There are 12.9 million premature births annually worldwide [1] and despite the magnitude of the problem, there is no established early pregnancy screening test or effective treatment for women once a high risk of spontaneous preterm birth (sPTB) is ascertained. The associated morbidity, mortality and high health costs are well documented. Only 39% of those infants born <26 weeks’ gestation survive and 13% of these suffer severe cerebral palsy or sensory impairment [2]. Despite considerable efforts to introduce new therapies for the prevention and treatment of spontaneous preterm labour, sPTB rates are still rising; 6% of births in the UK are premature. sPTB is thought to be the result of multiple aetiologies influenced by a wide number of genetic, biological, psychosocial and environmental factors (e.g. multiple pregnancy, infection, placental abruption and stress) yet the chronology and aetiology of sPTB is insufficiently understood. Early sPTB likely results from a complex interaction of maternal and/or fetal inflammatory responses that culminate in progressive cervical shortening and myometrial contractions.
Detection of a short cervix using transvaginal ultrasonography has emerged as a useful predictor of sPTB in both low and high risk pregnancies [3, 4] and risk of preterm birth is inversely related to cervical length; the shorter the cervix, the higher the risk of preterm birth. In clinical practice, once a woman has been identified as being at higher risk of sPTB by virtue of a short cervix, a decision regarding prophylactic treatment must be made. Three interventions have been proposed to treat patients with a short cervix; cervical cerclage [5, 6], cervical pessary [7] or vaginal progesterone therapy [8–10]. There is little evidence to guide clinicians as to which of these three interventions is the best to use and so the treatment received predominantly depends on the centre a woman is treated in and her clinician’s preference.
A cerclage is the insertion of a ‘purse string’ suture around the cervix under regional anaesthesia. There is little consensus on the optimal procedure or technique (e.g. low/high vaginal, abdominal, tape/nylon, single/multiple, endocervical/purse string) or timing of insertion (elective, ultrasound indicated, pre-conceptual). Furthermore, the mechanism of action is not understood; cerclage may offer a degree of structural support, but also plays a role in maintaining a biochemical barrier protecting membranes against exposure to ascending pathogens. It also is known to induce an inflammatory response, which may encourage tissue repair. A ‘history indicated’ cerclage is inserted in early pregnancy (8–14 weeks’) in women who have a history of late miscarriage or preterm birth. The largest randomised controlled trial comparing history-indicated cerclage with expectant management (n = 1292), demonstrated that benefit of cerclage was only seen in women with three prior fetal losses/premature deliveries, where their risk of preterm birth reduced by more than half [6].
‘The benefit of cerclage following confirmation of cervical shortening (ultrasound indicated cerclage), has been reported in a subgroup of high risk women (history of preterm second-trimester loss or birth before 36 weeks of gestation) who have a cervix <25 mm in length, with meta-analysis [5] demonstrating a significant reduction in delivery before 35 weeks of gestation [relative risk (RR) 0.57; 95% confidence interval (CI) 0.33–0.99] for women with prior second trimester miscarriage, and RR 0.61; 95% CI 0.40–0.92 for women with prior preterm birth] when compared with expectant management.’
The Arabin pessary is a round and cone shaped flexible silicon device which is designed to be inserted into the vagina and sit in the upper fornix, to support and incline the cervix, with the intention to prevent premature cervical shortening and preterm birth. Goya et al. [7], [11] reported a multicentre randomised controlled trial (n = 385) on pessary use in unselected women screened by transvaginal ultrasound (TVS) and showed that in women with a short cervical length (<25 mm) between 18 and 22 weeks, the pessary reduced the rate of sPTB <34 weeks’ gestation compared with controls (6% vs 27%, odds ratio 0 · 18, 95% CI 0 · 08 to 0 · 37; p < 0 · 0001), with a significant difference detected in the occurrence of composite poor neonatal outcome. In a subsequent smaller RCT, 108 Asian women with a singleton pregnancy and a cervical length <25 mm at routine second-trimester TVS were randomized to either pessary or control group. The mean gestational age at delivery was 38.1 weeks in the pessary group compared with 37.8 weeks in the expectant management group, with no significant differences in the rates of delivery before 28, 34 or 37 weeks [12].
