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Keywords:

  • Cervical fluid phIGFBP-1;
  • preterm delivery

Abstract

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

Please cite this paper as: Rahkonen L, Rutanen E-M, Nuutila M, Sainio S, Saisto T, Paavonen J. Elevated levels of decidual insulin-like growth factor binding protein-1 in cervical fluid in early and mid-pregnancy are associated with an increased risk of spontaneous preterm delivery. BJOG 2010;117:701–710.

Objective  To study whether elevated levels of decidual insulin-like growth factor binding protein-1 (IGFBP-1) in the cervical fluid of unselected asymptomatic women in early or mid-pregnancy are associated with spontaneous preterm delivery (PTD).

Design  Prospective population-based cohort study.

Setting  Maternity Clinics, University Central Hospital, Helsinki, Finland.

Population  A total of 5180 unselected pregnant women.

Methods  Cervical swab samples were collected during the first and second trimester ultrasound screening. The concentration of IGFBP-1 was measured by immunoenzymometric assay, which detects the decidual phosphoisoforms of IGFBP-1 (phIGFBP-1). Concentrations of 10 micrograms/l or more were considered to be elevated.

Main outcome measure  Spontaneous PTD.

Results  In the first trimester, 24.5% of women, and in the mid-second trimester, 20.2% of women, had an elevated cervical fluid phIGFBP-1 level. The rates of spontaneous PTD before 32 and before 37 weeks of gestation were higher in women with an elevated cervical fluid phIGFBP-1 level, compared with women who had cervical phIGFBP-1 of <10 micrograms/l (1.1% versus 0.3% and 5.7% versus 3.2%, respectively). An elevated phIGFBP-1 level in the first trimester was an independent predictor for PTD before 32 and before 37 weeks of gestation, with odds ratios of 3.0 (95% CI 1.3–7.0) and 1.6 (95% CI 1.2–2.3), respectively. Cervical phIGFBP-1 levels of 10 micrograms/l or more in the first trimester predicted PTD before 32 and before 37 weeks of gestation, with sensitivities of 53.8% and 37.0%, respectively. The negative predictive values were 99.7% and 96.8%.

Conclusions  Elevated cervical fluid phIGFBP-1 levels in the first trimester were associated with an increased risk of spontaneous PTD.


Introduction

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

Preterm delivery (PTD) (before 37 weeks of gestation) is a multifactorial phenomenon, and remains a significant obstetric problem. Its frequency varies from 5.0% to 15.0%, depending on population, and it is the most important cause of perinatal morbidity and mortality. More than half of preterm deliveries are spontaneous, preceded by preterm prelabour rupture of membranes (PPROM) or preterm labour.1,2 Although many risk factors, such as demographic and behavioural characteristics of the mother, history of vaginal bleeding in current pregnancy and maternal nutritional status have been identified, PTD is still difficult to predict.3 In recent years, a great number of molecules involved in multiple pathophysiologic pathways leading to spontaneous PTD have been evaluated as biomarkers to identify women at risk for spontaneous PTD.4–10 However, their value in clinical practice is limited.

Genital tract infection, both occult and clinical, has been linked to PTD in multiple studies.2,11,12 PPROM and preterm labour may be the first symptoms of ascending infection into the choriodecidual space. It is thought that microorganisms ascend from the vagina into the uterus, leading to bacterial invasion of the choriodecidual space and tissue disruption at the choriodecidual interface. Tissue disruption, on the other hand, results in leakage of chorionic and decidual products into the cervix and vagina.4 Many chorion/decidual products have been evaluated as markers for PTD.4–10 In most studies, the performance of potential marker molecules has been evaluated among women with uterine contractions or preterm labour during the late-second trimester or third trimester.

