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Prevention of spontaneous preterm birth: universal cervical length assessment and vaginal progesterone in women with a short cervix: time for action!

      Related article, page 161.
      In this issue of the Journal, Romero et al
      • Romero R.
      • Conde-Agudelo A.
      • Da Fonseca E.
      • et al.
      Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
      report the results of an individual patient data (IPD) meta-analysis on the use of daily vaginal progesterone in women with a midtrimester short cervix (≤25 mm) in the prevention of preterm birth (PTB).
      An IPD meta-analysis is a type of systematic review in which the original research data for each participant of each study are sought directly from the investigators responsible for the studies. The IPD approach enables data verification, reanalysis of the data in a consistent way, and standardization of outcomes across trials and allows the investigation of whether an intervention is more or less effective for different patient subgroups.
      Romero et al
      • Romero R.
      • Conde-Agudelo A.
      • Da Fonseca E.
      • et al.
      Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
      analyzed data from 5 high-quality randomized controlled trials and demonstrated that allocation to vaginal progesterone was associated with a significant decrease in the risk of PTB occurring at <28 to <36 weeks of gestation. There was also a significant reduction in the frequency of respiratory distress syndrome, composite neonatal morbidity and mortality, birthweight <1500 g and <2500 g, and admission to the neonatal intensive care unit. Moreover, there was a clear trend toward a decrease in the risk of neonatal death and the requirement for mechanical ventilation.
      The subtext of this important work is a call for a change in how we practice obstetrics. This editorial will explore the rationale for, and feasibility of, such a change. To begin with, I will briefly describe the background of this paper.
      Preterm birth, with its collateral effects on neonatal mortality, short- and long-term infant morbidity and astronomical healthcare costs, is the foremost problem in modern obstetrics. In developed countries 75% of perinatal mortality occurs in preterm babies, but greater attention is now being focused on early preterm births (<32 weeks of gestation), which represent 1–2% of all births but account for about 60% of all neonatal mortality and nearly 50% of all long-term neurological morbidity.
      • Hack M.
      • Fanaroff A.A.
      Outcomes of children of extremely low birthweight and gestational age in the 1990s.

      EURO-PERISTAT Project with SCPE and EUROCAT. European Perinatal Health Report. The health and care of pregnant women and babies in Europe in 2010. 2013. Available at: www.europeristat.com.

      The morbidities include respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, sepsis, and retinopathy of prematurity. Long-term complications include cognitive disorders, social and behavioral problems, and cerebral palsy.
      This recital of the well-known complications of preterm birth does not convey the devastating financial, social, and emotional effects on the parents or the affected children.
      • Brehaut J.C.
      • Kohen D.E.
      • Garner R.E.
      • et al.
      Health among caregivers of children with health problems: findings from a Canadian population-based study.
      In the United States, the short-term hospital costs during the first year of life of preterm birth/low-birthweight infants, were estimated to be $5.8 billion,
      • Russell R.B.
      • Green N.S.
      • Steiner C.A.
      • et al.
      Cost of hospitalization for preterm and low birth weight infants in the United States.
      and estimates for the annual societal economic burden in the United States was at a minimum, $26.2 billion in 2007.
      Institute of Medicine (United States) Committee on Understanding Premature Birth and Assuring Healthy Outcomes.
      These costs have certainly increased in the last decade.
      These facts will be well known to some readers of this Journal, but they bear repeating because whatever issues are discussed in this editorial, they exist in the background—the enormous human and financial cost of PTB.
      The overall PTB rate peaked in the United States in 2006 at 12.8% and fell by 14% until 2014, a decrease attributed by some to the remarkably successful campaign to reduce the number of teenage pregnancies
      • Delnord M.
      • Blondel B.
      • Zeitlin J.
      What contributes to disparities in the preterm birth rate in European countries?.
      ; however, it has risen again over the past 2 years and now stands at 9.8%,

      March of Dimes Perinatal Data Center; 2017. Available at: https://www.marchofdimes.org/mission/prematurity-reportcard.aspx. Accessed January 9, 2018.

