogl et al. chorion will detach, causing proteins to leak into the cer- The clinical trial was approved by the Committee for Med- vical canal (5). Studies of IGFBP-1 and cervical ripeness in ical Research Ethics of Health Region IV (19.06.02, 106-01), post-term pregnancies are lacking. In the clinical setting of Norway, and was registered in the Clinical Trial Registration post-term assessment, it would be useful to be able to predict (ClinicalTrials.gov, NCT00385229). Computerized random- imminent spontaneous onset of labor, or conversely identify ization without stratification was used.
cases where induction of labor will fail.
For the purpose of this study, we defined two cohorts. For The aim of this study was to compare the diagnostic per- parturients who were randomized to expectant management, formance of IGFBP-1 test with the Bishop score and vaginal we considered spontaneous onset of labor and delivery within ultrasound scanning, with respect to time to spontaneous 72 hours (3 days) as the outcome of interest. Among the onset of labor and delivery in expectant management, and induced parturients, we considered delivery within 24 hours the time to delivery interval with induction in post-term after induction. The diagnostic information of the IGFBP- 1 test, Bishop score and cervical length were related to theoutcome in these cohorts.
Material and methods Descriptive results are reported as median (range). Pear- son's chi-squared test was used to compare categorical out- This study originated from a randomized controlled trial of comes, and the Mann-Whitney U-test to analyze continuous post-term pregnancy management at St. Olav's University variables. The diagnostic performance of each procedure was Hospital between September 2002 and July 2004. In Nor- determined according to the usual definitions of sensitivity, way, pregnancies are dated by the 18-week ultrasound scan, specificity, positive and negative predictive value and likeli- and the duration of pregnancy is defined as 282 days. De- hood ratio (9). Mc Nemar's test was used for paired com- tailed information about inclusion criteria, induction meth- parison of test characteristics. Cases with missing values on ods and study design has been published elsewhere (6). In one or more item were excluded from the respective analyses.
brief, women were invited for a post-term follow-up 1 week A Kaplan-Meier plot with log-rank test was used to visualize after the estimated day of delivery (at 289 [±2] days of gesta- and assess the respective time courses. Logistic regression was tion). All participants were informed and gave written con- employed to investigate the impact of parity and body mass sent. Women were randomly allocated to either immediate index (BMI) with respect to spontaneous onset of labor and induction of labor (within 24 hours of randomization) or se- delivery within 72 hours. Cox regression analysis was used to rial antenatal monitoring every third day until spontaneous investigate the additional impact of parity and BMI regarding delivery. The study included women with singleton pregnan- induction to delivery. Cesarean section and delivery after 24 cies, fetus in cephalic presentation and no pre-labor rupture hours were considered censored.
of membranes. The study showed that both expectant man- No power analysis was performed for this study specifically.
agement and induction of labor led to equally good outcomes Regarding the precision of test characteristics (such as sensi- for the neonate as well as and the parturient.
tivity), the length of the confidence intervals varied between A cervical assessment was done at the time of randomiza- 0.10 and 0.20 given that approximately 50–100 observations tion, including IGFBP-1-test, transvaginal ultrasound mea- were available for analysis (Tables 2 and 4).
surements of the cervical length and a digital examination A p-values <0.05 were considered to indicate statistical to assess the Bishop score (7). For the IGFBP-1-test (Actim significance and all tests were two-tailed. SPSS (SPSS Inc., Partus Test, Medix Biochemica, Kauniainen, Finland), a cer- Chicago, IL, USA) version 15, and the statistical software R vical secretion sample was obtained using a sterile dacron were used for statistical analyses (10).
swab that was left in the cervix for 10–15 seconds. The swabwas swirled in a test extraction solution for 10 seconds, and a dipstick in the solution indicated positive test if two blue Baseline characteristics of the study population are shown lines appeared. The women were examined by transvaginal in Table 1. In the expectant management group, 59 (23%) ultrasound in the dorsal lithotomy position. Cervical length of 254 women were induced due to medical reasons, one was measured according to the method described by Valentinet al. (8). Cervical length <26 mm was considered a ‘short' Table 1. Baseline characteristics of the study population (n = 391).
When the cervix was unfavorable (Bishop score ≤5), 50-μg Caucasian (n, %) misoprostol was placed at 6-hourly intervals in the posterior Para 0 (n, %) Daily smoking (n, %) fornix for induction of labor. Dinoprostone 0.5 mg intracer- vically every 12 hours was used when the uterus was scarred.
Women who had a favorable cervix (Bishop score ≥6) wereinduced by amniotomy, followed by oxytocin infusion.
Note: SD, standard deviation; BMI, body mass index.
