The Journal of Maternal-Fetal & Neonatal Medicine
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Risk factors for spontaneous preterm delivery after arrested episode of preterm labor Anat Shmuely, Amir Aviram, Tali Ben-Mayor Bashi, Eran Hadar, Haim Krissi, Arnon Wiznitzer & Yariv Yogev To cite this article: Anat Shmuely, Amir Aviram, Tali Ben-Mayor Bashi, Eran Hadar, Haim Krissi, Arnon Wiznitzer & Yariv Yogev (2015): Risk factors for spontaneous preterm delivery after arrested episode of preterm labor, The Journal of Maternal-Fetal & Neonatal Medicine To link to this article: http://dx.doi.org/10.3109/14767058.2015.1016420
Published online: 03 Mar 2015.
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Date: 29 September 2015, At: 23:35
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1016420
ORIGINAL ARTICLE
Risk factors for spontaneous preterm delivery after arrested episode of preterm labor Anat Shmuely1, Amir Aviram1,2, Tali Ben-Mayor Bashi1,2, Eran Hadar1,2, Haim Krissi1, Arnon Wiznitzer1, and Yariv Yogev1,2 Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel and 2Affiliated to The Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
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Abstract
Keywords
Introduction: We aimed to identify specific risk factors for spontaneous preterm delivery (PTD) among women with arrested preterm labor (PTL). Method: A retrospective study of women admitted due to imminent PTL and intact membranes, which did not progress to PTD within 24 h from admission. Eligibility was limited to singleton gestations at 24 + 0/7–33 + 6/7 weeks of gestations with no known chromosomal or structural anomalies. All women were treated with corticosteroids and tocolysis. Comparison was made between those who delivered at 537 + 0/7 weeks of gestation (study group) to women who delivered at 37 + 0/7 weeks of gestation (controls). Results: Overall, 301 women were recruited, of which 85 (28.2%) delivered before 37 + 0/7 weeks and 216 (71.8%) delivered at term. Advanced cervical dilatation was found to be an independent risk factor for PTD [for women with no past PTD: adjusted odds ratio (aOR) 1.66, 95% CI: 1.06–2.61 for each 1 cm dilatation; for women with past PTD: aOR 2.81, 95% CI: 1.02–7.73 for each 1 cm dilatation]. Among women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission (OR: 1.20, 95% CI: 1.09–1.32 for each earlier week) and short cervical length (OR: 1.04, 95% CI: 1.01–1.08 for each decrease of 1 mm in cervical length). Conclusion: Advanced cervical dilatation, earlier gestational age at the episode of arrested PTL, and short cervical length are specific risk factors for PTD in women with arrested PTL. These findings may assist in counseling women and direct further investigation.
Labor, prematurity, preterm delivery
Introduction Preterm delivery (PTD) is a major public health burden worldwide [1], affecting as much as 12% of all births in USA. Known risk factors associated with PTD include past preterm birth, sonographic cervical shortening throughout pregnancy, prior conization of the cervix and others [2,3]. Nonetheless, most of preterm deliveries result from spontaneous preterm labor (PTL) in women without known risk factors [4], and most women with preterm uterine contractions and cervical dynamics eventually deliver at term [5]. Controversy exists whether women with arrested episode of threatened PTL are still at higher risk for actual PTD. Some have suggest that preterm uterine contractions, even in the absence of cervical dynamics, should be considered as a potential risk factor for PTL [6,7]; however, others have found the opposite [8,9]. However, most studies were limited by
Adress for correspondence: Prof. Yariv Yogev, Helen Schneider Hospital for Women, Rabin Medical Center, Petah-Tikva 49100, Israel. E-mail: [email protected]
History Received 21 October 2014 Revised 5 December 2014 Accepted 4 February 2015 Published online 3 March 2015
limited study sample size [9], incoherent definitions of arrested PTL [7,8] and selected population bias [7]. Thus, we aimed to identify specific risk factors for spontaneous PTD and to assess pregnancy outcome in women with an episode of arrested PTL.
Methods A retrospective cohort study of all women who were admitted to a tertiary, university affiliated medical center, with imminent PTL in the presence of intact membranes between January 2011 and December 2013. Eligibility was limited to singleton pregnancies at 24 + 0/7–33 + 6/7 weeks of gestation with no known chromosomal or structural malformations. Women with multiple gestations, cervical cerclage, pregnancies complicated by placental abruption, chorioamnionitis, stillbirth or major fetal anomalies, and women who underwent indicated delivery prior to 37 weeks of gestation or did not deliver in our medical center were excluded. Women with PTL, defined as a cervical dilatation 43 cm and painful uterine contractions, were also excluded. The study was approved by the local Institutional Review Board.
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According to our departmental protocol, all women underwent fetal heart monitoring and tocodynamometry, pelvic examination for cervical dilatation and effacement, as well as ultrasound assessment for biophysical profile, placental location and amniotic fluid index.
