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1. Carbonell JL, Rodriguez J, Velazco A, Tanda R, Sanchez C, Barambio S, Chami S, Valero F, Mari J, de Vargas F, Salvador I. Oral and vaginal misoprostol 800 mcg every 8 h for early abortion. Contraception. 2003 Jun;67(6):457-462.
This study evaluated the efficacy and safety of 800 mcg misoprostol every 8 hours for 24 hours for medical abortion; the treatment was repeated if abortion did not occur in the first 24 hours. The first misoprostol doses were always self-administered into the vagina; the second and third doses could be administered orally or vaginally depending on the amount of bleeding. Four-hundred and fifty-two women with gestations between 36 and 63 days LMP were recruited into the study. Complete abortion occurred in 409/452 (90.5%; 95% confidence interval [CI] 87%, 93%) patients.
2. Singh K, Fong YF, Dong F. A viable alternative to surgical vacuum aspiration: repeated doses of intravaginal misoprostol over 9 hours for medical termination of pregnancies up to eight weeks. BJOG. 2003 Feb;110(2):175-80.
One hundred and fifty pregnant women with pregnancies up to eight weeks of gestation who requested medical abortion were given an initial dose of 800 mcg of vaginal misoprostol. A further dose of 400 mcg was repeated every 3 hours for a maximum of three doses. The complete abortion rate, defined as successful cases that did not require vacuum aspiration, was 84.7% and 96.0% at 15 days and 43 days after initial administration of vaginal misoprostol.
3. Zikopoulos KA, Papanikolaou EG, Kalantaridou SN, Tsanadis GD, Plachouras NI, Dalkalitsis NA, Paraskevaidis EA. Early pregnancy termination with vaginal misoprostol before and after 42 days gestation. Hum Reprod. 2002 Dec;17(12):3079-83.
One hundred and sixty women seeking medical termination of a pregnancy of <56 days were given 800 mcg of vaginal misoprostol, repeated every 24 hours for a maximum of three doses. The overall complete abortion rate was 91.3%. In group A (gestation <42 days) complete abortion occurred in 96.3% of women, whereas in group B (gestation = 42-56 days) complete abortion occurred in 86.3% of women (P < 0.025). The two groups did not differ significantly with respect to side-effects (incidence of pain, bleeding, nausea, diarrhoea, fever and headache).
4. Jain JK, Dutton C, Harwood B, Meckstroth KR, Mishell DR Jr. A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy. Hum Reprod. 2002 Jun;17(6):1477-82.
Two-hundred and fifty women with gestations < or = 56 days were allocated by a random number table to receive either 200 mg mifepristone orally or placebo followed 48 hours later by 800 mcg vaginal misoprostol. Administration of misoprostol was repeated every 24 hours up to three doses if abortion failed to occur. Abortion success was defined as complete abortion without the use of surgical aspiration. Successful medical abortions occurred in 114 out of 119 subjects (95.7%) after mifepristone followed by vaginal misoprostol and 110 out of 125 subjects (88.0%) after placebo and vaginal misoprostol.
5. Tang OS, Miao BY, Lee SW, Ho PC. Pilot study on the use of repeated doses of sublingual misoprostol in termination of pregnancy up to 12 weeks gestation: efficacy and acceptability. Hum Reprod. 2002 Mar;17(3):654-8.
Fifty women requesting medical abortion at up to 12 weeks since LMP were given 600 mcg misoprostol sublingually every 3 hours for a maximum of 5 doses. The overall complete abortion rate was 86% (95% confidence interval: 74-93). The mean number of doses of misoprostol required was 4.1 +/- 1.1. Diarrhoea, fever and chills were the most common side-effects.
6. Tang OS, Ho PC. Pilot study on the use of sublingual misoprostol for medical abortion. Contraception. 2001 Nov;64(5):315-7.
Sublingual administration of misoprostol was used by 25 women with first trimester, non-viable intrauterine gestation and by 18 women requesting mid-trimester termination of pregnancy. Twenty-three women (92%, 95% CI 75, 98) with first trimester, non-viable gestation had complete abortion after sublingual misoprostol. All women (100%, 95% CI 82, 100) requesting second trimester abortion aborted, with a median induction-to-abortion interval of 11.6 hours.
7. Jain JK, Harwood B, Meckstroth KR, Mishell DR. Early pregnancy termination with vaginal misoprostol combined with loperamide and acetaminophen prophylaxis. Contraception. 2001 Apr;63(4):217-21.
Two-hundred women with an intrauterine pregnancy < or =56 days gestational age were enrolled in the study. One-hundred participants (group 1) ingested 4 mg of loperamide and 500 mg of acetaminophen before the vaginal placement of 800 mcg of misoprostol moistened with 2 mL of saline. If abortion had not occurred, the same regimen was repeated every 24 hours (maximum three doses). One-hundred participants (group 2) from the same clinic who previously underwent the same misoprostol regimen without prophylactic medication served as a control group. The rate of successful abortion was not statistically significantly different between the two groups (group 1 93%, group 2 89%). There was a significantly lower incidence of diarrhea in group 1 (23%) compared with group 2 (44%) (OR 0.38, 95% CI 0.20-0.73, p = 0.003).
8. Carbonell JL, Rodriguez J, Aragon S, Velazco A, Tanda R, Sanchez C, Barambio S, Chami S, Valero F. Vaginal misoprostol 1000 micrograms for early abortion. Contraception. 2001 Mar;63(3):131-6.
Three-hundred women with gestations between 42 and 63 days LMP received vaginal misoprostol every 24 hours up to a maximum of three doses for abortion. Complete abortion occurred in 279/300 (93.0%, 95% CI 90, 96) patients. Mean expulsion time was 8.1 +/- 3.0 hours for those who aborted after the first misoprostol dose. The frequencies of nausea and diarrhea were high.
9. Carbonell JL, Velazco A, Varela L, Tanda R, Sanchez C, Barambio S, Chami S, Valero F, Aragon S, Mari J. Misoprostol for abortion at 9-12 weeks’ gestation in adolescents. Eur J Contracept Reprod Health Care. 2001 Mar;6(1):39-45.
A group of 150 adolescents with gestations between 63 and 84 LMP days received 800 mcg of vaginal misoprostol every 24 hours, up to a maximum of three doses, for abortion. Complete abortion occurred in 126/150 (84.0%, 95% confidence interval 77-89) patients. The frequencies of nausea and vomiting were statistically significantly higher when compared to those obtained for adult females. Vaginal bleeding lasted for 13.2 +/- 3.8 days (median 13 days, range 1-22 days). The mean expulsion time was 8.0 +/- 3.4 hours (median 8 hours, range 1-14 hours) for all subjects who aborted after the first misoprostol dose.
10. Velazco A, Varela L, Tanda R, Sanchez C, Barambio S, Chami S, Valero F, Aragon S, Mari J, Carbonell JL. Misoprostol for abortion up to 9 weeks’ gestation in adolescents. Eur J Contracept Reprod Health Care. 2000 Dec;5(4):227-33.
One hundred and fifty adolescents with gestations between 35 and 63 days LMP received 800 mcg of vaginal misoprostol every 24 hours, up to a maximum of three main doses, for abortion. Complete abortion occurred in 133/150 (88.7%, 95% confidence interval 82-93) patients. The frequencies of nausea, vomiting and diarrhea were statistically significantly higher when compared to those obtained for adult females. Vaginal bleeding lasted for 12.7 +/- 5.7 days (median 12 days, range 1-23 days). The mean expulsion time was 6.8 +/- 2.4 hours (median 6 hours, range 3-14 hours) for those who aborted after the first misoprostol dose.
11. Ngai SW, Tang OS, Chan YM, Ho PC. Vaginal misoprostol alone for medical abortion up to 9 weeks of gestation: efficacy and acceptability. Hum Reprod. 2000 May;15(5):1159-62.
This randomized study investigated the efficacy of misoprostol with water versus misoprostol alone for first trimester medical abortion in women at </= 9 weeks of gestation. Eighty women were randomly assigned to group 1 (water added to misoprostol) and group 2 (misoprostol alone). Vaginal misoprostol 800 mcg was given on days 1, 3 and 5. If the woman did not require vacuum aspiration during the period up to the return of first menstruation after medical abortion, the outcome was classified as complete abortion. The complete abortion rate appeared higher when water was added but the difference did not reach statistical significance. Gastro-intestinal side-effects were common but well tolerated in both groups. With an overall complete abortion rate of 85%, the method is probably not a clinically acceptable.
12. Carbonell JL, Varela L, Velazco A, Tanda R, Barambio S, Chami S. Vaginal misoprostol 600 micrograms for early abortion. Eur J Contracept Reprod Health Care. 2000 Mar;5(1):46-51.
The objective of this study was to evaluate the efficacy and safety of the vaginal self-administration of 600 mcg misoprostol up to a maximum administration of three doses in a 24-hour period, one every 8 hours, for abortion up to 9 weeks’ gestation. A group of 90 women with gestations from 35 to 63 days LMP participated in the study. All women who aborted received a single additional dose of 600 mcg misoprostol. Complete abortion occurred in 57/89 (64%, 95% confidence interval 53-74%) subjects. The mean expulsion time was 7.4 +/- 3.8 hours (median 7.2 hours, range 3-20 hours) for all women who aborted within the first 24 hours of the administration of misoprostol. Thirty-two cases failed to abort, 28 cases due to failure of the method, of which 24 had a negative cardiac rhythm after the third dose, and four cases due to the doctor’s decision.
13. Bugalho A, Mocumbi S, Faundes A, David E. Termination of pregnancies of <6 weeks gestation with a single dose of 800 microg of vaginal misoprostol. Contraception. 2000 Jan;61(1):47-50.
Women with < or =42 days of amenorrhea, pregnancy confirmed by ultrasound, received 800 mcg of vaginal misoprostol once and were observed for 1 week. The gestational sac was measured before misoprostol administration, and 24 hours and 7 days afterward. After 1 week, those who had not aborted received a second dose of 800 mcg. Those who had not aborted by 24 hours later were treated by vacuum aspiration of the endometrial cavity. Twenty-four hours after treatment, 71.8% had aborted, and 87.1% aborted 3 days after treatment. After the second dose, 7 days later, the cumulative abortion rate reached 92.1%. None of the subjects who aborted required curettage or vacuum aspiration. The main complaints were pain (84.5%), nausea (21.4%), and headache (17.5%).
14. Jain JK, Meckstroth KR, Park M, Mishell DR Jr. A comparison of tamoxifen and misoprostol to misoprostol alone for early pregnancy termination. Contraception. 1999 Dec;60(6):353-6.
A clinical trial was conducted with a study group of 150 healthy women with pregnancies of </=56 days gestational age who desired pregnancy termination. Subjects were randomized to ingest either 20 mg of tamoxifen (group 1) or placebo (group 2) twice daily for 1 day, followed 48 hours later by vaginal administration of 800 mcg of saline-moistened misoprostol. This dose of misoprostol was repeated 24 hours later and 8 days later if an abortion had not occurred. Complete abortion occurred in 709 (93.3%) in group 1 and 68 (90.7%) in group 2. The mean duration of uterine bleeding was 7.9 days and 8.2 days in group 1 and group 2, respectively. In group 1, 94.3% who aborted bled for <14 days, and in group 2, 95.6%.
15. Tang OS, Wong KS, Tang LC, Ho PC. Pilot study on the use of repeated doses of misoprostol in termination of pregnancy at less than 9 weeks of gestation. Adv Contracept. 1999; 15(3):211-6.
Twenty women were given 800 mcg of vaginal misoprostol as an initial dose followed by 400 mcg of vaginal misoprostol every 3 hours for 4 doses. Fourteen women (70%, 95% confidence interval: 48, 85%) had a complete abortion. Two women (10%) had a missed abortion, and two (10%) had an ongoing pregnancy. Two women (10%) had an incomplete abortion. The interval between the first dose of misoprostol and the passage of tissue mass was 25.3 +/- 34.4 hours (median: 15 hours).The duration of vaginal bleeding was 23.6 +/- 20.4 days (median: 14 days). Side-effects were mild.
16. Jain JK, Meckstroth KR, Mishell DR Jr. Early pregnancy termination with intravaginally administered sodium chloride solution-moistened misoprostol tablets: historical comparison with mifepristone and oral misoprostol. Am J Obstet Gynecol. 1999 Dec;181(6):1386-91.
One hundred women at </=56 days’ gestation received 800 mcg misoprostol intravaginally using sodium chloride solution-moistened tablets. The dose was repeated 24 hours later if a gestational sac persisted on ultrasonographic examination. These 100 subjects (group 1) were then matched with 100 subjects who had received 600 mg mifepristone followed by 400 mcg misoprostol orally as part of a large multicenter American trial (group 2). In 88 of the 100 women in group 1 and 94 of the 100 women in group 2, abortion occurred and a surgical procedure was not required. Abortion rates were not influenced by gestational age in either group. Prostaglandin-related side effects of fever and chills, vomiting, diarrhea, and uterine pain were all significantly higher in group 1. Excessive uterine bleeding was uncommon in both groups, and no subjects received blood transfusions.
17. Ozeren M, Bilekli C, Aydemir V, Bozkaya H. Methotrexate and misoprostol used alone or in combination for early abortion. Contraception. 1999 Jun;59(6):389-94.
A total of 108 subjects who had requested elective termination of pregnancy and medical abortion at 9 weeks gestation or less were randomized into three groups. Group 1 took 50 mg/sq. m im methotrexate on day 1, and a second dose was given if the human chorionic gonadotropin level had increased by 50% of the initial level on day 4. Group 2 took 800 mcg vaginal misoprostol on day 1 and a repeat dose was given if ultrasound showed a gestational sac on day 4. Reexamination was done on day 7. Group 3 took 50 mg/sq. m im methotrexate, which was followed 3 days later by 800 mcg vaginal misoprostol; subjects were reexamined on day 7. In group 1, complete abortion occurred in 69% of the subjects; in group 2, in 58% of the subjects; in group 3, in 89% of the subjects. Vaginal bleeding in subjects who successfully aborted began within 16 +/- 4 days in group 1 after the first dose, and within 24 hours in 18 (86%) of the 21 subjects in group 2 and 27 (84%) of the 32 subjects in group 3 after the misoprostol dose. The drugs caused no serious or prolonged side effects.
18. Esteve JL, Varela L, Velazco A, Tanda R, Cabezas E, Sanchez C. Early abortion with 800 micrograms of misoprostol by the vaginal route. Contraception. 1999 Apr;59(4):219-25.
A group of 720 volunteer subjects with gestations from 35 to 63 days received 800 mcg of vaginal misoprostol every 24 hours up to a maximum of three doses for abortion. Complete abortion occurred in 644 of 720 (89.4%, 95% CI 87, 92) subjects. The mean decrease in hemoglobin was statistically significant (p = 0.0001). There were 14 subjects with clinically significant decreases in hemoglobin, but only two required transfusions. Vaginal bleeding lasted 6.7 +/- 3.9 days, spotting 8.1 +/- 4 days, and total bleeding 14 +/- 5.3 days. Mean expulsion time was 8.0 +/- 3.4 hours.
19. Carbonell JL, Varela L, Velazco A, Tanda R, Sanchez C. Vaginal misoprostol for abortion at 10-13 weeks’ gestation. Eur J Contracept Reprod Health Care. 1999 Mar;4(1):35-40.
A group of 180 women with gestations from 64 to 91 days, self-administered 800 mcg of vaginal misoprostol every 12 hours for a maximum of three doses without performance of postexpulsion systematic preventive curettage. Successful abortion occurred in 153/180 (85%) subjects (95% confidence interval (CI) 79-90). The decrease of hemoglobin was statistically significant (p = 0.0001) but clinically unimportant: 12.1 mg/dl (SD 1.1) before treatment and 11.7 mg/dl (SD 1.1) afterwards. The mean expulsion time for patients who aborted after the first dose was 8.3 +/- 3.6 hours (median 8 hours, range 2-12 hours). Vaginal bleeding lasted 6 +/- 3 days, spotting 7 +/- 3 days and total bleeding 13 +/- 4 days. The median dose of misoprostol administered was 1780 mcg (range 1400-3000 mcg).
20. Carbonell Esteve JL, Varela L, Velazco A, Cabezas E, Tanda R, Sanchez C. Vaginal misoprostol for late first trimester abortion. Contraception. 1998 May;57(5):329-33.
A group of 120 women with gestations from 64 to 84 received 800 mcg of misoprostol vaginally every 24 hours, for a maximum of three doses. Complete abortion occurred in 104 women (87%); 87 women (73%) aborted after a single dose, 11 (9%) required two doses, and 6 (5%) received a third dose. The remaining 16 women (13%) underwent surgical abortion. Mean hemoglobin decreased from 12.2 mg/dl before treatment to 11.6 mg/dl after abortion—a difference that was statistically but not clinically significant. Side effects—which disappeared within 2 hours—included nausea (22%), vomiting (17%), diarrhea (54%), dizziness (25%), headache (19%), and chills (72%). Although 99% of subjects reported pelvic pain, only 10% requested an analgesic for pain relief. Vaginal bleeding persisted for a mean of 8 days.
21. Carbonell JL, Varela L, Velazco A, Fernandez C, Sanchez C. The use of misoprostol for abortion at < or = 9 weeks’ gestation. Eur J Contracept Reprod Health Care. 1997 Sep;2(3):181-5.
A total of 175 women seeking elective abortion at < or = 63 days’ gestation received 800 mcg of misoprostol vaginally. This dose was repeated at 48 and 96 h if abortion did not occur. Afterwards, up to three additional 600- or 400-mcg doses of misoprostol were administered if the uterus was not empty, as judged by ultrasound. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure), side-effects and vaginal bleeding. Complete abortion occurred in 161/175 (92.0%; 95% CI 87-96%) subjects and 14/175 (8.0%; 95% CI 4-13%) cases failed. The immediate success rate was 77.7% with the first dose, 13.7% with the second dose and 0.6% with the third dose. The third dose of misoprostol showed very little efficacy. Vaginal bleeding lasted 5.5 +/- 2.8 days, spotting 5.7 +/- 3.1 days and total bleeding 11.2 +/- 3.0 days.
22. Carbonell JL, Varela L, Velazco A, Fernandez C. The use of misoprostol for termination of early pregnancy. Contraception. 1997 Mar;55(3):165-8.
A group of 141 women with pregnancies of less than 70 days LMP received up to 3 doses of 800 mcg of misoprostol every 48 hours. Failure was defined as the need for surgical abortion and success as the complete expulsion of the products of conception. In total, 132 cases (93.6%, 95% CI 89.4-97.8) aborted and 9 cases (6.4%) failed. The decrease in hemoglobin was statistically significant (p = 0.001) but without clinical repercussions; before treatment: 11.95 mg/dI (SD 1.19) and after: 11.14 (SD 1.20). The third dose of misoprostol showed very little efficacy.
23. Koopersmith TB, Mishell DR Jr. The use of misoprostol for termination of early pregnancy. Contraception. 1996 Apr;53(4):238-42.
Fifty-eight women with pregnancies less than 10 weeks gestation who desired pregnancy termination received varying dosages of vaginal misoprostol, either alone or in combination with laminaria or tamoxifen. The overall success rate for a complete abortion was 61%. The use of laminaria or tamoxifen did not affect success rates. Abortions occurred within 24 hours of administration of misoprostol. Side effects were minimal.
24. Bugalho A, Faundes A, Jamisse L, Usta M, Maria E, Bique C. Evaluation of the effectiveness of vaginal misoprostol to induce first trimester abortion. Contraception. 1996 Apr;53(4):244-6.
Two doses, 200 and 400 mcg, of misoprostol, administered vaginally every 12 hours, up to four times, were tested in 101 and 133 healthy women, respectively, for interruption of pregnancies with 35 through 77 days of amenorrhea. The proportion of women who aborted increased with longer duration of treatment and was significantly higher with 400 than with 200 mcg (66 versus 46 percent at 48 hours). Abortions were classified as incomplete or complete, according to the presence or not of embryonic tissue in the uterine cavity, diagnosed by vaginal sonography. Vacuum aspiration was carried out in all cases not classified as complete abortion 48 hours after the initiation of treatment, or earlier in case of persistent bleeding or woman’s request.
25. Creinin MD, Vittinghoff E. Methotrexate and misoprostol vs. misoprostol alone for early abortion. A randomized controlled trial. JAMA. 1994 Oct 19;272(15):1190-5.
A total of 61 women who had requested elective termination of pregnancy and medical abortion at 56 days’ gestation or less were randomized into two groups. Intramuscular administration of 50 mg of methotrexate per square meter of body surface area followed 3 days later by vaginal administration of 800 mcg of misoprostol (group 1) or the same dose of misoprostol given alone (group 2). The misoprostol dose was repeated 24 hours later if abortion had not occurred. Complete abortion occurred in 28 (90%) of 31 patients in group 1 and 14 (47%) of 30 patients in group 2 (P < .001). There were three treatment failures in group 1: two ongoing pregnancies (6%) and one incomplete abortion (3%). There were 16 treatment failures in group 2: eight ongoing pregnancies (27%), and eight incomplete abortions (27%). Methotrexate side effects were minimal. Misoprostol side effects were diarrhea in 18% and nausea and vomiting in 5%.
Summary – Misoprostol Alone for Early Abortion
| Author | Sample size | Gestational age | Regimens | Efficacy |
| Carbonell JL (1) | 452 | < 63 days | 800 mcg vag q8h x 3 (self-administered) | 90.5% |
| Singh K (2) | 150 | < 56 days | 800 mcg vag plus 400 mcg q3h up to 3 doses | 84.7% |
| Zikopoulos KA (3) | 160 | < 56 days | 800 mcg vag q24h up to 3 doses | 91.3% |
| Jain JK (4) | 250 | < 56 days | 800 mcg vag q24 h up to 3 doses | 88.0% |
| Tang OS (5) | 50 | < 84 days | 600 mcg sublingual q3h up to 5 doses | 86.0% |
| Tang OS (6) | 25 | < 84 days | Varying doses of sublingual misoprostol | 92.0% |
| Jain JK (7) | 100 | < 56 days | 800 mcg vag q24h up to 3 doses | 89.0% |
| Carbonell JL (8) | 300 | 42-63 days | 000 mcg vag q24h up to 3 doses | 93.0% |
| Carbonell JL (9) | 150 | 63-84 days | 800 mcg vag q24h up to 3 doses | 84.0% |
| Velazco A (10) | 150 | 35-63 days | 800 mcg vag q24h up to 3 doses | 88.7% |
| Ngai SW (11) | 80 | < 63 days | 800 mcg vag q48h up to 3 doses | 85.0%1 |
| Carbonell JL(12) | 90 | < 63 days | 600 mcg vag q8h up to 3 doses (self-administered) | 64.0% |
| Bugalho A (13) | n/a | < 42 days | 800 mcg vag + 800 mcg vag 7 days afterward IFN2 | 92.1%3 |
| Jain JK (14) | 150 | < 56 days | 800 mcg vag q24h x 2 + 800 mcg 8 days afterward IFN | 90.7% |
| Tang OS (15) | 20 | < 63 days | 800 mcg vag + 400 mcg vag q3h x 4 | 70.0% |
| Jain JK (16) | 100 | < 56 days | 800 mcg vag + 800 mcg 24 hours afterward IFN4 | 80.0% |
| Ozeren M (17) | 108 | < 63 days | 800 mcg vag + 800 mcg 24 hours afterward IFN | 58.0% |
| Esteve JL (18) | 720 | 35-63 days | 800 mcg vag q24h up to 3 doses | 89.4% |
| Carbonell JL (19) | 180 | 64-91 days | 800 mcg vag q12h up to 3 doses | 85.0% |
| Carbonell JL (20) | 120 | 64-84 days | 800 mcg vag q24h up to 3 doses | 87.0% |
| Carbonell JL (21) | 175 | < 63 days | 800 mcg vag q48h up to 3 doses + 400-600 mcg IFN | 92.0%5 |
| Carbonell JL (22) | 141 | < 70 days | 800 mcg vag q48h up to 3 doses | 93.6% |
| Koopersmith TB (23) | 58 | < 70 days | Varying dosages of vaginal misoprostol | 61.0% |
| Bugalho A (24) | 101 | 35-77 days | 200 mcg vag q12h up to 4 doses | 66.0%6 |
| Creinin MD (25) | 61 | < 56 days | 800 mcg vag + 800 mcg 24 hours afterward IFN | 47.0% |
1 The complete abortion rate appeared higher when water was added but the difference did not reach statistical significance.
2 IFN = if necessary (i.e. woman had not yet aborted)
3 Cumulative abortion rate.
4 Misoprostol was administered in the form of sodium chloride solution-moistened tablets.
5 The third dose of misoprostol showed very little efficacy (0.6%).
6 Abortion rate at 48 hours.
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MISOPROSTOL FOR TREATMENT OF INCOMPLETE ABORTION:
AN INTRODUCTORY GUIDEBOOK
CONTRIBUTORS: JENNIFER BLUM, JILLIAN BYNUM, RASHA DABASH, AYISHA DIOP, JILL DUROCHER, ILANA DZUBA, MELANIE PEŃA, SHEILA RAGHAVAN, BEVERLY WINIKOFF
EDITORS: SHEILA RAGHAVAN AND JILLIAN BYNUM
ACKNOWLEDGEMENTS: WE ARE GRATEFUL TO THE WILLIAM AND FLORA HEWLETT FOUNDATION, DAVID AND LUCILE PACKARD FOUNDATION AND SWEDISH INTERNATIONAL DEVELOPMENT COOPERATION AGENCY, WHOSE FUNDING HAS SUPPORTED OUR WORK ON MISOPROSTOL FOR TREATMENT OF INCOMPLETE ABORTION AND HAS MADE THE DEVELOPMENT OF THIS GUIDEBOOK POSSIBLE.
Entire content Copyright © 2009 Gynuity Health Projects. This material may not be reproduced without written permission from the authors. For permission to reproduce this document, please contact Gynuity Health Projects at pubinfo@gynuity.org.
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Table of Contents
I. Introduction…… 1
II. Overview of misoprostol for incomplete abortion………………. 3
• What misoprostol is and how it works
• Formulation
• Efficacy in treating incomplete abortion
• Safety
• Acceptability
• Comparison to other treatment methods
• Misoprostol is an important new treatment for incomplete abortion
III. Treatment of incomplete abortion using misoprostol………… 8
• Who can receive misoprostol for treatment of incomplete abortion?
• Who can provide misoprostol for treatment of incomplete abortion?
• Dose and timing
• Route of administration
• Safety of misoprostol for treatment of incomplete abortion
IV. Service design, visit schedule and managing complications……………. 14
• Ultrasonography
• Provider experience
• Schedule of clinic visits
• Managing side effects and complications
• Follow-up
V. Counseling, information provision and service delivery……… 20
• Choosing a method
• Establishing eligibility
• Preparing women for what to expect
• Family planning and contraceptive services
• Reproductive and other health services
• Provider and staff training
• Community and service provider partnerships
• Desirable (but not required) facilities and supplies
VI. Integrating misoprostol into existing postabortion care services……….. 29
VII. Missed abortion…………. 30
VIII. Looking forward…………. 32
IX. Appendix…….. 34
• Frequently Asked Questions
X. References…… 38
I. Introduction
The launch of this guidebook follows closely the inclusion of misoprostol for the management of incomplete abortion and miscarriage in the World Health Organization’s Model List of Essential Medicines in April, 2009.1 The Expert Committee on the Selection and Use of Essential Medicines decided that misoprostol is as effective as surgery and perhaps safer and cheaper in some settings. This new status marks a turning point in the role of misoprostol from a promising technology to an established, internationally recognized essential medicine for the treatment of incomplete abortion.
Approximately one in five recognized pregnancies are spontaneously miscarried in the first trimester2 and an additional 22% end in induced abortion.3 An incomplete abortion can result from either spontaneous or induced pregnancy loss and occurs when products of conception are not completely expelled from the uterus.
Incomplete abortion is closely related to unsafe abortion in many parts of the world. Where abortion services are restricted, women may seek pregnancy terminations from unskilled providers, have procedures performed in environments lacking minimal medical standards, or both.4 Some women may resort to self-induction. These conditions increase the likelihood that women will experience abortion complications and will seek treatment for incomplete terminations.5 Safe and effective treatment for incomplete abortion is an important way to reduce abortion-related morbidity and mortality, particularly in settings where legal abortion is restricted.
Incomplete abortion can be treated with expectant management, which allows for spontaneous evacuation of the uterus, or active management, using surgical or medical methods. Expectant management is not preferred by many providers due to its relatively low efficacy and the fact that the time interval to spontaneous expulsion is unpredictable.6 The standard of care for active management varies by setting but has traditionally been surgery with general or local anesthesia. Surgical methods are highly effective for treatment of incomplete abortion. However, these treatments require trained providers, special equipment, sterile conditions and often anesthesia, all of which are limited in many settings.6
Medical methods for treatment of incomplete abortion require few resources and can be administered by low- and mid-level providers.7 Such technologies could increase access to services for women far from surgical care facilities. Misoprostol is the most common and thoroughly studied form of medical management and offers a highly effective alternative treatment for women wishing to avoid invasive surgery and anesthesia.8 In environments with few resources and limited access to surgical methods, such as primary and secondary care centers, misoprostol allows for the vast majority of cases to be treated without needing referral to higher level facilities.8 Additionally, misoprostol is widely available, easy to administer, stable at room temperature, accessible, and inexpensive in most countries. Misoprostol offers women and providers a safe, effective, and non-invasive treatment option for incomplete abortion that is particularly useful where supplies are limited and skilled providers are few. In settings where special postabortion care (PAC) services have been introduced to address morbidity and mortality associated with unsafe abortion, misoprostol can be integrated easily within existing services.
Information about this Guidebook
This guidebook was created for providers and policymakers who are interested in learning about misoprostol to treat incomplete abortion, whether arising from spontaneous or induced pregnancy loss. The goal of this guidebook is to synthesize the available literature to provide appropriate, effective and safe clinical guidelines for use of misoprostol in treatment of incomplete abortion. Chapter II focuses on the efficacy, safety, and acceptability of misoprostol for treatment of incomplete abortion, while Chapters III through V outline who can be offered the method, recommended regimens, schedule of clinic visits, management of side effects, counseling, and service delivery. Chapter VI addresses how misoprostol can be integrated into existing PAC services and Chapter VII provides brief information on missed abortion.
II. Overview of misoprostol for incomplete abortion
A. What misoprostol is and how it works
Misoprostol (with a variety of trade names, the most common being Cytotec®) is registered in over 80 countries, mostly for prevention of gastric ulcers secondary to long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). Misoprostol is a prostaglandin E1 analog which, like natural prostaglandins, affects more than one type of tissue, including the stomach lining and the smooth muscle of the uterus and cervix.6,9,10 Over the last two decades, research on use of misoprostol in reproductive health has burgeoned due to its very effective uterotonic and cervical ripening properties.6,10 At present, misoprostol is an accepted and widely used treatment for cervical ripening, induction of abortion in the first and second trimester, prevention and treatment of postpartum hemorrhage, and incomplete abortion. At the same time, few misoprostol products have been registered for reproductive health uses.
B. Formulation
Misoprostol is most commonly manufactured as a 200 mcg tablet intended for oral administration, although 100 mcg pills also exist in some countries.10 Vaginal formulations are also available in some places, mostly as a 25 mcg suppository, but also in larger doses. Misoprostol has several important advantages over other agents with uterotonic properties. For example, it is stable at ambient temperature11 while other products require refrigeration or freezing. Some other products are only administered by injection.9 Misoprostol is less expensive and more widely available than other treatments.11 With new misoprostol products and generics appearing each year, its price can be expected to decrease as availability increases.
C. Efficacy in treating incomplete abortion
Misoprostol is effective in emptying the uterus because of its ability to induce uterine contractions and to soften the cervix. Misoprostol for treatment of incomplete abortion has been well documented in women presenting with uterine size less than or equal to a pregnancy at 12 weeks since last menstrual period (LMP).12 Successful use of misoprostol implies complete evacuation of the uterus without recourse to surgical intervention. Infrequently, surgical completion may be needed for retained products of conception, heavy bleeding, or at the request of the woman. The efficacy rates found in the literature are inconsistent due to differences in regimens, time to determination of success, and inclusion and exclusion criteria. However, recent studies have attempted to standardize these variables and have achieved high efficacy. Overall, in studies that each enrolled more than 100 women and used misoprostol in at least one treatment arm (600 mcg oral or 400 mcg sublingual misoprostol) with at least 7 days before follow-up, efficacy averaged 95% (see Table 1), with success rates as high as 99%.13
Table 1: Misoprostol and Manual Vacuum Aspiration (MVA) for treatment of incomplete abortion
Year * Author * N * Treatment * Time to Success * Success
2009 * Diop A, et al.14 * 150; 150 * 600 mcg oral misoprostol; 400 mcg sublingual misoprostol * Days 7 & 14 * 94.6%; 94.5%
2007 * Bique C, et al.15 * 123 * 600 mcg oral misoprostol; MVA * Days 7 & 14 * 91%; 100%
2007 * Dao B, et al.16 * 227 * 600 mcg oral misoprostol; MVA * Days 7 & 14 * 94.5%; 99.1%
2007 * Shwekerela B, et al.13 * 150 * 600 oral misoprostol; MVA * Days 7 & 14 * 99%; 100%
2005 * Ngoc NTN, et al.17 * 150; 150 * 600 oral single or double dose * Day 7 * 95.3%; 93.8%
2005 * Weeks A, et al.18 * 160 * 600 mcg oral misoprostol; MVA * Days 7 to 14 * 96.3%; 91.5%
• 150 women received an additional 600 mcg oral misoprostol dose at 4 hrs (Ngoc NTN, et al.)