      which is higher than most European countries where rates vary from 5% to 9%, with the lowest rates in the Nordic countries.
      • Delnord M.
      • Blondel B.
      • Zeitlin J.
      What contributes to disparities in the preterm birth rate in European countries?.
      Most estimates of gestational age in the United States are based on the last menstrual period, which have a systematic tendency to overestimate the duration of pregnancy.
      • Savitz D.A.
      • Terry Jr., J.W.
      • Dole N.
      • Thorp Jr., J.M.
      • Siega-Riz A.M.
      • Herring A.H.
      Comparison of pregnancy dating by last menstrual period, ultrasound scanning, and their combination.
      This has led to the belief that if first-trimester ultrasound estimates were adopted in America as in Europe, the PTB rates would fall,
      • Delnord M.
      • Blondel B.
      • Zeitlin J.
      What contributes to disparities in the preterm birth rate in European countries?.
      which might be true for late iatrogenic preterm births but may increase the recorded number of early spontaneous PTBs.
      Spontaneous preterm birth with or without prelabor rupture of the membranes accounts for two thirds of PTBs,
      • Goldenberg R.L.
      The management of preterm labor.
      with the remainder occurring as a result of obstetrically indicated preterm delivery. Spontaneous PTBs are the biggest challenge because they are highly represented in early PTB and are associated with a higher mortality and a greater number of neonatal complications.
      • Saigal S.
      • Doyle L.W.
      An overview of mortality and sequelae of preterm birth from infancy to adulthood.
      For many years women with a history of spontaneously delivering a baby preterm were the focus of preventative treatment such as cerclage
      • Berghella V.
      • Odibo A.O.
      • Tolosa J.E.
      Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial.
      or synthetic progestogen in the form of 17-alpha hydroxyprogesterone caproate (17OHP-C) injections
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      • Romero R.
      • Stanczyk F.Z.
      Progesterone is not the same as 17alpha-hydroxyprogesterone caproate: implications for obstetrical practice.
      with some reported success. However, although a history of spontaneous PTB confers a higher risk for recurrent PTB, it accounts for only 7% of women who deliver prematurely,
      • Khalifeh A.
      • Berghella V.
      Universal cervical length screening in singleton gestations without a previous preterm birth: ten reasons why it should be implemented.
      so although important for the individual couples, this has made little impact on the overall problem of spontaneous PTB rates.
      In the 1980s, attempts were made to stop premature labor with a variety of tocolytic agents, but this was not successful
      • Gyetvai K.
      • Hannah M.E.
      • Hodnett E.D.
      • Ohlsson A.
      Tocolytics for preterm labor: a systematic review.
      in significantly prolonging gestation and this treatment is used now only to delay birth for 48 hours to allow steroid therapy or allowing maternal transfer to an appropriate center equipped for optimal neonatal care.
      The reasons for this failure came with a greater understanding of the role of progesterone in the etiology of spontaneous PTB. This is discussed at length by Romero et al
      • Romero R.
      • Conde-Agudelo A.
      • Da Fonseca E.
      • et al.
      Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
      in the IPD meta-analysis published today. Progesterone promotes myometrial quiescence and inhibits cervical ripening by downregulating the production of cytokines and also has effects on the chorioamniotic membranes.
      • Kumar D.
      • Springel E.
      • Moore R.M.
      • et al.
      Progesterone inhibits in vitro fetal membrane weakening.
      • Kumar D.
      • Moore R.M.
      • Mercer B.M.
      • et al.
      In an in vitro model using human fetal membranes, 17-alpha hydroxyprogesterone caproate is not an optimal progestogen for inhibition of fetal membrane weakening.
      Premature initiation of cervical shortening is proposed to be due to a functional progesterone blockade, which may lead to a loss of the mucus plug (which has antimicrobial properties)
      • Hein M.
      • Valore E.V.
      • Helmig R.B.
      • Uldbjerg N.
      • Ganz T.
      Antimicrobial factors in the cervical mucus plug.
      • Hein M.
      • Helmig R.B.
      • Schonheyder H.C.
      • Ganz T.
      • Uldbjerg N.
      An in vitro study of antibacterial properties of the cervical mucus plug in pregnancy.
      and a variable grade intraamniotic inflammation.
      • Romero R.
      • Avila C.
      • Santhanam U.
      • Sehgal P.B.
      Amniotic fluid interleukin 6 in preterm labor. Association with infection.
      • Vaisbuch E.
      • Hassan S.S.
      • Mazaki-Tovi S.
      • et al.
      Patients with an asymptomatic short cervix (≤15 mm) have a high rate of subclinical intraamniotic inflammation: implications for patient counseling.
      • Kiefer D.G.
      • Peltier M.R.
      • Keeler S.M.
      • et al.
      Efficacy of midtrimester short cervix interventions is conditional on intraamniotic inflammation.
      • Kiefer D.G.
      • Keeler S.M.
      • Rust O.A.
      • Wayock C.P.
      • Vintzileos A.M.
      • Hanna N.
      Is midtrimester short cervix a sign of intraamniotic inflammation?.
      • Tarca A.L.
      • Fitzgerald W.
      • Chaemsaithong P.
      • et al.
      The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery.
      Unscheduled sonographic shortening of the cervix, which is a manifestation of cervical effacement, is part of the terminal common pathway in a substantial number of cases of spontaneous preterm births.
      Concurrent with these new concepts came the discovery that a sonographic short cervix in the midtrimester
      • Andersen H.F.
      • Nugent C.E.
      • Wanty S.D.
      • Hayashi R.H.
      Prediction of risk for preterm delivery by ultrasonographic measurement of cervical length.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network.
