Ultrasound Obstet Gynecol 2019; 53: 529–534 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.19118. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Should phenotype of previous preterm birth influence management of women with short cervix in subsequent pregnancy? Comparison of vaginal progesterone and Arabin pessary A. CARE1 , B. MULLER-MYHSOK2,3 , E. OLEARO4 , T. TODROS4 , J. CARADEUX5,6 , M. GOYA7 , M. PALACIO5,8 , E. CARRERAS7 and Z. ALFIREVIC1 1 Harris Wellbeing Preterm Birth Centre, Department of Women and Children’s Health Research, Liverpool Women’s Hospital, Liverpool, UK; 2 Waterhouse Building, University of Liverpool, Liverpool, UK; 3 Max Plank Institute of Psychiatry, Munich, Germany; 4 Obstetrics and Gynecology Unit 2, Department of Surgical Sciences, University of Turin, Turin, Italy; 5 Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clı́nic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona, Spain; 6 Fetal Medicine Unit, Clı́nica Dávila, Santiago, Chile; 7 Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain; 8 Center for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain K E Y W O R D S: Arabin pessary; PPROM; preterm birth; short cervix; vaginal progesterone ABSTRACT resulted in earlier delivery in women with previous PPROM than in any other subgroup (P < 0.0001). Linear Objective To investigate whether the classification of a regression analysis showed a clear effect of PPROM previous spontaneous preterm birth (sPTB) as preterm history (P < 0.0001), combination of PPROM history and labor (PTL) with intact membranes (IM) or as preterm treatment (P = 0.0003) and cervical length (P = 0.0004) prelabor rupture of membranes (PPROM) impacts the on gestational age at birth. efficacy of cervical pessary or vaginal progesterone for prevention of sPTB in pregnant women with short cervix Conclusions Cervical pessary may be a less efficacious on transvaginal ultrasound. treatment option for women with previous PPROM; however, these results require prospective validation Methods This was a retrospective cohort study of asymp- before change in practice is recommended. Phenotype tomatic high-risk singleton pregnancies with a short of previous preterm birth may be an important risk cervix and history of sPTB, treated using Arabin pes- predictor and treatment effect modifier; this information sary or vaginal progesterone for primary PTB prevention, should be reported in future clinical trials. © 2018 conducted at four European hospitals. A log-rank test The Authors. Ultrasound in Obstetrics & Gynecology on Kaplan–Meier curves was used to assess the difference published by John Wiley & Sons Ltd on behalf of the in performance of pessary and progesterone, according International Society of Ultrasound in Obstetrics and to history of PTL-IM or PPROM. Linear regression Gynecology. analysis was used to evaluate significant predictors of ges- tational age at delivery. INTRODUCTION Results Between 2008 and 2015, 170 women were treated with a pessary and 88 with vaginal progesterone. The presentation of preterm birth remains important In women treated with a pessary, rate of sPTB < 34 weeks for identifying the cause, estimating the risk of recurrence was 16% in those with a history of PTL-IM and 55% and implementing preventative strategies in subsequent in those with a history of PPROM. In women treated pregnancies. A broad classification system of preterm birth with progesterone, rate of sPTB < 34 weeks was 13% based on presentation includes iatrogenic preterm birth, in those with a history of PTL-IM and 21% in those spontaneous preterm labor (PTL) with intact membranes with a history of PPROM. Treatment with a pessary (IM) and preterm prelabor rupture of membranes Correspondence to: Dr A. Care, Harris Wellbeing Preterm Birth Centre, Department of Women and Children’s Health Research, Liverpool Women’s Hospital, Crown Street, Liverpool, L8 7SS, UK (e-mail: angharad.care@liv.ac.uk) Accepted: 5 June 2018 © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd ORIGINAL PAPER on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. 530 Care et al. (PPROM), each accounting for approximately one-third each unit to classify cases as correctly as possible. Any of all preterm births1 . woman who had a history of both PTL-IM and PPROM More recently, preterm birth classifications have used was included in the PPROM group. PPROM was defined an increasingly complex conceptual framework based on as a diagnosis of spontaneous rupture of the membranes at severe maternal, fetal and placental conditions causally least 12 h prior to delivery. Excluded were all women with associated with preterm birth2 . At present, it is difficult a history of a short cervix only (i.e. no history of preterm to know how to apply this classification system to the birth/PPROM), women treated prophylactically due to management of subsequent pregnancy; many observable a history of PTL-IM or PPROM but without having a pregnancy characteristics fall across a minimum of short cervix, cases