Original Article
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What Is the Risk of Preterm Delivery after Arrested Preterm Labor? Femke F. Wilms, MD1 Jolande Y. Vis, MD, PhD2 Laura de Wit-Zuurendonk, MD1 Martina M. Porath, MD, PhD1 Ben Willem J. Mol, MD, MSc, PhD3
Veldhoven, The Netherlands 2 Department of Clinical Chemistry and Hematology, University Medical Center, Utrecht, The Netherlands 3 The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia
Address for correspondence Femke Wilms, MD, Department of Obstetrics and Gynecology, Máxima Medical Centre, P.O. Box 7777, 5500 MB Veldhoven, The Netherlands (e-mail: [email protected]).
Am J Perinatol 2015;32:63–70.
Abstract
Keywords
► arrested preterm labor ► cervical length ► fetal fibronectin ► preterm delivery
Objective The aim of this study is to assess if women with arrested preterm labor (PTL) have an increased risk of preterm delivery (PTD) compared with healthy pregnant women, and if digital examination, fetal fibronectin (fFn) and cervical length (CL) are prognostic markers for PTD after arrested PTL. Study Design Prospective-matched cohort study among women with arrested PTL (cases) and healthy pregnant women (controls). Results We included 74 index cases and 74 controls. PTD occurred in 20 (27%) index cases and in 5 (7%) controls (hazard ratio [HR], 4.5; 95% confidence interval [CI], 1.7–12). A dilatation of the cervix 1 cm (HR, 9.1 [95% CI, 3.3–25], an fFn positive status (HR, 13 [95% CI, 4.3–40]), and a CL < 15 mm (HR, 11 [95% CI, 3.1–38]) increased this risk in cases compared with controls. Knowledge of the fFn result had additional value over the cervical dilatation or CL in the prediction of persistent PTD, with an increased risk in case of a positive fFn test. Conclusion Women stay at increased risk for PTD after arrested PTL. This risk further increased in case of 1 cm cervical dilatation, CL < 15 mm and/or a positive fFn status.
Preterm delivery (PTD) is one of the most important problems in modern obstetric care in the Western world. Of all deliveries, 5 to 13% occur preterm and it is the major cause of perinatal mortality and neonatal morbidity.1,2 PTD can either be preceded by premature rupture of the membranes or by regular uterine contractions leading to cervical changes. Women with symptoms of preterm labor (PTL) are treated with tocolysis to prolong pregnancy, and antenatal corticosteroids to prepare the fetal lungs for a life independent of the mother.3–9 Accurate prediction of those women with symptoms of PTL who will deliver prematurely is difficult. Only a small portion ( 5%) of these symptomatic women delivers
within 7 days after admission to the hospital, whereas approximately 50 to 70% delivers after 37 weeks’ gestation.10–13 Digital examination of the cervix is often the first test performed in the assessment of the risk of PTD in women with symptoms of PTL. Little research has been performed to assess the predictive value for PTD in women with symptoms of PTL. Digital examination on its own seems to be of limited use in the prediction of PTD in symptomatic women. With a cutoff value of 2 cm cervical dilatation the likelihood ratio (LR) for the prediction of PTD before a gestational age (GA) of 37 weeks for a positive test was 2.4 (95% confidence interval [CI],
received February 22, 2014 accepted March 1, 2014 published online May 16, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1374818. ISSN 0735-1631.
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1 Department of Obstetrics and Gynecology, Máxima Medical Centre,
Risk of Preterm Delivery after Arrested Preterm Labor 1.4–3.8) with a corresponding LR for a negative test of 0.48 (95% CI, 0.27–0.78).14 The positive LR for the effacement of the cervix with a cutoff of 40% was of 2.0 (95% CI, 1.1–3.2) and the negative LR was 0.54 (95% CI, 0.3–0.9).14 Cervical length (CL) measurement and the fetal fibronectin (fFn) test can improve the risk assessment of PTD within 7 days after admission. The likelihood of PTD within 7 days after presentation in women with symptoms of PTL for a CL below 15 is 5.7 (95% CI, 3.8–8.65), compared with the LR of 0.5 (range, 0.3–0.8) for a CL above 15 mm.15–17 The fFn is 4.2 times (95% CI, 3.5–5.0) more likely to be positive in symptomatic women who will deliver within 7 to 10 days after testing, than in symptomatic women who stay pregnant beyond than that period of time. The corresponding LR for the negative test is 0.29 (95% CI, 0.22–0.38).18 The test is of particular clinical interest if its result is negative, virtually ruling out a PTD within the following 7 days. Combining the two tests improves the prediction of PTD within 7 days after presentation, especially when adding fFn in women with a CL between 16 and 30 mm. No additional value was found for fFn testing if the CL was below 15 mm or above 30 mm.10,11,19–21 Thus, even after performing these additional tests, we treat substantially more women than actually deliver within 7 days. If pregnancy continues after arrested PTL, some women might remain at higher risk for PTD, and some may be reassured. Yet, no large studies have focused on risk prediction of PTD after arrested PTL, which leaves room for improvement to individualize and optimize prenatal care in these women. We therefore studied women with arrested PTL after treatment with tocolysis and antenatal corticosteroids, to evaluate their persistent risk of PTD and evaluate the prognostic value of the digital examination of the cervix, the fFn test, and the CL.
Methods We performed a prospective matched cohort study among women with a singleton pregnancy, who were discharged after receiving treatment for threatened PTL in 2006. In the Netherlands, first assessment of initially healthy pregnant women with symptoms of PTL is most often performed by midwives by digital examination before referral to a hospital. If women are at high risk of PTD, they will be referred to one of the 10 perinatal centers with a tertiary referral function to receive further treatment.
Participants and Interventions The women were a subset of a prospective observational cohort study performed in 2006 in three Dutch hospitals to evaluate the predictive value of fFn in 101 women presenting with symptoms of PTL at a GA between 24 and 34 weeks. This cohort study was approved by the institutional review board (IRB) of Leiden University Medical Centre (number, P0–050).22 PTL was defined as uterine contractions leading to cervical changes. At the time of the study, the use of CL measurement was not universally implemented. Therefore, women with any cervical changes due to uterine contractions American Journal of Perinatology
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Wilms et al. at initial assessment or at reassessment after a couple of hours of observation, either by digital examination or by measurement of the CL by vaginal ultrasound, were enrolled. Exclusion criteria were preterm ruptured membranes, cerclage of the cervix, cervical dilation of more than 3 cm at admission, and previous treatment for PTL in the current pregnancy. Vaginal blood loss in the past 24 hours was not a reason for exclusion. At admission, an fFn test (QuikCheck fFn, Adeza; Sunnyvale, CA; cutoff 0.050 μg/mL) was taken. Providers were blinded to the results of the fFn tests until all included women had delivered. Treatment consisted of hospital admission, tocolysis, and administration of antenatal corticosteroids. The tocolytic drug of first choice in our hospital at the time of this study was nifedipine, administered in a 5-day reducing regime. Of the included women in the original observational cohort study, 13% delivered within 7 days after admission. The women with arrested PTL who were discharged home were the subset of women eligible for this study. These women are referred to as the index cases. The original cohort study included multiple pregnancies, but these were excluded for this analysis. Index cases were matched to a control group of healthy pregnant women without an episode of PTL. Women in the control group were recruited from midwifery practices in the same region and from our own perinatal center. The controls were matched for age, parity, and previous PTD. Controls were randomly matched to the cases during their pregnancy at the same GA as the GA at admission of their matched cases. They received care as usual and their charts were only reviewed retrospectively after delivery. Therefore, this part of the study was not subjected to the Dutch Medical Research Involving Human Subjects Act (WMO), since the WMO states that IRB approval is only needed if the study participants have to be physically present during the study, and no IRB approval is necessary in The Netherlands in retrospective studies or status studies looking at patient records.23
Outcomes, Subgroups, and Sample Size Primary outcome was PTD, which was defined as delivery at a GA before 37 weeks. Secondary, we assessed the effect of the GA at PTL, digital examination, CL, and fFn status on the risk of PTD before 37 weeks gestation after arrested PTL. The power analysis was based on the hypothesis that 28% of the women in the index group would deliver preterm after a treated episode of PTL in comparison to 8% of the women in a healthy population.13 On the basis of this assumption, at least 57 cases in each group were needed (α ¼ 0.05 and β ¼ 0.80).