      was associated with an increased risk of spontaneous PTB in women with single and multiple gestations, irrespective of whether they had a history of PTB. Various cutoffs were assessed, but the consensus is now settling on a cervical length of 25 mm at 18–24 weeks’ gestation as identifying about 50% of spontaneous PTBs and providing the best likelihood ratios for birth before 32 and 34 weeks.
      Goldenberg et al
      • Goldenberg R.L.
      • Iams J.D.
      • Mercer B.M.
      • et al.
      The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network.
      in a US population found that 1.9% of unselected women who delivered <32 weeks’ gestation had a cervical length <25 mm at 22–24 weeks; 48% of these were detected with a positive likelihood ratio of 5.35, fulfilling the criteria for a moderately useful screening test.
      • Honest H.
      • Forbes C.A.
      • Duree K.H.
      • et al.
      Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.
      Barros-Silva et al
      • Barros-Silva J.
      • Pedrosa A.C.
      • Matias A.
      Sonographic measurement of cervical length as a predictor of preterm delivery: a systematic review.
      in a detailed meta-analysis of 16 studies concluded that a positive relationship was established between short cervix and preterm delivery in virtually all studies.
      The majority of these studies showed a high specificity and positive likelihood ratio, while the sensitivity and negative likelihood ratio were variable and globally poor. This is to be expected because spontaneous PTB is a heterogeneous condition with many aetiological pathways.
      • Romero R.
      • Dey S.K.
      • Fisher S.J.
      Preterm labor: one syndrome, many causes.
      A short cervix serves to identify one of many pathways, albeit a very important one.
      The Fetal Medicine Foundation in London, United Kingdom, developed a model to predict preterm birth based on observations in more than 39,000 consecutive unselected pregnant women by combining maternal risk factors such as age and history of PTB with midtrimester cervical length.
      • To M.S.
      • Fonseca E.B.
      • Molina F.S.
      • Cacho A.M.
      • Nicolaides K.H.
      Maternal characteristics and cervical length in the prediction of spontaneous early preterm delivery in twins.
      The authors reported that the prediction of preterm delivery before 32 weeks at a fixed false-positive rate of 10% was 38% for maternal factors (including previous spontaneous PTB, maternal age, ethnic group, body mass index, cigarette smoking, and previous cervical surgery), 55% for cervical length, and 69% for combined testing.
      • To M.S.
      • Fonseca E.B.
      • Molina F.S.
      • Cacho A.M.
      • Nicolaides K.H.
      Maternal characteristics and cervical length in the prediction of spontaneous early preterm delivery in twins.
      The next step of this story was the introduction of vaginal progesterone either as a gel containing 90 mg natural progesterone or as a 200 mg vaginal tablet containing micronized natural progesterone. This treatment has been used for 25 years in in vitro fertilization programs for luteal support following embryo transfer
      • Zarutskie P.W.
      • Phillips J.A.
      A meta-analysis of the route of administration of luteal phase support in assisted reproductive technology: vaginal versus intramuscular progesterone.
      and is licensed on both sides of the Atlantic for this indication.
      Vaginal progesterone generates higher levels of endometrial progesterone compared with intramuscular progesterone despite lower blood concentrations of progesterone, suggesting a mechanism of direct transport between the vagina and endometrium.
      • Cicinelli E.
      • de Ziegler D.
      • Bulletti C.
      • Matteo M.G.
      • Schonauer L.M.
      • Galantino P.
      Direct transport of progesterone from vagina to uterus.
      • Miles R.A.
      • Paulson R.J.
      • Lobo R.A.
      • Press M.F.
      • Dahmoush L.
      • Sauer M.V.
      Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study.
      As a result, vaginal progesterone, which has an excellent safety profile and few side effects in the doses described in the previous text, appears to be particularly suited to arresting or preventing cervical shortening and decreasing the risk of spontaneous PTB in this subgroup of patients.
      • O'Brien J.M.
      • Defranco E.A.
      • Adair C.D.
      • et al.
      Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
      Two multicenter randomized clinical trials showed that vaginal progesterone in women with a short cervix in midgestation reduced the rate of preterm birth (defined as births at <34 or <33 weeks of gestation) by 44–45%.
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      A subsequent IPD meta-analysis
      • 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.
      of 5 high-quality trials including 775 women (388 allocated to vaginal progesterone, 387 allocated to placebo) showed that vaginal progesterone, in addition to significantly reducing spontaneous PTB at <28 to <35 gestational weeks, significantly reduced admissions to the neonatal intensive care unit, the rate of respiratory distress syndrome, the requirement for mechanical ventilation, and composite neonatal morbidity/mortality.
      This resulted in a call for the implementation of universal cervical length screening for all pregnant women between 18 and 24 weeks of gestation and vaginal progesterone for those with a cervical length of ≤25 mm.
      • Conde-Agudelo A.
      • Romero R.
      Vaginal progesterone to prevent preterm birth in pregnant women with a sonographic short cervix: clinical and public health implications.
      Subsequently the Society for Maternal-Fetal Medicine,
      Society for Maternal-Fetal Medicine Publications Committee
      Progesterone and preterm birth prevention: translating clinical trials data into clinical practice.
      the American College of Obstetricians and Gynecologists,
      American College of Obstetricians and Gynecologists
      Prediction and prevention of preterm birth. ACOG Practice bulletin no. 130.
      and the National Institute for Health and Care Excellence

