1. Catherine Y Spong, MD Chief, Pregnancy & Perinatology Branch National Institute of Child Health & Human Development National Institutes of Health Progesterone Supplementation and Prevention of Preterm Birth

2. Conflict of Interest Statement I have no conflict of interest related to the content of this presentation

3. Objectives to describe the problem of prematurity to describe the mechanism of progesterone action to define the patient population who meets the criteria for progesterone administration to prevent preterm birth

4. Preterm Delivery: A Public Health Priority 1 in 8 infants is born preterm 542,893 preterm births each year (2006) leading cause of hospitalization among pregnant women leading cause of death among African-American infants associated with developmental disabilities

5. Leading Causes of Neonatal Mortality, 2001 (N / 100,000 live births) 4,322 3,875 1,491 998 943 http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_09.pdfhttp://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_09.pdf Table H. Deaths and percentage of total deaths for the 10 leading causes of neonatal and postneonatal deaths: United States, 2001 Leading cause of black infant mortality Second leading cause of all infant mortality

6. Preterm Birth: Outcome  1 out of 5 children with mental retardation  1 out of 3 children with vision impairment  Almost half of children with cerebral palsy Accounts for

7. Preterm Birth: Long Term Outcome For the baby: Increased risk for cardiovascular disease (MI, stroke, hypertension) as an adult Increased risk for diabetes as an adult Possible increase in cancer risk For the mother: Increased risk for subsequent preterm delivery Age Adjusted Relative Risk Birthweight (lbs) Rich-Edwards 1997 Birth Weight and Coronary Heart Disease Lower BW=higher CHD risk

8. Progestins Steroid hormone Exogenous or synthetic forms of progesterone Produced by corpus luteum, adrenals, placenta Maintains pregnancy Exerts biologic effects on Immune response Myometrium Chorioamniotic membranes Cervix

9. Actions Delays cervical collagen degradation Myometrial: Decreases conduction of contractions Increases threshold for stimulation Decreases spontaneous activity Decreases number of oxytocin receptors Prevents formation of gap junctions

10. Progestin formulations 17  hydroxyprogesterone caproate Esterified derivative of 17  hydroxyprogesterone Substantial progestational activity, long duration of action Micronized progesterone in a gel Micronized progesterone suppositories

11. Trials of Progestogens Results of several small trials in the 1960’s and 1970’s suggested progesterone therapy may be effective in preventing preterm birth Not all trials showed positive results Meta-analyses produced conflicting results The most successful trials employed 17-  Hydroxyprogesterone Caproate, (17P)

12. Meta-analysis of 17P in pregnancy 5 trials: high risk women with 17P Pooled analysis of results showed: Reduction in rates of preterm birth Odds ratio 0.50, 95% CI: 0.30-0.85 Reduction in rates of low birthweight Odds ratio 0.46, 95% CI: 0.27-0.80 Keirse MJNC. Brit J Obstet Gynecol 1990;97:149

13. Prior preterm birth Preterm birth Multifetal gestation Short cervix Progestins & Prematurity Prevention

14. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study University of Sao Paulo Medical School, Brazil RCT double-blind, placebo controlled 1996-2001 Rx: daily Progesterone (100 mg) vs placebo as vaginal suppository from 24 – 34 wks Da Fonseca et al AJOG 2003;188:419-24

15. Methods 157 high risk singleton pregnancies, 15(9.5%) lost to follow-up; Prior sPTD (avg 33 wks) Prophylactic cervical cerclage Uterine malformation Analyzed remaining 142 70 placebo 72 progesterone Da Fonseca et al AJOG 2003;188:419-24

16. Characteristics Qualifying delivery (wks) 33.3 33.4 Maternal age (yrs) 27.6 26.8 Caucasian68% 71% Risk Factor Prior PTD90% 97% Uterine malformation5.6% 1.4% Incompetent cervix4.1% 1.4% ProgPlacebo Da Fonseca et al AJOG 2003;188:419-24