in which cervical-length data were not two classifications, and interventions for prevention available, multifetal pregnancies, congenital abnormali- remain limited. The only presentation for which there is ties diagnosed in the fetus and cases with cervical cerclage effective intervention in singleton pregnancy to prevent used as a first-line therapy. Short cervix was defined spontaneous preterm birth (sPTB) is history of sPTB by individual hospital protocols, but was either a single and/or a short cervix3,4 . measurement of ≤ 25 mm or < 3rd centile for gestational There is increasing evidence from systems biology (the age9 . Ethical approval was obtained at each hospital for computational and mathematical modeling of complex use of patient data to be analyzed retrospectively. biological systems) that sPTB with IM at labor and The primary outcome was gestational age at delivery. PPROM have distinct biological pathways5 . An autoim- For the primary analysis, we excluded all women who mune/hormonal regulation axis may exist for spontaneous had been additionally treated with a cervical cerclage, and PTL-IM, whilst pathways implicated in the etiology of who had swapped treatment or had additional treatment PPROM include hematological/coagulation function dis- based on clinical perception that the primary treatment order, collagen metabolism, matrix degradation and local was failing. Secondary analysis included all women based inflammation. Additionally, the dissimilarity of clinical on an intention-to-treat principle. risk factors for PPROM and PTL-IM suggests that there are different underlying pathophysiological pathways6 . Statistical analysis It is therefore reasonable to hypothesize that treat- ments for short cervix may exert different biological and Demographic variables included in the analysis were environmental interactions and effects resulting in dif- age, ethnicity, body mass index (BMI), smoking, ferent pregnancy outcomes. Although exact mechanisms cervical surgery, number of term deliveries, number of action remain to be established, the actions of vagi- of PTL-IM, number of PPROM, gestational age at earliest nal progesterone and pessary are likely to have different PTL-IM/PPROM and treatment for short cervix. SPSS mechanisms of therapeutic effect. A pessary is a device that Statistics for Windows, Version 22.0 (IBM Corp., provides mechanical support and increases the uterocer- Armonk, NY, USA) was used to calculate P-values using vical angle at the cervix7 , whereas vaginal progesterone one-way ANOVA, Kruskal–Wallis test, Mann–Whitney has anti-inflammatory properties and inhibits produc- U-test, chi-square test or Fisher’s exact test, as appropri- tion of stimulatory prostaglandins (PG) and expression of ate. Subsequently, demographics were compared between contraction-associated protein genes in the myometrium8 . women who had previously experienced PTL-IM and The aim of this study was to investigate the effectiveness those who had previously experienced PPROM. A of vaginal progesterone and Arabin pessary for preventing log-rank test on Kaplan–Meier curves was performed to sPTB in women with a short cervix on transvaginal assess the difference in performance of vaginal proges- ultrasound, according to classification of previous sPTB terone and Arabin pessary according to history of PTL-IM as PTL-IM or PPROM. or PPROM, using the software package R (R Founda- tion for Statistical Computing, Vienna, Austria; https: //cran.r-project.org/). In order to establish which clinical METHODS characteristics are significant predictors of gestational This was a retrospective cohort study of asymptomatic age at delivery and by what magnitude they contribute high-risk singleton pregnancies with a short cervix to this pregnancy outcome, linear regression analysis was and history of sPTB, conducted between 2008 and performed, using type of treatment, cervical length and 2015 at four hospitals, one in Liverpool, UK (Liverpool phenotype of previous sPTB as potential predictors. Women’s Hospital), two in Barcelona, Spain (Vall d’Hebron; Hospital Clinic Barcelona) and one in Turin, RESULTS Italy (Università degli Studi Torino). All four hospitals used either cervical Arabin pessary (a CE-certified pessary; Data on 258 women with a history of PPROM and/or CE 0482/EN ISO 13485: 2003 annex III of the council PTL-IM who had subsequent treatment for short cervix directive 93/42 EEC) or vaginal progesterone 200 mg with Arabin pessary or vaginal progesterone were nocte as a primary treatment for preterm birth prevention. obtained from the four participating obstetric centers All women were classified into one of two groups: history in Europe between 2008 and 2015 (Figure 1). Arabin of PTL-IM ≤ 34 weeks or history of PPROM ≤ 34 weeks. pessary was the primary therapy in 170 women, 10 (6%) Classification was performed by preterm birth experts at of whom required an additional therapy or change in © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2019; 53: 529–534. