Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 273–283
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Prevention of preterm delivery in twin pregnancy Line Rode, MD, PhD, Senior Registrar, Ann Tabor, MD. Dr.Med.Sci., Consultant * Center of Fetal Medicine, Department of Obstetrics, Copenhagen University Hospital, 2100 Rigshospitalet, Denmark
Keywords: twin pregnancy preterm delivery prenatal ultrasonography cervical length cerclage cervical pessary progesterone
The incidence of twin gestation has increased markedly over the past decades, mostly because of increased use of assisted reproductive technologies. Twin pregnancies are at increased risk of preterm delivery (i.e. birth before 37 weeks of gestation). Multiple gestations therefore account for 2–3% of all pregnancies but constitute at least 10% of cases of preterm delivery. Complications from preterm birth are not limited to the neonatal period, such as in retinopathy of prematurity, intraventricular haemorrhage, necrotising enterocolitis, respiratory disorder and sepsis; they can also constitute sequelae such as abnormal neurophysiological development in early childhood and underachievement in school. Several treatment modalities have been proposed in singleton high-risk pregnancies. The mechanism of initiating labour may, however, be different in singleton and twin gestations. Therefore, it is mandatory to evaluate the proposed treatments in randomised trials of multiple gestations. In this chapter, we describe the results of trials to prevent preterm delivery in twin pregnancies. Ó 2013 Elsevier Ltd. All rights reserved.
Prevention of preterm delivery in twin pregnancies The diversity in the causes of preterm delivery is reflected in the many different treatments that have been investigated and used for the prevention of preterm delivery in high-risk pregnancies. Some treatments have been directed towards reducing myometrial activity or inflammation, and others have used more mechanical approaches to prevent cervical shortening and contractions.
* Corresponding author. Tel.: þ45 3545 0610; Fax: þ45 3545 4749. E-mail address: [email protected] (A. Tabor). 1521-6934/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2013.11.002
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For many years, bed rest has been widely used in the prevention of preterm delivery based on results from observational studies suggesting an association between hard physical activity and risk of preterm delivery. Bed rest, however, has been shown to entail potentially severe psychological and physiological maternal adverse effects [1]. A large meta-analysis investigating the effect in singleton pregnancies found no evidence of effect of bed rest, and concluded that bed rest should not be used routinely in the prevention of preterm delivery in singleton pregnancies [2]. Bed rest for multiple gestations may improve fetal growth, but a recent meta-analysis concurrently found that risk of preterm delivery may be increased in women with uncomplicated twin pregnancies [3]. A frequent cause of preterm delivery is intrauterine infections, which may in part be caused by bacterial stimulation of the biosynthesis of prostaglandins [4,5]. It has been shown that the lower the gestational age at delivery, the higher the rate of intrauterine infection [6]. Little information is available for twin cohorts. In singleton pregnancies, antibiotics have been used to treat bacterial vaginosis during pregnancy, for prevention of preterm delivery in women with preterm labour and intact membranes, or for the prevention of preterm delivery in women with preterm rupture of membranes [7]. Treatment with antibiotics may eradicate bacterial vaginosis. A recent review, however, concluded that, at present, little evidence is available of a preventive effect on preterm delivery by screening and treating women with asymptomatic bacterial vaginosis [8]. Similar results have been found for the treatment of women with preterm labour without membrane rupture. In these women, treatment with antibiotics may significantly reduce the risk of maternal infections, such as chorioamnionitis and endometritis. Meta-analyses have not found any statistically significant differences in other maternal and neonatal outcomes, including mean gestational age at delivery and rate of preterm delivery [9]. In women presenting with membrane rupture, infection seems to be either a cause or a consequence of preterm rupture of membranes. Some bacteria may produce proteases, which weaken the membranes leading to preterm rupture of membranes. In addition, infection may be secondary to rupture of membranes. Treatment with antibiotics for women with preterm rupture of membranes seems to improve short-term outcome by reducing the risk of delivery within 7 days of membrane rupture and risk of chorioamnionitis. Concurrently, risk of neonatal infection is decreased [5]. A follow-up study of children after the ORACLE trial, however, suggested that, among women with prelabour rupture of membranes, the prescription of antibiotics had little effect on health and educational achievement of children at age 7 years; in fact, prescription of the examined antibiotics (i.e. erythromycin and co-amoxiclav) for women with spontaneous preterm labour was associated with increased risk of cerebral palsy [10,11]. In conclusion, antibiotics may, therefore, be effective once membrane rupture has occurred, but evidence of a preventive effect of antibiotics in asymptomatic women is lacking. Progesterone Progesterone is vital for early pregnancy, and it also plays an important but not fully elucidated role later in pregnancy. Progesterone treatment in early pregnancy is used for luteal phase support after assisted reproduction technology to supplement a corpus luteum that may be functioning suboptimally owing to either ovulation induction or oocyte retrieval [12]. Progesterone may be administered vaginally as gel or pessaries containing micronised progesterone, which is progesterone identical to the form produced by the placenta and, therefore, is often referred to as natural progesterone. The synthetic compound 17-alpha-hydroxyprogesterone caproate (17-OHPC) is administered intramuscularly. Micronised progesterone may also be administered as oral treatment, but owing to a first-pass hepatic metabolism if administered orally, parenteral progesterone treatments are more effective[13]. Vaginal progesterone treatment is often considered more convenient for the patient and easier to use than intramuscular treatment. In addition, uterine first-pass may increase availability of progesterone to the myometrium. The most common side-effects to vaginal progesterone treatment are local irritation and vaginal discharge, whereas intramuscular treatment has side-effects such as injection site pain, itching, and swelling [13,14]. Accumulating evidence has shown that progesterone supplementation in the second and third trimester of pregnancy significantly reduces risk of preterm delivery in high-risk singleton pregnancies. As early as the 1950s, Arpad Csapo [15] suggested that progesterone supplementation could
