Progeterone in Miscarriage

Progesterone- “Pro-Gestation”
• Essential for pregnancy preparation,
implantation, support and continuation
• Preparation of the endometrium for
implantation (secretory changes)
• Imunomodulator- induces the Th2 response,
essential for normal pregnancy
• Increases NO production → increases uterine
blood flow and endothelial adaptation
• Decreases contractility of myometrium

Source of progesterone
• Secreted by the
corpus luteum until
7-9 weeks of
pregnancy, when
the placenta takes
over this function

Progesterone Deficiency Causing
Miscarriage
• Mifepristone blocks progesterone receptors causing abortion1
• Lutectomy up to 7 weeks gestation results in miscarriage butpregnancy can
be maintained if progesterone treatment is given2,3
• Defective corpus luteum in ART may produce low levels of progesterone,
insufficient for endometrial ripening, implantation or placentation3
• Abnormal embryo: low hCG from genetic aberrations can lead to low
progesterone levels2
Low progesterone may be a mechanism or a cause of
miscarriage2
1. Spitz IM et al. N Engl J Med. 1998. 30; 338(18):1241-7;
2. Schindler AE. Gynecol Endocrinol 2004; 18(1): 51-57;
3. Engmann L & Benadiva C. Semin Reprod Med. 2010; 28(6):506-12;
4. Verhaegen J et al. BMJ. 2012; 27:345-355.

Miscarriage- Facts And Figures
Background Risk of
Miscarriage
10-20%
Pre-clinical Pregnancy Loss 60%
Recurrent Miscarriage (RM) 1 %
Unexplained RM 50 %
Successful pregnancy
without intervention
75%

Progesterone- Mainly 2 forms
Natural Micronized
Progesterone (NMP)
Dydrogesterone
Selectivity to P4
receptor
More selective
Route Oral, vaginal, IM Oral
Bioavailability Better
Metabolism May increase risk of
obstetric cholestasis
Less metabolic load
on liver

Progeterone- Which Route?
Oral Vaginal IM
•Easiest way •Higher uterine
concentration
•Optimum blood
level
•Can be taken
anywhere
•Needs privacy •Extremely painful
•Better acceptable
and tolerable to
women
•10% may have
vaginal dryness/
irritability
•Abscess formation
Route of administration- Does NOT affect the outcome1,2
1. Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511
2. Van der Linden et al. Cochrane Database of Systematic Reviews 2015

• 4 RCTs including 411 women with threatened miscarriage
• Miscarriage was significantly less likely to occur on progestins than
placebo or no treatment (risk ratio 0.53; 95% CI 0.35 to 0.79)
• No evidence of increase in the rate of APH, HDP, or congenital
abnormalities.
• Trials are clinically heterogenous and methodologically poor
• The evidence suggesting benefit of progestins for women with
recurrent miscarriage and with threatened miscarriage, remains
preliminary and additional well designed studies are required to
confirm these findings.
• Wahabi HA, Fayed AA, Esmaeil SA, Al Zeidan RA.. Cochrane Database Syst Rev. 2011
Dec 7;(12):CD005943

• 15 RCTs including 2,118 women
• For an unselected population of women in the1st trimester of
pregnancy, there is no evidence of benefit of progestin for
prevention of miscarriage
• no evidence to support the routine use of progestogen to prevent
miscarriage in early to mid-pregnancy.
• Sub-group analysis of 4 of these trials included 223 women with
recurrent miscarriage shows the odds of miscarriage are
significantly decreased by progestin treatment (Peto OR 0.38, 95%
CI 0.20 to 0.70)
• Treatment for these women may be warranted
• Haas DM, Ramsey PS. Cochrane Database Syst Rev. 2013 Oct 31;(10):CD003511.

A systematic review of dydrogesterone for the
treatment of recurrent miscarriage
• 2 RCTs and one non-randomized comparative trial, including
509 women
• The adverse and side effects seemed to be minimal.
• Although all the predictive and confounding factors could not
be controlled for, the results show a significant reduction of
29% in the odds for miscarriage when dydrogesterone is
compared to standard care indicating a real treatment effect.
• Carp H. Gynecol Endocrinol. 2015 Jun;31(6):422-30
Miscarriage
rate
OR for
miscarriage
Absolute reduction in
miscarriage
Dydrogesterone 10.5% 0.29 [CI 0.13–
0.65]
13%
Control 23.5%

PROMISE Trial
First Trimester PROgesterone Therapy in Women with a
History of Unexplained Recurrent MIScarriage
Coomarasamy A., et al. N Eng J Med 2015;373:2141-8