Statistical Analysis The proportions of PTD between the index and control groups were compared with chi square test. Cox proportional hazards regression analysis was performed, providing a risk for PTD, calculated from the time from admission for PTL until delivery, censored at 37 weeks of gestation. Time from followup until PTD before a GA of 37 weeks was evaluated with a Kaplan–Meier curve. To assess the relationship between the
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Wilms et al.
Fig. 1 Flow diagram.
GA at the first assessment for PTL and the risk of PTD, GAs at delivery were compared for three different groups by GA at admission for PTL (24–276/7 weeks, 28–316/7 weeks, and 32–346/7 weeks). Cox proportional hazards regression analyses were performed to assess the influence of dilatation of the cervix, the CL and fFn status on the persistent risk of PTD in the time from admission until delivery, censored at 37 weeks’ gestation. For the digital examination, a receiver operator characteristics (ROC) curve was computed to determine the best cutoff value. For the CL, a cutoff of 15 mm was used based on literature.15–17 To evaluate whether fFn influences the predictive value of cervical dilatation or CL measurement on the outcome PTD within 7 days, interaction terms were used. If the p value for interaction was below 0.05, HRs were reported for the index cases and controls. All statistical analyses were performed using SPSS software, version 21.0 (SPSS Inc. Chicago, IL)
Results The initial cohort consisted of 101 women with PTL, of whom 13 women (13%) delivered within 7 days after admission. Of the remaining 88 women who did not deliver after this episode of PTL and were discharged from the hospital, 9 were pregnant with twins and therefore excluded for this study. Matched controls were found for 74 index cases of the 79 eligible women, which would be sufficient based on our power calculation (►Fig. 1). The median gestational age (GA) at inclusion was 293/7 (inter quartile range [IQR], 275/7–313/7 weeks) weeks in both groups. The median age of the cases was 30 years (IQR, 26–33 years) versus 31 years IQR, 27–34 years) in the controls. As a
result of matching, parity in both the groups was comparable, with 41 women (55%) in each group being multiparous, of whom 13 (18%) had a previous PTD (►Table 1). The median GA at delivery was 382/7 (IQR, 363/7–393/7 weeks) weeks in the index cases, compared with 396/7 (IQR, 391/7–404/7 weeks) weeks in the controls. Delivery before 37 weeks occurred in 20 (27%) index cases, and in 5 (7%) controls (p ¼ 0.001) (►Table 2). Of the index cases, nine women (12%) delivered before 34 weeks, compared with none of the women in the control group (p ¼ 0.002).The index cases were at higher risk for PTD compared with the controls (hazard ratio [HR], 4.5 [95% CI, 1.7–12.1]) (►Table 2). Time from admission to PTD of index and control women is expressed in a Kaplan–Meier plot (►Fig. 2).
Gestational Age at Admission Of the index cases, 20 women (27%) were admitted with symptoms of PTL at a GA between 24 and 276/7 weeks, 37 Table 1 Baseline characteristics Maternal characteristic
Index cases (n ¼ 74)
Controls (n ¼ 74)
Gestational age at inclusion, wka
293/7 (275/7–313/7)
Matched
Age, ya
30 (26–33)
31 (27–34)
33 (45)
33 (45)
Parity Nulliparous, n (%) Multiparous, n (%)
41 (55)
41 (55)
Previous PTD, n (%)
13 (18)
13 (18)
Abbreviations: IQR, inter quartile range; PTD, preterm delivery. a Data given as median (IQR). American Journal of Perinatology
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Risk of Preterm Delivery after Arrested Preterm Labor
Risk of Preterm Delivery after Arrested Preterm Labor
Wilms et al.
Table 2 Delivery before a gestational age of 37 weeks Delivery < 37 weeks GA Cases (n ¼ 74), N (%) Total Dilatation CL
fFn
HR PTD < 37 wk (95% CI)
20/74 (23)
Controls (n ¼ 74), N (%) 5/74 (7)
HR PTD < 37 wk (95% CI) 4.5 (1.7–12.1)
< 1 cm
4/36 (11)
1 cm
14/31 (45)
5.4 (1.8–16.5)
9.1 (3.3–25.2)
15 mm
6/10 (60)
4.4 (1.6–11.9)
11 (3.1–38)
> 15 mm
11/57 (19)
Positive
14/28 (50)
Dilation < 1 cm
2/10 (20)
1 cm CL 15 mm > 15 mm
1.6 (0.44–6.1)
2.5 (0.84–7.5) 5.7 (2.2–15.2)
13.0 (4.3–39.7) 3.6 (0.69–18.3)
11/16 (69)
16.5 (5.7–47.9)
5/7 (71)
26.8 (17.4–96.8)
6/17 (35)
6.0 (1.8–19.7)
Negative
4/46 (9)
2.0 (0.60–6.4)
Dilation < 1 cm
2/26 (8)
1.1 (0.21–5.5)
3/15 (20)
3.5 (0.83–14.5)
1/3 (33)
4.1 (0.48–35.5)
5/40 (13)
1.9 (0.56–6.7)
1 cm CL 15 mm > 15 mm
Abbreviations: CI, confidence interval; CL, cervical length; fFn, fetal fibronectin; GA, gestational age; HR, hazard ratio; PTD, preterm delivery; wk, weeks. 9.5% missing
(50%) between 28 and 316/7 weeks, and 17 (23%) between 32 and 346/7 weeks. The median GA at delivery in the group of women admitted between 24 and 276/7 weeks was 383/7 (IQR, 360/7–393/7 weeks) weeks, in the group of women admitted between 28 and 316/7 weeks 385/7 (IQR, 363/7–396/7 weeks) weeks, and in the group of women admitted between 32 and 346/7 weeks 380/7 (IQR, 363/7–391/7 weeks) weeks.
