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miscarriage.pptx

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miscarriage.pptx

  1. 1. HOW TO REDUCE MISCARRIAGE ? Prof. Hesham Al-Inany 1
  2. 2. Concept • Prevention is better than Cure
  3. 3. Prevention vs Reduction • Can we prevent Miscarriage ? • Can we reduce Miscarriage rate?
  4. 4. Introduction Miscarriage: Sporadic – Recurrent ACOG 2015: Two or more : Because the risk of a recurrent loss is fairly high after 2 losses (26%), we have to start work-up after 2 losses. Specifically with AMA
  5. 5. MATERNAL AGE Maternal age Clinical Preclinical < 20 y 12.2 % 20 % 20-24 14.3 29 25-29 13.7 30 30-34 15.5 35 35-39 18.7 40 40-44 33.8 45 > 44 53.8 65 Human Reproduction 12:387,2012
  6. 6. Etiology Even an extensive workup will fail to find a recognizable cause in up to 50% of cases Mostly attributed to : Immune system Aneuploidy So how to reduce ?
  7. 7. AGENDA 2 3 4 INTRODUCTION 1 Immunomodulation CONCLUSION AND TAKE HOME MESSAGE NIPGT
  8. 8. PROGESTERONE Progesterone (ng/ml) Progesterone Weeks of pregnancy 4 8 12 14 16 20 24 28 32 36 40 100.0 50.0 10.0 5.0 1.0 0.5 0.1 0.05 Plasma levels of Progesterone in pregnancy are of 125-200 ng/ml (vs 11 ng/ml of luteal phase) Decrease of pregestrone plasma levels is associated with triggering of labor in most animal species
  9. 9. PROGESTERONE: IMMUNOLOGIC PROPERTIES  CITOCHINE TH2 (IL-3, IL-4, IL-10…)  PIBF production by TH2 Lymphocytes Direct inhibition of NK cells  LIF production by Lymphocyte  PP14 endometrial production  T-Suppressor (CD4)/T-Cytotoxic (CD8) RATIO CELL-MEDIATED RESPONSE HUMORAL MEDIATED RESPONSE Lymphocyte B, Plasma cells Lymphocyte T, NK cells
  10. 10. Progesterone Arachidonic Acid Prostaglandins Immunomodulation PROGESTERONE INDUCED BLOCKING FACTOR “PIBF” Phospholipase A2 Phospholipase C CYTOKINE BALANCE IL -2; 12 ; IFN gamma; IFN alfa IL - 4; 5; 10 NK cells Activity
  11. 11. Additional Role of Progesterone 2.0 2.5 3.0 3.5 4.0 4.5 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 UC Frequency/min 0% 5% 10% 15% 20% 25% <3.0 3.1-4.0 4.1-5.0 >5.0 (Fanchin et al, 1998) (De Ziegler et al, 1996) UC/min UC = uterine contractions.
  12. 12. WAYS OF ADMINISTRATION OF PROGESTERONE INTRAMUSCULAR ? TRANSVAGINAL ? ORAL ?
  13. 13. Convenience and Side Effects Intramuscular pain Local Reaction, Severe Allergic Reaction (rare) Vaginal irritation, and soreness
  14. 14. LOTUS STUDY A double-blind, double-dummy, randomized, multicenter, multinational study comparing the efficacy, safety and tolerability of oral dydrogesterone 30 mg versus MVP capsules 600 mg daily for luteal support in IVF • 38 sites, in 7 countries: Austria, Belgium, Finland, Germany, Israel, Russia, Spain
  15. 15. 1066 Participants Screening and enrolment Day–14 Days 2–7 Embryotransfer Post-treatment safety evaluationevery 2 months Follow-up 30 days or6 months after deliverya Oral dydrogesterone 30 mg (n=520) MVP 600 mg (n=511) Day–1 Week 12 ofgestation End of treatment OR and treatment start Week 10 of treatment Ultrasound performed Day 1 Weeks of Gestation Week 4 Week 8 Pregnancy test (serum β hCG and urine striptest) Weeks of Treatment
  16. 16. PATIENT FLOW Assessed for eligibility (n=1143) Excluded (n=112) • Screening failures (n=104) • Terminated prematurely (n=8) Full analysis sample (n=497) • Excluded from analysis: • Embryo transfer not successful (n=22) • Did not receive allocated intervention (n=1) Per protocol sample (n=492) • Excluded from analysis: • Excluded from the full analysis sample (n=23) • Major protocol deviations unrelated to treatment (n=5) Lost to follow-up (n=5) Discontinued (n=342) Allocated to oral DYD (n=520) • Received allocated intervention(n=519) – Safety Sample • Did not receive allocated intervention (n=1) Lost to follow-up(n=5) Discontinued (n=364) Allocated to MVP(n=511) • Received allocated intervention(n=510) – Safety Sample • Did not receive allocated intervention (n=1) Full analysis sample (n=477) • Excluded from analysis: • Embryo transfer not successful (n=33) • Did not receive allocated intervention (n=1) Per protocol sample (n=475) • Excluded from analysis: • Excluded from the full analysis sample (n=34) • Major protocol deviations unrelated to treatment (n=2) Randomized (n=1031)
