|ORIGINAL CONTRIBUTION: NEWER PREDICTIVE MARKERS IN OBSTETRICS
|Year : 2014 | Volume
| Issue : 1 | Page : 17-22
Role of phosphorylated insulin-like growth factor-binding protein-1 and cervical length measurements in predicting pre-term delivery
Nivedita Sarda1, Seema Singhal1, Niharika Dhiman2, Kusum Dogra1, Archana Agarwal3
1 Department of Obstetrics and Gynaecology, Safdarjung Hospital and Vardhman Mahavir Medical College, New Delhi, India
2 Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Rishikesh, Dehradun, Uttarakhand, India
3 Department of Diagnostic Radiology, Safdarjung Hospital and Vardhman Mahavir Medical College, New Delhi, India
|Date of Web Publication||3-May-2014|
Dr. Seema Singhal
E2, Ansari Nagar (West) AIIMS Campus, New Delhi
Source of Support: None, Conflict of Interest: None
Preterm birth is the leading cause of perinatal morbidity and mortality. It is of great clinical importance to find markers that could help in identifying women with threatened pre-term labor who have the highest risk of pre-term delivery and who might benefit from timely admission. The objective of the present study was to evaluate the use of cervical phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) in the prediction of pre-term delivery and to assess its association with cervical length measured by trans vaginal sonography (TVS), as a predictive diagnostic test.
We enrolled 100 women between 20 and 35 weeks of gestation. Fifty subjects who had presented with symptoms of pre-term labor were recruited as Group A and another 50 with risk factors for pre-term birth but with no symptoms at the time of presentation as Group B. All the participants were subjected to cervical length measurement and rapid bed side test to detect phIGFBP-1 in cervicovaginal secretions.
Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of both tests were calculated and compared in terms of period of gestation at delivery and time lapse between test and delivery. Qualitative data were analyzed by using Chi-square test and Fisher's exact test, whereas quantitative data were analyzed by using unpaired Student's t test and Mann-Whitney test. P value < 0.05 was considered significant.
In the symptomatic group, sensitivity, specificity, PPV, and NPV of phIGFBP-1 in predicting delivery within 48 h, 7 days, 14 days, and preterm delivery (≤37 weeks) was 100%, 100%, 100%, and 76% (sensitivity), 52.6%, 60.6%, 62.5%, and 56% (specificity), 40%, 56.7%, 60%, and 63% (PPV) 100%, 100%, 100%, and 70% (NPV), respectively. Sensitivity, specificity, PPV, and NPV of cervical length in predicting pre-term delivery in symptomatic group was 20%, 96%, 83.3%, and 54.5%, respectively. In the asymptomatic group, sensitivity, specificity, PPV, and NPV of phIGFBP-1 in predicting pre-term delivery was 0%, 87.5%, 0%, and 77.8% and that of cervical length was 0%, 95%, 0%, and 79.2%, respectively.
The results of the present study suggest that phIGFBP-1 has high NPV for prediction of pre-term labor. Pre-term birth is very unlikely if the results of both tests, that is, phIGFBP-1 and cervical measurements are negative and therefore it could be of value in reduction of maternal morbidity by preventing unnecessary interventions.
Keywords: Preterm delivery, rapid phIGFBP-1 test, ultrasonographic cervical length
|How to cite this article:|
Sarda N, Singhal S, Dhiman N, Dogra K, Agarwal A. Role of phosphorylated insulin-like growth factor-binding protein-1 and cervical length measurements in predicting pre-term delivery. Astrocyte 2014;1:17-22
|How to cite this URL:|
Sarda N, Singhal S, Dhiman N, Dogra K, Agarwal A. Role of phosphorylated insulin-like growth factor-binding protein-1 and cervical length measurements in predicting pre-term delivery. Astrocyte [serial online] 2014 [cited 2023 Oct 4];1:17-22. Available from: http://www.astrocyte.in/text.asp?2014/1/1/17/131857
| Introduction|| |
Pre-term birth is the leading cause of perinatal morbidity and mortality.  Despite advances in perinatal care, the incidence of pre-term birth continues to rise, primarily due to increased multiple pregnancies as a result of assisted reproduction.  Also, several women such as those who have had a prior pre-term birth are considered to be at increased risk for pre-term delivery in a subsequent pregnancy. Although designated as "high risk," most of these women do not deliver prematurely in subsequent pregnancies.  At present there is no standard prenatal management of this population and, without an accurate method for estimating the recurrence of preterm birth, unnecessary interventions will continue to be performed. It would be of great clinical importance to find markers that could help in identifying pregnant women with threatened pre-term labor who have the highest risk of pre-term delivery and who might benefit from timely admission and appropriate treatment. 
