2. TWO PARTS
Part - I
Role of progesterone in
preterm birth
Part - II
Role of progesterone in
Infertility treated patients
3. Preterm Birth
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For both mother & child preterm birth is a disaster.
It is one of the grimmest & heart breaking statistics
in medicine
Puts a Huge Financial
Burden
4. Key facts (WHO - 2012)
• Every year, 15 million babies are born preterm
and this number is rising.
• 1.1 million babies die annually from preterm
birth complications.
Three-quarters of them can be saved with
current, cost-effective interventions, even
without intensive care facilities.
5. Incidence of Preterm Birth in India
•
15 - 21%
(Singh, Singh, & Shikha, 2007)
• Extreme prematurity contributes to more than
28% of neonatal deaths.
• 2/3 of preterm births occur bet. 34-37 wks.
Preterm births in
United States: 11.6%,
Sweden: 5.6%,
China: 7.4%.
6. The 10 countries with the greatest number of
preterm births:
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India:
China:
Nigeria:
Pakistan:
Indonesia:
The United States of America:
Bangladesh:
The Philippines:
The Democratic Republic of Congo:
Brazil:
3 519 100
1 172 300
773 600
748 100
675 700
517 400
424 100
348 900
341 400
279 300
7. Every 5 minutes 50
preterm babies are
born world wide
The Lancet Editorial 2006;368:339
8. How do we quantify the emotional toll
It is a devastating scenario, to say the least
12. PREDICTORS OF PTL
Prev. history of PTL
Uterine abnormalities
Cervical abnormalities
Advanced maternal age
Obesity
Lower socio – economic
group
STDs during pregnancy
Multiple Pregnancy
A history of spontaneous preterm
birth is one of the strongest predictors
for a preterm birth in a subsequent
pregnancy
13. Interventions to prevent PTB
Prenatal care
Social support
Lifestyle changes
Smoking cessation
Improved nutrition
Trials of acute care of PTL
show little benefit in
prevention of PTB
Cerclage
Infections
Home uterine activity monitoring
Tocolytic medications
14. Progesterone in Preterm
Progesterone is “indispensable” for
normal pregnancy
“Progesterone deficient state” has
been proposed to be a Mechanism
in Preterm Labor
Arpard Csapo
15. Pro = For
Gesterone = Gestation
Progesterone
“see – saw theory”
Csapo Am J Anat 1956
17. Evidence that suspension of
progesterone action is important
in human parturition
Administration of anti-progestins
(RU-486 or onapristone) can induce
abortion and cervical ripening
Kovacs L et al. Contraception 1984; 29: 399
Crowley WF. N EJM 1986; 18: 1607
Chwalisz K. 1994 Human Reproduction 1994;9:131
Bygdeman et al. Human Reproduction 1994;9:120
18. HOW PROGESTERONE
WORKS ? for successful
Favorable changes in the endometrium
implantation & maintenance of pregnancy
Suppresses immunity to prevent rejection of fetal cells
Induces myometrial quiescence by suppressing
Cytokines
PGs
Response to oxytocin
Prevents formation of gap junction
Nature’s Natural Immunosuppresant
19. Cervix is the predominant site of
supplemental progesterone
action
• Modulate gene expression in cervix
both in presence and absence of
inflammation.
• Blocks type 1 collagen degradation
in cervix.