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potentially help maintain human pregnancy until term. The first larger study to investigate the effect of progesterone treatment for prevention of preterm delivery was carried out by Papiernik–Berkhauer in 1970 [16]. Since then, several studies have been conducted, and it is now quite well-established that progesterone treatment prevents preterm delivery in women with singleton pregnancies and a short cervix at 23 weeks of gestation [17–20], a history of previous preterm delivery, or both [21–25]. A recent individual patient data meta-analysis concluded that vaginal progesterone treatment (90– 200 mg/day) reduces risk of delivery before 33 weeks of gestation by about 45% in women with singleton pregnancies and a short cervix at 20–23 weeks’ gestation [20]. Risk of composite neonatal morbidity and mortality was reduced with a RR of 0.6 (95% CI 0.4 to 0.8). Another meta-analysis showed that, in women with a history of previous preterm delivery, the relative risk of delivery before 32 weeks of gestation is 0.6 (95% CI 0.5 to 0.8), with a corresponding statistically significant reduction in perinatal complications [26]. The precise mechanism for the preventive effect of progesterone on preterm delivery is unknown. The hormone seems to decrease the risk of preterm uterine contractions, whereas no effect is seen once labour is initiated. This may be the result of an inhibitory effect of progesterone on the amount of gap junctions in the myometrium by suppression of genes for gap junction proteins [27]. Progesterone also suppresses gene transcription for calcium channels and oxytocin receptors [27]. In addition, progesterone has been suggested to be anti-inflammatory and inhibits cervical ripening by suppressing proinflammatory cytokines, which reduces concentration of prostaglandins in the cervix [28]. In-vitro studies suggest that lymphocytes exposed to progesterone during pregnancy produce progesteroneinduced blocking factor, which is capable of blocking lymphocyte function. Furthermore, Norwitz et al. [29] found that medroxyprogesterone acetate, a synthetic variant of the human hormone, inhibited the plasminogen activator system in decidual cells. Progesterone may also have pregnancyprolonging actions by inhibiting decidual activation, which is believed to be necessary for spontaneous onset of labour. Luo et al. [30] showed that progesterone may inhibit apoptosis in fetal membranes and thereby prevent rupture of membranes and preterm labour. As the pathophysiology of preterm delivery is likely to be different in singleton and twin pregnancies, results from singleton pregnancies may not be directly transferred to twin or higher order of multiple pregnancies. Until 2007, only one randomised-controlled trial had investigated the effect of progesterone treatment in twin pregnancies [31]. The frequency of preterm delivery among twin pregnancies was not reduced, but sample size was small (77 women) and the power of the study was less than 0.4 (preterm delivery was found in 30.9% in the study group versus 23.7% in the control group). More importantly, treatment was initiated late in pregnancy (28–33 weeks) [31]. Several randomised-controlled trials that have included women with twin pregnancies were planned and carried out since 2003, and more than 10 randomised placebo-controlled trials have been published to date examining the effect of progesterone treatment in women with twin pregnancies (Table 1) [18,32–41]. The published randomised-controlled trials, which vary in size from 24 to 675, included twin pregnancies, and some studies have used vaginal natural progesterone (90–400 mg/day) [18,32,34,37,38,40,41], whereas others have used the intramuscularly administered 17-OHPC (200– 250 mg/day) [33,35,36,39]. In most randomised-controlled trials, treatment was started before 24 weeks’ gestation, and continued until 34 weeks’ gestation. Although most populations have been rather unselected, one study included twin pregnant women with a short cervical length only [18], and another only pregnancies conceived by in-vitro fertilisation and intracytoplasmic sperm injection [32]. Despite the differences in study design and population characteristics, none of the published trials have shown a significant effect of progesterone treatment in these relatively unselected cohorts of twin pregnancies. The results of a meta-analysis including all the published trials showed an odds ratio of 1.0 (95% CI 0.9 to 1.2) for delivery before 34 weeks in women treated with progesterone compared with women given placebo (Fig. 1), indicating neither a beneficial nor a harmful effect of progesterone treatment on preterm delivery less than 34 weeks in this group of pregnant women. One trial randomised women with twin pregnancies to placebo, 200 mg vaginal progesterone or 400 mg progesterone [40], and found no advantages of 400 mg over 200 mg. Similarly, randomisedcontrolled trials including singleton pregnancies have not indicated increased effect of 200 mg vaginal progesterone over 90–100 mg vaginal progesterone [20]. It is noteworthy that Senat et al. [42]
276
Author, year
Progesterone treatment
Gestational age
Active treatment, N
Fonseca et al., 2007 [18]
Vaginal natural progesterone, 200 mg/day Intramuscular 17a-OHPC, 250 mg/week Vaginal natural progesterone, 90 mg/day Intramuscular 17a-OHPC, 250 mg/week Intramuscular 17a-OHPC, 250 mg/week Vaginal natural progesterone, 100 mg/day Vaginal natural progesterone, 200 mg/day Intramuscular 17a-OHPC, 250 mg/week Vaginal natural progesterone, 2*200 mg/day
24–34 weeks
11
13
16–20 weeks to 35 weeks 24–34 weeks
325
Rouse et al., 2007 [39] Norman et al., 2009 [37] Briery et al., 2009 [33] Combs et al., 2011 [35] Cetingos et al., 2011 [34] Rode et al., 2011 [38] Lim et al., 2011 [36] Aboulghar et al., 2012 [32] Serra et al., 2012 [40]
Wood et al., 2012 [41]
Vaginal natural progesterone, 200 or 400 mg/day Vaginal natural progesterone, 90 mg/day
17a-OHPC, 17-alpha-hydroxyprogesterone caproate.
Placebo treatment, N
Population characteristics
Primary outcome
330
Cervical length less than 25 mm and twin pregnancy. Diamniotic twin pregnancy.
247
247
Twin pregnancy.
16
14
Twin pregnancy.
Spontaneous delivery less than 34 weeks. Delivery or fetal death less than 34 weeks. Delivery or fetal death less than 35 weeks. Delivery less than 35 weeks.
20–30 weeks to 34 weeks 16–24 weeks to 34 weeks 24–34 weeks
160
78
Dichorionic twin pregnancy.
Composite neonatal morbidity.
39
28
Delivery less than 37 weeks.
20–24 to 34 weeks
334
341
150 high-risk pregnant women with follow up. Diamniotic twin pregnancies.
Delivery less than 34 weeks.
16–20 weeks to 36 weeks 18–24 to 37 weeks
327
326
Multiple pregnancy, 653 twins.
Adverse neonatal outcome.
49
42
Delivery less than 34 weeks.
20–34 weeks
97 (200 mg) 97 (400 mg)
96
Dichorionic pregnancies conceived by in-vitro fertilisation and intracytoplasmic sperm injection. Dichorionic twin pregnancies.
Delivery less than 37 weeks.
16–20 to 35 weeks
42
42
Twin and triplet pregnancies.
Gestational age at delivery.
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Table 1 Characteristics of the published randomised placebo-controlled trials, including women with twin pregnancies.
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Fig. 1. Meta-analysis of the preventive effect of progesterone on delivery before 34 weeks’ gestation in twin pregnancies.
