Management of Short Cervix during Pregnancy: A Review

Transcription

1 Prematurity Special Issue 245 Management of Short Cervix during Pregnancy: A Review Jennifer Gilner, MD, PhD 1 Joseph Biggio, MD 2 1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina 2 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama Address for correspondence Jennifer Gilner, MD, PhD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University School of Medicine, Box 3967, Durham, NC ( jennifer.gilner@duke.edu). Am J Perinatol 2016;33: Abstract Keywords preterm birth short cervix cervical insufficiency progesterone cervical cerclage cervical pessary Value of a Cervical Length Measurement during Pregnancy Shortening of the uterine cervix, as measured by transvaginal ultrasound, represents a quantifiable marker at the convergence of spontaneous preterm birth (PTB) pathways initiated by many different etiologies. Postulated causes of short cervix have been recently reviewed by Romero et al, and include congenital, iatrogenic, and pathologic triggers such as inflammation or inappropriate activation of labor pathways. 1 Irrespective of underlying etiology, the predictive relationship between cervical length and risk of spontaneous PTB has been thoroughly established in both unselected and high-risk populations. 2 5 Norms have been established for cervical length beginning in the mid-trimester of gestation, and measurements are reproducible when performed by trained sonographers. 3,6 8 The transvaginal approach is the gold standard for measurement, as it allows for more precise Sonographic evaluation of the uterine cervix has evolved as one of the best clinical tools available for the prediction of subsequent spontaneous preterm birth (PTB), particularly when combined with prior poor obstetric history. There is a growing body of evidence describing interventions for short cervix that reduce the risk of preterm delivery and improve neonatal outcomes. Yet, given the significant heterogeneity in the pathways that lead to PTB, understanding the specific clinical characteristics of women who may benefit from a given intervention is critical to appropriate implementation. The three primary management strategies that have demonstrated improvement in obstetric and/or perinatal outcomes for appropriately selected women with a sonographically short cervix (vaginal progesterone, cervical cerclage, and pessary) are the subject of this review. In addition, the unique considerations of multiple pregnancies are discussed separately from singletons. visualization of the internal and external cervical os, and avoids many potential pitfalls of transabdominal measurement (e.g., maternal body habitus and view obstruction by fetal parts) Although published studies have used varying cutoffs to define short cervix, a generally accepted threshold is a transvaginal measurement < 25 mm, which correlates with the 10th centile in an unselected population in the midtrimester. 3 There is a continuum of cervical competence, as demonstrated by increasing risk of preterm delivery with decreasing cervical length. 3 At the severe end of this spectrum, once the second trimester cervix length becomes nonmeasurable, the risk of delivery before 32 weeks rises to 75%, and the median interval between diagnosis and delivery is 3 weeks. 12 Although some controversy exists regarding optimal cervical length screening regimens, most experts agree that women with a prior PTB should have at least one transvaginal received November 18, 2015 accepted November 24, 2015 published online January 20, 2016 Copyright 2016 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 246 Management of Short Cervix during Pregnancy Gilner, Biggio cervical length in the mid-trimester. Often, it is prudent to follow serial cervical length measurements (every 1 2 weeks), particularly among women with a prior early spontaneous PTB or multiple prior preterm deliveries. It is debatable whether cervical length should be universally assessed among women without a history of a prior PTB; each center should develop a standardized approach. Universal screening is predicted as a cost-effective approach in decision analyses; however, prospective data on the effectiveness of a screening program for reducing PTB and neonatal morbidity are lacking and are needed before widespread implementation can be encouraged. 13,14 Progesterone Treatment for Short Cervix among Women with a Prior Preterm Birth Intramuscular 17P Administration of weekly intramuscular 17-α hydroxyprogesterone caproate beginning at 16 to 20 weeks and continued through 36 weeks of gestation is currently standard of care in the United States for women with a history of a prior spontaneous PTB. The efficacy of intramuscular 17P among women with prior PTB who also have a sonographic short cervix is uncertain. However, in a secondary analysis from a randomized controlled trial (RCT) examining the role of cervical cerclage for women with a previous spontaneous PTB (< 34 weeks) and sonographic short cervix (< 25 mm), those women who received 17P but were randomized to no cerclage had lower rates of previable delivery (< 24 weeks), and their babies had a lower incidence of perinatal death. In this study, the rate of PTB < 35 weeks for women treated with 17P was similar regardless of whether a cerclage was placed. 