Miscarriage is the commonest complication in pregnancy. One in four pregnancies ends this way. The physical experience can be awful in itself, but in the words of a patient, "the grief of miscarriage can last forever." The commonest question for women who have experienced miscarriage is simple--why did it happen? The answer is rarely apparent. Many so-called "treatments" to prevent miscarriage are unproven. But recent research suggests some miscarriages may be prevented with progesterone. In this talk for clinicians, I explored the most recent evidence.

1. Is there a place for
progesterone in the
management of
miscarriage?
Dr Matthew Prior
1

2. Matthew Prior
• Consultant in Reproductive
Medicine, Newcastle, UK.
• PhD from University of
Nottingham.
• RCOG Council 2014 - 2017.
• Academic and clinical interest
in miscarriage.
2

3. Background
• Priorities for research in miscarriage.1
• Inadvertent P-hacking of the effect of progestogens in
pregnancy? 2
• Progesterone to prevent miscarriage: a critical
evaluation of randomized evidence.3
3
Coomarasamy, 2020 AJOG
2
Prior, 2017 BJOG
1
Prior, 2017 BMJ Open
3

4. Agenda
1. Miscarriage
2. Progesterone treatment
3. Two trials
4. Implications for practice
4

5. Miscarriage
• One in four pregnancies.
• Impact:
• Physical
• Psychological
5

6. The grief of miscarriage can last
forever
— Julia Bueno
6

7. Case Study
• 30 years old
• 7 miscarriages
• 4 cytogenetics normal
• last miscarriage trisomy 12
• Investigations normal
• 6 weeks pregnant
• woke up this morning with
spotting
7

8. "Doctor, please help me"
— what are her options?
8

9. What unanswered questions about miscarriage would you
like to see answered by research? 1
Generic causation
Support
Prevention
Specific causation
Investigation
Prognosis
Treatment
Diagnosis
Systems
Management
Risk factors
Incidence
Pathology
Society
Terminology
Screening
Follow up
Association with other conditions
Twins
Do embryos feel pain
0 100 200 300 400
1
Prior, 2017 BMJ Open
9

10. Why did it happen?
10

11. Top 10 priorities for miscarriage research 1
1. Research into preventative treatments.
2. Emotional aspects in general.
3. Investigation.
4. Relevance of pre-existing medical conditions.
5. Emotional support as a treatment.
6. Importance of lifestyle factors.
7. Importance of genetic and chromosomal causes.
8. Preconception tests.
9. Investigation after different numbers of miscarriage.
10. Male causal factors.
1
Prior, 2017 BMJ Open
11

12. Miscarriage treatment options
What does Cochrane say?
12

13. What about
progesterone?
13

14. Case Study
• Young woman - 6 miscarriages
• Pregnant - progesterone
• Live birth
• Pregnant again – progesterone
• Miscarriage
• Pregnant yet again –
progesterone
• Live birth
14

15. The clue is in the name
Pro-gest-erone
“Pro” [Latin] prefix:
“in favour of“
“Gestare” [Latin] to bear:
“period between conception & birth”
“[er]one” [informal] suffix:
“hormone”
15

16. Progesterone is essential for pregnancy
• Removal of corpus luteum or anti-progestogen ends
pregnancy.
• But no human progesterone deficiency state has been
described.
16

17. Steroid hormones
17

18. A treatment for miscarriage?
18

19. Finding a treatment?
1. Problem: Identify a cause for miscarriage
• Luteal Phase Defect
2. Test: Identify an accurate test for the cause
• Salivary Progesterone
• Serum Progesterone
• Endometrial histology
3. Treatment: Find an effective treatment
• Progesterone
19

20. Progesterone as a treatment?
1. Identify a cause for miscarriage
• LPD poorly defined
2. Identify an accurate test for the cause
• Diagnostic value unclear
• Prognosis unclear
• Direction of causality
3. Find an effective treatment
• Which patients to target for a trial?
20

21. Looking for evidence 4
Study
El-Zibdeh 2005
Goldzieher 1964
Le Vine 1964
Swyer 1953
Total
Progesterone
events / total
11/82
1/8
4/15
7/27
3/74
Control
events / total
14/48
4/10
1/17
8/15
9/20
Odds Ratio
M-H, Fixed, [95% CI]
0.38 [0.15, 0.92]
0.21 [0.02, 2.48]
0.32 [0.07, 1.47]
0.43 [0.12, 1.47]
0.36 [0.19, 0.68]
0.10 0.20 0.50 1.0 2.0 5.0 10.0
Favours Progesterone Favours Control
4
Coomarasamy, 2011 BMJ
21

