Roziana Ramli MD, MMed(ObGyn)

Hospital Sultanah Nur Zahirah,K.Trg

IS MISCARRIAGE PREVENTABLE? AND

THE USE OF PROGESTERONE IN EARLY PREGNANCY

NO ONE TELLS A PREGNANT MUM…..

1. Yess!! Pregnant at last!

2. But, the good news might not last all that long…………………….

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)

ANXIETY….

THE HOPEFUL - VIPSPrevious miscarriage

Recurrent miscarriages

Infertility

Mature mum

First time mum

Previous bad obstetric history e.g IUD

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:

ULTRASOUND

• Diagnosis?

• Then what?

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,

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?

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.

TO ADMIT OR NOT?

• Patient’s profile

• Severity of vaginal bleeding

• Association with abdominal pain

• Physical examination findings

• Ultrasound findings

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,

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.

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.

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,

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:

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.

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

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

50%

50%

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

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%.

Favourable prognostic factors Adverse prognostic factors

HistoryAdvancing gestational age Maternal age >34 years

Increasing number of previous miscarriages

Sonography

Fetal heart activity at presentationFetal bradycardia

Discrepancy between GA and CRLEmpty GS >15-17 mm

Maternal serum biochemistryNormal levels of these markers Low β hCG values

Free β hCG value of 20 ng/mlβ hCG increase <66% in 48 hrsBioactive/immunoreactive ratio hCG <0.5Progesterone <45 nmol/l in 1st trimesterInhibin A <0.553 MOMCA125 level ≥43.1 U/mL in 1st trimester

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,

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).

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]

HCG?

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).

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)

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)

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?

THE MANAGEMENT OF THREATENED ABORTIONPAUL 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

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

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

%

Levels of Progesterone during Pregnancy

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 reach125-200 ng/ml (vs 11ng/mL during luteal phase)

• 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.

Indirect Evidence of Progesterone Efficacy

Aksoy S et al. Eur J Obstet Gynecol Reprod Biol. 1996;67:5-8.

100

200

300

400

500

4 8 12 20 Weeks of Pregnancy

Prog

este

rone

Con

cent

ratio

n

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

Serum progesterone (ng/ml)

Qureshi NS., et al. Maturitas 2009;65S:S35-41

Spontaneous miscarriage

Intrauterinepregnancy

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%)

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

Mol BW, Lijmer JG, Ankum WM, et al. Hum Reprod 1998;3:3220-3227

DOES THIS APPROACH WORK?

• ?

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

CH3

COCH3

CH3

O

H

Duphaston®

(dydrogesterone)

CH3

COCH3

CH3

O

H

progesterone

Duphaston : more studies – basic and clinical

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

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

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).

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

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.

IS MISCARRIAGE PREVENTABLE?

YESNO