15 Despite this, data are limited regarding the use of 17P in women with a short cervix, and additional high-quality studies are needed. Vaginal Progesterone A secondary analysis of an RCT of vaginal progesterone gel versus placebo given to women with a prior PTB examined the subset of women with a sonographic short cervix < 28 mm at enrollment. 16 Among this uniquely defined high-risk cohort, PTB < 32 weeks of gestation was 0% in the progesterone treatment arm, compared with 29.6% in the placebo arm (p ¼ 0.014). In addition, there was neonatal benefit, with fewer neonatal intensive care unit (NICU) admissions and shorter NICU stays among those randomized to progesterone. 17 Another planned secondary analysis from this RCT found a significant reduction in the incidence of short cervix among women randomized to receive vaginal progesterone, suggesting that vaginal progesterone may attenuate or prevent cervical shortening among those women with a prior PTB. 18 Progesterone Treatment for Short Cervix in the Absence of a History of Prior Preterm Birth Intramuscular 17P Among women without a prior PTB, 17P has no effect on PTB rate or neonatal outcomes. In a multicenter study of nulliparous women with a cervical length < 30 mm, weekly 17P injections had no effect on the rate of delivery less than 37 weeks and did not improve neonatal outcomes. 19 In the absence of a history of prior PTB, 17P should not be used for PTB prophylaxis in women found to have a short cervix. Vaginal Progesterone The efficacy of vaginal progesterone among women with a sonographically short cervix has been demonstrated by two large RCTs and one meta-analysis of independent patientlevel data Fonseca et al randomized 413 women with a cervical length 15 mm on routine transvaginal ultrasonography to receive vaginal micronized progesterone (200 mg) or placebo between 24 and 34 weeks of gestation. The incidence of delivery before 34 weeks was reduced to 19.2% in the vaginal progesterone group, compared with 34.4% in the placebo group (relative risk [RR], 0.56; 95% confidence interval [CI], ). 20 Eighty-five percent of the women included in this study had no prior history of PTB. In a subgroup analysis of women without a history of PTB, a significant reduction in the PTB rate (< 34 weeks) was noted in women with a short cervix ( 15 mm) who received progesterone. 20,23 In the second large RCT (the PREGNANT trial), Hassan et al reported that administration of vaginal progesterone gel (90 mg) to women with a cervical length of 10 to 20 mm resulted in a significant reduction in the rate of preterm delivery < 33 weeks (8.9% in treated vs. 16.1%; RR, 0.55; 95% CI, ) as well as < 35 and < 32 weeks of gestation. Moreover, the study demonstrated a significant reduction in respiratory distress syndrome (RR, 0.39; 95% CI, ). These findings were consistent in the subgroup of women without a prior PTB. 21,23 A recent meta-analysis of individual patient-level data (including the two above studies) investigated the effect of vaginal progesterone among women with asymptomatic short cervix ( 25 mm). 16,20,21,24,25 This analysis demonstrated a reduction in the risk of PTB < 33 weeks (RR, 0.58; 95% CI, ) gestation among women who received vaginal progesterone (the primary outcome of the metaanalysis). Women who received vaginal progesterone also had a lower risk of PTB < 28, < 30, and < 35 weeks of gestation, and their neonates had a 43% reduction in composite neonatal morbidity/mortality and lower risk of respiratory distress syndrome. 22 Although the above data are compelling, vaginal progesterone for management of short cervix in the absence of a prior PTB remains somewhat controversial. The Food and Drug Administration failed to grant approval for indicated use of vaginal progesterone for the prevention of PTB in the setting of a short cervix. Many clinicians currently prescribe off-label vaginal progesterone to women diagnosed with a short cervix, and there is no consensus regimen for its use. Specific progesterone formulation and dosing has varied across trials, and there are insufficient data to determine if one formulation is more effective than others. 26 Moreover, given the evidence supporting vaginal progesterone as an efficacious intervention for short cervix, some authorities

