Miscarriage is pregnancy loss before 22 weeks’ gestation based on the LMP or if gestation age is unknown, it is the loss of an embryo or a fetus of less than 500g.

1. Treating Threatened Miscarriage
– What does the evidence say?

2. WHAT IS MISCARRIAGE?
• Miscarriage is pregnancy loss before 22 weeks’
gestation based on the LMP or if gestation age is
unknown, it is the loss of an embryo or a fetus of less
than 500g.
So why does it matter?

3. WHY DOES IT MATTER?

4. Miscarriage: Why Does It Matter?
• It is the most prevalent complication in pregnancy, affecting 1 in 4 pregnancies.
• Psychological Morbidity;
 Level of distress has been shown to be equivalent to stillbirth at term.
 After a miscarriage 30%–50% of women experience anxiety symptoms and 10%–
15% experience depressive symptoms, , which commonly persist up to 4 months
(3).
• Physical Complications;
 Vaginal bleed.
 Infection.
 Surgical or medical evacuation and its associated morbidities.
• Mortality
• Socio-economic effect.

5. Even if the pregnancy survives > 22 weeks
Threatened miscarriage is associated with:
• Increased rate of antepartum
haemorrhage.
• PROM.
• Preterm delivery.
• IUGR.

6. Can We Help Our Patient in
Preventing Miscarriage?
• Complete miscarriage.
• Septic miscarriage.
• Inevitable miscarriage.
• Threatened miscarriage.
• History of Recurrent miscarriage.

7. The Question Is ……
History of recurrent
miscarriage
Threatened Miscarriage
Miscarriage
PREVENTABLE?
Pregnancy
Continues
Late Complications

8. THREATENED MISCARRIAGE

9. Therapeutic Strategies for Management of
Threatened Miscarriage
Proposed treatment include:
• Bed rest.
• HCG injection.
• Progestagen.

10. Bed Rest
• The hypothesis:
Hard work and hard physical activity during pregnancy
are associated with miscarriage, bed rest might reduce
the risk.
(Lapple 1990).
• The fact:
Most of the causes of miscarriage are not related to
physical activity.

11. Aleman A, 2005

12. In Addition…
• Bed rest may increase the likelihood of thromboembolic
events. (Kovacevich 2000)
• Muscle atrophy and symptoms of musculoskeletal and
cardiovascular deconditioning. (Maloni1993; Maloni
2002)
• May be stressful and costly for women and their family.
(Crowther 1995; Gupton 1997; Maloni 2001; May1994)
• May induce self blame feelings in case of failure to
comply to the prescribed treatment of bed rest.

13. Role of hCG?
• Human chorionic gonadotrophin (hCG) is secreted by the
syncytiotrophoblast.
• It promotes the corpus luteum to secrete progesterone and
helps in maintaining the pregnancy.
Objective of Meta-analysis:
To assess the effectiveness of hCG in the treatment of
threatened miscarriage compared to placebo and no treatment
of any other intervention.
Size ofstudy
There was no statistically significant difference in the incidence of miscarriage
between hCG and 'no hCG' (placebo or no treatment) groups.
(Risk ratio (RR) 0.66; 95% CI 0.42 to 1.05)
Deevaselvan et al, Cochrane 2010

14. Role of Progestagens
• Progestational agents have been prescribed since 1950s to prevent
miscarriages.
• The progestagens are one of the five major classes of steroid
hormones which binds to progesterone receptor:
• 2 types of Progestagens:
- Natural Progesterone.
- Synthetic form/Progestin.
The main sites of progesterone biosynthesis are:
• The ovaries and the adrenal cortices in non-pregnant.
• The ovaries in early pregnancy followed by the placenta.

15. Pro – Gestagens = Pro - Pregnancy
Physiological role of Progestagens in maintaining pregnancy:
• Enhances implantation by:
 Inhibiting endometrial proliferation.
 Promoting differential of the endometrium.
 Immunomodulatory Effect:
 Affect cytokines balance.
 Inhibit natural K cells activities at the fetomaternal interface.
 Promoting the synthesis of Progesterone Induced Blocking Factors
(PIBF) by lymphocytes, favouring production of pregnancy protecting
antibodies.
• Prevent myometrial contactility.
• Prevent cervical dilatation.

16. A fetus is a semi-allograft

17. Immunology Revisited

18. Figure 2 CD4+T cells can differentiate into type 1 (Th1) or type 2 (Th2) helper cells.
J C Warning et al. Reproduction 2011;141:715-724
© 2011 Society for Reproduction and Fertility

19. Favourable for Pregnacy

20. PIBF and the Th1-Th2 balance
• Progesterone- induced blocking factor (PIBF) is
an immunomodulatory molecule secreted by
lymphocytes.
PIBF

21. Further substantiated by…..
• Leutectomy prior to 7 weeks causes
miscarriage.
• Low progesterone levels have been linked to
increase risk of first trimester miscarriage.
• Progesterone antagonist (mifepristone) has
been successfully used in induction of
abortion.

22. Studies on Progestagen in The Prevention of
Threatened Miscarriage: The Challenges.
• Various type of progestagens have been utilised:
 Oral progestagens:
• Dydrogesterone.
- Good safety and tolerability profile.
- Structurally similar to natural progesterone.
- Good oral bioavailabity.
- No androgenic effects on the fetus.
• Micronized Progesterone
• Vaginal progesterone – Micronized progesterone.
• IM Progestagen-
• Hydorxyprogesteron caproate.
• Progesterone
• Various dosages .
• Various Methodology.
• Small size of the studies.

