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.
Highlights
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Progesterone does not reduce the rate of preterm delivery in unselected twin cohorts.
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Progesterone may prevent preterm delivery in women with twin pregnancy and short cervix.
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Cerclage should not be used in the prevention of preterm delivery in twin pregnancy.
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.
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 . 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 . 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 .
A frequent cause of preterm delivery is intrauterine infections, which may in part be caused by bacterial stimulation of the biosynthesis of prostaglandins . It has been shown that the lower the gestational age at delivery, the higher the rate of intrauterine infection . 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 . 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 . 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 . 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 . 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 . 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 sub-optimally owing to either ovulation induction or oocyte retrieval . 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 . 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 .
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 suggested that progesterone supplementation could 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 . 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 , a history of previous preterm delivery, or both . 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 . 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 .
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 . Progesterone also suppresses gene transcription for calcium channels and oxytocin receptors . 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 . In-vitro studies suggest that lymphocytes exposed to progesterone during pregnancy produce progesterone-induced blocking factor, which is capable of blocking lymphocyte function. Furthermore, Norwitz et al. found that medroxyprogesterone acetate, a synthetic variant of the human hormone, inhibited the plasminogen activator system in decidual cells. Progesterone may also have pregnancy-prolonging actions by inhibiting decidual activation, which is believed to be necessary for spontaneous onset of labour. Luo et al. 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 . 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) . 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 ) .
| Author, year | Progesterone treatment | Gestational age | Active treatment, N | Placebo treatment, N | Population characteristics | Primary outcome |
|---|---|---|---|---|---|---|
| Fonseca et al., 2007 | Vaginal natural progesterone, 200 mg/day | 24–34 weeks | 11 | 13 | Cervical length less than 25 mm and twin pregnancy. | Spontaneous delivery less than 34 weeks. |
| Rouse et al., 2007 | Intramuscular 17α-OHPC, 250 mg/week | 16–20 weeks to 35 weeks | 325 | 330 | Diamniotic twin pregnancy. | Delivery or fetal death less than 34 weeks. |
| Norman et al., 2009 | Vaginal natural progesterone, 90 mg/day | 24–34 weeks | 247 | 247 | Twin pregnancy. | Delivery or fetal death less than 35 weeks. |
| Briery et al., 2009 | Intramuscular 17α-OHPC, 250 mg/week | 20–30 weeks to 34 weeks | 16 | 14 | Twin pregnancy. | Delivery less than 35 weeks. |
| Combs et al., 2011 | Intramuscular 17α-OHPC, 250 mg/week | 16–24 weeks to 34 weeks | 160 | 78 | Dichorionic twin pregnancy. | Composite neonatal morbidity. |
| Cetingos et al., 2011 | Vaginal natural progesterone, 100 mg/day | 24–34 weeks | 39 | 28 | 150 high-risk pregnant women with follow up. | Delivery less than 37 weeks. |
| Rode et al., 2011 | Vaginal natural progesterone, 200 mg/day | 20–24 to 34 weeks | 334 | 341 | Diamniotic twin pregnancies. | Delivery less than 34 weeks. |
| Lim et al., 2011 | Intramuscular 17α-OHPC, 250 mg/week | 16–20 weeks to 36 weeks | 327 | 326 | Multiple pregnancy, 653 twins. | Adverse neonatal outcome. |
| Aboulghar et al., 2012 | Vaginal natural progesterone, 2*200 mg/day | 18–24 to 37 weeks | 49 | 42 | Dichorionic pregnancies conceived by in-vitro fertilisation and intracytoplasmic sperm injection. | Delivery less than 34 weeks. |
| Serra et al., 2012 | Vaginal natural progesterone, 200 or 400 mg/day | 20–34 weeks | 97 (200 mg) 97 (400 mg) | 96 | Dichorionic twin pregnancies. | Delivery less than 37 weeks. |
| Wood et al., 2012 | Vaginal natural progesterone, 90 mg/day | 16–20 to 35 weeks | 42 | 42 | Twin and triplet pregnancies. | Gestational age at delivery. |
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) , whereas others have used the intramuscularly administered 17-OHPC (200–250 mg/day) . 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 , and another only pregnancies conceived by in-vitro fertilisation and intracytoplasmic sperm injection . 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 , and found no advantages of 400 mg over 200 mg. Similarly, randomised-controlled trials including singleton pregnancies have not indicated increased effect of 200 mg vaginal progesterone over 90–100 mg vaginal progesterone . It is noteworthy that Senat et al. 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 = 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 mid-gestation. Some of the randomised-controlled trials including twin pregnancies have measured cervical length before treatment with progesterone or placebo was initiated , but to date information has only been published for a total of 52 women with twin pregnancies and a short cervix. Romero et al. 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. 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 . 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 . 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 , 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) . Furthermore, Caritis et al. found that women with higher plasma concentration of 17-OHPC delivered at earlier gestational ages.
The previously mentioned results of the ORACLE children study 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 . 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 and for singletons until the age of 48 months for pregnancies treated with 17-OHPC . These two studies have not shown signs of harmful longer-term 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 corresponding to a known suggested diabetogenic effect of progesterone . The association between progesterone treatment and gestational diabetes has not been confirmed in subsequent publications . Recently, Serra et al. found a non-significant dose-dependent 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 .
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 sub-optimally owing to either ovulation induction or oocyte retrieval . 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 . 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 .
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 suggested that progesterone supplementation could 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 . 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 , a history of previous preterm delivery, or both . 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 . 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 .
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 . Progesterone also suppresses gene transcription for calcium channels and oxytocin receptors . 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 . In-vitro studies suggest that lymphocytes exposed to progesterone during pregnancy produce progesterone-induced blocking factor, which is capable of blocking lymphocyte function. Furthermore, Norwitz et al. found that medroxyprogesterone acetate, a synthetic variant of the human hormone, inhibited the plasminogen activator system in decidual cells. Progesterone may also have pregnancy-prolonging actions by inhibiting decidual activation, which is believed to be necessary for spontaneous onset of labour. Luo et al. 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 . 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) . 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 ) .