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Definitions Gestational age (GA) was determined according to last menstrual period and was confirmed by first-trimester CRL measurement. Threatened PTL was defined as the presence of at least three regular and painful uterine contractions within 30-min period with one or more of the following: cervical dilatation41 cm, sonographic short cervical length (525 mm) or cervical dynamics (change in dilatation of 41 cm in two consecutive examinations performed 2 h apart). Arrested PTL was diagnosed among women with imminent PTL who did not progress to delivery within a time frame of 24-h admission. Protocol Tocolysis with Nifedipine, Indomethacin or Tractocile was provided according to physician preference together with betamethasone (24 mg of betamethasone divided into two doses of 12 mg injected intra-muscularly 24 h apart) for fetal lung maturation. Women were discharged after 24–48 h, upon completion of tocolysis and betamethasone course if PTD was not developed, without maintenance tocolytic treatment. Data collection Data were obtained from our departmental electronic records. Demographic and obstetrical variables were collected, including maternal age, parity, gravidity, history of preterm deliveries, congenital mullerian anomalies, prior cervical procedures (such as conization), history of abortions, GA at hospitalization and delivery, fetal presentation, amniotic fluid volume, mode of delivery, indication for obstetrical intervention and neonatal outcome. The study group included all women admitted with threatened PTL who did not progress to delivery (arrested PTL) during the index admission and were discharged from the hospital, but eventually delivered537 completed weeks of gestation. The control group included women with an episode of arrested PTL who ultimately delivered at or beyond 37 weeks of gestation. Statistical analysis Statistical analysis was performed using the IBM SPSS software (version 20.0; SPSS Inc., Chicago, IL). Continuous variables were compared using the Student’s t-test and categorical variables by 2 or Fisher’s exact test. Appropriate adjusted odds ratios were calculated using a logistic regression model. Statistical significance was defined as p value of 50.05. In order to establish the independent contribution of each factor to actual PTD, and since univariate analysis demonstrated a significant difference in the rate of past PTD, we divided our cohort into two groups: women with previous PTD and women without previous PTD.
J Matern Fetal Neonatal Med, Early Online: 1–6
Results Overall, during the study period, 27 130 women delivered in our center, of which 1360 (5%) were diagnosed with PTL. Of this population, 1059 were excluded due to incompatibility with the inclusion criteria (multiple gestation, immediate delivery, placental abruption, chorioamnionitis, indicated PTD, fetal anomalies or still birth), leaving 301 (0.01%) women who were included in the study. Overall, 216 (71.7%) women delivered at term and 85 (28.3%) women had a PTD. Patient characteristics The demographic and obstetrical characteristics are shown in Table 1. The study group was characterized by a higher rates of women with previous PTD (23.5 versus 12.5%, p ¼ 0.02), previous multiple cesarean sections (5.9 versus 0.5%, p ¼ 0.008) and bicornuate uterus (3.5 versus 0%, p ¼ 0.02). There were no statistically significant differences between the groups with regards to maternal age, gravidity and parity, number of prior PTD or number of hospitalizations for premature contractions during the index pregnancy. Other features, such as prior dilation and curettage, prior preterm premature rupture of membranes, PCOS, endometriosis and pregnancies achieved by in vitro fertilization, were also not found to be significantly different between the groups. Hospitalization characteristics Obstetrical history parameters are shown in Table 2. Mean GA at hospitalization was lower for women in the PTD group (28.5 ± 3.4 versus 29.7 ± 2.9 weeks, p ¼ 0.003), as was the sonographic measurement of the cervical length 26.7 ± 8.8 versus 29.4 ± 8.6 mm, p ¼ 0.014). Cervical dilatation on pelvic examination was more advanced among women in the study group (0.6 ± 0.8 versus 0.3 ± 0.6 cm, p ¼ 0.004). Pregnancy outcome Higher rate of women delivered 528, 534 and 537 weeks of gestation (p50.001 for all) in the study group (Table 3). The rate of spontaneous vaginal delivery decreased (61.2 versus 80.6%, p50.001) and the rate of cesarean section increased for women in the study group in comparison to the control group (35.3 versus 11.1%, p50.001). As for neonatal outcome, a significant higher rate of NICU hospitalizations, IVH, hypoglycemia, NEC, sepsis, respiratory disorders and jaundice were found in the study group (Table 3). Independent risk factors for PTD among women with arrested PTL We performed a multivariate logistic regression analysis incorporating GA at admission (weeks), sonographic cervical length (mm) and cervical dilatation (cm). In the subgroup of women without a history of PTD, factors associated independently with risk for preterm birth were lower GA at hospitalization, higher cervical dilatation at admission and shorter sonographic cervical length (Table 4). In the subgroup of women with past PTD, only advanced cervical dilatation at
Arrested preterm labor and preterm delivery
DOI: 10.3109/14767058.2015.1016420
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Table 1. Demographic and obstetrical characteristics for the study and control group.
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Characteristics
Study group preterm (n ¼ 85)
Control group term (n ¼ 216)
p value
30.6 ± 5.7 2.5 ± 1.5 1.9 ± 1.1 40 (47.1) 1.52 ± 0.80 7 (8.2) 5 (5.9) 20 (23.5) 1.40 ± 0.50 0 (0.0) 8 (9.4) 0.13 ± 0.46 0 (0.0) 3 (3.5) 3 (3.5) 3 (3.5) 1 (1.2) 13 (4.3) 33.0 ± 3.1 7 (8.2) 25 (29.4) 53 (62.4)
29.8 ± 5.3 2.2 ± 1.6 1.7 ± 1.0 120 (55.6) 1.38 ± 0.67 20 (9.3) 1 (0.5) 27 (12.5) 1.15 ± 0.36 3 (1.4) 19 (8.8) 0.10 ± 0.35 2 (0.9) 0 (0.0) 2 (0.9) 6 (2.8) 7 (3.2) 21 (9.7) 38.7 ± 1.3 – – –
0.29 0.15 0.08 0.18 0.15 0.780 0.008 0.02 0.07 0.561 0.87 0.57 40.99 0.02 0.14 0.72 0.45 0.17 50.001 – – –
Maternal age, years* Gravidity, n* Parity, n* Nulliparity, n (%) Hospitalizations for premature contractions, n* Previous single CS, n (%) Previous multiple CS, n (%) Prior PTD, n (%) Number of prior PTD, n* PPROM history, n (%) D&C history, n (%) Previous D&C, n* Recurrent abortions, n (%) Bicornuate, n (%) Endometriosis, n (%) PCOS, n (%) Fibroid, n (%) ART, n (%) GA at delivery, weeks* 528, n (%) 534, n (%) 537, n (%)
D&C, dilation and curettage; PCOS, polycystic ovaries syndrome; ART, artificial reproductive technologies; APLA, antiphospholipid antibody syndrome. *Data are presented as mean ± standard deviation.
