Prediction and Prevention of Preterm Birth: What have we learned since 2001?

Prediction and Prevention of Preterm Birth
Preterm birth is the leading cause of neonatal mortality in the United States, and preterm labor precedes approxi-mately 50% of preterm births (1,2). Neonatal intensive care has improved the survival rate for neonates at the cusp of viability, but it also has increased the proportion of survivors with disabilities (3). The incidence of multiple births also has increased along with the associated risk of preterm delivery (4). The purpose of this document is to describe the various methods proposed for identifying and treating asymptomatic women at increased risk of preterm birth and the evidence for their roles in clinical practice.
Used with permission. Copyright the American College of Obstetricians and Gynecologists.

The very good news about preterm deliveries in the United States is that for the fifth year in a row, the preterm birth (PTB) rate has fallen.¹ In 2011 prematurity complicated 11.7% of all US births, down from the peak of 12.8% in 2006. The largest drop has been in the late preterm (34 to 36 weeks) group, which has fallen from 9.15% in 2006 to 8.28% in 2011. Although these trends are going in the right direction, it is clear that work still needs to be done to better understand both predictors and prevention of PTB. So what is new in the October 2012 Practice Bulletin: Prediction and
Prevention of Preterm Birth?² To be succinct: progesterone is back, cervical length is hot, and cerclage is
still unclear.

Clinical predictors of PTB in 2012 are similar to those mentioned in the 2001 practice bulletin: prior PTB, smoking, vaginal bleeding during index pregnancy, and short cervix.^2,3 However, in the intervening 11 years, the efficacy of potential interventions aimed at these risk factors has been refined. Screening for salivary estriol, fetal fibronectin, and bacterial vaginosis (BV) and use of home uterine activity monitoring were questioned in 2001. In the current practice bulletin, estriol is not even mentioned and we now know that there is no utility in home uterine monitoring, BV, or fetal fibronectin screening for PTB in low-risk women.^4-6 Prior PTB continues to remain one of the strongest risk factors for subsequent PTB.⁷ Although we have known for years that a short cervix is associated with PTB, very important new data have refined this association and identified a treatment strategy to reduce PTB in these women.^8,9

The only screening tools that identify women who are at risk of spontaneous PTB and for whom we have an intervention that reduces that risk are obtaining a history of previous spontaneous PTB and second-trimester cervical length screening. If a patient’s prior delivery was a spontaneous PTB (delivery initiated by spontaneous rupture of membranes or preterm labor) and her current pregnancy is singleton, then she should be offered progesterone supplementation from 16 to 24 weeks until 34 to 37 weeks’ gestation.^10-12 Administering progesterone has been shown to be effective in reducing PTB in such women. This intervention has been given a level A recommendation by the American College of Obstetricians and Gynecologists (ACOG)² which, in my opinion, means it should be recommended to appropriate women.

Screening for cervical length

Now we come to the short cervix. There are at least 2 randomized trials of women with singleton pregnancies with a demonstrated short cervix in the second trimester who, when randomized to vaginal progesterone supplementation, had a significantly lower risk of PTB.^8,13 One trial used a cervical length <15 mm at 20 to
25 weeks, and the other trial used a cervical length of
10 mm to 20 mm at 19 to 23 weeks. These findings are compelling but several details should be noted. Both studies screened more than 24,000 women and identified only a small percentage (approximately 2%) who met the criteria for a short cervix. Cervical length measurements were all performed with transvaginal ultrasound in the second trimester. Measuring cervical lengths after
25 weeks has not been shown to be useful.

So the obvious next question is: Should second-trimester cervical length screening become universal? Two decision and economic analyses have concluded that cervical length screening and subsequent treatment with progesterone in appropriate women are cost-effective.^14,15

ACOG recommended treating women with progesterone who had an “incidentally” identified short cervix in the second trimester and gave this a level A recommendation.² However, they did not mandate universal cervical length screening but
said it can be considered and gave that statement a level B recommendation.

Placement of cerclage

Now what about cerclage? Does it have any role now that we are more commonly measuring cervical length? In women with no prior PTB but a current short cervix, cerclage placement did not significantly reduce PTB.^16,17 In women with a prior PTB and a short cervix, the utility of cerclage is complex. In such women with a cervical length <25 mm there was no benefit of cerclage placement in reducing PTB <35 weeks.¹⁸ However, there was a significant reduction in births <24 weeks. If the cervix was <15 mm, cerclage placement demonstrated a significant decrease in PTB <35 weeks.¹⁸

Based on these data and several other studies, ACOG suggests that cerclage use is associated with reduction in PTB in women with prior PTB and short cervix.² However, this becomes confusing because there are not yet data indicating that cerclage adds additional benefit to progesterone treatment in these women (ie, those with a prior PTB and a short cervix). ACOG offers a diagram to direct management of the woman with a prior PTB and a short cervix that recommends giving progesterone and considering a cerclage. However, one of their recommendations also states: “Insufficient evidence exists to assess if progesterone and cerclage together have an additive effect in reducing the risk of preterm birth in women at high risk for preterm birth.”