A diagnostic test for predicting pre-term birth has been sought for decades, but none of those available appear to be sufficiently sensitive or specific.  Biochemical and biophysical techniques can be employed for the prediction of pre-term delivery.  Assessment of cervical length by transvaginal sonography is the most extensively studied marker. Studies have found sensitivities ranging from 68% to 100% and specificities from 44% to 79%.  Trans vaginal sonography (TVS), however, is limited by the need for skilled operators and advanced ultrasound equipment. Over the past decade, detection of various biochemical markers has been primarily investigated as potential diagnostic tools of pre-term labor.
The accuracy of phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) has recently been evaluated as a biomarker in the prediction of pre-term delivery.  IGFBP-1 is a subgroup of proteins of insulin-like growth system, and constitutes one of the major proteins of human deciduas. The function of this protein is in the control mechanism of fetal, placental growth, and development. Isolating a highly phosphorylated isoform of IGFBP-1 that is absent from amniotic fluid but released from deciduas to cervical canal can be determined by using unique antibodies. The identification of phIGFBP-1 would thus be indicative of the occurrence of labor process and predictive of pre-term delivery. Vaginal identification of phIGFBP-1 has been proposed as an option in predicting pre-term delivery in symptomatic patients. ,,
A rapid bed side test kit is available to detect phIGFBP-1 in the cervicovaginal secretions above the level of 10 μg/L. , This test is simple, easy to perform, does not need too much of skill and therefore can be used at places where optimum care for premature neonates are not available and therefore timely transfer of women with actual risk for pre-term delivery is likely to improve the outcome. Further studies are needed to explore the use of this test in pregnant women presenting with threatened pre-term labor.
In present study, we evaluated ph1GFBP-1 bedside rapid test in pregnant women presenting with threatened pre-term labor for predicting pre-term labor in symptomatic and asymptomatic patients. The objective of this study was to evaluate the use of cervical phIGFBP-1 in the prediction of pre-term delivery and to assess its association with cervical length as measured by transvaginal scan, as a predictive diagnostic test.
| Material and Methods|| |
A prospective observational study was conducted and a total of 100 subjects were recruited. In the present study, 50 pregnant women with a period of gestation between 20 and 35 weeks, who presented with symptoms of pre-term labor, such as pelvic pressure, low abdominal cramps, uterine contraction, and discharge per vaginum were recruited as Group A. Another 50 pregnant women attending antenatal outpatient department between gestational age of 20 and 35 weeks having a high-risk factor for pre-term birth, such as multiple pregnancy, history of pre-term birth or second trimester abortion but had no symptoms of pre-term labor at the time of presentation were recruited as Group B. Women who were in active pre-term labor were excluded from the study. Pre-term labor was defined as the presence of uterine contractions of sufficient frequency and intensity to effect progressive effacement and dilation of the cervix prior to 24-37 weeks gestation. Hence women who had presented with symptoms of pre-term labor, premature rupture of membranes, cervical dilatation > 3 cm, excessive bleeding per vaginum, other maternal and fetal indications requiring termination of pregnancy such as intrauterine growth retardation, lethal congenital malformations, and severe pre-eclampsia were also excluded from the study.
An informed consent was obtained from all the participants. Gestational age was calculated from last menstrual period and first trimester ultrasound. A detailed history, general physical examination, and per abdomen examination were done. Cervix was then exposed by bivalve speculum. Swab was held in endocervix for 10-15 s. Sample was then extracted into specimen extraction buffer; swab was stirred in buffer for 10 s. Test dip stick was dipped into buffer tube, until liquid reached the result area. Dip stick was then taken out, held in horizontal position, and read after 5 min. Two lines, that is, one test line and one control line were interpreted as positive result. One distinct line, that is, one control line was interpreted as negative result. Absence of distinct control line meant invalid result. Cervical length was assessed by TVS with 5 MHz vaginal probe transducer. The cervical length was measured by the distance between the upper and the lower ends of the closed segment of the endocervical canal. The cervical length less than 25 mm was used as a cutoff point for predicting pre-term delivery, which represents the 10th percentile of cervical length measurement.