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compared treatment with 500 mg 17-OHPC twice weekly with no treatment, and did not find a preventive effect but rather risk of preterm delivery before 32 weeks increased (29% in the 17-OHPC treated women compared with 12%; P ¼ 0.007). In conclusion, it is now well established that neither 17-OHPC nor vaginal progesterone treatment has no evidence of effect for the prevention of preterm delivery in unselected twin cohorts. It is not likely that studies using higher doses of progesterone in twin pregnancies will show more effective results in unselected twin cohorts. Few studies on selected twin populations corresponding to subgroups of high-risk pregnancies within twin cohorts have been carried out. As previously mentioned, progesterone treatment has mainly been shown to be effective for preventing preterm delivery in high-risk singleton pregnancies, namely in women with a history of previous preterm delivery and women with a short cervix at midgestation. Some of the randomised-controlled trials including twin pregnancies have measured cervical length before treatment with progesterone or placebo was initiated [18,33,34,36,38], but to date information has only been published for a total of 52 women with twin pregnancies and a short cervix. Romero et al. [20] published an individual patient data meta-analysis of these cases where vaginal progesterone treatment had been used. This meta-analysis yielded a non-significant relative risk of 0.7 (95% CI 0.3 to 1.4) for preterm delivery before 33 weeks of gestation. When evaluating the risk of composite neonatal morbidity and mortality (defined as occurrence of respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, neonatal sepsis, or neonatal death), effect of progesterone treatment was statistically significant (RR 0.5, 95% CI 0.3 to 0.9) in this sub-population of 52 twin pregnancies. Romero et al. [20] found no evidence of different benefit of vaginal progesterone treatment in twin pregnancies than in singleton pregnancies. These findings, however, should be confirmed in randomised-controlled trials aimed at investigating the effect of progesterone treatment in women with twin pregnancies and a short cervix. Information on the effect of progesterone treatment in women with twin pregnancies and a history of previous preterm delivery is limited. A large collaboration between all published and ongoing randomised-controlled trials, including twin pregnant women, has been initiated by Mol and Schuit [43]. This large individual patient data meta-analysis will include data from 13 studies randomising a total of more than 3500 women with twin pregnancies. This meta-analysis will be able to perform subgroup analyses of high-risk twin pregnant women and compare effect of vaginal progesterone treatment with 17-OHPC treatment. This latter comparison will be important, as a recent meta-analysis of perinatal outcome in women treated with progesterone for prevention of preterm delivery suggested that progesterone treatment may have adverse effects in multiple pregnancies [44]. Risk ratio for perinatal death was 1.6 (95% CI 1.01 to 2.4), risk ratio for respiratory distress syndrome was 1.2 (95% CI 1.04 to 1.4), and risk ratio for composite adverse outcome was 1.2 (95% CI 1.03 to 1.4), but too few studies were included to allow sufficient subgroup analyses comparing vaginal and systemic treatment. A safety signal has been suggested for 17-OHCP [45], but not for micronised progesterone, in part because a triplet study comparing 17-OHPC with placebo treatment showed significantly increased risk of midtrimester fetal loss (13 losses in women treated with 17-OHPC compared to none in the placebo group) (P < 0.02) [46]. Furthermore, Caritis et al. [47] found that women with higher plasma concentration of 17-OHPC delivered at earlier gestational ages. The previously mentioned results of the ORACLE children study [48] stress the importance of carrying out long-term follow up of infants after interventions aimed at prolonging gestational age at delivery. Pathological processes associated with increased risk of preterm delivery, such as infection, may affect infant outcome, and may potentially even increase risk of neonatal complications in relation to pregnancy prolonging treatments [48]. By 2013, information on longer-term follow up of infants born to mothers treated with progesterone is available for twins until the age of 18 months for pregnancies treated with vaginal progesterone [38] and for singletons until the age of 48 months for pregnancies treated with 17-OHPC [49]. These two studies have not shown signs of harmful longerterm effects of micronised progesterone or 17-OHPC, but further long-term follow-up studies are needed. Potential maternal adverse effects of progesterone treatment constitute a possible increased risk of gestational diabetes [50] corresponding to a known suggested diabetogenic effect of progesterone [51]. The association between progesterone treatment and gestational diabetes has not been confirmed in subsequent publications [52,53]. Recently, Serra et al. [40] found a non-significant dose-dependent
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trend towards higher incidence of intrahepatic cholestasis. This is in accordance with a previously reported increased risk of intrahepatic cholestasis in association with oral progesterone treatment during second- and third-trimester pregnancy [54–56]. Cerclage Cervical cerclage to reinforce the cervix by placing a cervical stitch was described in the 1950s by Shirodkar [57] and McDonald [58]. Indications for both types of cerclage have been obstetrical history, physical examination, ultrasound findings, or a combination of the above. In high-risk singleton gestations, cerclage reduces the rate of preterm delivery before 35 weeks as well as composite perinatal mortality and morbidity [59]. A meta-analysis of five randomised trials that included a total of 504 women with singleton gestations, previous preterm delivery, and cervical length less than 25 mm before 24 weeks showed that, having a McDonald or Shirodkar cerclage reduced the rate of preterm delivery before 35 weeks (RR 0.7, 95% CI 0.6 to 0.9) as well as composite perinatal mortality and morbidity (RR 0.6, 95% CI 0.5 to 0.9) [59]. The effect of cerclage and progesterone in high-risk singleton pregnancies has not been directly compared in a randomized trial, but, in an indirect meta-analysis, the results of the above-mentioned meta-analysis were compared with four randomised studies evaluating the effect of progesterone with placebo [60]. Vaginal progesterone and cerclage were equally efficacious in the prevention of preterm delivery in women with singleton gestations, previous preterm delivery and a short cervix in the second trimester. Three randomised trials have also included twin gestations [61–63]. Rust et al. [63] included 14 twin pregnancies among the 113 patients in a study from the USA, with seven allocated to the study group having a McDonald cerclage and seven in the control group having no cerclage. Multiple gestation correlated with decreased gestational age at delivery, but not with increased neonatal morbidity [63]. In a Dutch study [61], 35 women were also randomised to a McDonald cerclage or no surgical treatment. In this smaller trial, cerclage reduced the rate of preterm delivery before 34 weeks as well as compound perinatal morbidity. Unfortunately, no details are given on multiple gestations, but they constituted a limited part of the study population [59,61]. In the last trial, 61 women were randomly assigned to McDonald cerclage or bed rest [62]. This trial included four twin gestations, three assigned to the cerclage group and one assigned to the control group. All three twin gestations in the cerclage group had early preterm births at 20, 21 and 22 weeks of gestation, respectively, whereas the twin gestation randomised to the control group delivered at 34 weeks’ gestation [62]. Thus, although the data from randomised trials are sparse, data from these three trials have subsequently been reviewed in a meta-analysis, including a total of 49 twin pregnancies [64]. The rate of preterm delivery before 35 weeks was 75.0% (18 out of 24) in the cerclage group compared with 36.0% (9 out of 25) in the control group, giving a relative risk of 2.2 (95% CI 1.2 to 4.0), whereas the perinatal mortality rate was 22.9% in the cerclage group compared with 6.0% in the control group, resulting in a non-significant relative risk of 2.7 (95% CI 0.8 to 8.5). Although the effect of cerclage in twin pregnancies has not been properly assessed in adequately sized randomised trials, it must be concluded that cervical cerclage in twin pregnancies actually seems to increase the rate of preterm delivery. It cannot be excluded that twin gestations with shortened cervical length may benefit from insertion of an emergency cerclage, as suggested by a small retrospective analysis of 14 cases [65]. Several pathophysiologic processes may lead to cervical shortening, and it is unclear why insertion of cerclage seems to improve perinatal outcome in high-risk singleton pregnancies, whereas the opposite is true in twin pregnancies. Increased uterine activity, subclinical infection, or placental abruption, may be more common in twin pregnancy, and may be exacerbated by the presence of a foreign body in the cervical stroma [63]. Arabin pessary Cervical pessaries have also been used for many years to prevent preterm birth. Their mechanism of action is to tightly seal the cervical canal to prevent an ascending infection through the mucus plug,