  17. 17. Results aPercentages are based on the number of subjects in the full analysis sample with data available. BMI values were calculated from the following populations: bn=496; cn=476; dn=972 Copyright ClearanceCenter, Inc. Oral DYD (n=497) MVP (n=477) Total population (N=974) Mean age, years (SD) 32.5 (4.5) 32.5 (4.4) 32.5 (4.4) Age category, n (%)a ≤35 years of age 352 (70.8) 348 (73.0) 700 (71.9) >35 years of age 145 (29.2) 129 (27.0) 274 (28.1) Race or ethnicity, n (%)a Caucasian 485 (97.6) 453 (95.0) 938 (96.3) Black or African American 9 (1.8) 14 (2.9) 23 (2.4) Asian 4 (0.8) 9 (1.9) 13 (1.3) Other 0 (0.0) 2 (0.4) 2 (0.2) Mean BMI, kg/m2 (SD) 23.3 (3.1)b 23.2 (3.1)c 23.2 (3.1)d Prior treatment, n (%)a 30 (6.0) 25 (5.2) 55 (5.6)
  18. 18. OUTCOMES Oral DYD (30 mg) MVP (600 mg) Total population Number of subjects who underwent embryo transfer, n 497 477 974 Subjects who underwent embryo transfer after ICSI, n (%)a 368 (74.0) 338 (70.9) 706 (72.5) Day of embryo transfer after oocyte retrieval, n (%)a <5 days 350 (70.4) 328 (68.8) 678 (69.6) ≥5 days 147 (29.6) 149 (31.2) 296 (30.4) Number of embryos transferred, n (%)a 1 212 (42.7) 217 (45.5) 429 (44.1) 2 278 (55.9) 252 (52.8) 530 (54.4) >2 7 (1.4) 8 (1.7) 15 (1.5) Number of subjects who had at least one newborn, n (%)a 172 (34.6) 142 (29.8) 314 (32.2)
  19. 19. NNT Pregnan cy rate % (n/N) Difference in pregnancyratea (OralDYD– MVP) 95% CI Oral DYD MVP FAS 37.6 (187/497) 33.1 (158/477) 4.7 –1.2, 10.6 PPS 37.6 (185/492) 33.1 (157/475) 4.7 –1.2, 10.6 NNT with oral DYD to obtain a benefit versus MVP would be 22 Non-inferiority margin Favors MVP -15 -10 -5 0 5 10 Favors oral DYD 15
  20. 20. LBR Rates of live births were similar between the two treatment groups, withnumerical differences in favor of oral DYD In the FAS, the NNT with oral DYD to obtain a benefit versus MVP would be 21 (95%CI for absolute risk reduction of NNT [benefit] 9.3 to NNT [harm]125]) Live birt h rate % (n/N) Difference in pregnancyrate (OralDYD– MVP) 95% CI Oral DYD MVP FAS 34.6 (172/497) 29.8 (142/477) 4.9 –0.8, 10.7 PPS 34.6 (170/492) 29.9 (142/475) 4.7 –1.1, 10.5 Non-inferiority margin Favors MVP -15 -10 -5 0 5 10 Favors oralDYD 15
  21. 21. 2018: PROMISE Trial: RPL
  22. 22. Cochrane 2019
  23. 23. 2020: PRISM Trial : Threatened abortion live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (RR, 1.28; 95% CI, 1.08–1.51; P=.004 NNT = 8
  24. 24. 2021 : Cost analysis • An average cost of £204 per pregnancy, the use of progesterone was cost-effective in reducing miscarriage rate.
  25. 25. 75% • Consultants in UK prescribe progesterone for reducing miscarriage rate
  26. 26. AGENDA 2 3 4 INTRODUCTION 1 Immunomodulation TAKE HOME MESSAGE NIPGT
  27. 27. Aneuploidy Preimplantation genetic screening (PGS) is widely used to select in vitro-fertilized embryos free of chromosomal abnormalities and to improve the clinical outcome of in vitro fertilization (IVF) (Xu et al. 2016)  However PGS is invasive , requires specialized skills, suffers from false +ve and –ve. (Huang et al., 2019)
  28. 28. PGT Braude, P., Pickering, S., Flinter, F. et al. Preimplantation genetic diagnosis. Nat Rev Genet 3, 941–953 (2002). https://doi.org/10.1038/nrg953
  29. 29. NIPGT NIPGT is a less-invasive technique to assess the genetic and chromosomal defects. The goal of the NIPGT is to utilize the cell free embryonic DNA (cfeDNA) in assessment of chromosomal status of the embryo (NIPGT-A). Kuznyetsov et al., 2019 & Cimadomo et al., 2016)
  30. 30. Methods for NIPGT Embryo spent culture medium Blastoceol fluid Combined Embryo spent culture medium + blastoceol fluid CELL FREE EMBRYONIC DNA Palini et al., 2013, Tobler et al., 2015 & Gianaroli et al., 2014 (Assou et al. 2014, Xu et al., 2016 Blendares et AL., 2018)al Jiao et al., 2019, Li et al.,2018​​
  31. 31. Combined Embryo spent culture medium + blastoceol fluid Kuznyetsov et al. (2018) N47 Day 4-6 embryos (28thawed- 19 fresh)
  32. 32. Should We Offer IVF/NIPGT to Couples with Unexplained RPL? Rationale Evidence Improve subsequent live birth rate No evidence to support using IVF for this purpose Shorten the time to conceive To date, IVF has not shown any benefit Improve embryo quality by sperm selection, PGT-A and morphological evaluation Might improve pregnancy outcome but powered studies needed Improving implantation Evidence lacking, so can’t be recommended. Improve synchrony between endometrium and embryo Might be justified in order to avoid non optimal timing of intercourse or conception. • Only if AMA
  33. 33. TAKE HOME MESSAGE Ø Progesterone Can help to prevent miscarriage Ø NIPGT in recurrent miscarriage in AMA is yet to be tested.
  34. 34. 98 THANK YOU

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