Table 2. Hospitalization characteristics for the study and control group.
Parameter GA at hospitalization, weeks* Sonographic cervical length, mm* Cervical dilation, cm* Cervical effacement, %* Tocolysis, n (%) Nifedipine, n (%) Indomethacin, n (%) Tractocile, n (%) Betamethasone, n (%) Rescue betamethasone treatment, n (%) Delivery within 48 hy, n (%) Delivery within 7 daysy, n (%) Delivery within 14 daysy, n (%)
Study group preterm (n ¼ 85)
Control group term (n ¼ 216)
p value
28.47 ± 3.362 26.7 ± 8.8 0.6 ± 8 43.9 ± 28.5
29.7 ± 2.9 29.4 ± 8.6 0.3 ± 0.6 38.2 ± 28.2
0.003 0.014 0.004 0.114
107 (49.5) 30 (13.9) 16 (7.4) 210 (97.2) 16 (7.4) NA NA NA
0.568 0.179 0.001 0.730 0.563 NA NA NA
39 7 18 82 8 6 16 43
(45.9) (8.2) (21.2) (96.5) (9.4) (7.1) (18.9) (37.8)
*Data are presented as mean ± standard deviation. yPercentage out of preterm births.
admission remained significantly associated with the risk for preterm birth (Table 4). We further sought to establish the role of association between short cervical length as measured by a sonogram at admission and time to delivery (Table 5). We found the among women with no past PTL, each decrease of 1 mm in cervical length was associated with an increased risk for delivery within 7 and 14 days, but not in 48 h. This association was not found to be significant among women with past PTL.
Discussion In this study, we aimed to evaluate specific risk factors for spontaneous PTD in women with arrested PTL. Our main
findings were: (i) the rate of PTD among women with an episode of arrested PTL was 28.3%; (ii) among women with arrested PTL, advanced cervical dilatation was found as an independent risk factor for PTD independently of past PTD history; (iii) in women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission and short cervical length measured by a transvaginal sonogram. The rate of preterm deliveries (537 weeks of gestation) among our cohort was 28.3%, more than twice the reported 12% PTD rate in the general population [1,10,11]. Nonetheless, since these 12% include versatile circumstances, such as preterm premature rupture of the membranes, women without an episode of arrested PTL, indicated PTD and so forth, it cannot be used as reference in cases of women with
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Table 3. Pregnancy outcome for the study and control group.
Parameter
Study group preterm (n ¼ 85)
Control group term (n ¼ 216)
p value
52 (61.2) 3 (3.5) 30 (35.3) 55 (64.7) 2072 ± 623 45 (52.9) 5 (5.9) 0 (0.0) 0 (0.0) 8 (9.4) 2 (2.4) 4 (4.7) 1 (1.2) 1 (1.2)
174 (80.6) 18 (8.3) 24 (11.1) 119 (55.1) 3121 ± 435 17 (7.9) 3 (1.4) 1 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
50.001 0.14 50.001 0.13 50.001 50.001 0.03 40.99 NA 50.001 0.08 0.006 0.28 0.28
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Mode of delivery, n (%) Spontaneous vaginal delivery Operative vaginal delivery Cesarean section Male neonate, n (%) Birth weight, g* NICU, n (%) Neonatal asphyxia, n (%) Neonatal seizures, n (%) Neonatal HIE, n (%) Neonatal IVH, n (%) Grade 1 Grade 2 Grade 3 Grade 4
NICU, neonatal intensive care unit; HIE, hemorrhagic ischemic encephalopathy; IVH, intraventricular hemorrhage. *Data are presented as mean ± standard deviation.
Table 4. Odds ratio for PTD among women with arrested PTL.
Parameter No history of prior PTL GA at hospitalization (each earlier week) Sonographic cervical length (each decrease of 1 mm) Cervical dilation (each increase of 1 cm PRIOR PTL GA at hospitalization (each earlier week) Sonographic cervical length (each decrease of 1 mm) Cervical dilation (each increase of 1 cm) Number of past PTL (each additional PTL)
Table 5. The odds ratio of short cervical length (each 1 mm) for PTD within 48 h, 7 days and 14 days among women with arrested PTL.
