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Keywords:

  • cervical length;
  • cervical phosphorylated insulin-like growth factor-binding protein-1;
  • preterm delivery;
  • transvaginal cervical ultrasonography

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Objective

To evaluate the efficacy of cervical length measurement in combination with a bedside assessment of phosphorylated insulin-like growth factor-binding protein-1 (phIGFBP-1) as a predictor of preterm delivery in asymptomatic pregnant women with a history of preterm birth.

Methods

Cervical length was measured using transvaginal sonography 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 to 34 weeks. Receiver–operating characteristics (ROC) curves were constructed to compare the performance of phIGFBP-1 at different gestational ages, and cervical length at 22–24 weeks, in predicting preterm delivery.

Results

The rate of spontaneous delivery before 37 and 34 weeks was 23.8% and 11.4%, respectively. Women with cervical lengths less than 20 mm had a risk of spontaneous preterm delivery before 34 and 37 weeks of 43.5% and 69.6%, respectively. The performance of phIGFBP-1 levels as a predictor of preterm 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).

Conclusion

Both cervical length and phIGFBP-1 measurement are useful in the prediction of preterm delivery in patients with a history of preterm birth and the combined method of measuring cervical length at 22–24 weeks and phIGFBP-1 at 30 weeks improves upon either method used alone. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Preterm delivery is a leading cause of neonatal morbidity and mortality. Early preterm delivery, before 32 weeks' gestation, is associated with a high risk of neonatal death or severe handicap1, 2. The incidence of preterm birth at our tertiary hospital in the last few years has remained at around 22.5%, and half of these preterm deliveries result from spontaneous preterm labor3.

Women who have had a prior preterm birth are considered to be at increased risk for preterm delivery in a subsequent pregnancy. However, although designated as ‘high risk’, most of these women do not deliver prematurely in subsequent pregnancies4. 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.

Biochemical and biophysical techniques can be employed for the prediction of preterm delivery. The use of fetal fibronectin levels and cervical length as measured by transvaginal ultrasound examination has been widely described in the prediction of preterm birth5–10. Recent studies have looked at levels of the phosphorylated insulin-like growth factor-binding protein-1 (phIGFBP-1), a protein secreted by decidual cells, which leaks into cervical secretions when fetal membranes detach from the decidua before the onset of labor11. Vaginal identification of phIGFBP-1 has been proposed as an option in predicting preterm delivery in symptomatic patients12–15.

The aim of this study was to assess the efficacy of bedside assessment of phIGFBP-1 in combination with cervical-length measurement as a predictor of preterm delivery in asymptomatic pregnant women with a history of preterm birth.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

This study was carried out in the Hospital das Clinicas, in São Paulo, Brazil. Permission was obtained from the Ethical Commission of the Obstetric Clinic and a written consent form was signed after detailed information had been given to every patient selected for the study.

Among the patients who sought prenatal care at our center between May 2001 and April 2003, we evaluated 127 asymptomatic pregnant women (i.e. women with no symptoms of possible preterm labor) with a history of at least one previous spontaneous preterm delivery before 37 weeks' (< 259 days) gestation. Patients with multiple pregnancies, a clinical history of cervical incompetence, previous cervical surgery and previous preterm labor in the current pregnancy were not included in the study. Gestational age was calculated on the basis of the last menstrual period and by ultrasound examination (up to 12 weeks). Nine women were lost to follow-up, and therapeutic premature deliveries were performed in 13 women, thus 105 completed the study. In all patients, microscopic examination of cervicovaginal secretions and culture for Trichomonas vaginalis, Candida albicans, Gardnerella vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, and group B Streptococcus were performed at the first prenatal consultation. Patients with positive cultures were treated with specific antibiotics and examination cultures were performed to confirm cure.

