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HOW TO REDUCE
MISCARRIAGE ?
Prof. Hesham Al-Inany
1
Concept
• Prevention is better than Cure
Prevention vs Reduction
• Can we prevent Miscarriage ?
• Can we reduce Miscarriage rate?
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
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
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 ?
AGENDA
2
3
4
INTRODUCTION
1
Immunomodulation
CONCLUSION AND TAKE HOME MESSAGE
NIPGT
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
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
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
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.
WAYS OF ADMINISTRATION OF
PROGESTERONE
INTRAMUSCULAR
?
TRANSVAGINAL
?
ORAL
?
Convenience and Side Effects
Intramuscular
pain
Local Reaction,
Severe Allergic Reaction
(rare)
Vaginal
irritation, and soreness
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
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
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)
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)
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)
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
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
2018: PROMISE Trial: RPL
Cochrane 2019
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
2021 : Cost analysis
• An average cost of £204 per pregnancy, the use of
progesterone was cost-effective in reducing miscarriage rate.
75%
• Consultants in UK prescribe progesterone for reducing
miscarriage rate
AGENDA
2
3
4
INTRODUCTION
1
Immunomodulation
TAKE HOME MESSAGE
NIPGT
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)
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
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)
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​​
Combined Embryo spent culture medium +
blastoceol fluid
Kuznyetsov et al. (2018)
N47 Day 4-6 embryos (28thawed- 19 fresh)
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
TAKE HOME MESSAGE
Ø Progesterone Can help to prevent
miscarriage
Ø NIPGT in recurrent miscarriage in AMA is
yet to be tested.
98
THANK
YOU

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miscarriage.pptx

  • 1. HOW TO REDUCE MISCARRIAGE ? Prof. Hesham Al-Inany 1
  • 2. Concept • Prevention is better than Cure
  • 3. Prevention vs Reduction • Can we prevent Miscarriage ? • Can we reduce Miscarriage rate?
  • 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. 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. 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 ?
  • 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. 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. 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. 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.
  • 13. WAYS OF ADMINISTRATION OF PROGESTERONE INTRAMUSCULAR ? TRANSVAGINAL ? ORAL ?
  • 14. Convenience and Side Effects Intramuscular pain Local Reaction, Severe Allergic Reaction (rare) Vaginal irritation, and soreness
  • 15. 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
  • 16. 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
  • 17. 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)
  • 18. 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)
  • 19. 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)
  • 20. 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
  • 21. 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
  • 24. 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
  • 25. 2021 : Cost analysis • An average cost of £204 per pregnancy, the use of progesterone was cost-effective in reducing miscarriage rate.
  • 26. 75% • Consultants in UK prescribe progesterone for reducing miscarriage rate
  • 28. 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)
  • 29. 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
  • 30. 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)
  • 31. 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​​
  • 32. Combined Embryo spent culture medium + blastoceol fluid Kuznyetsov et al. (2018) N47 Day 4-6 embryos (28thawed- 19 fresh)
  • 33. 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
  • 34. TAKE HOME MESSAGE Ø Progesterone Can help to prevent miscarriage Ø NIPGT in recurrent miscarriage in AMA is yet to be tested.