3 Management of Short Cervix during Pregnancy Gilner, Biggio 247 have recommended universal cervical length screening including asymptomatic women without a prior preterm delivery. 27 Cervical Cerclage A cervical cerclage is a surgically placed circumferential suture around the uterine cervix to mechanically close the cervical canal. Transvaginal approaches are most common and include McDonald or Shirodkar techniques. Selection of technique and suture material is subject to the preference or experience of the surgeon, as there is no established superior method. 28 Transabdominal cerclage is generally reserved for women in whom anatomic limitations prevent transvaginal approach, or prior transvaginal cerclage has failed. 29 This form of mechanical therapy has traditionally been indicated for cervical insufficiency, as a way to provide anatomic reinforcement. However, the diagnosis of cervical insufficiency is challenging because the potentially indolent nature of cervical insufficiency (painless cervical dilation) can trigger more clinically apparent signs such as labor or rupture of membranes. 30 The strongest evidence for benefit of cerclage in the setting of a short cervix comes from a meta-analysis of patient-level data derived from five randomized trials, compiling data from a total of 504 women (250 cerclage procedures) Among women with singleton gestations and a prior PTB in whom a sonographic diagnosis of short cervix was made, cerclage reduced PTB < 37 weeks by 30% and composite perinatal morbidity and mortality by 36%. The number of cerclage procedures needed to prevent one perinatal death in this group is estimated at Furthermore, for women with a history of PTB, especially if the diagnosis of cervical insufficiency is questionable, data indicate they may be safely monitored with transvaginal ultrasound. For those who do not develop cervical shortening, additional procedures such as cerclage placement may be avoided. Sonographic monitoring with subsequent ultrasound-indicated cerclage in women with a prior PTB has equivalent obstetric outcomes to history-indicated cerclage, but only a fraction (36 42%) of the monitoring cohort ultimately require cerclage. 37,38 There is currently no evidence for benefit of cerclage based on an ultrasound finding of a short cervix intheabsenceofa prior history of PTB. A meta-analysis of four randomized trials that included 607 women (with 305 cerclage procedures) with asymptomatic cervical shortening (< 25 mm) on transvaginal ultrasonography demonstrated that cerclage placement does not prevent PTB in all patients. Although a subgroup analysis of singleton pregnancies with short cervix (552 patients; 278 cerclage procedures) demonstrated a 26% reduction in PTB at less than 35 weeks following cerclage placement, when restricted to low-risk women (no prior PTB) the reduction was not statistically significant. 39 Current practice guidelines published by the American College of Obstetricians and Gynecologists support cerclage use in singleton pregnancies among women with prior PTB (< 34 weeks) and short cervical length by ultrasonography (< 25 mm) before 24 weeks of gestation. In the absence of a history of prior PTB, there is insufficient evidence at this time to recommend cerclage placement for an ultrasound diagnosis of asymptomatic cervical shortening. 30 Patients with acute cervical insufficiency (painless dilation and effacement) are not to be confused with patients identified by ultrasound screening; emergent cerclage may be an appropriate consideration in that setting. Pessary The use of a pessary device to prevent recurrent pregnancy loss represents revival of a simple procedure that was initially published as an observational series by Cross in Lancet in He employed a Bakelite ring to encircle the cervix, pushed up to the level of the internal os, then removed at 39 weeks of gestation. In his series of 13 women with prior pregnancy loss attributed to a structurally weak or damaged cervix (including one with suspected double uterus ), ring (pessary) placement resulted in eight term deliveries and three ongoing pregnancies at the time of publication, representing an increase in live birth rate from 20% before pessary use to 62% following pessary use. Since that time there have been various reports of pessary devices used in obstetrical application to reduce preterm delivery. 41 Before 2003, evidence is sporadic, primarily retrospective case series, and the choice of patient population is incompletely reported, thus generating interest in the possibility that a pessary may reduce PTB, but falling short of foundational evidence to support widespread use of this treatment. 42 Renewed interest in the use of a pessary to reduce PTB has come with increasing sonographic surveillance of cervical length. Contemporary data are primarily focused on the Arabin pessary device, a silicone ring-shaped pessary designed for prematurity prevention. The Arabin cervical pessary is designed to close the cervix and can be placed in the office (as opposed to a surgical procedure such as cerclage), and is easily removed close to term. Advantages of this approach include ease of application, relatively low cost of use, and minimal side effect profile. Increase in vaginal discharge is the primary reported negative effect of pessary use. 43 Proposed mechanisms for pessary-mediated prevention of PTB include alteration of the cervical angle to deflect pressure of the pregnancy to the lower uterine segment, prevention of opening of the internal os, and protection of the cervical mucus plug. 44 The pilot (nonrandomized) study of Arabin pessary use, published in 2003, focused on 12 women with singleton pregnancies, high risk as definedbypriorptborsymptoms of preterm labor in the current pregnancy, who were also found to have cervical length 15 mm. These women had a pessary placed between 22 and 24 weeks of gestation and outcomes were compared with women from a retrospective database with cervical length < 10th percentile. In pessary-treated patients, there were no preterm deliveries, as compared with 6 of the 12 matched controls without pessaries. 45