      National Institute for Health and Care Excellence. Preterm labor and birth. NICE guideline. 2015. Available at: https://www.nice.org.uk/guidance/ng25. Accessed January 9, 2018.

      recommended vaginal progesterone treatment in women with a sonographic short cervix in the midtrimester but stopped short of recommending universal screening for cervical length. However, the International Federation of Gynecology and Obstetrics
      FIGO Working Group on Best Practice in Maternal-Fetal Medicine
      Best practice in maternal-fetal medicine.
      has endorsed universal cervical length screening.
      The consensus that vaginal progesterone was effective in the prevention of spontaneous PTB in women with a singleton gestation and a short cervix was disturbed after the publication of a large Medical Research Council–funded multicenter trial (OPPTIMUM) from the United Kingdom
      • Norman J.E.
      • Marlow N.
      • Messow C.M.
      • et al.
      Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
      involving 1228 women with singleton pregnancies, which found no effect of vaginal progesterone on reducing PTB at <34 weeks or fetal death, a composite of neonatal morbidity and mortality, or cognitive scores in children at 2 years of age.
      The inclusion criteria at the commencement of the study in 2008 were based on a history of PTB or cervical surgery and a positive fetal fibronectin test and did not include cervical length measurements, but these were included after an early interim analysis. Measurements were not performed on a universal screening basis but on individual physician’s request (undefined).
      Romero et al
      • Romero R.
      • Conde-Agudelo A.
      • Da Fonseca E.
      • et al.
      Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
      have in today’s issue presented an updated version of their IPD meta-analysis,
      • 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.
      including individual patient data from the OPPTIMUM trial (generously provided by Professor Jane Norman of the United Kingdom) from women who had cervical length measurements performed in this trial. The inclusion of these data in the new IPD meta-analysis now includes 974 women (498 receiving vaginal progesterone, 476 placebo) and has resulted in a stronger beneficial effect of vaginal progesterone in women with a short cervix of ≤25 mm. The new finding is that vaginal progesterone administered to women with a midtrimester short cervix significantly reduces the risk of preterm birth over a wide range of gestational ages (beginning at <28 weeks and extending to <36 weeks) and birthweight <2500 g.
      The significant reduction in respiratory distress syndrome previously described
      • 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.
      was confirmed but not strengthened because information about the occurrence of respiratory distress was not collected in the OPPTIMUM study. The authors have in this issue renewed the previous recommendation from this group for universal cervical length measurement at 18–24 weeks and vaginal progesterone treatment for those with a short cervix.
      The benefits of vaginal progesterone in women with a short cervix are not achieved with the administration of 17OHP-C. For example, vaginal progesterone has been shown to be effective in women with a short cervix, while 17OHP-C was not.
      • Grobman W.A.
      • Thom E.A.
      • Spong C.Y.
      • et al.
      17 Alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm.
      There is now evidence that natural and synthetic progestogens are not equivalent and that their efficacy, indications, and safety profile are different.
      • Romero R.
      • Stanczyk F.Z.
      Progesterone is not the same as 17alpha-hydroxyprogesterone caproate: implications for obstetrical practice.
      In conclusion, there is now convincing evidence that vaginal progesterone given to women with a short cervix in midgestation reduces the risk of PTB by approximately 40% across all gestational ages before 37 weeks with a significant reduction in neonatal mortality and morbidity.
      • Romero R.
      • Conde-Agudelo A.
      • Da Fonseca E.
      • et al.
      Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.

      Is there an alternative to vaginal progesterone?

      Two alternatives to vaginal progesterone for women with a short cervix are currently being considered in clinical practice. Cervical cerclage has been used for 50 years in the treatment of women with congenital or acquired weakness of the cervix.
      • Suhag A.
      • Berghella V.
      Cervical cerclage.
      This is usually diagnosed following an early second-trimester miscarriage and the appearance of cervical shortening in a subsequent gestation, so it is a reasonable assumption that the short cervix associated with spontaneous PTB may also be amenable to cerclage.
      Initial studies indicated that there was a beneficial effect in women with a prior spontaneous PTB and a short cervix in midgestation,
      • Berghella V.
      • Rafael T.J.
      • Szychowski J.M.
      • Rust O.A.
      • Owen J.
      Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis.
      but the authors of a meta-analysis postulated that some of the women who benefited may have had an element of true cervical insufficiency.
      A recent meta-analysis
      • Berghella V.
      • Ciardulli A.
      • Rust O.A.
      • et al.
      Cerclage for sonographic short cervix in singleton gestations without prior spontaneous preterm birth: systematic review and meta-analysis of randomized controlled trials using individual patient-level data.
      of 5 randomized controlled trials comparing cerclage with no cerclage including 419 singleton gestations without prior spontaneous preterm birth and a cervical length <25 mm found no statistical differences in spontaneous PTB <35 weeks to <24 weeks or improved neonatal outcome in the cerclage group. In subgroup analyses there was a weak effect of cerclage in women with a cervical length <10 mm, women who received tocolytics, and those who received antibiotics.
      Vaginal progesterone may be less effective in women with cervical lengths <10 mm, which were excluded from the study of Hassan et al,
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      so the role of cerclage and antibiotics
      • Putra M.
      • Dai J.
      • Gill N.
      • Patwardhan M.S.
      Abstract 8. Infectious Diseases Society in Obstetrics and Gynecology. The use of azithromycin for short cervix with suspected intraamniotic inflammation: a propensity score matched retrospective cohort study.
      should continue to be investigated in this subgroup of women. The Arabin pessary
      • Arabin B.
      • Alfirevic Z.
      Cervical pessaries for prevention of spontaneous preterm birth: past, present and future.
      is an alternative less invasive approach to cerclage, but there is lack of agreement as to its efficacy in women with a short cervix in the midtrimester.
      • Goya M.
      • Pratcorona L.
      • Merced C.
      • et al.
      Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial.
      • Hui S.Y.
      • Chor C.M.
      • Lau T.K.
      • Lao T.T.
      • Leung T.Y.
      Cerclage pessary for preventing preterm birth in women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial.
      • Nicolaides K.H.
      • Syngelaki A.
      • Poon L.C.
      • et al.
      A randomized trial of a cervical pessary to prevent preterm singleton birth.
      • Saccone G.
      • Ciardulli A.
      • Xodo S.
      • et al.
      Cervical pessary for preventing preterm birth in singleton pregnancies with short cervical length: a systematic review and meta-analysis.

