1. Progesterone…We can prevent some prematurity if we try
James Keller MD

2. OBJECTIVES
To review early studies concerning progesterone use in the management of preterm labor
To review recent studies concerning progesterone use to prevent preterm delivery
To review safety issues surrounding progesterone use in pregnancy

3. Preterm and Low Birth Weight Births in the United States
1991
2001
2010 US Objective
Preterm
10.8%
11.9%
7.6%
Low Birth Weight
7.1%
7.7%
5.0%
PRETERM DELIVERY IS BAD…..AND NOT GETTING BETTER
March of Dimes PeriStats,
In 2001, there were 476,250 preterm births in the United States, representing % of live births.
Between 1991 and 2001 the rate of infants born preterm in the United States increased more than 10%, i.e., not just the apparent 1.1% absolute increase indicated in this slide.
The rate of preterm birth in the United States is highest for African Americans (17.6%), followed by Native Americans (12.8%), Hispanics (11.4%), Whites (10.6%) and Asians (10.2%).*
In 2000, charges for hospital stays for infants with any diagnosis of prematurity was estimated at $11.9 billion.
In the US, infants born to mothers less than 20 or over 35 years are more likely than infants born to mothers to be preterm.
Some risk factors for preterm birth and low birth weight include: previous preterm and/or low birth weight birth, multiple birth, smoking, unplanned pregnancy, infections and poor nutrition.

4. Prevention of Preterm Birth-Goldenberg NEJM 1998

5. OBLIGATORY CONFUSING AND CONDESCENDING SLIDE

6. MECHANISM OF ACTION OF PROGESTERONE
Inhibit formation of myosin light chain kinase
Inhibit release of calcium
Inhibition of the formation of gap junctions
Blocking of the action of oxytocin
May inhibit production of or block action of prostaglandins
All of the above keep uterine muscle from contacting in an organized regular manner-the hallmark of effective labor
In reality these considerations remain unproven in the human population

7. PROGESTERONE TO PREVENT PRETERM DELIVERY
HISTORY AND LITERATURE REVIEW

9. PROGESTOGEN ADMINISTRATION IN PREGNANCY MAY PREVENT PRETERM DELIVERY
BJOG 1990
Marc J N C Kierse

10. PROGESTOGEN ADMINISTRATION IN PREGNANCY MAY PREVENT PRETERM DELIVERY
Meta –analyses published in response to two other meta-analyses, both of which used several different progestational agents
Analysis examined only 17 alpha-hydroxyprogesterone caproate (17P)
Provides no support for use of 17P to prevent miscarriage

11. PROGESTOGEN ADMINISTRATION IN PREGNANCY MAY PREVENT PRETERM DELIVERY
Five of the seven trials reviewed included data on preterm delivery
All but one showed fewer preterm deliveries in the treated groups
Only two trials looked at preterm labor, which was also decreased in the treated group

12. PROGESTOGEN ADMINISTRATION IN PREGNANCY MAY PREVENT PRETERM DELIVERY
Miscarriage X
Preterm birth X
Perinatal death X
Odds Ratio
1.0
2.0
5.0
0.2
0.5

13. Prevention of Recurrent Preterm Delivery by 17 alpha-Hydroxyprogesterone Caproate
The second article to be published in 2003 appeared in the June 12 issue of the New England Journal of Medicine.
In addition to Dr. Meis, 20 coauthors are listed on the title page of the article (maximum permitted by NEJM) plus another 42 members of the NICHD MFM Units Network in the appendix.
A correction published in a subsequent issue added one more coauthor--Steven Gabbe of Vanderbilt University.

14. Prevention of Recurrent Preterm Delivery by 17 alpha-Hydroxyprogesterone Caproate
Patients between 15 and 20 weeks gestation recruited at 19 centers, with a previous spontaneous preterm delivery(or pprom) between 20 and 37 weeks gestation
Excluded for multiple gestation, fetal anomaly, progesterone or heparin therapy, cerclage, hypertension, seizure disorder
The second article to be published in 2003 appeared in the June 12 issue of the New England Journal of Medicine.
In addition to Dr. Meis, 20 coauthors are listed on the title page of the article (maximum permitted by NEJM) plus another 42 members of the NICHD MFM Units Network in the appendix.
A correction published in a subsequent issue added one more coauthor--Steven Gabbe of Vanderbilt University.