4 248 Management of Short Cervix during Pregnancy Gilner, Biggio Two additional nonrandomized studies subsequently reinforced the idea that the Arabin pessary may prolong pregnancy in women with sonographic short cervix. 46,47 The first trial, by Acharya et al, included 32 women undergoing cervical length ultrasound screening due to PTB risk factors (prior preterm delivery, prior cervical cone biopsy, prior second trimester loss, or multiple gestation), who had a pessary placed for cervical length 25 mm, and demonstrated an average gestational age at delivery of 35 weeks for singletons. 46 The second of these trials, by Sieroszewski et al, identified study participants for pessary placement primarily by cervical length 15 to 30 mm at < 28 weeks of gestation. 47 There was no control group, but 83% of patients with the Arabin pessary delivered after 37 weeks (presumably the remaining 17% had spontaneous preterm delivery), which was compared with the published result of 25% spontaneous PTB rate in patients with 16 to 30 mm cervical length from the Fetal Medicine Foundation. 48 The first RCT of pessary use in patients with short cervix was published in 2012 by Goya et al. In this trial, entitled Pesario Cervical para Evitar Prematuridad, approximately 12,000 women were screened by transvaginal ultrasound between 20 and 23 weeks of gestation and randomized if found to have a cervical length of 25 mm or less. Of 385 women enrolled, 192 were randomized to pessary placement. Half of the participants were nulliparous, and 11% of women in each group had a prior history of PTB. The primary outcome of spontaneous birth before 34 weeks was significantly reduced to 6% in the pessary group, compared with 27% in the expectant management (control) group (odds ratio, 0.18; 95% CI, ). 49 Composite adverse neonatal outcomes were also reduced in the study, though these numbers were primarily driven by the reduction in respiratory distress syndrome. The study was underpowered for assessment of uncommon adverse neonatal outcomes, so this result warrants validation. Conflicting results were found in a smaller randomized trial from China recently published by Hui et al. This study screened 4,400þ women, found 203 with a cervical length (CL) < 25 mm at 20 to 24 weeks, and enrolled 108 women (53 pessary/55 expectant management). The rate of PTB < 34 weeks was lower than expected based on previous reports of women with short cervix and did not vary between treatment (9.4%) and control (5.5%) groups (p ¼ 0.46), although the study was underpowered and analyzed before meeting projected enrollment goals. 50 Interestingly, prior history of cervical incompetence was an exclusion criterion for the trial. Determination of the Optimum Therapy: Comparison between Management Options There is a paucity of level 1 data to provide head-to-head comparison of the primary treatment options for asymptomatic women identified as high risk for PTB. Using a cohort comparison approach across three separate trials, Alfirevic et al described the PTB rates and perinatal outcomes for cerclage, vaginal progesterone, or cervical pessary in 243 highrisk women, as defined by prior history of PTB (17 0/7 33 6/7 weeks) and a short cervix (< 25 mm). 51 Their results demonstrated similar effectiveness of these three available treatment options in women with a singleton pregnancy, prior PTB, and short cervix by transvaginal ultrasound. Using the methodologic approach of indirect comparison meta-analysis, Conde-Agudelo et al examined four studies evaluating vaginal progesterone versus placebo along with five studies evaluating cerclage versus no cerclage. Both interventions demonstrated a significant reduction in PTB < 32 weeks and composite perinatal morbidity. Importantly, adjusted indirect meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in altering the negative outcomes associated with PTB. Thus, for the prevention of PTB in a patient with prior PTB history and sonographic short cervix, either treatment approach is reasonable, supported by evidence, and providers can take into account patient preference, cost, comfort, or other considerations. 52 Special Cases: Multiple Pregnancy Twins account for a disproportionate share of the PTB burden, comprising 10% of all preterm deliveries in the United States and approximately 23% of very preterm deliveries (< 32 weeks). 53 Unfortunately, there is no conclusive evidence that the treatment modalities previously discussed for reducing the burden of PTB in singleton pregnancies can be used to prolong pregnancy in multiple gestations. Furthermore, a retrospective review of 262 twin pregnancies revealed that routine cervical length screening in twins did not alter delivery timing or neonatal outcomes, but lengthened maternal antepartum hospital stay. 54 Thus, while short cervix remains a strong predictor of preterm delivery in multiple gestations, 55 the lack of effective intervention raises debate over the utility of cervical length screening in this population. A proposed hypothesis regarding the disparate results between twin and singleton pregnancies is that there are differing etiologies of PTB in twins or multiples, such as uterine distention, contractions, or preterm labor. 