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Is miscarriage preventable? gynae symposium

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    • 1. Roziana Ramli MD, MMed(ObGyn) Hospital Sultanah Nur Zahirah,K.Trg IS MISCARRIAGE PREVENTABLE? AND THE USE OF PROGESTERONE IN EARLY PREGNANCY
    • 2. NO ONE TELLS A PREGNANT MUM….. 1. Yess!! Pregnant at last! 2. But, the good news might not last all that long…………………….
    • 3. 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)
    • 4. ANXIETY….
    • 5. THE HOPEFUL - VIPS Previous miscarriage Recurrent miscarriages Infertility Mature mum First time mum Previous bad obstetric history e.g IUD
    • 6. 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:
    • 7. ULTRASOUND • Diagnosis? • Then what?
    • 8. 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,
    • 9. 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?
    • 10. 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.
    • 11. TO ADMIT OR NOT? • Patient’s profile • Severity of vaginal bleeding • Association with abdominal pain • Physical examination findings • Ultrasound findings
    • 12. 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,
    • 13. 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.
    • 14. 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.
    • 15. 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,
    • 16. 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:
    • 17. 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.
    • 18. 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
    • 19. 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
    • 20. 50% 50%
    • 21. 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
    • 22. 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%.
    • 23. 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
    • 24. 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,
    • 25. 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).
    • 26. 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]
    • 27. HCG?
    • 28. 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).
    • 29. 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)
    • 30. 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)
    • 31. 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?
    • 32. 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
    • 33. 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
    • 34. 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 %
    • 35. 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)
    • 36. • 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
    • 37. 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%)
    • 38. 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
    • 39. DOES THIS APPROACH WORK? • ?
    • 40. 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
    • 41. CH3 COCH3 CH3 O H Duphaston® (dydrogesterone) CH3 COCH3 CH3 O H progesterone Duphaston : more studies – basic and clinical
    • 42. 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
    • 43. 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
    • 44. 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).
    • 45. Wahabi HA et al. Cochrane Collaboration. Progestogen for treating threatened miscarriage 2007
    • 46. 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.
    • 47. IS MISCARRIAGE PREVENTABLE? YESNO