1. 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

2. 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

3. 17- alpha-Hydroxyprogesterone (250mg) IM Weekly from wk reduces recurrent PTD (RCT Double blind, 2:1 ratio) Progesterone Group: N= 310 Placebo: N= 153 Meis PJ et al, NEJM 2003; 348:
Outcome
Progesterone
N= 306
Placebo
N= 153
Relative Risk
(95% CI)
Del < 37 wks
111 (36.3%)
84 (54.9%)
0.66 ( )
<37w, Black
64 (35.4%)
47 (52.2%)
0.68 ( )
<37w, non-B
47 (37.6%)
37 (58.7%)
0.64 ( )
Del <35 wks
63 (20.6%)
47 (30.7%)
0.67 ( )
Del < 32 wks
35 (11.4%)
30 (19.6%)
0.58 ( )

4. Meis et al, New England Journal of Medicine, 2003
Outcome
17P
Placebo RR
95% CI
BW <2500
27.2%
44.1%
0.66
BW <1500
8.6%
13.9%
0.62
NN death
2.6%
5.9%
0.44
IVH
1.3%
5.2%
0.25
NEC 0% NA
Suppl O2
14.9%
23.8%
RDS
9.5%
15.1%
0.63

5. 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 )
17 P
specifically
29.3% vs 40.9%
OR 0.45 (95% CI )
BW <2500g
20.3% vs 28.4%
OR 0.50 (95% CI )
CONCLUSION: ‘The use of progestational agents and 17 alpha hydroxyprogesterone caproate reduced the incidence of preterm birth and low birthweight newborns’.

6. 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.

7. 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

8. 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

9. 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

10. 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 completed weeks
Therapy continued until 36 completed weeks gestation

11. 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

12. 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

13. 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 88