PROMISE Trial- Study Details
Sponsor • UK National Institute for Health Research
• Treatment (active and placebo) provided by Besins Healthcare
Location of study • 36 centers in the UK
• 9 centers in the Netherlands
Type of study Multi-center, double-blind, randomized, placebo-controlled
Inclusion criteria • Unexplained recurrent miscarriage (≥ 3 miscarriages)
• Women 18–39 years of age
• Spontaneous conception
Objectives • Live births after 24 completed weeks of gestation (primary)
• Clinical pregnancy at 6–8 weeks
• Ongoing pregnancy at 12 weeks
• Miscarriage (before 24 weeks)
• Gestational age at delivery
• Neonatal outcomes at 28 days
• Congenital abnormalities
Treatment Utrogestan® (MVP) 400 mg BID Vaginal suppositories
After a positive UPT and no later than 6 weeks of gestation
Treatment ended at 12 weeks of gestation

PROMISE Trial- Results
Study group
(MVP)
Control group
(Placebo)
Total
participants: N=
836
N=404 N=432
Live Birth rate 65.8% 63.3% RR 1.04 (95% CI: 0.94, 1.15)
Not significant
Miscarriage No significant difference
Ectopic
pregnancy
No significant difference
Stillbirth No significant difference
Neonatal
outcomes
No significant difference

PROMISE Trial- Conclusion
• Progesterone therapy
in the 1st trimester of
pregnancy did not
result in a significantly
higher rate of live
births among women
with a history of
unexplained recurrent
miscarriages

Ongoing trial
• A randomized double-blind controlled trial of the use of
dydrogesterone in women with threatened miscarriage in the first
trimester: a randomized controlled trial
Principal
Investigator
Diana Man Ka Chan
Location of
study
2 public hospitals in Hong Kong: Queen Mary Hospital and
Kwong Wah Hospital
Randomized to 1. dydrogesterone 40 mg PO, followed by 30 mg PO
2. placebo
until 12completed weeks of gestation or 1 week after the
bleeding has stopped, whichever is longer
Participants A total of 400 patients presenting with 1st-trimester
threatened miscarriage
Primary
Outcome
percentage of miscarriage before 20 weeks of gestation

Recommendation 1 Grade
For an unselected population of women in the
first trimester of pregnancy, there is no evidence
of benefit of progestin for prevention of
miscarriage.
Consensus-based
recommendation
Recommendation 2 Grade
For women presenting with a clinical diagnosis
of threatened miscarriage, there is now
preliminary evidence of a reduction in the rate
of spontaneous miscarriage with the use of
progestins.
Consensus-based
recommendation
RANZCOG (C-Obs 29a) Statements-Guidelines/Obstetrics/Progesterone-Support-of-the-
Luteal-Phase-and-Early 7/09/2016

FOGSI Position Statement 2015
• No evidence of harm and some evidence of benefit, although
not coming from huge multicentric trial
Threatened Miscarriage
Relative risk reduction in miscarriage rate of 47%
1. Micronized Progesterone: 400 mg/day vaginally till 20
weeks of pregnancy
2. Dydrogesterone: 10 mg BD orally till 20 weeks of pregnancy
• Decision should be based on clinician's discretion until
strong evidence is available to recommend routine use
• http://www.fogsi.org/fogsi-gcpr

Is progesterone Safe?
• No significant differences in the rates of preterm
birth, neonatal death, or fetal congenital
anomalies- between progestogen therapy vs
placebo/control 1-4
• No studies reported adverse maternal effects 1-4
• Progesterone should be used with caution in
patients with cardiovascular diseases, with
impaired LFT & cholestasis 4
1. Wahabi HA, et al. Cochrane Database Syst Rev. 2011 Dec 7;(12):CD005943
2. Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511
3. Coomarasamy A., et al. N Eng J Med 2015;373:2141-8
4. FOGSI Position Statement 2015. http://www.fogsi.org/fogsi-gcpr

• Mothers of children born with congenital heart disease
received more dydrogesterone during 1st trimester of
pregnancy than mothers of children in the control group
[adjusted OR2.71; (95 % CI 1.54–4.24); P = 0.001]
• Review showed a lower number of CHD in offsprings
exposed to Dydrogesterone (n=75) vs those not exposed
to dydrogesterone (n=127)
• Causality for CHD cannot be detrmined via this publication
since it is a retrospective case controlled study
• Risk of residual confounding was very high
• Overall level of evidence for an association between
dydrogesterone and an increased risk of CHD is thus
classified as very low

Conclusion
• Progesterone may have some beneficial role in
preventing miscarriage
• Routine use is still controversial
• No association with maternal or fetal adverse
effects or congenital anomalies
• Optimum formulation, route, dose, and
duration are yet to be defined

Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (Obst & Gynae- Gold Medalist)
DNB, FIAOG
• Assistant Professor: SRIMSH,
Durgapur
• Consultant: Hindusthan Health Point
Hospital, Kolkata
• Secretary, Perinatology
Committee: BOGS- 2016-17
• Managing Committee Member:
BOGS- 2016-17

Progeterone in Miscarriage

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Progeterone in Miscarriage