Both subjects and treating obstetrician were blinded to the result of the tests, and the treatment was given as per hospital protocol. All the patients in symptomatic group were admitted in the hospital and were administered betamethasone and tocolytic medications if indicated as per hospital protocol. All the patients were followed up to delivery. Time from test to delivery was noted whether it was within 48 h or 3-7 days or 8-14 days or >14 days. A note was made of gestational age at delivery. Test result and pre-term delivery were co-related with cervical length (similar protocol was followed for both the groups). Qualitative data were analyzed by using Chi-square test and Fisher's exact test, whereas quantitative data were analyzed by using unpaired Student's t test and Mann-Whitney test. Positive predictive value (PPV) and negative predictive value (NPV) of both the tests were calculated and compared in terms of period of gestation at delivery and time lapse between test and delivery. P value < 0.05 was considered significant. SPSS statistical software version 12.0 was used for data analysis.
| Results|| |
General characteristics of participants were comparable in both the groups [Table 1]. In asymptomatic high-risk group, 70% of women had previous history of second trimester abortion and 30% had a history of previous pre-term labor.
|Table 1: Comparison of Obstetric Variables in Symptomatic (Group A) and Asymptomatic (Group B) Groups|
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Efficacy of phIGFB-1 in Predicting the Risk
In the symptomatic group, 30 women out of 50 had positive phIGFBP-1 results. Forty percent of those with positive test result (n=12/30) delivered within 48 h and 56.6% (n=17/30) delivered within 7 days. Sixty percent (18/30) of women with positive test delivered within 14 days and 40% (12/30) delivered after 14 days. Twenty women out of 50 in the symptomatic group had negative phIGFB-1 and none of them delivered within 14 days. In the symptomatic group, the number of patients delivering pre-term, that is, ≤37 weeks of gestation and patients delivering at term, that is, >37 weeks of gestation was also observed. A 63.33% (n=19/30) of women with positive test result and 30% (n=6/20) of patients with a negative test result delivered pre-term. On the other hand, 11/30 women with positive test result and 14/20 with negative result delivered after 37 weeks of gestation. Sensitivity, specificity, PPV, and NPV of phIGFBP-1 in the symptomatic group for predicting the risk of delivery within 48 h, 7 days, 14 days, and within 37 weeks was then calculated [Table 2] and [Table 3]. In asymptomatic high-risk group, the test results of phIGFBP-1 were positive in only five patients, whereas 45 (90%) had a negative test result. However, all the women in the asymptomatic group whether positive or negative for the test, delivered >14 days after the test; therefore no statistics could be computed.
|Table 2: Efficacy of phIGFBP-1 in Predicting Delivery in Symptomatic Group|
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|Table 3: Efficacy of PhIGFBP-1 in Predicting Pre-term Delivery (≤37 Weeks in Symptomatic vs Asymptomatic High-risk Group|
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Efficacy of Cervical Length in Predicting the Risk
Mean cervical length in symptomatic group (Group-A) was 36.554±4.43 mm. Thirty-four (68%) patients had cervical length > 35mm. Ten patients (20%) had cervical length 26-35 mm and six women (12%) had cervical length ≤ 25mm. Out of six patients with cervical length ≤ 25 mm, five patients (83.3%) delivered within 14 days, whereas out of 44 patients with cervical length > 25 mm 34 patients (72.7%) delivered after 14 days. Efficacy of cervical length in predicting the risk of pre-term delivery was also analyzed. Five out of six (83.3%) patients with cervical length ≤25 mm delivered pre-term. Out of 44 patients having cervical length > 25 mm, 54.5% (n=24/44) patients delivered at term and 20 (45.4%) delivered pre-term.
