Progesterone & Prevention of Preterm Delivery Michael Paidas, M.D. Associate Professor Co-Director, The Yale Blood Center for Women and Children Department of Obstetrics, Gynecology & Reproductive Sciences Yale University School of Medicine Food and Drug Administration Advisory Committee for Reproductive Health Drugs August 29, 2006 1

Preterm Delivery PTD and Low birth weight represent the leading cause of infant mortality PTD Rate Over 12% in USA, and rising Cost: 13.6 billion dollars in 2001 No effective Treatment, but antenatal steroids will reduce prematurity complications Progesterone as a prevention

17- alpha-Hydroxyprogesterone (250mg) IM Weekly from 16-206 wk reduces recurrent PTD (RCT Double blind, 2:1 ratio) Progesterone Group: N= 310 Placebo: N= 153 Meis PJ et al, NEJM 2003; 348: 2379-85 Outcome Progesterone N= 306 Placebo N= 153 Relative Risk (95% CI) Del < 37 wks 111 (36.3%) 84 (54.9%) 0.66 (0.54- 0.81) <37w, Black 64 (35.4%) 47 (52.2%) 0.68 (0.51-0.90) <37w, non-B 47 (37.6%) 37 (58.7%) 0.64 (0.47-0.87) Del <35 wks 63 (20.6%) 47 (30.7%) 0.67 (0.48-0.93) Del < 32 wks 35 (11.4%) 30 (19.6%) 0.58 (0.37- 0.91)

Meis et al, New England Journal of Medicine, 2003 Outcome 17P Placebo RR 95% CI BW <2500 27.2% 44.1% 0.66 0.51-0.87 BW <1500 8.6% 13.9% 0.62 0.36-1.07 NN death 2.6% 5.9% 0.44 0.17-1.13 IVH 1.3% 5.2% 0.25 0.8-0.82 NEC 0% NA Suppl O2 14.9% 23.8% 0.42-0.92 RDS 9.5% 15.1% 0.63 0.38-1.05

10 trials N= 1,339 subjects PTD rate Prog v placebo Odds Ratio Progestational Agents: meta- analysis and systematic review Sanchez- Ramos et al. Obstet Gynecol 2005; 105: 273-9 10 trials N= 1,339 subjects PTD rate Prog v placebo Odds Ratio PTD (<37wks) (# need to Rx 10) 26.2% vs 35.9% OR 0.45 (95% CI 0.25-0.80) 17 P specifically 29.3% vs 40.9% OR 0.45 (95% CI 0.22-0.93) BW <2500g 20.3% vs 28.4% OR 0.50 (95% CI 0.36-0.71) CONCLUSION: ‘The use of progestational agents and 17 alpha hydroxyprogesterone caproate reduced the incidence of preterm birth and low birthweight newborns’.

ACOG Committee Opinion, Number 291 November, 2003 Use of Progesterone to Reduce Preterm Birth Progesterone supplementation greatly reduces preterm birth in a select group of women Progesterone has been studied only as a prophylactic measure in asymptomatic women, not as a tocolytic More research needed for patients with other high risk factors Although a small study of vaginal suppositories supports its use, a larger study is needed.

Progesterone: Actions Relaxation of myometrial smooth muscle Blocking action of oxytocin Inhibits formation of gap junctions Inhibits uterine prostaglandin production Inhibits T-Lymphocyte mediated processes Creates barrier to entry of pathogens into uterus Influences decidual cell hemostasis Blunts the increase in Interleukin -11 by Interleukin -I beta and thrombin. J Clin Endocrinol 2005; 90(9): 5279

Extravasation of clotting factors PTD: Pathogenesis Stress Infection Decidual hemorrhage Uterine distension Decidual Hemorrhage Extravasation of clotting factors FVIIa/TF CTX FXa Thrombin uPA + tPA plasmin 2o infection (?) clot Active MMPs ECM Degradation contractions rupture of membranes cervical change

Thrombin induces decidual cell IL-8 expression Thrombin has a role in neutrophil trafficking Preterm IL-8 promotes infiltration of neutrophils into the decidua. Neutrophils are a rich source of proteases that degrade the extracellular matrix B D Abruption

17-P Therapy Candidates At risk for spontaneous preterm delivery, i.e., documented history of a previous spontaneous birth at less than 37 weeks GA Current pregnancy between 16-20 completed weeks Therapy continued until 36 completed weeks gestation

17P: Safety No androgenic activity 17P: naturally occurring metabolite of progesterone Produced naturally in large quantities by placenta during pregnancy No androgenic activity Side effects: Pain or irritation at the injection site, headache, dizziness, fatigue, depression, water retention, breakthrough bleeding. Precaution: can affect carbohydrate metabolism Fetus: Safe, according to extensive reviews

Limited Product Availability Currently: no commercial mass-produced brand name or generic 17P (250 mg/ml) available on the market. Extensive experience with 17P Delalutin®, Hylutin®, Prolutinib Depot®, Prodorox®, Hydrogest® Corporate availability will increase physician access to 17P

Michael J. Paidas, M.D. Associate Professor Co-Director The Yale Blood Center for Women and Children Yale University School of Medicine 333 Cedar Street New Haven, Ct 06520-8063 203 785-7894 Email: michael.paidas@yale.edu 88