1. Roziana Ramli MD, MMed(ObGyn)
Hospital Sultanah Nur Zahirah,K.Trg
IS MISCARRIAGE PREVENTABLE?
AND
THE USE OF PROGESTERONE IN EARLY
PREGNANCY

4. NO ONE TELLS A PREGNANT MUM…..
1. Yess!! Pregnant at last!
2. But, the good news
might not last all that
long…………………….

5. FACTS AND FIGURES
• Vaginal bleeding: most common cause of
consultation in early pregnancy
• Nearly 1/3rd. of women will experience bleeding in
their first trimester
• ? First sign of a possible miscarriage (10-20% of all
recognised pregnancies)

6. ANXIETY….

7. THE HOPEFUL - VIPS
Previous miscarriage
Recurrent miscarriages
Infertility
Mature mum
First time mum
Previous bad obstetric history e.g IUD

8. AND THE HISTORY GOES…
• Puan Rohana, 41 yo, married for 5 years
• Now, 2nd pregnancy with h/o of miscarriage @ 8/52
• At 6/52 pregnancy, had PV spotting
• Examination unremarkable, vaginal exam: closed
cervix
• Ultrasound:

9. ULTRASOUND
• Diagnosis?
• Then what?

10. THEN WHAT?
• Questions:
1. To admit or not to admit?
2. What about bed rest?
3. How to address her fears?
4. Is miscarriage preventable?
5. What about medicine?
• Look at the evidence ladies & gentlemen,

11. THEN WHAT?
• Questions:
1. To admit or not to admit?
2. How to address her fears?
3. Is miscarriage preventable?
4. What about bed rest?
5. What about medicine?

12. TO ADMIT OR NOT ?
• 50 000 inpatient admissions in the UK annually (Dept
of Health statistics, 2005)
• Management of women referred to early pregnancy
assessment unit (EPAU): care and cost effectiveness.
Bigrigg MA, Read MD, BMJ 1991;302:577–9
• An effective unit should be in a dedicated area:
• good quality ultrasound,
• easy access to lab (for rh grouping, sensitive UPT
and -hCG assay)
• gynaecological procedures.

13. TO ADMIT OR NOT?
• Patient’s profile
• Severity of vaginal bleeding
• Association with abdominal pain
• Physical examination findings
• Ultrasound findings

14. THEN WHAT?
• Questions:
1. To admit or not to admit?
2. What about bed rest?
3. How to address her fears?
4. Is there any medicine to give?
• Look at the facts ladies & gentlemen,

16. BED REST DURING PREGNANCY FOR
PREVENTING MISCARRIAGE
• Aleman A, Althabe F, Belizán JM, Bergel E. Bed rest during pregnancy for preventing
miscarriage. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.:
CD003576. DOI: 10.1002/14651858.CD003576.pub2
• No statistically significant difference in the risk of miscarriage in the
bed rest group versus the no bed rest group (placebo or other
treatment) (risk ratio (RR) 1.54, 95% confidence interval (CI) 0.92 to 2.58).
• Neither bed rest in hospital nor bed rest at home showed a
significant difference in the prevention of miscarriage.
• Authors' conclusions:
• There is insufficient evidence of high quality that supports a policy of
bed rest in order to prevent miscarriage in women with confirmed
fetal viability and vaginal bleeding in first half of pregnancy.

17. Author Design N Sonography Intervention Intervention/no intervention
Cochrane 2 studies
Systematic Review 84 yes Bedrest RR 1.54 ; 0.92-2.58
Pregnancy outcome in studies with various therapeutic regimens
Aleman A et al. Bed rest during pregnancy for preventing miscarriage.
The Cochrane Database of Systematic Reviews 2005
• Little evidence of its value.
• Physical activity: rarely a/w increased risk of miscarriage
• Lack of activity: thromboembolic events, back pain, muscle
atrophy and bone loss.
• Bed rest: emotional, familial and economic stress as well as self-
blame if fail to comply and subsequently suffer a miscarriage.