22. Plausible effect size
• Background miscarriage rate (25%)
• Half chromosomal (12.5%)
• Non-chromosomal miscarriages (including LPD) (12.5%)
• Progesterone problem (assume ½) related miscarriages (7%)
• If progesterone prevents ½ of these miscarriages,
miscarriages prevented: (3.5%)
• Uplift in live birth (3.5%)
22

23. A progesterone RCT?
1. Very large trial
2. Enrichment
23

24. Enrichment
Unselected
1000 women
Enriched
1000 women
Problem 50 (5%) Problem 200 (20%)
24

25. Enrichment
• Previous miscarriages
25

26. Fetal karyotype with the number of previous miscarriages5
5
Ogasawara, 2000 Fert Steril
26

27. Two trials
— PROMISE and PRISM
27

28. PROMISE
— PROgesterone in recurrent MIScarriagE
28

29. PROMISE
• Population
• Women with unexplained recurrent miscarriages trying to conceive
naturally.
• Intervention
• 400 mg progesterone taken vaginally twice daily from no later than 6 weeks
until 12 weeks.
• Comparison
• Placebo.
• Outcome
• Live birth beyond 24 weeks.
29

30. Primary Outcome6
Progesterone
(LB / total)
Placebo
(LB / total)
RR (95% CI)
Live birth ≥ 24
weeks
262/398
(65.8%)
271/428
(63.3%)
1.04
(0.94, 1.15)
p=0.45
6
Coomarasamy, 2015 NEJM
30

31. Case Study
32 years old
- 6 miscarriages
- No live births
- Investigations – normal
- Requests progesterone
• Based on the PROMISE trial,
would you recommend
progesterone for this woman?
31

32. Fetal karyotype with the number of previous miscarriages5
5
Ogasawara, 2000 Fert Steril
32

33. Subgroup Effects 6
Previous losses
(n)
Progesterone
(LB / total %)
Placebo
(LB / total %)
Increase in LB p-value
3 148/218 (67.9%) 159/236 (67.4%) +0.5% 0.91
4 61/82 (74.4%) 70/103 (68.0%) +6.4% 0.33
5 28/55 (50.9%) 21/48 (43.8%) +7.1% 0.47
6 or more 27/47 (57.4%) 20/40 (50.0%) +7.4% 0.49
6
Coomarasamy, 2015 NEJM
33

34. Analyses
Previous miscarriages
Pre-specified
3
≥4
Post-hoc
3
4
5
≥6
All Participants
Progesterone
events / total
148/128
114/180
148/128
60/79
28/55
26/46
262/398
Control
events / total
159/236
112/192
159/236
70/103
21/48
21/41
271/428
Risk Ratio
95% CI
1.01 [0.89, 1.14]
1.09 [0.92, 1.28]
1.01 [0.89, 1.14]
1.12 [0.93, 1.34]
1.16 [0.77, 1.76]
1.10 [0.75, 1.63]
1.04 [0.94, 1.15]
0.75 1.0 1.25 1.5 1.75
Favours Control Favours Progesterone
34

35. PRISM
— PRogesterone In Spontaneous Miscarriage
35

36. Meta-analysis of studies of progesterone in women with
early pregnancy bleeding 7
Study
Misto 1967
Ehrenskjold 1967
Gerhard 1987
Palagianon 2004
Omar 2005
El-Zibdeh 2009
Pandian 2009
Summary
Progesterone
events / total
0/7
14/72
0/17
4/25
3/74
15/86
12/96
48/377
Control
events / total
2/9
23/81
1/17
8/25
11/80
15/60
27/95
87/367
Risk Ratio
M-H, Fixed, 95% CI
0.25 [0.01, 4.50]
0.68 [0.38, 1.23]
0.33 [0.01, 7.65]
0.50 [0.17, 1.45]
0.29 [0.09, 1.02]
0.70 [0.37, 1.32]
0.44 [0.24, 0.82]
0.39 [0.53, 0.73]
0.10 0.20 0.50 1.0 2.0 5.0 10.0
Favours Progesterone Favours Control
7
PRISM Protocol, 2016, NIHR Journals Library
36

37. PRISM
• Population
• Women with early pregnancy bleeding.
• Intervention
• 400 mg progesterone taken vaginally twice daily until 16 weeks.
• Comparison
• Placebo.
• Outcome
• Live birth beyond 34 weeks.
37