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and, perhaps more importantly, to support the cervix by changing the angle of the cervical canal [66]. That a mechanical effect may be provided by a cervical pessary was supported by the results of an magnetic resonance imaging observational study of 73 women at high-risk of preterm delivery [67]. The median utero-cervical angle immediately after pessary placement was significantly smaller compared with the value before placement in the subgroup who delivered at 34 weeks or more. In the eight women who delivered before 34 weeks, no change was observed in median utero-cervical angle before and after pessary placement. The effect of a cervical pessary has unfortunately not yet been well investigated in randomised trials. In singleton pregnancies, only one randomised trial has been properly designed and recruited the planned sample size [68]. Insertion of a silicone device as cervical pessary in 385 singleton pregnancies with a cervical length of 25 mm or less at 18–22 weeks of gestation was shown to decrease the rate of preterm birth before 34 weeks of gestation from 27% to 6% [69], as well as the rate of preterm birth before 32 and 28 weeks. The rate of neonatal paediatric care was also reduced in the pessary group (RR 0.2; 95% CI 0.1 to 0.4). The suggested mechanism of action of the cervical pessary could also be effective in multiple gestations. Two small pilot studies have so far been reported. In the first study, 23 women with a cervical length less than 25 mm before 24 weeks were matched with 23 women treated expectantly [70]. In the pessary group, gestational age at delivery was significantly higher than in the control group (35weeks þ 6 days compared with 33weeks þ 2 days). The second study assessed the effect of a cervical pessary in eight women with monochorionic twins and cervical length less than 25 mm at the time of laser therapy for twin-to-twin transfusion syndrome compared with a historic control group [71]. The median gestational at delivery was 32 weeks in the pessary group compared with 28 weeks in the controls. These two small studies thus suggest that the cervical pessary may play a role in prolonging pregnancy in twin pregnancies with a short cervix, but conclude that the effect should be assessed in randomised trials. Several randomised trials in multiple pregnancies are registered with www.clinicaltrials.gov, and one protocol from the Netherlands has been published [72]. Preliminary data from this trial, which recruited 813 women with multiple pregnancies from 40 hospitals in the Netherlands, showed no difference in the primary outcome, composite bad neonatal condition (i.e. perinatal death or severe morbidity), between study and control group [73]. Forty-two (11%) women in the pessary group and 42 (11%) in the control group who had at least one child with a composite adverse neonatal outcome (RR 1.0; 95% CI 0.7 to 1.5). The rate of adverse neonatal outcome was, however, lower in the prespecified subgroup of women who had a short cervical length, below 25th percentile at 16–20 weeks of gestation. No difference was observed in rate of preterm delivery before 32 weeks (9% v 12%, RR 1.0; 9% CI 0.7 to 1.5), nor before 37 weeks of gestation (54% v 57%, RR 0.9; 95% CI 0.8 to 1.0). These data have so far only been reported as an abstract. It will be interesting to see the results of other randomised trials in multiple pregnancies, and especially in women with a short cervical length. It seems that several of the described methods of treatment may be more effective in women with a short cervix. The information provided by a quantitative assessment of the cervical length may be supplemented by information arising from new examination methods such as cervical elastography [69,70]. This non-invasive method evaluates cervical remodelling during pregnancy by estimating hydration status, tissue softness, stiffness, actual collagen arrangement, or both [69]. Because of its qualitative nature, elastography assessment is difficult to standardise, and it is hoped that it may help triage women for different treatments, by more accurately and more qualitatively describing the cervix before and during treatment [74,75]. Conclusion Several treatment modalities have attempted to prevent preterm delivery in twin pregnancies. The effect of progesterone has been investigated in several randomised trials in twin pregnancies, and progesterone does not reduce the rate of preterm delivery in unselected twin cohorts. Vaginal natural progesterone treatment, but not synthetic 17-a-hydroxyprogesterone caproate, may prevent preterm delivery and decrease risk of composite neonatal morbidity and mortality in women with a twin pregnancy and a short cervix. A randomised-controlled trial designed to examine the effect in women
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with a twin pregnancy and a short cervix is required before progesterone treatment can be recommended to this group of high-risk pregnancies. Longer-term follow up until the age of 18 months does not suggest a harmful effect of progesterone treatment in twin pregnancies but further longer-term follow-up studies are needed. Data for cerclage are sparse, and stem from randomised trials including both singleton and twin pregnancies. Cerclage seems to increase the rate of preterm delivery and of neonatal mortality, and should not be used in the prevention of preterm delivery in twin pregnancy. Insertion of a cervical pessary, which supports the cervix and changes the angle of the cervical canal, is being evaluated in several randomised trials. Preliminary results indicate no effect of this treatment either in unselected twin populations.
Practice points Cervical length measurement at 20–23 weeks of gestation identifies twin pregnancies at high risk of preterm delivery. Progesterone does not reduce the rate of preterm delivery in twins in general. Progesterone may reduce the rate of preterm delivery in twin pregnancies with a short cervix. Cerclage does not reduce the rate of preterm delivery in twin pregnancy. A cervical pessary such as the Arabin pessary has not been properly evaluated in twin pregnancies, but randomised clinical trials are being conducted.
Research agenda A randomised-controlled trial of vaginal progesterone in twin pregnancies with a short cervix. The value of cervical pessary to prevent preterm delivery in twin pregnancies with a short cervix. Investigation into the structural changes in the cervix using elastography, to elucidate the mechanism of effect of cervical vaginal pessary.
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Progesterone control of interleukin-8 production in endometrium and choriodecidual cells underlines the role of the neutrophil in menstruation and parturition. Hum Reprod 1994;9:253–8. [29] Norwitz ER, Snegovskikh V, Schatz F, et al. Progestin inhibits and thrombin stimulates the plasminogen activator/inhibitor system in term decidual stromal cells: implications for parturition. Am J Obstet Gynecol 2007;196:382–8. [30] Luo G, Abrahams VM, Tadesse S, et al. Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod Sci 2010;17:532–9. [31] Hartikainen-Sorri AL, Kauppila A, Tuimala R. Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy. Obstet Gynecol 1980;56:692–5. [32] Aboulghar MM, Aboulghar MA, Amin YM, et al. The use of vaginal natural progesterone for prevention of preterm birth in IVF/ICSI pregnancies. Reprod Biomed Online 2012;25:133–8. [33] Briery CM, Veillon EW, Klauser CK, et al. Progesterone does not prevent preterm births in women with twins. South Med J 2009;102:900–4. [34] Cetingoz E, Cam C, Sakalli M, et al. Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebocontrolled trial. Arch Gynecol Obstet 2011;283:423–9. [35] Combs CA, Garite T, Maurel K, et al. 17-hydroxyprogesterone caproate for twin pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2011;204:221–8. *[36] Lim AC, Schuit E, Bloemenkamp K, et al. 17alpha-hydroxyprogesterone caproate for the prevention of adverse neonatal outcome in multiple pregnancies: a randomized controlled trial. Obstet Gynecol 2011;118:513–20. *[37] Norman JE, Mackenzie F, Owen P, et al. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet 2009;373:2034–40. *[38] Rode L, Klein K, Nicolaides KH, et al. Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone. Ultrasound Obstet Gynecol 2011;38: 272–80. *[39] Rouse DJ, Caritis SN, Peaceman AM, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med 2007;357:454–61. *[40] Serra V, Perales A, Meseguer J, et al. Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial. BJOG 2013;120:50–7.