Digital Examination Among the 74 index cases, 36 (49%) women had no cervical dilatation, 23 (31%) women had a cervical dilatation of 1 cm, in 6 (8%) women the dilatation was 2 cm, and in 2 (3%) women it was 3 cm. The best cutoff for the cervical dilatation determined by a ROC curve was 1 cm (using cervical dilatation < 1 cm as a positive test result and a cervical dilatation 1 cm as a negative test result) (sensitivity 78% and specificity 65%, with an area under curve of 0.69) (►Fig. 3). Of the 36 index cases, 4 (11%) with a cervical dilatation < 1 cm delivered prematurely, compared with 14 of the 31 (45%) index cases with a cervical dilatation of 1 cm (p ¼ 0.002) (►Table 2). A cervical dilatation of 1 cm increased the risk for delivery before 37 weeks as compared with cases with less dilatation (HR, 5.4 [95% CI, 1.8–16.5]). Cases with a cervical dilatation 1 cm had an increased risk of PTD compared with controls (HR, 9.1 [95% CI, 3.3–25.2]), while cases with a dilatation < 1 cm were not at higher risk of PTD compared with controls (HR, 1.6 [95% CI, 0.44–6.1]) (►Table 2).
Cervical Length
Fig. 2 Kaplan–Meier plot. Time from admission to preterm delivery: cases vs. controls. PTD, preterm delivery; PTL, preterm labor. American Journal of Perinatology
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Index cases had a mean CL at admission of 28 mm (SD 14 mm). Ten index cases had a CL 15 mm, of whom 6 (60%) delivered preterm and 57 had a CL > 15 mm, of whom 11 (19%) delivered prematurely (p ¼ 0.006) (►Table 2). A CL 15 mm increased the risk for delivery before 37 weeks as compared with cases with a CL > 15 mm (HR, 4.4 [95% CI, 1.6–11.9]). In comparison to the control group, index cases
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who had < 1 cm dilatation and a negative fFn test, cases with 1 cm dilatation and a negative fFn test and cases with < 1 cm dilatation and a positive fFn test (►Table 2).
The mean CL in the index cases with a positive fFn test was 23 mm (SD 15 mm) and differed significantly from the mean CL in the index cases with a negative fFn test (31 mm) (SD 13 mm) (p ¼ 0.03). Compared with the prediction model of CL as a sole predictor of persistent PTD, the model fit did improve if fFn was added (chi square 7.20, p ¼ 0.007). In comparison to controls, the risk of delivery before 37 weeks was increased in index cases who had a positive fFn test and a CL > 15 mm (HR, 6.0 [95% CI, 1.8–19.7]) and in cases with a positive fFn test and a CL 15 mm (HR, 26.8 [95% CI, 7.4–96.8]). No significant increase in this risk could be found in index cases with a negative fFn and either a CL > 15 mm or a CL 15 mm (►Table 2).
Discussion Fig. 3 ROC curve of cervical dilatation for preterm delivery. ROC, receiver operator characteristics.
with a CL 15 mm were at higher risk of PTD (HR, 11 [95% CI, 3.1–38]), whereas the risk in cases with a CL > 15 mm did not differ significantly from the control group (HR, 2.5 [95% CI, 0.84–7.5]).
Fetal Fibronectin Among the 74 index cases, fFn tests were positive in 28 women. These 28 women had a median GA at delivery of 365/7 (IQR, 332/7–390/7 weeks) weeks. The 46 index cases with a negative fFn test had a median GA at delivery of 390/7 (IQR, 374/7–395/7 weeks) weeks. Of the 28 the fFn positive index cases, 14 (50%) delivered prematurely. Among the fFn negative cases, four (9%) women delivered preterm (p ¼ 0.001) (►Table 2). In comparison to the women of the control group, index women with a positive fFn test were at increased risk of PTD (HR, 13.0 [95% CI, 4.3–39.7]), while no significant difference in delivery rates before 37 weeks was found between the fFn negative cases and the controls (HR, 2.0 [95% CI, 0.60– 6.4]). The index cases with a positive fFn test were at higher risk for PTD weeks compared with the fFn negative cases (HR, 5.7 [95% CI, 2.2–15.2]).
Digital Examination and Fetal Fibronectin The mean cervical dilatation in the index cases with a positive fFn test was 0.85 cm ( SD, 0.83) and differed significantly from mean cervical dilatation of 0.46 cm (SD 0.7) in the index cases with a negative fFn test (p ¼ 0.037). Compared with the prediction model of digital examination as a sole predictor of persistent PTD, the model fit improved if fFn was added to the model (chi square 8.648, p ¼ 0.003). In comparison to controls, the risk of delivery before 37 weeks was increased in index cases who had 1 cm dilatation and a positive fFn test (HR, 16.5 [95% CI, 5.7–47.9]). No difference was found among index cases
Main Findings In this prospective matched cohort study, we found that women who remain undelivered after an episode of PTL remain at increased risk of PTD as compared with low risk pregnant women without such symptoms (HR, 3.8 [95% CI, 1.4–10]). Especially women with dilatation of the cervix of 1 cm, a positive fFn test or a CL below 15 mm remained at higher risk for PTD compared with healthy pregnant women, whereas this difference was not found in women with a dilatation < 1 cm and in women with a CL above 15 mm and/or a negative fFn test. The knowledge of the fFn status improved the prediction of persistent PTD in women with arrested PTL when added to examination of the cervical dilatation of CL measurement. A fibronectin positive status further increases the persistent risk of PTL.
Strengths and Limitations To our best knowledge, our study is unique in comparing the risk of PTD in women after arrested PTL to the risk of PTL in a healthy population of pregnant women. Even though the mean CL and the median GA at delivery of the women who remained pregnant after an episode of threatened PTL might suggest we studied a low risk population, their PTD risk was higher than the overall PTD risk in the Netherlands. The incidence of PTD in singleton pregnancies in the Netherlands is 6% before 37 weeks and 0.9% before 32 weeks’ gestation.24 The incidence of PTD in our control group is comparable. We do acknowledge that even stronger evidence for persistent risk of PTD might have been found if we would have structurally incorporated the measurement of the CL, in combination with the fFn test, in the risk assessment and diagnosis of PTD. Furthermore, the digital examination, CL and the fFn status of the control group were unknown as the data from this group were extracted from charts of healthy pregnant women. The data concerning the digital examination, the CL and the fFn status were collected at admission of the index cases, but these data were not available at discharge. American Journal of Perinatology
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Cervical Length and Fetal Fibronectin
Risk of Preterm Delivery after Arrested Preterm Labor Another limitation of our study was the small sample size. The absence of a significantly different instantaneous risk for PTD between the control group and women with a long cervix and a negative fFn test might be due to insufficient power. The small sample size also limits us in the number of risk factors for PTD that were evaluated.