38. Primary Outcome8
Progesterone
(LB / total)
Placebo
(LB / total)
RR (95% CI)
Live birth ≥ 34
weeks
1513/2025
(75%)
1459/2013
(72%)
1.03
(1.00, 1.07)
p=0.08
8
Coomarasamy, 2019, NEJM
38

39. Primary Outcome8
Live birth ≥ 34 weeks
Outcome
Primary
Progesterone
events / total
1513/2025
Control
events / total
1459/2013
Risk Ratio
95% CI
1.03 [1.00, 1.07]
0.95 1.0 1.05 1.1
Favours Control Favours Progesterone
8
Coomarasamy, 2019, NEJM
39

40. Case Study
27 years old
- One previous miscarriage
- 6 weeks pregnant
- Anxious regarding Covid-19
- Spotting
- Requests progesterone
• Based on the PRISM trial,
would you recommend
progesterone for this woman?
40

41. Subgroup analysis8
Number of
previous
miscarriages
Progesterone Placebo Risk Ratio
(95% CI)
P-value
0 824/1111 (74%) 840/1127 (75%) 0.99 (0.95, 1.04) 0.71
1-2 591/777 (76%) 534/738 (72%) 1.05 (1.00, 1.12) 0.07
≥3 98/137 (72%) 85/148 (57%) 1.28 (1.08, 1.51) 0.004
Any number of
previous
miscarriages (≥1)
689/914 (75%) 619/886 (70%) 1.09 (1.03 – 1.15) 0.003
8
Coomarasamy, 2019, NEJM
41

42. Biological gradient8
Previous miscarriages
0
1
2
≥3
Summary
Progesterone
events / total
824/1111
413/547
178/230
98/137
1513/2025
Control
events / total
840/1127
367/502
167/236
85/148
1459/2013
Risk Ratio
95% CI
0.99 [0.95, 1.04]
1.04 [0.97, 1.12]
1.08 [0.97, 1.19]
1.28 [1.08, 1.51]
1.03 [1.00, 1.07]
0.75 1.0 1.25 1.5
Favours Control Favours Progesterone
8
Coomarasamy, 2019, NEJM
42

43. Overall effect on live birth3
Study
PRISM
PROMISE
Total
Progesterone
events / total
1513/2025
262/398
1775/2423
Control
events / total
1459/2013
271/428
1730/2441
Risk Ratio
95% CI
1.03 [1.00, 1.07]
1.04 [0.94, 1.15]
1.03 [1.00, 1.07]
0.90 1.0 1.1 1.2
Favours Control Favours Progesterone
3
Coomarasamy, 2020 AJOG
43

44. Implications for practice
44

45. Who should we prescribe progesterone for?
1. Women with recurrent miscarriage?
2. Women with ‘higher order’ recurrent miscarriage?
3. Women with threatened miscarriage?
4. Women with threatened miscarriage and a
miscarriage history?
45

46. First do no harm...
Rate of congenital anomalies
Progesterone Placebo RR (95% CI) P-value
PROMISE 8/266 11/276 0.75 (0.31,
1.85)
p=0.54
PRISM 53/1574 51/1551 1.00 (0.69,
1.47)
p=0.99
46

47. Doctor, please help me
— what are your options?
47

48. Suggested protocol
Bleeding?
YesNo
Less than 12 weeks gestation
Standard care
Less
than 4 previous
losses?
Progesterone
Previous
miscarriage?
No No
Yes
Progesterone
Yes
Standard care
Higher order recurrent
miscarriage
Threatened miscarriage +
≥ 1 previous loss
RR = 1.12 (0.95 – 1.32)
NNT = 14
RR = 1.09 (1.03 – 1.15)
NNT (1 or 2 misc) = 25
NNT (3 or more) = 8
Yes
48

49. https://www.youtube.com/
watch?
v=MjrYSVZ4-94#action=share
49

50. Acknowledgements
Professor Arri Coomarasamy Professor Jim Thornton
University of Birmingham University of Nottingham
50

51. Suggested protocol
Bleeding?
YesNo
Less than 12 weeks gestation
Standard care
Less
than 4 previous
losses?
Progesterone
Previous
miscarriage?
No No
Yes
Progesterone
Yes
Standard care
Higher order recurrent
miscarriage
Threatened miscarriage +
≥ 1 previous loss
RR = 1.12 (0.95 – 1.32)
NNT = 14
RR = 1.09 (1.03 – 1.15)
NNT (1 or 2 misc) = 25
NNT (3 or more) = 8
Yes
51