Insulin-like growth factor binding protein-1 (IGFBP-1) is a major protein of human decidua. Its highly phosphorylated isoform (phIGFBP-1), produced by decidua, can be detected by monoclonal antibody 6303 (Mab 6303).13,14 In our early studies, cervical fluid phIGFBP-1 concentrations of 10 micrograms/l or more were measured in only 5% of asymptomatic women between 23 and 37 weeks of gestation;8 therefore, levels of 10 micrograms/l or more were considered to be elevated after 22 weeks of gestation. Cervical fluid phIGFBP-1 has been examined as a biomarker for the prediction of PTD among patients with preterm uterine contractions or preterm labour at between 23 and 37 weeks of gestation. In these rather small studies the cervical fluid phIGFBP-1 levels of 10 micrograms/l or more have predicted PTD with sensitivities varying from 40.0% to 89.5%, and negative predictive values from 90% to 100%.8,10,15–17

In the present study, we examined whether elevated cervical fluid phIGFBP-1 levels in unselected asymptomatic women in the first or mid-second trimester are associated with spontaneous PTD. We previously reported cervical fluid phIGFBP-1 levels, and factors affecting them, in the first and mid-second trimester in part of the cohort enrolled for the present study.18

Methods

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

The prospective study was carried out by the three units of the Maternity Clinic of the Department of Obstetrics and Gynaecology, University Hospital, Helsinki, Finland, between April 2005 and December 2006. Before the study the primary outcome was defined as spontaneous PTD before 37 weeks of gestation. The local medical ethics committee approved the study.

Information about the prospective study was mailed to 15 641 consecutive women who had registered for ultrasound screenings as part of routine antenatal care in the first trimester (between 12 + 0 and 13 + 6 weeks of gestation, based on the last menstrual period), and in the second trimester (between 18 + 0 and 20 + 6 weeks of gestation). A total of 5180 (33.1%) volunteers participated in the study and gave informed consent. Eighty women (1.5%) were excluded because of miscarriage, and 75 (1.4%) women delivered in other hospitals, and so gestational age at delivery was unknown. In addition, 29 women with induced PTD were excluded. PhIGFBP-1 results were missing in 12 (0.2%) cases in the first trimester study population, and in 38 (0.7%) cases in the second trimester. Three hundred and twenty-eight women (6.3%) dropped out from the study for personal reasons between the first and the second examination. Thus, a total of 4984 women in the first trimester and 4630 women in the second trimester were included in the final analysis. Cervical fluid phIGFBP-1 levels for a part of this cohort (the first 1702 women) were reported in our previous study.18

Speculum examination was performed first, and a polyester swab sample of the cervical fluid from the external part of the cervical canal for phIGFBP-1 determination was obtained, as described previously.18 Thereafter, gestational age was confirmed by transvaginal ultrasonography. Demographic data were obtained at the first visit, and a history of vaginal bleeding before the first examination, or between the first and the second examination, and whether sexual intercourse had occurred within the last 48 hours was ascertained on both visits. Body mass index (BMI) in early pregnancy and smoking habits of all participants were obtained from the forms filled from each pregnancy for the National Institute for Health and Welfare, Finland. A BMI > 30 kg/m² was used as a cut-off for obesity. All women had intact fetal membranes based on their history and speculum examination, and none had vaginal bleeding at the time of examination.

The cervical fluid samples were frozen and stored at −20°C until the phIGFBP-1 concentration was measured by immunoenzymometric assay, as described previously.18 The assay detects all phosphorylated isoforms of IGFBP-1, including the highly phosphorylated isoform that is produced by the decidua and is not present in the amniotic fluid.13,14 The detection limit of the assay is 0.3 micrograms/l. A phIGFBP-1 concentration of 10 micrograms/l or more was considered to be elevated, as in previous studies.8,18 The laboratory was blinded to the clinical status of the patients.

The outcome measures were spontaneous PTD before 32 and before 37 weeks of gestation. Spontaneous PTD was defined as a PTD after the spontaneous onset of contractions or PPROM, regardless of whether the delivery was vaginal, by caesarean section, or, in the case of membrane rupture, induced. Information of delivery and problems during pregnancy were collected from the patient’s hospital records.

Data were analysed by Microsoft Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) for Windows v16.0. Because the phIGFBP-1 concentration data did not follow a normal distribution, not even after logarithmic transformation, unpaired comparisons were performed with the Mann–Whitney U test. The phIGFBP-1 concentrations of 10 micrograms/l or more and <10 micrograms/l were categorical variables, and were compared by chi-square test and Fisher’s exact test, as appropriate. Multivariate analysis of factors increasing the risk for PTD was performed by logistic regression. The covariates included were parity, twin pregnancy, in vitro fertilisation (IVF), history of PTD, smoking, BMI, history of vaginal bleeding and a phIGFBP-1 concentration of 10 micrograms/l or more. Logistic regression was also used to evaluate the influence of previous vaginal bleeding and nulliparity on cervical fluid phIGFBP-1.18 The receiver operating characteristic (ROC) curves were constructed and areas under the curves were determined to evaluate the accuracy of cervical fluid phIGFBP-1 in the prediction of PTD. P < 0.05 was considered to be statistically significant.