D. Safety
Misoprostol has been used by millions of men and women worldwide since its approval in 1988 for prevention of gastric ulcers associated with chronic NSAID use. Importantly, misoprostol has been used safely for incomplete abortion in many countries. Misoprostol has not been associated with long-term effects on women’s health, and prolonged or serious side effects are virtually nonexistent.
E. Acceptability
Women and providers find misoprostol for treatment of incomplete abortion to be highly acceptable. Many women report that they would choose misoprostol again if they were to need treatment for incomplete abortion in the future. Research in low-resource settings in several countries has indicated that over 90% of women were “very satisfied” or “satisfied” with misoprostol treatment.13,16,17,18
F. Comparison to other treatment methods
Incomplete abortion can be treated with expectant, surgical, or medical management. Expectant management involves allowing the uterus to evacuate the products of conception spontaneously without provider intervention. Generally, expectant management results in lower success rates compared to active (surgical or medical) management.19 Surgical evacuation procedures include dilatation and curettage (D&C;), electric vacuum aspiration (EVA), and manual vacuum aspiration (MVA). These methods achieve a high success rate (91.5-100%) but carry a small risk of serious complications including infection, cervical laceration and uterine perforation. Most important, in many settings, surgical management may not be feasible. Misoprostol provides an effective, safe, and acceptable treatment option for women who do not have access to surgical treatment or who wish to avoid invasive procedures. Rates of gynecological infection after expectant, surgical, and medical management of incomplete abortion are low (2-3%) and do not differ by method of treatment.20 Additionally, experience has shown that women find misoprostol to be as acceptable as MVA; in fact, in some studies, more women have reported being “very satisfied” with misoprostol treatment than MVA treatment.13,16,18 Refer to Table 2 for a comparison of methods of management of incomplete abortion.
Table 2: Comparing expectant, medical and surgical management of incomplete abortion
Who can offer the treatment? * What is needed to offer the treatment? * What are the risks?
Expectant * Mid-level and skilled providers * Ability to diagnose the problem * Failure; need for medical or surgical completion
Medical * Mid-level and skilled providers * Above plus drug supplies * Failure; need for surgical completion; side effects
Surgical * Skilled providers * All of the above plus sterilized equipment, surgical supplies, and a special room * Cervical laceration; uterine perforation; infrequent failure
G. Misoprostol is an important new treatment for incomplete abortion
In countries where legal abortion is restricted, the PAC model provides a framework for care of women experiencing complications from unsafe abortion (see page 7). Treatment of incomplete abortion is an essential component of PAC services, and misoprostol can serve as an effective treatment option. Misoprostol treatment can be readily integrated into existing PAC services with basic provider training. Importantly, misoprostol is a safe and effective treatment option for PAC where there are no other treatment options or where there are few skilled providers.
Essential elements of postabortion care where abortion services are restricted21
1. Community and service provider partnerships
• Prevent unwanted pregnancies and unsafe abortion
• Mobilize resources to help women receive appropriate and
timely care for complications from abortion
• Ensure that health services reflect and meet community expectations and needs
2. Counseling
• Identify and respond to women’s emotional and physical health needs and other concerns
3. Treatment
• Treat incomplete and unsafe abortion and potentially life-threatening complications
4. Contraceptive and family planning services
• Help women prevent an unwanted pregnancy or practice birth spacing
5. Reproductive and other health services
• Preferably provided on-site, or via referrals to other accessible facilities in providers’ networks
III. Treatment of incomplete abortion using misoprostol
A. Who can receive misoprostol for treatment of incomplete abortion?
Eligibility criteria
Misoprostol can be used for early, uncomplicated incomplete abortion.
Eligible women have the following:
• Open cervical os
• Vaginal bleeding or history of vaginal bleeding during this pregnancy
• Uterine size of less than or equal to 12 weeks’ LMP
Assessment of uterine size
Providers should assess a woman’s uterine size prior to misoprostol administration. A woman with a uterus 12 weeks’ LMP or smaller is eligible for treatment with misoprostol. Uterine size can be estimated by conducting a physical exam. Precise dating of the initial gestational age is unnecessary as long as the uterine size at presentation for treatment is equivalent to a pregnancy of 12 weeks’ LMP or less.
Women who are NOT eligible have the following:
• Known allergy to misoprostol or other prostaglandin
• Suspected ectopic pregnancy
• Signs of pelvic infection and/or sepsis
• Hemodynamic instability or shock
Precautions to use of misoprostol for treatment of incomplete abortion:
• Intrauterine device (IUD) in place: Women who have an IUD in place should have the IUD removed before misoprostol administration.
• Information to women who are breastfeeding: Misoprostol is quickly metabolized in the body,22,23 however, small amounts of misoprostol or its metabolite may appear in breast milk. No adverse effects in nursing infants have been reported, and there are no known consequences of such exposure.24 If there is any concern, women can be advised to discard the breast milk produced for the first few hours after misoprostol administration.
• Uterine size larger than 12 weeks’ LMP: Misoprostol may be used with caution in women with a uterine size larger than 12 weeks’ LMP (e.g. uterine enlargement due to fibroids).
Myth: Misoprostol is not an appropriate treatment for women in rural areas
Misoprostol may be the most appropriate treatment choice for rural women because care can be provided by mid-level providers in the absence of surgical equipment and ultrasound. If a treatment facility is unable to provide surgical completion in the event of method failure, a referral clinic can provide this care.
B. Who can provide misoprostol for treatment of incomplete abortion?
Misoprostol can be provided by mid-level and skilled providers practicing in primary, secondary and tertiary care facilities. The most important skill is to know who could benefit from the treatment. Providers who are offering other reproductive health services may already have the skills needed to offer misoprostol as a treatment option for incomplete abortion.
Myth: Only physicians can administer misoprostol for treatment of incomplete abortion
Given the nature of misoprostol treatment (oral medication), trained non-physician health workers can be effective treatment providers, increasing the number of providers. In some areas, nurses, midwives and other non-physician trained providers are already using misoprostol for treatment of incomplete abortion.
C. Dose and timing
High efficacy rates with acceptable side effect profiles have been obtained with both a single 600 mcg oral dose13,14,15,16,18 and with a single 400 mcg sublingual dose of misoprostol.14 Recent research has shown that these two regimens work equally well.14 Repeated dosing within a short interval does not seem to improve efficacy.25 The recommended dosing regimen is a single administration of either 600 mcg oral or 400 mcg sublingual misoprostol (see Table 3). The lower dose may be advantageous in settings where cost of misoprostol is a concern. Success of misoprostol for treatment of incomplete abortion in the first trimester is independent of gestational age at the time of miscarriage/abortion.26
Table 3: Recommended regimens of misoprostol for treatment of incomplete abortion12,27
Dose Misoprostol * Route of Administration
600 mcg * oral
400 mcg * sublingual
Madagascar: Adapting the 400 mcg sublingual misoprostol regimen for PAC into national reproductive health norms and protocols
A large maternity hospital in Madagascar recently completed a study comparing a 400 mcg sublingual dose to a 600 mcg oral dose of misoprostol for treatment of incomplete abortion.14 Shortly after the launch of the study, it became clear to providers that treatment with the misoprostol regimen yielded high efficacy rates in addition to increased access and improved services. Over-burdened doctors saw their workload decrease as in-patient PAC patients were screened and treated by nurse midwives. Patient follow-up was also managed by these mid-level service providers. Given the lower cost of a 400 mcg versus 600 mcg dose and the similarity in efficacy, the Ministry of Health added a 400 mcg sublingual misoprostol regimen for the treatment of incomplete abortion to the Reproductive Health Norms and Protocols.
Future plans in Madagascar include expanding the use of misoprostol for incomplete abortion to lower levels of the healthcare system. The focus will be on providing training and developing curricula for lower level providers. Misoprostol’s potential may best be realized as a first-line treatment in community-level health facilities when used by lower level health providers such as nurses and midwives.
D. Route of administration
Misoprostol for incomplete abortion has been administered vaginally, orally, and sublingually.14,28,29,30 A number of studies have demonstrated very high efficacy (greater than 90%) and acceptability using the oral route.13,14,15,16,18 The oral route is effective, simple, and acceptable to both women and providers. Recent experience has shown that lower dose sublingual administration is as effective as oral administration.14 If misoprostol is taken sublingually, the woman holds the pills under her tongue for about 30 minutes. Any remaining pill fragments can be swallowed with water.
E. Safety of misoprostol for treatment of incomplete abortion
Misoprostol has been studied for treatment of incomplete abortion in many settings. It has been used safely by thousands of women seeking postabortion care with almost no side effects. Misoprostol has not been associated with long-term effects on women’s health.
Frequently cited safety concerns include:
• Excessive bleeding: Excessive bleeding warranting transfusion is rare;31 misoprostol for treatment of incomplete abortion is no more likely to result in transfusion than other treatments.19
• Anemia: Misoprostol treatment is not associated with increased risk of anemia. A recently completed study shows no clinically significant difference in change in hemoglobin between women treated with misoprostol or MVA for incomplete abortion. Very few women had clinically significant drops in hemoglobin (0.3% misoprostol, 0.9% MVA).32
• Infection: Risk of infection is low. The rate of infection in women who receive misoprostol for treatment of incomplete abortion is similar to the rate in women who receive other treatments.19,20 There is no evidence that misoprostol increases the risk of infection.
• Ectopic pregnancy: Misoprostol will not cause, complicate, or treat an ectopic pregnancy. Suspected ectopic pregnancy is a contraindication to use of the method.12 However, it is possible to confuse symptoms of ectopic pregnancy (e.g. pelvic pain and bleeding) with those of spontaneous pregnancy loss. Careful evaluation before treatment and good clinical judgment are essential to identify women with suspected ectopic pregnancies so that they may be referred for appropriate diagnosis and treatment.
• Use in women with history of cesarean section: There is no clinical reason to withhold misoprostol from women with previous cesarean sections. Such women have not been excluded in studies of misoprostol for treatment of incomplete abortion; misoprostol used for incomplete abortion according to the guidelines above is generally safe in this population.
• Teratogenic effects: Women seeking PAC services do not have viable pregnancies; therefore concerns about the potential teratogenic effects of misoprostol are not relevant for this indication.
IV. Service design, visit schedule and managing complications
A. Ultrasonography
Ultrasound machinery is not essential to provide misoprostol for treatment of incomplete abortion. Misoprostol can be offered in PAC facilities and at levels of care that lack ultrasound equipment or where ultrasound is too costly. An incomplete abortion can be diagnosed by clinical history and examination; complete evacuation can be assessed using the same set of clinical techniques.33 Several recent studies in low-resource settings rarely used ultrasound to diagnose incomplete abortion (<5% of diagnoses were confirmed via ultrasound) or to confirm uterine evacuation.13,14,15,18
Ultrasound can be used if the provider has expertise in the technique: the biggest danger is in over-interpretation of normal amounts of debris in the uterus, leading to unnecessary surgical completion. Providers should be aware that women treated successfully with misoprostol have been found to have a wide range of endometrial thicknesses on ultrasound at follow-up; therefore it is recommended that the decision to perform surgical evacuation be based on clinical signs rather than ultrasound findings.34 Unnecessary intervention to evacuate the uterus may occur when providers see debris on ultrasound but misinterpret its clinical significance.35
Myth: Ultrasound is necessary prior to and after misoprostol for treatment of incomplete abortion
Many providers are concerned about offering misoprostol where ultrasound may not be available. However, ultrasound is not necessary to use misoprostol for treatment of incomplete abortion. Clinical history and examination are sufficient for diagnosis of incomplete abortion; complete evacuation can be assessed in the same way. Experience has shown the safety and efficacy of misoprostol in the absence of routine ultrasound.13,14,15,18 Providers can refer women to facilities with ultrasound if they are uncertain of the woman’s status following misoprostol treatment.
B. Provider experience
The effectiveness of misoprostol as a treatment option for postabortion care services is in part dependent on provider familiarity with and confidence in the regimen. Clinical assessment of when and if surgical intervention is medically necessary is subjective and dependent on experience with the method. Providers who are confident and familiar with the regimen are more likely to make clinical judgments that avoid surgical intervention.36 An inexperienced provider may feel uncomfortable allowing misoprostol to take its course or may misjudge the status of completion and decide to intervene surgically. Accordingly, as providers become comfortable with misoprostol for treatment of incomplete abortion, success rates will generally rise.25
C. Schedule of clinic visits
A woman who chooses misoprostol for treatment of her incomplete abortion usually has one initial visit and could be encouraged to make a follow-up visit. During the initial visit the diagnosis of incomplete abortion is made, the woman is counseled, she is provided information about what to expect with treatment, and misoprostol is administered. Depending on the healthcare system and provider
and patient preference, the woman can take misoprostol either at the clinic or at home. There is no medical reason to observe women in the clinic following misoprostol administration.
Myth: Women should be observed at the clinic following administration of misoprostol or until the abortion is complete
There is no medical reason to observe women in the hospital or the clinic following administration of misoprostol. Women can be sent home with the misoprostol to administer later or immediately after taking it at the clinic. They should be informed of potential side effects, how to handle them, and when to seek additional care. Several recent experiences in low resource areas have followed these guidelines and achieved high efficacy with low rates of complications.13,15,16,18
Providers should also be sure to allow sufficient time for misoprostol to work, as time to complete the process can vary from one day to several weeks.37 To avoid unnecessary surgical intervention, the follow-up visit to assess health status should be scheduled no less than 7 days after misoprostol administration. This visit schedule is associated with consistently high success rates, but the method does fail for approximately 1 out of every 20 women. Unless medically necessary for hemostatic or infection control, surgical intervention prior to 7 days is not recommended. Women should be advised that medical help can be sought at any point during treatment if needed.
Myth: Misoprostol is not as safe as surgical methods; misoprostol has a higher rate of heavy bleeding compared to surgical methods
Women should be informed of what to expect following treatment with misoprostol, and when to seek care for heavy bleeding. Excessive bleeding requiring transfusion is no more likely to result from misoprostol for treatment of incomplete abortion than from surgical management. Some research shows that more women report heavy bleeding with medical management compared to surgical management,15,16,18 while other research finds similar bleeding patterns following treatment with either misoprostol or surgical methods.32,38
D. Managing side effects and complications
Side effects associated with misoprostol treatment of incomplete abortion are well-studied and generally easy to manage. Each woman should be informed about potential side effects and how to handle them. Women should also be instructed to seek additional care (either at the clinic or at an emergency facility) in the event of very heavy and/or prolonged bleeding or persistent fever. Table 4 lists common side effects and management strategies.
Table 4: Common side effects of misoprostol and their management when used for treatment of incomplete abortion
Description * Management
Pain/cramping * Cramping typically starts within the first few hours and can begin as early as 30 minutes following misoprostol administration. Pain may be stronger than that typically experienced during a menstrual period. * > Sitting or lying comfortably > Hot water bottle or heating pad > Paracetamol/acetaminophen > Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen
Chills/fever * Chills are a transient but common side effect of misoprostol. Fever is less common and does not necessarily indicate infection. Temperature elevation generally does not last more than a few hours. Though infection is rare, fever or chills that persist for longer than 24 hours may indicate infection.* > Reassurance that chills and fever are common side effects of misoprostol > Antipyretics if needed > Women should be instructed to contact a medical provider if fever or chills persist for more than 24 hours or develop more than one day after taking misoprostol
Bleeding * Generally, vaginal bleeding will commence within an hour of misoprostol administration. Bleeding typically lasts an average of 5 to 8 days (but may continue up to 2 weeks). Spotting can persist until the next menstrual period. * > Give women information on expected bleeding > Women should be instructed to notify a health care provider if they experience the following: • Soaking more than 2 extra large sanitary pads (or local equivalent) per hour for more than 2 consecutive hours • Sudden heavy bleeding after bleeding has slowed or stopped for several days • Continuous bleeding for several weeks with dizziness or light-headedness
Heavy bleeding * Heavy and/or prolonged bleeding that causes a significant change in hemoglobin is uncommon. A few women will present with heavy bleeding according to the guidelines above. * > Surgical completion if bleeding is profuse or prolonged > Administration of intravenous fluids if there is evidence of hemodynamic compromise > Transfusion should be provided only when clearly medically indicated
Nausea/vomiting * Nausea and vomiting may occur and typically resolve within 2 to 6 hours.12 * > Reassure women that nausea and vomiting are possible side effects > An antiemetic may be used if necessary
Diarrhea * Diarrhea is a common, transient side effect of misoprostol that should resolve within a day. * > Reassure women that diarrhea is sometimes associated with misoprostol use and passes quickly
Infection * Documented endometrial and/or pelvic infection is rare. Infection is typically treated with oral antibiotics. * > If infection is suspected the woman should be evaluated > If there are signs of sepsis or severe infection women should be given immediate surgical evacuation and antibiotic coverage > Severe infections could require hospitalization and parenteral antibiotics
E. Follow-up
If routine follow-up is scheduled by the providers, it should be planned for no less than 7 days after misoprostol treatment. Very few follow-up visits prove to be medically necessary for the woman. Women should be educated about the symptoms of retained tissue and infection so they will know when a follow-up visit is medically necessary.
Women who return for follow-up should be asked to report side effects and bleeding patterns. Bimanual exam will help the provider assess whether the uterus is firm, involuted, and pre-pregnancy size. Experience in low-resource settings has shown that patient history and clinical exam are sufficient to assess whether the process is complete.13,14,15,18 If a woman is thought to have retained products of conception but is not experiencing any signs of infection or severe bleeding, she should be offered the choice between an additional follow-up visit in approximately one week and an immediate surgical evacuation (either by D&C;or suction aspiration). Women may also be offered an additional dose of misoprostol at the follow-up visit, as this may offer some benefit.
V. Counseling, information provision and service delivery
Information provision is an important component of postabortion care. Women should be informed about medical conditions, test results, treatment and pain management options, side effect management, follow-up care, and where and when to seek help in the case of complications.21 Counseling and information provision are particularly important when using misoprostol for treatment of incomplete abortion. By preparing women for what to expect, providers can reduce the likelihood that women will experience anxiety and request an unnecessary surgical intervention. Women who are comfortable and confident in the method may be more likely to have a positive, satisfactory experience.
A. Choosing a method
If the provider offers more than one treatment method, the woman should be given a brief description of each and allowed to choose the treatment that she prefers, provided there are no clinical contraindications to the use of any specific method. It is important to provide complete, accurate, and unbiased information to enable women to choose the most appropriate method for themselves. (For a comparison of expectant, surgical, and medical methods refer to Chapter II.) Providers should take the time to explain to women that if misoprostol or expectant management fails, they may need to have surgical intervention. Table 5 compares some advantages and disadvantages of surgical and medical treatment for incomplete abortion as cited by women.
Table 5: Advantages and disadvantages of misoprostol treatment compared to surgical treatment of incomplete abortion as cited by women
Misoprostol Treatment * Surgical Treatment (D&C;, MVA, EVA)
Advantages * > can avoid surgery and anesthesia > more natural, like menses > women can be more in control, involved > simple to administer > in-patient care not needed * > quicker > provider controlled > woman can be less involved
Disadvantages * > bleeding, cramping and side effects (real or feared) > waiting, uncertainty * > invasive > small risk of uterine or cervical injury > small risk of infection > loss of privacy, autonomy
B. Establishing eligibility
It is important that providers screen each woman to ensure that she meets criteria for eligibility (see Chapter III). Below is a brief check-list on how to determine if a woman is eligible to use misoprostol.
• Ask questions: Providers should ask questions to determine whether the woman’s symptoms might indicate an ectopic pregnancy. Women with suspected ectopic pregnancies should be referred for appropriate diagnosis and treatment. Providers also need to ask the woman if she has an allergy to misoprostol or another prostaglandin.
• Clinical examination, including bimanual exam: Providers should confirm that the woman has an open cervical os and uterine size of less than 12 weeks’ LMP.
• Rule out signs of severe infection: Evaluate the woman for significant uterine tenderness, fever >38°C, and foul smelling discharge. If the woman has two or more of these symptoms, she should be given an immediate surgical evacuation and not misoprostol.
• Rule out hemodynamic instability: Assess the woman’s blood pressure/pulse. Women with very low systolic blood pressure and very high pulse rates may need surgical evacuation. Reassess such women to determine if their vital signs are indicative of hemodynamic instability or fear/anxiety.
• Assess whether any additional precautions should be taken: Determine if the woman has an IUD in place and if so, remove the IUD prior to misoprostol treatment. Ask whether the woman is currently breastfeeding. While there are no known consequences of exposure to breast milk among nursing infants, if the woman is concerned, she can be advised to discard breast milk for the first few hours after misoprostol administration.
Myth: Misoprostol is not an appropriate treatment if the provider suspects that the woman may have interfered with her pregnancy
Providers are commonly concerned about treatment with misoprostol in women who they believe have interfered with their pregnancy. If a woman presents with signs of severe infection, she should be given immediate surgical treatment. Otherwise, misoprostol can be offered for treatment even if the drug was used to induce the abortion. Repeated misoprostol doses for treatment of incomplete abortion have been reported with no adverse effects.17,25 Numerous studies have shown that treatment with misoprostol works well for women who may have induced their abortions with misoprostol.14,16
C. Preparing women for what to expect
A discussion of misoprostol treatment with women seeking services for incomplete abortion should include the following:
• Answering women’s questions: Women should be given the opportunity to ask questions and should receive satisfactory answers prior to selecting a treatment method.
• Misoprostol information: Explain how misoprostol is administered and how it works. Inform women that misoprostol will cause the uterus to contract and expel the remaining products of conception.
• Success rate: Explain that approximately 1 of every 20 women treated with misoprostol requires a surgical procedure to complete the process.
• Understanding the method: Explain that the contents of the uterus are likely to pass in the week after the misoprostol administration.
• Side effects: Explain that women who take misoprostol will likely experience pain, cramping, and bleeding. They may also experience chills, fever, nausea or diarrhea. Inform women that these side effects generally dissipate after a few hours although bleeding similar to a period may continue for days.
• Follow-up care: Women can be encouraged to return to the clinic in one to two weeks to assess whether the method was successful.
• Possible complications: Women should be given a complete description of possible complications. Signs and symptoms of serious complications should be carefully explained. It may be useful, where possible, to give women a telephone number to call with questions or concerns. All women should be advised to seek emergency care if they experience serious complications (see Chapter IV for complications that require medical attention).
• Cost: In treatment facilities where postabortion care is paid for by the woman, the cost of treatment options should be discussed.
D. Family planning and contraceptive services
All women should be informed that fertility returns quickly following a first trimester pregnancy loss. By discussing family planning options with women during treatment for incomplete abortion, providers can help prevent future unwanted pregnancies. Providers should bear in mind that incomplete abortion can result from either spontaneous or induced pregnancy loss, and, while some of the
women may be seeking contraception, others may want information on becoming pregnant again.
The following topics should be discussed with women:
• Reassure the woman that generally there is no reason to believe that she would have difficulty carrying another pregnancy to term in the future.
• Women who wish to become pregnant again are frequently advised to wait until they experience at least one normal menstrual period before attempting to conceive.
• Women not wishing to become pregnant in the near term should be offered contraception that they can begin immediately. These women should receive appropriate contraceptive information. An appropriate contraceptive method will depend on the needs and preferences of each woman, as well as local availability. Refer to Table 6 for contraceptive options and when they can be offered following misoprostol for treatment of incomplete abortion. Some contraceptives can be offered at the first visit while others can be integrated into a follow-up visit, if planned.
Table 6: Contraceptive methods and when they can be safely offered following misoprostol for treatment of incomplete abortion
Contraceptive method * When method can be offered
Condoms * At first visit
Oral contraceptives * At first visit
Contraceptive jellies, foams, tablets or films * At first visit
Cervical cap * Fitting should be delayed until bleeding has stopped and the uterus has returned to pre-pregnancy size (after the first menstrual period)
Diaphragm * At first visit
Injectables * At first visit
Implants * At first visit
Intrauterine devices (IUDs) * At a follow-up visit
Sterilization * Women seeking sterilization may want to opt for surgical treatment for incomplete abortion, since sterilization and completion of the abortion can be done at the same time
E. Reproductive and other health services
It is important to use the follow-up visit to determine whether the woman needs any additional reproductive or other health services. Linking such services with postabortion care allows providers to address other health issues while women are in contact with health care providers. If the facility cannot provide these additional services, appropriate referrals can be made. Other health services might include:21
• Sexually Transmitted Infection (STI) education, testing and treatment
• Infertility diagnosis and treatment
• Hygiene education
• Referral and counseling for cases of sexual and/or domestic violence
• Screening for anemia
F. Provider and staff training
Comprehensive training on how to use misoprostol for treatment of incomplete abortion will improve provider comfort and skill with the method. Experience with misoprostol treatment for postabortion care suggests that as provider familiarity with and confidence in the method increase, success rates and satisfaction will increase as well. A basic training course on misoprostol for treatment of incomplete abortion should include the following elements:
• Mechanism of action
• Misoprostol availability, storage, efficacy, and acceptability
• Eligibility, contraindications, and precautions
• Diagnosis of incomplete abortion
• Role of ultrasonography
• Regimens for using misoprostol for treatment of incomplete abortion
• Counseling when using misoprostol as a treatment option for incomplete abortion
• Management of side effects and potential complications
• Follow-up and assessment of health status
• Provision of contraceptive and family planning services following abortion
• Provision of reproductive and other health services following abortion
Case studies are generally quite helpful in training providers, particularly when discussing evaluation of health status and side effect management. Additionally, role play and group activities are often effective for training on counseling and eligibility.
G. Community and service provider partnerships
Collaboration between community members, lay health workers, service providers and traditional healers is critical in improving women’s reproductive health.21 For example, misoprostol may be the most appropriate treatment option for rural women, because it can be provided by mid-level providers in the absence of skilled surgical providers or equipment; however, the method is not 100% effective, and providers who cannot perform surgical completion should be able to refer women to skilled providers in the event of method failure. Similarly, if the facility cannot provide emergency care, providers should be able to recognize any danger signs and refer women to appropriate facilities.
H. Desirable (but not required) facilities and supplies
• Ultrasound equipment: As discussed above, ultrasonography is not necessary for service provision. However, ultrasound may be useful for diagnosis of rare complications.
• Pain medications/antiemetics: These medications can be given to women in advance to be taken as needed to alleviate possible side effects.
• Anti-RhD immunoglobulin: Currently, there is incomplete evidence on use of anti-RhD immunoglobulin for very early first trimester abortion. If local standard of care indicates anti-RhD immunoglobulin for Rh negative women receiving treatment for incomplete abortion, then this treatment should be provided in conjunction with misoprostol.
VI. Integrating misoprostol into existing postabortion care services
Misoprostol for incomplete abortion can be integrated easily into existing PAC services. Providers who practice surgical evacuation (D&C;, MVA, EVA) for PAC can add misoprostol to their treatment choices, preferably allowing women to decide between surgical and medical methods. The basic requirements for misoprostol for treatment of PAC are trained staff and misoprostol pills. Staff should be able to diagnose incomplete abortion, determine eligibility for misoprostol treatment, confirm completed abortion, and refer to and/or provide women with emergency care if necessary. Accordingly, PAC providers already have many of the skills needed to offer misoprostol for treatment of incomplete abortion. Providers not currently offering PAC services but who are currently offering family planning services, pre-natal care, or other reproductive health services can integrate misoprostol for treatment of incomplete abortion provided they have access to a referral facility in the rare case of method failure or complication.
Integrating misoprostol into existing PAC services: Experience in two Egyptian hospitals
In 2008, a clinical study at El Galaa Teaching Hospital in Cairo and Shatby Maternity Hospital in Alexandria compared misoprostol to MVA for treatment of incomplete abortion.32 Almost 700 women were treated for incomplete abortion with high success rates (misoprostol 98.3%, MVA 99.7%). Bleeding and side effects reported by women were comparable and women were highly satisfied with their misoprostol treatment.
Integrating misoprostol into existing PAC services through the pilot study provided an important experience for providers by helping them gain confidence in the efficacy and safety of a 400 mcg sublingual regimen. Providers were initially reluctant to allow women to leave the hospital immediately after misoprostol administration, but with experience saw no reason for extending women’s stay. They also became convinced of the importance of clinical history and examination in PAC treatment, and viewed ultrasonography not as a routine primary diagnostic tool but as a way to confirm clinical assessment. These changes in providers’ attitudes and practices have resulted in the acceptance of misoprostol as a good treatment option for incomplete abortion and successful expansion of PAC services.
VII. Missed abortion
While information presented in this guidebook pertains to use of misoprostol for treatment of incomplete abortion, misoprostol can also be used to treat missed abortion/anembryonic gestation. Missed abortion/anembryonic gestation is diagnosed by ultrasonography and is defined as a pregnancy in which there is no embryo (empty sac) or unrecognized fetal death. Women experiencing a missed abortion generally have little or no bleeding and no other overt signs or symptoms.39
The recommended regimens for missed abortion/anembryonic gestation are 800 mcg of misoprostol administered vaginally or 600 mcg of misoprostol offered sublingually.39 Table 7 lists several studies that have examined a range of regimens with success rates from 50-93%.
Table 7: Misoprostol for early pregnancy failure: missed abortion/anembryonic gestation
Year * Author * N * Dose Misoprostol (mcg) * Additional Dose Misoprostol * Time to Success * Success
2007 * Shankar M, et al.40 * 75 * 800 vaginal * 400 oral 3 hrs apart up to 2 doses starting the next day * Day 7-10 * 77.3%
2007 * Sharma D, et al.41 * 50 * 600 sublingual * 600 every 3 hrs up to 1800 * 72 hrs * 86%
2006 * Tang OS, et al.42 * 180 * 600 sublingual * 600 every 3 hrs to up to 1800; 90 pts received 400 sublingual daily for 7 additional days * Day 9 * 92% non-extension group; 93% extension group
2006 * Vejborg TS, et al.43 * 254 * 400 vaginal or 800 vaginal * None * Day 2-4 * Missed: 43% 400 mcg; 59% 800 mcg Anembryonic: 36% 400 mcg; 47% 800 mcg
2005 * Agostini A, et al.44 * 276 * 800 vaginal * None * 24 hrs * 65.2%
2005 * Blohm F, et al.45 * 64 * 400 vaginal * None * Day 6-7 * 81%
2005 * Kovavisarach E, et al.46 * 114 * 600 or 800 vaginal * None * 24 hrs * 46% 600 mcg; 68% 800 mcg
2005 * Lister MS, et al.47 * 18 * 800 vaginal * 800 vaginal at 24 hrs if necessary * 48 hrs * 83%
2005 * Sifakis S, et al.48 * 108 * 400 vaginal * 400 vaginal every 4 hrs up to 1200 per day for 3 days * Day 3 * 91%
2005 * Zhang J, et al.49 * 454 * 800 vaginal * 800 vaginal on day 3, if necessary * Day 8 * 88% missed abortion; 81% anembryonic gestation
2004 * Bagratee JS, et al.50 * 45 * 600 vaginal * 600 vaginal on day 2, if necessary * Day 7 * 87%
2004 * Davis AR, et al.51 * 77 * 800 dry vaginal or 800 moistened vaginal * None * Day 30 * 85%
2004 * Gilles JM, et al.52 * 80 * 800 vaginal dry or moistened * Dose repeated at 48 hrs if necessary * Day 7 * 85%
2004 * Graziosi GC, et al.53 * 79 * 800 vaginal * 800 vaginal at 24 hrs if necessary * 48 hrs * 53%
2004 * Murchison A, et al.54 * 44 * 800 vaginal * 800 vaginal at 24 hours if necessary * 48 hrs * 78%
2004 * Ngoc NTN, et al.55 * 198 * 800 oral or 800 vaginal * None * Day 2 & Day 7 * Day 2: 42% oral; 53% vaginal Day 7; 89% oral; 93% vaginal
2004 * Taner CE, et al.56 * 54 * 200 oral and 800 vaginal * None * 24 hrs * 89%
2003 * Al Inizi SA, et al.57 * 27 * 400 vaginal * 400 vaginal every 12 hrs up to 4 doses * 48 hrs * 70%
2003 * Tang OS, et al.58 * 80 * 600 vaginal or 600 sublingual * Dose repeated every 3 hrs to a maximum of 1800 * Day 7 * 87.5% (weighted avg)
2002 * Kovavisarach E, et al.59 * 27 * 400 vaginal * None * 24 hrs * 63%
2002 * Muffley PE, et al.60 * 25 * 800 vaginal * 800 vaginal at 24 and 48 hrs if necessary * Day 3 * 60%
2002 * Wood SL, et al.61 * 25 * 800 vaginal * 800 vaginal at 24 hrs, if necessary * 48 hrs * 80%
2001 * Demetroulis C, et al.62 * 26 * 800 vaginal * None * 8-10 hrs * 77%
2001 * Ngai SW, et al.63 * 25 * 400 vaginal * 400 vaginal day 3 and day 5 * Day 15 * 80%
2000 * Ayres de Campos D, et al.64 * 74 * 600 vaginal (saline moistened) * 600 vaginal at 4-5 hrs, if necessary * 10-12 hrs * 57%
1999 * Autry A, et al.65 * 9 * 800 vaginal * None * Days 10-14 * 89%
1999 * Chung TKH, et al.66 * 321 * 400 oral * 400 oral every 4 hrs, up to 3 doses * 24 hrs * 50%
1998 * Zalanyi S, et al.67 * 25 * 200 vaginal 200 every 4 hrs up to 800 * 10 hrs * 88%
1997 * Creinin M, et al.68 * 20 * 400 oral or 800 vaginal Dose repeated at 24 hrs if necessary * Day 3 * 25% oral; 88% vaginal
1997 * Herabutya Y, et al.69 * 43 * 200 vaginal * None * 24 hrs * 83%
VIII. Looking forward
Given its safety, efficacy, and ease of use, misoprostol is an important option for the treatment of women with incomplete abortion. This guidebook shows how misoprostol can be provided in low-resource settings where demand for services may be high and availability of skilled providers and equipment are often scarce. Misoprostol can increase access to treatment for those who need it most—women who suffer complications from clandestine induced abortions.