At the second-trimester ultrasound examination, women had been given the option of cervical assessment by transvaginal ultrasound examination. Those who consented were asked to empty their bladders and were placed in the dorsal lithotomy position. The ultrasound probe was inserted into the vagina and placed at the anterior fornix, and the cervical length was measured as previously described16, 17. Management of the pregnancies was not influenced by the ultrasound findings and all doctors performing cervical measurements had certification for cervical assessment by The Fetal Medicine Foundation, London.

A rapid strip test (Actim Partus Test; Medix Biochemica, Kauniainen, Finland) was performed to detect phIGFBP-1 in cervical secretions every 3 weeks from 24 to 34 weeks of gestation. At sampling all patients had intact membranes and no vaginal bleeding. The patients reportedly maintained sexual abstinence for 48 hours prior to sampling.

After a sterile speculum had been inserted into the vagina, a dacron swab was applied to the external cervix for 10–15 s in order to absorb cervical secretions. The swab was placed in a test tube and rinsed in buffer solution for approximately 15 s. The buffer solution contained sodium phosphate, sodium chloride, EDTA, Tween®-20, bovine serum albumin, aprotinin and proclin 300. The swab was then withdrawn and the dipstick was placed into the tube. The lower end of the dipstick was kept in the solution until the liquid front entered the reaction area. After 20 s the dipstick was removed and placed on a surface in a horizontal position. A positive result appeared in 5 min as two blue lines on the dipstick, and a negative result as a single blue line. If no line was seen, a new sample was taken. A result for a given patient was assumed to be positive when phIGFBP-1 was detected in at least one of the samples. The technology of rapid testing is based on immunochromatography, where phosphorylated anti-phIGFBP-1 adheres to latex particles during migration.

Statistical analysis

The clinical relevance of phIGFBP-1 findings in cervical secretions was determined as it correlated with the evolution of pregnancy to preterm delivery. Logistic regression analysis was used to investigate the performance of testing phIGFBP-1 levels in cervical secretions in combination with cervical length measurement as a predictor of spontaneous delivery for this high-risk group. Multiple logistic regression analysis was subsequently performed to determine the significant independent contribution of those variables yielding a P-value of < 0.05. Receiver–operating characteristics (ROC) curves were constructed and the area under the curve (AUC) was used to compare the predictive value of phIGFBP-1 at different gestational ages, and cervical length at 22–24 weeks, in predicting spontaneous preterm delivery at ≤34 weeks' gestation. All statistical analyses were performed using MedCalc (Version 8.0.0.1 MedCalc Software, Mariakerke, Germany).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

One hundred and five singleton pregnant women were identified and followed up. The rate of spontaneous delivery before 37 and 34 weeks was 23.8% (25/105) and 11.4% (12/105), respectively. The mean gestational age at delivery was 38 ± 2 weeks. The median maternal age was 28 ± 5.0 years. Tables 1 and 2 show the rate of spontaneous preterm birth related to clinical and obstetric history, cervical length and phIGFBP-1. No difference was observed in the number of previous preterm births or maternal demographic characteristics between groups that delivered at term or prematurely. Table 3 shows the positive predictive value for spontaneous preterm birth related to cervical length and phIGFBP-1. The rate of preterm delivery was significantly higher for women with a short cervix (< 20 mm) and who were phIGFBP-1-positive, than in women with a long cervix who were phIGFBP-1-negative.

Table 1. Demographic details and rate of spontaneous preterm delivery at ≤34 weeks and < 37 weeks' gestation
Characteristicn (%)Delivery at ≤ 34 weeks (n = 12) (n (%))Delivery at < 37 weeks (n = 25) (n (%))
Ethnicity
 Non-white44 (41.9)6/44 (13.6)12/44 (27.3)
 White61 (58.1)6/61 (9.8)13/61 (21.3)
Age (years)
 ≤ 183 (2.9)1/3 (33.3)2/3 (66.7)
 19–3494 (89.5)11/94 (11.7)23/94 (24.5)
 ≥ 358 (7.6)0/8 (–)0/8 (–)
Prior spontaneous preterm birth
 One41 (39.0)5/41 (12.2)10/41 (24.4)
 Two49 (46.7)6/49 (12.2)11/49 (22.4)
 ≥ Three15 (14.3)1/15 (6.7)4/15 (26.7)
Table 2. Positive predictive value for spontaneous preterm birth among patients with previous history of preterm delivery according to different screening tests and different cut-offs
Screening testRate of occurrence (n (%))Delivery at ≤ 34 weeks (n = 12) (n (%))Delivery at < 37 weeks (n = 25) (n (%))
  1. CL, cervical length; phIGFBP-1, phosphorylated insulin-like growth factor-binding protein-1.