      Dugoff L, Berghella V, Sehdev H, Mackeen AD, Goetzl L, Ludmir J. Prevention of Preterm Birth with Pessary in Singletons (PoPPS): a randomized controlled trial. Ultrasound Obstet Gynecol 2017 Sep 20. https://doi.org/10.1002/uog.18908. [Epub ahead of print].

      Weekly injections of 17OHP-C have been used extensively in women with a history of spontaneous PTB for more than 25 years. This treatment gained popularity in the United States following a double-blinded study
      • Meis P.J.
      • Klebanoff M.
      • Thom E.
      • et al.
      Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
      of 310 women given 17OHP-C and 153 placebo, which found a significant reduction in spontaneous PTB before 37, 35, and 32 weeks.
      Subsequently a secondary analysis of patients given 17OHP-C as part of a large trial of cerclage in women with previous spontaneous PTB
      • Berghella V.
      • Figueroa D.
      • Szychowski J.M.
      • et al.
      17-Alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length.
      and a short cervix showed no additional benefit of 17OHP-C over cerclage but some effect when given alone. However, 2 recent studies have not supported its use.
      A recent prospective cohort study
      • Nelson D.B.
      • McIntire D.D.
      • McDonald J.
      • Gard J.
      • Turrichi P.
      • Leveno K.J.
      17-Alpha hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study.
      recruited 430 consecutive women with prior births ≤35 weeks who were treated with 17OHP-C and compared the pregnancy outcome against those of a historical control group; the overall rate of recurrent preterm birth was 25% for the cohort compared with 16.8% as the historical referent rate. Additionally, a randomized controlled trial
      • Winer N.
      • Bretelle F.
      • Senat M.V.
      • et al.
      17 Alpha-hydroxyprogesterone caproate does not prolong pregnancy or reduce the rate of preterm birth in women at high risk for preterm delivery and a short cervix: a randomized controlled trial.
      of 17OHP-C in women at high risk for preterm delivery with a short cervix was ended early after an interim analysis showed no evidence of an effect and a continuation of the trial was considered futile.
      The lack of effect of 17OHP-C in this population has been attributed to the fact that 17OHP-C, unlike vaginal progesterone, does not prevent shortening of the cervix.
      • Durnwald C.P.
      • Lynch C.D.
      • Walker H.
      • Iams J.D.
      The effect of treatment with 17 alpha-hydroxyprogesterone caproate on changes in cervical length over time.
      In conclusion, vaginal progesterone appears to be the prophylactic method of choice for women with a short cervix in the midtrimester.

      Is vaginal progesterone effective in twin gestations?

      Preterm birth is the most important factor determining neonatal morbidity and mortality among twin gestations. More than 50% of women with a dichorionic or monochorionic twin pregnancy will give birth prematurely, and the risk of preterm birth <37 and <32 weeks’ gestation is 8- to 9-fold higher in twins than in singleton gestations.
      The IPD meta-analysis in this issue concerns preterm birth in singleton gestations but because cervical length in midtrimester
      • Souka A.P.
      • Heath V.
      • Flint S.
      • Sevastopoulou I.
      • Nicolaides K.H.
      Cervical length at 23 weeks in twins in predicting spontaneous preterm delivery.
      is even more predictive of spontaneous PTB in twins than singletons, it would be reasonable to explore whether vaginal progesterone would be effective in the prevention of spontaneous PTB in twins. In other words, should twin gestations be included in a universal cervical length screening program?
      The effect of vaginal progesterone in asymptomatic twin pregnancies with a midtrimester short cervix (≤25 mm) was analyzed in an IPD meta-analysis
      • Romero R.
      • Conde-Agudelo A.
      • El-Refaie W.
      • et al.
      Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data.
      of 6 randomized controlled trials (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment). Administration of vaginal progesterone to women with a twin gestation and a sonographic short cervix in the midtrimester reduced the risk of preterm birth occurring at <30 to <35 gestational weeks, neonatal mortality, and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment.
      More data are required to assess the effect of vaginal progesterone in twin gestations with a short cervix because it appears that the same mechanism of the shortening of the cervix might be operating in twins as in singletons and that vaginal progesterone might be beneficial in the subgroup of twins with a short cervix. In view of the high incidence of short cervix in a twin gestation, this could be an important development.
      An important etiological factor in twin gestations is assisted conception, especially in vitro fertilization (IVF) treatment. IVF is responsible for 1.6% of all births but 36% of all twins and 76% of triplets born in the United States.
      • Kulkarni A.D.
      • Jamieson D.J.
      • Jones Jr., H.W.
      • et al.
      Fertility treatments and multiple births in the United States.
      The rate of twin gestation has fallen slightly in the last few years because of the move toward single blastocyst transfer, but the incidence remains unacceptably high. Research in IVF twins is needed to establish whether vaginal progesterone is effective in this subgroup.