Professional associations such as the American College of Obstetricians and Gynecologists recommend misoprostol for postabortion care and the World Health Organization has added misoprostol for the management of incomplete abortion and miscarriage to its Model List of Essential Medicines.1,7 These recommendations are based on a review of the large body of research on medical management of incomplete abortion which shows that misoprostol matches the safety and efficacy of surgical treatments. Additionally, non-surgically-trained, mid-level providers can use the method, thereby reducing the burden of care in higher level facilities that possess the equipment and skills needed for surgical treatment. Misoprostol introduction at secondary- and primary-level health facilities can increase treatment options for women while cutting costs to the healthcare system.
The stage is now set for misoprostol introduction into services. Misoprostol can be easily integrated into existing postabortion care services or established as a treatment option where other options do not exist. Suggestions provided in this guidebook can help facilitate the use of misoprostol in a simple, low-tech manner.
To optimize the use of misoprostol for treatment of incomplete abortion, adequate training for providers is needed along with a sustainable supply of drug. Next steps in programmatic research could include the development of suitable service delivery models and cost-benefit analyses that compare misoprostol to surgical methods. It will be helpful to learn more about the use of misoprostol in rural settings, among populations with high rates of untreated infection, along with documentation of any heavy bleeding and other complications. These efforts can help build momentum among policymakers to approve, promote, and scale-up the use of misoprostol systematically for treatment of incomplete abortion.
Ultimately, safe and effective induced abortion services are needed to prevent complications of abortion, not just to treat them. Services to treat incomplete abortion therefore do not obviate the need for access to family planning and safe abortion services for all women. For those who do require treatment of incomplete abortion, misoprostol should complement access to safe surgical treatment, since surgical treatment will sometimes be necessary depending upon the woman’s condition, her preferences, and for back-up in case of failure of any initial treatment. Comprehensive programs to treat incomplete abortion with roles for both misoprostol and surgical services will enhance the quality of services offered to women, providing a range of treatment options and appropriate care.
Misoprostol can revolutionize how, where and by whom services can be provided to treat incomplete abortion. Misoprostol has the potential to reduce complications arising from spontaneous and induced abortion in low-resource settings where access and availability to safe and effective treatment options are still lacking. Misoprostol is an important technology for women’s health, and the time to move forward is now.
IX. Appendix
FREQUENTLY ASKED QUESTIONS
Questions may arise during trainings or service delivery regarding misoprostol’s use for this new indication. Below is a list of frequently asked questions and possible answers that may be helpful.
• Is misoprostol safe for treatment of incomplete abortion?
Yes, misoprostol has been used safely to treat incomplete abortion in thousands of women worldwide. There have been fewer than a dozen hospitalizations mostly for minor treatments, among over two thousand women treated in recent clinical studies.
• What are the advantages of misoprostol if a safe surgical alternative is available?
Misoprostol is a safe alternative to surgical evacuation. It may be preferable to some women who fear surgery, treatment under anesthesia, and prefer out-patient care. In addition, it may be less expensive for healthcare systems.
• Are women satisfied with misoprostol for treatment of incomplete abortion?
Yes, satisfaction levels are high among women receiving treatment with misoprostol. Most women report that they would choose misoprostol if treatment were needed again in the future. Offering women a choice of treatment methods is optimal in settings where feasible.
• What skills are needed to offer misoprostol for treatment of incomplete abortion?
Providers must be able to identify women in need of treatment for incomplete abortion and must be able to diagnose severe infection which requires immediate surgical care. A woman with a uterus 12 weeks’ LMP or smaller is eligible for treatment. Uterine size can be estimated by providers by conducting a physical exam. Surgical skills are not needed to offer misoprostol.
• What type of referral system is needed?
Women with incomplete abortion who wish to be treated with misoprostol and who meet criteria for treatment can be treated without referral. More than nine out of ten women who were previously referred to a higher level of care will not require referral once misoprostol is available. Any referral system already in place for postabortion care can be used for women not eligible for misoprostol and for complicated cases.
• Is ultrasound necessary prior to and after the use of misoprostol for incomplete abortion?
No, ultrasound is not required when offering misoprostol for treatment of incomplete abortion. An incomplete abortion can be diagnosed by clinical history and examination; a complete evacuation following misoprostol treatment can be assessed using the same set of clinical techniques. The biggest drawback in use of ultrasound is over-interpretation of normal amounts of debris in the uterus, leading to unnecessary surgical completion.
• Is misoprostol safe for women who have never given birth and experience a miscarriage?
Yes, misoprostol is a safe method for women experiencing a miscarriage who have never given birth.
• Is misoprostol safe to use for women with a previous cesarean section?
Yes, there is no clinical reason to withhold misoprostol for treatment of incomplete abortion in women with a previous cesarean section. A number of trials studying the drug’s utility for treatment of incomplete abortion have not excluded these women. (Uterus of < 12 weeks’ LMP size will ensure that misoprostol remains safe for women with uterine scars.)
• Can a woman with incomplete abortion be treated with misoprostol even if she may have already taken misoprostol (to induce abortion)?
Yes. Some providers have expressed concerns about giving women misoprostol again if they have already taken it before presenting at the health facility. Misoprostol can be offered for treatment even if the drug was used to induce the abortion. Repeated misoprostol doses for treatment of incomplete abortion have been reported with no adverse effects. Numerous studies have shown that treatment with misoprostol works well for women who may have induced their abortions with misoprostol.
• If the woman is beyond 12 weeks’ LMP, can misoprostol be used?
The guidance in this booklet for misoprostol use in incomplete abortion applies when the uterine size is not larger than expected in a 12-week pregnancy. The length of amenorrhea may be longer than 12 weeks, however, since some of the contents of the uterus may have already been expelled. Typically, lower doses are needed for efficacy and safety when the uterus is larger.
• If a woman presents with signs of infection, should she be given misoprostol?
Women presenting with two or more signs of infection (significant uterine tenderness, fever >38°C, foul smelling discharge) should be given an immediate surgical evacuation and antibiotic coverage.
• What are the side effects of misoprostol treatment
Expected side effects include pain, cramps, nausea, vomiting, fever, and chills. These side effects are easily managed, transient, and generally mild. A majority of women report the side effects to be tolerable.
• Do women who receive misoprostol for treatment of incomplete abortion become anemic?
No, this treatment is not associated with increased risk of anemia. In fact, data from a recently completed study on this point shows no clinically significant difference in change in hemoglobin between women treated with misoprostol or with MVA. Very few women had clinically significant drops in hemoglobin.
• Does treatment with misoprostol increase the risk of infection?
No, there is no evidence that misoprostol treatment increases the risk of infection.
• Should women be given antibiotics routinely along with misoprostol?
No, routine antibiotic coverage is not necessary. Local norms regarding antibiotic use should be followed. The provider may determine that the woman requires antibiotic coverage based on history or clinical exam.
• Is a follow-up visit required?
In many settings, follow-up visits are the standard of care following both surgical and medical treatment. Given the very high efficacy rates reported with both surgical and medical treatments, few follow-up visits prove medically necessary, however. It is important to educate the woman about the signs of retained tissue and infection so that she will know when a follow-up visit is needed to protect her health (see page 19).
• At the follow-up visit, if ultrasound examination reveals no debris but thickening of the endometrium, is surgical evacuation necessary?
No. Studies have shown that the thickness of the endometrium is not a good predictor of the need for surgery. It is recommended that the decision to perform surgical evacuation be based on clinical signs rather than ultrasound findings.
• If the abortion is not complete at the follow-up visit is it safe to give the woman another dose of misoprostol and ask her to return one week later?
Yes, if the abortion is not complete at the follow-up visit and the woman is clinically stable and willing to continue to wait for her uterus to empty, she can be offered another dose of misoprostol.
• Can contraception be used after misoprostol care?
Yes, contraception can be offered to women after misoprostol treatment, as with standard postabortion care services. Almost all contraceptives can be offered at the first visit while an IUD can be integrated into a follow-up visit, if planned.X. References
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41. Sharma D, Singhal SR, Rani XX. Sublingual misoprostol in management of missed abortion in India. Tropical Doctor 2007; 37(1): 39-40.
42. Tang OS, Ong CY, Tse KY, et al. A randomized trial to compare the use of sublingual misoprostol with or without an additional 1 week course for the management of first trimester silent miscarriage. Human Reproduction 2006; 21(1):189-192.
43. Vejborg TS, Rorbye C, Nilas L. Management of first trimester spontaneous abortion with 800 or 400 ug vaginal misoprostol. International Journal of Gynecology & Obstetrics 2006; 92: 268-269.
44. Agostini A, Ronda I, Capelle M, et al. Influence of clinical and ultrasound factors on the efficacy of misoprostol in first trimester pregnancy failure. Fertility & Sterility 2005; 84(4):1030-1032.
45. Blohm F, Friden BE, Milsom I, et al. A randomised double blind trial comparing misoprostol or placebo in the management of early miscarriage. British Journal of Obstetrics & Gynecology 2005; 112: 1090-1095.
46. Kovavisarach E, Jamnansiri C. Intravaginal misoprostol 600 mcg and 800 mcg for the treatment of early pregnancy failure. International Journal of Gynecology & Obstetrics 2005; 90: 208-212.
47. Lister MS, Shaffer LE, Bell JG, et al. Randomized, double-blind, placebo-controlled trial of vaginal misoprostol for management of early pregnancy failures. American Journal of Obstetrics & Gynecology 2005; 193(4): 1338-1343.
48. Sifakis S, Angelakis E, Vardaki E, et al. High dose misoprostol used in outpatient management of first trimester spontaneous abortion. Archives
of Gynecology & Obstetrics 2005; 272: 183-186.
49. Zhang J, Gilles JM, Barnhart K, et al for the National Institute of Child Health Human Development (NICHD) Management of Early Pregnancy Failure Trial. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. New England Journal of Medicine 2005; 353(8): 761-769.
50. Bagratee JS, Khullar V, Regan L, et al. A randomized controlled trial comparing medical and expectant management of first trimester miscarriage. Human Reproduction 2004; 19(2): 266-271.
51. Davis AR, Robilotto CM, Westhoff CL, et al. Bleeding patterns after vaginal misoprostol for treatment of early pregnancy failure. Human Reproduction 2004; 19(7): 1655-1658.
52. Gilles JM, Creinin MD, Barnhardt K, et al for the National Institute of Child Health and Human Development Management of Early Pregnancy Failure Trial. A randomized trial of saline solution-moistened misoprostol versus dry misoprostol for first-trimester pregnancy failure. American Journal of Obstetrics & Gynecology 2004; 190(2): 389-394.
53. Graziosi GC, Mol BW, Reuwer PJ, et al. Misoprostol versus curettage in women with early pregnancy failure after initial expectant management: A randomized trial. Human Reproduction 2004; 19(8): 1894-1899.
54. Murchison A, Duff P. Misoprostol for uterine evacuation in patients with early pregnancy failures. American Journal of Obstetrics & Gynecology 2004;
190: 1445-1446.
55. Ngoc NTN, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. International Journal of Gynecology & Obstetrics 2004;
87: 138-142.
56. Taner CE, Nayki U, Pirci A. Misoprostol for medical management of first-trimester pregnancy failure. International Journal of Gynecology & Obstetrics 2004; 86: 407-408.
57. Al Inizi SA, Ezimokhai M. Vaginal misoprostol versus dinoprostone for the management of missed abortion. International Journal of Gynecology & Obstetrics 2003; 83(1): 73-74.
58. Tang OS, Lau WN, Ng EH, et al. A prospective randomized study to compare the use of repeated doses of vaginal and sublingual misoprostol in the management of first trimester silent miscarriages. Human Reproduction 2003; 18: 176-181.
59. Kovavisarach E, Sathapanachai U. Intravaginal 400ug misoprostol for pregnancy termination in cases of blighted ovum: A randomized controlled trial. Australian and New Zealand Journal of Obstetrics & Gynaecology 2002; 42(2): 161-163.
60. Muffley PE, Stitely ML, Gherman RB. Early intrauterine pregnancy failure: A randomized trial of medical versus surgical treatment. American Journal of Obstetrics & Gynecology 2002; 187: 321-326.
61. Wood SL, Brain PH. Medical management of missed abortion: A randomized clinical trial. Obstetrics & Gynecology 2002; 99: 563-566.
62. Demetroulis C, Saridogan E, Kunde D, et al. A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure. Human Reproduction 2001; 16(2): 365-369.
63. Ngai SW, Chan YM, Tang OS, et al. Vaginal misoprostol as medical treatment for first trimester spontaneous miscarriage. Human Reproduction 2001; 16(7):1493-1496.
64. Ayres-de-Campos, Teixeira-da-Silva J, Campos I, et al. Vaginal misoprostol in the management of first-trimester missed abortions. International Journal of Gynecology & Obstetrics 2000; 71: 53-57.
65. Autry A, Jacobsen G, Sandhu R, et al. Medical management of non-viable early first trimester pregnancy. International Journal of Gynecology & Obstetrics 1999; 67: 9-13.
66. Chung TK, Lee DT, Cheung LP, et al. Spontaneous abortion: a randomized, controlled trial comparing surgical evacuation with conservative management using misoprostol. Fertility & Sterility 1999; 71(6):1054-1059.
67. Zalanyi S. Vaginal misoprostol alone is effective in the treatment of missed abortion. British Journal of Obstetrics & Gynecology 1998; 105: 1026-1035.
68. Creinin MD, Moyer R, Guido R. Misoprostol for medical evacuation of early pregnancy failure. Obstetrics & Gynecology 1997; 89: 768-772.
69. Herabutya Y, O-Prasertsawat P. Misoprostol in the management of missed abortion. International Journal of Gynecology & Obstetrics 1997; 56: 263-266.
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INSTRUÇÕES PARA USO: MISOPROSTOL PARA TRATAMENTO DE ABORTAMENTO INCOMPLETO E ESPONTÂNEO
ANTECEDENTES
Misoprostol é um análogo de prosta-glandina E1 comumente aprovado para uso na prevenção e tratamento de úlceras gástricas resultantes da administração crônica de drogas antiinflamatórias não esteróides (AINE). Como o misoprostol também induz contrações uterinas, é comumente utilizado, fora da indicação aprovada, para tratamento das falhas da gestação precoce, incluindo o abortamento incompleto ou retido. Estudos têm demonstrado que o misoprostol pode ser usado efetivamente e com segurança para essas indicações. Esta informação é apresentada como orientação aos provedores de saúde treinados.
INDICAÇĂO E USO
O misoprostol é indicado para tratamento de abortamento incompleto e espontâneo para mulheres que se apresentam com tamanho do uterino menor do que ou igual a 12 semanas a partir da data da última menstruação.
O uso de misoprostol para abortamento incompleto tem uma taxa de sucesso de 66-100% usando as doses recomendadas. O uso de misoprostol para abortamento retido tem uma taxa de sucesso de 60-93% usando a dose recomendada.
CONTRA-INDICAÇÕES
- HistĂłria de alergia ao misoprostol ou a outra prostaglandina
- Suspeita de gravidez ectĂłpica
- Sinais de infecção pélvica e/ou sepse
- Sintomas de instabilidade hemo-dinâmica ou choque
PRECAUÇÕES
- Mulheres elegĂveis para receber misoprostol, mas com DIU inserido, devem ter o DIU removido antes da administração da droga.
- Aconselha-se prudĂŞncia quando tratando de mulheres com um problema de sangramento conhecido ou atualmente tomando anticoa-gulantes.
- O misoprostol pode ser usado com precaução em pacientes com tamanho uterino maior do que 12 semanas a partir da data da última menstruação, mas com idade gestacional conhecida menor ou igual a 12 semanas (por exemplo, aumento do útero devido a mioma).
- Pequenas quantidades de misoprostol ou de seu metabolito ativo podem aparecer no leite materno. NĂŁo se conhecem conseqĂĽĂŞncias disso e nenhum efeito adverso sobre o bebĂŞ amamentado tem sido relatado.
EFEITOS E EFEITOS COLATERAIS
Efeitos e efeitos colaterais prolongados ou graves sĂŁo raros.
SANGRAMENTO
Após a administração do misoprostol, o sangramento tipicamente perdura por duas semanas, com dias adicionais de manchas que podem ir até a próxima menstruação.
A mulher deve ser instruĂda a contactar um provedor de saĂşde se algo do seguinte acontecer: (1) se ela encharcar mais que dois absorventes higiĂŞnicos extra grandes por hora, por mais do que duas horas consecutivas, (2) se ela repentinamente começar a ter um grande sangramento, apĂłs o sangramento ter diminuĂdo ou parado por vários dias apĂłs ter tomado misoprostol, (3) se ela estiver sangrando continuamente por várias semanas e começa a sentir tontura ou perda de equilĂbrio.
CĂ“LICAS
As cĂłlicas normalmente começam dentro das primeiras horas e podem iniciar tĂŁo cedo como em 30 minutos apĂłs a administração do misoprostol. A dor pode ser mais forte do que a vivenciada durante uma menstruação regular. As drogas anti-inflamatĂłrias nĂŁo esterĂłides (AINE) ou outros analgĂ©sicos podem ser usados para alĂvio da dor sem afetar o sucesso do mĂ©todo.
FEBRE E/OU CALAFRIOS
Calafrios são efeitos colaterais comuns, mas são transitórios. Febre é menos comum e não necessariamente indica infecção. Um antitérmico pode ser usado para aliviar a febre, se necessário. Se febre ou calafrios persistirem além de 24 horas após tomar o misoprostol, a mulher pode ter uma infecção e deve procurar atenção médica.
NĂUSEA E VĂ”MITO
Náusea e vômito podem ocorrer, mas passarão dentro 2 a 6 horas após tomar o misoprostol. Um anti-emético pode ser usado se necessário.
DIARRÉIA
Diarréia pode também ocorrer após a administração do misoprostol, mas deve parar dentro de um dia.
DOSAGEM E ADMINISTRAÇĂO
Abortamento incompleto: O esquema recomendado para tratamento de abor-tamento incompleto com misoprostol Ă© o de uma dose Ăşnica de 600 mcg de misoprostol por via oral OU uma dose Ăşnica de 400 mcg de misoprostol por via sublingual (sob a lĂngua).
Abortamento retido: Na situação quando o diagnóstico de abortamento retido é certo e/ou o colo está firmemente fechado, o esquema recomendado é de uma dose única de 800 mcg de misoprostol por via vaginal.
As mais altas taxas de sucesso são alcançadas com o seguimento prolongado (7 a 14 dias) para completar o processo de expulsão. A intervenção cirúrgica não é recomendada antes de 7 dias após a administração do tratamento, a menos que medicamente necessária.
Notas:
- Há também evidências de que uma dose repetida pode aumentar a eficácia.
- O misoprostol provavelmente também funciona bem quando colocado entre a bochecha e a gengiva (bucal).
Citação sugerida:
Declaração de Consenso: Instruções para uso – Misoprostol para tratamento de abortamento incompleto e espontâneo. Reunião de Espertos sobre Misoprostol, patrocinada pelo Reproductive Health Technologies Project e Gynuity Health Projects, 9 de junho de 2004. Nova York, NY.
Para uma lista de referências da literatura apoiando este documento ou para maiores informações, acesse a página www.gynuity.org ou www.rhtp.org.
Este documento será periodicamente revisado e atualizado com informações atuais e desenvolvimentos de pesquisa
© 2008 Gynuity Health Projects e Reproductive Health Technologies Project
Atualizado junho 2008
إرشادات الإستخدام تعليمات استخدام عقار ميزŮبرŮستŮŮ„ لعلاج الإجهاض Ůالإجهاض غير الŮامل\
الخلŮŮŠŘ©
الميزŮبرŮستŮŮ„ ينتمي إلى مجمŮعة البرŮستŮجلاندينات (هـ 1)ŘŚ المسجلة Ů„Ů„Ůقاية من Ůعلاج Ř§Ů„Ů‚Ř±Ř Ř§Ů„Ů…ŘąŘŻŮŠŘ© الناتجة عن الاستخدام المزمن Ů„Ů„ŘŁŘŻŮŮŠŘ© غير السترŮŮŠŘŻŮŠŘ© المضادة للالتهاب. Ůلأن ميزŮبرŮستŮŮ„ يسبب تقلصات بالرŘŮ…ŘŚ Ůإنه يستخدم خارج إطار تعليمات الاستخدام المدŮنة على بطاقة الدŮاء لعلاج الإجهاض المبŮر، ŮŮ‚ŘŻ أظهرت الدراسات ŘĄŮ…Ůانية استخدام ميزŮبرŮستŮŮ„ بشŮŮ„ Ůعال Ůآمن ŮŮŠ تل٠الŘالات.
التعليمات التالية تستهد٠إرشاد Ů…Ů‚ŘŻŮ…ŮŠ الخدمة الصŘŮŠŘ© الŘاصلين على التدريب.
ŘŻŮاعي الاستخدام
ŮŠŮص٠ميزŮبرŮستŮŮ„ لعلاج الإجهاض غير الŮامل Ůالإجهاض الŮامل لدى السيدات Ř°Ůات الأرŘام المساŮŮŠŘ© أ٠الأقل ŮŮŠ الŘجم لاثني عشر أسبŮعاً منذ ŘŘŻŮŘ« آخر ŘŻŮرة Ř·Ů…Ř« عند الŮŘ´Ů.
ŮŠŘظى استخدام ميزŮبرŮستŮŮ„ ŮŮŠ علاج الإجهاض غير الŮامل بنسبة Ů†Ř¬Ř§Ř ŘŞŘŞŘ±Ř§ŮŘ Ř¨ŮŠŮ† 66-100%ŘŚ ŮŮŮŠ علاج Ř§Ů„Ř·Ř±Ř Ř¨ŮŠŮ† 60-93% Ůذل٠بشرط الالتزام بالجرعات المقررة.
Ů…Ůانع الاستخدام
1- الŘساسية للميزŮبرŮستŮŮ„ ŘŁŮ Ů„ŘŁŮŠ نŮŘą من البرŮستŮجلاندينات
2- الش٠ŮŮŠ ŮجŮŘŻ ŘŮ…Ů„ خارج الرŘŮ…
3- ŮجŮŘŻ علامات ŘŘŻŮŘ« التهاب ŘŁŮ ŘŞŮ„ŮŘ« ŮŮŠ تجŮي٠الŘŮض
4- ظهŮر أعراض اختلال الدŮرة الدمŮŮŠŘ© أ٠الصدمة.
ŘŞŘذيرات
1- يجب إزالة Ů…Ůانع الŘŮ…Ů„ الرŘŮ…ŮŠŘ© (اللŮلب) قبل استخدام ميزŮبرŮستŮŮ„.
2- يراعى الŘذر عند استخدام هذا العقار للسيدات اللŮاتي يعانين من مشاŮŮ„ نز٠دمŮŮŠ أ٠اللŮاتي يستخدمن مضادات التجلط.
3- Ů‚ŘŻ يستخدم ميزŮبرŮستŮŮ„ بŘذر للمريضات Ř°Ůات الأرŘام الأŮبر ŮŮŠ الŘجم من 12 أسبŮع، على أن ŘŞŮŮن Ůترة الŘŮ…Ů„ ŘŁŮ‚Ů„ من أ٠تساŮŮŠ 12 أسبŮŘą (مثال: تضخم الرŘŮ… الناتج عن التليŮ).
4- ربما تظهر Ůميات ضئيلة من الميزŮبرŮستŮŮ„ أ٠من منتجات أيضه الŮعالة ŮŮŠ Řليب الرضاعة. Ů„Ůن Ů„Ů… تسجل ŘŁŮŠ آثار على الأطŮال الرضع نتيجة Ů„Ř°Ů„Ů.
الآثار Ůالآثار الجانبية
من النادر ŘŘŻŮŘ« ŘŁŮŠ آثار جانبية خطيرة ŘŁŮ Ř·ŮŮŠŮ„Ř© المدى.
1- النزيŮ
بعد استخدام ميزŮبرŮستŮŮ„ŘŚ يستمر النزي٠لمدة أسبŮعين ŮŮŠ المعتاد، على أن ينخŮض هذا النزي٠إلى قطرات لعدة أيام أخرى، Ůمن المألŮ٠أن يستمر ذل٠إلى ŘŻŮرة الطمث التالية.
ŮŠŮ†ŘµŘ Ř¨Ř§Ů„ŘłŘąŮŠ إلى استشارة طبيب مختص ŮŮŠ الŘالات التالية:
- تشبع ŘŁŮثر من ŮŮطتين صŘيتين Ůبيرتين ŮŮŠ الساعة ŮŮ„Ů…ŘŻŘ© ŘŁŘ·ŮŮ„ من ساعتين متتاليتين. – Řالة النزي٠الشديد بعد Ůترة من انقطاعه أ٠انخŮاض Ůميته لعدة أيام. – ŘŞŮاصل النزي٠لعدة أسابيع ŮالإŘساس بالدŮار ŘŁŮ Ř®ŮŘ© الرأس.
2- التقلصات
تبدأ التقلصات عادة خلال الساعات القليلة الأŮلى لاستخدام عقار ميزŮبرŮستŮŮ„ŘŚ ŮŮ‚ŘŻ تبدأ مبŮرا بعد 30 ŘŻŮ‚ŮŠŮ‚Ř© من الاستخدام. ŮŮ‚ŘŻ ŮŠŮŮن الألم ŘŁŘ´ŘŻ من الألم المعتاد ŮŮŠ Řالات الطمث العادية، ŮŮŠŮ…Ůن استخدام الأدŮŮŠŘ© غير السترŮŮŠŘŻŮŠŘ© المضادة للالتهاب ŘŁŮ ŘŁŮŠŘ© Ů…ŘłŮنات آلم أخرى لا تؤثر على عمل الميزŮبرŮستŮŮ„.
3- الŘمى Ů/أ٠القشعريرة
تعتبر القشعريرة من الآثار الجانبية الشائعة لاستخدام ميزŮبرŮستŮŮ„ŘŚ Ů„Ůنها ŮŮŠ العادة لا تستمر Ř·Ůيلاً، أما الŘمى Ůهي ŘŁŮ‚Ů„ Ř´ŮŠŮعاً، Ůهي لا تعد مؤشراً على ŮجŮŘŻ التهاب. ŮŮŠŮ…Ůن استخدام خاŮض Řرارة إذا لزم الأمر. Ů„Ůن إذا استمرت الŘمى أ٠القشعريرة Ů„Ů…ŘŻŘ© 24 ساعة بعد استخدام ميزŮبرŮستŮŮ„ŘŚ Ů‚ŘŻ ŮŠŮŮن ذل٠مؤشراً على إصابة السيدة بالالتهاب، ŮŮŠŮ†ŘµŘ Ř¨Ř§ŘłŘŞŘ´Ř§Ř±Ř© طبيب ŮŮŠ هذه الŘالة.
4- القيء Ůالغثيان
Ů‚ŘŻ ŮŠŘŘŻŘ« غثيان Ůقيء ŮŮ„Ůن يزŮلان بعد 2-6 ساعات من استخدام ميزŮبرŮستŮŮ„ŘŚ ŮŮŠŮ…Ůن استخدام مضاد للقيء إذا لزم الأمر.
5- الإسهال
Ů‚ŘŻ ŮŠŘŘŻŘ« الإسهال أيضا Ůأثر جانبي لاستخدام ميزŮبرŮستŮŮ„ŘŚ ŮيزŮŮ„ بعد ŮŠŮŮ… ŮاŘŘŻ من الاستخدام.
الجرعة Ůطريقة الاستخدام
الإجهاض غير الŮامل: النظام Ř§Ů„Ů…Ů‚ŘŞŘ±Ř Ů„ŘąŮ„Ř§Ř¬ الإجهاض غير الŮامل باستخدام ميزŮبرŮستŮŮ„ ه٠جرعة ŮاŘŘŻŘ© من 600 Ů…ŮŠŮرŮجرام عن طريق الŮŮ… أ٠جرعة ŮاŘŘŻŘ© من 400 Ů…ŮŠŮرŮجرام ŘŞŘŘŞ اللسان.
الطرŘ: ŮŮŠ Řالة التأŮŘŻ من تشخيص الطرŘŘŚ Ů/ŘŁŮ Ůان عنق الرŘŮ… مغلقاً ŮŠŮŮن النظام Ř§Ů„Ů…Ů‚ŘŞŘ±Ř Ů‡Ů Ř¬Ř±ŘąŘ© ŮاŘŘŻŘ© من 800 Ů…ŮŠŮرŮجرام تؤخذ مهبلياً.
ŘŞŘŞŘŮ‚Ů‚ أعلى درجات Ř§Ů„Ů†Ř¬Ř§Ř Ů„ŘąŮ‚Ř§Ř± ميزŮبرŮستŮŮ„ عند المتابعة المتŮاصلة (من 7 إلى 14 ŮŠŮŮ…) لإعطاء الŮرصة لاŮتمال الإجهاض. Ůلا ŮŠŮ†ŘµŘ Ř¨Ř§Ů„ŘŞŘŻŘ®Ů„ الجراŘŮŠ قبل سبعة أيام بعد انتهاء استخدام ميزŮبرŮستŮŮ„ ما Ů„Ů… ŘŞŮن هنا٠ضرŮرة طبية.
ملاŘظات
- هنا٠مؤشرات أيضا على أن ŘŞŮرار الجرعة يؤدي إلى زيادة الŮعالية – يعمل ميزŮبرŮستŮŮ„ بشŮŮ„ ŘŁŮضل إذا ما Ůضع بين الŮجنة Ůاللثة ŘŁŮ ŘŞŘŘŞ اللسان.
- للاقتباس، الرجاء استخدام التنŮيه التالي:*
بيان Ů…ŘŞŮŮ‚ عليه: تعليمات استخدام – الميزŮبرستŮŮ„ لعلاج الإجهاض غير الŮامل ŮالطرŘ. اجتماع الخبراء بخصŮص الميزŮبرستŮŮ„ المنظم من قبل مشرŮŘą ŘŞŮنŮŮ„Ůجيات الصŘŘ© الإنجابية ŮGynuity للمشاريع الصŘŮŠŘ©. 9 Řزيران 2004. مدينة نيŮŮŠŮرŮŘŚ نيŮŮŠŮرŮ.
لقائمة المراجع الداعمة لهذه المطŮŮŠŘ© Ůلمزيد من المعلŮمات الرجاء زيارة المŮاقع التالية: www.gynuity.org ŘŁŮ www.rhtp.org.
ستتم مراجعة ŮŘŞŘ·Ůير هذه المطŮŮŠŘ© بشŮŮ„ ŘŻŮري Ů„ŘŞŘąŮŘł نتائج ŘŁŘŘŻŘ« الأبŘاث Ůالدراسات ŮŮŠ هذا المجال.
© Gynuityللمشاريع الصŘŮŠŘ©ŘŚ 2008 ŮمشرŮŘą ŘŞŮنŮŮ„Ůجيات الصŘŘ© الإنجابية نقŘŘŞ ŮŮŠ 2008Improving Current Therapies and Exploring New Options in Abortifacient Technology
MEETING SUMMARY
June 2004
Editor Tess Aldrich, MSc
Participants:
Tess Aldrich, MSc
David Baird, MD
Marc Bygdeman, MD
Sharon Cameron, MD (rapporteur)
Lise Duranteau, MD
Hamish Fraser, PhD, DSc
Kristina Gemzell Danielsson, MD, PhD
Anna Glasier, MD
John Jain, MD
Axel Mundigo, PhD
Oi Shan Tang, MD
Beverly Winikoff, MD, MPH
Summary:
On June 22, 2004 Gynuity Health Projects convened a small group of international experts in the field of medical abortion and women’s health for a symposium entitled “Improving Current Therapies and Exploring New Options in Abortifacient Technology.” In this one-day meeting held in Edinburgh, Scotland, the group discussed current activities around novel abortifacient development and debated how best to balance resources between this research and efforts to improve existing medical abortion regimens. Participants included basic science researchers, social scientists, clinicians, and pharmaceutical industry experts. Much of the meeting focused on promising research avenues and drug candidates including antiprogestins, other antihormones, prostaglandins and analogues, antifolates and antimetabolites, and angiogenesis inhibitor drugs. More broadly, participants explored the qualities of an “ideal” abortifacient, as well as the social and political considerations involved in developing and promoting new therapies. Among the priority areas identified for future collaborative work were: 1) continuing to introduce medical abortion in countries where it is currently unavailable; 2) developing single-dose regimens for mifepristone-misoprostol medical abortion; 3) establishing the minimum technology required for medical abortion; and 4) improving medical abortion for gestations >9 weeks.