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Am J Perinatol 2012;29:665–72. [46] Combs CA, Garite T, Maurel K, et al. Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2010;203:248–9. [47] Caritis SN, Simhan HN, Zhao Y, et al. Relationship between 17-hydroxyprogesterone caproate concentrations and gestational age at delivery in twin gestation. Am J Obstet Gynecol 2012;207:396–8. [48] Marlow N, Pike K, Bower E, et al. Characteristics of children with cerebral palsy in the ORACLE children study. Dev Med Child Neurol 2012;54:640–6. [49] Northen AT, Norman GS, Anderson K, et al. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol 2007;110:865–72. [50] Waters TP, Schultz BA, Mercer BM, et al. Effect of 17alpha-hydroxyprogesterone caproate on glucose intolerance in pregnancy. Obstet Gynecol 2009;114:45–9. [51] Picard F, Wanatabe M, Schoonjans K, et al. Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation. Proc Natl Acad Sci USA 2002;99:15644–8. [52] Wolfe K, Dearmond C, How H, et al. The rates of abnormal glucose challenge tests and gestational diabetes in women receiving 17alpha-hydroxyprogesterone caproate. Am J Perinatol 2011;28:741–6. [53] Gyamfi C, Horton AL, Momirova V, et al. The effect of 17-alpha hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies. Am J Obstet Gynecol 2009;201:392–5. [54] Benifla JL, Dumont M, Levardon M, et al. [Effects of micronized natural progesterone on the liver during the third trimester of pregnancy]. Contracept Fertil Sex 1997;25:165–9. [55] Noblot G, Audra P, Dargent D, et al. The use of micronized progesterone in the treatment of menace of preterm delivery. Eur J Obstet Gynecol Reprod Biol 1991;40:203–9. [56] Stanczyk FZ. Pharmacokinetics of progesterone administered by the oral and parenteral routes. J Reprod Med 1999;44(2 Suppl.):141–7. [57] Shirodkar VN. A new method of operative treatment for habitual abortion in the second trimester of pregnancy. Antiseptic 1955;52:299–303. [58] Mcdonald IA. Suture of the cervix for inevitable miscarriage. J Obstet Gynaecol Br Emp 1957;64:346–50. [59] Berghella V, Keeler SM, To MS, et al. Effectiveness of cerclage according to severity of cervical length shortening: a metaanalysis. Ultrasound Obstet Gynecol 2010;35:468–73. [60] Conde-Agudelo A, Romero R, Nicolaides K, et al. Vaginal progesterone vs. cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis. Am J Obstet Gynecol 2013;208:42.e1–42.e18. [61] Althuisius SM, Dekker GA, Hummel P, et al. Final results of the Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106–12. [62] Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. Am J Obstet Gynecol 2004;191:1311–7. [63] Rust OA, Atlas RO, Reed J, et al. Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help. Am J Obstet Gynecol 2001;185:1098–105. [64] Berghella V, Odibo AO, To MS, et al. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005;106:181–9. *[65] Levin I, Salzer L, Maslovitz S, et al. Outcomes of mid-trimester emergency cerclage in twin pregnancies. Fetal Diagn Ther 2012;32:246–50. *[66] Arabin B, Alfirevic Z. Cervical pessaries for prevention of spontaneous preterm births: past, present and future. Ultrasound Obstet Gynecol 2013;42:390–9. [67] Cannie MM, Dobrescu O, Gucciardo L, et al. Arabin cervical pessary in pregnant women at high-risk of premature birth: an MR imaging observational follow-up study. Ultrasound Obstet Gynecol 2013;42:426–33. [68] Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary for preventing preterm birth. Cochrane Database Syst Rev 2013;(5):CD007873. [69] Goya M, Pratcorona L, Merced C, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 2012;379:1800–6. [70] Arabin B, Halbesma JR, Vork F, et al. Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? J Perinat Med 2003;31:122–33. [71] Carreras E, Arevalo S, Bello-Munoz JC, et al. Arabin cervical pessary to prevent preterm birth in severe twin-to-twin transfusion syndrome treated by laser surgery. Prenat Diagn 2012;32:1181–5. [72] Hegeman MA, Bekedam DJ, Bloemenkamp KW, et al. Pessaries in multiple pregnancy as a prevention of preterm birth: the ProTwin Trial. BMC Pregnancy Childbirth 2009;9:44. [73] Liem S, Schuit E, Bais J, et al. Pessaries in multiple pregnancy as a prevention of preterm birth (ProTWIN): a randomized controlled trial [abstract]. Am J Obstet Gynecol 2013;208(Suppl. 1):S2. [74] Feltovich H, Hall TJ. Quantitative imaging of the cervix: setting the bar. Ultrasound Obstet Gynecol 2013;41:121–8. [75] Hernandez-Andrade E, Hassan SS, Ahn H, et al. Evaluation of cervical stiffness during pregnancy using semiquantitative ultrasound elastography. Ultrasound Obstet Gynecol 2013;41:152–61.
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8
Prevention of preterm delivery in twin pregnancy Line Rode, MD, PhD, Senior Registrar, Ann Tabor, MD. Dr.Med.Sci., Consultant * Center of Fetal Medicine, Department of Obstetrics, Copenhagen University Hospital, 2100 Rigshospitalet, Denmark
Keywords: twin pregnancy preterm delivery prenatal ultrasonography cervical length cerclage cervical pessary progesterone
The incidence of twin gestation has increased markedly over the past decades, mostly because of increased use of assisted reproductive technologies. Twin pregnancies are at increased risk of preterm delivery (i.e. birth before 37 weeks of gestation). Multiple gestations therefore account for 2–3% of all pregnancies but constitute at least 10% of cases of preterm delivery. Complications from preterm birth are not limited to the neonatal period, such as in retinopathy of prematurity, intraventricular haemorrhage, necrotising enterocolitis, respiratory disorder and sepsis; they can also constitute sequelae such as abnormal neurophysiological development in early childhood and underachievement in school. Several treatment modalities have been proposed in singleton high-risk pregnancies. The mechanism of initiating labour may, however, be different in singleton and twin gestations. Therefore, it is mandatory to evaluate the proposed treatments in randomised trials of multiple gestations. In this chapter, we describe the results of trials to prevent preterm delivery in twin pregnancies. Ó 2013 Elsevier Ltd. All rights reserved.
Prevention of preterm delivery in twin pregnancies The diversity in the causes of preterm delivery is reflected in the many different treatments that have been investigated and used for the prevention of preterm delivery in high-risk pregnancies. Some treatments have been directed towards reducing myometrial activity or inflammation, and others have used more mechanical approaches to prevent cervical shortening and contractions.
* Corresponding author. Tel.: þ45 3545 0610; Fax: þ45 3545 4749. E-mail address: [email protected] (A. Tabor). 1521-6934/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2013.11.002
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For many years, bed rest has been widely used in the prevention of preterm delivery based on results from observational studies suggesting an association between hard physical activity and risk of preterm delivery. Bed rest, however, has been shown to entail potentially severe psychological and physiological maternal adverse effects [1]. A large meta-analysis investigating the effect in singleton pregnancies found no evidence of effect of bed rest, and concluded that bed rest should not be used routinely in the prevention of preterm delivery in singleton pregnancies [2]. Bed rest for multiple gestations may improve fetal growth, but a recent meta-analysis concurrently found that risk of preterm delivery may be increased in women with uncomplicated twin pregnancies [3]. A frequent cause of preterm delivery is intrauterine infections, which may in part be caused by bacterial stimulation of the biosynthesis of prostaglandins [4,5]. It has been shown that the lower the gestational age at delivery, the higher the rate of intrauterine infection [6]. Little information is available for twin cohorts. In singleton pregnancies, antibiotics have been used to treat bacterial vaginosis during pregnancy, for prevention of preterm delivery in women with preterm labour and intact membranes, or for the prevention of preterm delivery in women with preterm rupture of membranes [7]. Treatment with antibiotics may eradicate bacterial vaginosis. A recent review, however, concluded that, at present, little evidence is available of a preventive effect on preterm delivery by screening and treating women with asymptomatic bacterial vaginosis [8]. Similar results have been found for the treatment of women with preterm labour without membrane rupture. In these women, treatment with antibiotics may significantly reduce the risk of maternal infections, such as chorioamnionitis and endometritis. Meta-analyses have not found any statistically significant differences in other maternal and neonatal outcomes, including mean gestational age at delivery and rate of preterm delivery [9]. In women