Results

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

A total of 4984 pregnant women in the first trimester, and 4630 pregnant women in the second trimester, were included in the analyses. Demographic, behavioural and clinical characteristics, and obstetric outcome, of the study population at the first and the second trimester examinations are shown in Table 1-A and -B. The data from the first trimester sampling and the mid-second trimester sampling were analysed separately.

Table 1.   Characteristics and obstetric outcomes in (A) the first trimester study population (n = 4984) and (B) the second trimester study population (n = 4630)
(A)DeliveryDelivery
<32 weeks (n = 26)≥32 weeks (n = 4958)P<37 weeks (n = 189)≥37 weeks (n = 4795)P-value
Maternal age (years)31.4 (21–42)30.0 (15–47)NS29.8 (18–42)30.1 (15–47)NS
Nulliparity (%)42.349.3NS55.049.0NS
Twin pregnancy (%)3.80.60.0456.30.4<0.001
History of preterm delivery (%)19.23.1<0.00110.12.9<0.001
IVF* (%)7.73.3NS6.33.20.018
Smoking** (%)20.811.2NS21.010.9<0.001
History of vaginal bleeding during current pregnancy (%)23.19.40.01717.69.1<0.001
BMI (kg/m²)***23.2 (17.7–36.58)23.5 (16.4–59.8)NS23.7 (16.6–43.1)24.5 (16.4–59.8)NS
BMI > 30 kg/m² (%)17.47.1NS8.87.1NS
Gestational age at examination (weeks)12.9 (10.8–13.7)12.8 (7.0–17.3)NS12.7 (7.8–17.1)12.8 (7.0–17.3)NS
Gestational age at delivery (weeks)27.9 (22.3–31.7)40.1 (32.0–42.8)<0.00134.5 (22.3–36.8)40.3 (37.0–42.8)<0.001
Birth weight (g)1196 (480–3100)3564 (1200–5445)<0.0012575 (480–4188)3575 (1915–5445)<0.001
(B)DeliveryDelivery
<32 weeks (n = 21)≥32 weeks (n = 4609)P<37 weeks (n = 167)≥37 weeks (n = 4463)P-value
  1. Mean (range) or %.

  2. BMI, body mass index; IVF, in vitro fertilisation; NS, nonsignificant.

  3. *22, data missing.

  4. **284, data missing.

  5. ***326, data missing.

  6. Mann–Whitney U test and chi-square test, Fisher’s exact test when appropriate.

  7. Mean (range) or %.

  8. BMI, body mass index; IVF, in vitro fertilisation; NS, nonsignificant.

  9. *22, data missing.

  10. **258 data missing.

  11. ***298 data missing.

  12. Mann–Whitney U test and chi-square test, Fisher’s exact test when appropriate.

Maternal age (years)30.7 (21–42)30 (15–47)NS29.8 (18–42)30.0 (15–47)NS
Nulliparity (%)42.949.6NS55.749.3NS
Twin pregnancy (%)4.80.60.0126.60.4<0.001
History of preterm delivery (%)19.03.1<0.00110.22.9<0.001
IVF* (%)4.83.3 (3.3)NS6.631.20.014
Smoking** (%)26.311.10.03521.710.7<0.001
History of vaginal bleeding during current pregnancy (%)35.011.70.00120.911.4<0.001
BMI (kg/m²)***24.6 (17.7–31.3)23.5 (16.4–59.8)NS23.8 (16.6–36.8)23.5 (16.4–59.8)NS
BMI >30 kg/m² (%)11.17.4NS8.67.3NS
Gestational age at examination (weeks)19.3 (18.7–20.4)19.3 (16.4–23.0)NS19.2 (17.7–20.4)19.3 (16.4–23.0)NS
Gestational age at delivery (weeks)24.6 (22.3–31.7)40.1 (32.0–42.8)<0.00135.6 (22.3–36.8)40.2 (37.0–42.8)<0.001
Birth weight (g)1100 (480–3100)3563 (1200–5445)<0.0012472 (480–4188)3591 (1920–5445)<0.001