      Performance of universal cervical length assessment in singleton gestations

      This will depend on the population being studied, the cervical length cutoff used (ie, ≤15 mm, ≤20 mm, ≤25 mm) the gestational age of the screen, the prevalence of both spontaneous PTB and short cervix in the population being screened, and the gestational age threshold to be predicted (eg, <34 weeks, <32 weeks).
      There is a consensus growing that by increasing the cutoff to 25 mm, the sensitivity will improve, although this will be at the expense of lowering the positive predictive value. A high sensitivity is desirable to include as many high-risk women to have treatment. There is also a growing consensus that the screening should be done between 18 and 24 weeks’ gestation, presumably to fit in with the gestation of the second-trimester fetal anatomic survey.
      It is unlikely that the performance will be the same at each end of this time period, and further research is needed to identify the optimum timing window. For example, Heath et al
      • Heath V.C.
      • Southall T.R.
      • Souka A.P.
      • Elisseou A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery.
      in a large observational study achieved excellent results by screening at 23 weeks, with 58% of women who delivered <32 weeks being identified with a cervical length ≤15 mm.
      With a first-trimester scan now being used to identify the majority of anatomic and chromosome anomalies, the midtrimester scan would perhaps be more useful at 22–24 weeks when the cervical length performance might be more effective as would uterine artery Doppler to predict preeclampsia and fetal growth restriction. After all, the uterine artery is only 2 cm lateral to the cervix.
      Performance will also be determined by compliance for screening. Temming et al
      • Temming L.A.
      • Durst J.K.
      • Tuuli M.G.
      • et al.
      Universal cervical length screening: implementation and outcomes.
      in a large study of women offered a cervical length measurement at the fetal anatomic survey found that women with singleton gestations were more likely to decline cervical length screening if they were African American, obese, multiparous, younger than 35 years, or smoked; rates of spontaneous preterm birth before 28 weeks were higher in those who declined the measurement. Screening directed only to women deemed to be high risk on maternal characteristics would, I believe, be regarded as discriminatory.
      Compliance is vitally important. A sense of we are all in this together should be engendered among patients and a public health program would help to achieve this aim. Some of the real-world studies discussed in the following text have successfully done this.
      Esplin et al
      • Esplin M.S.
      • Elovitz M.A.
      • Iams J.D.
      • et al.
      Predictive accuracy of serial transvaginal cervical lengths and quantitative vaginal fetal fibronectin levels for spontaneous preterm birth among nulliparous women.
      in a multicenter observational study of 9410 women found that cervical length screening had a low area under the receiver-operating characteristic curve (0.67) for predicting spontaneous PTB. In this observational study, there were 2 previously unresearched screening gestations: 16–22 and 22–30 weeks. Screening in the later period at a cutoff ≤25 mm identified only 23.3% of cases of spontaneous preterm birth <37 weeks but 52% of women who delivered before 32 weeks, which would have allowed treatment in this vulnerable group.
      The authors calculated that a routine measurement at 16–22 weeks would entail 247 women being screened to identify 1 case of spontaneous PTB before 37 weeks. This mirrors calculations of Parry et al
      • Parry S.
      • Simhan H.
      • Elovitz M.
      • Iams J.
      Universal maternal cervical length screening during the second trimester: pros and cons of a strategy to identify women at risk of spontaneous preterm delivery.
      using data from the randomized trial of Fonseca et al
      • Fonseca E.B.
      • Celik E.
      • Parra M.
      • Singh M.
      • Nicolaides K.H.
      Progesterone and the risk of preterm birth among women with a short cervix.
      based on a hypothetical cohort of 10,000 women; they calculated that 25 preterm births <34 weeks would be prevented by universal cervical length assessment and vaginal progesterone treatment and that 400 ultrasound examinations for each of these spontaneous PTBs would be required to achieve this effect.
      The equivalent calculation for the study by Hassan et al
      • Hassan S.S.
      • Romero R.
      • Vidyadhari D.
      • et al.
      Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
      for spontaneous PTB <33 weeks was 17 and 588. These figures would come as no surprise to physicians involved in screening programs. For example, for cervical cancer 1140 women will have a smear for every invasive cancer detected.
      • Gates T.J.
      Screening for cancer: evaluating the evidence.
      Screening requires hard work, but the dividend for future generations of citizens should never be forgotten.