56 Several of the putative etiologies for PTB in multiples may lead to cervical change that is distinct from structural cervical insufficiency, so it stands to reason that interventions that were developed around prevention of cervical insufficiency may have limited impact on PTB prevention in multiple gestations. In addition, the available evidence for management of multiple gestations with short cervical length is limited by analysis of relatively unselected populations and the data on high-risk patients are from secondary analyses. Progesterone Multiple Gestations In stark contrast to outcomes in singleton pregnancies, the use of 17P intramuscular progesterone does not reduce PTB rates in twin or triplet gestations, even in a selected high-risk population, defined by cervical length less than 25 mm Using cervical length norms derived from a cohort of exclusively twin pregnancies, PTB risk is increased in women with a cervical length < 36 mm (25th percentile); yet 17P did not prevent PTB < 35 weeks of gestation in this group based on

5 Management of Short Cervix during Pregnancy Gilner, Biggio 249 secondary analysis of an RCT of twin gestations exposed to 17P or placebo. 61 Increased dosing for patients with twin pregnancy, based on the principle of altered pharmacokinetics in twin pregnancy, not only failed to prolong twin pregnancies but also resulted in higher rates of PTB before 32 weeks in patients receiving 17P. 60 The use of vaginal progesterone in unselected twin pregnancies does not reduce the rate of preterm delivery < 34 weeks, based on the results of the PREDICT trial, a doubleblind, placebo-controlled, randomized trial of vaginal progesterone versus placebo in twin gestations. 24 Data on the use of vaginal progesterone in twin pregnancies have been more promising when focus is placed on the subgroup of twin pregnancies with a short cervix. A secondary analysis of twin gestations with short cervix in the PREDICT trial reported PTB < 34 weeks in 29.4% of women treated with progesterone, as compared with 40% of women treated with placebo, although the result was not statistically significant. 62 Similarly, the subset of twin gestations in the Fetal Medicine Foundation RCT of vaginal progesterone in women with a short cervix reported a nonsignificant reduction in preterm delivery < 34 weeks. 20 There were 29 twin pregnancies included in a recent meta-analysis of individual patient-level data examining the effect of vaginal progesterone treatment on asymptomatic short cervix ( 25 mm). Although the change in PTB before 33 weeks was not statistically significant in twin pregnancies with or without vaginal progesterone, the composite neonatal morbidity/mortality was significantly lower in twin pregnancies that received vaginal progesterone (RR, 0.52; 95% CI, ). The twin groups within these study populations were small, but the results draw attention to a potential twin gestation patient who may benefit from administration of vaginal progesterone. 56 Cerclage Multiples with Short Cervix Given that short cervix defines the singleton population with greatest cerclage benefit, several cerclage studies in twins have restricted enrollment to women with a short cervix. However, cerclage placement in this population has not shown improvement in gestational age at delivery or reduction in perinatal death. 63 Of particular concern is the notion that cerclage placement in twin pregnancy with short cervix may in fact cause harm, as implied from a 2005 patient-level meta-analysis of trials which demonstrated a significant increase in preterm delivery < 35 weeks in twin pregnancies receiving cerclage (75 vs. 36% in control group; RR, 2.15; 95% CI, ). 39 These data should be interpreted with caution due to small sample number (n ¼ 49). In fact, a 2015 repeat meta-analysis of only the cerclage RCTs which included women with asymptomatic twin gestations and short cervix now reports RR of delivery < 35 weeks in the cerclage group of 1.63 (95% CI, ). This more detailed meta-analysis solely on the twin data supports the concept of no effect of cerclage, rather than a detrimental effect, and results are calculated by a random effects model rather than a fixed effects model. 64 A recent cohort study examined 128 twin gestations, including 21 (16.4%) who underwent cerclage for a cervical length 25 mm. Decreasing cervical length was significantly associated with a shorter length of gestation, lower combined birth weight, delivery at 34 weeks, preterm premature rupture of fetal membranes, and very low birth weight. None of these outcomes were altered by cerclage placement. 