Pregnancy Failure and Misoprostol — Time for a Change
http://www.100md.com
《新英格兰医药杂志》
Pregnancy failure in the first trimester is one of the commonest reasons for women to seek emergency medical services. Indeed, curettage for this indication was responsible for up to three quarters of all nighttime emergency gynecologic interventions in one review.1 The term "pregnancy failure" is, however, not a clinical one but, rather, describes a range of conditions in which an implanted fertilized ovum ceases to develop to the point of viability. Included in the category of early pregnancy failure are spontaneous abortion (both complete, in which all the products of conception have been expelled, and incomplete, in which some products remain), anembryonic gestation (in which no embryo has developed), and missed abortion (occult embryonic or fetal death, in which a pregnancy has ended, but no clear symptoms herald this event).
Arguably, the most common reason for early pregnancy failure is unwanted pregnancy and subsequent induced abortion. When good-quality medical services for elective termination of pregnancy are unavailable, women presenting for care after botched or incomplete procedures are often misclassified as having complications of spontaneous pregnancy loss. Women who have undergone clandestine or illegal procedures may be unwilling to disclose this fact, and so the causes of pregnancy failure (and the reliability of diagnoses) differ in places in which abortion services are available and those in which they are restricted. For example, after passage of New York State's liberalized abortion law in 1970, recorded rates of spontaneous abortion fell by 20 percent in Brooklyn's municipal and affiliated hospitals.2 The rates of misclassification are likely to be even higher in places in which abortion is highly stigmatized or illegal. In Romania, recorded rates of spontaneous abortion declined by over 40 percent after the legalization of abortion in 1990.3
The treatment most commonly offered to women with these conditions is surgical emptying of the uterus, with the use of sharp curettage or electric or manual vacuum aspiration, depending on local practice standards. Expectant management (waiting for the process of pregnancy loss to end spontaneously) is also sometimes offered to women with uncomplicated clinical presentations. But waiting is a slower route to resolution of the problem, and some women still will need surgery. Nonetheless, many women are willing to accept these inconveniences to avoid an invasive procedure.
In the past decade, the prostaglandin E1 analogue misoprostol — an available, safe, and relatively inexpensive drug originally approved by the Food and Drug Administration for the prevention of gastric ulcers during long-term use of nonsteroidal antiinflammatory drugs — has been suggested as an alternative approach to managing early pregnancy failure.4 Indeed, misoprostol has been proposed (and in some places widely used) for a variety of other obstetrical or gynecologic indications: induction of labor, preparation of the cervix for surgical procedures, prevention or treatment of postpartum hemorrhage, and pregnancy termination. Although the use of misoprostol for these indications has become increasingly common worldwide, such uses have remained "off label," and the pharmaceutical industry has largely looked the other way in matters of drug development and product registration for these potential uses. As a result, many studies have been limited by small numbers of subjects, as well as by the use of idiosyncratic regimens and nonstandard or vague definitions of cases and outcomes.
In this issue of the Journal, Zhang et al. report the results among 652 women with early pregnancy failure who were randomly assigned (in a 3:1 ratio) either to receive misoprostol (one or two 800-μg doses vaginally) or to undergo vacuum aspiration5; women assigned to misoprostol underwent vacuum aspiration if medical therapy was unsuccessful. The results convincingly demonstrate the efficacy, safety, and acceptability of misoprostol to treat pregnancy failure (mostly missed abortion and anembryonic gestations) and show that this treatment may be an option that is preferable to surgery for some women. Indeed, in this series, over 80 percent of women given medical treatment needed no surgical intervention. Overall, the medically and surgically treated groups had similar and highly favorable ratings of their treatments.
The results of this report, together with those of earlier reports,6,7,8,9,10,11,12 provide clinicians with information they need to use this medication responsibly for the management of early pregnancy failure. However, some questions remain.
Existing studies demonstrate that the use of misoprostol is more effective than expectant management (nonintervention) for early pregnancy failure, the other main alternative to immediate surgical treatment.6,7,8 Missed abortion appears to be slightly less easily and less successfully resolved with the use of misoprostol therapy than is incomplete abortion.5,13 This finding suggests that whereas surgery is more of a "one size fits all" proposition for treating early pregnancy failure, medical treatment may not be. In addition, the lowest effective dose of misoprostol for each condition for which it is used is not yet clear, and this dose may turn out to be different for different categories of pregnancy loss.5,7 We also do not know whether repeated doses of misoprostol consistently result in greater efficacy than a single dose followed by sufficient time for it to work.9
Questions also remain about the route of administration, with almost every imaginable variant having been used. (Oral, vaginal, rectal, buccal, and sublingual use have all been reported.) Some studies suggest that vaginal application of misoprostol increases the success rate and reduces side effects as compared with oral or other routes, whereas the results of other studies indicate that the various routes are equally efficacious and have similar rates of side effects.10,11,12 Many studies of vaginal administration have used misoprostol tablets developed and registered for oral use. But the normal procedures of drug registration will make it impossible for a pharmaceutical company to register an oral tablet for vaginal use without considerable additional expenditure on studies and, possibly, reformulation of the tablet. So far, no company has made such an investment, in part because it would be almost impossible for such a product to compete successfully with the inexpensive misoprostol tablets currently available.
Although the study by Zhang et al. was conducted in the United States, the development of nonsurgical treatments for early pregnancy failure may have the most importance outside our country. In resource-constrained environments, high-quality surgical care is not readily available to all. The consequences of unsafe abortion are estimated to account for about 13 percent of all maternal deaths worldwide, almost all of which occur in developing countries.14 Misoprostol therapy as an alternative to surgery appears to be highly acceptable to women wherever it has been tested,5,10 and recent evidence shows clearly that using misoprostol instead of aspiration in an outpatient setting reduces the cost of services.15 It is likely that women offered misoprostol can be treated and discharged more promptly than those who undergo surgery.5 In addition, treatment with pills does not require the immediate availability of sterilized equipment, operating rooms, or surgically skilled personnel.