Parameter No history of prior PTL Delivery within 48 h Delivery within 7 days Delivery within 14 days Prior PTL Delivery within 48 h Delivery within 7 days Delivery within 14 days
Adjusted odds ratio
95% confidence interval
p value
1.08 1.10 1.09
0.84–1.60 1.03–1.18 1.03–1.14
0.37 0.006 0.002
0.97 0.91 0.86
0.64–1.48 0.72–1.14 0.73–1.00
0.91 0.40 0.06
arrested PTL. Corroborating with our results, Wilms et al. [12] found that women with an episode of PTL had a 27% risk for PTD, compared with 7% of women without such episode. It is worth mentioning that the methodology of their study differed from ours as they compared women with and without an episode of arrested PTL, while in our study all women had an episode of arrested PTL. Yet, it is reasonable to assess, based on their cohort and ours, that the risk for PTD among women with an episode of arrested PTL is significantly higher than in the general population [12]. We may assume, that the activation of different pathways associated with delivery
Adjusted odds ratio
95% confidence interval
p value
1.20 1.04 1.66
1.09–1.32 1.01–1.08 1.06–2.61
50.001 0.03 0.03
1.14 0.96 2.81 3.99
0.91–1.44 0.88–1.05 1.02–7.73 0.88–18.16
0.26 0.38 0.04 0.07
(uterine activity, cervical ripening) occur earlier among these women, and even though arrested and not leading to immediate delivery, these processes are not fully reversed, thus translating into a higher rate of preterm deliveries. We also found that the rate of past PTD was higher in our study group (23.5 versus 12.5%, p ¼ 0.02). It is well known that past PTD is a significant risk factor for future PTD [2,3,13], although episodes of threatened PTL were found to be strongly associated with spontaneous preterm deliveries even in women without a history of PTD [14]. Alleman et al. [13] sought to create a predictive model for PTD, and found that past PTD is one of the few predictors both easily available and used at the population level for identifying future PTD and a primary indication to offer treatment. Therefore, we divided our cohort into to sub groups: women with and without a history of past PTD. Among our cohort, advanced cervical dilatation on pelvic examination was found to be an independent risk factor for PTD unrelated to history of past PTD. Previous studies have also found this parameter to be of high predictive value in similar situations [12,15]. In these studies, no differentiation between women with or without a history of preterm birth was performed. Our study, on the other hand, has demonstrated that advanced cervical dilatation is an independent risk factor for current PTD regardless of past PTD, thus strengthening
Arrested preterm labor and preterm delivery
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DOI: 10.3109/14767058.2015.1016420
this variable as a marker for potential preterm birth. This finding may further reflect the pathological initiation of the birth process prematurely, leading ultimately to preterm birth later in pregnancy, even after imminent birth was arrested during the index episode. For women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission and short cervical length measured by transvaginal sonogram. Short cervical length was additionally found to be an independent risk factor for delivery within 7 and 14 days of examination. Previous studies have shown [16,17,18] that for women with threatened PTL, cervical length measurement, with or without positive fibronectin in vaginal secretions, is an independent predictor of PTD in women with PTL, although its predictive accuracy as a single measure is relatively limited. Some have also found a 15-mm cutoff for PTD within 7 days [19–21]. Although some of these studies did not distinguish between women with and without a history of past PTD, the basic premise of cervical length as a predictor for PTD still implies, again reflecting the premature commencement of the birth process. With regards to gestational week at admission, Hiersch et al. [22] found that women who presented earlier in pregnancy with threatened PTL had a lower mean GA at delivery and were more likely to experience PTD at 535 or 32 weeks of gestation [22]. We may argue that the earlier the pathological cascade of birth begins, the greater the pathology, thus leading to earlier delivery. We did not find similar results among women with prior PTD, but this may be attributed to the relatively low prevalence of women with such a history in our cohort. Patients’ history, such as prior dilation and curettage, number of PTD, PCOS and other gynecological problems, were not found to predict PTD in our cohort, similar to other studies [14,23]. One study has demonstrated that such characteristics have changed markedly over a 23 years’ period [24], with a marked increase in maternal age and nulliparous women. This study also found that variables pertaining to previous and current obstetric complications (previous preterm birth, previous caesarean section, pre-eclampsia and antepartum hemorrhage) were the most influential predictors of preterm birth. These findings might be explained by the complex mechanism of PTD, and the different individual factors attributing to the risk of PTD, yet to be understood. As expected, neonatal outcomes of women with PTD were worse than those of women that delivered at term. These outcomes included a significant higher rate of NICU hospitalizations, IVH, hypoglycemia, NEC, sepsis, respiratory disorders and jaundice. Our study is not without limitations. It is limited by its retrospective design, and is lacking certain demographic data such as maternal BMI and previous GA at delivery at the last PTD. With regards to women with past PTD, no data could be extracted as to the reason of the past PTD, nor as to progesterone treatment during the current pregnancy. Nevertheless, its strengths lie in its coherent and stringent definitions and protocols, since it was carried out in a single tertiary obstetrical center, with a single departmental protocol. Therefore, the data provided by the study are reliable and consistent.
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In summary, the risk of PTD among women with singleton gestation and an episode of arrested PTL is higher than in the general population and approaches 30%. Independent risk factors for PTD among such women include advanced cervical dilatation, and for women without a history of prior PTD also lower GA and shorter sonographic cervical length at admission. Additional larger and prospective studies are needed to further evaluate and characterize this unique and important population and to strive at finding new interventions to prevent PTD in women with arrested PTL.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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21. Fuchs IB, Henrich W, Osthues K, et al. Sonographic cervical length in singleton pregnancies with intact membranes presenting with threatened preterm labor. Ultrasound Obstet Gynecol 2004;24:554–7. 22. Hiersch L, Yogev Y, Domniz N, et al. The role of cervical length in women with threatened preterm labor: is it a valid predictor at any gestational age? Am J Obstet Gynecol 2014;211:532.e1–9. 23. Morken NH, Ka¨llen K, Jacobsson B. Predicting risk of spontaneous preterm delivery in women with a singleton pregnancy. Paediatr Perinat Epidemiol 2014;28:11–22. 24. Hammond G, Langridge A, Leonard H, et al. Changes in risk factors for preterm birth in Western Australia 1984–2006. BJOG 2013;120:1051–60.