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. Comparison of Arabin pessary and vaginal progesterone 531 Screened women attending specialist preterm birth prevention clinic (n = 3325) Excluded (n = 3067): • Did not require treatment for short cervix (n = 2086) • No history of PTL-IM or PPROM (n = 930) • Multiple pregnancy (n = 12) • Cerclage as primary treatment (n = 36) • No delivery details recorded (n = 3) Cases identified for analysis (n = 258) Changed treatment or received additional treatments (included in secondary analysis only) (n = 31) Included in primary analysis (n = 227) Previous PTL-IM (n = 167) Previous PPROM (n = 60) Vaginal progesterone Arabin pessary Vaginal progesterone Arabin pessary (n = 38) (n = 129) (n = 29) (n = 31) Figure 1 Flowchart showing inclusion of women in study. PPROM, preterm prelabor rupture of membranes; PTL-IM, preterm labor with intact membranes. treatment. Vaginal progesterone treatment was used in PPROM were more likely to deliver earlier than those with 88 women, 21 (24%) of whom received an alternative or a history of PTL-IM (35 weeks vs 38 weeks, P ≤ 0.001). additive treatment following further cervical shortening. Using a log-rank test on Kaplan–Meier survival curves, The 31 women with alternative or additive therapy were a four-way comparison was performed to assess if there excluded from the primary analysis. Demographic data was any difference in the duration of pregnancy between for the full cohort according to center and treatment four distinct groups: (1) previous PPROM and treated group are shown in Table S1. The demographics of the with Arabin pessary; (2) previous PTL-IM and treated 227 women included in the primary analysis are shown with Arabin pessary; (3) previous PPROM and treated according to center in Table 1 and according to treatment with vaginal progesterone; and (4) previous PTL-IM and classification of previous sPTB in Table 2. Significant and treated with vaginal progesterone. Overall, the differences in demographics between hospital populations difference between the four groups was highly significant included tobacco use, cervical surgery and gestational age (P < 0.0001) due to much earlier gestational age at at treatment, with the Turin center screening until a later delivery in women with previous PPROM and treated gestational age than the other three hospitals (Table 1); with Arabin pessary (Figure 2). When only women treated however, there was no statistically significant difference in with progesterone were compared, there was no difference gestational age at delivery between the centers (P = 0.45). in the duration of pregnancy between those with previous BMI was slightly lower in the group with history of PPROM and those with previous PTL-IM (P = 0.365). PPROM who were treated with progesterone, although The results remained qualitatively unchanged when the it was felt that such a small difference, while statistically 31 women who received a combination of treatments significant, would not be clinically important. Cervical were included (intention-to-treat analysis; Figure S1). The surgery rate was found to be higher in this group median gestational age at delivery for women on vaginal (24%), but this did not affect treatment performance as progesterone (n = 21; 10 with previous PPROM) who had measured by gestational age at delivery. In women treated additional treatment or change in treatment was 38 weeks with Arabin pessary, there was a significantly greater (range, 18–41 weeks) compared with 27 weeks (range, proportion who had PPROM in the index pregnancy in 19–38 weeks) in the Arabin pessary group (n = 10; six those who had previously experienced PPROM compared with previous PPROM). with those with a history of PTL-IM (32% vs 9%, The shortest cervical lengths at treatment were clustered P ≤ 0.001) (Table 2). Overall, women with a history of in the group with previous PPROM and treated with © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2019; 53: 529–534. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. 532 Care et al. Table 1 Characteristics of 227 women with short cervix and previous preterm labor with intact membranes (PTL-IM) or preterm prelabor rupture of membranes (PPROM), according to center Liverpool Women’s Barcelona Hospital Clinic University of Hospital Vall d’Hebron Barcelona Turin Characteristic (n = 77) (n = 98) (n = 20) (n = 32) P Age (years) 31 ± 5 31 ± 5 33 ± 5 32 ± 4 0.514* BMI 25 ± 5 26 ± 3 23 ± 5 25 ± 4 0.100* Ethnicity — Caucasian 66 (86) 57 (58) 18 (90) 28 (88) Black 9 (12) 8 (8) 0 (0) 3 (9) Asian 1 (1) 10 (10) 0 (0) 0 (0) Indian 1 (1) 0 (0) 0 (0) 0 (0) Hispanic 0 (0) 23 (23) 2 (10) 0 (0) Tobacco use 26 (34) 21 (21) 4 (20) 3 (9) 0.039† Cervical surgery 15 (19) 1 (1) 2 (10) 3 (9) < 0.001† Gestational age at treatment (weeks) 21 (14–28) 22 (19–24) 23 (9–29) 25 (15–32) 0.001‡ Cervical length at treatment (mm) 20 (3–29) 20 (5–25) 21 (9–24) 20 (0–27) 0.401‡ Arabin pessary 38 (49) 98 (100) 0 (0) 24 (75) — Vaginal progesterone 39 (51) 0 (0) 20 (100) 8 (25) — Date