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Role of Dydrogesterone in Threatened Abortion Dr Sharda Jain
- 1. Role of Dydrogesterone in Threatened Abortion Dr. Sharda Jain Dr Jyoti Agrwal
- 2. PAN DGF ( DELHI GYNAECOLOGIST FORUM) CME ON DYDROGESTERONE ON 3/2 /22 *EXPERINCE SHARING By EXPERTS* • Dr Uma Rai(DGF *E*) • Dr Sangeetaa Gupta(DGF *E*) • Dr Neerja Varshney(DGF *E*) • Dr Surjeet Kapoor(DGF *E*) • Dr Rupam arora(DGF *E*) • Dr Meenakshi Ahuja(DGF *S* ) • Dr.Harsha khullar(DGF *C* ) • Dr Mamta mittal(DGF *N*) • Dr Leena Sreedhar(DGF *D*) • Dr.Dipti Nabh(DGF *E*) • Dr. Shama Batra(DGF *E*) • Dr Poonam Paul(DGF *SW*)
- 3. Same happen with the medical treatment
- 4. Grace fully
- 5. By regularly updating myself
- 6. 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 after pregnancy test is +) • Around 70 % of conceptions are lost prior to live birth 55 -60% pregnancies before + pregnancy test
- 7. Defining threatened Abortion - 15% A threatened abortion :PAIN or BLEEDING or BOTH Causes minimal spotting / bleeding but has not progressed to a stage where recovery is impossible 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 S/S * light bleeding * cervical os closed * Ut corresponds to dates * Fetal Cardiac activity +
- 8. Still - Why Women Does Not Discard Pregnancy ??? Preg Mismatched Organ Transplant
- 9. 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 allogenic embryo from immunologic rejection Progesterone is not only essential for conception and implantation, but also throughout pregnancy until term
- 10. Beside Aneuploidy, Low Progesterone Levels Is Associated With Increased Risk Of Miscarriage
- 12. ALL PROGESTOGENS USED ARE SYNTHETIC
- 13. Not all progestogens are equally suitable as they differ not only with respect to their potency, route of administration, bioavailability
- 14. 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 ??
- 15. Debate on Which is a better progesterone ? Wrt Bioavailability, Side effects, Ease of use ,Outcome Debate ended in 2019!!
- 17. 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
- 18. PRISM TRIAL • There was No significant increase in live births with NM .progesterone in the first trimester among women with bleeding in early pregnancy.
- 19. Clinical Evidence in Threatened abortion Starting favoring DYDROGESTERONE Since 2000 or decade earlier.
- 20. 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: • 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
- 21. Dydrogesterone in threatened abortion: Pregnancy Outcome2005 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
- 22. Influence of Oral Dydrogesterone and Vaginal Progesterone on Threatened Abortion Lee HJ, et al 2017 THE META ANALYSIS 9 RCT’s (n=913)
- 23. 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
- 24. 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
- 25. Efficacy & the safety of progestogens in the treatment of threatened miscarriage 7 Trials Wahabi HA, et al 2018 Cochrane Review
- 26. 2018 - Concluded that Dydrogesterone Vs No Rx 95% CI 0.38- 0.85 Vaginal Progesterone Vs Placebo 95% CI 0.47-1.21 RR 0.57 RR 0.75 Treatment with dydrogesterone compared to no treatment probably reduces miscarriage risk Treatment with vaginal progesterone Compared to placebo , probably has little or no effect in reducing the miscarriage rate
- 27. 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
- 28. 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 Reviewed Data of 2017 ,18 ,19
- 29. Dydrogesrone had clear advantage to Treat threatened miscarriage Trials included (2019) 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
- 31. Oral management with Dydrogesrerone was associated with a lower risk of miscarriage compared with vaginal NMP administration
- 32. 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
- 33. 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
- 34. 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
- 35. 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
- 36. 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
- 37. 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
- 38. 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
- 39. 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
- 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 Safety of NMP & Dydrogesterone 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
- 41. Comparing Dydrogesterone with NMP • The orally-active progestogen Dydrogesterone is quite attractive . 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 41
- 42. 40mg Followed By STAT 20mg or 30mg PER DAY THREATENED MISCARRIAGE 10 10 10 10 Until Symptoms Remit
- 43. 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.
- 44. 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
- 45. Immunomodulating Effects of Dydrogesterone and Positive Outcomes Patki A, et al. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72. Th: T helper; IFNγ: Interferon gama; TNFα: Tumor necrosis factor-alpha. Harmful cytokine Embryo/fetus T-helper 1 cell response activated Tumor necrosis factor- , interleukin-2 Abortion of fetus Natural killer cells Immunological reactions during recurrent pregnancy loss Lymphokine-activated killer cells …Caring hearts, healing hands
- 46. Dydrogesterone Induces PIBF Production Patki A, et al. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72. PIBF: Progesterone induced blocking factor. Immunological reactions during successful pregnancy Dydrogesteron e induces PIBF production. Progesterone receptor activation Progesterone-induced blocking factor Blocks cascade reaction, shift to T-helper type 2 Embryo-protective immunomodulation Protection of embryo/fetus …Caring hearts, healing hands
- 47. 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
- 48. FOGSI Position Statement(2015 0 on dose 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.