      Costs required of introducing a nationwide program

      Bloom and Leveno
      • Bloom S.L.
      • Leveno K.J.
      Unproven technologies in maternal-fetal medicine and the high cost of US health care.
      in a provocative commentary entitled Unproven technologies in maternal-fetal medicine threw down the gauntlet on costs of introducing a cervical screening program in the United States calculating that universal cervical length screening would incur approximately $175 million in actual health care expenditures per year. The cost of a transvaginal ultrasound scan for cervical length in their rather back-of-the-envelope analysis of expenditure was $237. The authors did not discuss any of the 6 detailed cost-effectiveness analyses,
      • Cahill A.G.
      • Odibo A.O.
      • Caughey A.B.
      • et al.
      Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis.
      • Werner E.F.
      • Han C.S.
      • Pettker C.M.
      • et al.
      Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis.
      • Werner E.F.
      • Hamel M.S.
      • Orzechowski K.
      • Berghella V.
      • Thung S.F.
      Cost-effectiveness of transvaginal ultrasound cervical length screening in singletons without a prior preterm birth: an update.
      • Einerson B.D.
      • Grobman W.A.
      • Miller E.S.
      Cost-effectiveness of risk-based screening for cervical length to prevent preterm birth.
      • Crosby D.A.
      • Miletin J.
      • Semberova J.
      • Daly S.
      Is routine transvaginal cervical length measurement cost-effective in a population where the risk of spontaneous preterm birth is low?.
      • Pizzi L.T.
      • Seligman N.S.
      • Baxter J.K.
      • Jutkowitz E.
      • Berghella V.
      Cost and cost effectiveness of vaginal progesterone gel in reducing preterm birth: an economic analysis of the PREGNANT trial.
      all of which showed that universal screening was cost saving or cost effective, depending on the incidence of short cervical length at screening.
      Werner et al
      • Werner E.F.
      • Han C.S.
      • Pettker C.M.
      • et al.
      Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis.
      in their original cost analysis model predicated his calculation on an incidence of spontaneous PTB <34 weeks of 2.1% and a prevalence of 1.7% for cervical length <15 mm at 18–24 weeks. Using standard costing estimates of neonatal and long-term care, the authors found that universal cervical length screening and vaginal progesterone were cost saving compared with no screening.
      More recently this group of investigators
      • Werner E.F.
      • Hamel M.S.
      • Orzechowski K.
      • Berghella V.
      • Thung S.F.
      Cost-effectiveness of transvaginal ultrasound cervical length screening in singletons without a prior preterm birth: an update.
      revised their calculations and found that even with an incidence as low as 0.8% for cervical length ≤20 mm at screening and an incidence of 1.3% for spontaneous PTB <34 weeks, the model showed that universal screening was cost effective compared with no screening.
      Einerson et al
      • Einerson B.D.
      • Grobman W.A.
      • Miller E.S.
      Cost-effectiveness of risk-based screening for cervical length to prevent preterm birth.
      in their economic model demonstrated that a policy of universal cervical length screening and vaginal progesterone excluding women with previous spontaneous PTB was more cost effective than screening a high-risk population only (including African-American or Hispanic race/ethnicity, tobacco use, previously indicated PTB or cervical surgery) or no screening. Therefore, universal cervical length screening is either cost saving or cost effective, depending on the prevalence of both spontaneous PTB and short cervix in the population being screened.

      Implementing a screening program

      In most developed countries including the United States,
      American College of Obstetricians and Gynecologists
      Ultrasonography in pregnancy. ACOG Practice bulletin no. 101.
      a midtrimester ultrasound examination is standard of practice, principally to study fetal anatomy, determine placental location, identify multiple gestations, and early fetal growth restriction. If universal cervical length measurement was introduced, it is reasonable to expect that it would be conducted by the same sonographer who performs the fetal anatomy scan, which is a highly skilled examination.
      The cervical length examination to measure the functional cervix is relatively easy for an experienced sonographer. Most midtrimester scans are performed by the sonographer facing the woman so the initiation of a transvaginal scan could take place without the woman changing position or the bed being moved. Obviously it is very important that the examination is performed properly according to the recommendations of organizations such as the Fetal Medicine Foundation or the Society for Maternal-Fetal Medicine sponsored certification method,
      Society for Maternal-Fetal Medicine Publications Committee
      Progesterone and preterm birth prevention: translating clinical trials data into clinical practice.
      and images of the measurement should be stored for audit.
      In a well-organized department, the examination should take no more than 10 minutes. However, it is usually recommended to observe the cervix for about 30 seconds after the external and internal os have been visualized to detect dynamic changes that will shorten the functional length of the cervix; this process can be speeded up by 10 seconds of gentle fundal pressure.
      The debate about transabdominal scanning of the cervix, I believe, is already lost in favor of transvaginal ultrasound screening. Women are now accustomed to transvaginal ultrasound scans in gynecology and fertility clinics, and in the United Kingdom, it is rare to receive a request from a patient for a transabdominal scan, especially if it is explained that transvaginal ultrasound is more accurate,
      • To M.S.
      • Skentou C.
      • Cicero S.
      • Nicolaides K.H.
      Cervical assessment at the routine 23-weeks' scan: problems with transabdominal sonography.
      • Hernandez-Andrade E.
      • Romero R.
      • Ahn H.
      • et al.
      Transabdominal evaluation of uterine cervical length during pregnancy fails to identify a substantial number of women with a short cervix.
      is not subject to artefact and shadowing, and any measurement <35 mm would have to be checked by a transvaginal scan anyway.
      • Khalifeh A.
      • Berghella V.
      Not transabdominal!.
      In the study of Son et al
      • Son M.
      • Grobman W.A.
      • Ayala N.K.
      • Miller E.S.
      A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate.
      described in the following text, 17,590 women accepted transvaginal ultrasound for cervical length (ie, 99.9% of eligible women).

      Does universal transvaginal sonographic cervical length assessment and vaginal progesterone work in the real world?