First trimester sampling

The cervical fluid phIGFBP-1 levels ranged from <0.3 to 174.0 micrograms/l. The median phIGFBP-1 concentration was higher in women with spontaneous delivery before 32 weeks of gestation compared with women who delivered at 32 weeks of gestation or later (12.0 micrograms/l versus 2.5 micrograms/l, = 0.004). The median phIGFBP-1 concentration in women who delivered before 37 weeks of gestation was also higher compared with women who had a term delivery (3.7 micrograms/l versus 2.5 micrograms/l, P < 0.001) (Figures 1 and 2). Nulliparity and previous vaginal bleeding were associated with elevated cervical fluid phIGFBP-1 levels: nulliparity versus multiparity gave an odds ratio (OR) of 1.3 (95% CI 1.1–1.5), and a history of vaginal bleeding versus no bleeding gave an OR of 1.7 (95% CI 1.4–2.1).

image

Figure 1.  Boxplots of cervical fluid phosphoisoforms of insulin-like growth factor binding protein-1 (phIGFBP-1) concentrations in the first trimester of women with spontaneous delivery before 32 weeks of gestation, and at 32 weeks of gestation or later.

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image

Figure 2.  Boxplots of cervical fluid phosphoisoforms of insulin-like growth factor binding protein-1 (phIGFBP-1) concentrations in the first trimester of women with spontaneous delivery before 37 weeks of gestation, and at 37 weeks of gestation or later.

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When a cervical fluid concentration of 10 micrograms/l was used as the cut-off, 24.5% of women had an elevated cervical fluid phIGFBP-1 level. The rates of spontaneous PTD before 32 and before 37 weeks of gestation were higher in women with an elevated cervical fluid phIGFBP-1 level compared with women who had cervical phIGFBP-1 levels of <10 micrograms/l (1.1% versus 0.3%, < 0.001; 3.2% versus 5.7%, P < 0.001, respectively) (Table 2).

Table 2.   Associations between gestational age at delivery and cervical fluid phIGFBP-1 levels of <10 micrograms/l and of 10 micrograms/l or more in the first trimester (n = 4984)
 DeliveryDelivery
<32 weeks≥32 weeksP-value<37 weeks≥37 weeksP-value
  1. Data shown n (%); chi-square test.

  2. phIGFBP-1, phosphoisoforms of insulin-like growth factor binding protein-1.

phIGFBP-1 ≥10 micrograms/l14 (1.1)1206 (98.9)<0.00170 (5.7)1150 (94.3)<0.001
phIGFBP-1 <10 micrograms/l12 (0.3)3752 (99.7)119 (3.2)3645 (96.8)

An elevated cervical fluid phIGFBP-1 level in the first trimester increased the risk of subsequent spontaneous PTD before 32 (OR 3.6; 95% CI 1.7–7.9) and before 37 weeks of gestation (OR 1.9; 95% CI 1.3–2.5). Multiple logistic regression analysis confirmed that, even when other risk factors were accounted for, an elevated cervical fluid phIGFBP-1 level was an independent predictor of PTD before 32 (OR 3.0; 95% CI 1.3–7.0) and before 37 weeks of gestation (OR 1.6; 95% CI 1.2–2.3) (Table 3).

Table 3.   Unadjusted and adjusted odds ratios for preterm delivery: first trimester (n = 4984)
 Unadjusted OR (95% CI)Adjusted OR (95% CI)Unadjusted OR (95% CI)Adjusted OR (95% CI)
Preterm delivery <32 weeks (n = 26)Preterm delivery <32 weeks (n = 26)Preterm delivery <37 weeks (n = 189)Preterm delivery <37 weeks (n = 189)
  1. BMI, body mass index; IVF, in vitro fertilisation; phIGFBP-1, phosphoisoforms of insulin-like growth factor binding protein-1.

