Preterm birth is the leading cause of neonatal death and resulting handicap in survivors. Multiple conditions and mechanisms result in preterm birth to include infection or inflammation, uterine distension, physical or psychological stress, uterine bleeding, short or incompetent cervix, and genetics. Given the multitude of causes for preterm birth, it is not surprising there are many treatments to prevent preterm birth such as intramuscular progesterone, vaginal progesterone, cervical cerclage, and pessary. Determining the best treatment for a given patient can be confusing. The purpose of this manuscript is to clarify which treatment option is best suited for a given patient at risk for preterm delivery.

Since 2006, the U.S. early preterm birth (defined as birth prior to 34 weeks gestational age) rate has declined from 3.66% to 3.40%, and the late preterm birth (defined as birth between 34 and 36 weeks gestational age) rate has declined from 9.15% to 7.99%. Significant racial disparities exist in preterm birth rates with non-hispanic blacks having the highest rates and non-hispanic whites the lowest.¹ Most of the change in the preterm birth rate over the last two decades has been among infants born late preterm, which comprise the bulk of all preterm births (70.4 percent in 2012).²

Multiple conditions and mechanisms result in preterm birth to include infection or inflammation, uterine distension, physical or psychological stress, uterine bleeding, short or incompetent cervix, and genetics with the strongest risk factor being previous preterm birth.³ Preterm birth can be reduced by preventing elective delivery preterm delivery; prescribing effective contraception to allow conditions associated with preterm birth such as short inter-delivery interval, tobacco use, illicit drug use, low pre-pregnancy weight, and poor nutritional status to be corrected prior to conception; and reducing the rate of multiple gestations. Given the multitude of causes for preterm birth, it is not surprising there are many treatments to prevent preterm birth such as intramuscular progesterone, vaginal progesterone, cervical cerclage, and pessary. Determining the best treatment for a given patient can be confusing. The purpose of this manuscript is to clarify which treatment option is best suited for a given patient at risk for preterm delivery.

Progesterone
The exact manner by which progesterone prevents preterm birth is not known, but there are multiple proposed mechanisms with the evidence favoring two:

1. Progesterone has an anti-inflammatory effect that counteracts the inflammatory process leading to preterm birth and
2. Providing a local increase in progesterone in gestational tissues counteracts the functional decrease in progesterone leading to preterm birth.⁴

Intramuscular (IM) injections of 17-alpha-hydroxyprogesterone caproate (17P) have been evaluated in several trials (Table 1). While weekly IM injections of 17P has been shown to decrease the risk of recurrent preterm birth,⁵ it has been shown not to be beneficial in the setting of short cervix, twin gestation, or following preterm labor successfully arrested with tocolysis.^6-9

Given its ease of administration as compared to intramuscular progesterone, the use of vaginal progesterone in patients at risk for preterm birth may be preferred. While vaginal progesterone gel 90mg qam did not decrease risk of recurrent preterm birth in women with a prior spontaneous preterm birth,¹⁰ use of progesterone gel in singleton gestations with no history of preterm birth but with sonographically short cervix (10-20mm at 19 to 23-6/7 weeks) was found to reduce the incidence of preterm birth prior to 28, 33, and 35 weeks.¹¹ Similarly, treatment of patients carrying a singleton gestation found to have cervical length <15mm at 20-25 weeks with micronized vaginal progesterone 200mg qhs resulted in a 44% decrease in preterm birth prior to 34 weeks.¹² The use of vaginal progesterone of different formulations to include 90mg gel,¹³ 200mg pessary¹⁴ and 100mg suppository¹⁵ to reduce the risk of preterm birth in twin gestations has been evaluated without success.

Cerclage
Cervical cerclage is used to provide extrinsic support to compensate for inherent cervical weakness as seen with cervical incompetence. Cerclage has been shown to reduce the incidence of recurrent preterm birth in women with a current singleton gestation and history of preterm birth when the cervix was found to be <15-25mm prior to 23-24 weeks.^16,17 Consequently, most experts use cervical length of 15-25mm as their threshold for cerclage placement in a patient with a prior spontaneous preterm birth.^15,18 Cerclage placement in women without a history of prior spontaneous preterm birth and short cervix has not been associated with a reduction in preterm birth¹⁸ and use of cerclage in twin gestation with cervical length <25mm has been associated with a twofold increase in preterm birth.¹⁹

Indications for cerclage in women with singleton gestations are:

1. History indicated
2. Physical examination indicated and
3. Ultrasound finding of short cervix with a history of prior preterm birth.¹⁸

A history indicated (prophylactic) cerclage is placed in a patient with a history of one or more unexplained 2nd trimester loss related to painless cervical dilation in the absence of labor or abruption or a history of prior cerclage due to painless cervical dilation. Prophylactic cerclages are typically placed at 13-14 weeks gestation. Physical examination indicated (rescue or emergency) cerclage is placed in patients with advanced cervical dilation in the absence of labor or abruption. There is limited data from one small trial²⁰ which suggests benefit from rescue cerclage. Ultrasound indicated cerclage is placed in a patient with a prior history of spontaneous preterm birth with unclear history who is followed in a subsequent singleton pregnancy with serial sonographic evaluation of cervical length from 16-24 weeks gestation and found to have shortening less than 25mm before 24 weeks gestation. Cerclage placement should be limited to the 2nd trimester before viability and evidence is lacking for benefit of cerclage solely for prior surgery on cervix or Mullerian anomaly. Cerclage removal is recommended at 36 to 37 weeks but should be removed sooner for cervical change, painful uterine contractions, or vaginal bleeding associated with preterm labor.¹⁸

Pessary
While no benefit to reducing preterm birth in twins have been found with the use of 17P, vaginal progesterone, or cerclage, recent studies have shown benefit of the vaginal pessary in reducing preterm birth in both singleton and twin gestations with cervical shortening.²¹ Pessaries have been used for centuries for the non-surgical management of uterine or vaginal vault prolapse. Pessaries designed for the treatment of prolapse were the first pessaries used for the purpose of preventing preterm birth. More recently, however, pessaries designed specifically for this purpose have been designed.^22,23 There are several hypotheses as to how pessaries may prevent preterm birth. Ultrasound and MRI examinations have suggested that the pessary changes the angle of the cervix relative to the uterus to a more acute angle which might prevent direct pressure on the membranes at the level of internal os.^24-26 In addition, the pessary night prevent further dilation of the internal OS (Figure 1 & 2).