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Risk factors for spontaneous preterm delivery after arrested episode of preterm labor Anat Shmuely, Amir Aviram, Tali Ben-Mayor Bashi, Eran Hadar, Haim Krissi, Arnon Wiznitzer & Yariv Yogev To cite this article: Anat Shmuely, Amir Aviram, Tali Ben-Mayor Bashi, Eran Hadar, Haim Krissi, Arnon Wiznitzer & Yariv Yogev (2015): Risk factors for spontaneous preterm delivery after arrested episode of preterm labor, The Journal of Maternal-Fetal & Neonatal Medicine To link to this article: http://dx.doi.org/10.3109/14767058.2015.1016420
Published online: 03 Mar 2015.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [University of Lethbridge]
Date: 29 September 2015, At: 23:35
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1016420
ORIGINAL ARTICLE
Risk factors for spontaneous preterm delivery after arrested episode of preterm labor Anat Shmuely1, Amir Aviram1,2, Tali Ben-Mayor Bashi1,2, Eran Hadar1,2, Haim Krissi1, Arnon Wiznitzer1, and Yariv Yogev1,2 Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel and 2Affiliated to The Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel
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1
Abstract
Keywords
Introduction: We aimed to identify specific risk factors for spontaneous preterm delivery (PTD) among women with arrested preterm labor (PTL). Method: A retrospective study of women admitted due to imminent PTL and intact membranes, which did not progress to PTD within 24 h from admission. Eligibility was limited to singleton gestations at 24 + 0/7–33 + 6/7 weeks of gestations with no known chromosomal or structural anomalies. All women were treated with corticosteroids and tocolysis. Comparison was made between those who delivered at 537 + 0/7 weeks of gestation (study group) to women who delivered at 37 + 0/7 weeks of gestation (controls). Results: Overall, 301 women were recruited, of which 85 (28.2%) delivered before 37 + 0/7 weeks and 216 (71.8%) delivered at term. Advanced cervical dilatation was found to be an independent risk factor for PTD [for women with no past PTD: adjusted odds ratio (aOR) 1.66, 95% CI: 1.06–2.61 for each 1 cm dilatation; for women with past PTD: aOR 2.81, 95% CI: 1.02–7.73 for each 1 cm dilatation]. Among women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission (OR: 1.20, 95% CI: 1.09–1.32 for each earlier week) and short cervical length (OR: 1.04, 95% CI: 1.01–1.08 for each decrease of 1 mm in cervical length). Conclusion: Advanced cervical dilatation, earlier gestational age at the episode of arrested PTL, and short cervical length are specific risk factors for PTD in women with arrested PTL. These findings may assist in counseling women and direct further investigation.
Labor, prematurity, preterm delivery
Introduction Preterm delivery (PTD) is a major public health burden worldwide [1], affecting as much as 12% of all births in USA. Known risk factors associated with PTD include past preterm birth, sonographic cervical shortening throughout pregnancy, prior conization of the cervix and others [2,3]. Nonetheless, most of preterm deliveries result from spontaneous preterm labor (PTL) in women without known risk factors [4], and most women with preterm uterine contractions and cervical dynamics eventually deliver at term [5]. Controversy exists whether women with arrested episode of threatened PTL are still at higher risk for actual PTD. Some have suggest that preterm uterine contractions, even in the absence of cervical dynamics, should be considered as a potential risk factor for PTL [6,7]; however, others have found the opposite [8,9]. However, most studies were limited by
Adress for correspondence: Prof. Yariv Yogev, Helen Schneider Hospital for Women, Rabin Medical Center, Petah-Tikva 49100, Israel. E-mail: [email protected]
History Received 21 October 2014 Revised 5 December 2014 Accepted 4 February 2015 Published online 3 March 2015
limited study sample size [9], incoherent definitions of arrested PTL [7,8] and selected population bias [7]. Thus, we aimed to identify specific risk factors for spontaneous PTD and to assess pregnancy outcome in women with an episode of arrested PTL.
Methods A retrospective cohort study of all women who were admitted to a tertiary, university affiliated medical center, with imminent PTL in the presence of intact membranes between January 2011 and December 2013. Eligibility was limited to singleton pregnancies at 24 + 0/7–33 + 6/7 weeks of gestation with no known chromosomal or structural malformations. Women with multiple gestations, cervical cerclage, pregnancies complicated by placental abruption, chorioamnionitis, stillbirth or major fetal anomalies, and women who underwent indicated delivery prior to 37 weeks of gestation or did not deliver in our medical center were excluded. Women with PTL, defined as a cervical dilatation 43 cm and painful uterine contractions, were also excluded. The study was approved by the local Institutional Review Board.
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According to our departmental protocol, all women underwent fetal heart monitoring and tocodynamometry, pelvic examination for cervical dilatation and effacement, as well as ultrasound assessment for biophysical profile, placental location and amniotic fluid index.