- 49. TENDER LOVING CARE Threatened Miscarriage Dydrogestrone + MagicalEffects
- 51. To conclude... • Evidence supports superiority of oral dydrogesterones over NMP • Oral DYD may replace MVP as the standard of care owing to the ease of oral administration
- 52. 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.
Notas do Editor
- We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups.
- Introduction: Threatened miscarriage is a common problem during pregnancy. Methods: The aim of this prospective, open, randomised study was to determine whether dydrogesterone was more effective than conservative management alone in preventing miscarriage in women with vaginal bleeding up to week 16 of pregnancy. Women were excluded if they had a history of recurrent miscarriage. A total of 191 women were randomised to dydrogesterone (40 mg stat followed by 10 mg twice daily) or conservative management (control group). The treatment was considered successful if the pregnancy continued beyond 20 weeks of gestation. Results: The success rate in the dydrogesterone group was statistically significantly higher than that in the control group (87.5% vs. 71.6%; p < 0.05). Miscarriage occurred in 12.5% of women in the dydrogesterone group compared with 28.4% in the control group (p < 0.05). There were no differences between the groups with regard to the incidence of Caesarean section, placenta praevia, antepartum haemorrhage, preterm labour (weeks 28–36), pregnancy-induced hypertension or low birth weight The women were randomised to receive treatment with dydrogesterone (40 mg stat followed by 10 mg twice daily) or conservative management with bed rest only (control group). Randomisation was achieved by asking the patients to select a sealed envelope containing one of the treatment options. Treatment continued until 16 weeks of gestation and the women were followed up until the end of pregnancy. Women using dydrogesterone were not specifically recommended bed rest. The treatment was considered successful if the pregnancy continued beyond 20 weeks of gestation
- The treatment group comprised patients who received dydrogesterone 40 mg stat, followed by 10 mg twice a day. until the bleeding stopped. They were also recommended bed rest and received folic acid. The control group comprised patients who were managed conservatively with bed rest and folic acid only. The patients were also advised to avoid sexual intercourse. The subjects were followed up until 20 weeks gestation. Objective: To determine whether therapy with dydrogesterone in threatened abortion during the first trimester of pregnancy will improve pregnancy outcome. Design: Prospective open study. Subjects: Pregnant women presenting to the obstetric and gynaecology clinic admitting center with vaginal bleeding before 13 weeks gestation were evaluated for entry into the study. Women were excluded if they had a history of recurrent miscarriage. Method: Eligible subjects were randomized to receive either dydrogesterone 40 mg stat dose followed by 10 mg twice a day for one week or conservative therapy. Results: One hundred and 54 women were recruited. There was no statistically significant differences between the two groups with regard to pre-treatment status. The continuing pregnancy success rate was significantly (p = 0.037) higher in women treated with dydrogesterone (95.9%) compared with women who received conservative treatment (86.3%). The odds ratio of the success rate between dydrogesterone treatment and non-treatment was 3.773 (95% confidence interval: 1.009–14.108). Conclusion: Corpus luteal support with dydrogesterone has been shown to reduce the incidence of pregnancy loss in threatened abortion during the first trimester in women without a history of recurrent abortion. © 2005 Elsevier Ltd. All rights reserved.
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- Dydrogesterone benefits from a prolonged effect compared with micronized vaginal progesterone, as it is rapidly absorbed and gives stable plasma levels of the drug1,2 Vaginal progesterone allows targeted delivery (to the uterus) with minimal systemic side effects2 However, absorption of vaginal progesterone takes 4–5 hours compared with only 30 minutes to 2.5 hours for dydrogesterone (oral administration)1,2 Dydrogesterone also has a long, stable effect, with a mean terminal half-life of 5–7 hours, whereas progesterone concentration in the uterus decreases after 5 hours1,2 The figure shows the results of vaginal application of progesterone to perfused uteri in vitro.2 Endometrial extraction of progesterone (tissue absorption) peaked 5 hours after application. Progesterone levels in the venous outflow represent the amount of drug leaving the organ and were highest in the first 2 hours after administration. References Abbott Laboratories. Company Core Data Sheet. Dydrogesterone. 5 July 2017 Bulletti C, de Ziegler D, Flamigni C, et al. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod 1997;12(5):1073–1079.
- Until symptoms remit
- Progesterone acts via its own receptor to produce a mediator protein known as progesterone-induced blocking factor (PIBF). It favors the development of human T helper (Th) cells producing Th2-type cytokines and promotes the production of interleukin (IL)-4, while inhibiting embryotoxic Th1 cytokine production. In women with recurrent spontaneous abortion, dydrogesterone inhibits the production of the Th1 cytokines, interferon-gama, and tumor necrosis factor-alpha (TNFα) from lymphocytes and upregulates production of the Th2 cytokines IL-4 and IL-6, thereby inducing a Th1 to Th2 cytokine shift. Reference Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
- Dydrogesterone also induces progesterone-induced blocking factor (PIBF) production. Thus, apart from progestogenic properties, dydrogesterone has been shown to have immunomodulating effects, which favor a successful pregnancy. Reference Patki A, Pawar VC. Modulating fertility outcome in assisted reproductive technologies by the use of dydrogesterone. Gynecol Endocrinol. 2007;23 (Suppl 1):68–72.
- She should be treated compassionately and with sensitivity TENDER LOVING CARE