In asymptomatic high-risk group (Group B), the mean cervical length was 37.230±4.9mm. Only two (4%) patients in the asymptomatic high-risk group had cervical length ≤ 25 mm and both delivered after 14 days. Out of 48 women with cervical length > 25 mm, 42 women (87.5%) delivered after 14 days. On considering the period of gestation, only two (4%) had cervical length ≤ 25 mm and all of them delivered at term. Forty-eight women had cervical length > 25 mm and 38 of them (79.2%) delivered at term and 20.8% (n=10) delivered pre-term. Statistical significance of cervical length for predicting the risk of delivery within 48 h, 7 days, 14 days, and within 37 weeks was also calculated [Table 4] and [Table 5]. In the symptomatic group, cervical length < 25 mm is very specific and PPV of the test in predicting pre-term delivery is very high 83.3%. When cervical length findings were combined with phIGFBP-1, NPV increased significantly [Table 6]. Cervical length < 25mm had high NPV in asymptomatic high-risk women (79.2%). When cervical length is combined with phIGFBP-1, it does not increase the NPV in predicting pre-term delivery (<37 weeks), although there is a slight increase in the likelihood ratio (LR) of the test. The findings were statistically insignificant [Table 6] and [Table 7].
|Table 4: Efficacy of Cervical Length in Predicting Delivery within 14 Days|
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|Table 5: Efficacy of Cervical Length in Predicting Delivery Before 37 Weeks|
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|Table 6: Co-relation Between Cervical Length and phIGFBP-1 in Predicting Pre-term Labor in Symptomatic Group|
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|Table 7: Co-relation Between Cervical Length and phIGFBP-1, in Predicting Pre-term Labor in Asymptomatic High-risk Group|
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| Discussion|| |
The results of the present study suggest that phIGFBP-1 had a high NPV for prediction of pre-term labor and therefore it could be of value in reduction of maternal morbidity by preventing unnecessary interventions. The main clinical value of the present study is that pre-term birth is very unlikely if the results of both the tests, that is, phIGFBP-1 and cervical measurements, are negative. This may help to avoid unnecessary transfer, hospitalization, and treatment of women with false pre-term labor.
The results of the present study were consistent with the study conducted by Akercan et al who showed that phIGFBP-1 in cervical secretions is of value in predicting delivery in patients with signs and symptoms of pre-term labor and that its absence provides reassurance that pregnancy is not in danger of pre-term delivery.  In their study, sensitivity, specificity, PPV, and NPV were 78%, 87%, 73%, and 90%, respectively. Almost all patients with negative results in asymptomatic control group delivered after 37 weeks of gestation as in the present study. Similarly, another study reported sensitivity, specificity, PPV, and NPV of rapid phIGFBP-1 for predicting pre-term delivery as 89.9%, 94.1%, 94.4%, and 88.9%. Positive LR for delivery at <37 weeks was 15.2 (95% confidence interval 2.6-102.5).  This study also reported sensitivity, specificity, PPV, and NPV of phIGFBP-1 in predicting delivery within 1 week as 93.8%, 85%, 83.3%, and 94.1%. Authors concluded that a patient who had positive phIGFBP-1 in cervical secretions had six times more chances to deliver within a week than a patient with negative test results. However, our study had different study design, population group, and sample size. All these differences could lead to the difference in NPV of the present study. One prospective study compared 63 symptomatic and 58 asymptomatic women between 22 and 36 weeks gestational age and reported an increased risk of pre-term delivery in women with positive phIGFBP-1 test results in cervical secretions. 