CL at 22–24 weeks
 < 20 mm23/105 (21.9)10/23 (43.5)16/23 (69.6)
 21–25 mm24/105 (22.9)3/24 (12.5)
 > 25 mm58/105 (55.2)2/58 (3.4)6/58 (10.3)
Positive phIGFBP-1
 at 24–26 weeks8/105 (7.6)1/8 (12.5)1/8 (12.5)
 at 27–29 weeks18/105 (17.1)5/18 (27.8)8/18 (44.4)
 at 30–31 weeks22/104 (21.1)10/22 (45.5)13/22 (59.1)
 at 32–34 weeks18/104 (17.3)10/18 (55.6)12/18 (66.7)
Table 3. Positive predictive value for spontaneous preterm birth in patients with a previous history of preterm delivery, combining cervical length of < 20 mm at 24 weeks and phosphorylated insulin-like growth factor-binding protein-1 at 24, 28 and 30 weeks
Screening testn (%)Delivery at ≤ 34 weeks (n (%))Delivery at < 37 weeks (n (%))
24 weeks
 Both negative75/105 (71.4)2/75 (2.7)9/75 (12.0)
 One positive28/105 (26.7)9/27 (33.3)15/27 (55.6)
 Both positive2/105 (1.9)1/2 (50.0)1/2 (50.0)
 P < 0.0001< 0.0001
28 weeks
 Both negative72/105 (68.6)1/72 (1.4)7/72 (9.7)
 One positive24/105 (22.9)7/24 (29.2)12/24 (50.0)
 Both positive9/105 (8.6)4/9 (44.4)6/9 (66.7)
 P < 0.0001< 0.0001
30 weeks
 Both negative72/104 (69.2)5/72 (6.9)
 One positive19/104 (18.3)4/19 (21.1)10/19 (52.6)
 Both positive13/104 (12.5)8/13 (61.5)10/13 (76.9)
 P < 0.0001< 0.0001

The median cervical length at 24 weeks was 27 ± 8 mm. The 10th and 5th centiles of cervical length were 16 mm and 13 mm, respectively. Cervical length < 20 mm had a positive predictive value (PPV) for spontaneous delivery before 34 and 37 weeks of 43.5% (10/23) and 69.6% (16/23), respectively. A cervical length of > 20 mm was associated with a PPV of just 3.5% for spontaneous delivery before 34 weeks.

Cervical length < 20 mm had a sensitivity for the detection of preterm birth before 34 and 37 weeks of 83.3% (10/12) and 64% (16/25), respectively. Furthermore, there was a significant positive correlation between cervical length and neonatal birth weight. Birth weight among patients with cervical lengths < 20 mm and > 20 mm were 2350 ± 502 g and 3004 ± 328 g, respectively (P < 0.0001). Table 4 shows the logistic regression analyses for cervical length at 22–24 weeks, and phIGFBP-1 at 24, 27, 30 and 34 weeks of gestation.

Table 4. Univariate and multivariate analysis in the prediction of spontaneous preterm delivery at ≤ 34 weeks and < 37 weeks of gestation for cervical length (CL) at 22–24 weeks and phosphorylated insulin-like growth factor-binding protein-1 at 24, 27, 30 and 34 weeks
VariableUnivariate analysisMultivariate analysis
Delivery at ≤ 34 weeksDelivery at < 37 weeksDelivery at ≤ 34 weeksDelivery at < 37 weeks
OR (95% CI)POR (95% CI)POR (95% CI)POR (95% CI)P
  1. OR, odds ratio.