ENVISIONING AN IDEAL ABORTIFACIENT: WHAT ARE WE LOOKING FOR?
Before discussing promising avenues of research on new abortifacients, meeting participants explored together the different properties that an “ideal” abortion method might possess. The group suggested the following characteristics:
1) High Efficacy. While there will never be an ongoing pregnancy rate of 0%, a rate of < 1% could be considered ideal. This was felt to be important in order to minimize the potential for teratogenic effects associated with large doses of prostaglandins during pregnancy. Furthermore, a high ongoing pregnancy rate would have important implications for health services, given the need for careful follow-up of women who had been treated. In the U.S., where many clinics have a very low ongoing pregnancy rate (reportedly around 0.5%), service delivery is actually designed as though there were a 2-4% ongoing rate. This inevitably requires greater resources and could pose practical problems in low-resource settings.
2) Single dose regimen. Administering mifepristone and misoprostol together could be more appealing to women as this would simplify the treatment protocol and avoid the need for an additional visit to receive the prostaglandin. This may also result in overall cost savings for the method. A study conducted several years ago used a slow release prostaglandin vaginal pessary of gemeprost for medical abortion in the first trimester (Cameron IT, Baird DT. Contraception 1986; 33:121-125). The hygroscopic pessary consisted of PGE1 (3mg gemeprost) incorporated into a strip of polyethelene oxide-based hydrogel, 30 mm in length. In this study, 12 out of 13 women treated had a complete abortion. The median quantity of prostaglandin used from the pessary was 53%. From a technological point of view, participants noted that a PGE2 (dinoprost) removable pessary is currently in existence for cervical ripening for induction of labor in pregnant women at term.
These studies raise the possibility of developing a combination of oral mifepristone and a vaginal slow-release preparation of misoprostol for a “single point in time administration” medical abortion regimen. A discussion followed on the idea of inventing an enteric-coated, time-release oral misoprostol preparation, for use with mifepristone in a single dose regimen. Although this would have potential advantages in that it would be administered orally and could have fewer GI side effects, participants felt that it might be difficult to maintain oral PG within the GI tract long enough for mifepristone to exert a significant effect.
Researchers in the U.S. are also experimenting with shorter intervals between mifepristone and misoprostol administration. The group noted research by Creinin et al, comparing mifepristone 200mg followed by vaginal misoprostol 800µg either 6-8 hours or 24 hours later, for medical abortion in women up to 63 days gestation. Findings show good efficacy for the two regimens.
3) Very low morbidity. An ideal abortifacient would have an adverse event rate of virtually 0.
4) Reduced pain. Participants suggested that an agent that caused cervical dilation prior to the onset of significant uterine activity could result in less pain, since the products of conception (POC) could be expelled through a dilated cervix with reduced uterine contractility. It was suggested that a nitric oxide donor (NO) could be a possible cervical ripening agent; indeed, NO donors have been found in some studies to be possible alternatives to induce cervical ripening in second trimester abortion.
5) Less post-abortion bleeding. An agent that caused dissolution of the placenta or re-absorption of the pregnancy might result in less bleeding and pain. Absence of bleeding altogether could also be disadvantageous as the woman might worry that she was still pregnant. It was suggested that a luteolytic agent would result in regression of the corpus luteum and lead to earlier resumption of ovarian activity with reduced post-abortion bleeding than with current medical methods.
6) Effective longer than up to 49 days gestation. Ideally, a regimen would be applicable to over 49 days LMP and would not require accurate (ultrasound) gestational age dating.
7) Effective in early but not advanced pregnancy. Participants discussed the possibility that a therapy could be used after the first missed menses in the absence of pregnancy testing, without disrupting or harming a pregnancy if taken in late pregnancy. The group suggested that such a method might be marketed as a “menstrual inducer” or “regulator.” Furthermore, such a preparation might lend itself to over-the-counter (OTC) availability.
8) Orally active. Although the preferred route of administration is partly culturally dependent, an oral preparation would likely be preferred by many women as well as be advantageous in countries where abortion is conducted under clandestine circumstances; in politically restrictive environments, vaginally placed tablets have the potential disadvantage of being “discoverable.” Furthermore, participants suggested that there could be positive psychological significance for the woman in swallowing a pill (e.g. more control, less invasive), rather than having it administered to her by a health professional.
9) Self-administered. Similarly, the ability to administer the treatment oneself may be seen as an advantage by many women and certainly simplifies service delivery.
10) Predictable and rapid return to ovulation. Since hCG levels after an abortion help to maintain the corpus luteum, a luteolytic agent that would cause regression of the corpus luteum would lead to earlier resumption of the normal menstrual cycle.
11) Provides ongoing contraception after the abortion procedure. Perhaps this could be provided by an antiprogestin-impregnated intrauterine device or vaginal ring.
12) Cost. An ideal abortifacient would be inexpensive and accessible in all countries.
NOVEL ABORTIFACIENTS: PROMISING AVENUES OF RESEARCH AND DRUG CANDIDATES
Antiprogestins: Participants viewed mifepristone as possessing many qualities of an “ideal” antiprogestin, since it is administered as a single dose (200mg), lasts 72 hours and is virtually free of side effects. Furthermore, it is relatively inexpensive to manufacture. In view of these qualities and the abundant clinical experience with mifepristone, the group felt that it would not be worthwhile investing efforts and resources in developing other antiprogestins for abortion. Similarly, participants did not believe that further studies to examine efficacy of reduced doses of mifepristone (< 200mg) were indicated, since large numbers of subjects and very low drug doses would be required to show any important difference.
Participants also discussed the simplified, reduced-dose regimen of mifepristone medical abortion, which consists of 200mg mifepristone followed by 400µg misoprostol taken at home. Results from a recent multi-center U.S. trial testing this simplified regimen for medical abortion up to 49 days LMP show similar efficacy rates as the U.S. registration trial.
Other antihormones: A combination of a progesterone synthesis inhibitor (3b hydroxysteroid dehydrogenase inhibitor), such as epostane or trilostane, together with mifepristone, might result in increased release of endogenous prostaglandins and have a synergistic effect on myometrial contractility. Although epostane is very difficult to obtain, trilostane is availble (at least in the UK). It could be worthwhile to conduct a small study comparing uterine activity in women treated with trilostane and mifepristone and those treated with mifepristone alone, to test the hypothesis that combined treatment has therapeutic advantages. However, as detailed above, the trial would have to be quite large.
The group discussed briefly the potential of LH receptor antagonists for use as abortifacients in early pregnancy. Although such agents do not currently exist, it is likely that they will be developed in the future. Participants also discussed studies conducted with other anti-hormones such as tamoxifen and danazol, neither of which appears to be promising. Similarly, there do not seem to be any promising drug candidates at present among hCG antagonists.
Prostaglandins and analogues: Participants noted that prostaglandins alone have been proven to be effective abortifacients. Although the dose and regimens for gemeprost-only regimens have previously been established, the lowest and most effective dose regimens for misoprostol remain undetermined.
Antifolates and antimetabolites: These drugs, including methotrexate as used with misoprostol, offered no advantage over antiprogestin and prostaglandins with regard to efficacy.
Participants concluded that mifepristone with misoprostol is clearly more effective than any misoprostol-alone regimen, or regimens using anti-folates or other antimetabolites; however, establishing a single-dose regimen remains a priority for mifepristone-misoprostol medical abortion.
Angiogenesis inhibitors: Current research by Hamish Fraser’s group at the Human Reproductive Sciences Unit of the University of Edinburgh, studies the manipulation of angiogenesis in the female reproductive tract. Although there are no published data on the capacity of these compounds to interrupt pregnancy in animals, it is very probable that companies that have developed angiogenesis inhibitor drugs do indeed have this data.
Current studies in Edinburgh are being done on primates (marmosets), in which ovulation occurs within two weeks of giving birth, with a > 90% chance of becoming pregnant again. His current and planned studies are examining the effects of angiogenesis inhibitors in the female marmoset reproductive tract in 1) the post ovulatory period, 2) around the time of implantation, and 3) in the post-implantation period. Although they observed a significant reduction in progesterone secretion as a result of inhibiting angiogenesis in the corpus luteum, with antibody to vascular endometrial growth factor (VEGF) they have not observed a significant effect on pregnancy rates in the treated animals. They have not examined implantation sites within the endometrium but are planning to do so.
A VEGF inhibitor in the mid- to late luteal phase (when angiogenesis is diminishing in the corpus luteum), was also associated with a significant reduction in progesterone secretion, suggesting an effect of treatment on vessel permeability. There may be potential for other novel angiogenic inhibitors for abortion, such as inhibitors of angiopoietins. Angiopoietins work in part to stabilize vasculature, and there is growing interest in their role in the female reproductive tract. Two-methoxyestradiol, a weak estrogen and naturally occurring compound, has been shown to possess antiangiogenic properties.
It was suggested that if angiogenesis inhibitors were used after a missed menses, they might be combined with a prostaglandin as a form of pregnancy termination. The third week after ovulation is the time of most intense endometrial angiogenesis. The embryo itself is the site of extremely rapid angiogenesis, initiated just after implantation.
More basic science on these agents is required before they can be considered for abortifacient research. A rough timeline for developing this line of research would be ten years.
Finally, a growing body of research has provided preliminary evidence on the role of angiogenesis in normal pregnancy. So far there do not appear to be teratogenic effects of VEGF antagonists on marmosets; of those who became pregnant despite VEGF inhibition, no malformations were seen in their offspring. Certain pharmaceutical companies are investing in anti-angiogenesis therapies as well as mifepristone to treat endometriosis. The group felt that it was worth continuing research on the topic and there could even be a system of “scouts” to help to keep track of research as it progresses, to identify new leads relevant to abortifacients.
INVESTIGATING EXISTING THERAPIES TO IMPROVE EFFICACY AND ACCEPTABILITY
1) Routes of administration
Participants agreed that more research is needed to determine the comparative efficacy of the vaginal, oral, buccal, and sublingual route for misoprostol administration.
2) Dose
With the existing regimen of 200mg mifepristone followed by varying doses of misoprostol, the group felt that a priority should be to establish a “one dose fits all” regimen for up to 9 weeks LMP, rather than having separate regimens for different gestational ages.
3) Gestational age limits
All participants agreed on the importance of creating a regimen that is not dependent on ultrasound to assess gestational age. In this respect, it is important to have a method that is effective up to at least 9 weeks gestation. Similarly, medical abortion protocols should ideally not need to rely on ultrasound for assessment at follow–up visits, especially since this practice leads to higher rates of unnecessary intervention. It was pointed out that in the U.S., family practitioners are increasingly providing medical abortions and often do not have access to ultrasound. However, in some settings, hCG testing can be even less feasible than ultrasound for pregnancy dating. Instead, it was suggested that a simple screening guide could be developed to assess which women should be evaluated with ultrasound.
SOCIAL AND POLITICAL CONSIDERATIONS IN DEVELOPING AND PROMOTING NEW ABORTIFACIENTS
The group identified several important challenges with respect to abortifacient use and service delivery innovation. Putting the drugs on the Essential Drugs List maintained by the WHO remains a priority. [ed note: now accomplished 2005.] Another challenge is translating research findings into policy. As an example, there is now a great deal of evidence that home use of misoprostol is safe and preferred by women providers, yet research to this service delivery option remains.
In the midst of these political and social challenges, the group also discussed strategies for promoting abortifacient R&D;and the introduction of medical abortion in new settings. There are economic grounds alone for developing and promoting safe medical methods, based on the cost of the complications of poorly performed abortions.
Furthermore, changing the indication for use of medical methods from abortion to “menstrual induction” might increase applicability of the method, in some setting where vacuum aspiration is already used in this. Another potential strategy is to relax the restrictions on medical abortion that have been applied in some jurisdictions. For example in Germany, medical abortion is permitted up to 7 weeks gestation, but a fetal heart beat must be evident on ultrasound. Since 7 weeks is just around the limit when ultrasound can detect fetal cardiac activity, this prohibitively tight restriction means that many women are unable to access a medical method.
Finally, participants suggested that clinical studies continue to be an important strategy for introducing medical methods in new settings such as in developing countries, in part since the activity involves training service providers, empowering them to share their experiences with colleagues, and helping to advance their career objectives. Small studies with mifepristone can help gain acceptance and access where it is unavailable.
RESEARCH AND DEVELOPMENT AND THE PHARMACEUTICAL INDUSTRY
All participants agreed that a major obstacle to R&D;is the difficulty of securing commercial sponsorship of studies involving medical abortion. Participants agreed that a priority should be identifying a broader number of companies, to market mifepristone.
OUTLINING AN AGENDA FOR ABORTIFACIENT TECHNOLOGY RESEARCH AND DEVELOPMENT
Balancing research efforts and priorities
Participants agreed that more scientific research is required with medical abortifacients, but that public awareness of medical methods is also needed as is continued training of physicians involved in service delivery.
Priority areas for R&D;
The meeting was concluded by identifying priority activities relating to research, service delivery, and enhancing collaboration:
• A main priority is introducing medical abortion in countries where it is unavailable, particularly in developing countries. Activities aimed at influencing clinical and opinion leaders within a country are key to these efforts. Setting up a clinical study of existing medical methods with an appropriate medical team(s), possibly linked to a research project exploring a specific aspect of service delivery in that country, would interest medical opinion makers. In addition, future research might include studies with nurses and midwives as vehicles for change, in promoting medical abortion in new settings. Large-scale programs for medical abortion should introduce existing regimens that have been shown to be safe and effective.
• Other priorities identified include determining the lowest effective dose of misoprostol that could be used with mifepristone, and the development of a single-dose mifepristone/misoprostol regimen.
• Priority was also given to fine-tuning aspects of service delivery, such as identifying the minimum technology required for safe and effective medical abortion services (including minimizing reliance on ultrasound, hCG assays) and establishing criteria for satisfying safety concerns relating to home treatment (e.g. guidelines for emergency services).
• The group highlighted the importance of improving medical abortion for women with gestations > 9 weeks LMP. Efficacy rates of 90-95% have been reported for medical abortion at 14-16 weeks (mifepristone and misoprostol regimens), but 10-12 weeks remains a “grey area,” and can also pose service delivery challenges, since closer medical supervision can be required for the procedure. Furthermore, medical abortion at these later gestations may be less acceptable to women than surgical methods. Nonetheless, surgical procedures > 14 weeks require very skilled professionals who may not always be available when such procedures are needed. In such cases medical management may be a safer alternative. Medical abortion for 2nd trimester pregnancy was seen as an important area of research.
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HƯỚNG DẨN SỬ DỤNG: HƯỚNG DẨN SỬ DỤNG
CĆ SỞ
Misoprostol lĂ má»™t chất đồng váşn của prostaglandin E1 thường được Ä‘Äng kĂ˝ sá» dụng trong dá»± phòng vĂ Ä‘iá»u trị loĂ©t dạ dầy do sá» dụng dĂ i hạn những thuốc kháng viĂŞm khĂ´ng corticosteroid (KVKC). Vì misoprostol cĹ©ng gây nĂŞn cơn gò tá» cung nĂŞn thường được dĂąng ngoĂ i Ä‘Äng kĂ˝ Ä‘á» phòng ngừa bÄng huyáşżt sau sanh (BHSS). Xá» trĂ tĂch cá»±c trong giai Ä‘oạn ba của chuyá»n dạ (XTTCGÄIII) Ä‘ĂŁ được chứng minh lĂ má»™t phương pháp Ä‘á» giảm BHSS. XTTCGÄIII của chuyá»n dạ bao gồm việc sá» dụng dá»± phòng chất co cơ, kĂ©o dây rốn cĂł kiá»m soát, vĂ xoa đáy tá» cung trong giai Ä‘oạn ba. Trong Ä‘iá»u kiện khĂ´ng cĂł sáşłn chất co cơ chĂch, nhiá»u nghiĂŞn cứu Ä‘ĂŁ chÄ© rõ misoprostol cĂł thá» sá» dụng hiệu quả vĂ an toĂ n Ä‘á» dá»± phòng BHSS. Những thĂ´ng tin sau đây được trình bĂ y Ä‘á» hĆ°á»›ng dáş©n những nhĂ cung cấp dịch vụ chÄm sĂłc sức khỏe trong các cơ sở y táşż cá»™ng đồng, nơi mĂ sá»± tiáşżp cáşn oxytocin bị hạn cháşż.
CHá» ÄỊNH VĂ€ CĂCH DĂ™NG
Misoprostol được chỉ định trong phòng ngừa bÄng huyáşżt sau sanh thường ngĂŁ âm đạo.
Sá» dụng misoprostol trong phòng ngừa BHSS rất hiệu quĂ Ä‘á» lĂ m giảm lượng máu mất sau sanh ngĂŁ âm đạo. Khi so sánh vá»›i khĂ´ng sá» dụng chất co cơ trong giai Ä‘oạn ba của chuyá»n dạ, misoprostol lĂ m giảm lượng máu mất sau sanh.
Nhiá»u nghiĂŞn cứu cho thấy misoprostol khĂ´ng hiệu quả báş±ng oxytocin, vĂ tương đương vá»›i ergometrine uống náşżu khĂ´ng nĂłi lĂ tốt hơn.
CHá»NG CHá» ÄỊNH
Tiá»n sá» dị ứng vá»›i misoprostol hay những prostaglandins khác.
THẬN TRỌNG
Nhà cung cấp phải chắc rằng không có thai thứ hai trong song thai không được biết trứơc khi cho misoprostol. Nếu không chắc chắn hay nếu người đở sanh không đủ kinh nghiệm đỠquyết định, tốt hơn hết misoprostol nên cho sau khi sổ nhau.
Má»™t lượng nhỏ misoprostol hay hoạt chất biáşżn dưởng của nĂł cĂł thá» qua sá»a. KhĂ´ng cĂł tác dụng ngoại Ă˝ nĂ o được ghi nháşn ở tráş» bĂş máşą (Derman et al 2006).
HIỆU QUẢ VĂ€ TĂC DỤNG PHỤ
Tác dụng phụ kéo dà i hay nghiêm trọng hiếm gặp.
RUN
Run là tác dụng phụ thường gặp nhất của misoprostol khi sỠdụng sau sanh. Nó thường xảy ra trong vòng giờ đầu sau khi dùng misoprostol. Tác dụng nà y thoáng qua và tan biến từ 2 – 6 giờ sau sanh.
Sá»T
Sốt Ăt gáş·p hơn run vĂ khĂ´ng cần thiáşżt lĂ má»™t chỉ Ä‘iá»m của nhiá»m trĂąng. TÄng thân nhiệt thường Ä‘i trĆ°á»›c run, đạt đỉnh Ä‘iá»m 1 – 2 giờ sau dĂąng misoprostol, vĂ dần biáşżn mất trong vòng 2-8 giờ. Thuốc hạ sốt cĂł thỠđược dĂąng Ä‘á» hạ nhiệt, náşżu cần. Náşżu sốt hay run kĂ©o dĂ i quá 24 giờ, sản phụ cần được theo dỏi Ä‘á» loại trừ nhiá»m trĂąng.
TIĂŠU CHĂY, BUá»’N NĂ”N VĂ€ Ă“I
Tiêu chảy có thỠcũng xảy ra sau khi sỠdụng misoprostol nhưng phải chấm dứt trong vòng một ngà y. Buồn nôn và ói có thỠxảy ra và chấm dứt từ 2 đến 6 giờ sau dùng misoprostol. Thuốc chống ói có thỠsỠdụng được nếu cần.
ÄAU QUẶN BỤNG
Äau quáş·n hay Ä‘au co thắt tá» cung, nhĆ° thường xảy ra sau khi sanh con, thường bắt đầu trong vòng vĂ i giờ đầu vĂ cĹ©ng cĂł thá» rất sá»›m trong vòng 30 phĂşt sau sá» dụng misoprostol. Thuốc kháng viĂŞm khĂ´ng steroid hay những giảm Ä‘au khác cĂł thá» dĂąng Ä‘á» giảm Ä‘au mĂ khĂ´ng ảnh hưởng Ä‘áşżn sá»± thĂ nh cĂ´ng của phương pháp.
CHẢY MĂU SAU SANH
Chảy máu nhiá»u, trĆ°á»›c hay sau sổ nhau, cần được chÄm sĂłc bổ sung ngay. Misoprostol khĂ´ng nĂŞn cho thĂŞm trong vòng 6 giờ sau liá»u đầu tiĂŞn.
LIỀU LƯỢNG VĂ€ CĂC SỬ DỤNG
Phác đồ được khuyáşżn cáo cho phòng ngừa BHSS vá»›i misoprostol lĂ má»™t liá»u duy nhất 600 mcg misoprostol uống sá» dụng trong giai Ä‘oạn ba của chuyá»n dạ.
LĆŻU Ăť
Hiện tại, khĂ´ng cĂł đủ chứng cứ Ä‘á» khuyáşżn cáo má»™t liá»u misoprostol thấp hơn cho phòng ngừa BHSS trong các cơ sở y táşż cọng đồng. Khi cĂł thĂŞm những chứng cứ vá» những liá»u thấp hơn (trong khoảng từ 200-400mcg), HĆ°á»›ng dáş©n Sá» dụng nầy sáş˝ được xem xĂ©t hiệu Ä‘Ănh vá»›i những thĂ´ng tin vá» liá»u tối Ć°u.
ÄỀ NGHỊ GHI:
HĆ°á»›ng dáş©n Sá» dụng: Misoprostol trong Phòng ngừa BÄng huyáşżt Sau sanh. Tổng quan do các chuyĂŞn gia do Gynuity Health Projects tổ chức. Tháng 7, 2007.
Cần thĂŞm thĂ´ng tin, vui lòng truy cáşp www.gynuity.org.
TĂ i liệu nầy sáş˝ được hiệu Ä‘Ănh vĂ cáşp nháşt thường kỳ vá»›i những thĂ´ng tin hiện hĂ nh vĂ những phát triá»n của nghiĂŞn cứu.
© Gynuity Health Projects
Tháng 2007
KULLANMA YÖNERGESİ: POSTPARTUM KANAMANIN ÖNLENMESİ İÇİN MİSOPROSTOL
GENEL BÄ°LGÄ°
Misoprostol bir prostaglandin E1 analoğudur. Genelde, steroid olmayan anti enflamatuvar ilaçların (NSAİDs) kronik kullanımında gastrik ülseri önlemek ve tedavi etmek için kullanılmaktadır. Uterin kontraksiyonlarını uyarmasından dolayı da postpartum kanamanın (PPK) önlenmesi amacıyla etiket dışı kullanılmaktadır. Doğum eyleminin üçüncü evresinin aktif yönetimi (AMTSL), PPK’nın azaltılması için kanıtlanmış bir yöntemdir. AMTSL, üçüncü evrede proflakitk uterotonik uygulanması, kontrollü kord traksiyonu ve uterus masajını kapsamaktadır. Geleneksel enjektabl uterotonik bulunmadığı durumlarda, misoprostolün PPK’nın önlenmesi amacıyla güvenli ve etkili biçimde kullanılabileceği araştırmalarla gösterilmiştir. Bu bilgi, oksitosinin bulunamadığı sağlık birimlerinde çalışan sağlık personeline rehberlik etmek için hazırlanmıştır.
ENDÄ°KASYON VE KULLANIM
Misoprostol, normal vajinal doğum sonrası postpartum kanamanın önlenmesi amacıyla kullanılabilmektedir.
Misoprostol PPK’nın önlenmesi amacıyla kullanıldığında, vajinal doğumdan sonra postpartum kan kaybının azalmasında etkilidir. Doğum eyleminin üçüncü evresinde proflaktik amaçla uterotonik kullanılmadığı durumlarla karşlaştırıldığında msioprostol postpartum kan kaybını azaltmaktadır. Yapılan araştırmalarla misoprostolün etkinliğinin oksitosinden daha az olduğunu ancak ağızdan kullanılan ergometrin kadar iyi olduğu ortaya konmuştur.
KONTRENDÄ°KASYONLAR
Misoprostol veya diğer prostaglandinlere karşı allerji öyküsü.
Ă–NLEMLER
- Misoprostol uygulanmadan önce teşhis edilmemiş bir diğer ikiz eşinin olmadığı saptanmalıdır. Eğer şüpheli bir durum söz konusu ise, veya doğumu yaptıracak olan kişi karar verebilecek nitelikte değilse, plasentanın doğumundan sonra misoprostolün verilmesi daha uygun olacaktır.
- Az miktarlarda misoprostol veya aktif metaboliti anne sĂĽtĂĽnde bulunabilir. Anne sĂĽtĂĽyle beslenen bebeklerde yan etkiler bildirilmemiĹźtir (Derman et al 2006).
ETKÄ°LER VE YAN ETKILER
Uzun süren veya ciddi etkiler ve yan etkiler ender görülür.
TÄ°TREME
Postpartum misoprostol uygulandıktan sonra titremenin görülmesi yaygın bir yan etkidir. Misoprostol kullanıldıktan sonra genellikle ilk bir saat içinde gelişmektedir. Bu yan etki geçicidir ve doğumdan sonra 2-6 saatte hafiflemektedir.
YĂśKSEK ATEĹž
Yüksek ateş titremeden daha az görülmektedir ve enfeksiyon belirtisi olmayabilir. Genelde, ateş yükselmeden önce titreme başlamaktadır, misoprostol kullanıldıktan 1-2 saat sonra en yüksek noktaya ulaşmaktadır ve 2-8 saat içinde hafiflemektedir. Gerektiğinde, ateşi düşürmek için ateş dürücü ilaç (antipiretik) kullanılabilir. Titreme veya yüksek ateş 24 saatten uzun sürerse kadında enfeksiyon gelişmiş olabilir derhal kliniğe başvurmalıdır.
Ä°SHAL, BULANTI, KUSMA
Misoprostol kullandıktan sonra ishal gelişebilir ancak, bir gün içinde düzelir. Misoprostol kullandıktan sonra bulantı, kusma olabilir ve 2-6 saatte geçebilir. Gerektiğinde kusmayı engelleyici ilaç (antiemetik) kullanılabilir.
KRAMPLAR
Kramplar veya ağrılı uterus kontraksiyonları doğumdan sonra, genellikle ilk bir kaç saat içinde başlamaktadır ve misoprostol kullanıldıktan sonra en erken 30 dakikada başlayabilmektedir. Ağrıyı hafifletmek amacıyla steroid olmayan anti-enflamatuvar ilaçlar (NSAİDs) veya diğer ağrı kesiciler (analjezikler) kullanılabilir. Yöntemin başarısını etkilemezler.
POSTPARTUM KANAMA
Plasentanın doğumundan önce veya sonra aşırı kanamanın olduğu durumlarda vaka, derhal destek tedavi için uygun merkeze sevk edilmelidir. llk doz uygulandıktan sonraki 6 saat içinde ilave misoprostol verilmemelidir.
DOZ VE KULLANIM BİÇİMİ
Postpartum kanamanın önlenmesi amacıyla doğum eyleminin üçüncü evresinde tek doz 600 mcg misoprostol ağızdan verilmelidir.
Notlar:
Toplum sağlık merkezlerinde PPK’nın önlenebilmesi amacıyla kullanılabilen düşük doz misoprostol rejimi ile ilgili yeterli kanıt bulunmamaktadır. Düşük dozlar (200-400 mcg) il ilgili daha fazla kanıt oluşursa bu bilgiler yeniden değerlendirilerek optimum doz hakkında bilgilerle güncellenecektir.
Ă–NERILEN ALINTILAR:
Kullanım Yönergesi: Postpartum Kanamanın Önlenmesi İçin Misoprostol. Uzman değerlendirmesi Gynuity Health Projects tarafından düzenlenmiştir. Teemmuz 2007.
Ayrıntılı bilgi için bakınız www.gynuity.org.
Bu doküman, en son bilgiler ve araştırma sonuçları kullanılarak periyodik olarak gözden geçirilmekte ve güncelleştirilmektedir.
© 2007 Gynuity Health Projects.
Temmuz 2007
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ĐНСТРУКЦĐĐŻ Đš ПРĐМЕНЕНĐĐ®: ЛЕЧЕНĐĐ• НЕПОЛНОГО ĐБОРТРРНЕСОСТОЯВШЕГОСЯ Đ’Đ«ĐšĐДЫШРС ПОМОЩЬЮ ПРЕПĐĐ ĐТРМĐЗОПРОСТОЛ
ПРЕДПОСЫЛКĐ
МизопроŃтол, являющийŃŃŹ аналогом проŃтагландина E1, применяетŃŃŹ, как правило, для профилактики и лечения язв желŃдка, образŃющихŃŃŹ при длительном приеме неŃтероидных противовоŃпалительных препаратов (НПВП). Đ’ Ńвязи Ń Ń‚ĐµĐĽ, что мизопроŃтол также вызывает Ńокращение маточной ĐĽŃŃĐşŃлатŃры, он чаŃŃ‚Đľ иŃпользŃетŃŃŹ не по ĐżŃ€ŃŹĐĽĐľĐĽŃ Đ˝Đ°Đ·Đ˝Đ°Ń‡ĐµĐ˝Đ¸ŃŽ при патологии ранних Ńроков беременноŃти, в том чиŃле при неполном аборте и неŃĐľŃтоявŃемŃŃŹ выкидыŃе. ĐŃŃледования показали, что при неполном аборте и неŃĐľŃтоявŃемŃŃŹ выкидыŃе применение мизопроŃтола являетŃŃŹ безопаŃным и эффективным. Данная информация являетŃŃŹ Ń€ŃководŃтвом для квалифицированного медицинŃкого перŃонала.
ПОКĐĐ—ĐĐťĐĐŻ РПРĐМЕНЕНĐĐ•
МизопроŃтол показан для лечения неполного аборта и неŃĐľŃтоявŃегоŃŃŹ выкидыŃĐ° в ŃĐ»Ńчае, еŃли при ĐľŃмотре размер матки ŃоответŃтвŃет ŃŃ€ĐľĐşŃ Đ±ĐµŃ€ĐµĐĽĐµĐ˝Đ˝ĐľŃти 12 недель поŃле начала поŃледнего менŃŃ‚Ń€Ńального цикла или менее.
Применение мизопроŃтола при неполном аборте эффективно в 66 -100% ŃĐ»Ńчаев при иŃпользовании рекомендŃемой дозы. Применение мизопроŃтола при неŃĐľŃтоявŃемŃŃŹ выкидыŃе эффективно в 60 -93% ŃĐ»Ńчаев при иŃпользовании рекомендŃемой дозы.
ПРОТĐВОПОКĐĐ—ĐĐťĐĐŻ
- ĐťĐĐ›ĐЧĐĐ• Đ’ ĐĐťĐМНЕЗЕ ĐЛЛЕРГĐРНРМĐЗОПРОСТОЛ ĐЛРДРУГĐĐ• ПРОСТĐĐ“Đ›ĐНДĐНЫ
- Подозрение на внематочнŃŃŽ
- Признаки инфекции органов малого Ń‚Đ°Đ·Đ° и/или ŃепŃиŃ
- Симптомы нарŃŃения гемодинамики или коллапŃĐ°
МЕРЫ ПРЕДОСТОРОЖНОСТĐ
- Đ•Ńли Ń Đ¶ĐµĐ˝Ń‰Đ¸Đ˝Ń‹ нет противопоказаний Đş применению мизопроŃтола, но в матке ŃŃтановлено внŃтриматочное противозачаточное ŃредŃтво, его ŃледŃет Ńдалить перед введением препарата.
- Đ•Ńли Ń Đ¶ĐµĐ˝Ń‰Đ¸Đ˝Ń‹ нет противопоказаний Đş применению мизопроŃтола, но в матке ŃŃтановлено внŃтриматочное противозачаточное ŃредŃтво, его ŃледŃет Ńдалить перед введением препарата.
- МизопроŃтол ŃледŃет назначать Ń ĐľŃторожноŃŃ‚ŃŚŃŽ пациенткам, размер матки которых больŃе, чем при беременноŃти Ńроком 12 недель поŃле начала поŃледнего менŃŃ‚Ń€Ńального цикла, при том, что извеŃтно, что Ńрок беременноŃти не превыŃает 12 недель (например, Ńвеличение матки в Ńвязи Ń Đ˝Đ°Đ»Đ¸Ń‡Đ¸ĐµĐĽ фиброматозных Ńзлов).
- НебольŃое количеŃтво мизопроŃтола или его активных метаболитов может попаŃŃ‚ŃŚ в грŃдное молоко. Нет информации, ŃвидетельŃтвŃющей Đľ поŃледŃтвиях попадания этих вещеŃтв в грŃдное молоко, и нет Ńообщений об их неблагоприятном воздейŃтвии на детей, находящихŃŃŹ на грŃдном вŃкармливании.
ОСЛОЖНЕНĐĐŻ РПОБОЧНЫЕ ДЕЙСТВĐĐŻ
Длительные или Ńерьезные ĐľŃложнения и побочные дейŃтвия наблюдаютŃŃŹ редко.