Cervical length < 25 mm has been found to have the best predictive accuracy in various studies. In a well-designed blinded multicenter observational study, 15 women with prior pre-term birth at less than 32 weeks, serial measurement of cervical length by TVS had a good prediction of pre-term birth before 35 weeks of gestation.  With this method and using cervical length cutoff as 25 mm, the sensitivity, specificity, and PPV of abnormal test were 69%, 80%, and 55%, respectively. The accuracy of cervical measurements also depends on the gestational age. Thus in women with clinical risk factors for pre-term birth, the PPV for pre-term birth of a cervical length < 25mm at 14-18 weeks is 70%, whereas it drops to 40% when the abnormal test is found between 18 and 20 weeks.  Rahkonen et al evaluated the performance of cervical phIGFBP-1 testing and cervical length measurement in the prediction of pre-term birth among 246 patients with self-reported uterine contractions and intact membranes.  The overall rate of spontaneous pre-term delivery ≤ 34 weeks was 4.1%. Short cervix, positive phIGFBP-1, combination of both and clinician's judgment were all associated with pre-term delivery ≤ 34 weeks or within 14 days (P < 0.01). The NPVs for delivery ≤ 34 weeks were 97.4, 97.6, 97.1, and 98.7%, respectively, and within 14 days was 9.7, 5.5, 107.3, and 17.1, respectively. The negative LRs were 0.6, 0.6, 0.7, 0.3 and 0.5, 0.3, 0.6, 0.2. The authors concluded that the rapid phIGFBP-1 test has a high NPV for pre term delivery, comparable to that of ultrasonographic cervical length measurement.
Another study where cervical length was measured using TVS at 22-24 weeks of gestation in 105 singleton pregnancies and a rapid strip test was performed to detect phIGFBP-1 in cervical secretions from 24-34 weeks. Women with cervical length less than 20 mm had a risk of spontaneous pre term delivery before 34 and 37 weeks of 43.5% and 69.6% respectively. The performance of phIGFBP-1 levels as a predictor of pre term delivery was significantly higher when the test was carried out at 30 weeks gestation. Cervical assessment in combination with phIGFBP-1 at 30 weeks had the steepest ROC curve (area under the curve=0.93; 95% CI, 0.88-0.98, p<0.001) Authors concluded that both cervical length and phIGFBP-1measurement are useful in the prediction of pre term delivery in patients with history of pre-term birth and the combined method was better than either method used alone. 
In 2010 a prospective observational was conducted to evaluate the efficacy of combining phIGFBP-1 and trans vaginal cervical length and compared this with either method used alone in predicting pre term labor. A much higher NPV, PPV, specificity of the combination test was seen compared with phIGFBP-1 or cervical length alone (NPV: 97.8% vs 97.7% vs 97.1%, PPV: 80.0% vs 51.1% and cervical length 23.5%; Specificity 97.8% vs 93.5%vs 71.1% respectively) The cervical dilatation 2 cm with combined positive test indicated a higher likelihood of pre term labor (P = 0.001). 
The test phIGFBP-1 has a high efficacy to predict delivery <34 weeks among women with signs and symptoms of pre-term labor, the high NPV of this test to predict the pre-term labor <34 weeks gestation as well as within 7 days of delivery may be of value in the reassurance of patients, avoiding unnecessary medical interventions. For deliveries <34 weeks gestation, the test had a sensitivity, specificity, PPVs, NPVs, and positive LRs and negative LRs of 70%, 74%, 48%, 88, 2.8, and 0.39, respectively.  In a retrospective study that was done to evaluate the role of phIGFBP-1 in 40 patients with twin pregnancies to predict the risk of pre-term delivery, a total of 95% of women were screened negative for the test. None of the women delivered before 30 weeks, 7.50% delivered between 30 and 33+6 weeks, and 87.5% delivered after 34 weeks. Two women (50%) were screened positive for phIGFBP-1 test; one of them had a spontaneous pre-term delivery at 30 weeks, whereas the other patient delivered at 38 weeks. It was concluded that women with twin pregnancies that have negative phIGFBP-1 have a low risk of delivery before 34 weeks in absence of other obstetric complications. Hence correlating with literature the high NPV of phIGFBP-1 may be of great importance in predicting the risk of pre-term delivery and thus avoiding overtreatment of patients with uterine contractions. 
| Conclusion|| |
Cervical phIGFBP-1 alone is a useful tool for predicting women who are at risk for pre-term delivery before 32-34 weeks and within 48 hours and 7 days of assessment. It is a simple, easy, rapid, safe, and valuable method for predicting pre-term labor and holds the promise in identifying those symptomatic women who are least likely to deliver prematurely and thus has the potential to reduce unnecessary treatment and health care burden. This one step rapid dip stick test can be done by clinicians, nurses, or laboratory technicians in both urban and rural settings. If facilities available, this can be combined with measurement of cervical length and this will further increase the NPV and LR in predicting pre-term delivery in symptomatic women.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]