Predicting Preterm Delivery In Symptomatic Women Biology Essay

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Assessing the probability of preterm delivery is still a clinical challenge and might prevent unnecessary and potentially risky interventions with reduction of treatment costs.

Objective: To evaluate the use of terleukin-6 (IL-6) compared with fetal fibronectin (fFN) and cervical length in the prediction of preterm delivery in symptomatic women.

Patients and methods: One hundred and fifteen women between 24 and 34 weeks gestational age, with threatened preterm delivery were enrolled in this study. Specimen of cervicovaginal fluid was collected for fFN and IL-6 measurments then transvaginal scan to assess cervical length was performed.

Results

The prevalence of preterm delivery was 21.8% before 37 weeks, 18.8% before 34 weeks. The rate of spontaneous delivery was 5.4% within 7 days and 9.1% within 2 weeks. ROC curves were significant for IL-6, fFN and cervical length for prediction of preterm delivery at different gestational ages (p<0.05). When comparing the performance of the 3 test variables, AUC were not significantly different between them in predicting preterm delivery (p>0.05). IL-6 had a significant positive correlation with fFN levels, and inverse correlation with cervical length, gestational age at delivery and interval exploration to delivery. However, there was no correlation between IL-6 value and gestational age at the time of sampling.

Conclusion: CVF IL-6 appears a promising marker for predicting preterm delivery and has a similar utility to CVF fFN and cervical length for predicting preterm birth in symptomatic women.

Key words: preterm delivery, fetal fibronectin, IL-6, cervical length.

Introduction

Preterm delivery remains a major cause of perinatal morbidity and mortality (1) and its rate has not declined over the last two decades despite the improvement in perinatal management (2). Preterm delivery is now thought to be a syndrome initiated by multiple mechanisms, including infection or inflammation, uteroplacental ischemia or hemorrhage, and other immunologically mediated processes (3). Commonly used methods to predict preterm delivery, such as obstetrical history or symptoms and epidemiological risk factors, are neither sensitive nor specific (2, 3). Assessing the probability of preterm delivery is still a clinical challenge and is important because it might prevent unnecessary and potentially risky interventions and could reduce treatment costs (4). Several different approaches have been used to lower the incidence of preterm birth and defining risk factors for prediction of preterm delivery is a reasonable goal (5).

Fetal fibronectin (fFN), an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes between the chorion and the decidua, has been studied as a predictor of preterm delivery [6]. This high molecular weight glycoprotein seems to play an essential role in maintaining the integrity of the chorionic-decidual interface. fFN is found at very low levels in cervicovaginal (CVF) secretions under normal conditions. Levels ≥50 ng/mL at or after 22 weeks' gestation have been associated with an increased risk of spontaneous preterm birth (7,8,9).

Transvaginal cervical length (CL) measurement is the other validated test to predict preterm birth in women with threatened preterm labor as well as in asymptomatic high-risk and low-risk women (3,8). A CL measurement of 25 mm or less is generally considered an excellent indicator of an increased risk of preterm delivery, particularly among women with preterm labor. Several studies have reported that fFN screening and CL measurement provided similar results in predicting the risk of preterm delivery (10,11,12,13). Availability of one of the two tests may be an issue in some facilities because the ultrasound expertise for CL measurement may not be always available in small centers. On the other hand, fFN is a costly test to perform; therefore a test that performs similarly to fFN at a lower cost would be an attractive alternative (14).

Cytokines have been investigated as biomarkers of impending preterm delivery and may be involved in the etiology of preterm birth through their stimulation of prostaglandin synthesis (15). Increased serum and amniotic fluid concentrations of several cytokines, including interleukin (IL)-6, have been reported in women with preterm labor (16,17). The use of CVF fluid is a less invasive alternative to amniotic fluid testing for monitoring markers of preterm delivery. IL-6 is a phosphoglycoprotein which consists of 212 amino acids produced by fibroblasts, monocytes, macrophages, endometrial stromal cells, amnion, chorion, and decidual cells [18,19]. The purpose of this study was to evaluate the usefulness of measuring cervicovaginal proinflammatory cytokines (IL-6) and fetal fibronectin in addition to ultrasound CL measurement for the prediction of preterm delivery in patients with threatened preterm labor.