63 Another retrospective cohort study of twin gestations with a cervical length 25 mm compared 57 managed with cerclage to 83 expectantly managed. There was no difference in PTB or gestational age at delivery between groups. In the subgroup of women with a cervical length 15 mm, cerclage was associated with prolongation of pregnancy by 3 to 4 weeks and a 50% reduction in PTB before 34 weeks. 65 Given the conflicting data, there is a need for high-quality evidence regarding the effectiveness and appropriateness of cerclage for the treatment of twin gestations with a short cervix. Acute cervical change (the finding of cervical dilation in the absence of active labor or intra-amniotic infection) is the only clinical scenario with evidence to date which supports cerclage placement in twin gestation. Two retrospective cohort studies, focused on physical exam-indicated cerclage, have demonstrated that obstetric outcomes are similar between twin and singleton pregnancies receiving cerclage, in support of the concept that cerclage may have positive outcomes in twin pregnancies in the setting of acute cervical insufficiency. 66,67 In addition, although the level of evidence to support cerclage in this setting comes from retrospective cohorts, these are clinical scenarios that have a high likelihood of previable delivery in the absence of intervention. In all cases, the provider must carefully weigh the risks and benefits of the procedure when deciding the optimal management. Pessary Twins There are conflicting data from studies of pessary placement to reduce PTB rates in twin gestation. Two large randomized trials have examined the use of prophylactic placement of an Arabin pessary in unselected multiple gestations. The ProT- WIN trial randomized 813 women with multiple gestations to pessary placement at 16 to 20 weeks versus standard care regardless of cervical length. 68 There were no significant differences seen in the primary outcomes of the study (PTB rates at < 28, < 32, or < 37 weeks or composite perinatal outcome). The second study, published by Nicolaides et al, was a larger multicenter multinational trial of unselected twin pregnancies which randomized 1,180 women to Arabin pessary placement at 20 0/7 to 24 6/7 weeks or expectant management. This study also reported no significant differences in spontaneous PTB < 34 weeks with pessary placement. 69 Subgroup analyses have been published from both studies focusing on women with a short cervix. From the ProTWIN trial, among the subgroup of 133 women with a cervical length below the 25th percentile for the study population (< 38 mm before 20 weeks), pessary placement reduced PTB < 28 weeks (RR, 0.23; 95% CI, ) and < 32 weeks (RR, 0.49; 95% CI, ), as well as composite poor perinatal outcome (RR, 0.40; 95% CI, ). 68 In contrast, in the trial reported by Nicolaides et al, post hoc

6 250 Management of Short Cervix during Pregnancy Gilner, Biggio analysis of the subgroup of 214 women with short cervix ( 25 mm) demonstrated no beneficial effect of pessary placement. 69 Thus, the data regarding effectiveness of pessary use in twin gestations with short cervix are limited at this time; there is a need for additional high-quality evidence before pessary can be routinely recommended for this indication. Several such trials are currently underway in the United States and around the world. Summary Based on limited published comparison between these treatment options, there appears to be clinical equipoise among the use of cerclage, vaginal progesterone, or pessary for management of short cervix, when applied to appropriate patient populations. Level I evidence, in the form of large randomized trials or meta-analyses using patient-level data, exist for the use of progesterone or cerclage in precisely defined groups of women with singleton pregnancies. The ideal target group for clinical benefit with a cervical pessary is less clearly elucidated, perhaps owing to heterogeneous root causes of cervical change in the populations studied so far. The distinct situation of short cervix in multiple pregnancy presents yet another challenge, with unclear relationship (if any) to what we know about treatment for short cervix in singleton pregnancy. Improved understanding of the mechanism of premature cervical change may facilitate targeting these varied treatment options to individual patient scenarios. In the meantime, further large collaborative prospective studies are warranted to define the contribution of each treatment option for short cervix and how they may be combined for maximum effect. Conflicts of Interest None. Funding None. Note Dr. Biggio has previously received a community education grant from Lumara Health. References 1 Romero R, Yeo L, Miranda J, Hassan SS, Conde-Agudelo A, Chaiworapongsa T. 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7 Management of Short Cervix during Pregnancy Gilner, Biggio Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357(5): Hassan SS, Romero R, Vidyadhari D, et al; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, doubleblind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38(1): Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206(2):124.e1 124.e19 23 Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella. 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