Preventing Preterm Birth in Twins

Preventing Preterm Birth in Twins

Special Feature

By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

Synopsis:A recent review of the literature evaluating methods to decrease preterm birth in twins has shown little or no benefit of bed rest, cerclage, or 17 alpha-hydroxy progesterone, but there is some promise for vaginal progesterone and pessaries in women with twin pregnancies and short cervices.

Through the years, the format for virtually all ob/gyn clinical Alert articles has involved a review of a recent article followed by a comment on the meaning and impact of the study's results. This month I am straying from this ritual because a review of the recent literature regarding the prevention of preterm birth (PTB) in twins, which appeared in the August issue of Obstetrics and Gynecology, provides extremely important information on the management of multiple gestation, now occurring in at least one of every 40 pregnancies in the United States.

Zork et al objectively summarize recent data in the literature addressing a variety of methods that have been used to prevent twins from delivering even earlier than their now average gestational age of 35 1/2 weeks.¹One method in particular is very intriguing and I will save that for last.

Bed Rest

The lack of benefit of bed rest in pregnancy, in general, was covered in a recent article,²but in twins, specifically, data from a Cochrane database showed no effect of bed rest in twins, in general, and in those patients with twins and short cervices, in particular.

Progesterone

Progesterone has the ability to quiet smooth muscle in vitro, but recently the rationale for its prevention of PTB has gravitated toward its anti-inflammatory effect. Nevertheless, in twins there are many other factors that could be put into play. For example, the overstretching of the uterus could lead to release of cytokines that may soften the cervix. In addition, the over-distention can trigger the production of prostaglandins, which can cause the uterus to contract. Thus far, attempts to prevent PTB have involved delivery of progesterone through either of two pathways, employed so far mostly in singletons.

17 Alpha-hydroxy Progesterone Caproate

The seminal study by Meiss et al³created a wave of enthusiasm over its ability to decrease the chances of early delivery in patients with a history of PTB. Recently, a few studies have specifically addressed its use in twins. A 661-patient, randomized, clinical trial (RCT) from the Maternal-Fetal Medicine network did not demonstrate benefit from 17 alpha-hydroxy progesterone caproate (17P) in preventing PTB in twins,⁴and a subanalysis of these data showed no benefit even in patients with short cervices (< 25th percentile).⁵Another study from the Obstetrix Collaborative Research Network involving 240 twin pregnancies showed no greater ability to prolong pregnancy with 17P.⁶Of some concern was the fact that a separate RCT very recently suggested that 17P actually seemed to increase the rate of PTB prior to 32 weeks in patients with twins whose cervices were < 2.5 cm.⁷

Vaginal Progesterone

Although no recent RCTs have shown the ability of daily vaginal progesterone to significantly drop the rate of PTB in twins, Romero, using a meta-analysis of twin pregnancies separated out from five RCTs, found a significant decrease in composite perinatal morbidity and mortality in those treated with vaginal progesterone, as well as a trend (albeit non-significant) toward a decrease in PTB before 33 weeks (30.4% vs 44.8%).8

Cerclage

In one study specifically addressing elective cerclage in twin pregnancies, 22 patients randomly chosen to have cerclage had no improvement in average gestational age compared with 23 controls.⁹Interestingly, in a much quoted meta-analysis, Berghella found that in singleton pregnancies with short cervices (< 2.5 cm) there was benefit from cerclage, but in twins the procedure actually doubled the risk of PTB (relative risk, 2.15; 95% confidence interval [CI], 1.15-4.01).10

Pessary

A few small studies emerged from Europe suggesting the benefit of pessaries in women with singletons and short cervices, but data in twins have been difficult to come by until a paper was recently presented at this year’s Society for Maternal-Fetal Medicine meeting in San Francisco.¹¹In this study, 813 twins were randomly assigned either to having a pessary or no treatment, and the overall outcomes were no different between groups. However, when they broke out patients with cervical lengths that were
< 3.8 cm in the second trimester, there was a halving of PTB birth prior to 32 weeks in the pessary group (odds ratio [OR], 0.43; 95% CI, 0.21-0.89).

