Published studies indicate that the estimated rate of pregnancy loss is

1. Optimizing
The outcome of
Dr. Sharda Jain
Dr. Jyoti Agarwal
Threatened Abortion

2. So is Treatment !!

3. Published studies indicate that the
estimated rate of pregnancy loss is
– 30 % prior to implantation
– 30 % following
implantation, but before
the missed period
– 15 % as miscarriages
(clinical pregnancy loss)
• Around 70 % of
conceptions are lost
prior to live birth
Live births
Miscarriage
Early pregnancy loss
Failure of implantation
Fertilizations

4. Defining threatened Abortion
A threatened abortion :PAIN or BLEEDING or BOTH
WHO : In a threatened abortion – is a Live Pregnancy, the
cervical os remains closed.
Nearly 25% of pregnant women have some degree of
vaginal bleeding during the first two trimesters and about
50% of these progress to loss of the pregnancy.
TA can be challenging to the obstetricians

5. Threatened miscarriage occurs in
about 15 % of all clinically
recognised pregnancies

6. Emotional response to miscarriage
can be profound
20 - 50% of women suffer from
Major depression

7. Counseling !! Counseling !! Counseling
• Counseling definitely reduces the incidence
of adverse psychological sequealae
• Care should emphasize a couple centered
approach

8. TENDER LOVING CARE
Threatened Miscarriage
Dydrogestrone
+
MagicalEffects

10. TOGETHERNESS
SUPPORT OF
PARTNER

11. REKHI

12. EDGF 2019q qwertyuiop[]

13. Why Women Does Not
Discard Pregnancy ???

14. A Mismatched Organ Transplant
• Pregnancy is a puzzling
situation as the semi-
allogeneic embryo (50%
paternal)
is not rejected
• Progesterone plays an
important role in protecting
the allogeneic embryo from
immunologic rejection
Progesterone is not only essential for conception and
implantation, but also throughout pregnancy until term

15. Low Progesterone Levels Is Associated With
Increased Risk Of Miscarriage

16. Not all progestogens are equally suitable
as they differ not only with respect to their
potency, route of administration, bioavailability

17. Debate on
Which is a better progesterone ?
Wrt
Bioavailability, Side effects, Ease of use ,Outcome
Debate ends today !!

19. Dydrogesterone 1960
60 years

20. Clinical Evidence in favor
of Recent Verdict

21. What Ideal Progesterone Should have?
 Higher Bioavailability and Predictable
Plasma Concentration
 Lower Dosage and Dosing Convenience
 Favourable Tolerability
 Higher Compliance
Is ‘Retro’ Progesterone a solution ??

22. Dydrogesterone in threatened abortion:
Pregnancy Outcome2005
Study:
• N= 154 pregnant women with TA before 13 weeks were
given either Dydrogesterone 40 mg stat dose followed by
10 mg BD for 1 week or Placebo.
Results:
•Conclusion: Dydrogesterone has been shown to
reduce the incidence of pregnancy loss in
threatened abortion during the first trimester in
women with RPL
Omar MH, The Journal of Steroid Biochemistry and Molecular
Biology Volume 97, Issue 5, December 2005, Pages 421-425

23.  Total 4153 Women Were Participated In The Trial
 Duration Of Study : 34 Weeks
Group 1
• 400 mg of Micronized
Vaginal Progesterone
Twice Daily
• 2079 women
Group 2
• Placebo
• 2074 women
N Engl J Med 380;19 nejm.org May 9, 2019
PRIS
M
2019
2019

24. PRISM TRIAL
• There was No significant increase in live births with progesterone in the
first trimester among women with bleeding in early pregnancy.

25. PRISM TRIAL
VAGINAL NMP V/S PLACEBO:
• There was No significant increase in
live births with progesterone in the
first trimester among women with
bleeding in early pregnancy.

26. Influence of Oral Dydrogesterone and Vaginal
Progesterone on Threatened Abortion
Lee HJ, et al
2017
THE META
ANALYSIS
9 RCT’s
(n=913)

27. DYDROGESTERONE VS CONTROL GROUP
0
5
10
15
20
25
Drdrogesterone Placebo
series 2
Series 1
(P = 0.001)
Incidence of miscarriage was
significantly lower in the oral
dydrogesterone group than in
the control group

28. VAGINAL PROGESTERONE VS CONTROL GROUP
0
5
10
15
20
25
MVP PLACEBO
PLACEBO
MVP
(P = 0.30)
Incidence of miscarriage was lower
in the vaginal progesterone group
than in the control group, although
this difference was non significant

29. Efficacy & the safety of progestogens in the
treatment of threatened miscarriage
7
Trials
Wahabi HA, et al
2018
Cochrane
Review