are presented as mean ± SD, n (%) or median (range). *One-way ANOVA. †Chi-square test. ‡Kruskal–Wallis test. BMI, body mass index. Table 2 Demographics and pregnancy outcome of 227 women with short cervix included in primary analysis, according to treatment and previous spontaneous preterm birth classification Pessary (n = 160) Progesterone (n = 67) PTL-IM PPROM PTL-IM PPROM Parameter (n = 129) (n = 31) (n = 38) (n = 29) P Demographic data Age (years) 31 ± 5 32 ± 5 31 ± 6 32 ± 4 0.745* BMI 25 ± 4 25 ± 4 25 ± 4 23 ± 5 0.043* Ethnicity — Caucasian 92 (71) 17 (55) 33 (87) 27 (93) Black 11 (9) 5 (16) 3 (8) 1 (3) Asian 4 (3) 6 (19) 0 (0) 1 (3) Indian 1 (1) 0 (0) 0 (0) 0 (0) Hispanic 21 (16) 3 (10) 2 (5) 0 (0) Tobacco use 31 (24) 5 (16) 10 (26) 8 (28) 0.712† Cervical surgery 9 (7) 2 (7) 4 (11) 7 (24) 0.038† Gestational age at treatment (weeks) 22 (16–32) 22 (16–30) 22 (14–29) 22 (16–30) 0.941‡ Cervical length at treatment (mm) 20 (3–29) 17 (4–27) 21 (6–27) 22 (0–26) 0.021‡ Pregnancy outcome Gestational age at delivery (weeks) 38 (22–41) 29 (21–40) 38 (27–41) 37 (23–41) < 0.001‡ PPROM 11 (9) 10 (32) 4 (11) 9 (31) < 0.001† Preterm birth < 34 weeks 21 (16) 17 (55) 5 (13) 6 (21) < 0.001† Cesarean section 20 (16) 5 (16) 5 (13) 7 (24) 0.650† Date are presented as mean ± SD, n (%) or median (range). *One-way ANOVA. †Chi-square test. ‡Kruskal–Wallis test. BMI, body mass index; PPROM, preterm prelabor rupture of membranes; PTL-IM, preterm labor with intact membranes. Arabin pessary, with the median cervical length at type or PPROM history did not improve the prediction of treatment being lower in this group by 3–5 mm (Table 2; gestational age at delivery. P = 0.021). As shorter cervical length is a known risk factor for PTB, linear regression analysis was performed to determine if cervical length affected both the allocation DISCUSSION of group and outcome. The data confirmed that cervical length seems to be an independent predictor of gestational Analysis of data in this retrospective study has demon- age at birth (P = 0.0004). However, the strongest strated that history of PPROM may be an important variables in predicting earlier gestational age at delivery predictor of treatment success for short cervix in subse- in our dataset were history of PPROM (P < 0.0001) and quent pregnancy. The Arabin pessary does not appear a combination of history of PPROM and treatment type to have the same benefit in women who previously (P = 0.0003). Combining cervical length with treatment experienced PPROM compared with those with previous © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2019; 53: 529–534. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. Comparison of Arabin pessary and vaginal progesterone 533 1.00 Mixed results have been reported in subsequent clinical trials of pessary for short cervix, without satisfactory 0.75 explanation14–16 . As most studies collect limited data on PTB probability the observable characteristics of previous preterm births 0.50 or any other biomarkers, further individual patient data analyses are unlikely to provide better evidence of the 0.25 importance of various classifications of preterm labor as potential modifiers of treatment success. 0.00 We acknowledge that our data are retrospective and 0 100 200 300 we therefore cannot be certain that all classifications were Gestational age (days) assigned correctly. However, cases of sPTB and PPROM were reviewed by preterm birth experts at each unit to Figure 2 Kaplan–Meier survival curves demonstrating preterm classify each case as correctly as possible. We would birth (PTB) probability in 227 women with short cervix included in recommend that the results of this study be validated primary analysis, according to obstetric history and treatment: in a separate population before advising a change in previous preterm prelabor rupture of membranes (PPROM), clinical practice. Our data are not randomized and treated with Arabin pessary ( ); previous preterm labor with intact membranes (PTL-IM), treated with Arabin pessary ( ); therefore confounding as a cause of our results cannot be previous PPROM, treated with vaginal progesterone ( ); completely excluded. previous PTL-IM, treated with vaginal progesterone ( ). Although women in each group had a comparable dis- tribution of cervical lengths, the median measurement was PTL-IM. Vaginal progesterone may therefore be a more lowest, at 17 mm, in the group with a history of PPROM efficacious treatment option for these women. and treated with Arabin pessary. However, a history of The pathophysiological mechanism behind this effect is PPROM alone and PPROM interacting with treatment not clear. One possible theory is that the Arabin pessary type were both independent predictors of gestational age may exacerbate a dysbiotic vaginal microbial environ- at birth, irrespective of cervical length when treatment ment. Kindinger et al. investigated the effect of suture was initiated. Whether in fact a pessary exacerbates the material on the vaginal environment for a