КРОВОТЕЧЕНĐĐ•
ПоŃле приема мизопроŃтола кровотечение обычно длитŃŃŹ Đ´Đľ 2-Ń… недель, Đ° затем в течение неŃкольких дней отмечаютŃŃŹ кровяниŃтые выделения, которые могŃŃ‚ длитьŃŃŹ Đ´Đľ начала ŃледŃющего менŃŃ‚Ń€Ńального цикла.
Необходимо проинŃŃ‚Ń€Ńктировать Đ¶ĐµĐ˝Ń‰Đ¸Đ˝Ń ĐľŃ‚Đ˝ĐľŃительно того, что ей ŃледŃет ŃвязатьŃŃŹ Ń Đ˛Ń€Đ°Ń‡ĐľĐĽ, еŃли наблюдаетŃŃŹ что-либо из перечиŃленного ниже: (1) еŃли она иŃпользŃет больŃе двŃŃ… больŃих гигиеничеŃких прокладок в Ń‡Đ°Ń Đ˛ течение двŃŃ… чаŃов подряд, (2) еŃли кровотечение ŃменьŃилоŃŃŚ или прекратилоŃŃŚ через неŃколько дней поŃле приема мизопроŃтола, Đ° затем опять внезапно началоŃŃŚ Ńильное кровотечение, (3) еŃли кровотечение длитŃŃŹ неŃколько недель и появляетŃŃŹ головокрŃжение или ощŃщение предобморочного ŃĐľŃтояния.
СХВĐТКООБРĐЗНЫЕ БОЛĐ
Схваткообразные боли обычно появляютŃŃŹ в первые же чаŃŃ‹ и даже Ńже через 30 минŃŃ‚ поŃле приема мизопроŃтола. Боль может быть намного Ńильнее той, которая бывает при обычной менŃŃ‚Ń€Ńации. Для обезболивания можно применять неŃтероидные противовоŃпалительные препараты (НПВП) или Đ´Ń€Ńгие анальгетики, что не отразитŃŃŹ на ŃŃпеŃном выполнении процедŃры.
ОЗНОБ Đ/ĐЛРПОВЫШЕНĐĐ• ТЕМПЕРĐТУРЫ
Озноб являетŃŃŹ типичным, но преходящим побочным эффектом мизопроŃтола. ПовыŃение температŃры наблюдаетŃŃŹ реже и не вŃегда означает наличие инфекции. При необходимоŃти для понижения температŃры можно применять жаропонижающие ŃредŃтва. Đ•Ńли температŃра или озноб длятŃŃŹ более 24 чаŃов поŃле приема мизопроŃтола, Ń‚Đľ ŃŤŃ‚Đľ означает возможное наличие инфекции, и в этом ŃĐ»Ńчае женщина должна обратитьŃŃŹ Đ·Đ° медицинŃкой помощью.
ТОШНОТРРРВОТĐ
МогŃŃ‚ появитьŃŃŹ Ń‚ĐľŃнота и рвота, но эти Ńимптомы проходят в течение 2-6 чаŃов поŃле введения мизопроŃтола. При необходимоŃти можно применять противорвотные ŃредŃтва.
Đ”ĐĐĐ Đ•ĐŻ
Диарея может также появитьŃŃŹ поŃле введения мизопроŃтола, но она, как правило, проходит в течение дня.
Дозировка и ŃпоŃоб введения
Неполный аборт: РекомендŃемая Ńхема лечения неполного аборта Ń ĐżĐľĐĽĐľŃ‰ŃŚŃŽ мизопроŃтола – однократный пероральный прием 600 мкг мизопроŃтола ĐЛРоднократный ŃŃблингвальный (под ŃŹĐ·Ń‹Đş) прием 400 мкг мизопроŃтола.
НеŃĐľŃтоявŃийŃŃŹ выкидыŃ: Đ’ ŃĐ»Ńчае, еŃли диагноз неŃĐľŃтоявŃегоŃŃŹ выкидыŃĐ° не вызывает Ńомнений и/или, Ńейка матки плотно закрыта, рекомендŃетŃŃŹ ŃледŃющая Ńхема лечения – однократное введение 800 мкг мизопроŃтола интравагинально.
НаилŃчŃие показатели эффективноŃти метода Đ´ĐľŃтигаютŃŃŹ при проведении контрольного обŃледования не ранее, чем через 7-14 дней, необходимых для заверŃения процеŃŃĐ° изгнания плодного яйца. ХирŃргичеŃкое вмеŃательŃтво не рекомендŃетŃŃŹ проводить в течение 7 дней поŃле применения препарата, еŃли нет Đş Ń‚ĐľĐĽŃ ĐĽĐµĐ´Đ¸Ń†Đ¸Đ˝Ńких показаний.
Примечание:
- ĐмеютŃŃŹ данные, Ńказывающие на Ń‚Đľ, что иŃпользование повторных доз может повыŃить эффективноŃŃ‚ŃŚ метода.
- МизопроŃтол вероятно также эффективен, еŃли его принимать транŃбŃккально (помеŃтить Ń‚Đ°Đ±Đ»ĐµŃ‚ĐşŃ ĐĽĐµĐ¶Đ´Ń Ń‰ĐµĐşĐľĐą и деŃной).
РекомендŃемая ŃŃылка:
Заявление на ĐľŃнове конŃенŃŃŃĐ°: ĐĐ˝ŃŃ‚Ń€Ńкция Đş применению – Лечение неполного или неŃĐľŃтоявŃегоŃŃŹ выкидыŃĐ° Ń ĐżĐľĐĽĐľŃ‰ŃŚŃŽ препарата МизопроŃтол. Совещание ŃпециалиŃтов по МизопроŃтолŃ, организаторами которого являютŃŃŹ организации Reproductive Health Technologies Project и Gynuity Health Projects. 9 июня 2004Đł. Нью-Йорк, ŃŃ‚Đ°Ń‚ Нью-Йорк.
СпиŃок материалов, иŃпользованных для разработки данного докŃмента, Đ° также дополнительнŃŃŽ информацию ŃĐĽ. на www.gynuity.org или www.rhtp.org.
данный докŃмент периодичеŃки переŃматриваетŃŃŹ и корректирŃетŃŃŹ в ŃоответŃтвии Ń Ń‚ĐµĐşŃщей информацией и наŃчными разработками.
© 2008 Gynuity Health Projects and Reproductive Health Technologies Project
обновлено июнь 2008
ĐНСТРУКЦĐĐŻ Đš ПРĐМЕНЕНĐĐ®: ПРОФĐĐ›ĐКТĐКРПОСЛЕРОДОВОГО КРОВОТЕЧЕНĐĐŻ С ПОМОЩЬЮ ПРЕПĐĐ ĐТРМĐЗОПРОСТОЛ
ПРЕДПОСЫЛКĐ
МизопроŃтол, являющийŃŃŹ аналогом проŃтагландина E1, применяетŃŃŹ, как правило, для профилактики и лечения язв желŃдка, образŃющихŃŃŹ при длительном приеме неŃтероидных противовоŃпалительных препаратов (НПВП). Đ’ Ńвязи Ń Ń‚ĐµĐĽ, что мизопроŃтол также вызывает Ńокращение маточной ĐĽŃŃĐşŃлатŃры, он чаŃŃ‚Đľ иŃпользŃетŃŃŹ не по ĐżŃ€ŃŹĐĽĐľĐĽŃ Đ˝Đ°Đ·Đ˝Đ°Ń‡ĐµĐ˝Đ¸ŃŽ Ń Ń†ĐµĐ»ŃŚŃŽ профилактики поŃлеродового кровотечения (PPH). Đктивное ведение родов в третьем периоде (AMTSL) – иŃпытанный метод ŃменьŃения поŃлеродового кровотечения. AMTSL включает введение Ńтеротоников в профилактичеŃких целях, ĐľŃторожное вытягивание ĐżŃповины и ĐĽĐ°ŃŃаж матки в третьем периоде родов. ĐŃŃледования показали, что при отŃŃŃ‚Ńтвии обычных Ńтеротоников для инъекций, можно безопаŃно и эффективно иŃпользовать мизопроŃтол Ń Ń†ĐµĐ»ŃŚŃŽ профилактики поŃлеродового кровотечения. Приведенная ниже информация являетŃŃŹ Ń€ŃководŃтвом для квалифицированного медицинŃкого перŃонала в меŃŃ‚Đ°Ń…, где Đ´ĐľŃŃ‚ŃĐż меŃтного наŃеления Đş окŃĐ¸Ń‚ĐľŃ†Đ¸Đ˝Ń ĐľĐłŃ€Đ°Đ˝Đ¸Ń‡ĐµĐ˝.
ПОКĐĐ—ĐĐťĐĐŻ РПРĐМЕНЕНĐĐ•
МизопроŃтол показан для профилактики поŃлеродового кровотечения при нормальных родах через еŃтеŃтвенные родовые ĐżŃти.
МизопроŃтол, применяемый для профилактики поŃлеродового кровотечения, ŃпоŃобŃтвŃет ŃменьŃению поŃлеродового кровотечения при родах через еŃтеŃтвенные родовые ĐżŃти. При Ńравнении ŃĐľ ŃĐ»Ńчаями, когда в третьем периоде родов не применялиŃŃŚ Ńтеротоники Ń ĐżŃ€ĐľŃ„Đ¸Đ»Đ°ĐşŃ‚Đ¸Ń‡ĐµŃкой целью, мизопроŃтол Ńнижал объем поŃлеродовых кровопотерь. ĐŃŃледования показали, что мизопроŃтол менее эффективен, чем окŃитоцин, но его эффективноŃŃ‚ŃŚ равна или даже превыŃает таковŃŃŽ эргометрина для перорального приема.
ПРОТĐВОПОКĐĐ—ĐĐťĐĐŻ
Наличие в анамнезе аллергии на мизопроŃтол или Đ´Ń€Ńгие проŃтагландины.
МЕРЫ ПРЕДОСТОРОЖНОСТĐ
Перед назначением мизопроŃтола врачи должны ŃбедитьŃŃŹ, что нет второго близнеца. Đ•Ńли нет ŃверенноŃти, или еŃли врач, принимающий роды, недоŃтаточно квалифицирован для принятия такого реŃения, Ń‚Đľ Đ»ŃчŃе назначать мизопроŃтол поŃле отделения плаценты.
НебольŃое количеŃтво мизопроŃтола или его активных метаболитов может попаŃŃ‚ŃŚ в грŃдное молоко. СлŃчаи неблагоприятного воздейŃтвия мизопроŃтола на грŃдных детей не зарегиŃтрированы (Derman и Đ´Ń€., 2006).
ОСЛОЖНЕНĐĐŻ РПОБОЧНЫЕ ДЕЙСТВĐĐŻ
Длительные или Ńерьезные ĐľŃложнения и побочные дейŃтвия наблюдаютŃŃŹ редко.
ОЗНОБ
Озноб являетŃŃŹ наиболее типичным побочным эффектом мизопроŃтола, принимаемого поŃле родов. Как правило, озноб появляетŃŃŹ в течение чаŃĐ° поŃле приема мизопроŃтола. Đтот побочный эффект являетŃŃŹ преходящим, озноб проходит через 2-6 чаŃов поŃле родов.
ПОВЫШЕНĐĐ• ТЕМПЕРĐТУРЫ
ПовыŃение температŃры наблюдаетŃŃŹ реже, чем озноб, и не вŃегда Ńказывает на наличие инфекции. ПовыŃению температŃры чаŃŃ‚Đľ предŃеŃтвŃет озноб. МакŃимальное повыŃение температŃры наблюдаетŃŃŹ через 1-2 чаŃĐ° поŃле приема мизопроŃтола, и в течение 2-8 чаŃов температŃра поŃтепенно Ńпадает. При необходимоŃти можно принять жаропонижающее ŃредŃтво. Đ•Ńли температŃра или озноб не проходят через 24 чаŃĐ°, женщина должна обратитьŃŃŹ Đş врачŃ, чтобы иŃключить наличие инфекции.
Đ”ĐĐĐ Đ•ĐŻ, ТОШНОТРРРВОТĐ
Диарея также может появитьŃŃŹ поŃле приема мизопроŃтола, но она должна пройти в течение дня. МогŃŃ‚ появитьŃŃŹ Ń‚ĐľŃнота и рвота, но они, как правило, проходят через 2-6 чаŃов поŃле приема мизопроŃтола. При необходимоŃти можно принять противорвотное ŃредŃтво.
СХВĐТКООБРĐЗНЫЕ БОЛĐ
Схваткообразные боли или болезненные Ńокращения матки, чаŃŃ‚Đľ наблюдаемые поŃле родов, как правило, появляютŃŃŹ в первые же чаŃŃ‹ и даже Ńже через 30 минŃŃ‚ поŃле приема мизопроŃтола. Для обезболивания можно применять неŃтероидные противовоŃпалительные препараты (НПВП) или Đ´Ń€Ńгие анальгетики, что не отразитŃŃŹ на резŃльтатах лечения.
ПОСЛЕРОДОВОЕ КРОВОТЕЧЕНĐĐ•
Đ’ ŃĐ»Ńчае Ńильного кровотечения Đ´Đľ или поŃле отделения плаценты ŃледŃет Ńрочно принять дополнительные меры. ПовторнŃŃŽ Đ´ĐľĐ·Ń ĐĽĐ¸Đ·ĐľĐżŃ€ĐľŃтола не рекомендŃетŃŃŹ принимать ранее, чем через 6 чаŃов поŃле первой дозы.
ДОЗĐРОВКРРСПОСОБ ВВЕДЕНĐĐŻ
РекомендŃемая Ńхема приема мизопроŃтола в целях профилактики поŃлеродового кровотечения – однократный пероральный прием 600 мкг мизопроŃтола во время третьего периода родов.
ПРĐМЕЧĐĐťĐĐ•:
Đ’ наŃтоящее время нет Đ´ĐľŃтаточных подтвержденных данных, на ĐľŃновании которых можно было бы назначать более низкŃŃŽ Đ´ĐľĐ·Ń ĐĽĐ¸Đ·ĐľĐżŃ€ĐľŃтола для профилактики поŃлеродового кровотечения. По мере появления информации по более низким дозам (200-400 мкг), данная инŃŃ‚Ń€Ńкция бŃдет переŃмотрена, и в нее бŃĐ´ŃŃ‚ внеŃены изменения по оптимальной дозе.
РЕКОМЕНДУЕМĐĐŻ ССЫЛКĐ
ĐĐ˝ŃŃ‚Ń€Ńкция Đş применению: Профилактика поŃлеродового кровотечения Ń ĐżĐľĐĽĐľŃ‰ŃŚŃŽ препарата мизопроŃтол. ĐĐşŃпертиза организована Gynuity Health Projects. Đюль 2007Đł.
ДополнительнŃŃŽ информацию ŃĐĽ. на www.gynuity.org.
Đ”ĐННЫЙ ДОКУМЕНТ ПЕРĐОДĐЧЕСКРПЕРЕСМĐТРĐĐ’ĐЕТСЯ РКОРРЕКТĐРУЕТСЯ Đ’ СООТВЕТСТВĐРС ТЕКУЩЕЙ
ĐНФОРМĐЦĐĐ•Đ™ Đ ĐťĐУЧНЫМРРĐĐ—Đ ĐБОТКĐĐśĐ.
© Gynuity Health Projects
Đюль 2007Đł.
INSTRUÇÕES PARA USO: MISOPROSTOL PARA A PREVENÇĂO DE HEMORRAGIA PĂ“S-PARTO
ANTECEDENTES
Misoprostol Ă© um análogo de prostaglandina E1 geralmente registrado para prevenção e tratamento de Ăşlceras gástricas resultantes da administração crĂ´nica de anti-inflamatĂłrios nĂŁo esterĂłideos (ANES). Como o misoprostol tambĂ©m induz contrações uterinas, Ă© comumente utilizado, fora de sua indicação no registro, para prevenção de hemorragia pĂłs-parto (HPP). O manejo ativo do terceiro perĂodo (MATP) do trabalho de parto Ă© um mĂ©todo comprovado para redução da HPP. Ele consiste na administração profilática de uterotĂ´nicos, tração controlada do cordĂŁo umbilical e massagem uterina durante o terceiro perĂodo. Estudos tĂŞm demonstrado que o misoprostol pode ser usado efetivamente e de forma segura para a prevenção de HPP na indisponibilidade de uterotĂ´nicos convencionais injetáveis. A seguinte informação Ă© apresentada como guia para os provedores de saĂşde em serviços comunitários onde o acesso Ă ocitocina Ă© limitado.
INDICAÇĂO PARA USO
Misoprostol é indicado para prevenção da hemorragia pós-parto após um parto vaginal normal.
O uso de misoprostol para prevenção da HPP Ă© efetivo para reduzir o sangramento que se apresenta depois do parto vaginal. Quando comparado com a nĂŁo administração profilática de uterotĂ´nicos durante o terceiro perĂodo do parto, o emprego do misoprostol reduz o sangramento depois do parto. Estudos tĂŞm mostrado que o misoprostol Ă© menos efetivo que a ocitocina, mas tĂŁo ou mais efetivo do que a ergometrina por via oral.
CONTRAINDICAÇĂO
HistĂłria de alergia ao misoprostol ou outras prostaglandinas.
PRECAUÇÕES
- Os provedores devem confirmar que não exista um segundo gêmeo não diagnosticado antes de administrar o misoprostol. Se existe dúvidas, ou se o profissional que está atendendo não for qualificado para tomar a decisão, então é melhor administrar o misoprostol apenas depois da expulsão da placenta.
- Pequenas quantidades de misoprostol ou seu metabĂłlito ativo podem aparecer no leite materno. NĂŁo se relatou a existĂŞncia de efeitos adversos nos lactentes (Derman et al 2006).
EFEITOS E EFEITOS COLATERIAIS
SĂŁo raros os efeitos persistentes ou graves.
CALAFRIOS
Calafrios é o efeito colateral mais comum do misoprostol quando se administra após o parto. Geralmente ocorrem durante a primeira hora após sua administração. Esse efeito é transitório e pode durar de 2-6 horas após o parto.
FEBRE
Febre Ă© menos comum do que calafrios e nĂŁo necessariamente indica infecção. A temperatura corporal elevada Ă© freqĂĽentemente precedida por calafrios, com picos a 1-2 horas depois de ter administrado o misoprostol e cede gradualmente apĂłs 2-8 horas. Um antipirĂ©tico pode ser usado para controlar a febre, quando necessário. Se a febre ou os calafrios persistirem por mais de 24 horas, a mulher deve procurar atenção mĂ©dica para descartar uma possĂvel infecção.
DIARRÉIA, NĂUSEA E VĂ”MITO
Diarréia pode também ocorrer depois da administração do misoprostol, mas deve se resolver dentro de um dia. Náusea e vômito também podem ocorrer, mas desaparecem entre 2-6 horas da administração do misoprostol. Pode-se empregar um antiemético, se for necessário.
CĂ“LICAS
Cólicas ou contrações uterinas dolorosas, que normalmente ocorrem depois do parto, usualmente começam dentro das primeiras horas e podem também se iniciar tão cedo quanto 30 minutos após a administração do misoprostol. Medicamentos anti-inflamatórios não esteróideos ou outros analgésicos podem ser usados para aliviar a dor sem afetar o êxito do método.
SANGRAMENTO PĂ“S-PARTO
Em casos de sangramento excessivo, antes ou apĂłs a expulsĂŁo da placenta, a mulher deve ser referenciada imediatamente para cuidados adicionais. Doses extras de misoprostol nĂŁo devem ser dadas dentro de seis horas da dose inicial.
DOSAGEM E ADMINISTRAÇĂO
O esquema recomendado para a prevenção de hemorragia pĂłs-parto com misoprostol Ă© uma dose Ăşnica de 600mcg de misoprostol administrado por via oral durante o terceiro perĂodo do trabalho de parto.
Notas:
Atualmente, nĂŁo há evidĂŞncias suficientes para recomendar uma dosagem menor de misoprostol para prevenção de HPP em serviços de saĂşde a nĂvel comunitário. Ă€ medida que mais evidĂŞncias sobre doses menores (entre 200 e 400 mcg) estejam disponĂveis, estas INSTRUÇÕES PARA USO serĂŁo revisadas e atualizadas sugerindo doses Ăłtimas para serem empregadas.
CITAÇĂO SUGERIDA
Instruções para Uso: Misoprostol para a Prevenção de Hemorragia Pós-parto. Revisão de expertos organizada por Gynuity Health Projects. Julho 2007.
Para mais informação, visite o site www.gynuity.org.
Este documento será periodicamente revisado e atualizado com informações atuais e desenvolvimentos de pesquisa.
©2007 Gynuity Health Projects.
Julho 2007
CONSIGNES D’UTILISATION: LE MISOPROSTOL POUR LA PREVENTION DE L’HEMORRAGIE DU POSTPARTUM
RETROSPECTIVE
Le misoprostol est un analogue de la prostaglandine E1 gĂ©nĂ©ralement autorisĂ© pour la prĂ©vention et le traitement des ulcères gastriques dus Ă l’administration excessive d’anti-inflammatoires non stĂ©roĂŻdiens (AINS.) Le misoprostol est habituellement utilisĂ© sans autorisation de mise sur le marchĂ© pour la prĂ©vention de l’hĂ©morragie du post-partum (HPP) dans la mesure oĂą il provoque Ă©galement des contractions utĂ©rines. La gestion active de la troisième pĂ©riode de l’accouchement (GATPA) est une mĂ©thode vĂ©rifiĂ©e pour rĂ©duire l’HPP. La GATPA consiste Ă administrer un utĂ©rotonique prophylactique et Ă effectuer une traction contrĂ´lĂ©e du cordon ombilical et un massage utĂ©rin durant le troisième stade du travail. En l’absence d’utĂ©rotoniques conventionnels injectables disponibles, des Ă©tudes ont dĂ©montrĂ© que le misoprostol peut ĂŞtre utilisĂ© de manière efficace et sĂ»re pour la prĂ©vention de l’HPP. Les informations suivantes sont prĂ©sentĂ©es sous forme de directives Ă l’intention des prestataires de santĂ© dans les milieux communautaires oĂą l’accès Ă l’ocytocine est restreint.
INDICATIONS ET MODE D’EMPLOI
Le misoprostol est indiquĂ© pour la prĂ©vention de l’hĂ©morragie du post-partum suite Ă un accouchement normal par voie basse.
L’utilisation du misoprostol pour la prĂ©vention de l’HPP est efficace pour rĂ©duire les pertes sanguines post-partum suivant un accouchement par voie basse. Le misoprostol rĂ©duit les pertes sanguines post-partum par rapport Ă la non-administration prophylactique d’un utĂ©rotonique durant le troisième stade du travail. Des Ă©tudes ont indiquĂ© l’efficacitĂ© moindre du misoprostol par rapport Ă l’ocytocine et une efficacitĂ© supĂ©rieure ou Ă©gale Ă l’ergomĂ©trine par voie orale.
CONTRE-INDICATIONS
AntĂ©cĂ©dents d’allergie au misoprostol ou Ă d’autres prostaglandines.
PRECAUTIONS D’USAGE
- Les prestataires devraient confirmer l’absence de diagnostic d’un second jumeau avant de prescrire le misoprostol. En cas d’incertitude ou au cas oĂą l’accoucheuse ne serait pas qualifiĂ©e Ă prendre la dĂ©cision, la meilleure option serait alors de prescrire le misoprostol avant l’expulsion du placenta.
- De petites quantitĂ©s de misoprostol ou son mĂ©tabolite actif pourraient passer dans le lait maternel. Aucun effet indĂ©sirable sur les nourrissons qui tètent n’a Ă©tĂ© indiquĂ© (Derman et autres 2006).
EFFETS SECONDAIRES
Les effets secondaires prolongés ou graves sont rares.
FRISSONS
Les frissons constituent l’effet secondaire le plus courant du misoprostol suite Ă son administration post-partum. Ils surviennent habituellement durant la première heure après la prise du misoprostol. Cet effet secondaire est fugace et disparaĂ®t 2 Ă 6 heures après l’accouchement.
FIEVRE
La fièvre est moins courante que les frissons et n’indique pas nĂ©cessairement une infection. Une tempĂ©rature corporelle Ă©levĂ©e est souvent prĂ©cĂ©dĂ©e de frissons, culmine 1 Ă 2 heures suivant la prise du misoprostol et disparaĂ®t progressivement en l’espace de 2 Ă 8 heures. Un antipyrĂ©tique peut ĂŞtre utilisĂ© en vue de rĂ©duire la fièvre, le cas Ă©chĂ©ant. La femme devrait consulter un mĂ©decin afin d’exclure l’infection au cas oĂą la fièvre ou les frissons persisteraient.
DIARRHEE, NAUSEES ET VOMISSEMENTS
La diarrhĂ©e pourrait Ă©galement survenir suivant l’administration du misoprostol et devrait toutefois se dissiper 2 Ă 6 heures après la prise du misoprostol. Un antiĂ©mĂ©tique peut ĂŞtre utilisĂ© si nĂ©cessaire.
CRAMPES ABDOMINALES
Comme c’est le cas après l’accouchement, les crampes ou les contractions utĂ©rines douloureuses surviennent habituellement durant les toutes premières heures et pourraient survenir aussi tĂ´t que 30 minutes suivant l’administration du misoprostol. Les anti-inflammatoires non stĂ©roĂŻdiens (AINS) ou d’autres analgĂ©siques peuvent ĂŞtre utilisĂ©s pour le traitement de la douleur sans affecter la rĂ©ussite de la mĂ©thode.
SAIGNEMENTS POST-PARTUM
Les saignements excessifs avant ou après l’expulsion du placenta devraient ĂŞtre signalĂ©s immĂ©diatement pour des soins supplĂ©mentaires. Une dose supplĂ©mentaire de misoprostol ne devrait pas ĂŞtre administrĂ©e dans les six heures suivant la prise de la dose initiale.
POSOLOGIE ET MODE D’ADMINISTRATION
Le rĂ©gime posologique recommandĂ© pour la prĂ©vention de l’hĂ©morragie du post-partum par le misoprostol est une dose unique de 600 mcg de misoprostol par voie orale, administrĂ©e durant le troisième stade du travail.
Notes:
Il existe prĂ©sentement peu de donnĂ©es pour recommander une dose plus faible de misoprostol pour la prĂ©vention de l’hĂ©morragie du post-partum dans les milieux communautaires. Les prĂ©sentes consignes d’utilisation feront l’objet d’une revue et d’une mise Ă jour compte tenu des informations relatives Ă une dose optimale au fur et Ă mesure de la disponibilitĂ© de donnĂ©es supplĂ©mentaires portant sur des doses plus faibles (variant de 200 Ă 400mcg.).
REFERENCE SUGGEREE
Consignes d’utilisation: Le misoprostol pour la prĂ©vention de l’hĂ©morragie du post-partum. Examen effectuĂ© par des experts de Gynuity Health Projects. Juillet 2007.
Veuillez consulter www.gynuity.org pour de plus amples informations
Le present document fera l’objet d’un examen et d’une mise Ă jour periodique compte tenu des informations et des developpements courants de la recherche.
© 2007 Gynuity Health Projects.
Juillet 2007
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CONSIGNES D’UTILISATION: MISOPROSTOL DANS LE TRAITEMENT DE L’AVORTEMENT INCOMPLET ET DE LA FAUSSE-COUCHE SPONTANEE
GENERALITES
Le misoprostol est un analogue synthĂ©tique de la prostaglandine E1, commercialisĂ© pour la prĂ©vention et le traitement de l’ulcère gastrique liĂ© Ă l’utilisation chronique d’anti-inflammatoire non stĂ©roĂŻdien (AINS). Induisant Ă©galement des contractions utĂ©rines, il est souvent utilisĂ©, hors indications officielles, pour le traitement des arrĂŞts prĂ©coces de grossesse (avortement incomplet et grossesse arrĂŞtĂ©e). Des Ă©tudes ont montrĂ© l’efficacitĂ© et l’innocuitĂ© dans cette indication. Les informations suivantes sont Ă l’attention des professionnels de la santĂ©.
INDICATIONS
Le misoprostol est indiquĂ© dans le traitement de l’avortement incomplet et de la grossesse arrĂŞtĂ©e pour les femmes dont la taille de l’utĂ©rus est de moins de 12 semaines d’amĂ©norrhĂ©e. Le taux de rĂ©ussite avec les doses recommandĂ©es est compris entre 66 et 100% dans le cas d’un avortement incomplet et entre 60 et 93% dans le cas des grossesses arrĂŞtĂ©es.
CONTRE-INDICATIONS
- Allergie connue au misoprostol ou Ă d’autres prostaglandines.
- Suspicion de grossesse ectopique.
- Signe de péritonites et/ou de septicémie.
- Signes d’instabilitĂ© hĂ©modynamique ou de choc.
PRECAUTIONS
- Chez les femmes porteuses d’un stĂ©rilet, le retrait du stĂ©rilet est impĂ©ratif avant l’administration du misoprostol.
- Une attention toute particulière doit être donnée aux femmes porteuses de troubles de la coagulation ou sous traitement anti-coagulant.
- La prudence s’impose pour toute utilisation du misoprostol chez une femme ayant une hauteur utĂ©rine de plus de 12 semaines d’amĂ©norrhĂ©e alors que le terme est infĂ©rieur ou Ă©gal Ă 12 semaines
d’amĂ©norrhĂ©e (utĂ©rus fibromateux).
- Une infime portion de misoprostol ou d’un mĂ©tabolite actif pourrait ĂŞtre retrouvĂ© dans le lait maternel. Cependant aucun effet secondaire n’a Ă©tĂ© reportĂ© chez l’enfant nourri au sein.
EFFETS SECONDAIRES
Les effets secondaires prolongés ou graves sont rares.
SAIGNEMENTS
Les saignements commencent souvent le premier jour, en gĂ©nĂ©ral dans l’heure suivant la prise du misoprostol. Ils peuvent habituellement durer pendant deux semaines, mais des saignements peu importants (spotting) peuvent se prolonger jusqu‘Ă la menstruation suivante. La femme devra ĂŞtre avertie de contacter le prestataire dans chacun des cas suivants : (1) si le sang qu’elle perd imbibe deux serviettes hygiĂ©niques (modèle maxi) par heure pendant plus de deux heures, (2) si les saignements s’arrĂŞtent et reprennent soudainement et de façon abondante, (3) si les saignements se prolongent plusieurs semaines et si elle commence Ă avoir des Ă©tourdissements et des malaises.
CONTRACTIONS DOULOUREUSES
Les contractions dĂ©butent le plus souvent dans les premières heures, voire dans les 30 minutes seulement après l’administration du misoprostol. La douleur peut ĂŞtre bien plus intense que celle de règles normales. Des anti-inflammatoires non stĂ©roĂŻdiens (AINS) ou des analgĂ©siques pourront ĂŞtre prescrits pour le contrĂ´le de la douleur sans nuire pour autant Ă l’efficacitĂ© de la mĂ©thode.
FRISSONS ET/OU FIEVRE
Les frissons sont un effet secondaire frĂ©quent, mais transitoire. La fièvre est plus rare et n’indique pas obligatoirement une infection. Si besoin, un antipyrĂ©tique peut ĂŞtre prescrit. Si la fièvre ou les frissons persistent plus de 24 heures après la prise du misoprostol, ils peuvent ĂŞtre le signe d’une infection et la femme devra alors consulter un mĂ©decin.
NAUSEE ET VOMISSEMENTS
NausĂ©e et vomissements peuvent survenir. Ils disparaissent entre 2 et 6 heures après l’administration du misoprostol. Si besoin, un antiĂ©mĂ©tique peut ĂŞtre prescrit.
DIARRHEE
L’administration du misoprostol peut s’accompagner d’une diarrhĂ©e qui disparaĂ®t normalement en une journĂ©e.
POSOLOGIE ET MODE D’ADMINISTRATION
Pour les avortements incomplets, le schĂ©ma posologique recommandĂ© est le suivant : soit l’administration par voie orale d’une dose unique de 600 µg de misoprostol, soit l’administration par voie sublinguale (en les plaçant sous la langue) d’une dose unique de 400 µg de misoprostol.
Pour les grossesses arrĂŞtĂ©es, après confirmation du diagnostique et/ou col utĂ©rin complètement fermĂ©, le schĂ©ma posologique recommandĂ© est le suivant: administration par voie vaginale d’une dose unique de 800 µg de misoprostol.
On retrouve un taux de succès supĂ©rieur lorsqu’un suivi prolongĂ© est effectuĂ© (7 Ă 14 jours) ceci afin que l’expulsion ait le temps de se complĂ©ter. Un geste chirurgical n’est pas recommandĂ© avant 7 jours sauf s’il est mĂ©dicalement nĂ©cessaire.
Remarques:
- Il semble qu’une administration rĂ©pĂ©tĂ©e de misoprostol permette d’augmenter le taux de rĂ©ussite.
- Le misoprostol est très probablement aussi efficace quand on l’administre par voie buccale (en plaçant les comprimĂ©s entre la joue et la gencive).
Source Ă citer:
Consignes d’utilisation: Misoprostol dans le traitement de l’avortement incomplet et de la fausse-couche spontanĂ©e. Rencontre d’experts sur le misoprostol organisĂ©e par Reproductive Health Technologies Project et Gynuity Health Projects. 9 juin 2004. New York, NY.
