Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 1 CERVICAL PRIMING EVIDENCE FROM.

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1 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 1 CERVICAL PRIMING EVIDENCE FROM CLINICAL TRIALS Helena von Hertzen Department of Reproductive Health and Research World Health Organization Geneva, Switzerland

2 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 2 Cervical priming before surgical abortion important for women with: cervical anomalies / previous surgery cervical anomalies / previous surgery young women (<18 years) young women (<18 years) advanced pregnancy advanced pregnancy – nulliparous > 9 weeks – parous > 12 weeks WHO Scientific Group 1994

3 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 3 Laminaria tents Laminaria tents Prostaglandins Prostaglandins – – gemeprost – – misoprostol Mifepristone Mifepristone METHODS OF PRIMING

4 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 4 RESEARCH ON CERVICAL PRIMING Laminaria - gemeprost Laminaria - gemeprost Gemeprost - misoprostol Gemeprost - misoprostol Misoprostol - mifepristone Misoprostol - mifepristone Misoprostol dose, time interval and route of administration Misoprostol dose, time interval and route of administration

5 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 5 COMPLICATIONS AFTER LAMICEL AND GEMEPROST Lamicel Gemeprost p-value n = 317 n = 305 n % n % total complications 55 (17) 22 ( 7) < 0.05 signs of infection 44 (14) 17 ( 6) < 0.05 recurettage 15 ( 5) 4 ( 1) < 0.05 perforation 0 ( 0) 1 (0.3) NS readmission 25 ( 8) 6 ( 2) < 0.05 Lindelius A et al. 2003

6 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 6 ORAL MISOPROSTOL vs. GEMEPROST IN NULLIPAROUS WOMEN retrospective analysis Celentano C et al. 2004 misoprostol gemeprost p-value 800µg (2h) 1 mg (2h) number of women 662 84 baseline dilation (mm) 7 (2-10) 3 (2-10) <0.0001 baseline dilation ≥ 7mm (%) 538 (81) 22 (26) <0.0001 needing extra dilation (%) 440 (66.5) 72 (85.7) <0.0005

7 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 7 ORAL MISOPROSTOL VS. GEMEPROST IN NULLIPAROUS WOMEN side effects Celentano C et al. 2004 misoprostol (%) gemeprost(%) p-value n = 662 n = 84 vomiting 16.0 20.2 NS fever (38 o C) 12.7 10.7 NS diarrhoea 2.6 7.1 NS pain medication 3.6 19.0 <0.001 bleeding* ) 0.3 16.7 <0.001 hospital stay >24 h 0 4.5 <0.001 cervical injury 0 3.6 <0.001 *) emergency admission to operating room

8 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 8 USE OF MISOPROSTOL – LESS PAIN During surgery misoprostol (sl) control p-value Paracervical block not given given to all Pain score (mean) 2.5 (1.1) 5.4 (2.1) p <.001 mild 46 (92%) 12 (24%) moderate 2 (4%) 24 (48%) severe 2 (4%) 14 (28%) Saxena R 2003

9 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 9 MIFEPRISTONE - MISOPROSTOL 90 women randomized comparison: 200 mg mifepristone (24-48 h) 800 µg vaginal misoprostol (2-4 h) Baseline dilation greater in mifepristone group (p=.02) and further dilation easier (p=.06) Blood loss, operating time, acceptability similar (Ashok et al. 2000)

10 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 10 synthetic analogue of naturally occurring prostaglandin E 1 synthetic analogue of naturally occurring prostaglandin E 1 approved in > 80 countries (prevention and treatment of gastric and duodenal ulcers) approved in > 80 countries (prevention and treatment of gastric and duodenal ulcers) safe and well tolerated safe and well tolerated tablets can be kept at room temperature when packed in aluminium blisters tablets can be kept at room temperature when packed in aluminium blisters MISOPROSTOL (Cytotec ®)

11 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 11 MISOPROSTOL DOSE (vaginal) 200 µg 400 µg 600 µg 800 µg n = 30 n = 30 n = 30 n = 30 Cervical dilation ≥ 8mm (%) 23.3 96.7 100 100 More side-effects after 600 µg and 800 µg compared to 400 µg (pre-operative bleeding, pain, products of conception at os, fever) Conclusion: optimal dose = 400 µg (= 2 tablets of 200 µg) Singh et al. 1998

12 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 12 THE INTERVAL BETWEEN MISOPROSTOL AND VACUUM ASPIRATION 0.4 mg (3h) 0.6 mg (2h) 0.8 mg (2h) n = 60 n = 60 n = 60 cervical dilation ≥ 8mm 55 (91.7%) 11 (18.3%) 15 (25.0%) mean (mm) 8.1 6.7 6.8 p<0.001 blood loss 0.4 vs. 0.8 p = 0.03 pain, fever 0.6 vs. 0.8 p < 0.001

13 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 13 Oral - vaginal Oral - vaginal Vaginal -sublingual Vaginal -sublingual Sublingual - oral Sublingual - oral OPTIMAL ROUTE OF ADMINISTRATION

14 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 14 0 50 - 100 - 150 - 200 - 250 - 300 - 350 - 60 120 180 240 0 = = = = = = = = _ _ _ _ _ _ _ Time (minutes ) Plasma misoprostol concentration /pg/mL) vaginal administration - = Oral administration Mean plasma concentrations of misoprostol acid over time with oral and vaginal administration (Zieman, 1997)

15 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 15 SUBLINGUAL - ORAL 6 – 12 weeks sublingual oral significance (n=50) (n=50) Median ID (mm) 10 (2.8) 8 (2.3) <0.001 Mean blood loss (ml) 16 (6.9) 17 (7.4) 0.140 Mean time (min) 4.4 (1.5) 5.2 (1.8) 0.024 Pain score 2.6 (1.4) 3.5 (1.1) 0.43 No difference in side effects Saxena P 2004

16 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 16 SUBLINGUAL - VAGINAL 6 – 12 weeks sublingual vaginal (n=40) (n=40) Median ID (mm) 7.6 (1.3) 7.7 (.73) Cumulative force N 9.0 (9.8) 6.6 (5.4) Mean blood loss (ml) 52.1 (20.2) 48.3 (12.3) Tang OS 2004

17 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 17 Hamoda H et al 2004: Women ( 37+37 ) in sublingual group had more Nausea (p=0.008) Vomiting (p=0.01) Diarrhoea (p=0.01) Unpleasant mouth taste (p=0.0001) SUBLINGUAL - VAGINAL

18 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 18 CONCLUSIONS Misoprostol is cheap and effective for cervical priming Misoprostol is cheap and effective for cervical priming The optimal dose = 400 µg (2 tablets) The optimal dose = 400 µg (2 tablets) When given orally or vaginally, optimal dilation in 3 hours; sublingual route is also effective When given orally or vaginally, optimal dilation in 3 hours; sublingual route is also effective Procedure easier, less blood loss, less pain Procedure easier, less blood loss, less pain

19 Département santé et recherche génésiques Department of reproductive health and research Hvh_FIAPAC2004_VIENNA_priming 19 WHO trial – 14 centres in 9 countries - 4984 women - 0.4 mg misoprostol or placebo vaginally 3 h before vacuum aspiration - dilation, oper. time, blood loss, pain, complications, etc. Routine priming of cervix prior to VA: comparison of misoprostol and placebo