Patients and methods

The study was conducted at the Department of Obstetrics and Gynecology Taiba hospital from May 2008 to February 2010 and comprised 115 singleton pregnant women at 24 to 34 weeks' gestation and admitted with a clinical diagnosis of preterm delivery and intact membranes after providing informed consent. Preterm delivery was defined by the presence of regular uterine contractions occurring at least four times per 30 minutes, confirmed by external tocography, and significant cervical changes on digital examination. Exclusion criteria were preterm premature rupture of membranes, diagnosed intrauterine fetal growth retardation, multiple pregnancy, cervical cerclage, cervical dilatation > 3 cm, known fetal congenital anomaly, preeclampsia, or medically indicated preterm delivery before 34 weeks, vaginal bleeding, placenta previa or abruptio placentae.

At presentation to the hospital a sterile speculum examination was performed, a specimen of CVF was collected for fFN, as recommended by manufacturer, by using a Dacron® swab that was placed in the posterior fornix of the vagina for 10 seconds. Once the specimen was obtained, the swab was inserted into a tube containing 1 mL of fFN extraction buffer provided with the Specimen Collection Kit. fFN was measured with the Rapid fFN TLi TM Analyzer (Adeza Biomedical, Sunnyvale, Calif USA), a qualitative membrane immunoassay that uses a monoclonal anti-fFN antibody coupled to a blue microsphere and an immobilized polyclonal goat antifibronectin antibody. The intensities of the test and control lines on the device were interpreted with the TLi analyzer. Specimens with fFN concentrations >50 µg/L were interpreted as positive (4).

For IL-6 determination, CVF was collected with a cotton swab from the external cervical os. Subsequently It was transferred to Amies liquid medium (Copan Diagnostics Inc., CA). It was then stored in a -20 °C freezer until assay. IL-6 concentrations were assessed by Immulite 2000(DPC, LA, CA, USA) system immunoassay. IL-6 (L2K6P2) kit is a two solid phases immuno-metric assay, based on the capture of monoclonal antibodies for human IL- 6, and posterior polyclonal detection of alkaline phosphate labeled antibodies. The measurement unit used was pg/ml. The IL-6 cutoff was 210 pg/ml (15)

After collection of the cervical sample, a transvaginal sonographic measurement of CL was performed using a 6.5 MHz transvaginal probe (Aloka SSD 900). Transvaginal sonography was carried out by appropriately trained sonographers using a standard protocol (empty bladder, minimal pressure, measurement of the maximum length between the internal and external os, before and after Valsalva maneuver), as previously described (20,21). The clinical team was not blinded to the results of fFN, IL-6 testing and CL measurements.

The women were admitted to the delivery unit for further monitoring, management and follow up. Administration of tocolytics was determined by the attending obstetricians. Clinical data were then recorded and included demographic information, medical and obstetrical history. The study was approved by the Institutional Review Board of the hospital.

Outcomes

Outcome variables were the occurrence of preterm delivery within 7days and within 2 weeks of admission to the study, delivery at <34 and <37 weeks and admission-to-delivery interval.

Statistical analysis

Statistical analysis was performed by using SPSS Statistics Package (SPSS Inc., Chicago, IL). Chi-square test, Student's t test, Pearson's correlation, receiver operating characteristic (ROC) curves were used, p Values < 0.05 were considered significant. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive and negative likelihood ratio (LR) and confidence intervals (CI) for IL-6, fFN and CL were calculated.

Results

One hundred and fifteen women with threatened preterm delivery were enrolled in this study. Of whom 5 (4.3%) patients were lost to follow-up, so the data were available for analysis from 110 (95.6%). IL-6 had a significant positive correlation with fFN levels (r= 0.453, p= 0.005), and inverse correlation with cervical length(r = -0.71, p < 0.001), gestational age at delivery (r = -0.63, p < 0.001) and interval exploration to delivery (r = -0.38, p < 0.001). However, there was no correlation between IL-6 value and gestational age at the time of sampling.

Demographic characteristics of the study population are shown in Table 1.

Table 1: Demographic characteristics of study population.