Pour une liste de refĂ©rĂ©nce concernant ce document ou pour plus d’information, consultez les sites www.gynuity.org or www.rhtp.org.
Ce document sera régulièrement revu et mis à jour en fonction des données les plus récentes et des avancés de la recherche.
© 2008 Gynuity Health Projects et Reproductive Health Technologies Project
Mis Ă jour juin 2008
INSTRUCCIONES PARA EMPLEO: MISOPROSTOL PARA LA PREVENCIĂ“N DE LA HEMORRAGIA POSTPARTO
ANTECEDENTES
El misoprostol es un análogo de la prostaglandina E1 aprobado para la prevenciĂłn y tratamiento de las Ăşlceras gástricas asociadas a la administraciĂłn crĂłnica de medicamentos antinflamatorios no esteroideos (ANES). Como el misoprostol tambiĂ©n estimula las contracciones uterinas, es utilizado comĂşnmente, sin estar registrado su uso, para la prevenciĂłn de la hemorragia postparto (HPP). Se ha comprobado que el manejo activo de la tercera etapa del trabajo de parto es efectivo para la prevenciĂłn de la HPP. El manejo activo consiste en la administraciĂłn de uterotĂłnicos profilácticos, tracciĂłn controlada del cordĂłn y masaje uterino durante la tercera etapa. Estudios realizados, por otra parte, han confirmado que el misoprostol puede ser empleado en forma efectiva y segura para la prevenciĂłn de la HPP donde no hay disponibilidad de uterotĂłnicos inyectables. La siguiente informaciĂłn se presenta como guĂa para el personal de salud a nivel comunitario donde no hay fácil acceso a la oxitocina.
INDICACIONES Y USO
El misoprostol está indicado para la prevención de la hemorragia postparto después del parto vaginal normal.
La administración de misoprostol para la prevención de la HPP es efectiva para reducir el sangrado que se presenta después del parto vaginal. Al compararse con situaciones en que no se han empleado uterotónicos profilácticamente, el empleo de misoprostol reduce la pérdida de sangre después del parto. Según estudios, el misoprostol es menos efectivo que la oxitocina, pero es tan efectivo, o más
efectivo, que la ergometrina oral.
CONTRAINDICACIONES
Historia de alergia al misoprostol u otra prostaglandina.
PRECAUCIONES
- Los proveedores deben confirmar que no existe un embarazo gemelar no diagnosticado antes de administrar el misoprostol. Si no existe certeza, o quien está atendiendo el parto no está en capacidad de tomar la decisión, es mejor administrar el misoprostol después de la expulsión de la placenta.
- Pequeñas cantidades de misoprostol o su metabolito activo pueden aparecer en la leche materna. No se ha establecido la existencia de efectos secundarios en el lactante (Derman et al 2006).
EFECTOS SECUNDARIOS
Son poco frecuentes los efectos persistentes o severos.
ESCALOFRĂŤOS
Los escalofrĂos constituyen el efecto secundario más frecuente del misoprostol cuando se administra despuĂ©s del parto. Generalmente se presentan durante la primera hora de haberse administrado el misoprostol. Este efecto es transitorio y suele durar solamente 2-6 horas despuĂ©s del parto.
FIEBRE
La fiebre es un efecto menos comĂşn que los escalofrĂos y no necesariamente indica la presencia de una infecciĂłn. La temperatura elevada del cuerpo generalmente está precedida por escalofrĂos, alcanza su nivel máximo 1-2 horas despuĂ©s de haberse administrado el misoprostol, y cede gradualmente al cabo de 2-8 horas. Se puede emplear un antipirĂ©tico para el control de la fiebre, en caso de ser necesario. Si la fiebre o los escalofrĂos persisten por más de 24 horas, la mujer debe procurar atenciĂłn mĂ©dica para descartar una posible infecciĂłn.
DIARREA, NAUSEA Y VĂ“MITO
Se puede presentar diarrea despuĂ©s de la administraciĂłn de misoprostol, pero suele desaparecer el mismo dĂa. TambiĂ©n se pueden presentar nausea y vĂłmito, pero desaparecen despuĂ©s de 2-6 horas de haberse administrado el misoprostol. Se puede emplear un antiemĂ©tico, si se considera necesario.
CĂ“LICOS
Los cólicos o las contracciones uterinas dolorosas, que usualmente se presentan después del parto, pueden empezar dentro de las primeras horas e incluso a los 30 minutos de haberse administrado el misoprostol. Se pueden emplear medicamentos antinflamatorios no esteroideos u otros analgésicos para aliviar el dolor sin afectar el éxito del método.
SANGRADO POSTPARTO
El sangrado excesivo antes o después de la expulsión de la placenta requiere la remisión inmediata para cuidados adicionales. No se debe administrar misoprostol adicional hasta después de 6 horas de la dosis inicial.
DOSIS Y ADMINISTRACIĂ“N
El rĂ©gimen recomendado para la prevenciĂłn de la hemorragia postparto es una dosis Ăşnica de 600 mcg de misoprostol por vĂa oral, administrada durante la tercera etapa del trabajo de parto.
Notas:
En la actualidad, no existe evidencia suficiente para recomendar dosis menores de misoprostol para la prevención de la hemorragia postparto en servicios de salud a nivel comunitario. A medida que exista una mayor evidencia sobre dosis menores (entre 200 y 400 mcg), estas instrucciones serán revisadas y actualizadas sugiriendo la dosis óptima para ser empleada.
Cita Sugerida
Instrucciones para Empleo: Misoprostol para la PrevenciĂłn de la Hemorragia Postparto. RevisiĂłn de Expertos organizada por Gynuity Health Projects. Julio 2007.
Para mayor informaciĂłn, consultar www.gynuity.org .
Este documento será revisado y actualizado periódicamente de acuerdo con la información disponible y las nuevas investigaciones.
© 2007 Gynuity Health Projects.
Julio 2007
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BACKGROUND
Misoprostol is a prostaglandin E1 analog generally registered for prevention and treatment of gastric ulcers resulting from chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs). As misoprostol also induces uterine contractions, it is commonly used off-label for prevention of postpartum hemorrhage (PPH). Active management of the third stage of labor (AMTSL) is a proven method for reducing PPH. AMTSL consists of the administration of a prophylactic uterotonic, controlled cord traction, and uterine massage during the third stage. In the absence of availability of conventional injectable uterotonics, studies have demonstrated that misoprostol can be used effectively and safely for the prevention of PPH. The following information is presented for the guidance of healthcare providers in community-based settings where access to oxytocin is limited.
INDICATION AND USAGE
Misoprostol is indicated for prevention of postpartum hemorrhage after normal vaginal delivery.
Use of misoprostol for PPH prevention is effective in reducing postpartum blood loss following vaginal delivery. When compared with no prophylactic administration of a uterotonic during the third stage of labor, misoprostol lowers postpartum blood loss. Studies have shown misoprostol to be less effective than oxytocin, and as good as oral ergometrine if not better.
CONTRAINDICATIONS
History of allergy to misoprostol or other prostaglandins.
PRECAUTIONS
- Providers should confirm that there is no undiagnosed second twin before giving the misoprostol. If there is any uncertainty, or if the birth attendant is unqualified to make the decision, then misoprostol is best given after delivery of the placenta.
- Small amounts of misoprostol or its active metabolite may appear in breast milk. No adverse effects on nursing infants have been reported (Derman et al 2006).
EFFECTS AND SIDE EFFECTS
Prolonged or serious side effects are rare.
SHIVERING
Shivering is the most common side effect of misoprostol following its postpartum administration. It usually occurs within the first hour of taking misoprostol. This side effect is transient and will subside 2-6 hours after delivery.
FEVER
Fever is less common than shivering and does not necessarily indicate infection. Elevated body temperature is often preceded by shivering, peaks 1-2 hours after taking misoprostol, and gradually subsides within 2-8 hours. An antipyretic can be used for relief of fever, if needed. If fever or shivering persists beyond 24 hours, the woman should seek medical attention to rule out infection.
DIARRHEA, NAUSEA AND VOMITING
Diarrhea may also occur following administration of misoprostol but should resolve within a day. Nausea and vomiting may occur and will resolve 2 to 6 hours after taking misoprostol. An antiemetic can be used if needed.
CRAMPING
Cramping or painful uterine contractions, as commonly occurs after childbirth, usually begin within the first few hours and may begin as early as 30 minutes after misoprostol administration. Nonsteroidal anti-inflammatory drugs or other analgesia can be used for pain relief without affecting the success of the method.
POSTPARTUM BLEEDING
Excessive bleeding, before or after placental delivery, should be referred immediately for additional care. Additional misoprostol should not be given within six hours of the initial dose.
DOSAGE AND ADMINISTRATION
The recommended regimen for prevention of postpartum hemorrhage with misoprostol is a single dose of 600 mcg misoprostol orally administered during the third stage of labor.
Notes:
Currently, there is insufficient evidence to recommend a lower dose of misoprostol for PPH prevention in community-based settings. As more evidence becomes available on lower doses (ranging from 200-400mcg), these Instructions for Use will be reviewed and updated with information on an optimal dose.
Suggested Citation
Instructions for Use: Misoprostol for Prevention of Postpartum Hemorrhage. Expert review organized by Gynuity Health Projects. July 2007.
For more information, refer to www.gynuity.org.
This document will be periodically reviewed and updated with current information and research developments.
© 2007 Gynuity Health Projects.
July 2007
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إرشادات الإستخدام: الميزŮبرŮستŮŮ„ Ů„Ů„Ůقاية من نزي٠ما بعد الŮلادة
خلŮŮŠŘ©
الميزŮبرŮستŮŮ„ ينتمي إلى مجمŮعة البرŮستŮجلاندينات (هـ 1) المسجلة Ů„Ů„Ůقاية من Ůعلاج Ř§Ů„Ů‚Ř±Ř Ř§Ů„Ů…ŘąŘŻŮŠŘ© الناتجة عن الاستخدام المزمن Ů„Ů„ŘŁŘŻŮŮŠŘ© غير السترŮŮŠŘŻŮŠŘ© المضادة للالتهاب. أن الميزŮبرŮستŮŮ„ ŮŠŘŮز انقباضات الرŘŮ…ŘŚ لذل٠يستخدم بشŮŮ„ شائع خارج الŮصŮŘ© الطبية ŮŮŠ منع نزي٠ما بعد الŮلادة. Ů„Ů‚ŘŻ أثبتت الإدارة النشطة للمرŘŮ„Ř© الثالثة Ů„Ů„Ůلادة Ůاعلية ŮŮŠ تقليص نزي٠ما بعد الŮلادة. Ůتتضمن الإدارة النشطة للمرŘŮ„Ř© الثالثة من الŮلادة إعطاء قابض للرŘŮ…ŘŚ Ůتدلي٠الرŘŮ… Ůجذب آمن Ů„Ů„Řبل السري. ŮŮ‚ŘŻ أثبتت الدراسات أن ŮŮŠ Řال عدم ŘŞŮاŮر Řُقن قابضات الرŘŮ… التقليدية ŮŠŮ…Ůن لعقار الميزŮبرŮستŮŮ„ أن ŮŠŮŮن Ůعال Ůآمن ŮŮŠ منع نزي٠ما بعد الŮلادة.
المعلŮمات التالية Ů…Ů‚ŘŻŮ…Ř© Ů„Ů…Ů‚ŘŻŮ…ŮŠ الخدمات الصŘŮŠŘ© ŮŮŠ عيادات المجتمع المدني التي لا ŘŞŮ…Ů„Ů ŘĄŮ…Ůانية الŘصŮŮ„ على عقار الأŮŮسيتŮسين.
ŘŻŮاعي الاستخدام
ŮŠŮص٠الميزŮبرŮستŮŮ„ Ů„Ů„Ůقاية من نزي٠ما بعد الŮلادة الطبيعية.
إن استخدام الميزŮبرŮستŮŮ„ Ů„Ů„Ůقاية من نزي٠ما بعد الŮلادة ŮŠŮ‚Ů„Ů„ ŮŮ…ŮŠŘ© نز٠ما بعد الŮلادة الطبيعية. Ůعند مقارنته بالŘالات التي Ů„Ů… تعطى قابض للرŘŮ… Ůأجراء Ůقائي خلال المرŘŮ„Ř© الثالثة Ů„Ů„Ůلادة، Ůأن الميزŮبرŮستŮŮ„ ŮŠŮ‚Ů„Ů„ من ŮŮ…ŮŠŘ© الدم المŮŮ‚ŮŘŻŘ© بعد الŮلادة. أثبتت الدراسات أن الميزŮبرŮستŮŮ„ ŘŁŮ‚Ů„ Ůاعلية من عقار الأŮŮسيتŮسين Ůمماثل إن Ů„Ů… ŮŠŮن ŘŁŮضل من عقار الإرجŮمترين المأخŮŘ° عن طريق الŮŮ….
Ů…Ůانع الإستخدام
Řساسية من الميزŮبرŮستŮŮ„ أ٠البرŮستاجلاندينات بصŮŘ© عامة.
اŘتياطات
- يجب على Ů…Ů‚ŘŻŮ…ŮŠ هذا العقار التأŮŘŻ من عدم ŮجŮŘŻ جنين آخر داخل الرŘŮ… قبل اعطاء الميزŮبرŮستŮŮ„. Ůإذا Ůان هنا٠ش٠أ٠إذا Ůان الŘاضرŮن لعملية الŮلادة غير مؤهلين لاتخاذ القرار، ŮŘŁŮضل الŘŮ„ŮŮ„ ه٠إعطاء الميزŮبرŮستŮŮ„ بعد خرŮج المشيمة.
- ربما تظهر Ůميات ضئيلة من الميزŮبرŮستŮŮ„ أ٠من منتجات أيضه الŮعالة ŮŮŠ Řليب الرضاعة. Ů„Ůن Ů„Ů… تسجل ŘŁŮŠ آثار على الأطŮال نتيجة Ů„Ř°Ů„Ů (ديرمان Ůزملائه، 2006)
الآثار Ůالآثار الجانبية
من النادر ŘŘŻŮŘ« ŘŁŮŠ آثار جانبية خطيرة ŘŁŮ Ř·ŮŮŠŮ„Ř© المدى.
الرعشة الرعشة هي الأثر الجانبي الأŮثر Ř´ŮŠŮعاً للميزŮبرŮستŮŮ„. Ůهي ŘŞŘŘŻŘ« غالباً خلال الساعة الأŮلى من تناŮŮ„ الميزŮبرŮستŮŮ„. Ůهذا العرض الجانبي مؤقت Ůيستمر ما بين ساعتين إلى ست ساعات بعد الŮلادة.
الŘمى
الŘمى ŘŁŮ‚Ů„ Ř´ŮŠŮعاً من الرعشة، Ůلا تُعبر بالضرŮرة عن ŘŘŻŮŘ« التهاب. ŮŮثيراً ما ŘŞŮŮن الŘمى مصŘŮبة بالرعشة، Ůتصل إلى أقصاها خلال ساعة أ٠ساعتين من تناŮŮ„ الميزŮبرŮستŮŮ„ŘŚ ŮŘŞŮŮن مؤقتة Ů„Ůترة ما بين ساعتين أ٠ثماني ساعات. ŮŮŠŮ…Ůن استخدام خاŮض Ů„Ů„Řرارة من أجل علاج الŘمى. Ůإذا استمرت الرعشة أ٠الŘمى Ů„Ůترة تزيد على 24 ساعة، يجب أن تسعى السيدة Ů„Ů„ŘصŮŮ„ على مساعدة طبية من أجل التأŮŘŻ من عدم ŮجŮŘŻ التهاب.
الإسهال Ůالغثيان Ůالقيء
ŮŠŮ…Ůن أن ŮŠŘŘŻŘ« الإسهال Ůأثر جانبي لتناŮŮ„ الميزŮبرŮستŮŮ„ŘŚ ŮŮ„Ůنه لا يستمر Ů„ŘŁŮثر من ŮŠŮŮ…. Ůربما ŮŠŘŘŻŘ« الغثيان Ůالقيء Ůينتهيان ŮŮŠ خلال Ůترة من ساعتين إلى ست ساعات بعد تناŮŮ„ الميزŮبرŮستŮŮ„. ŮŮŠŮ…Ůن استخدام ŘŁŮŠ من مضادات القيء إذا لزم الأمر.
المغص / التقلصات
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لاŘظة:
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لاقتباس، الرجاء استخدام التنŮيه التالي:
إرشادات إستخدام: الميزŮبرŮستŮŮ„ لمنع نزي٠ما بعد الŮلادة. مراجعة الخبراء التي نظمت من قبل مُنظمة Gynuity Health Projects ŘŚ ŘŞŮ…Ůز 2007.
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ستتم مراجعة ŮŘŞŘ·Ůير هذه المطŮŮŠŘ© بشŮŮ„ ŘŻŮري Ů„ŘŞŘąŮŘł نتائج ŘŁŘŘŻŘ« الأبŘاث Ůالدراسات ŮŮŠ هذا المجال.
© Gynuity Health Projects
ŘŞŮ…Ůز 2007
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Mifepriston ile Tıbbi Düşük ve Ölümcül Enfeksiyon Hakkında Sıklıkla Sorulan Sorular
TEKNÄ°K VERSÄ°YON
GEÇMİŞ
Amerikan Gıda ve İlaç Kurulu (FDA), Mifeprex®’in misoprostol ile birlikte gebeliğin kimyasal madde ile sonlandırılması amacıyla kullanımını onayladığı 2000 yılından beri, ilacın kullanımından sonra ABD’de beş ölümcül enfeksiyon vakası bildirilmiştir. Kanada’da da klinik denemelerde bir vaka bildirilmiştir.1 ABD Hastalık Kontrolü Merkezi (U.S. Centers for Disease Control and Prevention) (CDC), Kaliforniya eyaleti ve yerel sağlık kuruluşları, New England Journal of Medicine2, dergisinin 1 Aralık 2005 sayısında Kaliforniya’da meydana gelen Clostridium sordellii’ ye bağlı dört ölüm vakası hakkında bildiri yayınlamışlardır. Ondan sonra güçlendirilmiş sürveyans çalışmalarında3 mifepriston ile tıbbi düşüğü takiben C. Perfringens enfeksiyonuna bağlı bir diğer ölüm vakası tespit edilmiştir. Tıbbi düşüğü destekleyen araştırmacılar, klinisyenler ve savunucular topluluğu da geniş spekülasyonlara neden olan bu ölümlerin neden ve nasıl meydana geldiğini açıklayamamışlardır. Bu ölümlerle ilgili belirsizlik ve genel tepki, yöntem hakkında daha iyi bilgilendirme yapılmasının ve dikkatlice hazırlanmış bilimsel olguların geniş çapta yayılmasının gerektiğinin önemini ortaya koymaktadır.
Sıklıkla Sorulan Sorular (SSS) ve cevapları listesinin amacı tıbbi düşük hizmeti sunan kişilerin ve kadın sağlığı savunucularının mifepriston-misoprostol ile tıbbi düşük sonrası ağır enfeksiyonların gelişmesi ile ilgili bilimsel açıdan bilgili ve sağduyulu bir biçimde konuşabilmelerini sağlamaktır. SSS, bu vakaların ölüm nedenleri, tıbbi düşük sonrası ölümcül C. Sordellii enfeksiyonu riski ve mifepriston-misoprostol ile tıbbi düşüğün güvenliği ile ilgili genel sorulardan oluşmaktadır.
GENEL SORULAR
Kuzey Amerika’daki ölümcül enfeksiyonların nedeni nedir?
Dördü ABD’de, biri Kanada’da meydana gelen beş ölümcül enfeksiyon vakasının nedeni Clostridium sordellii bakterilerine bağlanmıştır.
C. sordellii, çok nadir durumlarda süratle ölümcül toksinler salgılayan anaerobik bakterilerdir (yani, oksijensiz yaşayabilir). C. Sordellii hakkında bilgi tıpdan çok veterinerlikte bulunmaktadır. Toprakta bulunmaktadır ve koyunlarda ölümlere neden olduğu bilinmektedir. Sağlıklı kişilerin barsaklarında ve vajinalarında her hangi bir belirti vermeden veya toksik etki göstermeden bulunduğu belirlenmiştir. Bu asemptomatik durum “kolonizasyon” olarak bilinmekte ve kadınlar için bir sağlık sorunu olarak tanınmamaktadır. Normal, sağlıklı ve gebe olmayan kadınların yaklaşık %4-18’inin vajinalarında clostridium türleri bulunmaktadır4 ve bu kolonizasyonların %1’inin C. Sordellii olduğu tahmin edilmektedir.5 Hangi faktörlerin etkisiyle veya hangi koşullarda bakterilerin çoğaldığı ve toksin ürettiği bilinmemektedir. Bu toksinler, yaygın sistemik enfeksiyon zelliklerini gösteren bir klinik tabloya neden olmaktadırlar. Bakteriler antibiyotik ile tedavi edilebilmektedir. Ancak, toksinlerin etkisi – ekzotoksik şok – sadece antibiyotiklerle düzeltilememektedir. C. sordellii bildirilen enfeksiyon vakaların çoğunda ve obstetrik – jinekolojik vakaların birinde6 ölümle sonuçlanmıştır.
Sepsis ve ekzotoksik Ĺźok nedir?
Bakterilerin kan dolaşımında bulunduğu bir durumdur. Patojenlere ve kan dolaşımına salıverdikleri toksinlere karşı vücutta sistemik reaksiyonlar gelişmektedir. Ağır sepsisde bakteriler ve toksinlerden etkilenen vücut, enflamasyon ve kanın pıhtılaşmasına neden olan fizyolojik reaksiyonlar başlatmaktadır. Kardiyovasküler sistem yetmezliği gelişmeye başladığında kan basıncı düşer, vital organların oksijenasyonu bozulularak septik şok gelişir. Sepsis vakalarının çoğu ölümle sonuçlanmayabilir; ancak septik şok vakalarının P’si ölümcüldür.
Mifepriston ile tıbbi düşükten sonra enfeksiyona bağlı meydana gelen ölümler söylendiği gibi teknik açıdan “sepsis” (kanda bakterilerin bulunması) nedeniyle değil daha çok ekzotoksik şok nedeniyle olmuştur. Ekzotoksik şok, bakteriler tarafından kan dolaşımına salınan toksinler, ekzotoksinler sonucu gelişmektedir. Bakterilerin sadece ender türleri bu toksinleri salgılamaktadır. Bakteriyel toksinler kan dolaşımına salınmakta ve vücudun bağışıklık sistemini uyararak ekzotoksik şok oluşturmaktadırlar. Mifepriston sonrası ekzotoksik şok gelişen hastalarda yüksek ateş görülmemektedir; nabız hızlanmakta, kan basıncı düşmekte, karın ağrısı ve vücut organlarında yetmezlik gelişmektedir.
Kaliforniya veya Kanada’daki vakalarda olağanüstü bir durum söz konusu mudur?
Evet, C. sordellii enfeksiyonunun ortaya çıkması, sepsisle sonuçlanan ciddi enfeksiyonların kliniğinden farklıdır. Tipik olarak, isteyerek düşük, spontan düşük ve doğum sonrası ciddi enfeksiyonları ve sepsisi olan kadınlarda yüksek ateş ve yumuşak uterus görülmektedir. Ancak, C. sordellii enfeksiyonunun kliniği atipiktir. C. sordellii enfeksiyonu gelişen kadınların hiçbirinde yüksek ateş ve kan örneklerinde bakteriyemi tespit edilmemiştir. Muayenede uterusları yumuşak değildir. Klinik bulgulara oransız biçimde kendilerini hasta hissetmektedirler. Diğer bulgular:
• Taşikardi (hızlı nabız)
• Lökositoz (kanda akyuvar hücrelerinin sayısı artmış)
• Hemokonsantrasyon (kanda alyuvar hücreleri artmış ve hematokrit değeri çok yüksek)
C. sordellii tarafından salgılanan toksinler kan damarlarını etkileyerek geçirgenliğini arttırır. Kan damarlarından çevre dokulara sıvının geçmesine neden olur. Bu yolla, kanın sıvı kısmı kan damarlarından kaçar ve gerçekte kan daha yoğun hale gelir. Bu da hemokonsantrasyon, taşikardi ve düşük kan basıncı gibi klinik bulguları ortaya çıkarır. Ayrıca, toksinler dokularda nekroz, ödem, şiddetli ağrı ve uterus içinde hemorajik sıvı birikmesine neden olur, bu da şiddetli ağrıya neden olur. Bununla birlikte tüm bu değişiklikler ekzotoksik şok olarak bilinen bir dizi olayları başlatarak kaçınılmaz olarak kadınların ölümüne neden olur (yukarı bakınız.).
Mifepriston ile düşük sonrası ciddi enfeksiyon yaygın mıdır?
Hayır, tıbbi düşük sonrası ciddi enfeksiyon nadiren görülür. Mifepriston FDA tarafından 2000 yılında onaylandıktan sonra Amerika’da yaklaşık 600 000 kadın tıbbi düşük yapmak için mifepriston kullanmıştır. İlk 18 ayda mifepriston kullanan kadınlarda bildirilen tüm enfeksiyonların oranı çok düşüktür (%0.013)7. Bildirilen enfeksiyonların çoğunluğu ciddi değil ve ağızdan antibiyotikler verilerek ayaktan tedavi edilmiştir.
Mifepriston ile tıbbi düşük sonrası C. sordellii enfeksiyonuna yakalanan kadınlardaki risk faktörleri ortak mıdır?
Bugüne kadar, diğer tıbbi düşük yapan kadınlara kıyasla C. sordellii enfeksiyonu olan kadınları enfeksiyon gelişmesine yatkın kılan hiçbir ortak risk faktörü araştırmacılar tarafından teşhis edilememiştir. Ancak, henüz bilinmeyen bir maruziyet durumu veya koşullar kadınların C. sordellii enfeksiyonuna yakalnma riskini arttırmış olabilir. Amerika’da, ülke çapındaki tüm tıbbi düşük vakalarının sadece yaklaşık ’si Kaliforniya’da gerçekleşmesine rağmen bir vaka hariç tüm diğer vakaların hepsinin Kaliforniya’da meydana gelmesi bazı gözlemcileri şaşırtmaktadır. Bu konuyla ilgili araştırmalar devam etmektedir.
Tıbbi düşük yapan kadınlar dışında diğer kadınlarda da bu tür enfeksiyon riski var mıdır?
C. sordellii mifepriston ve misoprostol kullananlarda sınırlı kalmamaktadır, doğum sonrası (vajinal, sezaryen doğumlar), düşük yaptıktan sonra (spontan düşük) ve pelvik/abdominal cerrahi uygulandıktan sonra da enfeksiyon gelişebilmektedir. Son zamanlarda meydana gelen bir vaka dışında (spontan düşük sonrası) diğer tüm vakaların ölümcül olduğu belirlenmiştir. C. sordellii enfeksiyonu sadece doğurganlık çağındaki kadınlarda görülmemektedir. Diğer bilinen C. sordellii vakaları değişik yaş gruplarındaki erkekler ve obstetrik durumu olmayan kadınlarda, umblikal enfeksiyon, derin cilt enfeksiyonu, tendon transplantsyonu cerrahisinde, ortopedik cerrahide, motorlu taşıt kazalarından sonra da meydana gelebilmektedir. Bilinen bu vakaların hepsi olmasa da bazıları ölümle sonuçlanmıştır.
Tıbbi düşük sonrası gelişen bu tür olayları nasıl önleyebileceğimizi biliyor muyuz?
Tıbbi düşük sonrası C. sordellii enfeksiyonu gelişmesine neden olduğu bilinen ve şüphelenilen faktörlerle ilgili devam eden araştırmalar şimdiye kadar bir sonuca ulaşamamıştır. Bu durumun, bilimsel bir açıklaması olmadan gelecekte olası vakaların nasıl önlenebileceği konusunda kesin önerilerde bulunmamak gerekir. Örneğin, C. sordellii’nin toksin salgılamasını ve ekzotoksik şok geliştirmesini antibiyotiklerin önleyip önleyemeyeceği bilinmemektedir. Çünkü, bu tür enfeksiyonlar nadiren görülmektedir ve iyi bilinmemektedir. Bu nedenle FDA, mifepriston uygulamasından sonra proflaktik antibiyotiklerin kullanılmamasını önermektedir. Koruyucu antibiyotik kullanılması şiddetli veya ölümcül allerjik reaksiyonlar gibi ciddi yan etkilerin ve ilaca dirençli bakteri suşlarının oluşmasına neden olabilmektedir.8
Ölen kadınların klinik koşulları ve semptomları ile C. sordellii hakkındaki mevcut bilgiler Mifeprex kutularındaki prospektüslerde yer almaktadır. Misoprostol uygulandıktan sonra, 24 saatten uzun süren karın ağrısı, halsizlik, bulantı, kusma, ateşli veya ateşsiz ishal gibi durumlarda veya kendilerini iyi hissetmediklerinde, hastaların derhal sağlık hizmeti sunan kişiye başvurmaları için tedavi rehberinde ve hasta sözleşmesinde (The Medication Guide and Patient Agreement) bilgi verilmektedir.
C. sordellii enfekisyonunun diğer enfeksiyonlardan farklı belirtilerle ortaya çıkması sonucu teşhis ve tedavide gecikmelere neden olabileceği konusunda sağlık personelinin uyanık olması Mifeprex etiketinde vurgulanmaktadır. C. sordellii enfeksiyonu olan hastalarda yüksek ateş, bakteriyemi veya tıbbi düşük sonrası pelvik muayenede belirgin bulgular tespit edildiğinde, özellikle hasta misoprostol kullandıktan sonra 24 saatten uzun süren karın ağrısı, huzursuzluk veya genel kırıklık tarif ettiğinde (halsizlik, bulantı, kusma veya ishal gibi), sağlık hizmeti sunanlar ciddi enfeksiyon ve sepsis olasılığını dikkate almalıdırlar.
C. sordellii enfekisyonunun, ekzotoksik şok ve sepsisin nasıl tedavi edileceğini biliyor muyuz?
Hangi koşulda ortaya çıkarlarsa çıksınlar ekzotoksik şok ve sepsis ölüm riski taşıyan ciddi durumlardır. Ayaktan tedavi merkezinde değerlendirilen hastalarda septik şok veya ekzotoksik şok şüphesi varsa derhal bir hastaneye sevk edilmelidir. Sağlık personelinin tam kan sayımı yapması, serviks, endometrium ve kandan aerobik ve anaerobik kültürler alması önerilmektedir. İlaveten, gram boyama için endometriyal biopsi yapılmasına önem verilmelidir. C. sordellii ile uyumlu diğer klinik bulgularla birlikte Gram pozitif suşların saptandığı zaman derhal C. sordellii’e karşı korunma sağlayacak IV antibiyotik tedavisi (örn.; penisilinler, klindamisin, gentamisin) başlanmalıdır. Ancak, toksin yayılmaya başladıktan sonra antibiyotik tedavisinin etkili olup olamayacağına dair kanıt bulunmamaktadır. Tıbbi düşük sonrası gelişen C. sordellii enfeksiyonunun tedavisinde histerektominin etkili olup olmadığı bilinmemektedir.
C. sordellii enfeksiyonunun klinik belirtileri, semptomları ve tedavisi ile ilgili daha ayrıntılı bilgi için bakınız: Fjerstad M. Infection and medication abortion. Mife Matters 2005; 12:1-4 at www.gynuity.org.
Tıbbi düşük sonrası bilinen C. sordellii vakaları aslında gerçek sayıları yansıtmıyor olabilir mi?
Hayır, bildirilen enfeksiyon vakası sayıları tıbbi düşük sonrası gerçekte oluĹźan C. sordellii enfeksiyonu sayılarına çok yakındır ve buzdağının sadece görĂĽlen tepesi deÄźildir. Mifeprex’in dağıtımının kısıtlı olması ve yan etkilerinin bildirimi zorunlu olduÄźundan dolayı, Mifeprex kullanımı sonrası geliĹźen yan etkilerle ilgili, – MedWatch, FDA GĂĽvenlik Enformasyon ve Yan Etki Ä°hbarı Programı – tarafından bildirilen raporun diÄźer ilaçlarla ilgili raporlardan daha doÄźru ve eksiksiz olduÄźu düşünĂĽlmektedir. Yani, Mifeprex’i reçete eden tĂĽm hekimler, ciddi yan etkilerini Danco firmasına bildireceklerine dair bir sözleĹźme imzalamaktadırlar. Buna karşılık, gebelikle ilgili veya cerrahi düşüğe baÄźlı yan etkilerin bildirilmesi ile ilgili benzer bir baĹźka merkezi bildirim sistemi bulunmamaktadır. Ayrıca, ölĂĽmlerin bildirilmesi olasılığı yan etkilerin bildirilmesi olasılığından daha fazladır. Tıbbi düşük sonrası C. sordellii enfeksiyonlarına baÄźlı ölĂĽm oranı bu gĂĽne dek 0 olduÄźundan bunlar rapor edilmekte, araĹźtırılmakta ve hakkında yazılmaktadır.
Mifepriston ve misoprostol ile tıbbi düşük yapılması güvenli midir?