15. Prevention of Recurrent Preterm Delivery by 17 alpha-Hydroxyprogesterone Caproate
463 of 1039 eligible women randomized after consent, all received one placebo injection.
The second article to be published in 2003 appeared in the June 12 issue of the New England Journal of Medicine.
In addition to Dr. Meis, 20 coauthors are listed on the title page of the article (maximum permitted by NEJM) plus another 42 members of the NICHD MFM Units Network in the appendix.
A correction published in a subsequent issue added one more coauthor--Steven Gabbe of Vanderbilt University.

16. Local reactions more common in the 17P group
Prevention of Recurrent Preterm Delivery by 17 alpha-Hydroxyprogesterone Caproate
91.5% compliance
Local injection reactions such as soreness(34%), swelling (14%), itching(11%) and bruising(7%), were common
Local reactions more common in the 17P group
The second article to be published in 2003 appeared in the June 12 issue of the New England Journal of Medicine.
In addition to Dr. Meis, 20 coauthors are listed on the title page of the article (maximum permitted by NEJM) plus another 42 members of the NICHD MFM Units Network in the appendix.
A correction published in a subsequent issue added one more coauthor--Steven Gabbe of Vanderbilt University.

17. Prevention of Recurrent Preterm Delivery by 17 alpha-Hydroxyprogesterone Caproate RESULTS
OUTCOME
17P
PLACEBO RR
PTD<37
36%
55%
0.66( )*
SPONT
29%
45%
0.65( )*
BLACK
35%
52%
0.68( )*
PTD<35
21%
31%
0.67( )*
PTD<32
11.4%
19.6%
0.58( )*
The second article to be published in 2003 appeared in the June 12 issue of the New England Journal of Medicine.
In addition to Dr. Meis, 20 coauthors are listed on the title page of the article (maximum permitted by NEJM) plus another 42 members of the NICHD MFM Units Network in the appendix.
A correction published in a subsequent issue added one more coauthor--Steven Gabbe of Vanderbilt University.

18. FETAL AND NEONATAL OUTCOME
17P
placebo
RR(95%CI)
<2500gms
<1500gms
27.2%
8.6%
41.1%
13.9%
0.66( )
0.62( )
Neonatal death
2.6%
5.9%
0.4( )
RDS
9.5%
15.1%
0.63( )
IVH
Grade 3 or 4
1.3%
0.7%
5.2%
0.25( )
sepsis
3.0%
1.12( )

19. Prevention of Recurrent Preterm Delivery by 17 alpha-Hydroxyprogesterone Caproate
Rate of PTD in placebo group was very high (54.9), highlighting nature of participants
36% of treated patients still delivered preterm
6 women and 12 women would need to be treated to prevent ptd at <37 and <32 weeks respectively
The second article to be published in 2003 appeared in the June 12 issue of the New England Journal of Medicine.
In addition to Dr. Meis, 20 coauthors are listed on the title page of the article (maximum permitted by NEJM) plus another 42 members of the NICHD MFM Units Network in the appendix.
A correction published in a subsequent issue added one more coauthor--Steven Gabbe of Vanderbilt University.

20. da fonseca et al, Sao Paulo, Brazil; AJOG 2003
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
da fonseca et al, Sao Paulo, Brazil; AJOG 2003

21. da fonseca et al, Sao Paulo, Brazil; AJOG 2003
Authors state first study to use natural progestational agents
Study population included patients with singleton gestation, previous PTD, cerclage, or uterine malformation
142 patients assigned to progesterone suppository 100 mg nightly per vagina, or placebo
Medication administered weeks gestation

22. da fonseca et al, Sao Paulo, Brazil; AJOG 2003
Placebo
n=70
Progesterone
n=72 p
<37 weeks
20(28.5%)
10 (13.8%)
.03
<34 weeks
13(18.6%)
2(2.8%)
.002
Admission for PTL
22(31.4%)
14(19.4%) NS

23. da fonseca et al, Sao Paulo, Brazil; AJOG 2003
Many criticisms including poorly defined exclusion population, underpowered study and exclusion of 10 PPROM patients
Reanalysis with the PPROM Patients supported findings, but small sample size still leads to question
small size will be less troublesome if other studies using this protocol confirm results