17. Rates of Preterm Birth P<0.03 P<0.002 NS Prog Placebo Da Fonseca et al AJOG 2003;188:419-24

18. Gestational age (wk) Progesterone Placebo P<0.004 UC/hr Uterine contraction frequency 1 hr monitoring/wk Da Fonseca et al AJOG 2003;188:419-24

19. NICHD: MFMU Progesterone Trial Aim: To establish if weekly progesterone injections in women with prior spontaneous preterm delivery (sPTD) reduces the risk of PTD Design: double-masked, placebo-controlled trial Eligibility criteria: singleton pregnancy 16-20 wks with documented previous sPTD Intervention: progesterone or placebo Meis et al, N Engl J Med 2003 1 o outcome: delivery <37 wks Sample: 463 pregnant women

20. 19 Centers enrolled women with : Documented history of spontaneous preterm birth at 20 0 to 36 6 weeks’ gestation in a previous pregnancy Gestational age at entry of 15-20 3 weeks confirmed by ultrasound Singleton gestation, with no major fetal anomalies Meis et al, N Engl J Med 2003

21. Characteristics Qualifying delivery (wks) 30.5 31.3 Maternal age (yrs) 26.0 26.5 Married51% 46% African American59% 58% Mean BMI26.9 25.9 Smoking22% 19% 17-PPlacebo

22. Progesterone: Rates of Preterm Birth P<0.0001P<0.016P<0.018 Meis et al, N Engl J Med 2003 17P P=0.010P=0.004 African American Non African American

23. Progesterone prevents neonatal complications 17 P Placebo Meis et al, N Engl J Med 2003

24. Compliance and Side Effects Compliance with the weekly injections was excellent 91.5% of the women received their injections at the scheduled time Side effects were minor and were similar in the 17P and placebo groups

25. Effectiveness of Progesterone 5-6 women with a previous sPTB would need to be treated to prevent one birth <37 wks 12 women with a previous sPTB birth would need to be treated to prevent one birth <32 wks Meis et al, N Engl J Med 2003 Low dose ASA to prevent CVA, NNT=102 B-blocker use in MI patients to prevent cardiac death NNT=42

26. Progesterone prevents recurrent preterm delivery Weekly injections of progesterone prevented recurrent preterm birth and improved the neonatal outcome for pregnancies at risk Effective in preventing very early as well as later preterm birth Effective in both African American and Non-African American women Meis et al, N Engl J Med 2003

27. Impact of progesterone to prevent recurrent preterm birth 10,000 preterm births could have been prevented in 2002 if all eligible pregnant women at high risk for PTD received 17P Resulting in reduction of preterm birth of ~2% Petrini et al, Obstet Gynecol 2005; 105(2)

28. Progesterone gel and PTD 659 women with prior sPTB GA 18-22.9 wks, randomized Progesterone vaginal gel or placebo 90mg natural progesterone (Replens) Primary outcome: PTB<32 wks O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96

29. Characteristics Maternal age (yrs) 27.1 27.3 African American25% 28% Mean BMI26.6 26.4 Smoking22% 19% >1 Prior PTD24% 26% CL at randomization3.7 3.7 ProgPlacebo O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96

30. Vaginal progesterone gel and PTD % O’Brien et al, Ultrasound Obstet Gynecol 2007;30:687-96

31. Summary: Progesterone & recurrent PTD progesterone suppository & 17  OHPC IM: Significant reductions in PTD Progesterone gel: no effect on PTD 17P PTD progesterone

32. Prior preterm birth Preterm birth Multifetal gestation Short cervix Progestins & Prematurity Prevention

33. STTARS Seventeen alpha-hydroxyprogesterone caproate in Twins and Triplets: A Randomized Study) Double-masked placebo-controlled trial to determine whether 17  hydroxyprogesterone prevents preterm birth in multifetal pregnancies. Intervention: 17-OHPC (250mg IM) or placebo weekly beginning at 16-20 weeks Primary outcome: Preterm delivery < 35 wks 661 women randomized Rouse et al, NEJM 2007; 357:454-61

