Progesterone 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 but pregnancy 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 FiguresBackground 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 formsNatural Micronized Progesterone (NMP)

Dydrogesterone

Selectivity to P4 receptor

More selective

Route Oral, vaginal, IM OralBioavailability BetterMetabolism May increase risk of

obstetric cholestasisLess 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: CD0035112. Van der Linden et al. Cochrane Database of Systematic Reviews 2015

Is Progesterone Effective?

• 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 TrialFirst 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 DetailsSponsor • 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-controlledInclusion 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 suppositoriesAfter a positive UPT and no later than 6 weeks of gestationTreatment ended at 12 weeks of gestation

PROMISE Trial- ResultsStudy 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 differenceEctopic pregnancy

No significant difference

Stillbirth No significant differenceNeonatal 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 PO2. 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

Clinical Guidelines

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 GradeFor 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):CD0059432. Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD0035113. Coomarasamy A., et al. N Eng J Med 2015;373:2141-84. 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

Bertrand Russel

Thank You

Dr Sujoy DasguptaMBBS (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