presenting with membrane rupture, infection seems to be either a cause or a consequence of preterm rupture of membranes. Some bacteria may produce proteases, which weaken the membranes leading to preterm rupture of membranes. In addition, infection may be secondary to rupture of membranes. Treatment with antibiotics for women with preterm rupture of membranes seems to improve short-term outcome by reducing the risk of delivery within 7 days of membrane rupture and risk of chorioamnionitis. Concurrently, risk of neonatal infection is decreased [5]. A follow-up study of children after the ORACLE trial, however, suggested that, among women with prelabour rupture of membranes, the prescription of antibiotics had little effect on health and educational achievement of children at age 7 years; in fact, prescription of the examined antibiotics (i.e. erythromycin and co-amoxiclav) for women with spontaneous preterm labour was associated with increased risk of cerebral palsy [10,11]. In conclusion, antibiotics may, therefore, be effective once membrane rupture has occurred, but evidence of a preventive effect of antibiotics in asymptomatic women is lacking. Progesterone Progesterone is vital for early pregnancy, and it also plays an important but not fully elucidated role later in pregnancy. Progesterone treatment in early pregnancy is used for luteal phase support after assisted reproduction technology to supplement a corpus luteum that may be functioning suboptimally owing to either ovulation induction or oocyte retrieval [12]. Progesterone may be administered vaginally as gel or pessaries containing micronised progesterone, which is progesterone identical to the form produced by the placenta and, therefore, is often referred to as natural progesterone. The synthetic compound 17-alpha-hydroxyprogesterone caproate (17-OHPC) is administered intramuscularly. Micronised progesterone may also be administered as oral treatment, but owing to a first-pass hepatic metabolism if administered orally, parenteral progesterone treatments are more effective[13]. Vaginal progesterone treatment is often considered more convenient for the patient and easier to use than intramuscular treatment. In addition, uterine first-pass may increase availability of progesterone to the myometrium. The most common side-effects to vaginal progesterone treatment are local irritation and vaginal discharge, whereas intramuscular treatment has side-effects such as injection site pain, itching, and swelling [13,14]. Accumulating evidence has shown that progesterone supplementation in the second and third trimester of pregnancy significantly reduces risk of preterm delivery in high-risk singleton pregnancies. As early as the 1950s, Arpad Csapo [15] suggested that progesterone supplementation could
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potentially help maintain human pregnancy until term. The first larger study to investigate the effect of progesterone treatment for prevention of preterm delivery was carried out by Papiernik–Berkhauer in 1970 [16]. Since then, several studies have been conducted, and it is now quite well-established that progesterone treatment prevents preterm delivery in women with singleton pregnancies and a short cervix at 23 weeks of gestation [17–20], a history of previous preterm delivery, or both [21–25]. A recent individual patient data meta-analysis concluded that vaginal progesterone treatment (90– 200 mg/day) reduces risk of delivery before 33 weeks of gestation by about 45% in women with singleton pregnancies and a short cervix at 20–23 weeks’ gestation [20]. Risk of composite neonatal morbidity and mortality was reduced with a RR of 0.6 (95% CI 0.4 to 0.8). Another meta-analysis showed that, in women with a history of previous preterm delivery, the relative risk of delivery before 32 weeks of gestation is 0.6 (95% CI 0.5 to 0.8), with a corresponding statistically significant reduction in perinatal complications [26]. The precise mechanism for the preventive effect of progesterone on preterm delivery is unknown. The hormone seems to decrease the risk of preterm uterine contractions, whereas no effect is seen once labour is initiated. This may be the result of an inhibitory effect of progesterone on the amount of gap junctions in the myometrium by suppression of genes for gap junction proteins [27]. Progesterone also suppresses gene transcription for calcium channels and oxytocin receptors [27]. In addition, progesterone has been suggested to be anti-inflammatory and inhibits cervical ripening by suppressing proinflammatory cytokines, which reduces concentration of prostaglandins in the cervix [28]. In-vitro studies suggest that lymphocytes exposed to progesterone during pregnancy produce progesteroneinduced blocking factor, which is capable of blocking lymphocyte function. Furthermore, Norwitz et al. [29] found that medroxyprogesterone acetate, a synthetic variant of the human hormone, inhibited the plasminogen activator system in decidual cells. Progesterone may also have pregnancyprolonging actions by inhibiting decidual activation, which is believed to be necessary for spontaneous onset of labour. Luo et al. [30] showed that progesterone may inhibit apoptosis in fetal membranes and thereby prevent rupture of membranes and preterm labour. As the pathophysiology of preterm delivery is likely to be different in singleton and twin pregnancies, results from singleton pregnancies may not be directly transferred to twin or higher order of multiple pregnancies. Until 2007, only one randomised-controlled trial had investigated the effect of progesterone treatment in twin pregnancies [31]. The frequency of preterm delivery among twin pregnancies was not reduced, but sample size was small (77 women) and the power of the study was less than 0.4 (preterm delivery was found in 30.9% in the study group versus 23.7% in the control group). More importantly, treatment was initiated late in pregnancy (28–33 weeks) [31]. Several randomised-controlled trials that have included women with twin pregnancies were planned and carried out since 2003, and more than 10 randomised placebo-controlled trials have been published to date examining the effect of progesterone treatment in women with twin pregnancies (Table 1) [18,32–41]. The published randomised-controlled trials, which vary in size from 24 to 675, included twin pregnancies, and some studies have used vaginal natural progesterone (90–400 mg/day) [18,32,34,37,38,40,41], whereas others have used the intramuscularly administered 17-OHPC (200– 250 mg/day) [33,35,36,39]. In most randomised-controlled trials, treatment was started before 24 weeks’ gestation, and continued until 34 weeks’ gestation. Although most populations have been rather unselected, one study included twin pregnant women with a short cervical length only [18], and another only pregnancies conceived by in-vitro fertilisation and intracytoplasmic sperm injection [32]. Despite the differences in study design and population characteristics, none of the published trials have shown a significant effect of progesterone treatment in these relatively unselected cohorts of twin pregnancies. The results of a meta-analysis including all the published trials showed an odds ratio of 1.0 (95% CI 0.9 to 1.2) for delivery before 34 weeks in women treated with progesterone compared with women given placebo (Fig. 1), indicating neither a beneficial nor a harmful effect of progesterone treatment on preterm delivery less than 34 weeks in this group of pregnant women. One trial randomised women with twin pregnancies to placebo, 200 mg vaginal progesterone or 400 mg progesterone [40], and found no advantages of 400 mg over 200 mg. Similarly, randomisedcontrolled trials including singleton pregnancies have not indicated increased effect of 200 mg vaginal progesterone over 90–100 mg vaginal progesterone [20]. It is noteworthy that Senat et al. [42]
276
Author, year
Progesterone treatment
Gestational age
Active treatment, N
Fonseca et al., 2007 [18]
Vaginal natural progesterone, 200 mg/day Intramuscular 17a-OHPC, 250 mg/week Vaginal natural progesterone, 90 mg/day Intramuscular 17a-OHPC, 250 mg/week Intramuscular 17a-OHPC, 250 mg/week Vaginal natural progesterone, 100 mg/day Vaginal natural progesterone, 200 mg/day Intramuscular 17a-OHPC, 250 mg/week Vaginal natural progesterone, 2*200 mg/day
24–34 weeks
11
13
16–20 weeks to 35 weeks 24–34 weeks
325
Rouse et al., 2007 [39] Norman et al., 2009 [37] Briery et al., 2009 [33] Combs et al., 2011 [35] Cetingos et al., 2011 [34] Rode et al., 2011 [38] Lim et al., 2011 [36] Aboulghar et al., 2012 [32] Serra et al., 2012 [40]
Wood et al., 2012 [41]
Vaginal natural progesterone, 200 or 400 mg/day Vaginal natural progesterone, 90 mg/day
17a-OHPC, 17-alpha-hydroxyprogesterone caproate.
Placebo treatment, N
Population characteristics
Primary outcome
330
Cervical length less than 25 mm and twin pregnancy. Diamniotic twin pregnancy.