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Definitions Gestational age (GA) was determined according to last menstrual period and was confirmed by first-trimester CRL measurement. Threatened PTL was defined as the presence of at least three regular and painful uterine contractions within 30-min period with one or more of the following: cervical dilatation41 cm, sonographic short cervical length (525 mm) or cervical dynamics (change in dilatation of 41 cm in two consecutive examinations performed 2 h apart). Arrested PTL was diagnosed among women with imminent PTL who did not progress to delivery within a time frame of 24-h admission. Protocol Tocolysis with Nifedipine, Indomethacin or Tractocile was provided according to physician preference together with betamethasone (24 mg of betamethasone divided into two doses of 12 mg injected intra-muscularly 24 h apart) for fetal lung maturation. Women were discharged after 24–48 h, upon completion of tocolysis and betamethasone course if PTD was not developed, without maintenance tocolytic treatment. Data collection Data were obtained from our departmental electronic records. Demographic and obstetrical variables were collected, including maternal age, parity, gravidity, history of preterm deliveries, congenital mullerian anomalies, prior cervical procedures (such as conization), history of abortions, GA at hospitalization and delivery, fetal presentation, amniotic fluid volume, mode of delivery, indication for obstetrical intervention and neonatal outcome. The study group included all women admitted with threatened PTL who did not progress to delivery (arrested PTL) during the index admission and were discharged from the hospital, but eventually delivered537 completed weeks of gestation. The control group included women with an episode of arrested PTL who ultimately delivered at or beyond 37 weeks of gestation. Statistical analysis Statistical analysis was performed using the IBM SPSS software (version 20.0; SPSS Inc., Chicago, IL). Continuous variables were compared using the Student’s t-test and categorical variables by 2 or Fisher’s exact test. Appropriate adjusted odds ratios were calculated using a logistic regression model. Statistical significance was defined as p value of 50.05. In order to establish the independent contribution of each factor to actual PTD, and since univariate analysis demonstrated a significant difference in the rate of past PTD, we divided our cohort into two groups: women with previous PTD and women without previous PTD.
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Results Overall, during the study period, 27 130 women delivered in our center, of which 1360 (5%) were diagnosed with PTL. Of this population, 1059 were excluded due to incompatibility with the inclusion criteria (multiple gestation, immediate delivery, placental abruption, chorioamnionitis, indicated PTD, fetal anomalies or still birth), leaving 301 (0.01%) women who were included in the study. Overall, 216 (71.7%) women delivered at term and 85 (28.3%) women had a PTD. Patient characteristics The demographic and obstetrical characteristics are shown in Table 1. The study group was characterized by a higher rates of women with previous PTD (23.5 versus 12.5%, p ¼ 0.02), previous multiple cesarean sections (5.9 versus 0.5%, p ¼ 0.008) and bicornuate uterus (3.5 versus 0%, p ¼ 0.02). There were no statistically significant differences between the groups with regards to maternal age, gravidity and parity, number of prior PTD or number of hospitalizations for premature contractions during the index pregnancy. Other features, such as prior dilation and curettage, prior preterm premature rupture of membranes, PCOS, endometriosis and pregnancies achieved by in vitro fertilization, were also not found to be significantly different between the groups. Hospitalization characteristics Obstetrical history parameters are shown in Table 2. Mean GA at hospitalization was lower for women in the PTD group (28.5 ± 3.4 versus 29.7 ± 2.9 weeks, p ¼ 0.003), as was the sonographic measurement of the cervical length 26.7 ± 8.8 versus 29.4 ± 8.6 mm, p ¼ 0.014). Cervical dilatation on pelvic examination was more advanced among women in the study group (0.6 ± 0.8 versus 0.3 ± 0.6 cm, p ¼ 0.004). Pregnancy outcome Higher rate of women delivered 528, 534 and 537 weeks of gestation (p50.001 for all) in the study group (Table 3). The rate of spontaneous vaginal delivery decreased (61.2 versus 80.6%, p50.001) and the rate of cesarean section increased for women in the study group in comparison to the control group (35.3 versus 11.1%, p50.001). As for neonatal outcome, a significant higher rate of NICU hospitalizations, IVH, hypoglycemia, NEC, sepsis, respiratory disorders and jaundice were found in the study group (Table 3). Independent risk factors for PTD among women with arrested PTL We performed a multivariate logistic regression analysis incorporating GA at admission (weeks), sonographic cervical length (mm) and cervical dilatation (cm). In the subgroup of women without a history of PTD, factors associated independently with risk for preterm birth were lower GA at hospitalization, higher cervical dilatation at admission and shorter sonographic cervical length (Table 4). In the subgroup of women with past PTD, only advanced cervical dilatation at
Arrested preterm labor and preterm delivery
DOI: 10.3109/14767058.2015.1016420
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Table 1. Demographic and obstetrical characteristics for the study and control group.