      Despite a lack of official endorsement for universal cervical length assessment (except for the International Federation of Gynecology and Obstetrics, which has taken a leadership role), there are some green shoots appearing for those who espouse this policy.
      Two adequately sized real-world studies have been published recently based on a universal cervical length screening program compared with historical controls. Son et al
      • Son M.
      • Grobman W.A.
      • Ayala N.K.
      • Miller E.S.
      A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate.
      from Chicago, IL, and Newnham et al
      • Newnham J.P.
      • Kemp M.W.
      • White S.W.
      • Arrese C.A.
      • Hart R.J.
      • Keelan J.A.
      Applying precision public health to prevent preterm birth.
      from Western Australia in well-conducted and planned studies both reported significant reductions in spontaneous PTB after the implementation of universal cervical screening despite a low overall incidence of PTB in their populations.
      Son et al
      • Son M.
      • Grobman W.A.
      • Ayala N.K.
      • Miller E.S.
      A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate.
      introduced screening from 18 to 24 weeks in women without a history of PTB and with a recommendation for vaginal progesterone in women with a cervical length ≤20 mm. There was a significant reduction in the frequencies of spontaneous PTB following the introduction of screening at <37, <34, and <32 weeks despite a prevalence of cervical length ≤25 mm of 0.89% at screening and a rate of spontaneous PTB <34 weeks of 1.3%. The number needed to screen to prevent 1 case of preterm birth at <37 weeks of gestation was 143 and for <34 weeks was 500.
      In the study of Newnham et al,
      • Newnham J.P.
      • Kemp M.W.
      • White S.W.
      • Arrese C.A.
      • Hart R.J.
      • Keelan J.A.
      Applying precision public health to prevent preterm birth.
      the implementation of a multifaceted program in 2014 that included universal cervical length screening and treatment with vaginal progesterone to women with a cervical length ≤25 mm was followed by a statistically significant 7.6% reduction in the rate of preterm birth in 2015. The effect extended from the 28–31 week gestational age group onward. In both of these studies, surveillance of the projects was admirable and motivation of both staff and patients was high.
      A further cause for optimism in the 2015 survey
      • Khalifeh A.
      • Quist-Nelson J.
      • Berghella V.
      Universal cervical length screening for preterm birth prevention in the United States.
      of all 78 accredited maternal-fetal medicine fellowship programs in the United States was that 68% reported implementation of a universal cervical length screening program for low-risk women. I know of no equivalent initiatives in Europe, and it may not be long before PTB rates in the United States will be the envy of the world. There are important areas for future research, some of which have been discussed in the previous text. Perhaps the greatest priority is long-term follow-up studies along the lines of the OPPTIMUM trial, but calls for further research do not imply that we should not implement a program based on the IPD meta-analysis described in today’s Journal.

      Conclusion

      What is described in the manuscript published in this issue of the Journal represents a perfect marriage of technology and pharmacy fulfilling all the criteria for an effective screening test.
      • Khalifeh A.
      • Berghella V.
      Universal cervical length screening in singleton gestations without a previous preterm birth: ten reasons why it should be implemented.
      • Combs C.A.
      Vaginal progesterone for asymptomatic cervical shortening and the case for universal screening of cervical length.
      A simple ultrasound measurement of the cervix in the midtrimester (a biomarker) piggybacked onto an already existing screening test and a treatment for women at risk that is safe, efficacious, and cost effective, causing no discomfort or side effects that will make significant inroads into the greatest problem for mothers and babies worldwide. The IPD meta-analysis published today will hopefully be the final push toward universal cervical length measurement for all pregnant women in the midtrimester and vaginal progesterone for those with a short cervix.

      Final thoughts

      There was a time when changes in obstetric practice could be imposed on obstetricians without a shred of evidence to support them. In 1920 Joseph DeLee, the legendary American obstetrician at the Chicago Lying in Hospital and author of the best-selling obstetrical and gynecological textbook outlined his systematic approach to childbirth for physicians, which consisted of hospital delivery for all parturients, twilight sleep with scopolamine in the first stage of labor, ether anesthesia in the second, routine episiotomy and forceps delivery (ostensibly to prevent cerebral palsy), separation of mother and baby at birth, and avoidance of breast-feeding. This was widely adopted in the United States, and it took half a century to undo the harms that resulted from these interventionist policies.
      Historically, there are many other instances when obstetricians have blindly followed poorly researched advice to the detriment of their patient’s health. As a result we have turned full circle, and no new treatment can be introduced without putting it to several randomized trials with rigorous statistical analysis in which the chance association between treated and untreated or control has to be less than 1 in a hundred.
      And then there have to be confirmatory studies, which they themselves have to be gathered together in meta-analyses to determine whether the overall shift to benefit is significant. And only then begins the long process of persuading the colleges and numerous specialist associations that they should recommend this new advance and organize appropriate training programs before finally it is put to the individual woman for her consent by her treating physician.
      While this is laudable, it takes only one study that bucks the consensus to get cries for more and more studies. The point I want to make is whether we have perhaps gone too far and that overanalysis has led to indecision and impotence to do anything at all. Obviously all screening programs are resisted by governments because they are costly, but there is a big picture here, which is the terrible cost, both human and financial, of spontaneous preterm birth. Any simple strategy included in an already existing program that is safe, proven to be effective, and pays its way should be implemented.
      The IPD meta-analysis published today will hopefully be the final push toward universal cervical length measurement for all pregnant women and vaginal progesterone for those with a short cervix.

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