 2010 The Authors Acta Obstetricia et Gynecologica Scandinavica c  2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 57–62
M. D ¨ogl et al. IGFBP-1 and post-term pregnancy Figure 1. Expectant management group.
Kaplan-Meier curves showing the remaining
proportion of women in the monitoring groupwith spontaneous onset of labor delivering different hours after inclusion for positive and negative results of IGFBP-1 test.
woman declined to participate, two had cesarean delivery and versus 293 days (range 289–301) for women with a short and 19 were induced according to the protocol at gestational day long cervix, respectively (p = 0.002).
300. Thus, a cohort of 173 women was available for analysis Test characteristics with respect to spontaneous onset of of time to delivery, but as IGFBP-1 test results were missing labor and delivery within 72 hours of inclusion are shown in for seven women and Bishop score was missing in one, 166 Table 2. A positive IGFBP-1 test had higher sensitivity than the and 172 women were available for analysis. In the induction Bishop score (p = 0.007), but lower than cervical length mea- group, 35 (14%) women progressed to spontaneous labor surements (p < 0.001). The specificity for delivery within 72 before the scheduled appointment for induction, and one hours was highest for Bishop score ≥6 compared with IGFBP- woman had a cesarean delivery. Thus, a cohort of 218 women 1 and cervical length (p = 0.022 and p < 0.001, respectively).
was available for analysis of time to induced delivery, but as The specificity for positive IGFBP-1 was higher than for cer- IGFBP-1 test results were missing in nine women, the Bishop vical length <26 mm (p = 0.002) (Table 2). Analyzing women score in one and cervical length two women, 209, 217 and who were randomized to induction but proceeded to spon- 216 cases were available for analysis, respectively.
taneous labor before induction was actually done (data not In the expectant management group, 50 (30%) of 166 shown), led for all three assessment methods to a modest women had positive IGFBP-1 test results at inclusion. The improvement in sensitivity and positive predictive value, but median gestational age at delivery was 291 days (range unaltered specificity and a slightly lower negative predictive 287–297) for IGFBP-1 test positive women compared with value. In a stepwise logistic regression analysis, only IGFBP-1 293 days (range 289–301) for test negative IGFBP-1 women test and cervical length predicted spontaneous onset of labor (p < 0.001). The Kaplan-Meier plots of time to spontaneous and delivery within 72 hours; neither Bishop score, parity nor onset of labor and delivery after inclusion according to test BMI had significant impact (Table 3).
result are shown in Figure 1. Time to delivery was signifi- In the induction group, 59 (28%) of 209 women had posi- cantly shorter for women with a positive IGFBP-1 test result tive IGFBP-1 test results at inclusion. The median induction (log-rank test, p < 0.001).
to delivery time was 9 hours (range 2–59) for IGFBP-1 test In the expectant management group, 25 (15%) of 172 positive women compared with 13 (range 2–58) among the women had Bishop score ≥6 at inclusion. The median ges- negatives (p < 0.001). At inclusion 11 (5%) of 218, women tational age at delivery was 290 (range 288–297) versus 293 had Bishop score ≥6. The median induction to delivery time days (range 287–301) for women with Bishop score ≥6 and was 6 hours (range 2–17) versus 12 (range 3–59) for women ≤5, respectively (p = 0.001). Cervical length shorter than with Bishop score ≥6 and ≤5, respectively (p = 0.005). Cer- 26 mm at inclusion was found in 91 (53%) of 173 women.
vical length shorter than 26 mm was found in 93 (43%) of Median gestational age at delivery was 292 (range 287–298) 216 women at inclusion. Median induction to delivery time  2010 The AuthorsActa Obstetricia et Gynecologica Scandinavica c  2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 57–62
IGFBP-1 and post-term pregnancy M. D ¨ogl et al. Table 2. Spontaneous onset of labor and delivery with 72 hours in the expectant management group. Test characteristics for IGFBP-1 test, Bishop
Score and cervical length.
Length of cervix <26 mm Note: PPV: positive predictive value; NPV: negative predictive value; LR: likelihood ratio; PLR: positive likelihood ratio; NLR: negative likelihood ratio.
Table 3. Expectant management group. Parameter estimates and p-
IGFBP-1 test and cervical length <26 mm predicted earlier values from logistic regression analysis with respect to spontaneous onset delivery (Table 5). BMI did not contribute.
of labor and delivery within 72 hours.
Odds ratio estimate We found the IGFBP-1 test to be an independent predic- tor for successful induction within 24 hours in post-term pregnancies, performing equally well as cervical length and Bishop score, but with rather low sensitivity. In this popula- tion, we found high positive predictive values for induction to delivery within 24 hours with a positive IGFBP-1, sim- ilar to Bishop score ≥6 and cervical length <26 mm. The IGFBP-1 test was as good as Bishop score and cervical length in predicting induction to delivery in post-term pregnancies.