Nulliparity0.8 (0.3–1.6)1.1 (0.4–2.9)1.3 (1.0–1.7)1.6 (1.1–2.2)
Twin6.2 (0.8–46.8)7.1 (0.9–59.1)15.4 (7.5–31.8)13.5 (6.0–30.3)
IVF2.4 (0.6–10.4)1.6 (0.3–7.9)2.0 (1.1–3.7)1.5 (0.8–3.0)
History of preterm delivery7.5 (2.8–20.1)7.6 (2.4–24.1)3.7 (2.3–6.2)4.7 (2.6–8.3)
Smoking2.1 (0.8–5.9)2.2 (0.8–5.9)2.1 (1.5–3.2)2.0 (1.4–3.0)
BMI >30 kg/m²2.7 (0.9–8.1)2.6 (0.8–7.8)1.3 (0.7–2.2)1.2 (0.7–2.1)
History of vaginal bleeding2.9 (1.1–7.3)2.7 (1.0–7.3)2.1 (1.4–3.1)2.1 (1.4–3.1)
Cervical phIGFBP-1 ≥10 micrograms/l3.6 (1.7–7.9)3.0 (1.3–7.0)1.9 (1.3–2.5)1.6 (1.2–2.3)

The ROC curves illustrating the accuracy of cervical fluid phIGFBP-1 in the first trimester are shown in Figure 3. The area under the curve (AUC) with 95% CIs in predicting spontaneous PTD before 32 weeks of gestation was 0.66 (0.55–0.76), and before 37 weeks of gestation was 0.59 (0.54–0.63). The cut-off value of 10 micrograms/l in the first trimester predicted PTD before 32 and before 37 weeks of gestation with sensitivities of 53.8% and 37.0%, and false-positive rates of 24.3% and 24.0%, respectively. Negative predictive values were 99.7% and 96.8%, respectively.

image

Figure 3.  Receiver operating characteristic (ROC) curve of cervical fluid phosphoisoforms of insulin-like growth factor binding protein-1 (phIGFBP-1) levels in the first trimester for predicting preterm delivery before 32 weeks of gestation. The sensitivity and 100-specificity points for phIGFBP-1 values of 5, 10 and 20 micrograms/l are marked.

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Second trimester sampling

Cervical fluid phIGFBP-1 levels ranged from <0.3 to 204.0 micrograms/l. The median phIGFBP-1 concentration was higher in women with spontaneous delivery before 32 weeks of gestation compared with women who delivered at 32 weeks of gestation or later (7.5 micrograms/l versus 2.1 micrograms/l, = 0.003) (Figure 4). No difference was found in cervical fluid phIGFBP-1 concentrations between women with PTD before 37 weeks of gestation and those with term delivery (2.5 micrograms/l versus 2.1 micrograms/l, P = 0.059) (Figure 5). Nulliparity and previous vaginal bleeding were associated with phIGFBP-1 concentrations of 10 micrograms/l or more (OR 2.2, 95% CI 1.9–2.5; OR 1.6, 95% CI 1.3–2.0, respectively).

image

Figure 4.  Boxplots of cervical fluid phosphoisoforms of insulin-like growth factor binding protein-1 (phIGFBP-1) concentrations in the mid-second trimester of women with spontaneous delivery before 32 weeks of gestation, and at 32 weeks of gestation or later.

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image

Figure 5.  Boxplots of cervical fluid phosphoisoforms of insulin-like growth factor binding protein-1 (phIGFBP-1) concentrations in the mid-second trimester of women with spontaneous delivery before 37 weeks of gestation, and at 37 weeks of gestation or later.

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When a cervical fluid concentration of 10 micrograms/l was used as the cut-off, 20.2% of women had an elevated cervical fluid phIGFBP-1 level. The rates of spontaneous PTD before 32 and before 37 weeks of gestation were higher in women with an elevated cervical fluid phIGFBP-1 level compared with women who had cervical phIGFBP-1 of <10 micrograms/l (0.9% versus 0.4%, = 0.041; 5.1% versus 3.2%, = 0.005, respectively) (Table 4).

Table 4.   Associations between gestational age at delivery and cervical fluid phIGFBP-1 levels of <10 micrograms/l and >10 micrograms/l in the mid-second trimester (n = 4630)
 DeliveryDelivery
<32 weeks≥ 32 weeksP value<37 weeks≥ 37 weeksP value
  1. Data shown n (%); chi-square test.