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Characteristics
Study group preterm (n ¼ 85)
Control group term (n ¼ 216)
p value
30.6 ± 5.7 2.5 ± 1.5 1.9 ± 1.1 40 (47.1) 1.52 ± 0.80 7 (8.2) 5 (5.9) 20 (23.5) 1.40 ± 0.50 0 (0.0) 8 (9.4) 0.13 ± 0.46 0 (0.0) 3 (3.5) 3 (3.5) 3 (3.5) 1 (1.2) 13 (4.3) 33.0 ± 3.1 7 (8.2) 25 (29.4) 53 (62.4)
29.8 ± 5.3 2.2 ± 1.6 1.7 ± 1.0 120 (55.6) 1.38 ± 0.67 20 (9.3) 1 (0.5) 27 (12.5) 1.15 ± 0.36 3 (1.4) 19 (8.8) 0.10 ± 0.35 2 (0.9) 0 (0.0) 2 (0.9) 6 (2.8) 7 (3.2) 21 (9.7) 38.7 ± 1.3 – – –
0.29 0.15 0.08 0.18 0.15 0.780 0.008 0.02 0.07 0.561 0.87 0.57 40.99 0.02 0.14 0.72 0.45 0.17 50.001 – – –
Maternal age, years* Gravidity, n* Parity, n* Nulliparity, n (%) Hospitalizations for premature contractions, n* Previous single CS, n (%) Previous multiple CS, n (%) Prior PTD, n (%) Number of prior PTD, n* PPROM history, n (%) D&C history, n (%) Previous D&C, n* Recurrent abortions, n (%) Bicornuate, n (%) Endometriosis, n (%) PCOS, n (%) Fibroid, n (%) ART, n (%) GA at delivery, weeks* 528, n (%) 534, n (%) 537, n (%)
D&C, dilation and curettage; PCOS, polycystic ovaries syndrome; ART, artificial reproductive technologies; APLA, antiphospholipid antibody syndrome. *Data are presented as mean ± standard deviation.
Table 2. Hospitalization characteristics for the study and control group.
Parameter GA at hospitalization, weeks* Sonographic cervical length, mm* Cervical dilation, cm* Cervical effacement, %* Tocolysis, n (%) Nifedipine, n (%) Indomethacin, n (%) Tractocile, n (%) Betamethasone, n (%) Rescue betamethasone treatment, n (%) Delivery within 48 hy, n (%) Delivery within 7 daysy, n (%) Delivery within 14 daysy, n (%)
Study group preterm (n ¼ 85)
Control group term (n ¼ 216)
p value
28.47 ± 3.362 26.7 ± 8.8 0.6 ± 8 43.9 ± 28.5
29.7 ± 2.9 29.4 ± 8.6 0.3 ± 0.6 38.2 ± 28.2
0.003 0.014 0.004 0.114
107 (49.5) 30 (13.9) 16 (7.4) 210 (97.2) 16 (7.4) NA NA NA
0.568 0.179 0.001 0.730 0.563 NA NA NA
39 7 18 82 8 6 16 43
(45.9) (8.2) (21.2) (96.5) (9.4) (7.1) (18.9) (37.8)
*Data are presented as mean ± standard deviation. yPercentage out of preterm births.
admission remained significantly associated with the risk for preterm birth (Table 4). We further sought to establish the role of association between short cervical length as measured by a sonogram at admission and time to delivery (Table 5). We found the among women with no past PTL, each decrease of 1 mm in cervical length was associated with an increased risk for delivery within 7 and 14 days, but not in 48 h. This association was not found to be significant among women with past PTL.
Discussion In this study, we aimed to evaluate specific risk factors for spontaneous PTD in women with arrested PTL. Our main
findings were: (i) the rate of PTD among women with an episode of arrested PTL was 28.3%; (ii) among women with arrested PTL, advanced cervical dilatation was found as an independent risk factor for PTD independently of past PTD history; (iii) in women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission and short cervical length measured by a transvaginal sonogram. The rate of preterm deliveries (537 weeks of gestation) among our cohort was 28.3%, more than twice the reported 12% PTD rate in the general population [1,10,11]. Nonetheless, since these 12% include versatile circumstances, such as preterm premature rupture of the membranes, women without an episode of arrested PTL, indicated PTD and so forth, it cannot be used as reference in cases of women with
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Table 3. Pregnancy outcome for the study and control group.
Parameter
Study group preterm (n ¼ 85)
Control group term (n ¼ 216)
p value
52 (61.2) 3 (3.5) 30 (35.3) 55 (64.7) 2072 ± 623 45 (52.9) 5 (5.9) 0 (0.0) 0 (0.0) 8 (9.4) 2 (2.4) 4 (4.7) 1 (1.2) 1 (1.2)
174 (80.6) 18 (8.3) 24 (11.1) 119 (55.1) 3121 ± 435 17 (7.9) 3 (1.4) 1 (0.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
50.001 0.14 50.001 0.13 50.001 50.001 0.03 40.99 NA 50.001 0.08 0.006 0.28 0.28
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Mode of delivery, n (%) Spontaneous vaginal delivery Operative vaginal delivery Cesarean section Male neonate, n (%) Birth weight, g* NICU, n (%) Neonatal asphyxia, n (%) Neonatal seizures, n (%) Neonatal HIE, n (%) Neonatal IVH, n (%) Grade 1 Grade 2 Grade 3 Grade 4
NICU, neonatal intensive care unit; HIE, hemorrhagic ischemic encephalopathy; IVH, intraventricular hemorrhage. *Data are presented as mean ± standard deviation.
Table 4. Odds ratio for PTD among women with arrested PTL.
Parameter No history of prior PTL GA at hospitalization (each earlier week) Sonographic cervical length (each decrease of 1 mm) Cervical dilation (each increase of 1 cm PRIOR PTL GA at hospitalization (each earlier week) Sonographic cervical length (each decrease of 1 mm) Cervical dilation (each increase of 1 cm) Number of past PTL (each additional PTL)
Table 5. The odds ratio of short cervical length (each 1 mm) for PTD within 48 h, 7 days and 14 days among women with arrested PTL.