Figure 1 Transvaginal ultrasound showing cervical funneling in twin gestation at 22 weeks.

Figure 2 Transvaginal ultrasound showing improvement at 28 weeks with pessary (P) in place.

A large multicenter study recently found that use of a cervical pessary in nulliparous and multiparous patients (with and without a history of preterm birth) who were found to have a cervical length of less than 25mm at 20-23 weeks gestation reduced the risk of spontaneous preterm birth less than 28 weeks, 34 weeks, and 37 weeks. Another multicenter randomized trial was performed to assess whether a cervical pessary could effectively prevent poor pregnancy outcomes in twin gestations.²¹ Subjects were randomized to cervical pessary placed between 16 and 20 weeks’ gestation or no pessary. In unselected women with multiple pregnancy, prophylactic use of the cervical pessary did not reduce poor perinatal outcome. However, in a sub analysis the authors found benefit to pessary use in multiple gestations with CL <25th percentile (38mm) in regards to decrease in composite neonatal morbidity and decreased preterm delivery rate <32 weeks, but not before 37 weeks. Although promising, because this potential benefit was found in a secondary analysis of an otherwise negative study and after the criterion for a short cervix was revised, use of the pessary to reduce preterm birth in women with twins has not yet been widely adapted as the standard of care. There are more than 10 ongoing studies in various countries-including the Unites States - comparing pessary with other methods to prevent preterm birth such as progesterone and cerclage in both singleton and twin pregnancies.

(Could do with a conclusions section, and perhaps a table of recommendations for when to use each Rx listed. Would also include something about importance of remembering to give steroids for standard indications, but not simply for risk of PTB.)

While 17P, vaginal progesterone, cerclage, and pessaries have all been shown to reduce the risk of preterm birth there are specific clinical situations for the use of each (Table 2). Data on pessary use for the prevention of preterm birth is limited but promising. If validated in the current on-going studies, cervical pessary placement may have additional benefit for prevention of preterm birth in women with a short cervix carrying twins and singletons.

1. Brady E Hamilton, Joyce A Martin, Michelle JK Osterman, et al. Births: preliminary data for 2013. National Vital Statistics Report. 2014;63(2):1–20.
2. Joyce A Martin, Brady E Hamilton, Michelle JK Osterman, et al. Births: final data for 2012. National Vital Statistics Report. 2013;62(9):1–68.
3. Spong CY. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol. 2007;110(2 Pt 1):405–415.
4. Berghella V, Blackwell S, Anderson B, et al. Progesterone and preterm birth prevention. Am J Obstet Gynecol. 2012;206(5):376–386.
5. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379–2385.
6. Grobman WA, Thom EA, Spong CY, et al. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol. 2012;207(5):390.e1–390.e8.
7. Rouse DJ, Caritis SN, Peaceman AM, et al. A trial of 17 alpha-hydroxyprogesterone caproate to prevent premaurity in twins. N Engl J Med. 2007;357(5):454–461.
8. 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(3):221.e1–221.e8.
9. Rozenberg P, Chauveaud A, Deruelle P, et al. Prevention of preterm delivery after successful tocolysis in preterm labor with 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Am J Obstet Gynecol. 2012;206(3):206.e1–206.e9.
10. O'Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007;30(5):687–696.
11. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38(1):18–31.
12. Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357(5):462–469.
13. 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(3):272–280.
14. Iams JD. Latest research from the 2010 meeting of the Society for Maternal-Fetal Medicine. Am J Obstet Gynecol. 2010;202(3):207.
15. DeFranco EA, O'Brien JM, Adair CD, et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007;30(5):697–705.
16. Owen J, Hankins G, Iams JD, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol. 2009;201(4):375.e1–375.e8.
17. Berghella V, Rafael TJ, Szychowski JM, et al. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol. 2011;117(3):663–671.
18. American College of Obstetricians and Gynecologists. ACOG practice bulletin No.142: verclage for the management of cervical insufficiency. Obstet Gynecol. 2014;123(2 Pt 1):372–379.
19. 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(1):181–189.
20. 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(5):1106–1112.
21. Liem S, Schuit E, Hegeman M, et al. Pessaries for prevention of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, open-label randomised controlled trial. Lancet. 2013;382(9901):1341–1349.
22. 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(9828):1800–1806.
23. Arabin B, Alfirevic Z. Cervical pessaries for prevention of spontaneous preterm birth: past, present, future. Ultrasound Obstet Gynecol. 2013;42(4):390–399.
24. 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(2):122–133.
25. Goya M, Pratcorona L, Higueras T, et al. Sonographic cervical length measurement in pregnant women with a cervical pessary. Ultrasound Obstet Gynecol. 2011;38(2):205–209.
26. Cannie MM, Dobrescu O, Gucciardo L, et al. Arabin cervical pessary in women at high risk of preterm birth: a magnetic resonance imaging observational follow-up study. Ultrasound Obstet Gynecol. 2013;42(4):426–433.