  2. phIGFBP-1, phosphoisoforms of insulin-like growth factor binding protein-1.

phIGFBP-1 ≥10 micrograms/l8 (0.9)927 (99.1)0.04148 (5.1)887 (94.9)0.005
phIGFBP-1 <10 micrograms/l13 (0.4)3682 (99.6)119 (3.2)3576 (96.8)

The unadjusted and adjusted ORs for the second trimester cervical fluid phIGFBP-1 and other risk factors for predicting subsequent spontaneous PTD were analysed by logistic regression (Table 5). An elevated cervical fluid phIGFBP-1 level in the mid-second trimester increased the risk of subsequent spontaneous PTD before 32 and before 37 weeks of gestation (OR 2.4, 95% CI 1.0–5.9; OR 1.6, 95% CI 1.2–2.3). By multiple logistic regression analysis an elevated cervical fluid phIGFBP-1 was not an independent predictor of PTD.

Table 5.   Unadjusted and adjusted odds ratios for preterm delivery: second trimester (n = 4630)
 Unadjusted OR (95% CI)Adjusted OR (95% CI)Unadjusted OR (95% CI)Adjusted OR (95% CI)
Preterm delivery <32 weeks (n = 21)Preterm delivery <32 weeks (n = 21)Preterm delivery <37 weeks (n = 167)Preterm delivery <37 weeks (n = 167)
  1. BMI, body mass index; IVF, in vitro fertilisation; phIGFBP-1, phosphoisoforms of insulin-like growth factor binding protein-1.

Nulliparity0.7 (0.3–1.8)1.5 (0.5–4.7)1.3 (0.9–1.8)1.6 (1.1–2.4)
Twin8.8 (1.1–68.1)13.6 (1.6–115.2)19.6 (8.9–42.9)18.9 (8.2–43.6)
IVF1.5 (0.2–11.1)1.3 (0.2–10.9)0.5 (0.2–0.9)1.6 (0.8–3.2)
History of preterm delivery7.4 (2.5–22.3)10.5 (2.7–40.7)3.8 (2.2–6.5)5.2 (2.8–9.3)
Smoking2.9 (1.0–8.0)3.1 (1.1–9.1)2.3 (1.6–3.4)2.2 (1.5–3.4)
BMI >30 kg/m²1.6 (0.4–6.8)1.7 (0.4–7.6)1.2 (0.7–2.1)1.1 (0.6–2.0)
History of vaginal bleeding4.1 (1.6–10.3)5.2 (1.9–14.1)2.0 (1.4–3.0)2.0 (1.3–3.1)
Cervical phIGFBP-1 ≥ 10 micrograms/l2.4 (1.0–5.9)1.9 (0.7–5.3)1.6 (1.2–2.3)1.4 (1.0–2.1)

The ROC curves illustrating the accuracy of cervical fluid phIGFBP-1 in the second trimester are shown in Figure 6. The AUC (95% CI) in the prediction of spontaneous PTD before 32 weeks of gestation was 0.68 (0.56–0.80), and before 37 weeks of gestation was 0.54 (0.50–0.59). A cervical fluid phIGFBP-1 level of 10 micrograms/l or more predicted subsequent spontaneous PTD before 32 and before 37 weeks of gestation with sensitivities of 38.1% and 28.7%, and with false-positive rates of 20.1% and 19.9%, respectively. Negative predictive values were 99.6% and 96.8%, respectively.

image

Figure 6.  Receiver operating characteristic (ROC) curve of cervical fluid phosphoisoforms of insulin-like growth factor binding protein-1 (phIGFBP-1) concentrations in the mid-second trimester for predicting preterm delivery before 32 weeks of gestation. The sensitivity and 100-specificity points for phIGFBP-1 values of 5, 10 and 20 micrograms/l are marked.

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Discussion

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

Insulin-like growth factor binding protein-1 is a major protein product of human decidua.19 To our knowledge, this is the first study examining whether elevated levels of decidua-derived phIGFBP-1 in cervical fluid among unselected, asymptomatic women during early pregnancy are associated with an increased risk of subsequent spontaneous PTD. About one-third of the invited women participated in this study. The overall rate of PTD (including 29 induced preterm deliveries) in our study population was 4.4%, which is less than the average rate in Finland (5.2%),20 indicating that the study population represented predominantly low-risk women. Thus, the results can be interpreted as population based. For comparison, we also analysed the role of some known historical risk factors for PTD. In agreement with many studies, twin pregnancy, history of previous PTD and history of vaginal bleeding in the current pregnancy were the strongest predictors of spontaneous PTD.