Interpretation A prospective cohort study performed in the United States by McPheeters et al describes that 72% of the women admitted for threatened PTL, without immediate delivery, delivered at term.13 This is comparable to our results (77%). They found a PTD rate of 8% in women who had never been diagnosed with PTL, which corresponds to the PTD rate in our control group (7%). They did not provide information about the CL measurement or fFn status. Although the risk of neonatal mortality is relatively low in neonates born after 34 weeks’ gestation, neonates born late preterm appear to be less healthy than infants born at later GA.25–30 However, providing a clear advice on the further management of pregnant women with arrested PTL who remain at higher risk for PTD is difficult. Several treatment strategies have been assessed. Prolongation of hospital admission does not change the course of the pregnancy.31,32 There is no evidence to support bed rest.33 When these women are sent home they should be counseled about recurrence of symptoms of PTL. Prolongation of the pregnancy by maintenance tocolysis has been evaluated. Although a meta-analysis showed a prolongation of the mean number of days gained in patients receiving maintenance tocolysis, they found no difference in neonatal outcome.34 A large RCT evaluating the effectiveness of maintenance tocolysis with nifedipine in women with threatened PTL showed no statistically significant reduction in adverse perinatal outcomes when compared with placebo.35 Systematic reviews have shown that there is insufficient evidence to support the use of maintenance tocolysis with magnesium, terbutaline, or oxytocin antagonists in the prevention of PTD after threatened PTL.36–38 The reported effect of progesterone administration in women with arrested PTL after treatment with tocolysis is conflicting.39–42 Two relatively small RCT’s comparing 400 mg daily vaginal suppository versus no treatment39 and 341 mg 17-α-hydroxyprogesterone caproate (17P) intramuscularly twice weekly40 found a possible positive effect of the administration of progesterone after arrested PTL on the prolongation of pregnancy. A larger RCT comparing 17-α-hydroxyprogesterone caproate versus no treatment concluded that semiweekly injections of 17P did not prolong pregnancy significantly in women with tocolysis-arrested PTL.42 A limitation of all the three RCT’s was the lack of blinding.
Conclusion
under 15 mm. The knowledge of the fFn result improved the prediction of persistent PTD after arrested PTL over the cervical dilatation or CL measurement alone. Further research is recommended on the pathophysiological pathways that precede PTL and delivery, to improve identification of the women who actually will deliver premature and on the treatment strategies in women who remain at risk of PTD after arrested PTL.
Note This study has been presented at the Society for Maternal Fetal Medicine 31th Annual Meeting in San Francisco, February 11, 2011.
References 1 NIH Consensus Development Panel on the Effect of Corticosteroids
2 3 4
5
6
7
8
9
10
11
12
13
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for Fetal Maturation on Perinatal Outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995; 273(5):413–418 Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002; 360(9344):1489–1497 Iams JD. Prediction and early detection of preterm labor. Obstet Gynecol 2003;101(2):402–412 King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003;(1):CD002255 Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2005;(3):CD004452 Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50(4):515–525 Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97(1): 11–25 Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995; 173(1):322–335 Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;(3):CD004454 DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol 2013; 208(3):e1–e6 Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005;192(2): 350–359 Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol 2009;114(3): 631–640 McPheeters ML, Miller WC, Hartmann KE, et al. The epidemiology of threatened preterm labor: a prospective cohort study. Am J Obstet Gynecol 2005;192(4):1325–1329, discussion 1329–1330 Onderoğlu LS. Digital examination and transperineal ultrasonographic measurement of cervical length to assess risk of preterm delivery. Int J Gynaecol Obstet 1997;59(3):223–228
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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Risk of Preterm Delivery after Arrested Preterm Labor
16
17
18
19
20
21
22
23 24
25
26 27 28
cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. BMJ 2002;325(7359):301 Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound Obstet Gynecol 2003;22(3):305–322 Sotiriadis A, Papatheodorou S, Kavvadias A, Makrydimas G. Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis. Ultrasound Obstet Gynecol 2010;35(1):54–64 Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D; NICHD Maternal Fetal Medicine Units Network. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. Obstet Gynecol 1996;87(5 Pt 1):643–648 Wiegerinck MM, Vis JY, Mol BW. Re: Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis. Ultrasound Obstet Gynecol 2010;35(6):756–757, author reply 756–757 Tsoi E, Akmal S, Geerts L, Jeffery B, Nicolaides KH. Sonographic measurement of cervical length and fetal fibronectin testing in threatened preterm labor. Ultrasound Obstet Gynecol 2006;27(4): 368–372 Schmitz T, Maillard F, Bessard-Bacquaert S, et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labor. Am J Obstet Gynecol 2006;194(1):138–143 Wilms FF, van Stralen G, Porath MM, et al. Predicating imminent preterm labour based on a determination of foetal fibronectin in a vaginal smear [in Dutch]. Ned Tijdschr Geneeskd 2009;153:B398 Dutch Medical Research. Available at:http://www.ccmo.nl/en/yourresearch-does-it-fall-under-the-wmo Schaaf JM, Mol BW, Abu-Hanna A, Ravelli AC. Trends in preterm birth: singleton and multiple pregnancies in the Netherlands, 2000-2007. BJOG 2011;118(10):1196–1204 Arnon S, Dolfin T, Litmanovitz I, Regev R, Bauer S, Fejgin M. Preterm labour at 34–36 weeks of gestation: should it be arrested? Paediatr Perinat Epidemiol 2001;15(3):252–256 Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114(2):372–376 Adams-Chapman I. Neurodevelopmental outcome of the late preterm infant. Clin Perinatol 2006;33(4):947–964, abstract xi Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, Petrini JR. Differences in mortality between late-preterm and term singleton infants in the United States, 1995-2002. J Pediatr 2007;151(5): 450–456, e1
69
29 Ramachandrappa A, Jain L. Health issues of the late preterm infant.
Pediatr Clin North Am 2009;56(3):565–577 30 Engle WA, Kominiarek MA. Late preterm infants, early term
31
32
33
34
35
36
37
38
39
40
41
42
infants, and timing of elective deliveries. Clin Perinatol 2008; 35(2):325–341, vi Yost NP, Bloom SL, McIntire DD, Leveno KJ. Hospitalization for women with arrested preterm labor: a randomized trial. Obstet Gynecol 2005;106(1):14–18 Goulet C, Gévry H, Lemay M, et al. A randomized clinical trial of care for women with preterm labour: home management versus hospital management. CMAJ 2001;164(7):985–991 Sosa C, Althabe F, Belizán J, Bergel E. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 2004;(1):CD003581 Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999;181(2):484–490 Roos C, Spaanderman ME, Schuit E, et al; APOSTEL-II Study Group. Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial. JAMA 2013;309(1):41–47 Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2010;(7):CD000940 Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance therapy after threatened preterm labor for preventing preterm birth. Cochrane Database Syst Rev 2002;(4): CD003933 Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2009;(1):CD005938 Review Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2008;48(1):58–63 Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during preterm cervical ripening: effects of 17alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 2007; 196(5):e1–e4, discussion 421 Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009;200(3): 219–224 Rozenberg P, Chauveaud A, Deruelle P, et al; Groupe De Recherche En Obstétrique et Gynécologie. Prevention of preterm delivery after successful tocolysis in preterm labor by 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Am J Obstet Gynecol 2012;206(3):e1–e9
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What Is the Risk of Preterm Delivery after Arrested Preterm Labor? Femke F. Wilms, MD1 Jolande Y. Vis, MD, PhD2 Laura de Wit-Zuurendonk, MD1 Martina M. Porath, MD, PhD1 Ben Willem J. Mol, MD, MSc, PhD3
Veldhoven, The Netherlands 2 Department of Clinical Chemistry and Hematology, University Medical Center, Utrecht, The Netherlands 3 The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Australia
Address for correspondence Femke Wilms, MD, Department of Obstetrics and Gynecology, Máxima Medical Centre, P.O. Box 7777, 5500 MB Veldhoven, The Netherlands (e-mail: [email protected]).