247
247
Twin pregnancy.
16
14
Twin pregnancy.
Spontaneous delivery less than 34 weeks. Delivery or fetal death less than 34 weeks. Delivery or fetal death less than 35 weeks. Delivery less than 35 weeks.
20–30 weeks to 34 weeks 16–24 weeks to 34 weeks 24–34 weeks
160
78
Dichorionic twin pregnancy.
Composite neonatal morbidity.
39
28
Delivery less than 37 weeks.
20–24 to 34 weeks
334
341
150 high-risk pregnant women with follow up. Diamniotic twin pregnancies.
Delivery less than 34 weeks.
16–20 weeks to 36 weeks 18–24 to 37 weeks
327
326
Multiple pregnancy, 653 twins.
Adverse neonatal outcome.
49
42
Delivery less than 34 weeks.
20–34 weeks
97 (200 mg) 97 (400 mg)
96
Dichorionic pregnancies conceived by in-vitro fertilisation and intracytoplasmic sperm injection. Dichorionic twin pregnancies.
Delivery less than 37 weeks.
16–20 to 35 weeks
42
42
Twin and triplet pregnancies.
Gestational age at delivery.
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Table 1 Characteristics of the published randomised placebo-controlled trials, including women with twin pregnancies.
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Fig. 1. Meta-analysis of the preventive effect of progesterone on delivery before 34 weeks’ gestation in twin pregnancies.
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compared treatment with 500 mg 17-OHPC twice weekly with no treatment, and did not find a preventive effect but rather risk of preterm delivery before 32 weeks increased (29% in the 17-OHPC treated women compared with 12%; P ¼ 0.007). In conclusion, it is now well established that neither 17-OHPC nor vaginal progesterone treatment has no evidence of effect for the prevention of preterm delivery in unselected twin cohorts. It is not likely that studies using higher doses of progesterone in twin pregnancies will show more effective results in unselected twin cohorts. Few studies on selected twin populations corresponding to subgroups of high-risk pregnancies within twin cohorts have been carried out. As previously mentioned, progesterone treatment has mainly been shown to be effective for preventing preterm delivery in high-risk singleton pregnancies, namely in women with a history of previous preterm delivery and women with a short cervix at midgestation. Some of the randomised-controlled trials including twin pregnancies have measured cervical length before treatment with progesterone or placebo was initiated [18,33,34,36,38], but to date information has only been published for a total of 52 women with twin pregnancies and a short cervix. Romero et al. [20] published an individual patient data meta-analysis of these cases where vaginal progesterone treatment had been used. This meta-analysis yielded a non-significant relative risk of 0.7 (95% CI 0.3 to 1.4) for preterm delivery before 33 weeks of gestation. When evaluating the risk of composite neonatal morbidity and mortality (defined as occurrence of respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis, neonatal sepsis, or neonatal death), effect of progesterone treatment was statistically significant (RR 0.5, 95% CI 0.3 to 0.9) in this sub-population of 52 twin pregnancies. Romero et al. [20] found no evidence of different benefit of vaginal progesterone treatment in twin pregnancies than in singleton pregnancies. These findings, however, should be confirmed in randomised-controlled trials aimed at investigating the effect of progesterone treatment in women with twin pregnancies and a short cervix. Information on the effect of progesterone treatment in women with twin pregnancies and a history of previous preterm delivery is limited. A large collaboration between all published and ongoing randomised-controlled trials, including twin pregnant women, has been initiated by Mol and Schuit [43]. This large individual patient data meta-analysis will include data from 13 studies randomising a total of more than 3500 women with twin pregnancies. This meta-analysis will be able to perform subgroup analyses of high-risk twin pregnant women and compare effect of vaginal progesterone treatment with 17-OHPC treatment. This latter comparison will be important, as a recent meta-analysis of perinatal outcome in women treated with progesterone for prevention of preterm delivery suggested that progesterone treatment may have adverse effects in multiple pregnancies [44]. Risk ratio for perinatal death was 1.6 (95% CI 1.01 to 2.4), risk ratio for respiratory distress syndrome was 1.2 (95% CI 1.04 to 1.4), and risk ratio for composite adverse outcome was 1.2 (95% CI 1.03 to 1.4), but too few studies were included to allow sufficient subgroup analyses comparing vaginal and systemic treatment. A safety signal has been suggested for 17-OHCP [45], but not for micronised progesterone, in part because a triplet study comparing 17-OHPC with placebo treatment showed significantly increased risk of midtrimester fetal loss (13 losses in women treated with 17-OHPC compared to none in the placebo group) (P < 0.02) [46]. Furthermore, Caritis et al. [47] found that women with higher plasma concentration of 17-OHPC delivered at earlier gestational ages. The previously mentioned results of the ORACLE children study [48] stress the importance of carrying out long-term follow up of infants after interventions aimed at prolonging gestational age at delivery. Pathological processes associated with increased risk of preterm delivery, such as infection, may affect infant outcome, and may potentially even increase risk of neonatal complications in relation to pregnancy prolonging treatments [48]. By 2013, information on longer-term follow up of infants born to mothers treated with progesterone is available for twins until the age of 18 months for pregnancies treated with vaginal progesterone [38] and for singletons until the age of 48 months for pregnancies treated with 17-OHPC [49]. These two studies have not shown signs of harmful longerterm effects of micronised progesterone or 17-OHPC, but further long-term follow-up studies are needed. Potential maternal adverse effects of progesterone treatment constitute a possible increased risk of gestational diabetes [50] corresponding to a known suggested diabetogenic effect of progesterone [51]. The association between progesterone treatment and gestational diabetes has not been confirmed in subsequent publications [52,53]. Recently, Serra et al. [40] found a non-significant dose-dependent
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trend towards higher incidence of intrahepatic cholestasis. This is in accordance with a previously reported increased risk of intrahepatic cholestasis in association with oral progesterone treatment during second- and third-trimester pregnancy [54–56]. Cerclage Cervical cerclage to reinforce the cervix by placing a cervical stitch was described in the 1950s by Shirodkar [57] and McDonald [58]. Indications for both types of cerclage have been obstetrical history, physical examination, ultrasound findings, or a combination of the above. In high-risk singleton gestations, cerclage reduces the rate of preterm delivery before 35 weeks as well as composite perinatal mortality and morbidity [59]. A meta-analysis of five randomised trials that included a total of 504 women with singleton gestations, previous preterm delivery, and cervical length less than 25 mm before 24 weeks showed that, having a McDonald or Shirodkar cerclage reduced the rate of preterm delivery before 35 weeks (RR 0.7, 95% CI 0.6 to 0.9) as well as composite perinatal mortality and morbidity (RR 0.6, 95% CI 0.5 to 0.9) [59]. The effect of cerclage and progesterone in high-risk singleton pregnancies has not been directly compared in a randomized trial, but, in an indirect meta-analysis, the results of the above-mentioned meta-analysis were compared with four randomised studies evaluating the effect of progesterone with placebo [60]. Vaginal progesterone and cerclage were equally efficacious in the prevention of preterm delivery in women with singleton gestations, previous preterm delivery and a short cervix in the second trimester. Three randomised trials have also included twin gestations [61–63]. Rust et al. [63] included 14 twin pregnancies among the 113 patients in a study from the USA, with seven allocated to the study group having a McDonald cerclage and seven in the control group having no cerclage. Multiple gestation correlated with decreased gestational age at delivery, but not with increased neonatal morbidity [63]. In a Dutch study [61], 35 women were also randomised to a McDonald cerclage or no surgical treatment. In this smaller trial, cerclage reduced the rate of preterm delivery before 34 weeks as well as compound perinatal morbidity. Unfortunately, no details are given on multiple gestations, but