similar at-risk risk of preterm birth in women with previous PPROM or, population10 . They demonstrated that, compared with a alternatively, progesterone modifies the risk of PPROM braided suture, a monofilament material reduced the risk should be validated in future prospective studies. of preterm birth by an additional 11% and also reduced We did not explore the reasons for why 10% of women the rate of non-viable birth (< 24 weeks or intrauterine given Arabin pessary and 24% of those commenced death). This causal effect was further supported by on progesterone were given additional treatment; this evidence that, despite dysbiotic microbiomes being equal may reflect ongoing shortening of the cervix, lack of in prevalence prior to suture insertion, braided cerclage faith in the treatment by the clinician or patient, or led to a shift towards dysbiosis in just 4 weeks after physical discomfort with treatment. The concern for the insertion. The Arabin pessary is a cone-shaped silicone analysis was that patients requiring a second treatment device that, once sited around a cervix, remains in the may be at higher risk of delivering and that excluding vagina until removal prior to labor. We hypothesize that them would bias the results, particularly as there were a similar effect could be involved here but found no a greater percentage of these cases in the progesterone published studies investigating the possible impact of group. Our intention-to-treat analysis (including all cases) an Arabin pessary on surrounding vaginal microbiome. revealed that, irrespective of women changing or receiving One study examining ring pessaries for pelvic organ additional treatment, women with a history of PPROM prolapse in a non-pregnant population demonstrated that who received an Arabin pessary as first-line treatment they could exacerbate growth of pre-existing anaerobic remained at increased risk of delivering earlier than those bacteria11 . The foreign body of the pessary could receiving vaginal progesterone (Figure S1; P < 0.0001). provide a surface for colonization or, alternatively, many Regrettably, we were unable to test in our dataset Arabin pessary users report a marked increase in watery whether the phenotype of previous preterm birth is also discharge, which could affect vaginal microbial flora. In relevant for cervical cerclage. This may be potentially very contrast, vaginal progesterone does not have any adverse important given that a significant number of UK preterm impact on vaginal microbiota in pregnancy12 . birth prevention clinics still use cervical cerclage as a The effect of different outcomes in different populations first-line treatment for short cervix17 . may, at least in part, account for the variation that we The data from this study have fundamental implications have seen in recent years in the mixed outcomes of clinical for ongoing clinical trials on preterm birth treatments. trials of Arabin pessary for a short cervix. The landmark We argue that data collection should take into account paper that brought Arabin pessary into more frequent use the observable characteristics of previous preterm births as an alternative to vaginal pessary and cervical cerclage to allow subclassification of results based on history. in current clinical practice was the PECEP trial published In-depth classifications have been published2 but, as a in 2012, which reported a significant reduction in rate minimum, trying to identify subgroups of sPTB and of spontaneous delivery before 34 weeks of gestation13 . PPROM would be recommended. The authors acknow- © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2019; 53: 529–534. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. 534 Care et al. ledge that the classification of PPROM can be particularly REFERENCES challenging given the subjectivity surrounding ‘the begin- 1. 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Cerclage pessary for preventing by Besins Healthcare at no cost. No funding or stock was preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: A randomized controlled trial. Am J Perinatol 2013; 30: 283–288. received for this study. The remaining authors report no 17. Sharp AN, Alfirevic, Z. Provision and practice of specialist preterm labour clinics: a conflict of interest. UK survey of practice. BJOG 2014; 121: 417–421. SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Figure S1 Kaplan–Meier survival curves demonstrating preterm birth probability in 258 women with short cervix included in intention-to-treat analysis, according to classification of previous spontaneous preterm birth (sPTB) and treatment. IM, intact membranes; PPROM, preterm prelabor rupture of membranes. Table S1 Demographics and pregnancy outcome of 258 women with short cervix and previous preterm labor (PTL) with intact membranes or preterm prelabor rupture of membranes, according to center and treatment © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2019; 53: 529–534. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.