30. Efficacy & the safety of progestogens
in the treatment of threatened
miscarriage
696
7
Trials
6
Countries
Patients
Germany & Italy 2 trials
Iran 2 trials
Malaysia 1 trial
Turkey 1 trial
Jordan 1 trial

31. Concluded that
Dydrogesterone Vs No Rx
95% CI 0.38- 0.85
Treatment with dydrogesterone
compared to no treatment probably
reduces miscarriage risk
Vaginal Progesterone Vs Placebo
95% CI 0.47-1.21
Treatment with vaginal progesterone
Compared to placebo , probably has
little or no effect in reducing the
miscarriage rate
RR
0.57
RR
0.75

32. Wang XX, et al
2019
THE META
ANALYSIS
Efficacy of progesterone on threatened
miscarriage : Difference in drug types
Japan Society of Obstetrics and Gynecology 2019

33. Progesterone given in an effort to
Treat threatened miscarriage
Trials included
845
Women who faced
threatened miscarriage
Rx with Dydrogesterone RR = 0.49,95% CI 0.33 – 0.75
has a significant effect on reducing abortion rates
compared to
vaginal progesterone RR = 0.69 , 95% CI 0.40 – 1.19
From
8
RCT’s

34. 9
RCTS
included
913
Pregnant
women
7
RCTS
8
RCTS
included
included
2018 WAHABI HA, et al
696
Patients
845
Patients
2019 WANG et al
2017 lee et al
TOTAL 24 RCT’s 2454 Patients

35. Dydrogesterone in threatened miscarriage:
A Malaysian experience
• N=191 women were randomized to
Dydrogesterone (40 mg stat followed by
10 mg BD) or conservative management.
Study:
• The success rate in the Dydrogesterone group was
statistically significantly higher (87.5% vs.
71.6%; p < 0.05).
• Miscarriage occurred in 12.5% of Dydrogesterone
group compared with 28.4% in the control group
(p < 0.05).
Results:
Ramachandiran PU, Maturitas, Volume 695, Supplement
1, Dec’2000, Pages S47-S50

36. Int J Gynecol Obstet. 2021;00:1–11. 
wileyonlinelibrary

37. Oral management with Dydrogesrerone
was associated with a lower risk of
miscarriage compared with vaginal
NMP administration

38. Dydrogesterone & Micronized Progesterone
Are Synthesized From Natural Source
Progesterone
Undergoes processing Light technology bends it into
to become a curved retrosteroid structure
Micronized Progesterone Dydrogesterone
Dioscorea plants
Both progesterone and dydrogesterone are
produced from the same dioscorea plant
Shaped by light, enhances the progestogenic effects
(improves bioavailability,specificity & affinity for the
progesterone receptor potency & side effects)
Small changes can make a difference

39. Dydrogesterone is a Retroprogesterone,
with IMMUNOMODULATORY properties
Good Clinical Practice Recommendations. Position Statement on the use of Progestogens. Published by
Elsevier. http://www.fogsi.org/fogsi-gcpr/. Accessed on 16th Feb 2019
• Decrease in pro–inflammatory and increase in anti-
inflammatory cytokines in early pregnancy
• Increase in PIBF &
• TH2 – type & in TH1- type & NK cells
DYDROGESTERONE

40. Good Clinical Practice Recommendations. Position Statement on the use of Progestogens. Published by
Elsevier. http://www.fogsi.org/fogsi-gcpr/. Accessed on 16th Feb 2019
• High specific affinity for progesterone
receptors
• No affinity for androgen,
mineralocorticoid, glucocorticoid, &
estrogenic receptors
DYDROGESTERONE
Dydrogesterone has higher
progesterone receptor affinities

41. Dydrogesterone & Nitric Oxide
Good Clinical Practice Recommendations. Position Statement on the use of Progestogens. Published by
Elsevier. http://www.fogsi.org/fogsi-gcpr/. Accessed on 16th Feb 2019
• Influences Nitric Oxide production
which is a possible effect on survival of
embryo
• Improves blood flow , oxygen supply &
• Maintains quiescent myometrium
DYDROGESTERONE

42. Main Metabolite of Dydrogesterone
Good Clinical Practice Recommendations. Position Statement on the use of Progestogens. Published by
Elsevier. http://www.fogsi.org/fogsi-gcpr/. Accessed on 16th Feb 2019
• Retains immunomodulatory effects of
dydrogesterone
• Suppresses production of pro-inflammatory
cytokines IFN-γ &TNF-α
• Upregulates production of anti-inflammatory
cytokine IL-4
• increases nitric oxide synthesis
DIHYDRODYDROGESTERONE