We used the concentration of 10 micrograms/l as the cut-off for elevated cervical fluid phIGFBP-1 level, as previously reported.18 According to the ROC curve analysis, 10 micrograms/l appeared to be the optimal cut-off for cervical fluid phIGFBP-1 level in predicting PTD. In agreement with our previous data,18 between one-fourth and one-fifth of women had cervical fluid phIGFBP-1 levels of 10 micrograms/l or more until mid-pregnancy. Mechanism(s) accounting for the absence and presence of phIGFBP-1 in the cervical fluid in early pregnancy have not been well defined. The occurrence of chorionic/decidual products in cervicovaginal fluid between 23 and 37 weeks of gestation is believed to result from subclinical or clinical infection and tissue disruption at the choriodecidual interface, and has therefore been considered as an early sign for PTD. In early pregnancy, however, other explanations are more likely because the majority of women have detectable levels of chorionic or decidual proteins in cervicovaginal secretions.4,18,21 The most likely explanation is that the leakage of small quantities of chorionic/decidual products into the cervical canal is physiologic before the fusion of capsular and parietal decidua. This is supposed to be completed during the early second trimester. In keeping with our previous data in a smaller sample, nulliparity and a history of vaginal bleeding were associated with a two-fold average increase in the rate of elevated cervical phIGFBP-1 level. In the present study, the proportions of nulliparous and multiparous women were evenly distributed among women with preterm and term delivery, suggesting that parity had no significant influence on the phIGFBP-1 results. History of previous vaginal bleeding was more common in women with PTD, and may partly explain the elevated phIGFBP-1 levels. Sexual intercourse has no effect on cervical fluid phIGFBP-1 levels.18

Our study demonstrated that women with subsequent PTD before 32 weeks of gestation had significantly higher cervical fluid phIGFBP-l levels in both trimesters compared with women who delivered at after 32 weeks of gestation. Secondly, this study showed that the rates of PTD among women with an elevated cervical fluid phIGFBP-1 level, either during the first trimester or in the mid-second trimester, were higher compared with women with cervical phIGFBP-1 levels of <10 micrograms/l (Table 4). The risk of PTD before 32 weeks of gestation was increased by almost four-fold among women who had cervical phIGFBP-1 concentrations of 10 micrograms/l or more, compared with those with cervical phIGFBP-1 levels of <10 micrograms/l, in the first trimester. In the second trimester the difference was almost two-fold.

Various explanations for these associations can be considered. First, some women could have subclinical intrauterine infection already before pregnancy or in early pregnancy, and the elevated cervical fluid phIGFBP-1 levels simply represent infection-induced tissue disruption at the choriodecidual interface. This hypothesis is supported by Kekki’s (1999) study, in which the women who had simultaneous bacterial vaginosis and elevated phIGFBP-1 levels in cervical secretions in the early second trimester had an increased risk of peripartum infections.22 Considering the high frequency of elevated cervical fluid phIGFBP-1 levels in the whole study population, this is probably not the only explanation. One reason for a higher rate of preterm deliveries among women with elevated cervical fluid phIGFBP-1 in the first or mid-second trimester could be the following: infections ascending from the vagina before the fusion of the two decidual layers, as indicated by the leakage of phIGFBP-1 into the cervix, will more often become chronic, finally resulting in PTD. This theory is supported by observations that the earlier in pregnancy the abnormal microbial intrauterine invasion is detected, the greater the risk is for an adverse outcome.

Another explanation for an increased cervical fluid phIGFBP-1 level as well as for an increased rate of PTD among women with elevated phIGFBP-1 could be past decidual haemorrhage. Decidual haemorrhage that presents as vaginal bleeding is a well-known aetiologic factor of PTD. Although women with visible bleeding at the time of sampling were excluded, those with a history of vaginal bleeding were included. Among those, an elevated cervical fluid phIGFBP-1 level could be a marker of previous (occult or clinical) decidual haemorrhage and associated tissue disruption in decidua. A significant association between previous vaginal bleeding and elevated cervical fluid phIGFBP-1 levels, as seen in our previous study18 and in the present study, supports this hypothesis. Logistic regression analysis confirmed that both previous vaginal bleeding and elevated cervical fluid phIGFBP-1 levels in the first trimester also independently increased the risk for PTD.