they constituted a limited part of the study population [59,61]. In the last trial, 61 women were randomly assigned to McDonald cerclage or bed rest [62]. This trial included four twin gestations, three assigned to the cerclage group and one assigned to the control group. All three twin gestations in the cerclage group had early preterm births at 20, 21 and 22 weeks of gestation, respectively, whereas the twin gestation randomised to the control group delivered at 34 weeks’ gestation [62]. Thus, although the data from randomised trials are sparse, data from these three trials have subsequently been reviewed in a meta-analysis, including a total of 49 twin pregnancies [64]. The rate of preterm delivery before 35 weeks was 75.0% (18 out of 24) in the cerclage group compared with 36.0% (9 out of 25) in the control group, giving a relative risk of 2.2 (95% CI 1.2 to 4.0), whereas the perinatal mortality rate was 22.9% in the cerclage group compared with 6.0% in the control group, resulting in a non-significant relative risk of 2.7 (95% CI 0.8 to 8.5). Although the effect of cerclage in twin pregnancies has not been properly assessed in adequately sized randomised trials, it must be concluded that cervical cerclage in twin pregnancies actually seems to increase the rate of preterm delivery. It cannot be excluded that twin gestations with shortened cervical length may benefit from insertion of an emergency cerclage, as suggested by a small retrospective analysis of 14 cases [65]. Several pathophysiologic processes may lead to cervical shortening, and it is unclear why insertion of cerclage seems to improve perinatal outcome in high-risk singleton pregnancies, whereas the opposite is true in twin pregnancies. Increased uterine activity, subclinical infection, or placental abruption, may be more common in twin pregnancy, and may be exacerbated by the presence of a foreign body in the cervical stroma [63]. Arabin pessary Cervical pessaries have also been used for many years to prevent preterm birth. Their mechanism of action is to tightly seal the cervical canal to prevent an ascending infection through the mucus plug,
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and, perhaps more importantly, to support the cervix by changing the angle of the cervical canal [66]. That a mechanical effect may be provided by a cervical pessary was supported by the results of an magnetic resonance imaging observational study of 73 women at high-risk of preterm delivery [67]. The median utero-cervical angle immediately after pessary placement was significantly smaller compared with the value before placement in the subgroup who delivered at 34 weeks or more. In the eight women who delivered before 34 weeks, no change was observed in median utero-cervical angle before and after pessary placement. The effect of a cervical pessary has unfortunately not yet been well investigated in randomised trials. In singleton pregnancies, only one randomised trial has been properly designed and recruited the planned sample size [68]. Insertion of a silicone device as cervical pessary in 385 singleton pregnancies with a cervical length of 25 mm or less at 18–22 weeks of gestation was shown to decrease the rate of preterm birth before 34 weeks of gestation from 27% to 6% [69], as well as the rate of preterm birth before 32 and 28 weeks. The rate of neonatal paediatric care was also reduced in the pessary group (RR 0.2; 95% CI 0.1 to 0.4). The suggested mechanism of action of the cervical pessary could also be effective in multiple gestations. Two small pilot studies have so far been reported. In the first study, 23 women with a cervical length less than 25 mm before 24 weeks were matched with 23 women treated expectantly [70]. In the pessary group, gestational age at delivery was significantly higher than in the control group (35weeks þ 6 days compared with 33weeks þ 2 days). The second study assessed the effect of a cervical pessary in eight women with monochorionic twins and cervical length less than 25 mm at the time of laser therapy for twin-to-twin transfusion syndrome compared with a historic control group [71]. The median gestational at delivery was 32 weeks in the pessary group compared with 28 weeks in the controls. These two small studies thus suggest that the cervical pessary may play a role in prolonging pregnancy in twin pregnancies with a short cervix, but conclude that the effect should be assessed in randomised trials. Several randomised trials in multiple pregnancies are registered with www.clinicaltrials.gov, and one protocol from the Netherlands has been published [72]. Preliminary data from this trial, which recruited 813 women with multiple pregnancies from 40 hospitals in the Netherlands, showed no difference in the primary outcome, composite bad neonatal condition (i.e. perinatal death or severe morbidity), between study and control group [73]. Forty-two (11%) women in the pessary group and 42 (11%) in the control group who had at least one child with a composite adverse neonatal outcome (RR 1.0; 95% CI 0.7 to 1.5). The rate of adverse neonatal outcome was, however, lower in the prespecified subgroup of women who had a short cervical length, below 25th percentile at 16–20 weeks of gestation. No difference was observed in rate of preterm delivery before 32 weeks (9% v 12%, RR 1.0; 9% CI 0.7 to 1.5), nor before 37 weeks of gestation (54% v 57%, RR 0.9; 95% CI 0.8 to 1.0). These data have so far only been reported as an abstract. It will be interesting to see the results of other randomised trials in multiple pregnancies, and especially in women with a short cervical length. It seems that several of the described methods of treatment may be more effective in women with a short cervix. The information provided by a quantitative assessment of the cervical length may be supplemented by information arising from new examination methods such as cervical elastography [69,70]. This non-invasive method evaluates cervical remodelling during pregnancy by estimating hydration status, tissue softness, stiffness, actual collagen arrangement, or both [69]. Because of its qualitative nature, elastography assessment is difficult to standardise, and it is hoped that it may help triage women for different treatments, by more accurately and more qualitatively describing the cervix before and during treatment [74,75]. Conclusion Several treatment modalities have attempted to prevent preterm delivery in twin pregnancies. The effect of progesterone has been investigated in several randomised trials in twin pregnancies, and progesterone does not reduce the rate of preterm delivery in unselected twin cohorts. Vaginal natural progesterone treatment, but not synthetic 17-a-hydroxyprogesterone caproate, may prevent preterm delivery and decrease risk of composite neonatal morbidity and mortality in women with a twin pregnancy and a short cervix. A randomised-controlled trial designed to examine the effect in women
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with a twin pregnancy and a short cervix is required before progesterone treatment can be recommended to this group of high-risk pregnancies. Longer-term follow up until the age of 18 months does not suggest a harmful effect of progesterone treatment in twin pregnancies but further longer-term follow-up studies are needed. Data for cerclage are sparse, and stem from randomised trials including both singleton and twin pregnancies. Cerclage seems to increase the rate of preterm delivery and of neonatal mortality, and should not be used in the prevention of preterm delivery in twin pregnancy. Insertion of a cervical pessary, which supports the cervix and changes the angle of the cervical canal, is being evaluated in several randomised trials. Preliminary results indicate no effect of this treatment either in unselected twin populations.
Practice points Cervical length measurement at 20–23 weeks of gestation identifies twin pregnancies at high risk of preterm delivery. Progesterone does not reduce the rate of preterm delivery in twins in general. Progesterone may reduce the rate of preterm delivery in twin pregnancies with a short cervix. Cerclage does not reduce the rate of preterm delivery in twin pregnancy. A cervical pessary such as the Arabin pessary has not been properly evaluated in twin pregnancies, but randomised clinical trials are being conducted.
Research agenda A randomised-controlled trial of vaginal progesterone in twin pregnancies with a short cervix. The value of cervical pessary to prevent preterm delivery in twin pregnancies with a short cervix. Investigation into the structural changes in the cervix using elastography, to elucidate the mechanism of effect of cervical vaginal pessary.
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