Variable

n =110

Maternal age (years)*

27.3±4.9

Gestational age at examination (weeks)*

29.6±3.5

Gestational age at delivery (weeks)*

35.8±2.1

Parity

Nulliparous, n (%)

49(44.5%)

Multiparous, n (%)

61(55.5%)

Previous preterm delivery, n (%)

32(29.1%)

Delivery within 7 days, n (%)

6(5.4%)

Delivery within 15 days, n (%)

10(9.1%)

Delivery before 34 weeks, n (%)

13(18.8%)

Delivery before 37 weeks, n (%)

24(21.8%)

Admission to delivery interval (days)*

53.2±27.7

Cervical length (<25mm), n (%)

29(26.4%)

Positive fFN, n (%)

25(22.7%)

Positive IL-6, n (%)

23(20.9%)

* Data presented as mean ±SD; fFN: fetal fibronectin; IL-6: interleukin -6

The performance characteristics of IL-6, fFN and CL measurments to predict preterm delivery before 37, 34 and 32 weeks, within the first 7days and within 2 weeks after assessment are shown in Table 2. Each variable had a high NPV that was increased further with diminished time between sample collection and delivery. The diagnostic power of IL-6 and fFN decreased when predicting a longer interval from the test to delivery.

Table 2: Performance characteristics of IL-6 (>210 pg/ml), fFN (≥50 ng/ml) and cervical length (<25mm) in prediction of preterm delivery.

Delivery

Sensitivity (%) (95%CI)

Specificity (%) (95%CI)

PPV(%)

(95%CI)

NPV(%) (95%CI)

LR+

(95%CI)

LR-

(95%CI)

< 7 days

IL-6 +

83.3

(35.9-99.6)

82.6

(74.0-89.4)

21.6

(7.1-44.1)

98.9

(93.8-100.0)

4.81

(3.3-7.0)

0.20

(0.03-1.3)

fFN +

83.3

(35.9-99.6)

80.7

71.9 - 87.8

20.1

6.9-40.9)

98.8

(93.6 -100.0)

4.3

(3.0-6.3)

0.21

(0.03-1.3)

C L<25mm

66.6

(22.3-95.7)

75.9

66.6-83.8

13.7

3.7-31.9)

97.6

(91.4-99.7)

2.7

(1.6-4.9)

0.44

(0.1-1.4)

<2 weeks

IL-6 +

70.0

(34.-93.3)

84.0

75.3-90.6

30.5

13.2-52.9)

96.5

(90.2-99.3)

4.3

(2.9-6.6)

0.36

(0.1-1.0)

fFN +

80.0

(44.4-97.5)

83.0

74.2-89.8

32.0

(15.0 -53.5)

97.6

(91.7-99.7)

4.7

(3.4 - 6.5)

0.24

(0.06-0.9)

C L<25mm

80.0

(44.4-97.5)

79.0

(69.7-86.5)

27.6

(12.7- 47.3)

97.5

(91.3-99.7)

3.8

(2.7-5.3)

0.25

(0.07-0.9)

< 34 weeks

IL-6 +

69.2

(38.6-90.9)

85.5

(77.0-91.9)

39.1

(19.3-61.9)

95.4

(84.2-99.4)

4.8

(3.3-7.0)

0.36

(0.1-0.9)

fFN +

69.23

(38.6-90.9)

83.51

74.6-90.3

36.0

(17.6-57.9)

95.3

(88.4-98.7)

4.20

(2.9-6.1)

0.37

(0.1-0.9)

C L<25mm

84.6

(54.6-98.1)

81.4

(72.3-88.6)

37.9

(20.4-58.1

97.5

(91.4 - 99.7)

4.5

(3.5 - 5.9)

0.19

(0.05-0.7)

< 37 weeks

IL-6 +

58.3

(36.6-77.9)

89.5

(81.1-95.1)

60.8

(38.0-80.7)

88.5

(79.9-94.4)

5.5

(3.9-7.9)

0.47

(0.2-1.0)

fFN +

62.5

(40.6-81.2)

88.3

79.7-94.3

60.0

(38.2-79.2)

89.4

(80.9-95.0)

5.3

(3.9-7.4)

0.42

(0.2-0.9)

C L<25mm

87.5

(67.6-97.3)

90.7

(82.5-95.9)

72.4

(52.0- 87.5)

96.3

(89.6-99.2)

9.4

(8.0-11.1)

0.14

(0.04-0.5)

PPV : positive predictive value; NPV: negative predictive value

LR+ : likelihood ratio for a positive result; CL: cervical length;

LR+ : likelihood ratio for a positive result; fFN+: positive fetal fibronectin test

IL-6 +: positive interleukin -6 test

The area under the curve to predict preterm delivery [AUC (95%CI)] for IL-6, fFN and cervical length <25mm, were significant at different gestational ages (Table 3).