Am J Perinatol 2015;32:63–70.
Abstract
Keywords
► arrested preterm labor ► cervical length ► fetal fibronectin ► preterm delivery
Objective The aim of this study is to assess if women with arrested preterm labor (PTL) have an increased risk of preterm delivery (PTD) compared with healthy pregnant women, and if digital examination, fetal fibronectin (fFn) and cervical length (CL) are prognostic markers for PTD after arrested PTL. Study Design Prospective-matched cohort study among women with arrested PTL (cases) and healthy pregnant women (controls). Results We included 74 index cases and 74 controls. PTD occurred in 20 (27%) index cases and in 5 (7%) controls (hazard ratio [HR], 4.5; 95% confidence interval [CI], 1.7–12). A dilatation of the cervix 1 cm (HR, 9.1 [95% CI, 3.3–25], an fFn positive status (HR, 13 [95% CI, 4.3–40]), and a CL < 15 mm (HR, 11 [95% CI, 3.1–38]) increased this risk in cases compared with controls. Knowledge of the fFn result had additional value over the cervical dilatation or CL in the prediction of persistent PTD, with an increased risk in case of a positive fFn test. Conclusion Women stay at increased risk for PTD after arrested PTL. This risk further increased in case of 1 cm cervical dilatation, CL < 15 mm and/or a positive fFn status.
Preterm delivery (PTD) is one of the most important problems in modern obstetric care in the Western world. Of all deliveries, 5 to 13% occur preterm and it is the major cause of perinatal mortality and neonatal morbidity.1,2 PTD can either be preceded by premature rupture of the membranes or by regular uterine contractions leading to cervical changes. Women with symptoms of preterm labor (PTL) are treated with tocolysis to prolong pregnancy, and antenatal corticosteroids to prepare the fetal lungs for a life independent of the mother.3–9 Accurate prediction of those women with symptoms of PTL who will deliver prematurely is difficult. Only a small portion ( 5%) of these symptomatic women delivers
within 7 days after admission to the hospital, whereas approximately 50 to 70% delivers after 37 weeks’ gestation.10–13 Digital examination of the cervix is often the first test performed in the assessment of the risk of PTD in women with symptoms of PTL. Little research has been performed to assess the predictive value for PTD in women with symptoms of PTL. Digital examination on its own seems to be of limited use in the prediction of PTD in symptomatic women. With a cutoff value of 2 cm cervical dilatation the likelihood ratio (LR) for the prediction of PTD before a gestational age (GA) of 37 weeks for a positive test was 2.4 (95% confidence interval [CI],
received February 22, 2014 accepted March 1, 2014 published online May 16, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1374818. ISSN 0735-1631.
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1 Department of Obstetrics and Gynecology, Máxima Medical Centre,
Risk of Preterm Delivery after Arrested Preterm Labor 1.4–3.8) with a corresponding LR for a negative test of 0.48 (95% CI, 0.27–0.78).14 The positive LR for the effacement of the cervix with a cutoff of 40% was of 2.0 (95% CI, 1.1–3.2) and the negative LR was 0.54 (95% CI, 0.3–0.9).14 Cervical length (CL) measurement and the fetal fibronectin (fFn) test can improve the risk assessment of PTD within 7 days after admission. The likelihood of PTD within 7 days after presentation in women with symptoms of PTL for a CL below 15 is 5.7 (95% CI, 3.8–8.65), compared with the LR of 0.5 (range, 0.3–0.8) for a CL above 15 mm.15–17 The fFn is 4.2 times (95% CI, 3.5–5.0) more likely to be positive in symptomatic women who will deliver within 7 to 10 days after testing, than in symptomatic women who stay pregnant beyond than that period of time. The corresponding LR for the negative test is 0.29 (95% CI, 0.22–0.38).18 The test is of particular clinical interest if its result is negative, virtually ruling out a PTD within the following 7 days. Combining the two tests improves the prediction of PTD within 7 days after presentation, especially when adding fFn in women with a CL between 16 and 30 mm. No additional value was found for fFn testing if the CL was below 15 mm or above 30 mm.10,11,19–21 Thus, even after performing these additional tests, we treat substantially more women than actually deliver within 7 days. If pregnancy continues after arrested PTL, some women might remain at higher risk for PTD, and some may be reassured. Yet, no large studies have focused on risk prediction of PTD after arrested PTL, which leaves room for improvement to individualize and optimize prenatal care in these women. We therefore studied women with arrested PTL after treatment with tocolysis and antenatal corticosteroids, to evaluate their persistent risk of PTD and evaluate the prognostic value of the digital examination of the cervix, the fFn test, and the CL.
Methods We performed a prospective matched cohort study among women with a singleton pregnancy, who were discharged after receiving treatment for threatened PTL in 2006. In the Netherlands, first assessment of initially healthy pregnant women with symptoms of PTL is most often performed by midwives by digital examination before referral to a hospital. If women are at high risk of PTD, they will be referred to one of the 10 perinatal centers with a tertiary referral function to receive further treatment.
Participants and Interventions The women were a subset of a prospective observational cohort study performed in 2006 in three Dutch hospitals to evaluate the predictive value of fFn in 101 women presenting with symptoms of PTL at a GA between 24 and 34 weeks. This cohort study was approved by the institutional review board (IRB) of Leiden University Medical Centre (number, P0–050).22 PTL was defined as uterine contractions leading to cervical changes. At the time of the study, the use of CL measurement was not universally implemented. Therefore, women with any cervical changes due to uterine contractions American Journal of Perinatology
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Wilms et al. at initial assessment or at reassessment after a couple of hours of observation, either by digital examination or by measurement of the CL by vaginal ultrasound, were enrolled. Exclusion criteria were preterm ruptured membranes, cerclage of the cervix, cervical dilation of more than 3 cm at admission, and previous treatment for PTL in the current pregnancy. Vaginal blood loss in the past 24 hours was not a reason for exclusion. At admission, an fFn test (QuikCheck fFn, Adeza; Sunnyvale, CA; cutoff 0.050 μg/mL) was taken. Providers were blinded to the results of the fFn tests until all included women had delivered. Treatment consisted of hospital admission, tocolysis, and administration of antenatal corticosteroids. The tocolytic drug of first choice in our hospital at the time of this study was nifedipine, administered in a 5-day reducing regime. Of the included women in the original observational cohort study, 13% delivered within 7 days after admission. The women with arrested PTL who were discharged home were the subset of women eligible for this study. These women are referred to as the index cases. The original cohort study included multiple pregnancies, but these were excluded for this analysis. Index cases were matched to a control group of healthy pregnant women without an episode of PTL. Women in the control group were recruited from midwifery practices in the same region and from our own perinatal center. The controls were matched for age, parity, and previous PTD. Controls were randomly matched to the cases during their pregnancy at the same GA as the GA at admission of their matched cases. They received care as usual and their charts were only reviewed retrospectively after delivery. Therefore, this part of the study was not subjected to the Dutch Medical Research Involving Human Subjects Act (WMO), since the WMO states that IRB approval is only needed if the study participants have to be physically present during the study, and no IRB approval is necessary in The Netherlands in retrospective studies or status studies looking at patient records.23
Outcomes, Subgroups, and Sample Size Primary outcome was PTD, which was defined as delivery at a GA before 37 weeks. Secondary, we assessed the effect of the GA at PTL, digital examination, CL, and fFn status on the risk of PTD before 37 weeks gestation after arrested PTL. The power analysis was based on the hypothesis that 28% of the women in the index group would deliver preterm after a treated episode of PTL in comparison to 8% of the women in a healthy population.13 On the basis of this assumption, at least 57 cases in each group were needed (α ¼ 0.05 and β ¼ 0.80).