34. Characteristics: Maternal age (yrs) 30 30 Caucasian 67% 65% Ob history Nulliparous 46% 43% Prior PTD 6% 9% BMI 26.7 27.1 ProgPlacebo Rouse et al, NEJM 2007; 357:454-61 Progesterone and Twins

35. Twins: Delivery or Fetal Death Prior to 37, 35, 32 or 28 weeks Rouse et al, NEJM 2007; 357:454-61 17-OHPC Placebo Similar findings for triplets

36. Delivery or Fetal Death Before 35 Weeks By Conception Method & Chorionicity Rouse et al, NEJM 2007; 357:454-61 Similar findings for triplets

37. STTARS Seventeen alpha-hydroxyprogesterone caproate in Twins and Triplets: A Randomized Study) 17P did not reduce the rate of PTB in women with twins This lack of benefit applied: - whether conception was spontaneous or after ART or - whether there was a di- or monochorionic placentation - regardless of gestational age cutoff 17-OHPC was well tolerated with side effects limited to the injection site The rate of PTB in the placebo group was similar to national norms (34.9 vs 35.2 weeks) Rouse et al, NEJM 2007; 357:454-61

38. Prior preterm birth Preterm birth Multifetal gestation Short cervix Progestins & Prematurity Prevention

39. Cervical length Normal cervical length Short cervix with funneling

40. Relative risk of sPTD <35 wks by % of cervical length at 24 wks Iams et al, NEJM 1996 Cervical length at 24 wks predicts PTB risk

41. Considerations Study population heterogeneity Other risk factors for PTB multiple gestation prior preterm birth Gestational age assessment of cervical length Cervical length varies across gestational age Cut-off selected depends on time of screening

42. EGA at study (wks) OutcomeDiscriminatory point Hibbard et al N = 760 16-22< 35 weeks30 mm (10 th %) Taipale et al N = 3694 18-22< 37 weeks31 mm (9 th %) Iams et al N=2915 24< 35 weeks25 mm (10 th %) Fonseca 20-25 <37 weeks <15mm (1.7%) N=24,620 Cervical length assessment

43. 46 women with ≤ 28 mm cervical length 19 progesterone (4 without PTB + 15 with PTB) 27 placebo (5 without PTB + 22 with PTB) % “…these conclusions must be considered tentative...(and) hypothesis generating… (and)… further investigation is necessary. Specifically randomized clinical trials designed to test the effect of progesterone in women with a short cervix…” DeFranco et al, Ultrasound Obstet Gynecol 2007;30:697-705 Progesterone and short cervix: DeFranco subanalysis of O’Brien trial: progesterone gel

44. Progesterone and short cervix: Fonseca trial: progesterone suppository Cervical length 20-25 wks (24,620 women) 413 CL <15mm (1.7%) RCT: 250 women with cervical length ≤ 15mm Progesterone 200 mg* PV daily vs. placebo Micronized progesterone (Utrogestan, Besins International Belgium) Initiation of treatment at 24 weeks Fonseca et al, NEJM 2007; 357:462-9 *twice the dose of the daFonseca trial AJOG 2003

45. Maternal age (yrs) 29 29 Caucasian 37% 39% Ob history Nulliparous 57% 55% Prior PTD 12% 18% Twin gestation 9% 10% ProgPlacebo Fonseca et al, NEJM 2007; 357:462-9 Progesterone and short cervix: Fonseca trial: progesterone suppository