24. PROGESTERONE AND THE RISK OFPRETERM BIRTH AMONG WOMEN WITH A SHORT CERVIX Fonseca-Fetal Medicine Foundation NEJM 2007
Only 10% of PTD occur in patients with previous PTD
, eight hospitals in UK, Chile, Greece
All patients having 2nd trimester sono (20-25 weeks) were offered TVU cervical length
Exclusion criteria: anomalies, ctx, srom, cerclage
Treatment arm 200 mg progesterone capsules-inserted nightly from weeks
Primary outcome-delivery before 34 weeks

25. PROGESTERONE AND THE RISK OFPRETERM BIRTH AMONG WOMEN WITH A SHORT CERVIX
Median 22 weeks
Cx length 34 mm (0-6.7)
431 twins

26. PROGESTERONE AND THE RISK OFPRETERM BIRTH AMONG WOMEN WITH A SHORT CERVIX

27. PROGESTERONE AND THE RISK OFPRETERM BIRTH AMONG WOMEN WITH A SHORT CERVIX

28. PROGESTERONE AND THE RISK OFPRETERM BIRTH AMONG WOMEN WITH A SHORT CERVIX Fonseca-Fetal Medicine Foundation NEJM 2007
The study supports the use of Progesterone therapy in patients identified with a short cervix at weeks
Questions
Mass screenings
Length threshold

29. A TRIAL OF 17 ALPHAA-HYDROXYPROGESTERONE CAPROATE TO PREVENT PREMATURITY IN TWINS NICHHD NEJM 2007
14 sites,
weeks
Exclusion: monochorionic, discordant, cerclage, uterine anomaly, medical complication, heparin therapy (relative), major chronic disease, mfrt pts

30. A TRIAL OF 17 ALPHA-HYDROXYPROGESTERONE CAPROATE TO PREVENT PREMATURITY IN TWINS

31. Study does not support the use of 17P in twins
A TRIAL OF 17 ALPHAHYDROXYPROGESTERONE CAPROATE TO PREVENT PREMATURITY IN TWINS NICHHD NEJM 2007
Study does not support the use of 17P in twins
Triplets with same results
Did not look at present or past obstetric history-all of which has predicted response to progesterone
Dosage used same as singletons

32. Progesterone given as suppositories, 400 mg daily
PROGESTERONE FOR MAINTENANCE TOCOLYTIC THERAPY AFTER TREATENED PRETERM LABOUR: A RANDOMISED CONTROLLED TRIAL Borna et al, Aust NZ J Obstet Gyneacol, 2008
Seventy woman randomised to progesterone or no treatment after acute tocolysis
Progesterone given as suppositories, 400 mg daily
Woman similar with respect to history of preterm births (12%-13%)
GA at admission weeks

33. PROGESTERONE FOR MAINTENANCE TOCOLYTIC THERAPY AFTER TREATENED PRETERM LABOUR: A RANDOMISED CONTROLLED TRIAL Borna et al, Aust NZ J Obstet Gyneacol, 2008
OUTCOME
CONTROL (33)
PROGESTERONE (37)
P-VALUE
LATENCY (DAYS)
24.5
36.1
0.037
GA AT DELIVERY
(WEEKS)
34.5
36.7
0.041
RECURRENCE (%)
57.6
35.1
0.092
RDS (%)
36.4
10.8
0.021
NICU ADMITS (%)
39.4
29.3
0.205
NICU DAYS
3.8
3.4
0.83
VENTILATOR (%)
18.2
5.4
0.136

34. Sixty patients admitted for treatment of PTL from 25-34 weeks
Cervical length changes during preterm cervical ripening: effects of 17-α-hydroxyprogesterone caproate Fachchinetti et al AJOG 2007
Sixty patients admitted for treatment of PTL from weeks
Patients received Atosiban and steroids for 48 hours
Patients randomized to 341 mg 17P twice weekly or observation
Patients all less than 2 cm dilated
Looked at cx length change and rate of preterm delivery
Clinical characteristics of the 2 groups of randomly assigned patients
Characteristic Observation group 17P treatment group Significance
Age (y)* (22-33) (20-35) NS
Nulliparous women (n) 17 (73.9%) 16 (66.7%) NS
Previous PTD (n) 2 (8.7%) 1 (4.2%) NS
Gestational age (d)* ( ) ( ) NS
CL (mm)* (10-38) (5-44) NS
CL 25 mm (n) 17 (56%) 16 (53%) NS
Cervical dilation (n)
1 cm 10 (33%) 11 (37%) NS
2 cm 2 (7%) 1 (3%) NS