18. THEN WHAT?
• Questions:
1. To admit or not to admit?
2. What about bed rest?
3. How to address her fears?
4. Is miscarriage preventable?
5. What about medicine?
• Look at the facts ladies & gentlemen,

19. Vaginal bleeding in the first trimester of pregnancy
occurs in
about 25 % of pregnant women.
It is the commonest complication in early pregnancy
Hasan R et al. Association between first trimester vaginal bleeding and miscarriage.
Obstet Gynecol 2009;114: 860-7
FACTS:

20. Ectopic Pregnancy 1.5-2%
Miscarriage / non viable pregnancy 12-16%
Termination 16%
Ongoing Intra uterine Pregnancy 65-67%
Outcome of first trimester pregnancy
Herbert D; Lucke J; Dobson A . Pregnancy losses in young Australian women: findings from the
Australian Longitudinal Study on Women's Health. J. Womens Health Issues; 2009 ; 19: 21-9.
Blohm F, Friden B, Milsom I. Prospective longitudinal population based study of clinical
miscarriage in an urban swedisch population. BJOG 2008; 115: 176-8.

21. Ectopic Pregnancy 1.5-2% 8-18%
Miscarriage / non viable pregnancy 12-16% 46%
Termination 16% NA
Ongoing Intra uterine Pregnancy 65-67% 38-46%
Outcome of first trimester pregnancy
Herbert D; Lucke J; Dobson A . Pregnancy losses in young Australian women: findings from the
Australian Longitudinal Study on Women's Health. J. Womens Health Issues; 2009 ; 19: 21-9.
Blohm F, Friden B, Milsom I. Prospective longitudinal population based study of clinical
miscarriage in an urban swedisch population. BJOG 2008; 115: 176-8.
Bleeding/Pain

22. The short term consequences of early pregnancy bleeding
more than one half of those who bleed will loose their pregnancy
Van Oppenraay RHF et al. Predicting adverse obstetric outcome after early pregnancy
events and complications: .a review Human Reproduction Update 2009;15:409-421

23. 50%
50%

24. The short term consequences of early pregnancy bleeding
more than one half of those who bleed will loose their pregnancy
The long-term consequences of early pregnancy bleeding
In ongoing pregnancies, adverse outcomes are reported for
- very preterm delivery (< 34 weeks) OR 1.9 (1.6-2.2)
- low birth weight (<2500 g) OR 2.3 (1.9-2.7)
- ante partum haemorrhage OR 1.8 (1.7-2.0)
Van Oppenraay RHF et al. Predicting adverse obstetric outcome after early pregnancy
events and complications: .a review Human Reproduction Update 2009;15:409-421

25. Predictive value of the presence of an embryonic
heartbeat for live birth: comparison of women with
and without recurrent pregnancy loss.
Hyer JS, Fong S, Kutteh WH., Fertil Steril 2004 Nov;82(5):1369-73.
If heartbeat is visible, the probability of a continued
pregnancy is better than 95%.

26. Favourable prognostic factors Adverse prognostic factors
History
Advancing gestational age Maternal age >34 years
Increasing number of previous miscarriages
Sonography
Fetal heart activity at presentation Fetal bradycardia
Discrepancy between GA and CRL
Empty GS >15-17 mm
Maternal serum biochemistry
Normal levels of these markers Low β hCG values
Free β hCG value of 20 ng/ml
β hCG increase <66% in 48 hrs
Bioactive/immunoreactive ratio hCG <0.5
Progesterone <45 nmol/l in 1st trimester
Inhibin A <0.553 MOM
CA125 level ≥43.1 U/mL in 1st trimester

27. THEN WHAT?
• Questions:
1. To admit or not to admit?
2. How to address her fears?
3. What about bed rest?
4. What about medicine?
• Look at the facts ladies & gentlemen,

28. VITAMIN SUPPLEMENTATION FOR
PREVENTING MISCARRIAGE
• Rumbold A, Middleton P, Pan N, Crowther CA. Vitamin supplementation for preventing miscarriage.
Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD004073. DOI:
10.1002/14651858.CD004073.pub3 January 19, 2011
• 28 trials involving 96,674 women and 98,267 pregnancies
• No significant differences were seen between women taking
any vitamins compared with controls for total fetal loss (relative
risk (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.14), early or late
miscarriage (RR 1.09, 95% CI 0.95 to 1.25) or stillbirth (RR 0.86, 95% CI 0.65
to 1.13)
• Compared with controls, women given any type of vitamin(s)
pre or peri-conception were more likely to have a multiple
pregnancy (RR 1.38, 95% CI 1.12 to 1.70, three trials, 20,986
women).