Parameter No history of prior PTL Delivery within 48 h Delivery within 7 days Delivery within 14 days Prior PTL Delivery within 48 h Delivery within 7 days Delivery within 14 days
Adjusted odds ratio
95% confidence interval
p value
1.08 1.10 1.09
0.84–1.60 1.03–1.18 1.03–1.14
0.37 0.006 0.002
0.97 0.91 0.86
0.64–1.48 0.72–1.14 0.73–1.00
0.91 0.40 0.06
arrested PTL. Corroborating with our results, Wilms et al. [12] found that women with an episode of PTL had a 27% risk for PTD, compared with 7% of women without such episode. It is worth mentioning that the methodology of their study differed from ours as they compared women with and without an episode of arrested PTL, while in our study all women had an episode of arrested PTL. Yet, it is reasonable to assess, based on their cohort and ours, that the risk for PTD among women with an episode of arrested PTL is significantly higher than in the general population [12]. We may assume, that the activation of different pathways associated with delivery
Adjusted odds ratio
95% confidence interval
p value
1.20 1.04 1.66
1.09–1.32 1.01–1.08 1.06–2.61
50.001 0.03 0.03
1.14 0.96 2.81 3.99
0.91–1.44 0.88–1.05 1.02–7.73 0.88–18.16
0.26 0.38 0.04 0.07
(uterine activity, cervical ripening) occur earlier among these women, and even though arrested and not leading to immediate delivery, these processes are not fully reversed, thus translating into a higher rate of preterm deliveries. We also found that the rate of past PTD was higher in our study group (23.5 versus 12.5%, p ¼ 0.02). It is well known that past PTD is a significant risk factor for future PTD [2,3,13], although episodes of threatened PTL were found to be strongly associated with spontaneous preterm deliveries even in women without a history of PTD [14]. Alleman et al. [13] sought to create a predictive model for PTD, and found that past PTD is one of the few predictors both easily available and used at the population level for identifying future PTD and a primary indication to offer treatment. Therefore, we divided our cohort into to sub groups: women with and without a history of past PTD. Among our cohort, advanced cervical dilatation on pelvic examination was found to be an independent risk factor for PTD unrelated to history of past PTD. Previous studies have also found this parameter to be of high predictive value in similar situations [12,15]. In these studies, no differentiation between women with or without a history of preterm birth was performed. Our study, on the other hand, has demonstrated that advanced cervical dilatation is an independent risk factor for current PTD regardless of past PTD, thus strengthening
Arrested preterm labor and preterm delivery
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DOI: 10.3109/14767058.2015.1016420
this variable as a marker for potential preterm birth. This finding may further reflect the pathological initiation of the birth process prematurely, leading ultimately to preterm birth later in pregnancy, even after imminent birth was arrested during the index episode. For women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission and short cervical length measured by transvaginal sonogram. Short cervical length was additionally found to be an independent risk factor for delivery within 7 and 14 days of examination. Previous studies have shown [16,17,18] that for women with threatened PTL, cervical length measurement, with or without positive fibronectin in vaginal secretions, is an independent predictor of PTD in women with PTL, although its predictive accuracy as a single measure is relatively limited. Some have also found a 15-mm cutoff for PTD within 7 days [19–21]. Although some of these studies did not distinguish between women with and without a history of past PTD, the basic premise of cervical length as a predictor for PTD still implies, again reflecting the premature commencement of the birth process. With regards to gestational week at admission, Hiersch et al. [22] found that women who presented earlier in pregnancy with threatened PTL had a lower mean GA at delivery and were more likely to experience PTD at 535 or 32 weeks of gestation [22]. We may argue that the earlier the pathological cascade of birth begins, the greater the pathology, thus leading to earlier delivery. We did not find similar results among women with prior PTD, but this may be attributed to the relatively low prevalence of women with such a history in our cohort. Patients’ history, such as prior dilation and curettage, number of PTD, PCOS and other gynecological problems, were not found to predict PTD in our cohort, similar to other studies [14,23]. One study has demonstrated that such characteristics have changed markedly over a 23 years’ period [24], with a marked increase in maternal age and nulliparous women. This study also found that variables pertaining to previous and current obstetric complications (previous preterm birth, previous caesarean section, pre-eclampsia and antepartum hemorrhage) were the most influential predictors of preterm birth. These findings might be explained by the complex mechanism of PTD, and the different individual factors attributing to the risk of PTD, yet to be understood. As expected, neonatal outcomes of women with PTD were worse than those of women that delivered at term. These outcomes included a significant higher rate of NICU hospitalizations, IVH, hypoglycemia, NEC, sepsis, respiratory disorders and jaundice. Our study is not without limitations. It is limited by its retrospective design, and is lacking certain demographic data such as maternal BMI and previous GA at delivery at the last PTD. With regards to women with past PTD, no data could be extracted as to the reason of the past PTD, nor as to progesterone treatment during the current pregnancy. Nevertheless, its strengths lie in its coherent and stringent definitions and protocols, since it was carried out in a single tertiary obstetrical center, with a single departmental protocol. Therefore, the data provided by the study are reliable and consistent.
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In summary, the risk of PTD among women with singleton gestation and an episode of arrested PTL is higher than in the general population and approaches 30%. Independent risk factors for PTD among such women include advanced cervical dilatation, and for women without a history of prior PTD also lower GA and shorter sonographic cervical length at admission. Additional larger and prospective studies are needed to further evaluate and characterize this unique and important population and to strive at finding new interventions to prevent PTD in women with arrested PTL.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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