23. Wahabi 2011

24. Progestagen vs Placebo or No Treatment in Threatened Miscarriage
Outcome: Miscarriage
Wahabi, 2011.

26. The Author concluded:
• Progestagen treatment reduced the risk of miscarriage by
47%, CI 21% to 65%.
• In the subgroup:
• Women treated with vaginal progesterone, the result was not
significant.
• Women treated with dydrogesterone, the result was significant.
“ The result of the SR should be approached with caution due
to poor methodological quality of some of the included trials
and small number of participants”

27. A Systemic Review of Dydrogesterone for The Treatment
of Threatened Miscarriage
Carp, Gynacological Endocrinology,2012.
There was statistically significant reduction in OR for miscarriage after treatment.
11% absolute reduction in miscarriage rate.

28. The Fetus Survived Miscarriage, What Next?
Wahabi,2011

30. What Do We Know So Far?
• Dydrogesterone significantly reduce risk of
miscarriage.
• Progesterone and dydrogesterone are safe in
pregnancy.
• Small studies.

31. The Issues
• Who should we treat?
• What’s the standard regime?
• What are current expert bodies
recommendations?
• Should we treat?

32. Who Should We Treat?
• The likelihood of miscarriage after detection of fetal heartbeat is 9% with
a range of 3.4% - 19.2%.
• Prospective data indicates that the presence of any of these three risk
factors (fetal bradycardia, discrepancy between gestational sac and crown
to rump length, and discrepancy between menstrual and sonographic age
by more than one week) increases the rate of abortion from 6% when
none are present to 84% when all three are present.
• Single serum progesterone measurement of at least 25 ng/ml carries a
97% likelihood for viable intrauterine pregnancy. However progesterone
secretion is pulsatile.
• Therefore, the diagnosis & treatment with progestagen is empirical.

33. What’s the Standard Regime?
El Zibdeh, 2009
Pandian,2009
Omar,2005

34. Current Opinion by Expert Body
• The guideline development
group (GDG) agreed that the
most important outcomes were;
 The rate of term pregnancy
 Miscarriage and pregnancy rate
beyond 20 weeks of gestation.
• The group had hoped that there
would be evidence regarding
long-term outcomes of
progesterone use, but none was
reported in the included studies.

35. Current Recommendation by Authoritative
Body
• Overall, the GDG felt that the evidence was insufficient to
recommend the use of progesterone or dydrogesterone.
• This was partly because:
 There was no demonstrated significant difference in the
rate of term birth.
 but mainly because of concern about the lack of long-term
safety data.
• The group felt strongly that further, high quality studies
investigating both the efficacy and safety of progesterone
and progestogens were needed, and decided that this was
a priority area for research.

36. Enter the PRISM trial

37. • The primary aim of the PRISM trial is:
 To test the hypothesis that in women presenting with vaginal bleeding in the first trimester,
progesterone (400 mg vaginal capsules, twice daily), started as soon as possible after a scan
has demonstrated a visible intrauterine gestation sac, and continued to 16 completed weeks
of gestation, compared with placebo, increases maternities with live births beyond 34
completed weeks by at least 5%.
 Additional secondary aims are:
 To test the hypothesis that progesterone improves other pregnancy and neonatal
outcomes, including gestation at birth and survival at 28 days of neonatal life.
 To test the hypothesis that progesterone, compared with placebo, is not associated with
substantial adverse effects to the mother or the neonate, including chromosomal
anomalies in the newborn.
 To explore differential or subgroup effects of progesterone in prognostic subgroups,
including age, fetal heart activity, gestation at presentation, amount of bleeding and body
mass index.
 To perform a cost-effectiveness analysis.
• Still recruiting.

38. RECURENT MISCARRIAGES &
PROGESTERONE

39. Causes of Recurrent Miscarriages
• Antiphospholipids syndrome.
• Uterine structural abnormality.
• Parenteral chormosomal
rearrangements.
• Thrombophilia.
• Infection.
• Unexplained: Immunological problems.
Treat
accordingly

41. What do Expert Bodies say?

42. Enter the PROMISE trial
• The PROMISE: PROgesterone in early MIScarriage
 Test the hypothesis that in women with unexplained recurrent
miscarriages, progesterone (400mg pessaries, twice daily), started as soon
as possible after a positive pregnancy test (at < 6 weeks gestation) and
continued to 12 weeks of gestation, compared to placebo, increases live
births beyond 24 completed weeks of pregnancy by at least 10%.
• Secondary aims
 To test the hypothesis that progesterone improves various pregnancy and
neonatal outcomes.
 To test the hypothesis that progesterone, compared to placebo, does not
incur substantial adverse effects to the mother or the neonate.
 To explore differential or subgroup effects of progesterone in various
prognostic subgroups.
 To perform an economic evaluation for cost-effectiveness.

43. Result of PROMISE trial

44. Result of PROMISE trial
• N=826
0
20
40
60
80
100
Rate of live birth
Placebo
Progesterone
• Rate difference, 2.5
percentage points; 95% CI,
−4.0 to 9.0
• There were no significant
between-group differences
in the rate of adverse
events

45. Is there light at the end of the tunnel?

47. In the meanwhile…..Progestagen for Treatment of
Threatened Miscarriage: To give or Not to Give?
• Patient will demand treatment which is risk free & decreases the
chance of miscarriage.
• Counselling is essential:
• Progesterone/Dydrogesterone reduce the rate of miscarriage.
• No increase in congenital abnormalities.
• Lack of long term safety data.
• At the end of the day, the patient will make the informed choice.
• Watchout for PRISM.

48. • Geller PA, Kerns D, Klier CM. Anxiety following miscarriage and the subsequent
pregnancy: A review of the literature and future directions. Journal of
Psychosomatic Research 2004;56: 35–45.

49. Thank you……..