46. ProgesteronePlaceboOR (95%CI) PTD < 34 weeks19%34%0.56 (0.36 – 0.86) Composite morbidity8%14%0.59 (0.26 – 1.25) Fonseca et al, NEJM 2007; 357:462-9 n=125 Progesterone reduced risk of PTD in women with short cervix No reduction in perinatal mortality or neonatal morbidity PTD<34 weeks Progesterone and short cervix: Fonseca trial: progesterone suppository

48. Very heterogeneous study group Includes women with prior PTD, multiple gestations Subgroup analysis of nulliparous women has OR that crosses unity Progesterone and short cervix: Fonseca trial: progesterone suppository

49. 19 to 23 6/67 weeks Singleton Cervix 10-20 mm Nullips and multips (with prior term and preterm birth) Outcome: PTB < 33 weeks N = 465 Hassan et al, 2011 Ultrasound Obstet Gynecol Progesterone and short cervix: Hassan trial: progesterone gel

50. * * *P <.05 PTB % Hassan et al, 2011 Ultrasound Obstet Gynecol Progesterone and short cervix: Hassan trial: progesterone gel

51. Primary outcome PTB<33wks RR 0.55 (95% CI 0.33-0.92) Number needed to treat = 14 60 women enrolled in violation of protocol 55 were with respect to EGA at enrollment Significantly more women who were enrolled early randomized to placebo Significantly more women who were enrolled late randomized to progesterone Progesterone and short cervix: Hassan trial: progesterone gel

53. Double-masked placebo-controlled trial to determine whether 17a hydroxyprogesterone prevents preterm birth in nulliparous women with short cervix (< 30mm) assessed between 16 and 22 3/7 wks. Intervention: 17-OHP (1 ml IM with 250mg) or placebo weekly Primary outcome: PTD < 37 wks Status: ongoing Progesterone and short cervix: Grobman MFMU trial: 17  OHPC

54. Progesterone & short cervix None of the trials were “screening” trials All screened and treated if positive Control group is not the same in treatment vs screening trial Applies to small % of the population 1.7% <15 mm 2.3% 10-20 mm

55. Prior preterm birth Preterm birth Multifetal gestation Short cervix Progestins & Prematurity Prevention Safety

56. Progestins: Safety Commonly used in first trimester “progesterone deficiency” ART – REI colleagues Follow-up studies Schardein Teratology 22, 251-70 (1980) Raman-Wilms et al Obstet Gynecol 85;141-9(1995) Northen et al Obstet Gynecol 110;865-72(2007)

57. Progesterone Follow-up study Aim: To determine whether there is a difference in achievement of developmental milestones and physical health between children exposed to progesterone and those exposed to placebo Northen et al, Obstet Gynecol 2007;110:865-72

58. No difference in physical exam p=0.5p=0.7p=0.5 17P Northen et al, Obstet Gynecol 2007;110:865-72 Congenital anomalies: 2% in both groups

59. Conclusions No difference in children exposed to 17P and placebo: achievement of developmental milestones or gender roles physical health congenital anomalies Northen et al, Obstet Gynecol 2007;110:865-72

60. What are we left with? Progesterone reduces recurrent PTB Progesterone for this indication will make little dent in the burden of preterm birth Not beneficial for multiple gestations Two studies show benefit for short cervix Anyone with cervix < 15 mm (1.7%) Singletons with cervix 10-20 mm (2.3%) Routine screening to identify 1-2% of population would be a large undertaking with minimal effect on PTB rate

61. Recommends the use of progesterone to prevent PTD for women with prior sPTD May be considered for use in asymptomatic women with a very short cervix Obstet Gynecol 2008;112:963-5

62. End notes Progesterone supplementation to high risk women is one opportunity for prevention It is not THE answer to PTD Future work needs to tailor the therapy to the underlying mechanism – the heterogeneity of preterm labor/delivery remains a limiting factor 17P PTD

63. to describe the problem of prematurity to describe the mechanism of progesterone action to define the patient population who meets the criteria for progesterone administration to prevent preterm birth Objectives…. Accomplished!

64. The goal: healthy children and mothers…