Table 3: Area under the curve (AUC) of IL-6(>210 pg/ml), fFN (≥50 ng/ml) and cervical length (<25mm) for prediction of preterm delivery.

Delivery

AUC (95%CI)

Z statistic 

P

Within 7 days

IL-6 +

0.83 (0.74 -0.89)

3.86

0.0001

fFN +

0.82 (0.73 -0.88)

3.74

0.0002

C L <25mm

0.71 (0.61-0.79)

1.98

0.0474

Within 2 weeks

IL-6 +

0.77 (0.68 - 0.84)

3.43

0.0006

fFN +

0.81 (0.73 - 0.88)

4.54

<0.0001

C L <25mm

0.79 (0.71 - 0.86)

4.23

<0.0001

< 34 weeks

IL-6 +

0.77 (0.68 - 0.84)

3.97

0.0001

fFN +

0.76 (0.67 - 0.83)

3.80

0.0001

C L <25mm

0.83 (0.74 - 0.89)

5.92

0.0001

< 37 weeks

IL-6 +

0.73 (0.64 - 0.81)

4.43

<0.0001

fFN +

0.75 (0.66 - 0.83)

4.76

<0.0001

C L <25mm

(0.89 (0.81 - 0.94)

10.31

<0.0001

AUC: area under the curve; 95%CI: 95% confidence interval 

CL: cervical length; fFN+: positive fetal fibronectin test; IL-6 +: positive interleukin -6 test.

When comparing the performance of the 3 test variables, the difference between AUC (95%CI) were not significant in predicting preterm delivery within 7 and 15 days of admission to the study and at < 34 weeks (p>0.05). However, The ROC curves demonstrated that prediction of preterm delivery at <37 weeks provided by cervical length appeared to be better than that provided by IL-6 and fFN (Table 4).

Table 4: Comparison of performance of IL-6(>210 pg/ml), fFN (≥50 ng/ml) and cervical length (<25mm) in prediction of preterm delivery.

Variable

< days

<15 days

<34 weeks

<37 weeks

IL-6 versus fFN

Difference between AUC (95%CI)

0.009

(-0.01-0.02)

0.045

(-0.05-0.14)

0.013

(0.01-0.02)

0.021

(-0.02-0.06)

P

0.1553

0.3705

0.1551

0.3173

IL-6 versus CL

Difference between AUC (95%CI)

0.117

(-0.04-0.28)

0.0250

(-0.07-0.12)

0.056

(-0.04-0.16)

0.152

(0.05-0.24)

P

0.1649

0.6253

0.2886

0.0015

fFN versus CL

Difference between AUC (95%CI)

0.107

(-0.05-0.27)

0.020

(0.01-0.03)

0.0666

(-0.03-0.17)

0.131

(0.04-0.22)

P

0.2012

0.0423

0.2052

0.0040

AUC: areas under the curve; 95%CI: 95% confidence interval 

CL: cervical length; fFN: fetal fibronectin test; IL-6: interleukin -6

Discussion

Preterm birth accounts for approximately three fourths of all neonatal deaths and approximately half of long-term neurologic disability (17). It is known that certain socio-demographic factors are associated with an increased risk of preterm delivery, as is the elevation of several biochemical markers. An ideal test to identify preterm delivery risk should be both sensitive and highly specific, allowing targeted management so as to optimize the care delivered to both mother and baby (22).