An elevated cervical fluid phIGFBP-1 level in the first trimester was a stronger predictor of PTD before 32 weeks of gestation than before 37 weeks of gestation. This is an interesting observation considering that subclinical infection at the choriodecidual interface, particularly in early pregnancy, has been especially associated with early PTD.21,23 The sensitivity of the first trimester cervical fluid phIGFBP-1 level, using a cut-off of 10 micrograms/l, in the prediction of subsequent PTD before 32 weeks of gestation was 53.8%. This is strikingly high considering the multifactorial aetiology and multiple pathophysiological pathways of PTD, as well as the timing of cervical fluid sampling among unselected asymptomatic women. In the mid-second trimester, the sensitivity of cervical phIGFBP-1 levels of 10 micrograms/l or more for the prediction of PTD was lower. The low positive predictive values of phIGFBP-1 levels in the first trimester and second trimester depend on the low rate of end points, especially for delivery before 32 weeks of gestation.

Adjusted analysis confirmed that elevated cervical fluid phIGFBP-1 levels in the first trimester was an independent predictor of PTD before 32 and before 37 weeks of gestation. The negative predictive value, seen in this study and previous studies, among symptomatic women at a later stage of pregnancy was high.10,15,17 However, the high rate of false-positive findings (physiologic) in early pregnancy limits the use of the cervical phIGFBP-1 level as a screening test for subsequent spontaneous PTD among asymptomatic women. Still, cervical fluid phIGFBP-1 level testing may be of value as an additional test in the assessment of preterm risk in selected cases in early pregnancy.

The strengths of this study were that it was population based with no selection bias, and that the sample size was large. Furthermore, all measurements were performed in a single laboratory without knowledge of clinical characteristics or other information. One weakness of this study may be that we did not test specific vaginal infections. Finally, we need to consider that any testing adds little or nothing to the outcome if we do not have the right interventions to prevent spontaneous PTD.24

Conclusion

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

We demonstrated a significant association between high levels of cervical fluid phIGFBP-1 in the first and mid-second trimester and subsequent PTD. An elevated phIGFBP-1 level in the first trimester was an independent predictor of spontaneous PTD, especially before 32 weeks of gestation. Because of its low positive predictive value, cervical fluid phIGFBP-1 testing is not appropriate to be used in the first or mid-second trimester for routine screening of asymptomatic pregnant women for PTD risk. However, because of its high negative predictive value, cervical fluid phIGFBP-1 level could play a role either alone or in combination with other markers and specific risk factors, when assessing the risk for PTD, and planning prenatal care and interventions in selected women.

Disclosure of interests

E-MR is the other inventor of a patented diagnostic method for determining the susceptibility to delivery, and a reagent kit for use therefore.

Contribution to authorship

The study was designed by JP, LR, and E-MR in collaboration with MN, SS, and TS. Data was collected by LR. Data analysis was performed by LR. The manuscript was drafted by LR, E-MR, and JP. All authors contributed to the final version of the manuscript. The final version of the manuscript was seen and approved by all authors. Funding was obtained by JP.

Details of ethics approval

This study was approved by the Institutional Review Board of the Department of Obstetrics and Gynaecology (17 February 2005, ref. no. 49/E8/05).

Funding

The study was funded by a grant (no. 1131/31/04) from the Finnish Funding Agency for Technology and Innovation (Tekes) and a Helsinki University Hospital research grant.

Acknowledgements

We gratefully acknowledge the contribution of Medix Biochemica, Kauniainen, Finland, especially Eivor Svens, MSc, who organised the analysis of phIGFBP-1. Midwifes from the Department of Obstetrics and Gynaecology, Helsinki University Hospital, are acknowledged for their valuable contribution. We greatly appreciate the expertise of Ville Hiilesmaa, MD, PhD, for his advice in statistical analyses.

References

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