Commentary

Most studies evaluating methods to prevent PTB in twins have yielded results that could be put in the "bummer" category. Bed rest, intramuscular progesterone, and vaginal progesterone do not seem to work in general, and cerclage may even make things worse. However, there is a hint that vaginal progesterone may help in those twin pregnancy patients with short cervices and there is even greater hope that pessaries could be of benefit in preventing PTB in these patients.

Prior to 2003, there has been only a sprinkling of case reports or small series where pessaries have been used to prevent PTB, mostly in singletons. Then Arabin published a pilot study in which none of the 12 patients with singletons and 23 patients with twins and short cervices delivered prior to 32 weeks when they were given pessaries (18-22 weeks).¹²

In an RCT, known as the PECEP study, involving 385 women with singletons and short cervices (< 2.5 cm), Goya et al reported a remarkable drop in PTB prior to 34 weeks (OR, 0.18; 95% CI, 0.08-0.37) and premature rupture of membranes (OR, 0.16; 95% CI, 0.03-0.58) in those with Arabin devices (a silicon cup-type pessary) compared with expectant management.¹³When another study with similar design but smaller numbers (n = 108) did not show benefit of these pessaries in a Chinese population,¹⁴some questions arose regarding the seemingly high rate of PTB in the PECEP control group.

It is unclear exactly how a pessary works, but the simplistic (and maybe correct) idea is that the axis of the lower uterine segment is changed so that the angle of the downward pressure vector is directed toward the posterior wall of the uterus, rather than at the cervix itself. In a clinical situation where there is strong pressure to do "something" rather than sitting on ones hands, the pessary, although construed as being somewhat intrusive, is far less invasive than a cerclage, and it can be removed and inserted by the patient with little trouble.

Nevertheless, solid proof of its efficacy will have to await the results of studies already in progress in the United States and Europe.

References

1. Zork N, et al. Decreasing prematurity in twin gestation. Obstet Gynecol 2013;122(2 PT 1):375-379.
2. Hobbins JC. Is prescribing bed rest unethical? OB/GYN Clinial Alert 2013;30:25-26.
3. Meis PJ, et al. Prevention of recurrent preterm delivery by 17 alpha hydroxy progesterone caproate. N Engl J Med 2003;348:2379-2385.
4. Rouse DJ, et al. A trial of 17-alpha hydroxy progesterone caproate to prevent prematurity in twins. N Engl J Med 2007;357:454-461.
5. Dunwald CP, et al. Second trimester cervical length and risk of preterm delivery in women with twins treated with 17-alpha hydroxy progesterone caproate. J Matern Fetal Neonatal Med 2010;23:1360-1364.
6. Combs CA, et al. 17-hydroxyprogesterone caproate for twin pregnancy: A double-blind, randomized clinical trial. Am J Obstet Gynecol 2011;204:221.e1-8.
7. Senat MV, et al. Prevention of preterm delivery by 17 alpha-hydroxyprogesterone caproate in asymptomatic twin pregnancies with a short cervix: A randomized controlled trial. Am J Obstet Gynecol 2013;208:194 e1-8.
8. Romero R, et al. Vaginal progesterone in women with an asymptomatic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: A systematic review and meta analysis of individual patient data. Am J Obstet Gynecol 2012;206:124 e1-19.
9. Dor J, et al. Elective cervical suture of twin pregnancies diagnosed ultrasonically in the first trimester following induced ovulation. Gynecol Obstet Invest 1982;13:55-60.
10. Berghella V, et al. Cerclage for short cervix on ultrasonography: Meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005;106:181-189.
11. Liem S, et al. Pessaries in multiple pregnancy as a prevention of preterm birth (ProTWIN): A randomized controlled trial. Am J Obstet Gynecol 2013;208(Suppl 1):S2.
12. Arabin B, et al. Is treatment with vaginal pessaries an option in patients with sonographically detected short cervix? J Perinat Med 2003;31:122-133.
13. Goya M, et al. Cervical pessary in pregnant women with a short cervix (PECEP): An open-label randomized control trial. Lancet 2012;379:1800-1806.
14. Hui SY, et al. Cerclage pessary for prevention of preterm birth in women with a short cervix at 20 to 24 weeks: A randomized controlled trial. Am J Perinatol 2012;30:283-288.