The results of this study showed that Positive CVF IL-6, CVF fFN values and CL measurements were associated with a statistically significant increased risk of delivery within 7days, within 2 weeks, before 34 or 37 weeks in women with threatened preterm delivery. The values of different tests in predicting preterm delivery at different gestational ages are shown in Table 2. When comparing the performance of the 3 test variables, the difference between AUC (95%CI) were not significant in predicting preterm delivery within 7days, 2 weeks or before 34 weeks. However, the ROC curves demonstrated that, prediction of preterm delivery before 37 weeks provided by cervical length appeared to be better than that provided by IL-6 or fFN. These findings are consistent with previous reports (4,14,15,17).

The results of the present study are in agreement with the fact that cervical length is a good predictor of preterm delivery, and the accuracy of the test improves in symptomatic women (cervical assessment distinguishes those likely to deliver with threatened preterm labor) (21). Also, fFN adds prognostic information to that provided by scanning cervical length in patients with preterm uterine contractions and intact membranes (12). The selective use of fFN after cervical length measurement is more specific than cervical length alone (13).

The results from this study showed that CVF IL-6 (for which reagent costs are $7/test compared to >$100/fFN assay) has similar utility to CVF fFN for predicting preterm birth with potential cost redution. The utility of both markers is in their high NPV and specificity which enable physicians to avoid unnecessary interventions in women who are unlikely to deliver early. Likelihood ratios provide an alternative criterion for evaluation of test diagnostic value. Negative likelihood ratios <0.2 are needed to provide strong diagnostic evidence in rule-out situations (14). By this criterion, given the negative likelihood ratios of 0.2 for CVF fFN at delivery within14 days and 0.2 for CVF IL-6 at delivery within 7 days, both tests can be rated strongly for ruling out preterm delivery at those gestational ages.

The high NPV of IL-6 and fFN for delivery within 7days (98.9% and 98.8% respectively, prevalence 5.4%) and 14 days 96.5% and 97.6% respectively, prevalence 9.1 %) are consistent with other studies (4,9,11,14,15).

Our results observed no correlation between gestational age at the time of sampling and the concentration of CVF IL-6. Woodworth el al (14) also reported no correlation between gestational age and CVF concentrations of IL-6 collected from symptomatic women at 24 and 34 of gestation Brik el al (15) reported similar findings with IL-6 in symptomatic women at 24 to 34 weeks of gestation. Furthermore, the present results found significant positive correlation with fFN (r= 0.453, p= 0.005) and an inverse correlation with cervical length(r = -0.71, p < 0.001), gestational age at delivery (r = -0.63, p < 0.001) and interval admission to delivery (r = -0.38, p < 0.001). These findings are consistent with previous reports (14, 15).

Previous cervical IL-6 cut-off points reported range from 20 to 250 ng/ml (14,15,19,23). There is no agreement in the literature on the sensitivity and specificity of cervical IL-6. In those studies which include symptomatic women, the sensitivity varies from 50.0% to 100.0% and specificity from 67.0% to 86.6% (24). This discrepancy can be explained by both the methods used for detecting CVF IL-6 are not standardized, and there are differences among the studies. Some authors used Amies medium for collection of the sample (23) and others used saline solution (24). Moreover, the definition of preterm delivery is not constant, some authors used below 34 and others used below 37weeks.

One consistent feature of all previous clinical studies performed, has been the disappointing magnitude of false positive fFN results which contributes to the low PPV of fFN for predicting preterm delivery. There could be a number of reasons for the degree of false positives apart from the possibility of occult contamination of the cervico-vaginal secretions by blood or plasma (4).

A systematic review showed that, IL-6 in CVF but not in plasma is strongly associated with spontaneous preterm birth in asymptomatic women, suggesting that inflammation at the maternal-fetal interface, rather than systemic inflammation, may play a major role in the etiology of such spontaneous preterm births. The demonstration of association between IL-6 and spontaneous preterm birth raises the question as to whether the evaluation of inflammatory cytokine reactivity may be valuable even in the clinical management of asymptomatic patients (17)

Conclusion

A negative IL-6 or fFN test is useful in ruling out an imminent preterm delivery, whereas the implication of a positive test is uncertain. It can be recommended in high risk women who fulfill the criteria of intact membranes, minimal cervical dilatation (<3 cm), and gestation between 24-34 weeks. CVF IL-6, therefore, appears a promising marker for predicting preterm delivery in high risk women while offering the potential for substantial cost reductions.

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