Evet, mifepriston ve misoprostol ile tıbbi düşük yapılması gĂĽvenlidir. Ä°statistik analizlere göre erken tıbbi düşük ve erken cerrahi düşük uygulanması benzer biçimde gĂĽvenlidir. Tıbbi düşük ve spontan düşük yapma benzer riskleri taşımaktadır. Hatta, çoÄźu zaman gebeliÄźin sonuna kadar devam etmesinden daha gĂĽvenlidir. C. sordellii enfeksiyonuna baÄźlı ölĂĽmcĂĽl durumlar meydana gelmiĹź olsa da, bu tĂĽr enfeksiyonlar nadiren görĂĽlmektedir. Mifeproston ile tıbbi düşük uygulanan 120 000 vakadan yaklaşık birinde meydana gelmiĹźtir. Bu durum, penisiline baÄźlı anaflaktik Ĺźok geliĹźme insidansından daha düşüktĂĽr (50 000 kullanımda %0.002 veya 1).9 Avrupa’da, tıbbi düşük yaygın biçimde uygulanıyor olsa da (1.5-2.0 milyon kadında) herhangi bir patojene baÄźlı enfeksiyöz ölĂĽmlerle ilgili rapor bulunmamaktadır. FDA, bu ölĂĽmcĂĽl vakalarda kullanılan hapların – mifepriston ve misoprostol – bakterilerle kontamine olmadığını belirlemiĹźtir. FDA, kaliforniyalı kadınların ölĂĽmleri ile mifepriston ve misoprostol arasında bir iliĹźkinin saptanmadığını ve herhangi bir sonuç çıkarmak için çok erken olduÄźunu raporlarında yinelemektedir. Haplar deÄźiĹźik kliniklerde, baĹźka hizmet sunucular tarafından uygulanmış ve deÄźiĹźik ilaç gruplarından gelmiĹźlerdir.10 Nadiren görĂĽlen ve ciddi olan bu olaylar hakkında CDC ve FDA gibi çeĹźitli kuruluĹźlar, araĹźtırmalar yĂĽrĂĽtmektedirler.11 CDC, FDA ve Ulusal Allerji ve Enfeksiyon Hastalıkları EnstitĂĽsĂĽ,11 Mayıs 2006’da, mevcut kanıtları deÄźerlendirmek, bilimsel toplumun faydalanması amacıyla araĹźtırma gereksinimlerini ve öncelikleri belirlemek ve vakaların tespit edilmesini geliĹźtirmek amacıyla bir çalıştay gerçekleĹźtirmiĹźlerdir.
NEDENLER VE MEKANÄ°ZMALAR
Mifepriston uygulandıktan sonra gelişen immünolojik değişiklerle tıbbi düşük sonrası C. sordellii enfeksiyon riski açıklanabilir mi?
Mifepriston kullanıldıktan sonra immünolojik değişikliklerin insanı sadece bir tür bakteriyel enfeksiyona karşı duyarlı hale getirmesi olasılığı çok düşüktür ve mifepristonun immün sistem yetmezliği geliştirdiğine dair bilimsel kanıt bulunmamaktadır. İmmün sistem ile ilgili bir durum olsa sadece C. sordellii enfeksiyonlarının değil diğer enfeksiyon türlerinin de artması beklenir. Avrupa’da tıbbi düşük için uygulanan mifepriston-misoprostol rejiminde mifepriston dozu, Amerika’da uygulanandan üç kat fazladır (600 mg’a nazaran 200 mg). Avrupa’da enfeksiyona bağlı ölüm veya ekzotoksik şok ile ilgili herhangi bir bilinen rapor bulunmamaktadır. Mifepriston, enfeksiyona yakalanma riskini arttıran immünolojik değişiklere neden olsa, Amerika’ya kıyasla Avrupa’da daha çok kadının enfeksiyon nedeniyle ölmesi beklenirdi, ancak Avrupa’da hiçbir kadın bu nedenle ölmemiştir. Ayrıca, Cushing Sendromu, meningioma gibi kronik durumlarda mifepriston yüksek dozda kullanılmaktadır ancak bu populasyonda da enfeksiyona bağlı ölüm ve/veya ekzotoksik şok rapor edilmemiştir.
Misoprostolün vajinal yolla uygulanması ile tıbbi düşük sonrası C. sordellii enfeksiyon riski açıklanabilir mi?
Enfekte olan kadnlar tarandan kullanılan misoprostol hapla kontamine olmuş olabilir mi?
FDA, mifepriston ve misoprostolün her ikisine de test yapmıştır ve herhangi bir kontaminasyon bulunamamıştır.
Vajinal uygulama kontaminasyona neden olabilir mi?
Misoprostolün vajinal yolla uygulanmasının enfeksiyon gelişmesini kolaylaştırıp kolaylaştırmadığı CDC tarafından incelenmiş olup, misoprostolün vajinal yolla uygulanmasının ölümleri etkileyen bir faktör olduğuna dair herhangi bir kanıt bulunamamıştır. Vajinal uygulama, kadınlarda enfeksiyon rsikini arttırabiliyor olsa, kadınların sıkça vajinal yolla uygulanan ürünler kullandıkları ve cinsel ilişki yaşadıkları dikkate alındığında, bu tür nadiren gelişen ciddi enfeksiyonların daha çok görülmesi beklenirdi.
Misoprostol, vajen ortamında değişikliklere neden olabilir mi?
Misoprostol uygulanması vajenin pH düzeyini değiştirmekte ve servikal değişikliklere de neden olmaktadır. Bu değişikliklerin her biri enfeksiyon riskini arttırabilmektedir. Ancak, bu tür değişikliklerin tıbbi düşük uygulanan kadınların C. sordellii enfeksiyonuna daha yatkın hale gelmesine neden olduğuna dair bir mekanizma veya bilimsel kanıt bulunmamaktadır. Doğumun başlatılması ve cerrahi müdahaleden önce serviksin yumuşaması için vajinal misoprostol yaygın biçimde kullanılmaktadır. Doğum sonrası vajinal flora ile düşük öncesi ve sonrası vajinal flora arasında farklılıklar olmasına rağmen, bu tür uygulamalardan sonra benzer enfeksiyonlar bildirilmemiştir.
Tıbbi düşük uygulanması C. sordellii enfeksiyon riskini açıklayabilir mi?
Herhangi bir servikal kanama veya dilatasyon vajenden yukarı uterusa doğru enfensiyonun ilerlemesi riskini rattırabilir, ancak C. sordellii’nin bulşaması için özel bir neden bulunmamaktadır.
FDA tarafından onaylanmamış bir rejimin (vajinal misoprostol) kullanılması C. sordellii enfeksiyonu riskini açıklayabilir mi?
FDA-onaylı rejimlerde, misoprostolün ağızdan kullanılması belirtilmiş olmasına rağmen mifepriston ile birlikte misoprostolün vajinal kullanılması Amerika’da prensiptir. Ağızdan uygulama hemen hemen hiç olmadığından dolayı çoğu ölümlerin vajinal misoprostol kullananlar arasında geliştiği tahmin edilmektedir. Dolayısıyla, ağızdan kullanıma karşı vajinal kullanım hakkında herhangi bir sonuç çıkarmak neredeyse mümkün değildir. Gerçekten de, Avrupa’da veya başka yerde yüzlerce, binlerce kadın misoprostolü vajinal yolla kullanmıştır ve bu kadınlarda benzer enfeksiyonlar görülmemiştir.
Mifepriston ile tıbbi düşük sonrası C. sordellii enfeksiyon riskini açıklayabilecek başka risk faktörleri var mıdır?
Araştırmacılar, mifepriston ile tıbbi düşük yapan bazı kadınların diğer kadınlara göre C. sordellii enfeksiyonuna yakalanma riskinin neden daha fazla olduğunu açıklayabilecek diğer risk faktörlerini bugüne kadar belirleyememişlerdir. Konu ile ilgili incelemeler devam etmektedir.
Bu ülkede, bu ölümlerin neden meydana geldiği sorulduğunda ne diyebilirim?
Bilimsel ve istatistiksel anlamı olan herhangi bir açıklama daha henüz bulunamadı demek en iyi yanıt olur. Asılsız söylentileri yaymaktansa veya sağlıksız kararlar almaktansa, şimdilik bu belirsizliği Kabul etmek daha iyi olur.
Ayrıntılı Bilgi İçin
• Danco Laboratories, Mifeprex® website. www.earlyoptionpill.com
• FDA, Center for Drug Evaluation and Research, Mifepristone Information. www.fda.gov/cder/drug/infopage/mifepristone/default.htm
• Richard Hausknecht, “Mifepristone and Misoprostol for Early Medical Abortion: 18 Months Experience in the United States,” Contraception 67:463-65 (2003).
• National Abortion Federation, Facts About Mifepristone. www.prochoice.org/about_abortion/facts/facts_mifepristone.html
Bu materyal Richard ve Rhoda Goldman Fonu’nun desteğiyle hazrlanmıştır
© Revised November 28, 2006 Gynuity Health Projects
1 Mifepristone is not available on the market in Canada. The Canadian woman who died had been enrolled in a clinical trial.
2 Fischer M, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion.
N Engl J Med 2005;353:2352-60.
3 Surveillance methods include monitoring of adverse event reports by the FDA, state health departments, academic partners, and Division of Reproductive Health Pregnancy Mortality Surveillance System.
4 Hammill HA. Normal vaginal flora in relation to vaginitis. Obstet Gynecol Clin N Am 1989;16:329-336.
5 Hatheway CL. Toxigenic clostridia. Clin Microbial Rev 1990;1:66.
6 The one known woman to survive C. sordellii became ill following a miscarriage (spontaneous abortion).
7 Hausknecht R. Mifepristone and misoprostol for early medical abortion: 18 months experience in the United States. Contraception. 2003;67:463-465.
8 “FDA Public Health Advisory,” FDA. July 22, 2005, www.fda.gov/cder/drug/advisory/mifeprex.htm.
9 Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: An investigation into its epidemiology. Arch Intern Med. 2001;161:15-21.
10 Fischer, et al, 2005.
11 “Questions and Answers on Mifeprex (mifepristone),” FDA. July 19, 2005, www.fda.gov/cder/drug/infopage/mifepristone/mifepristone-qa20050719.htm.
KULLANMA YĂ–NERGESÄ°: SON ADET TARÄ°HÄ°NDEN (SAT) Ä°TÄ°BAREN 9 HAFTAYA KADAR GEBELÄ°KLERÄ°N MÄ°SOPROSTOL Ä°LE SONLANDIRILMASI
GENEL BÄ°LGÄ°
Misoprostol, piyasada Cytotec® olarak bulunan bir prostaglandin analoğudur. Cytotec®, steroid olmayan anti- enflamatuvar ilaçların (NSAİDlar) kronik kullanımında gastrik ülseri önlemek için kullanılmaktadır. Cytotec® uterus kontraksiyonlarını indüklemesinden dolayı da genellikle gebeliğin sonlandırılmasında etiket dışı kullanılmaktadır. Misoprostolün gebeliğin sonlandırılması amacıyla kullanılabileceği araştırmalarla gösterilmiştir. Bu bilgi eğitimli tıbbi profesyonellere rehberlik etmek için sunulmaktadır.
ENDÄ°KASYON VE KULLANIM
Etkili rejimlerin uygulanma biçimi, baĹźarısı ve komplikasyon oranları gebeliÄźin sĂĽresi ile iliĹźkilidir. AĹźağıdaki bilgiler SAT’den itibaren 9 haftalık (63 gĂĽnlĂĽk) veya daha küçük gebelikleri ilgilendirmektedir. SAT’den itibaren 9 haftalık gebeliklerin sonlandırılması amacıyla misoprostol kullanımında baĹźarı oranı …-90’dır. GebeliÄźin sĂĽresinin bilinmesi önemlidir. Kadının yöntemi kullanmasının uygun olup olmadığını belirlemek amacıyla hesaplama son adet tarihinden itibaren yapılmaktadır.
KONTRENDÄ°KASYONLAR
– Dış gebelik şüphesi veya tanı konmamış adneksiyel kitle
– RİA’ ın varlığı (misoprostol uygulanmadan once çıkarılmalıdır)
– Misoprostol veya diğer prostoglandinlere karşı allerji öyküsü
Ă–NLEMLER
1. MİSOPROSTOL UYGULANDIKTAN SONRA DÜŞÜĞÜN OLMADIĞI, GEBELİĞİN DEVAM ETTİĞİ CANLI DOĞUMLARDA GÖRÜLEBİLEN TERATOJENİK ETKİLER
Hayvan deneylerinde, fareler üzerinde yapılan tek bir araştırmada misoprostolün teratojenik etkisi gösterilmiştir.
Intrauterin dönemde misoprostole maruz kalan 69 canlı doğum vakasında anomaliler görüldüğü bildirilmiştir. Bu vaka raporlarının değerlendirilmesi sonucunda bildirilen anomalilerin çoğunun santral sinir sistemi, üst ve alt extremitelerde olmak üzere sınıflandırılabileceği ortaya çıkmıştır. Tüm vakalarda en sık teşhis edilen anomaliler, pes ekinovarus (yumru ayak), VII, VI, V ve XII. Kraniyal sinirlerde anomali ve parmakların olmamasıdır (ageneziz).
İnsanlar üzerinde yapılan üç vaka-kontrol araştırmasında, misoprostole maruz kalan bebeklerde anomali görülme sıklığının yüksek olduğu gösterilmiştir. Ancak, gebelikte misoprostola maruz kalanlarda teratojenite riski oldukça düşüktür, misoprostole maruz kalan 1000 fötusun 10’unda görülebilmektedir. Toplumda, misoprostole maruz kalma riski nispeten sık olmasına rağmen, nüfusa dayalı kayıtlarda saptanan anomalilerin insidansı yüksek değildir.
2. EMZÄ°REN ANNELER
Misoprostol vücutta hızla metabolize edilmektedir. Anne serumunda bulunan maddelerin hemen hemen hepsinin anne sütünde de bulunmasına rağmen, aktif metabolitlerin (misoprostol asidi veya misoprostol) anne sütüne geçip geçmediği bilinmemektedir. Misoprostol kullandıktan sonraki 24 saat anne sütü verilmeyerek anne sütüyle beslenen bebeklerde karın kasılmaları ve ishal gelişmesi önelenebilir.
3. SAT’DEN İTİBAREN 9 HAFTADAN BÜYÜK GEBELİKLER
SAT’den ititbaren 9 haftadan büyük gebeliklerin sonlandırılması için misoprostol uygulanacağı zaman uyarmak gerekir. Gebeliğin ilk üç ayının (ilk trimester) sonlarına doğru düşüğün indüklenmesi amacıyla misoprostol rejiminin tavsiye edilebilmesi için yeterli kanıt bulunmamaktadır. Burada tarif edilen rejim ilk trimesterden ileri gebelikler için uygun değildir; burada belirtilen dozlar ileri gebeliklerde kullanılmak için çok yüksektir (Notlara bakınız).
ETKÄ°LER VE YAN ETKÄ°LER
Uzun süren veya ciddi etkiler ve yan etkiler ender görülür.
1. KANAMA
Kanama, genellikle misoprostol kullandıktan bir saat sonra, ilk gün içinde başlar. Kanama, tipik olarak 7 – 10 gün sürer, bir sonraki adet kanaması başlayana kadar lekelenme tarzında devam edebilir. Misoprostol kullanıldıktan sonra adet kanamalarının yeniden başlaması genellikle 4-6 hafta sonra gerçekleşir. Kanamanın olmasının düşüğün başarıyla sonlandığı anlamına gelmeyebileceğinin kavranması önemlidir.
Aşağıda belirtilen durumlardan herhangi biri meydana geldiğinde hizmet sunan ile bağlantı kurulması gerektiği kadınlara anlatılmalıdır: (1) eğer iki saat süresince her saatte 2 büyük hijyenik petten fazla pet ıslanıyorsa, (2) eğer kanama durmuş ise ve misoprostol kullandıktan iki hafta veya daha uzun bir süre sonra şiddetli ve yoğun bir biçimde tekrar kanama başlarsa, (3) eğer kanama sürekli, haftalarca devam ederse veya baş dönmeleri başlarsa veya başta boşluk hissedilirse, (4) misoprostol kullandıktan sonraki 7 günde hiç kanama olmazsa veya çok az olursa.
2. KRAMPLAR
Kramplar genellikle ilk gün içinde ve hatta misoprostol kullanıldıktan sonra en erken 30 dakikada başlayabilmektedir. Ağrı, normal adet sancısına oranla daha şiddetli olabilir. Ağrıyı hafifletmek amacıyla steroid olmayan anti-enflamatuvar ilaçlar (NSAİDlar) veya diğer ağrı kesiciler (analjezikler) kullanılabilir. Yöntemin başarısını etkilemezler.
3. TÄ°TREME VE/VEYA YĂśKSEK ATEĹž
Titreme, misoprostol kullanımında genellikle ortaya çıkan geçici bir yan etkidir. Yüksek ateş daha az görülür ve enfeksiyon belirtisi olmayabilir. Misoprostol kullandıktan sonra 24 saatten uzun süren üşüme, yüksek ateş olursa kadında enfeksiyon gelişmiş olabilir derhal kliniğe başvurmalıdır. Gerektiğinde, ateşi düşürmek için ateş dürücü ilaç (antipiretik) kullanılabilir.
4. BULANTI VE KUSMA
Misoprostol kullandıktan sonra bulantı, kusma olabilir ve 2-6 saatte geçer.
5. Ä°SHAL
Misoprostol kullandıktan sonra ishal gelişebilir ancak, bir gün içinde düzelmelidir.
DOZ VE KULLANMA BİÇİMİ
SAT’den ititbaren 9 haftalık gebeliklerin sonlandırılması amacıyla 800 mcg vajinal misoprostol uygulanır, 24 saat sonra tekrarlanması önerilmektedir .
Mevcut kanıtlar, tabletleri bir kaç damla su ile ıslattıktan sonra vajene uygulanmasının yöntemin başarısını arttırabileceğini göstermektedir.
Notlar:
– Misoprostol, yanak ve diş eti arasına (bukkal) veya dilaltına (sublingual) uygulandığında da etkili olabilmektedir.
– Birinci trimesterin geç döneminde misoprostol kullanımı ile ilgili yeterli kanıt bulunmamaktadır. Gebelik süresi ilerledikçe uterus misoprostole karşı daha duyarlı hale geldiğinden dolayı boşalmasının sağlanması için gereken doz miktarı azalmaktadır. Ancak, gebelik süresi ilerledikçe gebeliğin sonlanması için gereken zaman uzamaktadır ve daha fazla kanama olabilmektedir.
Önerilen Alıntılar:
Görüş birliği Beyanı: Kullanım Talimatı– SAT’den Itibaren 9 Haftaya Kadar Gebeliklerin Misoprotol Uygulanarak Sonlandırılması. Misoprostol konusunda uzmanlar toplantısı ,Reproductive Health Technologies Project and Gynuity Health Projects tarafından desteklenmiştir. 2003. Washington DC.
Bu dokümanı destekleyici literatür kaynakları listesi veya ayrıntılı bilgi için, bakınız www.gynuity.org veya www.rhtp.org.
BU DOKÜMAN, EN SON BILGILER VE ARAŞTIRMA SONUÇLARI KULLANILARAK PERIYODIK OLARAK GÖZDEN GEÇIRILMEKTE VE GÜNCELLEŞTIRILMEKTEDIR.
© 2003 Gynuity Health Projects and Reproductive Health Technologies Project
8/31/2004
KULLANMA YÖNERGESİ: MİSOPROSTOL İLE İNKOMPLET DÜŞÜK VE SPONTAN DÜŞÜK TEDAVİSİ
GENEL BÄ°LGÄ°
Misoprostol bir prostaglandin E1 analoğudur. Genelde, steroid olmayan anti enflamatuvar ilaçların (NSAİDlar) kronik kullanımında gastrik ülseri önlemek ve tedavi etmek için ruhsatlandırılmıştır. Ancak, uterin kontraksiyonlarını indüklemesinden dolayı gebeliğin erken sonlandığı, tamamlanmamış düşük (inkomplet abortus), missed abortus durumlarında da etiket dışı kullanılmaktadır. Misoprostolün bu tür endikayonlarda güvenli ve etkili biçimde kullanılabileceği araştırmalarla gösterilmiştir. Bu bilgi eğitimli sağlık hizmeti sunanlara rehberlik etmek için hazırlanmıştır.
ENDÄ°KASYON VE KULLANIM
Misoprostol, SAT’den itibaren 12 haftalık veya daha küçük gebeliklerde oluşan inkomplet düşük ve spontan düşüklerin tedavisinde kullanılabilmektedir.
İnkomplet düşükte önerilen dozlarda kullanılan misoprostol ile başarı oranı f-100’dür. Missed abortusda önerilen dozlarda içerisinde kullanılan misoprostol ile başarı oranı `-93’dür.
KONTRENDIKASYONLAR
- Misoprostol veya diğer prostoglandinlere karşı allerji öyküsü
- Dış gebelik (ektopik gebelik) şüphesi
- Pelvik enfeksiyon ve/veya sepsis belirtileri
- Hemodinaminin bozulduğu durumlar veya şok bulguları
Ă–NLEMLER
- Misoprostol kullanımı için uygun olan kadınlarda RİA varsa, RİA ilaç tedavisi uygulanmadan önce çıkarılmalıdır.
- Kanama bozuklukları olduğu bilinen veya halen antikoagülan ilaçlar kullanan kadınlara misoprostol tedavisi kullanırken gerekli önlemlerin alınması önerilmektedir.
- SAT’den itibaren 12 haftalık veya daha küçük gebeliklerde uterus boyutunun 12 haftadan büyük olduğu durumlarda misoprostol dikkatli bir biçimde kullanılabilmektedir (örn.; miyomlara bağlı olarak uterus büyümüş olabilir).
- Az miktarlarda misoprostol veya aktif metaboliti anne sütünde bulunabilir. Bununla ilgili sonuçlar bilinmemektedir. Anne sütüyle beslenen bebeklerde yan etkiler bildirilmemiştir.
ETKÄ°LER VE YAN ETKÄ°LER
Uzun süren veya ciddi etkiler ve yan etkiler ender görülür.
KANAMA
Genellikle misoprostol kullandıktan sonra kanama, tipik olarak iki hafta sürer, bir sonraki adet kanaması başlayana kadar lekelenme tarzında devam edebilir.
Aşağıda belirtilen durumlardan herhangi biri meydana geldiğinde hizmet sunan ile bağlantı kurulması gerektiği, kadınlara anlatılmalıdır: (1) eğer iki saat süresince her saatte 2 büyük hijyenik petten fazla pet ıslanıyorsa (2) eğer kanama bir kaç gün hafifledikten veya durduktan sonra aniden tekrar yoğun biçimde başlarsa (3) eğer kanama sürekli olarak haftalarca devam ederse veya baş dönmeleri başlarsa veya kafa içinde boşluk hissedilirse,
KRAMPLAR
Kramplar genellikle ilk gün içinde başlamaktadır ve misoprostol kullanıldıktan sonra en erken 30 dakikada başlayabilmektedir. Ağrı, normal adet sancısına kıyasla daha şiddetli olabilir. Ağrıyı hafifletmek amacıyla nonsteroidal anti-enflamatuvar ilaçlar (NSAİDlar) veya diğer ağrı kesiciler (analjezikler) kullanılabilir. Bu ilaçlar yöntemin başarısını etkilemezler.
YĂśKSEK ATEĹž VE/VEYA TÄ°TREME
Titreme, misoprostol kullanımında genellikle ortaya çıkan geçici bir yan etkidir. Yüksek ateş daha az görülür ve enfeksiyon belirtisi olmayabilir. Gerektiğinde, ateşi düşürmek için ateş düşürücü ilaç (antipiretik) kullanılabilir. Misoprostol kullandıktan sonra 24 saatten uzun süren titreme, yüksek ateş olursa kadında enfeksiyon gelişmiş olabilir, derhal kliniğe başvurmalıdır.
BULANTI VE KUSMA
Misoprostol kullandıktan sonra bulantı, kusma olabilir ve 2-6 saatte geçebilir. Gerektiğinde kusmayı engelleyici ilaç (antiemetik) kullanılabilir.
Ä°SHAL
Misoprostol kullandıktan sonra ishal gelişebilir ancak, bir gün içinde düzelmelidir.
DOZ VE KULLANIM BİÇİMİ
İnkomplet düşük: İnkomplet düşük tedavisinde önerilen rejim, tek doz 600 mcg misoprostol†un ağızdan veya tek doz sublingual 400 mcg misoprostol (dilatina) verilmesidir.
Missed abortus: Missed abortus tanısı kesin olduğunda ve/veya serviksin tamamen kapalı olduğu durumlarda tek doz 800 mcg vajinal misoprostol önerilmektedir.
Düşüğün tamalanmasını sağlamak amacıyla uzun süre izlendiğinde (7-14 gün) yüksek düzeyde başarıya ulaşılabilmiştir. Eğer tıbbi olarak gerekli olmazsa tedaviden sonra, 7 günden önce, cerrahi müdahale yapılması önerilmemektedir.
Notlar:
- Tekrarlanan dozun etkililiği arttırabileceğine dair kanıt bulunmaktadır.
- Misoprostol, yanakla diş eti arasına (bukkal) veya dilaltına (sublingual) uygulandığında da etkili olabilmektedir.
KAYNAK:
Ortak Görüş Bildirisi: Kullanma Yönergesi – Misoprostol Ile Inkomplet Düşük Ve Spontan Düşük Tedavisi. Misoprostol konusunda uzmanlar toplantısı, Reproductive Health Technologies Project and Gynuity Health Projects tarafından desteklenmiştir. June 9, 2004. New York, NY.
Bu dokümanı destekleyici literatür kaynakları listesi veya ayrıntılı bilgi için, bakınız www.gynuity.org or www.rhtp.org.
Bu doküman, en son bilgiler ve arastirma sonuçlari kullanilarak periyodik olarak gözden geçirilmekte ve güncellestirilmektedir.
© 2008 Gynuity Health Projects and Reproductive Health Technologies Project
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Quick Questions and Answers about Hormonal Contraception and HIV
I’ve heard that hormonal contraception – things like the Pill and Depo – can cause HIV infection. Is this true?
No, hormonal contraception (HC) does not cause HIV infection – the HIV virus does. If a woman is at risk of becoming infected with HIV, it is possible (though not yet proven) that using HC may increase her risk somewhat. But a woman at risk of contracting HIV who is using HC will still be at risk of contracting the virus even if she stops using HC. There are many factors that go into determining a woman’s risk of contracting HIV. Even if hormonal contraceptive use turns out to be one of these factors, there will still be many others. And many of these other factors – number of sexual partners; use or non-use of condoms; use of injecting drugs – have a stronger impact on risk than hormonal contraception is likely to have, even in a worst-case scenario. So we should not focus on hormonal contraception and forget about everything else. Looking at the “big picture” is the best way to reduce HIV risk for everyone.
Even if hormonal contraception doesn’t cause HIV infection, can it increase a woman’s chances of contracting HIV?
The answer isn’t clear, at present. Some studies have shown no association between hormonal contraceptive use and HIV transmission, while other studies (which were conducted among sex workers rather than among women in general)suggest that using HC results in a small increase in risk. The question is very difficult to study, however, in part because it involves sex and sexuality, which are difficult to research. So at this point, it is hard to be certain what is true and what isn’t. However, World Health Organization guidelines continue to place no restrictions on the use of hormonal contraceptives for women at risk of acquiring HIV. There is yet no compelling reason to conclude that HC has an effect on HIV transmission among women in general.
But how could using hormonal contraception affect HIV transmission?
Any sort of hormonal treatment has the potential to affect many of the body’s systems (think of how the Pill, for example, not only prevents pregnancy but can also cause breast tenderness, affect bone density, and protect against ovarian cancer). In the case of HIV and hormonal contraception, lab researchers have found at least seven plausible mechanisms through which use of HC might increase a woman’s chances of contracting or spreading the virus. But just because a mechanism is plausible doesn’t necessarily mean it is operating.
Has anyone looked at real people, outside the lab, to see if an effect of hormonal contraception on HIV transmission is really taking place?
Yes – but the results are mixed. Some studies have found no link, while others – conducted among sex workers, not among women in general – have found that using hormonal contraception increased a woman’s chances of contracting HIV, increased the likelihood of an infected woman spreading the virus to her sexual partners, and increased the speed at which disease developed in HIV-positive women. But it isn’t at all clear that the results of the studies among sex workers apply to women, in general –and there are additional problems. For one thing, many researchers have pointed out that women who use HC might be different from women who do not use HC in other ways, as well. For example, HC users might have more frequent sex, have more sexual partners, use condoms less frequently, and/or engage in more risky sexual practices. If any of these things are true, then the effect that HC seems to be having on HIV may, in reality, be an effect of these other behaviors on HIV instead. And since people are not always willing to talk openly about sex, it is hard to know whether these kinds of differences between HC users and non-HC users really exist or not.
I really rely on hormonal contraception. I would hate to stop using it unless there was a very good reason to do so.
This is the heart of the problem. HC provides huge benefits to women all over the world. It is a very effective form of contraception which a woman can use even without male cooperation, and one which she can stop using relatively quickly if she decides she wants to have a baby. Beyond this, HC actually saves lives every year, since in many parts of the world an unwanted pregnancy means that a woman is at risk of dying or being injured in childbirth or due to an unsafe abortion. HC is very useful. Any risks it may turn out to pose need to be weighed against its benefits.
What should women do, then? Should they keep using hormonal contraception? Should they stop?
The short answer to this question is that, given the current uncertainty about an HC/HIV link, there is no reason for women to change what they are already doing with regard to hormonal contraception. The longer answer is: If it turns out that HC does increase the chances of contracting and spreading HIV, different women may choose to do different things in response. For example: If you are only having sex with one partner, and you are pretty sure he is only having sex with you, and both of you are uninfected – then there would be no reason for you to change what you do at all. If you happen to live in a community with very high rates of HIV, and/or you cannot be sure of the HIV status or sexual behavior of your partner or partners – well, then continuing to use HC might not be a risk you want to take. If you live in a country with high maternal mortality and modest HIV rates, then the benefits you get from hormonal contraception might outweigh any risks it might bring. And so on – there are lots of other possibilities in between. What is clear is that there will never be a “one-size-fits-all” solution. What we all need to do is to pay attention to the results of future studies and, if the HC/HIV link turns out to be real, make our decisions about hormonal contraceptive use based on the specifics of our particular lives and circumstances.
For now, however, there is no reason for women, in general, to change their current choices and behavior with regard to HC.
If you want to know more about hormonal contraception and HIV, please turn to the next pages, where we talk about the subject in more detail.
Detailed Questions and Answers about Hormonal Contraception and HIV
1. There has been talk that using hormonal contraception may increase a woman’s chances of contracting or spreading HIV. Is this true?
At this point, it is difficult to say whether it is true or not. Over the past decade, a variety of studies have produced evidence suggesting that hormonal contraceptive use may result in a small increase in a woman’s chances of contracting or spreading HIV. On the other hand, other studies have found no such effect. And even if the effect turns out to be real, it is by no means obvious what should be done in response, since hormonal contraceptives bring great benefits to women, as well. This “Questions and Answers” sheet attempts to summarize what we do and don’t know on this subject to date, and to discuss possible ways we might respond to this knowledge.
2. When did scientists become concerned that hormonal contraception might affect HIV transmission?
It has long been known that hormonal treatments are capable of affecting many of the body’s systems. For example, oral contraceptive pills have effects not only on whether or not a woman gets pregnant, but also on things like her bone density and risks of cardiovascular disease and cancer. Thus, the question whether or not hormonal contraceptive use might affect how, and how easily, a woman can contract or transmit the HIV virus is, in theory, a reasonable one to ask.
Serious practical concern about the potential effects of hormonal contraception on HIV transmission arose in the middle of the 1990s, when experiments with monkeys suggested that hormonal contraception might very significantly thin the epithelium – or lining – of the vagina. This, in turn, could weaken the epithelium’s ability to function as a barrier to infection. Since this time, researchers have been investigating whether this, or any other effect relevant to HIV transmission, might occur in women using hormonal contraception, as well.
3. Is all hormonal contraception the same? Is all hormonal contraception implicated in possible effects on HIV transmission?
All hormonal contraception is not the same. There are many varieties, each with its particular formulation. All contain one of a class of hormones called “progestins,” while some also contain different hormones known as “estrogens.” This is important, because evidence to date suggests that – if there is an effect of hormonal contraception on HIV transmission – it is likely that it is progestins that have the most serious negative effect. Estrogens, on the other hand, may actually be somewhat protective.
Even in those hormonal contraceptives that contain estrogens, however, the progestin portion of the formulation is more active, or “dominant.” Not surprisingly, then, such evidence as we have to date suggests that “progestin-only” contraceptives (such as Depo-provera) may have a more serious effect on HIV transmission than “combined” contraceptives (such as the most common oral contraceptive pills), but that even “combined” hormonal contraceptives may have a net detrimental effect.