Xu H, AJOG, 2008
20. PROGESTERONE & PREVENTION
OF PRE TERM BIRTH
• Small trials in 1970’s and 80’s
• Suggested
– Reduction in preterm birth
21. Meta - analysis of 17P use
• Seven placebo – controlled trials
• 15 – 70%
• No significant
in PTB
in perinatal morbidity &
mortality
Conflicting evidence because
Mixed population in the study like recurrent pregnancy loss,
active PTL
Small no. of patients included in the studies
Variable dosing IM , vaginal
22. THE NATIONAL INSTITUTE OF
CHILD HEALTH & HUMAN
DEVELOPMENT (NICHD)
AND MATERNAL-FETAL MEDICAL
UNITS (MFMU) TRIAL
Meis, N Engl J Med 2003
Northen, Obst & Gynaecol. 2007
23. Participating Centers of the MFMU Network
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Wake Forest University
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University of Tennessee
•
University of AlabamaBirmingham
•
University of Utah
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Magee-Womens Hospital
•
Thomas Jefferson University
•
University of Miami
•
Columbia University
•
University of North Carolina
Case Western Reserve University
George Washington University
Wayne State University
University of Chicago
University of Cincinnati
University of Texas,
Southwestern
Ohio State University
University of Texas, San Antonio
Brown University
University of Texas, Houston
Northwestern University
29. Effectiveness of Treatment With 17P
• 6 women with a previous spontaneous
preterm birth would need to be treated to
prevent one birth <37 weeks
• 12 women with a previous spontaneous
preterm birth would need to be treated to
prevent one birth <32 weeks
30. 17 –P side effects
Symptom
%
Soreness
34.2
Swelling
14.1
Itching
11.3
Bruising
6.7
Rebarber, 2007, Diabetes Care
17-P associated with 3 x increased risk of
GDM single retrospective study
12.9% vs. 4.9%
31. 17 – P: Safety
17-P exposed infants
• Less perinatal morbidity
•
rates of NEC, IVH, need for O2
RDS, Bronchopulmonary dysplasia
No evidence of virilization of female offspring
Meis, N Engl J Med 2003
Northen, Obst & Gynaecol. 2007
32. 17 – P: Safety
4 year outcome of exposed children
No congenital anomalies
Normal neurological
development
Obstet Gynecol 2007;110:865–872.
33. Secondary analysis of RCT by
MFMU
Meta – analysis RCTs vs 33-47%
• 17P
Risk of PTB : 25-31%
recur. PTB if prev PTB < 34 wks
• 17P doesn’t
rec PCB if prev PTB > 34 wks
Sponge, Obstet Gynaecol 2005
35. ACOG Committee Opinion Oct 2008
Acknowledges the benefits of
progesterone in high risk populations
with prior PTB.
Further studies are needed to
evaluate
- Optimal Preparations
- Dosages
- Route of administration
36. MFMU Concluded
Weekly injections of 17- α
Hydroxyprogesterone Caproate can
provide significant and powerful
protection against recurrent preterm birth
and improve the neonatal outcome for
pregnancies at risk
17P cost effective
37. ACOG/MFMU Recommendations
• Recommended
– Prevention of recurrent PTB
• Current singleton pregnancy
• Prior preterm birth
• Considered
– Asymptomatic short cervix (<25mm)
– Routine screening not recommended
Obstetrics and Gynecology, Vol 112(4), 2008
38. VAGINAL PROGESTERONE TRIAL
RCT 142 patient with h/o 1 pre. PTB
Daily 100mg Vg suppo. from 24 to 34 wks of
pregnancy vs Placebo
Significant benefit :
Progesterone grp
Lower PTB < 37 wks ( 14% vs 29% )
Lower PTB < 34 wks (
3% vs 19% )
39. Vaginal progesterone trials
• deFonseca, Am J Obstet Gyneol, 2003
– 100mg micronized vaginal progesterone
– reduction in PTB <34 weeks in progesterone
group (2.7% vs. 18.6%)
• O’Brien, Ultrasound Ob/Gyn, 2007
– Vaginal progesterone gel, 600 patients
– 90 mg progesterone (Crinone®)
– No difference in PTB < 32 weeks
40. Oral Progesterone & PTL
Indian Study 2009
(Raj et al. Int. J Gynaecol Obstet
2009)
• RCT - 150 women with at least one PTB
• Received 100 mg of OMP or placebo twice a day
) from 18-24 weeks until 36 weeks
Indian Study Inference
Significant decrease in rate of PTB
Better birth weight of the new born
Shorter stay in NICU
Better APGAR score
41. Twin pregnancy
‘STOPPIT trial’
A randomised, doubleblind, placebo-controlled
study
• 500 women
• Daily vaginal
progesterone gel 90
mg (n=250) or to
placebo gel (n=250) for
10 weeks from 24 weeks'
gestation
42. PROGESTERONE IN TWIN PREGNANCY
Delivery before 34 weeks of pregnancy
• 24.7% progesterone group
• 19.4% - placebo group
Rate of adverse events - not different
The meta-analysis confirmed - progesterone
does not prevent early preterm birth in
women with twin pregnancy
Norman JE et al. Lancet 2009 Jun
Combs CA et al. AM J Obstet Gynecol. 2011
43. PROGESTERONE IN TRIPLET
PREGNANCY (56 women )
Composite neonatal morbidity - similar (38% vs 41%)
Mean gestational age at delivery - (31.9 vs 31.8 wk )
In triplet pregnancy - prophylactic treatment
with 17P did not reduce neonatal morbidity
or prolong gestation .