35. CLINICAL CHARACTERISITICS
Cervical length changes during preterm cervical ripening: effects of 17-α-hydroxyprogesterone caproate Fachchinetti et al AJOG 2007
CLINICAL CHARACTERISITICS
CHARACTERISTIC
17P
OBSERVATION
SIG
Age
29.9
29.8 NS
Nulliparous (%)
66.7 74
Previous PTD (%)
4.2
8.7
GA (days)
208.4
212.3
Cx length (mm)
24.5
22.8
Cx length <26mm (%) 53 56
Clinical characteristics of the 2 groups of randomly assigned patients
Characteristic Observation group 17P treatment group Significance
Age (y)* (22-33) (20-35) NS
Nulliparous women (n) 17 (73.9%) 16 (66.7%) NS
Previous PTD (n) 2 (8.7%) 1 (4.2%) NS
Gestational age (d)* ( ) ( ) NS
CL (mm)* (10-38) (5-44) NS
CL 25 mm (n) 17 (56%) 16 (53%) NS
Cervical dilation (n)
1 cm 10 (33%) 11 (37%) NS
2 cm 2 (7%) 1 (3%) NS

36. Cervical length changes during preterm cervical ripening: effects of 17-α-hydroxyprogesterone caproate Fachchinetti et al AJOG 2007
RESULTS
OUTCOME
17P
OBSERVATION P
Cx shortening at 7 days (mm)
0.83
2.37
.002
Cx shortening at 21 days
2.4
4.6
PTD <37 weeks (%) 16 57
.004
PTD <35 weeks (%) 10 23 NS
Latency (days)
35.3
19.1
.003
Clinical characteristics of the 2 groups of randomly assigned patients
Characteristic Observation group 17P treatment group Significance
Age (y)* (22-33) (20-35) NS
Nulliparous women (n) 17 (73.9%) 16 (66.7%) NS
Previous PTD (n) 2 (8.7%) 1 (4.2%) NS
Gestational age (d)* ( ) ( ) NS
CL (mm)* (10-38) (5-44) NS
CL 25 mm (n) 17 (56%) 16 (53%) NS
Cervical dilation (n)
1 cm 10 (33%) 11 (37%) NS
2 cm 2 (7%) 1 (3%) NS

37. SAFETY Progesterone is a category D drug
Positive evidence of human fetal risk exists, but benefits in certain situations may make use of the drug acceptable despite its risks
Black Box Warning
Is this warranted?

38. SAFETY All progesterones are not equal
You could not pay me enough to re-learn the differences-the key is that hydroxyprogesterone is a metabolic product of progesterone, which is produced in the corpus luteum-all pregnancies are exposed to high levels of this hormone
Progestins-may include all hormones with progesterone like activity-including testosterone derived progestins
Multiple studies have shown 17P has no androgenic activities

39. SAFETY
Studies suffer from confounding variables such as pregnancy complications, past history and co-administration of other drugs
The largest study to date followed 649 offspring exposed to 17P, and found only a non-significant increase in abnormal testes (1.8% vs1.2%) primarily undescended testes
The conclusion of this study, and the preponderance of reviews support the belief that there is no association between progesterone and birth defects

40. USE OF PROGESTERONE TO REDUCE PRETERM BIRTH ACOG COMMITTEE OPINION OCTOBER 2008
Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior spontaneous preterm birth due to spontaneous preterm labor or premature rupture of membranes. Current evidence does not support the routine use of progesterone in women with multiple gestations. Progesterone supplementation for asymptomatic women with an incidentally identified very short cervical length (less than 15 mm) may be considered; however, routine cervical length screening is not recommended.

41. SUMMARY
In a world where nothing seems to work, Progesterone seems effective in preventing PTD in subsets of high risk patients
This effectiveness, is supported by decades of studies and clinical experience