Finally, neither progesterone supplementation nor cerclage use has been shown to be efficacious in multiple gestations.¹⁹ In fact, cerclage may worsen outcome and increase PTB in multiple gestations.¹⁶

Summary

Inaccurate measurement of cervical length or measurement at the wrong gestational ages has the potential to result in many false-positive results, which will lead to mistreatment and overtreatment of women. We do not want to have another clinical scenario similar to the rollout of fetal heart rate monitoring in which our testing has resulted only in increased maternal morbidity (ie, increased cesarean delivery) without a demonstrated improvement in neonatal outcome. Hence,
pay good heed to the technique and timing of cervical length measurement.

Moving ahead, to prevent PTB, we should:

1. Give progesterone to women with a singleton gestation and a history of spontaneous PTB;

2. Give vaginal progesterone to women with a singleton gestation and current short cervix in the second trimester;

3. Consider offering cerclage to women with a singleton gestation and a history of a prior spontaneous PTB and a current short cervix, particularly if the length is <15 mm;

4. Perhaps screen all women for short cervix in the second trimester; and

5. Avoid the use of cerclage or progesterone in women with multiple gestations.OBG

Commentary REFERENCES

1.   Hamilton BE, Martin JA, Ventura SJ. Births: Preliminary Data for 2011. Natl Vital Stat Rep. 2012;61(5):1-20.

2.   Committee on Practice Bulletins-Obstetrics. American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012;120(4):964-973.

3.   American College of Obstetricians and Gynecologists. ACOG practice bulletin. Assessment of risk factors for preterm birth. Clinical practice guidelines for obstetrician-gynecologists. Number 31, October 2001. Obstet Gynecol. 2001;98(4):709-716.

4.   Andrews WW, Sibai BM, Thom EA, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol. 2003;101(5 pt 1):847-855.

5.   Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health & Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 2000;342(8):534-540.

6.   Dyson DC, Danbe KH, Bamber JA, et al. Monitoring women at high risk for preterm labor. N Engl J Med. 1998;338(1):15-19.

7.   Spong CY. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol. 2007;110(2 pt 2):405-415.

8.   Hassan SS, Romero R, Vidyadhari D, et al; PREGNANT Trial. 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.

9.   Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med. 1996;334(9):567-572.

10. Society for Maternal Fetal Medicine Publications Committee. ACOG Committee Opinion number 419 October 2008 (replaces no. 291, November 2003). Use of progesterone to reduce preterm birth. Obstet Gynecol. 2008;112(4):963-965.

11. Meis PJ, Klebanoff M, Thom E, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-2385. Erratum in: N Engl J Med. 2003;349(13):1299.

12. Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol. 2009;200(3):219-224.

13. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357(5):462-469.

14. Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis. Am J Obstet Gynecol. 2010;202(6):548.e1-548.e8.

15. Werner EF, Han CS, Pettker CM, et al. Universal cervical-length screening to prevent preterm birth: a cost-effectiveness analysis. Ultrasound Obstet Gynecol. 2011;38(1):32-37.

16. Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol. 2005;106(1):181-189.

17. To MS, Alfirevic Z, Heath VC, Cicero S, et al; Fetal Medicine Foundation Second Trimester Screening Group. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet. 2004; 363(9424):1849-1853.

18. 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.

19. Durnwald CP, Momirova V, Rouse DJ, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Second trimester cervical length and risk of preterm birth in women with twin gestations treated with 17-alpha hydroxyprogesterone caproate. J Matern Fetal Neonatal Med. 2010;23(12):1360-1364.

ACOG ABSTRACT REFERENCES

1.  Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Osterman MJ. Births: final data for 2008. Natl Vital Stat Rep. 2010;59(1):1-71. (Level II-3)

2.  Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84. (Level III)

3.  Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med. 2000;343(6):378-384. (Level II-2)

4.  Centers for Disease Control and Prevention (CDC). Preterm singleton births-United States, 1989-1996. MMWR Morb Mortal Wkly Rep. 1999;48(9):185-189. (Level II-3)