Combs CA et al. AM J Obstet Gynecol. 2010
44. VAGINAL PROGESTERONE
&
SHORT CERVIX
• Large multinational (53), randomised, double
blind, placebo- controlled trial
• 547 patients with h/o PTB or short cx <30mm
• TVS cervical length meaurements 18 wks
•
28 wks
• Daily intravaginal P4 gel 90 mg
Change in the cervical length >2mm
PTB 3.6% vs 18% in placebo
Ultrasound obst gynae 2009
45. TVS findings to suggest cervical
incompetence
• shortening of endocervical canal (< 25mm)
• Funneling of the internal os ( >1.5cm)
• Prolapse of membranes into the cervix
Normal cervix
Short length cervix
46. Progesterone Preserves Cervical Length
– Results from O’Brien et al.2009
Intravaginal progesterone preserves cervical length
&
reduces the rate of spontaneous early pre-term delivery
47. New international study
• 5 high quality RCT , 775 women, 827 infants
• Vaginal progesterone reduces rate of preterm
birth by 45%
• Vaginal P4 was effective in women with short
cervix.
• This is the first study to show that vag P4 is
effective in reducing the rate of neonatal
complications in twin gestation
Romero,etal AJOG 2012
48. Progesterone as a Tocolytic
• 6 trials have been reported
• Various progesterone compounds used
• None of the trials found a significant prolongation of
pregnancy .
Progesterone treatment of women
with active uterine contractions should
be discouraged outside of research
protocols
Cochrane database syst rev 2010 Jan
49. Take home
recommendations
For prevention of PTL in women with h/o PTL
17 alpha-hydroxy progesterone
250 mg im Weekly
or
Progesterone 100 mg daily Vaginally
SOGC RECOMMENDATION
Jan2008
J. Pbst. Gynecol Can 2008;
50. For Prevention of PTL in women with
short cervix (< 25 mm at 22-26 wks)
Progesterone 200 mg daily vaginally
The therapy should be started at 20
weeks gestation and stopped when
the risk of prematurity is low
SOGC RECOMMENDATION
Jan2008 J. Pbst. Gynecol Can 2008
51. Part - II
Role of progesterone in
Infertility
treated patients
53. Luteal phase defect
PROBLEMATIC AND CONTROVERSIAL
As
Currently there are no reproducible,
physiologically relevant and practical
clinical standard test to diagnose LPD
54. Progesterone and miscarriage
There is insufficient evidence to evaluate the
effect of progesterone supplementation in
pregnancy to prevent a miscarriage.
It was only in 2011 that Cochrane
meta analysis suggested that
progesterone supplementation has
beneficial effects in patients with
Recurrent Pregnancy Loss.
55. Recent Cochrane review concluded no
significant difference between different routes
of progesterone supplementation.
Equal number of studies support
both vaginal & intramuscular
route
56. Various routes
Oral
Easy route
Micronized form
Only 10 % absorbs
Not very effective.
First hepatic pass
Intramuscular
Reliable & consistent
plasma level of P4
Rapidly absorb in 2-8 hrs.
P4 level maintain for > 72
hrs.
Difficult &
very
painful inj
Side effects like sedation
Local reaction & abscess.
& hypnosis
Non compliance by pt.
Vaginal
Targeted organ delivery
High conc. In uterus
& endometrium
First uterine pass effect
Minimal systemic side
effect
Good Pt. compliance
Self administration,
no prick of needle
57.
58. New Evidence is coming up as large
PROMISE is
multicentre study
currently on the Way
PROMISE
PROgesterone in MIScarriagE trial
59. Good things do come in small
packages but definitely not this one.