Statistical Analysis The proportions of PTD between the index and control groups were compared with chi square test. Cox proportional hazards regression analysis was performed, providing a risk for PTD, calculated from the time from admission for PTL until delivery, censored at 37 weeks of gestation. Time from followup until PTD before a GA of 37 weeks was evaluated with a Kaplan–Meier curve. To assess the relationship between the
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Wilms et al.
Fig. 1 Flow diagram.
GA at the first assessment for PTL and the risk of PTD, GAs at delivery were compared for three different groups by GA at admission for PTL (24–276/7 weeks, 28–316/7 weeks, and 32–346/7 weeks). Cox proportional hazards regression analyses were performed to assess the influence of dilatation of the cervix, the CL and fFn status on the persistent risk of PTD in the time from admission until delivery, censored at 37 weeks’ gestation. For the digital examination, a receiver operator characteristics (ROC) curve was computed to determine the best cutoff value. For the CL, a cutoff of 15 mm was used based on literature.15–17 To evaluate whether fFn influences the predictive value of cervical dilatation or CL measurement on the outcome PTD within 7 days, interaction terms were used. If the p value for interaction was below 0.05, HRs were reported for the index cases and controls. All statistical analyses were performed using SPSS software, version 21.0 (SPSS Inc. Chicago, IL)
Results The initial cohort consisted of 101 women with PTL, of whom 13 women (13%) delivered within 7 days after admission. Of the remaining 88 women who did not deliver after this episode of PTL and were discharged from the hospital, 9 were pregnant with twins and therefore excluded for this study. Matched controls were found for 74 index cases of the 79 eligible women, which would be sufficient based on our power calculation (►Fig. 1). The median gestational age (GA) at inclusion was 293/7 (inter quartile range [IQR], 275/7–313/7 weeks) weeks in both groups. The median age of the cases was 30 years (IQR, 26–33 years) versus 31 years IQR, 27–34 years) in the controls. As a
result of matching, parity in both the groups was comparable, with 41 women (55%) in each group being multiparous, of whom 13 (18%) had a previous PTD (►Table 1). The median GA at delivery was 382/7 (IQR, 363/7–393/7 weeks) weeks in the index cases, compared with 396/7 (IQR, 391/7–404/7 weeks) weeks in the controls. Delivery before 37 weeks occurred in 20 (27%) index cases, and in 5 (7%) controls (p ¼ 0.001) (►Table 2). Of the index cases, nine women (12%) delivered before 34 weeks, compared with none of the women in the control group (p ¼ 0.002).The index cases were at higher risk for PTD compared with the controls (hazard ratio [HR], 4.5 [95% CI, 1.7–12.1]) (►Table 2). Time from admission to PTD of index and control women is expressed in a Kaplan–Meier plot (►Fig. 2).
Gestational Age at Admission Of the index cases, 20 women (27%) were admitted with symptoms of PTL at a GA between 24 and 276/7 weeks, 37 Table 1 Baseline characteristics Maternal characteristic
Index cases (n ¼ 74)
Controls (n ¼ 74)
Gestational age at inclusion, wka
293/7 (275/7–313/7)
Matched
Age, ya
30 (26–33)
31 (27–34)
33 (45)
33 (45)
Parity Nulliparous, n (%) Multiparous, n (%)
41 (55)
41 (55)
Previous PTD, n (%)
13 (18)
13 (18)
Abbreviations: IQR, inter quartile range; PTD, preterm delivery. a Data given as median (IQR). American Journal of Perinatology
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Table 2 Delivery before a gestational age of 37 weeks Delivery < 37 weeks GA Cases (n ¼ 74), N (%) Total Dilatation CL
fFn
HR PTD < 37 wk (95% CI)
20/74 (23)
Controls (n ¼ 74), N (%) 5/74 (7)
HR PTD < 37 wk (95% CI) 4.5 (1.7–12.1)
< 1 cm
4/36 (11)
1 cm
14/31 (45)
5.4 (1.8–16.5)
9.1 (3.3–25.2)
15 mm
6/10 (60)
4.4 (1.6–11.9)
11 (3.1–38)
> 15 mm
11/57 (19)
Positive
14/28 (50)
Dilation < 1 cm
2/10 (20)
1 cm CL 15 mm > 15 mm
1.6 (0.44–6.1)
2.5 (0.84–7.5) 5.7 (2.2–15.2)
13.0 (4.3–39.7) 3.6 (0.69–18.3)
11/16 (69)
16.5 (5.7–47.9)
5/7 (71)
26.8 (17.4–96.8)
6/17 (35)
6.0 (1.8–19.7)
Negative
4/46 (9)
2.0 (0.60–6.4)
Dilation < 1 cm
2/26 (8)
1.1 (0.21–5.5)
3/15 (20)
3.5 (0.83–14.5)
1/3 (33)
4.1 (0.48–35.5)
5/40 (13)
1.9 (0.56–6.7)
1 cm CL 15 mm > 15 mm
Abbreviations: CI, confidence interval; CL, cervical length; fFn, fetal fibronectin; GA, gestational age; HR, hazard ratio; PTD, preterm delivery; wk, weeks. 9.5% missing
(50%) between 28 and 316/7 weeks, and 17 (23%) between 32 and 346/7 weeks. The median GA at delivery in the group of women admitted between 24 and 276/7 weeks was 383/7 (IQR, 360/7–393/7 weeks) weeks, in the group of women admitted between 28 and 316/7 weeks 385/7 (IQR, 363/7–396/7 weeks) weeks, and in the group of women admitted between 32 and 346/7 weeks 380/7 (IQR, 363/7–391/7 weeks) weeks.