CL at 22–24 weeks0.87 (0.76–1.0)0.050.88 (0.81–0.96)0.0050.87 (0.77–0.99)0.0020.89 (0.82–0.96)0.005
phIGFBP-1 at 24 weeks0.43 (0.02–9.34)0.590.12 (0.005–2.95)0.194
phIGFBP-1 at 27 weeks0.25 (0.25–2.51)0.240.48 (0.05–4.14)0.48
phIGFBP-1 at 30 weeks60.5 (4.50–814.0)0.0027.41 (1.40–39.0)0.01816.3 (2.89–92.68)0.0365.9 (1.8–19.7)0.003
phIGFBP-1 at 34 weeks1.73 (0.30–13.6)0.604.30 (0.92–20.1)0.064

The ROC curves comparing the performance of phIGFBP-1 at different gestational ages in the prediction of spontaneous preterm delivery are shown in Figure 1. The performance of phIGFBP-1 was significantly better when levels were tested at 30 weeks (AUC for phIGFBP-1 performed at 24 weeks: 0.50 (range, 0.32–0.69); at 27 weeks: 0.65 (range, 0.46–0.84); at 30 weeks: 0.89 (range, 0.78–0.99); and at 34 weeks: 0.75 (range, 0.58–0.93)). A positive phIGFBP-1 result at 30 weeks' gestation had a detection rate for delivery at ≤ 34 weeks and at < 37 weeks of 83.3% and 56.0%, respectively. These results were better than those of tests carried out at earlier gestational ages.

thumbnail image

Figure 1. Receiver–operating characteristics curves for the performance of phosphorylated insulin-like growth factor-binding protein-1 (IGF) in the prediction of preterm delivery performed at different gestational ages between 24 and 34 weeks. Sources of the curves were: IGF-30 (equation image), IGF-34 (equation image), IGF-27 (equation image) and IGF-24 (equation image).

Download figure to PowerPoint

A positive phIGFBP-1 test was found to be inversely related to cervical length (Figure 2). However multivariate analysis showed that a positive phIGFBP-1 test at 30 weeks and cervical assessment at 22–24 weeks were independent predictors for preterm delivery at both ≤34 and <37 weeks of gestation: y = − 0.405 − 0.133 × cervical length + 2.795× (1 for phIGFBP-1-positive or 0 for phIGFBP-1-negative).

thumbnail image

Figure 2. Relationship between phosphorylated insulin-like growth factor-binding protein-1 (phIGFBP-1) positivity and cervical length in the prediction of preterm delivery (chi2 = 130.5; P < 0.0001).

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Cervical assessment at 22–24 weeks of gestation and phIGFBP-1 testing at 30 weeks of gestation had the steepest ROC curve (AUC = 0.93; 95% CI, 0.88–0.98, P < 0.001). Among the 12 patients with preterm delivery at ≤ 34 weeks in this study, 9 (75.0%) were identified by cervical assessment at 22–24 weeks. The phIGFBP-1 test at 30 weeks identified two further patients (16.7%). Among the 25 patients with preterm delivery before 37 weeks, 16 (64.0%) were identified by cervical assessment only and a further four patients by phIGFBP-1 at 30 weeks. Therefore, the association between cervical assessment and phIGFBP-1 at 30 weeks identified 11 out of the 12 patients (91.7%) who delivered at ≤ 34 weeks and 20 out of the 25 (80.0%) who delivered before 37 weeks.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The findings of this study show that firstly, the combination of cervical assessment at 22–24 weeks and phIGFBP-1 testing at 30 weeks of gestation is useful for the prediction of preterm birth; secondly, that mid-trimester cervical assessment is capable of identifying the majority of patients who will deliver at < 34 weeks; and thirdly, that the majority of pregnant women with a previous history of spontaneous preterm birth will deliver at term in the following pregnancy.