Vaginal progesterone is given as a potential therapy to sPTB in singleton pregnancies based on a Cochrane systematic review [8] reporting that prophylactic progesterone (intramuscular and vaginal administration of varying doses) was associated with a significant reduction in preterm birth <34 weeks (one study; 142 women; RR 0.15; 95% CI 0.04–0.64) and preterm birth at less than 37 weeks (four studies; 1255 women; RR 0.80; 95% CI 0.70–0.92). A meta-analysis of vaginal progesterone treatment given to all women with a short cervix <25 mm showed a reduction in preterm birth at <33 weeks; [RR, 0.58; 95% confidence interval [CI], 0.42 to 0.80), <35 weeks (RR, 0.69; 95% CI, 0.55 to 0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30 to 0.81) and neonatal composite morbidity and mortality (RR 0.57; 95% CI, 0.40 – 0.81) [9]. A recent large study suggested a lack of efficacy of vaginal progesterone and no long-term benefit at two years, adding to the uncertainty around progesterone use [10].
The plasma (and/or uterine) concentration of progesterone required to reduce sPTB is unknown, and the mechanism of action uncertain. It is, however, frequently used in clinical practice (usual dose 200–400 mg). The doses of vaginal progesterone used in completed trials are 100 mg (n = 142) or 200 mg (n = 250) [13]. Whilst vaginal progesterone use for the prevention of sPTB is unlicensed, it is commonly used in clinical practice in the UK and Europe and is also recommended for use in the USA by the Society for Maternal and Fetal Medicine. NICE recommends vaginal progesterone in women between 16+0 and 24+0 weeks with a cervical length <25 mm and no history of late miscarriage or sPTB.
Progesterone or cerclage are advised by NICE for women with a history of late miscarriage or preterm birth [14]. Currently cervical cerclage is the Royal College of Obstetricians (RCOG) recommended treatment for women with a short cervix <25 mm and a history of 1 or more late miscarriages or preterm birth [15].
However, there have been no direct comparison of these three interventions to inform guidelines as to the optimal management of all high risk women who develop a sonographic short cervix. Women at high risk of sPTB with a short cervix cannot, at present, be counselled as to which is the most suitable intervention to reduce their risk of delivering prematurely.
Our research group recently published an exploratory observational study [16] to evaluate the relationship between pro-inflammatory cytokines, cervical shortening and intervention, within which 37 women who developed a short cervix were randomised to treatment with vaginal progesterone (n = 17) or cervical cerclage (n = 19). A clinically important trend towards benefit (gestation at delivery) was noted in the cerclage group (mean gestation 33.7 weeks’ cerclage versus 31.5 weeks’ progesterone) although this result did not achieve statistical significance.
Alfirevic et al., [17] retrospectively compared three cohorts of women with previous sPTB <34 weeks and short cervix treated with cerclage (n = 142), vaginal progesterone (n = 59) or a pessary (n = 42). There were no significant differences in rates of perinatal loss, neonatal morbidity or sPTB, apart from a higher rate of sPTB before 34 weeks’ gestation in the vaginal progesterone vs pessary groups. It was concluded that randomized comparisons of these three management strategies, or combinations thereof, are needed to determine optimal management. If a randomised study, such as the one described here, showed that the three treatments were equally efficacious, then women and clinicians would have greater choice regarding treatment plans, expensive surgery (and potential complications) could be avoided. The pessary could be inserted at a later gestational age, when cerclage is no longer performed, potentially in an outpatient setting.
This randomised controlled trial will answer the current clinical dilemma of which is the most effective method to treat women at high risk of sPTB who develop a short cervix.
Hypothesis
Current treatments for ultrasound indicated cervical shortening in women at risk of preterm birth confer equal benefit in terms of reducing the numbers of births <37 weeks of gestation.
Aim
In a randomised controlled trial, to compare three evidence-based treatments for a short cervix detected by ultrasound scan in women at high risk of premature birth: cervical cerclage, cervical pessary and vaginal progesterone therapy.