29. UTERINE MUSCLE RELAXANT DRUGS FOR
THREATENED MISCARRIAGE
• Lede R, Duley L
• Obstetrics and Gynecology, University of Buenos Aires, Argentinian Institute for Evidence Based
Medicine, Av. Roque Saenz Peña 825, Buenos Aires, Argentina, 1035.
CONCLUSION:
• There is insufficient evidence to support the use of uterine
muscle relaxant drugs for women with threatened
miscarriage.
• PMID: 16034877 [PubMed - indexed for MEDLINE]

30. HCG?

31. HUMAN CHORIONIC GONADOTROPHIN
FOR THREATENED MISCARRIAGE
• Devaseelan P, Fogarty PP, Regan L. Human chorionic
gonadotrophin for threatened miscarriage. Cochrane
Database of Systematic Reviews 2010, Issue 5. Art. No.:
CD007422. DOI: 10.1002/14651858.CD007422.pub2
• hCG is secreted by the
syncytiotrophoblast to promote corpus
luteum to secrete progesterone and
helps in maintaining the pregnancy.
• 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%
confidence interval (CI) 0.42 to 1.05).

32. CAUSES OF MISCARRIAGE
• Chromosomal abnormalities (60%)
• Infections and diseases (CMV, Chlamydia, Mycoplasma, DM)
• Autoimmune diseases
• Low progesterone levels
• Other possible causes (radiation, chemo, drugs, smoking)

33. CAUSES OF MISCARRIAGE
• Chromosomal abnormalities (60%)
• Infections and diseases (CMV, Chlamydia, Mycoplasma, DM)
• Autoimmune diseases
• Low progesterone levels
• Other possible causes (radiation, chemo, drugs, smoking)

34. CAUSES OF MISCARRIAGE
• Chromosomal abnormalities (60%)
• Infections and diseases (CMV, Chlamydia, Mycoplasma, DM)
• Autoimmune diseases
• Low progesterone levels
• Other possible causes (radiation, chemo, drugs, smoking)
• Evidences?

35. THE MANAGEMENT OF THREATENED
ABORTION
PAUL BOULLE, M.B., CH.B., M.R.C.A.G., F.C.A.G. CS.A.), GYNAECOLOGIST AND
OBSTELRICIAN, DURBAN
S.A. MEDICAL JOURNAL 1966
• 1I. Psychology
• 2. Bed Rest
• 3. Sedation
• 4. Antispasmodics
• 5. Surgery
• 6. Hormones

39. INDIRECT EVIDENCE OF PROGESTERONE
EFFICACY
• Removal of the corpus luteum during
pregnancy  Abortion
• Luteal phase insufficiency
• Assisted reproductive technologies’
experience with progesterone
• RU 486 or Mifepristone (anti-progesterone) for
pregnancy termination

40. GESTATIONAL AGE
• Peak in bleeding coincides with
the development of a
hormonally functional placenta
• The shift from luteal to placental
production of progesterone: 7
weeks of pregnancy
Patterns and predictors of vaginal bleeding in the
first trimester of pregnancy; Reem Hassan et.al Ann
Epidemiol. 2010July; 20(7): 524-531
• The risk of threatened
miscarriage to proceed to full
miscarriage depends on GA
(Weiss et al., 2004; Schauberger et al.)
weeks pregnancy
%

41. 100.0
50.0
10.0
5.0
1.0
0.5
0.1
0.05
4 8 12 14 16 20 24 28 32 36 40
Progesterone (ng/mL)
Weeks of Pregnancy
Plasma levels during pregnancy reach
125-200 ng/ml (vs 11ng/mL during luteal phase)