Digital Examination Among the 74 index cases, 36 (49%) women had no cervical dilatation, 23 (31%) women had a cervical dilatation of 1 cm, in 6 (8%) women the dilatation was 2 cm, and in 2 (3%) women it was 3 cm. The best cutoff for the cervical dilatation determined by a ROC curve was 1 cm (using cervical dilatation < 1 cm as a positive test result and a cervical dilatation 1 cm as a negative test result) (sensitivity 78% and specificity 65%, with an area under curve of 0.69) (►Fig. 3). Of the 36 index cases, 4 (11%) with a cervical dilatation < 1 cm delivered prematurely, compared with 14 of the 31 (45%) index cases with a cervical dilatation of 1 cm (p ¼ 0.002) (►Table 2). A cervical dilatation of 1 cm increased the risk for delivery before 37 weeks as compared with cases with less dilatation (HR, 5.4 [95% CI, 1.8–16.5]). Cases with a cervical dilatation 1 cm had an increased risk of PTD compared with controls (HR, 9.1 [95% CI, 3.3–25.2]), while cases with a dilatation < 1 cm were not at higher risk of PTD compared with controls (HR, 1.6 [95% CI, 0.44–6.1]) (►Table 2).
Cervical Length
Fig. 2 Kaplan–Meier plot. Time from admission to preterm delivery: cases vs. controls. PTD, preterm delivery; PTL, preterm labor. American Journal of Perinatology
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Index cases had a mean CL at admission of 28 mm (SD 14 mm). Ten index cases had a CL 15 mm, of whom 6 (60%) delivered preterm and 57 had a CL > 15 mm, of whom 11 (19%) delivered prematurely (p ¼ 0.006) (►Table 2). A CL 15 mm increased the risk for delivery before 37 weeks as compared with cases with a CL > 15 mm (HR, 4.4 [95% CI, 1.6–11.9]). In comparison to the control group, index cases
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who had < 1 cm dilatation and a negative fFn test, cases with 1 cm dilatation and a negative fFn test and cases with < 1 cm dilatation and a positive fFn test (►Table 2).
The mean CL in the index cases with a positive fFn test was 23 mm (SD 15 mm) and differed significantly from the mean CL in the index cases with a negative fFn test (31 mm) (SD 13 mm) (p ¼ 0.03). Compared with the prediction model of CL as a sole predictor of persistent PTD, the model fit did improve if fFn was added (chi square 7.20, p ¼ 0.007). In comparison to controls, the risk of delivery before 37 weeks was increased in index cases who had a positive fFn test and a CL > 15 mm (HR, 6.0 [95% CI, 1.8–19.7]) and in cases with a positive fFn test and a CL 15 mm (HR, 26.8 [95% CI, 7.4–96.8]). No significant increase in this risk could be found in index cases with a negative fFn and either a CL > 15 mm or a CL 15 mm (►Table 2).
Discussion Fig. 3 ROC curve of cervical dilatation for preterm delivery. ROC, receiver operator characteristics.
with a CL 15 mm were at higher risk of PTD (HR, 11 [95% CI, 3.1–38]), whereas the risk in cases with a CL > 15 mm did not differ significantly from the control group (HR, 2.5 [95% CI, 0.84–7.5]).
Fetal Fibronectin Among the 74 index cases, fFn tests were positive in 28 women. These 28 women had a median GA at delivery of 365/7 (IQR, 332/7–390/7 weeks) weeks. The 46 index cases with a negative fFn test had a median GA at delivery of 390/7 (IQR, 374/7–395/7 weeks) weeks. Of the 28 the fFn positive index cases, 14 (50%) delivered prematurely. Among the fFn negative cases, four (9%) women delivered preterm (p ¼ 0.001) (►Table 2). In comparison to the women of the control group, index women with a positive fFn test were at increased risk of PTD (HR, 13.0 [95% CI, 4.3–39.7]), while no significant difference in delivery rates before 37 weeks was found between the fFn negative cases and the controls (HR, 2.0 [95% CI, 0.60– 6.4]). The index cases with a positive fFn test were at higher risk for PTD weeks compared with the fFn negative cases (HR, 5.7 [95% CI, 2.2–15.2]).
Digital Examination and Fetal Fibronectin The mean cervical dilatation in the index cases with a positive fFn test was 0.85 cm ( SD, 0.83) and differed significantly from mean cervical dilatation of 0.46 cm (SD 0.7) in the index cases with a negative fFn test (p ¼ 0.037). Compared with the prediction model of digital examination as a sole predictor of persistent PTD, the model fit improved if fFn was added to the model (chi square 8.648, p ¼ 0.003). In comparison to controls, the risk of delivery before 37 weeks was increased in index cases who had 1 cm dilatation and a positive fFn test (HR, 16.5 [95% CI, 5.7–47.9]). No difference was found among index cases
Main Findings In this prospective matched cohort study, we found that women who remain undelivered after an episode of PTL remain at increased risk of PTD as compared with low risk pregnant women without such symptoms (HR, 3.8 [95% CI, 1.4–10]). Especially women with dilatation of the cervix of 1 cm, a positive fFn test or a CL below 15 mm remained at higher risk for PTD compared with healthy pregnant women, whereas this difference was not found in women with a dilatation < 1 cm and in women with a CL above 15 mm and/or a negative fFn test. The knowledge of the fFn status improved the prediction of persistent PTD in women with arrested PTL when added to examination of the cervical dilatation of CL measurement. A fibronectin positive status further increases the persistent risk of PTL.
Strengths and Limitations To our best knowledge, our study is unique in comparing the risk of PTD in women after arrested PTL to the risk of PTL in a healthy population of pregnant women. Even though the mean CL and the median GA at delivery of the women who remained pregnant after an episode of threatened PTL might suggest we studied a low risk population, their PTD risk was higher than the overall PTD risk in the Netherlands. The incidence of PTD in singleton pregnancies in the Netherlands is 6% before 37 weeks and 0.9% before 32 weeks’ gestation.24 The incidence of PTD in our control group is comparable. We do acknowledge that even stronger evidence for persistent risk of PTD might have been found if we would have structurally incorporated the measurement of the CL, in combination with the fFn test, in the risk assessment and diagnosis of PTD. Furthermore, the digital examination, CL and the fFn status of the control group were unknown as the data from this group were extracted from charts of healthy pregnant women. The data concerning the digital examination, the CL and the fFn status were collected at admission of the index cases, but these data were not available at discharge. American Journal of Perinatology
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Cervical Length and Fetal Fibronectin
Risk of Preterm Delivery after Arrested Preterm Labor Another limitation of our study was the small sample size. The absence of a significantly different instantaneous risk for PTD between the control group and women with a long cervix and a negative fFn test might be due to insufficient power. The small sample size also limits us in the number of risk factors for PTD that were evaluated.