43. Dydrogesterone v/s Micronized Progesterone:
Bioavailability and Oral Administration
28%
Dydrogesterone
<5% Progesterone
100–300 mg
Progesterone
10 mg
Dydrogesterone
Oral bioavailability
Dydrogesterone requires a 10–20 times lower oral dose than
micronized progesterone, providing clear clinical benefits
Dydrogesterone has 5.6 times better oral bioavailability
than progesterone
Oral dose

44. Vaginal progesterone2
Progesterone diffuses through the entire
uterus by 4–5 hours, and then decreases
concentration after 5 hours
Venous blood outflow from the uterus
was highest in the first 2 hours
Vaginal route permits targeted
drug delivery for a short period of time
Dydrogesterone1
• Has quick-effect onset (rapidly absorbed, reaching maximal levels between 30 minutes and 2.5
hours after administration)
• Has a long, stable effect (mean terminal half-life is 5–7 hours)
Dydrogesterone reaches peak absorption levels more
rapidly than vaginal progesterone, and these levels are
maintained for a longer duration
-50
50
150
250
350
0
10
20
30
40
1 2 3 4 5 6 12
ng/100
mg
tissue
%
of
total
[
3
H]
progesterone
Hours of perfusion
Output of [3H] progesterone from the vein
Endometrial extraction of progesterone
Adapted from Bulletti C et al. Hum Reprod 1997; 12(5):1073−1079

45. Vaginal discharge Vaginal bleeding
Perineal irritation
Interference with
coitus
Side effects occurring at a
greater frequency in the
NMPgroup
1. Besins Healthcare (UK) Ltd. Utrogestan oral 100 mg capsules. SPC UK. 14 July 2017
2. Besins Healthcare (UK) Ltd. Utrogestan vaginal 200 mg capsules. SPC UK. 29 June 2017
3. Tomic V, et al. Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support:
randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2015;186:49–53
Safety and Tolerability

46. Good Clinical Practice Recommendations. Position Statement on the use of Progestogens.
Published by Elsevier. http://www.fogsi.org/fogsi-gcpr/. Accessed on 16th Feb 2019
Safety
Available evidence strongly supports its safety when used in
pregnancy
No statistically significant difference in congenital abnormalities
between newborns of mothers who received Dydrogesterone &
those who did not

47. Comparing Dydrogesterone with NMP
• The orally-active progestogen Dydrogesterone
is quite attractive from this perspective.
In contrast to natural progesterone,
 Potent: 20-30 mg daily (10–20 times lower oral dose)
 High bioavailability (28%) and half-life of 5–7 hours
 Non-androgenic, non-estrogenic, non-corticoid and
non-anabolic
 Immunomodulatory role
47

48. 40mg Followed By
STAT 20mg or 30mg
PER DAY
THREATENED MISCARRIAGE
10 10
10
10
Until Symptoms Remit

49. FOGSI Position Statement 2015
: Dydrogesterone
Dydrogesterone, a progestogen that has high
specific affinity for progesterone receptors, no
affinity for androgen, mineralocorticoid,
glucocorticoid, and estrogenic receptors.

50. FOGSI statement
Immunomodulatory Action
Enhances
Implantation
Affect
Cytokine
Balance
Inhibit
Natural
Killer Cell
Activity
Inhibit
Release of
Arachidonic
Acid
Immunomodula
tory Action
Decreasing pro-inflammatory
Increasing anti-inflammatory cytokines

51. Dydrogesterone and Nitric Oxide
 Dydrogesterone Increases Nitric Oxide.
 Nitric Oxide acts as a potent vasodilator and plays a major role
in Increasing Uterine Blood Flow and Endometrial Blood Flow
during luteal phase and early pregnancy.
Increased e NOS activity
Increased e NOS synthesis
Increased NO Production
J Reprod Infertil. 2014;15(3):142-146

52. FOGSI Position Statement on
Threatened Miscarriage:
• No evidence of harm .
• Threatened Miscarriage:
Dydrogesterone: 40 mg loading dose followed
by 20-30 mg daily till 7 days after bleeding stops.

53. To conclude...
• Recent studies, Meta analysis
supports superiority of oral
dydrogesterones over NMP
• Oral dydrogesterone can effectively
prevent miscarriage in pregnant
women experiencing threatened
abortion
• Oral DYD may replace MVP as the
standard of care owing to the ease of
oral administration

54. To conclude…
• High oral bioavailability
• Is Non-androgenic, non-estrogenic, non-corticoid and non-anabolic
• Offers Patient-friendly oral administration which improves patient
compliance .
• Provides better safety and patient tolerability
As compared to natural micronized
progesterone, Dydrogesterone has:
Possess immunomodulatory property
Dydrogesterone reduces the incidence of pregnancy loss in
threatened abortion and can effectively prevent miscarriage
in pregnant women experiencing threatened abortion.