42. • First-trimester P values
>25 ng/mL suggest a normal
IUP 98% of the time, while
pregnancies with P values
<5 ng/mL are non-viable.
100
200
300
400
500
4 8 12 20 Weeks of Pregnancy
ProgesteroneConcentration
nmol/l
Serum progesterone levels during pregnancy
First trimester
Second trimester
Third trimester
47 – 1159 nmol/l
50-310 nmol/l
2540- 636 nmol/l

43. Serum
progesterone (ng/ml)
Spontaneous
miscarriage
Intrauterine
pregnancy
0 - 4.9
5.0 - 9.9
10.0 - 14.9
15.0 - 19.9
20.0 - 24.9
1093 (85.5%)
46 (65.8%)
181 (31.3%)
59 (9.8%)
39 (7.7%)
2 (0.2%)
126 (17.8%)
338 (58.4%)
509 (84.4%)
451 (88.8%)

44. PROGESTERONE
• A meta-analysis of 26 studies showed that progesterone
values did well at discriminating between pregnancy
failure and viable intrauterine pregnancy.
• The most logical approach to manage threatened
miscarriage caused by low endogenous progesterone
therefore is by administering exogenous progesterone

45. DOES THIS APPROACH WORK?
• ?

46. Omar et al . Dydrogesterone in threatened abortion: pregnancy outcome.
J Steroid Biochem Mol Biol 2005; 97: 421-425
Mild to moderate vaginal bleeding
Gestational age < 13 weeks
No history of recurrent miscarriage
No loss of conception materials
Absence of systemic illness or fever
Absence of an empty sac of > 26 mm
Presence of gestational sac at 5 weeks
Presence of yolk sac at 5 – 6 weeks
Presence of cardiac activity at 7 weeks
Inclusion Intervention
Treatment group:
dydrogesterone 40 mg at presentation
plus
10 mg b.i.d. until bleeding stopped.
bed rest and folic acid.
Control group:
bed rest and folic acid only.
Women were followed up
until 20 weeks gestation
DYDROGESTERONE IN THREATENED MISCARRIAGE

47. CH3
COCH3
CH3
O
H
Duphaston®
(dydrogesterone)
CH3
COCH3
CH3
O
H
progesterone
Duphaston : more studies – basic and clinical

48. 154 Women included:
– 74 received dydrogesterone
– 80 in the control group
DYDROGESTERONE IN THREATENED MISCARRIAGE
Omar et al . Dydrogesterone in threatened abortion: pregnancy outcome.
J Steroid Biochem Mol Biol 2005; 97: 421-425

49. Pandian Ramachandhiran et al. Dydrogesterone in threatened miscarriage:
a Malaysian experience. Maturitas 2009; 65 Suppl 1:S47-50.
N= 191
p<0.05 OR: 0.36 95% CI 0.17 - 0.75).
DYDROGESTERONE IN THREATENED MISCARRIAGE

50. PROGESTOGEN FOR TREATING
THREATENED MISCARRIAGE (REVIEW)
• Wahabi HA, Fayed AA, Esmaeil SA, Al Zeidan RA. Progestogen for treating threatened
miscarriage. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.:
CD005943. DOI: 10.1002/14651858.CD005943.pub4
• Meta analysis of four studies (421 participants)
• There was evidence of a reduction in the rate of
spontaneous miscarriage with the use of
progestogens compared to placebo or no
treatment (risk ratio (RR) 0.53; 95% (CI) 0.35 to
0.79).

51. Wahabi HA et al. Cochrane Collaboration.
Progestogen for treating threatened miscarriage 2007

52. PROGESTOGEN FOR PREVENTING
MISCARRIAGE (REVIEW)
• Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane
Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003511. DOI:
10.1002/14651858.CD003511.pub2
• Meta analysis of fifteen trials (2118 women) are included
• No statistically significant difference in the risk of miscarriage
between progestogen and placebo or no treatment
group(Peto OR) 0.98; 95% (CI) 0.78 to 1.24)
• Statistically significant decrease in miscarriage rate
compared to placebo or no treatment (Peto OR 0.38; 95% CI
0.20 to 0.70) in subgroup patients with recurrent miscarriages.

53. IS MISCARRIAGE PREVENTABLE?
YESNO