Interpretation A prospective cohort study performed in the United States by McPheeters et al describes that 72% of the women admitted for threatened PTL, without immediate delivery, delivered at term.13 This is comparable to our results (77%). They found a PTD rate of 8% in women who had never been diagnosed with PTL, which corresponds to the PTD rate in our control group (7%). They did not provide information about the CL measurement or fFn status. Although the risk of neonatal mortality is relatively low in neonates born after 34 weeks’ gestation, neonates born late preterm appear to be less healthy than infants born at later GA.25–30 However, providing a clear advice on the further management of pregnant women with arrested PTL who remain at higher risk for PTD is difficult. Several treatment strategies have been assessed. Prolongation of hospital admission does not change the course of the pregnancy.31,32 There is no evidence to support bed rest.33 When these women are sent home they should be counseled about recurrence of symptoms of PTL. Prolongation of the pregnancy by maintenance tocolysis has been evaluated. Although a meta-analysis showed a prolongation of the mean number of days gained in patients receiving maintenance tocolysis, they found no difference in neonatal outcome.34 A large RCT evaluating the effectiveness of maintenance tocolysis with nifedipine in women with threatened PTL showed no statistically significant reduction in adverse perinatal outcomes when compared with placebo.35 Systematic reviews have shown that there is insufficient evidence to support the use of maintenance tocolysis with magnesium, terbutaline, or oxytocin antagonists in the prevention of PTD after threatened PTL.36–38 The reported effect of progesterone administration in women with arrested PTL after treatment with tocolysis is conflicting.39–42 Two relatively small RCT’s comparing 400 mg daily vaginal suppository versus no treatment39 and 341 mg 17-α-hydroxyprogesterone caproate (17P) intramuscularly twice weekly40 found a possible positive effect of the administration of progesterone after arrested PTL on the prolongation of pregnancy. A larger RCT comparing 17-α-hydroxyprogesterone caproate versus no treatment concluded that semiweekly injections of 17P did not prolong pregnancy significantly in women with tocolysis-arrested PTL.42 A limitation of all the three RCT’s was the lack of blinding.
Conclusion
under 15 mm. The knowledge of the fFn result improved the prediction of persistent PTD after arrested PTL over the cervical dilatation or CL measurement alone. Further research is recommended on the pathophysiological pathways that precede PTL and delivery, to improve identification of the women who actually will deliver premature and on the treatment strategies in women who remain at risk of PTD after arrested PTL.
Note This study has been presented at the Society for Maternal Fetal Medicine 31th Annual Meeting in San Francisco, February 11, 2011.
References 1 NIH Consensus Development Panel on the Effect of Corticosteroids
2 3 4
5
6
7
8
9
10
11
12
13
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for Fetal Maturation on Perinatal Outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995; 273(5):413–418 Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002; 360(9344):1489–1497 Iams JD. Prediction and early detection of preterm labor. Obstet Gynecol 2003;101(2):402–412 King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003;(1):CD002255 Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2005;(3):CD004452 Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50(4):515–525 Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97(1): 11–25 Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995; 173(1):322–335 Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;(3):CD004454 DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol 2013; 208(3):e1–e6 Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005;192(2): 350–359 Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol 2009;114(3): 631–640 McPheeters ML, Miller WC, Hartmann KE, et al. The epidemiology of threatened preterm labor: a prospective cohort study. Am J Obstet Gynecol 2005;192(4):1325–1329, discussion 1329–1330 Onderoğlu LS. Digital examination and transperineal ultrasonographic measurement of cervical length to assess risk of preterm delivery. Int J Gynaecol Obstet 1997;59(3):223–228
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25
26 27 28
cervicovaginal fetal fibronectin test in predicting risk of spontaneous preterm birth: systematic review. BMJ 2002;325(7359):301 Honest H, Bachmann LM, Coomarasamy A, Gupta JK, Kleijnen J, Khan KS. Accuracy of cervical transvaginal sonography in predicting preterm birth: a systematic review. Ultrasound Obstet Gynecol 2003;22(3):305–322 Sotiriadis A, Papatheodorou S, Kavvadias A, Makrydimas G. Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis. Ultrasound Obstet Gynecol 2010;35(1):54–64 Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D; NICHD Maternal Fetal Medicine Units Network. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. Obstet Gynecol 1996;87(5 Pt 1):643–648 Wiegerinck MM, Vis JY, Mol BW. Re: Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis. Ultrasound Obstet Gynecol 2010;35(6):756–757, author reply 756–757 Tsoi E, Akmal S, Geerts L, Jeffery B, Nicolaides KH. Sonographic measurement of cervical length and fetal fibronectin testing in threatened preterm labor. Ultrasound Obstet Gynecol 2006;27(4): 368–372 Schmitz T, Maillard F, Bessard-Bacquaert S, et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labor. Am J Obstet Gynecol 2006;194(1):138–143 Wilms FF, van Stralen G, Porath MM, et al. Predicating imminent preterm labour based on a determination of foetal fibronectin in a vaginal smear [in Dutch]. Ned Tijdschr Geneeskd 2009;153:B398 Dutch Medical Research. Available at:http://www.ccmo.nl/en/yourresearch-does-it-fall-under-the-wmo Schaaf JM, Mol BW, Abu-Hanna A, Ravelli AC. Trends in preterm birth: singleton and multiple pregnancies in the Netherlands, 2000-2007. BJOG 2011;118(10):1196–1204 Arnon S, Dolfin T, Litmanovitz I, Regev R, Bauer S, Fejgin M. Preterm labour at 34–36 weeks of gestation: should it be arrested? Paediatr Perinat Epidemiol 2001;15(3):252–256 Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114(2):372–376 Adams-Chapman I. Neurodevelopmental outcome of the late preterm infant. Clin Perinatol 2006;33(4):947–964, abstract xi Tomashek KM, Shapiro-Mendoza CK, Davidoff MJ, Petrini JR. Differences in mortality between late-preterm and term singleton infants in the United States, 1995-2002. J Pediatr 2007;151(5): 450–456, e1
69
29 Ramachandrappa A, Jain L. Health issues of the late preterm infant.
Pediatr Clin North Am 2009;56(3):565–577 30 Engle WA, Kominiarek MA. Late preterm infants, early term
31
32
33
34
35
36
37
38
39
40
41
42
infants, and timing of elective deliveries. Clin Perinatol 2008; 35(2):325–341, vi Yost NP, Bloom SL, McIntire DD, Leveno KJ. Hospitalization for women with arrested preterm labor: a randomized trial. Obstet Gynecol 2005;106(1):14–18 Goulet C, Gévry H, Lemay M, et al. A randomized clinical trial of care for women with preterm labour: home management versus hospital management. CMAJ 2001;164(7):985–991 Sosa C, Althabe F, Belizán J, Bergel E. Bed rest in singleton pregnancies for preventing preterm birth. Cochrane Database Syst Rev 2004;(1):CD003581 Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999;181(2):484–490 Roos C, Spaanderman ME, Schuit E, et al; APOSTEL-II Study Group. Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial. JAMA 2013;309(1):41–47 Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2010;(7):CD000940 Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance therapy after threatened preterm labor for preventing preterm birth. Cochrane Database Syst Rev 2002;(4): CD003933 Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2009;(1):CD005938 Review Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2008;48(1):58–63 Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during preterm cervical ripening: effects of 17alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 2007; 196(5):e1–e4, discussion 421 Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol 2009;200(3): 219–224 Rozenberg P, Chauveaud A, Deruelle P, et al; Groupe De Recherche En Obstétrique et Gynécologie. Prevention of preterm delivery after successful tocolysis in preterm labor by 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Am J Obstet Gynecol 2012;206(3):e1–e9
American Journal of Perinatology
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