4. What have we learned since the mid-90s about the effects of hormonal contraceptives on HIV in human beings?
A great deal of research on this topic has taken place since the mid-1990s. Some of it has been “lab-based” – that is, it has examined in detail the effects of hormonal contraceptives on particular bodily systems in women in an attempt to establish possible mechanisms through which hormonal contraceptives might affect acquisition and transmission of HIV. Less often, research has been “epidemiological” or “population-based” – that is, it has looked at groups of real people in an attempt to determine if hormonal contraceptive use actually seems to have an effect on HIV transmission in the real world. Although these two types of research often overlap, it can be helpful to discuss them separately, since the first type addresses itself to the question of how hormonal contractive use might plausibly affect HIV transmission, while the latter asks whether or not hormonal contraceptive use is actually having such an effect.
Lessons learned from lab-based research: Lab-based human research has established at least seven mechanisms or pathways through which hormonal contraceptive use might plausibly affect HIV transmission. Some of these mechanisms affect how susceptible a woman is to contracting the HIV virus, some affect how likely she is to pass it on to someone else, some affect how HIV disease develops in a woman who has been infected, and some affect two or more of these categories. These mechanisms are as follows:
i) Although the thinning of the vaginal epithelium that has been seen in human women is not nearly as dramatic as that seen in monkeys, it does appear possible that hormonal contraception – by thinning the epithelium, by decreasing its number of cell layers and changing the characteristics of certain of its cells, and/or by affecting its ratio of mature to immature cells – may reduce the barrier that a woman’s vaginal epithelium presents to HIV. This could, in turn, make her more susceptible to infection and/or more capable of transmitting the virus.
ii) Hormonal contraceptive use may make women more susceptible to contracting certain infections or irritations of the reproductive tract, such as Chlamydia and cervicitis (inflammation of the cervix). It may also “re-activate” a pre-existing Herpes simplex infection. Since active reproductive-tract infections compromise the body’s barrier against HIV, it is possible that these hypothesized effects of hormonal contraception might increase women’s chances both of contracting and of passing on the virus.
iii) One way that HIV invades the human body is by attacking certain types of cells in the reproductive tract, as well as cells that exhibit certain types of receptors on their outer membranes. Thus, any increase of these types of cells, or of cells “expressing” these receptor types, in a woman’s vagina might make her more susceptible to infection. There is some evidence that hormonal contraception may produce such an increase in susceptible cells in women.
iv) Organisms such as lactobacilli living in a woman’s vagina provide her with protection against certain infections. If hormonal contraception use leads to changes in the number or nature of these organisms, it may reduce a woman’s resistance to infection.
v) It is possible that the nature of the HIV virus as well as the way it behaves is different in women using hormonal contraception than in other women. Thus, women using hormonal contraception may be infected by a wider variety of HIV virus types, they may have a higher viral set point (the level of virus characteristic of the period after acute infection and before full-blown AIDS), and the virus may reproduce more readily in them. If some or all of these are true, HIV disease may progress faster in women using hormonal contraception, and they might be more liable than other women to pass the virus on to their sexual partners.
vi) It is possible that HIV-infected women who are using hormonal contraception shed more HIV virus into their vaginas than do other HIV+ women. This is another mechanism that could make these women more liable to pass on the virus.
vii) Some hormonal contraceptives may increase cervical “ectopy” – that is, the number of cells from the lining of the cervical canal that are exposed to the vagina. This, in turn, might possibly increase a woman’s susceptibility to HIV infection.
Lessons learned from population-based research: Even if lab-based research establishes plausible mechanisms by which hormonal contraceptive use might affect HIV transmission, this does not necessarily mean that such an effect actually takes place in the real world. To determine whether or not this is happening, researchers must conduct studies in actual human populations.
This sort of research faces many obstacles: Keeping track of a defined group of people over a lengthy period of time (often years) is difficult and expensive. Furthermore, measuring every factor relevant to HIV acquisition in real-life situations (rather than in the controlled conditions of the laboratory) is not a simple matter. Not surprisingly, then, relatively little population-based research has been completed, and that which has is imperfect.
Some population-based study found no statistically significant association between hormonal contraceptive use and increased HIV incidence. Other studies, however – which generally looked at sex workers, as opposed to women in the population at large – did find hormonal contraceptive use to be significantly associated with an increased risk of HIV acquisition, as well as with faster disease progression and a greater likelihood of HIV+ women spreading the disease to others.
Evidently, then, the matter is not settled – we must wait for more evidence from other well-designed studies. But both lab-based and population-based studies suggest that a hormonal contraception/HIV transmission interaction is at least a possibility; neither type of research, however, has yet proven that such an interaction actually taking place – especially among the general population of women.
5. What are the difficulties and problems with population-based research on a possible hormonal contraceptive/HIV link? Are they important enough to undermine the conclusions of this type of research?
When researchers examine population-based studies, one of the main things they are alert to is the possibility of “confounding.” In brief, this means the possibility that an effect which appears to be the result of a factor that the study is measuring is, in fact, the result of another, different factor that the study is not measuring – or at least not measuring accurately enough. To take a fictional example: If we assume that cigarette smokers tend to get less exercise than non-smokers, then a study which looked only at the relationship between exercise and lung cancer (without measuring cigarette smoking!) might conclude that less exercise leads to greater risk of lung cancer. In fact, of course, it is unlikely that this is true. What is more likely is that cigarette smoking (which was not measured in the study) is the real cause of increased lung cancer risk, and that lower exercise (which was measured in the study) is merely a behavior associated with cigarette smoking but not itself linked to greater risk of cancer. In this example, cigarette smoking is an unmeasured confounder which negates the exercise/lung cancer link that the study appeared to establish.
How does this relate to population-based research into a possible hormonal contraceptive/ HIV link? The danger, simply put, is that women who use hormonal contraception in the real world may differ in other ways, as well, from women who do not. If this is true, then any perceived greater incidence of HIV infection in these women might be the result not of their contraceptive use, but of some other factor contributing to their difference from other women. To take a hypothetical example – if it were true that women who use hormonal contraception tended to have more frequent sexual intercourse than other women, or more sexual partners, or sexual partners who were more likely to be infected with HIV, or more risky sexual practices, then any measured increase in HIV incidence in these women might be the result not of hormonal contraceptive use, but of these other factors.
One very good way to guard against confounding is to conduct a “randomized controlled trial” (RCT). In this type of study, a large group of study participants is randomly assigned to “treatment” or “control” groups – in the present case, this would be the group using hormonal contraception versus the group not doing so. Since the group of participants is large and their exposure to the “treatment” of interest is randomly determined, there is a very good chance that any potential confounders will be evenly distributed between the two groups and thus will not be able to affect results.
Conducting an RCT of hormonal contraception, however, is not easy. For one thing, it is not clear that it is ethical – certain contraceptives really are more appropriate for certain women than are others; assigning a study participant to use a contraceptive that is not appropriate to her needs probably would violate medical ethics. Beyond this, however, it may not be practicable: a woman who prefers Depo-provera, for example, may not be very likely to continue using a diaphragm, even if she has been assigned to this method. Since such a woman may very well go and obtain Depo-provera no matter what her assigned contraceptive is, it would be very hard to assure that the original, randomized groups of contraceptive users actually continued throughout the duration of the study.
Short of an RCT, the best way to guard against confounding is to measure any and all aspects of study subjects that may have an effect on the outcome of interest. In the hypothetical example above, if we had clear and accurate measurements of frequency of sexual activity, number of partners, infection status of partners, and type of sexual activity, we could correct for any differences in these factors, and thus better determine if a perceived difference in HIV incidence was due to hormonal contraception or to something else. The problem, however, is that these sorts of confounders are very difficult to measure accurately – and even more difficult to be confident of measuring accurately! We are talking, after all, about sex – a subject which most people consider private. Knowing that we are getting honest, correct answers on such topics, and answers which actually shed light on the topics’ most important aspects, is not easy. Furthermore, questions of this kind are probably subject to a more or less substantial “courtesy bias” from study participants. In other words, participants asked about condom use, for example, or number of sexual partners may feel some pressure to respond with the “right” answers – that is, the answers they believe the researchers wish to hear. In such cases, participants may respond that they use condoms regularly, or only have one sexual partner, even when this is not the case. This sort of bias presents yet another obstacle to accurately researching a possible HIV/hormonal contraception link.
Finally, there may be confounders affecting study results which researchers simply haven’t thought of at all. Needless to say, if researchers haven’t even realized that a given confounder might affect their results, they are not likely to measure the confounder accurately – or, indeed, to measure it at all. In this way, an unrecognized confounder could seriously undermine study results.
The upshot of all this is that it is very, very difficult to know whether any perceived association between hormonal contraceptive use and HIV incidence, progression, or transmissibility is in fact a real association, or rather the result of some unmeasured or inaccurately measure confounder. And knowing this makes a difference. The example cited above (on cigarette smoking, exercise, and lung cancer) may seem silly, but it is instructive, in that it shows how unmeasured confounding can lead to inaccurate conclusions and misguided interventions: Encouraging exercise to prevent lung cancer would have very little effect on cancer rates unless smoking were reduced, as well.
There is no “magic bullet” to fix this problem. All we can do is work to keep improving our study designs and measurement of confounders, use our best judgment when interpreting results, and be careful and cautious when recommending policy and service-delivery changes.
6. What should we do differently given what we know about the possible effects of hormonal contraception on HIV transmission?
As the discussion above makes clear, family planning programs and other providers of contraception should be cautious about changing what they do on the basis of what we know about this topic to date. Here are some important points to keep in mind:
i) Although there is credible evidence for an association between hormonal contraceptive use and various aspects of HIV infection, this association cannot currently be said to be either proven or established as causal –especially for women in the general population. Even small errors in measuring confounding factors could overturn the conclusions of the studies conducted to date. We must use our best judgment in evaluating existing evidence, while remaining alert to any changes in our understanding that future studies may bring.
ii) Even if the hormonal contraception/HIV association is confirmed and/or strengthened by future research, the best response to take is neither obvious nor uniform for all populations or all women. Some examples will help to make this point clear. Let us assume, for the moment, that using Depo-provera moderately increases a woman’s risk of contracting HIV (remember – this is merely an assumption for argument’s sake; we are not stating that such an increase in risk has actually been proved!). What this would mean would be very different for different women. For a woman in a relationship she has confidence is monogamous with an HIV-negative partner, for example, this finding would make almost no difference – her risk of acquiring HIV is very small to begin with, and a very small risk that is moderately increased remains very small. A similar situation might obtain for a woman who is less confident of her partner’s fidelity, but who lives in a community with low HIV prevalence and/or prevalence that is confined largely to one or two risk groups of which neither the woman nor her partner is a member. The implications of our hypothetical “finding” for a sex worker, on the other hand, or for a woman living in a community with high general prevalence of HIV, might be quite different. These women might have a large, ongoing risk of HIV acquisition, and moderately increasing this risk might very well be unacceptable. Thus, even if further research confirms an association between hormonal contraceptive use and increased HIV transmission, it is unlikely that any “one-size-fits-all” policy change will emerge as an appropriate response. This is all the more true when we consider that hormonal contraceptive use brings many benefits to women, as detailed below.
iii) In many parts of the world, women face a real, present, and grave danger of dying in childbirth. In some countries, this risk may be as great as 1 in 200 – or even 1 in 100 – for every child born. Furthermore, as evidence makes plain time and time again, women who have undesired pregnancies frequently seek to terminate them – even in countries where abortion is illegal and/or unsafe. In this context, it is easy to see that a dependable contraceptive method is not a “neutral” thing when it comes to women’s health. It is, rather, a means by which women can protect themselves from serious health risks associated with pregnancy and childbirth.
Hormonal contraceptives, when used correctly, are among the most dependable methods available. Beyond this, they provide a range of other benefits: They are woman-controlled, are easily reversible when a woman decides she wishes to become pregnant, and protect women against diseases such as ovarian cancer. They (especially Depo-provera) also offer women the possibility of concealing the fact that they are using contraception from others in their community – something which can be very important to women in places where family planning is frowned upon.
All in all, hormonal contraceptives offer a range of very important benefits to women around the world. Even if a hormonal contraceptive/HIV link is ultimately established, any risks from hormonal contraception must be weighed against these benefits – a process that will yield different conclusions for different populations and different women, as we saw above.
iv) Finally, it is important to keep any possible contribution of hormonal contraception to increased HIV risk in context. No matter what the findings ultimately are, it is important to remember that hormonal contraceptives do not and cannot cause HIV infection. HIV infection is caused by the HIV virus; other factors (possibly including hormonal contraceptive use) can increase or mitigate the risk, but they do not, in themselves, cause infection. And there are many, many factors – number of sexual partners (especially concurrent sexual partners); behavior of these partners; use of injecting drugs; use or nonuse of condoms during sex; type of sexual activity – that have a stronger effect on increasing or mitigating risk than hormonal contraceptives are likely to have under even a worst-case scenario. Furthermore, a woman who is at risk of contracting or spreading HIV when using hormonal contraception will also be at risk of contracting or spreading the virus if she stops using it. In focusing on the possibility that hormonal contraceptives might increase a woman’s HIV risk, we must be careful to remember that it is the whole complex of behaviors and situations facing a woman that determines her risk. Concentrating on ameliorating this entire complex, rather than on demonizing any one element in it, is the proper task for our anti-HIV efforts.
©2005 Gynutiy Health Projects
Updated 17-Jul-06
Summary of Meeting
“Hormonal Contraception and HIV Transmission: Links? Mechanisms? Implications?”
Gynuity Health Projects, New York, NY, May 4 and 5, 2005
Background and Introduction
Concern about a possible association between hormonal contraceptive (HC) use and increased risk of HIV infection has been mounting in recent years. A series of laboratory, clinical and epidemiological
studies have contributed to a growing body of evidence that suggests such an association may exist. As of now, however, the association remains speculative, and a causal relationship between HC use and changes in HIV risk has not been established. Given the enormity of the AIDS epidemic, especially among women, and the popularity of HC use in many settings, any evidence that HC use may increase the risk of HIV transmission or contribute to disease progression would have significant implications for policy, programs, and individual women’s decisionmaking.
With the support of the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, and the Rockefeller Foundation, Gynuity Health Projects convened a two-day meeting bringing together scientists, reproductive health programmers, researchers, policymakers and activists to:
• examine the evidence for any effect of HC use on transmission of HIV to and from women and/or on disease progression in already-infected women;
• debate and address the methodological challenges in researching this topic;
• discuss the implications of our current state of knowledge for policy and practice in providing contraception and family planning services; and
• identify further research that may be needed to answer outstanding questions.
Given the uncertainty, complexity and nuance of the topic, participants also debated appropriate strategies for presenting it to the public in a manner that is clear, comprehensible, and maximizes sound
policy and practice, while preserving women’s ability to make informed choices about contraceptive use and HIV risk. Due to the sometimes contradictory nature of the data and the lack of firm evidence of
causality, the meeting was characterized by debate and discussion. No clear consensus emerged.
The meeting began with an overview of geographic patterns of HC use and HIV infection drawing on data from the Demographic and Health Surveys. These data show that while there are many settings with high rates of both HC use and HIV prevalence, there are also areas where the two variables do not correspond. Given the diversity of these settings in terms of culture, religion, sexual practices, and a host of other risk factors, it is not possible to tease out from this data what contribution, if any, HC use may make to overall rates of HIV infection. However, given that there are many countries where high HIV prevalence coincides with high use of HC, the data do suggest that if a causal relationship between HC use and increased HIV risk is ultimately established, it would have significant implications for women and for reproductive health programs.
Another important background presentation reviewed the composition and mechanism of action of various types of hormonal contraception. Put simply, there are two basic formulations of these medications: one containing both progestin and estrogen (for example, combined oral contraceptive pills), and one containing only progestin (for example, DMPA (“Depo-provera”) and the “mini-pill”).
Many of the possible effects of HC on HIV (discussed in detail below) appear to be driven by progestin; estrogen may, in fact, have a somewhat protective effect. Nevertheless, even those methods of HC which contain both progestin and estrogen are “progestin-dominant” – that is, the effects of progestin outweigh those of estrogen. The result appears to be that, although the possible effects of HC on HIV are more strongly associated with progestin-only methods, they may be linked to combined methods, as well.
Evidence from the laboratory
Use of hormonal contraception may give rise to systemic and genital-tract changes, some of which could influence women’s risk of contracting and transmitting HIV as well as the progression of HIV disease in infected women. Several presentations examined evidence on this topic from laboratory studies of animals and humans.
Widespread alarm about the possibility of HC use contributing to HIV infection was first raised by studies of Simian Immunodeficiency Virus (SIV), a virus closely related to HIV, in rhesus macaque monkeys. In these studies, macaques treated with progestin-only hormonal contraceptives experienced a dramatic thinning of the vaginal lining, or epithelium, and were much more susceptible than untreated macaques to infection with the SIV virus. Researchers concluded that thinning of the vaginal epithelium had reduced the monkeys’ natural barrier to SIV, thus allowing for greater uptake of the virus.
Later experiments using low-dose progestin-only contraceptives in humans failed to find the kind of marked epithelial thinning among HC-treated women as was found in monkeys. Nevertheless, changes in
the vaginal epithelium (less dramatic thinning; decrease in number of cell layers; changes in the relative number of mature cells) appear to be one mechanism by which HC use might increase susceptibility to HIV among humans.
Beyond this, research in humans has established at least six other plausible mechanisms by which HC use might have an impact on HIV infection and disease progression:
• HC use may increase women’s susceptibility to acquiring RTIs/STIs (Chlamydia; cervicitis; candidiasis) and/or to expressing STIs with which they may already be infected (Herpes simplex).
Presence of an active RTI or STI could then, in turn, increase women’s susceptibility to HIV;
• HC use may increase cervical ectopy (the number of cells normally within the cervical canal which are exposed to the vagina), giving rise to increased uptake of HIV via these cells;
• HC use may disrupt populations of lactobacilli and other microorganisms which in the normal vaginal environment provide protection from certain pathogens, possibly including HIV;
• HC use may change the vagina’s immunologic environment so as to affect receptor cells (macrophages, T cells and dendritic cells) and co-receptor expression;
• HC use may increase the viral variety, set point, and expression of HIV in infected women;
• HC use may promote shedding of HIV into the vaginas of infected women, thus increasing their ability to transmit the virus to others.
These mechanisms appear to be activated primarily by progestin. They may be most strongly associated with use of progestin-only contraceptives (including DMPA), but may also operate in users of combined methods, such as oral contraceptive pills (OCs). Some evidence suggests that estrogen may have a protective effect: in macaques, estrogen gel applied vaginally has had a significant effect on preventing SIV transmission. However, the levels of estrogen in methods such as combined OCs may not be high enough to counter any negative effects which may arise from progestins.
The effects of both endogenous and exogenous hormones on HIV acquisition, disease progression, and transmission in women were presented in a comprehensive review of laboratory studies. In sum, these studies suggest that there may be some reason for concern about the effects of exogenous hormones (such as HC), although with important differences from what has been observed in animal models.
Effects that have been noted differ somewhat by type of HC, as summarized in the following table.
Table 1: Summary of effects of HC on HIV suggested by research to date1
Effect • Oral Contraceptive Pills • Injectable Progestins
Overall thickness, number of cell layers, and thickness of the glycogen layer of the vaginal epithelium • – ↓?
Cervical ectopy • ↑ • ↑?
Chlamydia infection • ↑ • ↑
Vaginal candidiasis • ↑ • ?
Vaginal lactobacillus population • ? • ↓
Reactivation of existing Herpes simplex infection • ↑? • ↑?
Genital inflammation • ↑ • ↑
Local immune effect (HIV-1 co-receptor expression) • ↑ • ↑
Systemic immune effect • ? • ?
Effect on HIV viral variety, set point and/or expression • ↑? • ↑?
Increased vaginal shedding of HIV in infected women • ↑ • ↑
Key: – no net effect â—Ź ↑ increases listed item or effect â—Ź ↓ decreases listed item or effect â—Ź ? effect unknown
A symbol followed by a question mark (?) indicates that the listed effect appears to function but remains questionable
Finally, very little is known about the effect of HC use on progression of HIV disease in women. Similarly, there is little information about any effect that HC use may have on the efficacy and side effects of high active anti-retroviral therapy (HAART). The scant evidence that does exist suggests that there may be some effects but they are likely to be subtle. More research in this area will be needed before any
definitive conclusions can be drawn.
Evidence from population-based studies:
The population-based studies of this topic conducted to date have used observational designs – no randomized controlled trials (RTCs) have been conducted (see discussion below). These studies have
sometimes – but not always – shown a clear association between hormonal contraceptive use and HIV incidence, transmission, and/or disease progression.2
Comparing these studies is difficult as they have differed in many important ways, including location, study population and design, and frequency of follow-up. Studies that have found no association include
those among general populations and sero-discordant couples in Uganda, Zambia, and Rwanda. On the other hand, studies among sex workers in Thailand and Kenya have demonstrated an association. Data from the Uganda and Kenya studies were presented in depth at the meeting.
A study conducted among sex workers in Mombassa, Kenya suggests that the use of hormonal contraception is associated with increased risk of HIV-1 acquisition and a higher viral set point in infected
women, which may lead to faster disease progression. This study also showed an association between HC use and Chlamydia acquisition, and an increase in vaginal HIV shedding among HIV+ women using HC. The study, begun in 1993, followed 1,650 sex workers from an existing cohort to measure HIV seroconversions by HC use (DMPA and OC) as compared with non-use. It included monthly follow-up measurements of HIV-1 sero-status, STI infection, contraceptive use and sexual behavior. This data has been analyzed and presented for several time periods, and has remained consistent. For the overall period 1993-2003 the hazard ratios for DMPA and OCs were 1.8 (95% CI 1.4-2.4, p<.001) and 1.5 (95% CI 1.0-2.1, p=.04), respectively. Using data from the more recent period 1997-2003 the respective HRs were 1.9 (95% CI 1.2-2.9) and 1.8 (95% CI 1.0-3.1). An additional study in this cohort showed an association between DMPA use and acquisition of varied virus types: HIV-1 viral diversity during primary infection was associated with use of DMPA at the time of HIV-1 acquisition (OR 3.0, 95% CI 1.3-6.9, p=0.005). Viral diversity, in turn, was associated with a higher plasma viral load and a faster decline in CD4 count.
The study in Rakai, Uganda, which involved secondary analysis of data gathered in a larger study of HIV incidence, measured HIV incidence among HC users (OC, injectable, or both) and non-users to ascertain the relative incidence rate ratio (IRR) between the two groups. Participants were interviewed every 10 months, and the study included data from sexually active, originally HIV negative females aged 15-49 years who completed at least 2 study clinic visits. Data were collected on a variety of risk factors, including marital status, number of sex partners, condom use and presence of genital ulcer disease (GUD). When data were adjusted for age, marital status, education status, number of sex partners, condom use, and presence of genital ulcer disease (GUD) there was no statistically significant increase in HIV risk recorded in either study population. The study showed an overall (non-significant) adjusted IRR of .98 for HC users (1.12 for pill users; .84 for injectible users) as compared with non-users. The most significant cofactors were number of sex partners and reported GUD. Especially given that GUD might, itself, be a consequence of HC use (since HCs may increase the likelihood of contracting certain STIs), and therefore possibly a variable that should not be adjusted for, these results underscore the critical importance that confounding and other sources of bias can play in the analysis of observational data.
Bias and Confounders:
A primary concern in interpreting these observational, population-based studies is the possible role of sources of bias, including confounding. This issue was discussed at length at several different points
during the meeting. The concern is that women who use HC may differ from non-HC users in ways that condition their risk of HIV acquisition. Confounders can affect both exposure and outcome variables.
The history of medical research makes it clear that unmeasured or improperly measured confounders can have a profound effect on the outcomes of a study. Small mistakes can sometimes significantly distort results and conclusions, as well as resulting program and policy actions. These caveats were explored eloquently and in depth in a discussion that touched on, among other examples, early (and subsequently discredited) “findings” of associations between OCs and breast cancer and vasectomy and prostate cancer. While randomization is considered to be the “gold standard” for combating confounding, it is not clear that randomized controlled trials are feasible when studying HC and HIV (see below).
Both known and unknown variables can confound study results. In any study, accurately determining, modeling and measuring even known confounders is challenging. In studies of HC and HIV, many of the potential confounders – for example, sexual behavior, sexual practices, number of partners, and condom use – can be especially tricky to research. These private and sometimes stigmatized matters present difficulties both to researchers and to participants: researchers are not certain how to elicit valid data, and recall and reporting on the part of participants is not always full, truthful, and/or accurate. Additionally, there may be a significant “courtesy bias” associated with questions on, for example, condom use: after years of condom promotion programs, study participants are likely to be well aware that using condoms at each sex act is the “correct” way to behave, and may be inclined to report such behavior to authorities (including study personnel) whether or not these reports are accurate. Measurement challenges like these, of particular relevance to researching HC and HIV, exacerbate the concerns about confounding which apply to any study. The meeting included a presentation on ACASI (Audio Computer-Assisted Self Interview), a novel approach to gathering information on sensitive subjects which may hold promise for improving the accuracy of data collection in future studies of a possible HC/HIV interaction.
Future Research:
Given the inconclusive and somewhat contradictory evidence to date, participants engaged in a lively discussion about what additional data would be desirable, and what types of research would be feasible, to help strengthen the base of evidence on a possible HC/HIV interaction. Participants suggested areas for additional work, including studies designed to yield a greater understanding of:
• The risk of infection with HIV and other STIs faced by women during the luteal phase of the normal menstrual cycle, a time when the vaginal epithelium naturally thins somewhat
• Differences in hormone effects on primary infection vs. disease progression vs. transmission of the disease from women to others
• The relevance of animal models, particularly the macaque/SIV model, to HIV acquisition in women
• Possible effects of HC use on highly active anti-retroviral therapy (HAART)
• The possible value of vaginally applied estradiol cream in strengthening the barrier offered by the vaginal epithelium and thus in protecting women from HIV
• Subtler aspects of the HC/HIV relationship, such as whether or not differences in length of use of HC modify any effects on HIV, or what the actual levels of various hormones are at the time a
woman becomes infected with the virus
• The effects of HC on specific immunological processes or elements (Toll-like receptors, CCR-5 coreceptors, and CXCR-4 co-receptors, for example)
• Other specific mechanisms (such as cervical ectopy, increased viral replication, and greater viral diversity) whereby HC might have effect on HIV
• How to best measure the immunologic environment of the vagina
There was also considerable interest in devising and exploring creative approaches to improving the identification and measurement of confounding factors and other sources of bias in HC/HIV studies.
Participants actively debated the feasibility and desirability of conducting randomized controlled trials (RTCs) to address the central questions of whether HC use increases HIV incidence, infectivity, or disease progression. While there was a range of views, in general participants thought that RTCs on this topic might not be practical or even necessary, and might present considerable ethical challenges. A major practical concern would be participants’ willingness and ability to continue using a contraceptive method they had been randomly assigned rather than one they had chosen. Presentations from the Rakai and Mombasa studies both underscored the methodological challenge presented by study participants switching among different HC methods; this would likely be an even greater obstacle in an RTC. Some attendees questioned whether random assignment would even be ethical, since it might involve assigning participants to a contraceptive method that could increase their risk of acquiring or transmitting HIV and/or developing HIV disease, and/or could result in women who seek highly effective contraception being randomized to a less-effective method.
Given the difficulties of conducting an RTC on this topic, and the challenges and costs of mounting large population-based studies in general, participants agreed it would be useful to explore opportunities to collect data on HC and HIV in the context of other large ongoing studies (for example, trials of vaginal microbicides or of diaphragm use). Such an approach would also present many challenges, but it might be able to make important contributions to the evidence base on the topic with a minimum of cost and logistical difficulty. Another similar approach that was suggested was to examine already-existing data sets gathered for other purposes to see if any of them could be re-analyzed to shed light on the HC/HIV nexus.
Implications for policies and programs
Some of the data presented at the meeting supports an association between HC use and HIV infection, transmission, and disease progression; as of now, however, an association of any kind, to say nothing of a causal association, cannot be said to have been proved. We therefore must approach the topic – and, in particular, recommendations for policy and programmatic changes – with caution. There was considerable debate at the meeting on the implications of current knowledge for policy, programs, and individual women’s decisions.
Several presenters and participants underscored the important contribution to women’s health and rights that HC use has made by reducing pregnancy-associated morbidity and mortality, as well as by affording women more reproductive autonomy and choice. The significance of these benefits is even greater in low-resource settings where the risk of death or disability from pregnancy- or abortion-related causes is high. Against this backdrop, a number of participants felt strongly that no change in policy or practice is currently warranted. Any change in policy or an individual’s contraceptive practice geared toward avoiding a possible increased risk of HIV by reducing HC use would need to carefully weigh other benefits and risks, as well, including those associated with pregnancy and, especially, unwanted pregnancy.
In contrast, a number of meeting participants found the laboratory and population-based evidence suggesting an association between HC and HIV compelling, and felt that policy and programmatic
changes may be warranted in certain settings and populations. Many women who are at high or unknown risk of HIV infection have few options for decreasing this risk, and providing them with
information that might help decrease this risk even slightly could be significant for individual women and for the course of the epidemic, particularly in high-HIV-prevalence areas or groups.
The principle most clearly highlighted by the discussion was the importance of context – of considering any increased risk of HIV that HC use may present within a host of other population and individual
factors. These include:
• the magnitude of any relative risks for HIV infection, progression, and/or transmission which may eventually be established in HC users;
• the HIV incidence and prevalence in a given community or group;
• the risk of maternal mortality and morbidity in a given locale;
• a woman’s individual risk of HIV and maternal mortality;
• the feasibility of other risk-reduction and contraceptive options
The importance of context was underscored by presentation at the meeting of a model suggesting that even if HCs are shown to increase HIV risk, in many settings, especially those with high pregnancyassociated morbidity and mortality, they may still bring enough benefits to warrant continued and possibly even increased use. Although the model presented was very simple, incorporating only four variables, it is an excellent example of the kind of multifaceted thinking that will need to take place if an intelligent response to a possible HC/HIV link is to be developed.
Unfortunately, this sort of complex and nuanced thinking will be difficult to maintain in the “real-world” situation of understaffed and ill-equipped health systems. Discussion therefore also focused on the
importance of striving for a service delivery model that integrates family planning, reproductive health, voluntary counseling and testing for HIV, and treatment and care for people living with HIV/AIDS.
Ideally, these services would equip providers and clients with the skills and information necessary to assess HIV risk and would tailor risk reduction strategies and contraceptive information and services to
each specific situation.
If further evidence suggests a strong association between HC and HIV, policymakers will need to consider a range of critical questions. Is excess risk associated with HC fuelling the HIV/AIDS epidemic?
Would discouraging HC use reverse or have a substantial impact on the epidemic? It is not at all clear that either of these questions can be answered in the affirmative. An extreme policy decision of, for
example, taking HC off the market in settings with high HIV incidence and high HC prevalence would likely have a small impact on reducing HIV relative to the impact of reduced sexual risk and increased
condom use, while it would deprive women of an effective and beneficial contraceptive. To address questions of this nature, WHO will shortly convene a regional meeting in Africa to promote evidencebased
discussion and decisionmaking on hormonal contraceptive use in the context of the HIV epidemic. This meeting will consider a wide range of evidence, including anticipated results from the study by
Morrison et al. (see note 1, above).3
Finally, there was a lively discussion about how best to convey information about HC and HIV to the public in a manner that is clear, nuanced and comprehensible, and that promotes appropriate
decisionmaking, discourages sensational reporting, and does not lead to ill-considered responses. Institutions associated with the Morrison, et al., study are developing a strategy for presenting their
findings; they and others anticipate an increase in attention and interest in this area when these results are released. The findings and attendant messages are likely to be subtle and complex, emphasizing that different actions and approaches are warranted in different settings and for different women. Acknowledging the limitations of traditional scientific presentation to convey such messages and the tendency of the media to simplify and sensationalize scientific findings, a number of participants suggested working together on a strategic and coordinated effort (perhaps making use of public- and
press-relations professionals) which might include varied materials for diverse audiences and seminars for journalists and key opinion leaders.
©2005 Gynuity Health Projects
1 This table is largely based on a presentation made at the meeting by Dr. Jared Baeten of Massachusetts General Hospital.
2 Unfortunately, data from a large, new study by Charles Morrison of Family Health International and colleagues had not been released at the time of the Gynuity Health Projects meeting. It is not known whether this new data, also from an observational study, will convincingly shift the weight of evidence in either direction. It is not likely, however, that the evidence will be significantly stronger or more unequivocal than that of previous observational studies.
3 This meeting – which had the benefit of some initial findings of the Morrison study, though not the full, final results – has since occurred (September 19-21, 2005, Nairobi, Kenya). At it, WHO reaffirmed that there is not enough evidence to change current practice with regard to hormonal contraceptive use, although there may be some reason to revisit this conclusion for women who are at high individual risk for acquiring the virus. The meeting’s final statement of recommendations reads: “There should be no restrictions on the use of COCs and DMPA by women at risk of acquiring HIV, consistent with the current WHO Medical Eligibility Criteria for Contraceptive Use guidelines. However, participants suggested that the WHO Family Planning Working Group at its next meeting review the classification regarding women at high individual risk of HIV infection to assess whether some caution on use of these methods may be appropriate, though the participants acknowledged that the benefits of using COCs or DMPA to prevent unintended pregnancy would in the majority of cases offset any excess risk of acquiring HIV infection.” For the full meeting statement, see http://www.who.int/reproductive-health/rtis/statement.html
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