Although prior preterm birth is the most important risk factor for recurrence of preterm delivery, most of these patients, who are labeled as high risk, will deliver at term in the following pregnancy. Thus a screening test for this population would select only those that are truly at a higher risk and therefore avoid unnecessary treatment.

A cervical length < 20 mm as measured by transvaginal ultrasonography at 22–24 weeks identified those patients who went on to deliver before 34 and 37 weeks at rates of around 65% and 83%, respectively, with a false-positive rate of 14.0%. This suggests that the option of cervical assessment should be offered to patients with a history of preterm birth.

In this high-risk group, interventions such as prophylactic tocolytics, bed rest, cerclage, ambulatory tocodynamometry, and antibiotics have been recommended and have been shown to be ineffective18–20. Recently, studies have found that progesterone treatment is effective at preventing recurrent preterm delivery, and the American College of Obstetricians and Gynecologists has stated that progesterone could be an option for these patients21–23. Although progesterone has been shown to be safe so far, the best approach from a cost–benefit perspective would be to ensure that the group thought to be at high risk based on their previous obstetrical history are in fact a high-risk group.

Heath et al.17 have previously demonstrated that the risk of preterm delivery increases when the cervical length is less than 20 mm, and that there is an exponential increase in the risk of preterm delivery when the cervix is shorter than 15 mm. In their study, the median cervical length was 36 mm and the 5th and 1st centiles were 23 mm and 15 mm, respectively. de Carvalho et al.10 found similar numbers in an unselected population, and the risk of preterm delivery also increased when the cervix was less than 20 mm. In their study, the median cervical length (27 mm) was shorter than that reported previously. This finding has raised questions about the etiology of the short cervix. Patients with a short cervix in their previous pregnancy could suggest a genetic origin—to test this would, however, be beyond the scope of this investigation. Infection may also play a part in short cervical lengths. Further studies are needed to address the etiology and the meaning of the short cervix in this population.

IGFBP-1, which is a major protein of human decidua, constitutes a subgroup of the IGFBP system. IGFBP-1 has a higher concentration in amniotic fluid than in serum; its concentration gradually increases in the amniotic fluid in the mid-trimester in comparison with its concentration in the maternal plasma24.

phIGFBP-1 is predominantly secreted in decidual cells and the liver. During the onset of delivery, the fetal membrane begins to detach from the decidual parietalis and small amounts of phIGFBP-1, which can be identified through the use of monoclonal antibodies, leak into the cervical secretions13. Studies have demonstrated that phIGFBP-1 collected from cervical secretions could identify patients at risk of premature delivery12–15. A bedside test for phIGFBP-1 in symptomatic patients at risk of preterm labor yielded a high detection rate (72–78%) and high negative predictive value (90–94%)25, 26. Thus vaginal identification of phIGFBP-1 appears to be a favorable option in the management of symptomatic patients25, 26. However, to the best of our knowledge this is the first study in which phIGFBP-1 has been tested in asymptomatic patients with a previous history of at least one preterm birth.

According to our findings, rapid phIGFBP-1 testing seems to be a useful way of predicting preterm birth in patients with prior preterm delivery. In addition, our data suggest that the best gestational age at which this test should be performed is 30 weeks. Finally, the combination of cervical length measurement at 22–24 weeks and this relatively new biochemical predictor of preterm birth demonstrates high detection rates for preterm delivery before 34 and 37 weeks (92% and 80%, respectively). Although validation of these results is required in a large population, our data should remind clinicians firstly that the majority of patients with a history of preterm birth will deliver at term in the following pregnancy and secondly, that the sequential approach we describe (cervical length measurement at 22–24 weeks and phIGFBP-1 testing at 27–30 weeks) could be considered an option in order to avoid unnecessary treatment.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References
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