To predict spontaneous onset of labor and delivery within 3 days, the IGFBP-1 test was found to have low sensitivity and high specificity.
A possible limitation of the study is that separate parity was only considered in the multivariate models. We did indeedfind inducibility to be associated with parity, in accordancewith other studies, but parity was not associated with spon-taneous onset of labor and delivery within 72 hours. Werefrained from further sub-analyses (sensitivity etc.), as the was 11 hours (range 2–36) versus 12 (range 3–59) for women study was not stratified by design.
with a short and long cervix (p = 0.01). In the survival anal- Strengths of the study are the relatively large sample size, ysis, 37 women were censored, 20 because of delivery beyond uniform dating of pregnancy by ultrasound scan and that 24 hours and 17 because of cesarean section. There were three only a few persons were involved in the examination of the women with a positive IGFBP-1 test in each of these groups.
participants (85% of the examinations were done by Runa Kaplan-Meier plots of the time from induction to delivery ac- cording to test results are shown in Figure 2. Time to delivery The IGFBP-1 test is quick and easy to use and may be was significantly shorter for women with a positive IGFBP-1 less uncomfortable for the women compared with traditional test result (log-rank test, p < 0.001).
methods such as the Bishop score or transvaginal ultrasound.
Test characteristics for induction to delivery within 24 It is, however, doubtful whether a new test could be recom- hours are given in Table 4. The most sensitive test for predict- mended on economic considerations, as the test implies more ing delivery within 24 hours was cervical length <26 mm, expenses without adding further information.
compared with IGFBP-1 test and Bishop score (p = 0.005, In the clinical setting of post-term follow-up, the abil- p < 0.001). A positive IGFBP-1 test was more sensitive for ity to predict spontaneous onset of labor within 72 hours delivery within 24 hours than Bishop score ≥6 (p < 0.001).
is warranted. Our findings of positive predictive values of The Cox regression analysis of time to delivery after in- Bishop score and cervical length are in agreement with the duction showed that multiparity, Bishop score ≥6, positive study of Rozenberg et al. However, their study was based on a  2010 The Authors Acta Obstetricia et Gynecologica Scandinavica c  2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 57–62
M. D ¨ogl et al. IGFBP-1 and post-term pregnancy Proportion of women not delivered 0,2 Figure 2. Induction group. Kaplan-Meier
curves showing the remaining proportion of
women in the induction group not deliveredwithin 24 hours according to IGFBP-1 test.
Cases with Cesarean section and delivery >24 Induction-to-delivery time (hours) hours were censored.
population of gestational week 39–40, and their predictive Vankayaalapati et al. found cervical length to be a significant cutoff was 7 days (11).
independent predictor in nulliparous women (14).
We found short cervical length, a high Bishop score and The results of this study are in accordance with the study of a positive IGFBP-1 test to be associated with a lower ges- Rane et al. in which cervical length, Bishop score and parity tational age at delivery, but only short cervical length and were found to be independent predictors of delivery within positive IGFBP-1 test were associated with spontaneous on- 24 hours after induction in prolonged pregnancies (15). Pan- set of labor. The comparative literature is conflicting. Both dis et al. found that parity, cervical length and Bishop score cervical length and Bishop score have been found to predict provided independent information with respect to delivery time to spontaneous onset of labor in prolonged pregnancies within 24 hours of induction, using multivariable Cox re- (12,13). Strobel et al. found Bishop score and cervical length gression analysis (16). Their study included women with to predict spontaneous onset of labor both within 24 hours pregnancies from 37 to 42 weeks of gestation and not only and 48 hours. Within 96 hours, only the Bishop score was found to be an independent predictor in nulliparous women.
In conclusion, the IGFBP-1 test could be used to as- In parous women, neither Bishop score nor cervical length sess inducibility, but compared to established procedures could be used to predict onset of labor within 96 hours (13).
as Bishop score and vaginal ultrasound measurements of Table 4. Test characteristics for IGFBP-1 test, Bishop Score and cervical length for induction to delivery within 24 hours.
Bishop score ≥6 Length of cervix <26 mm Note: PPV: positive predictive value; NPV: negative predictive value; LR: likelihood ratio; PLR: positive likelihood ratio; NLR: negative likelihood ratio;NA: not available.
 2010 The AuthorsActa Obstetricia et Gynecologica Scandinavica c  2010 Nordic Federation of Societies of Obstetrics and Gynecology 90 (2011) 57–62
IGFBP-1 and post-term pregnancy M. D ¨ogl et al. Table 5. Cox regression analysis of time to vaginal delivery within from
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