Despite its promise, the use of misoprostol for early pregnancy failure in resource-poor countries may face substantial obstacles. Where norms for the delivery of medical services are set by governments, off-label use of medications is frequently not allowed. In other cases, physicians may worry that off-label use of medication will result in sanctions or lack of reimbursement. Governments may also be hesitant to adopt a treatment officially that has not been registered or approved by their own or any internationally recognized regulatory agency.
For the future, both public and private sectors can work toward increasing the availability of dedicated misoprostol products for women's health indications. For now, clinicians have the opportunity to improve care for women by substituting a nonsurgical treatment for curettage or aspiration procedures, but they must be willing to make this transition in the context of the off-label use of a medication. That said, the report by Zhang et al., along with earlier peer-reviewed literature and wide community backing, provides support for such a transition.
Dr. Winikoff is president of Gynuity Health Projects, an organization that conducts research and other initiatives related to reproductive health techniques independent of support from the pharmaceutical industry.
Source Information
From Gynuity Health Projects, New York.
References
Mckee M, Priest P, Ginzler M, Black N. Can out-of-hours operating in gynaecology be reduced? Arch Emerg Med 1992;9:290-298.
Lanham JT, Kohl SG, Bedell JH. Changes in pregnancy outcome after liberalization of the New York State abortion law. Am J Obstet Gynecol 1974;118:485-492.
Johnston WR. Historical Abortion statistics, Romania. Johnston's archive. April 2005. (Accessed August 4, 2005, at http://www.johnstonsarchive.net/policy/abortion/ab-romania.html.)
Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:38-47.
Zhang J, Gilles JM, Barnhart K, Creinin MD, Westhoff C, Frederick MM. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353:761-769.
Chung TKH, Cheung LP, Leung TY, Haines CJ, Chang AMZ. Misoprostol in the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102:832-835.
Bagratee JS, Khullar V, Regan L, Moodley J, Kagoro H. A randomized controlled trial comparing medical and expectant management of first trimester miscarriage. Hum Reprod 2004;19:266-271.
Ngai SW, Chan YM, Tang OS, Ho PC. Vaginal misoprostol as medical treatment for first trimester spontaneous miscarriage. Hum Reprod 2001;16:1493-1496.
Blanchard K, Taneepanichskul S, Kiriwat O, et al. Two regimens of misoprostol for treatment of incomplete abortion. Obstet Gynecol 2004;102:860-865.
Ngoc NTN, Blum J, Westheimer E, Quan TTV, Winikoff B. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet 2004;87:138-142.
Pang MW, Lee TS, Chung TKH. Incomplete miscarriage: a randomized controlled trial comparing oral with vaginal misoprostol for medical evacuation. Hum Reprod 2001;16:2283-2287.
Tang OS, Lau WNT, Ng EHY, Lee SWH, Ho PC. A prospective randomized study to compare the use of repeated doses of vaginal and sublingual misoprostol in the management of first trimester silent miscarriages. Hum Reprod 2003;18:176-181.
Demetroulis C, Saridogan E, Kunde D, Naftalin AA. A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure. Hum Reprod 2001;16:365-369.
Unsafe abortion: global and regional estimates of the incidence of unsafe abortion and associated mortality in 2000. 4th ed. Geneva: World Health Organization, 2004.
Graziosi GCM, van der Steeg JW, Reuwer PHW, Drogtrop AP, Bruinse HW, Mol BWJ. Economic evaluation of misoprostol in the treatment of early pregnancy failure compared to curettage after an expectant management. Hum Reprod 2005;20:1067-1071.(Beverly Winikoff, M.D., M)
Arguably, the most common reason for early pregnancy failure is unwanted pregnancy and subsequent induced abortion. When good-quality medical services for elective termination of pregnancy are unavailable, women presenting for care after botched or incomplete procedures are often misclassified as having complications of spontaneous pregnancy loss. Women who have undergone clandestine or illegal procedures may be unwilling to disclose this fact, and so the causes of pregnancy failure (and the reliability of diagnoses) differ in places in which abortion services are available and those in which they are restricted. For example, after passage of New York State's liberalized abortion law in 1970, recorded rates of spontaneous abortion fell by 20 percent in Brooklyn's municipal and affiliated hospitals.2 The rates of misclassification are likely to be even higher in places in which abortion is highly stigmatized or illegal. In Romania, recorded rates of spontaneous abortion declined by over 40 percent after the legalization of abortion in 1990.3
The treatment most commonly offered to women with these conditions is surgical emptying of the uterus, with the use of sharp curettage or electric or manual vacuum aspiration, depending on local practice standards. Expectant management (waiting for the process of pregnancy loss to end spontaneously) is also sometimes offered to women with uncomplicated clinical presentations. But waiting is a slower route to resolution of the problem, and some women still will need surgery. Nonetheless, many women are willing to accept these inconveniences to avoid an invasive procedure.
In the past decade, the prostaglandin E1 analogue misoprostol — an available, safe, and relatively inexpensive drug originally approved by the Food and Drug Administration for the prevention of gastric ulcers during long-term use of nonsteroidal antiinflammatory drugs — has been suggested as an alternative approach to managing early pregnancy failure.4 Indeed, misoprostol has been proposed (and in some places widely used) for a variety of other obstetrical or gynecologic indications: induction of labor, preparation of the cervix for surgical procedures, prevention or treatment of postpartum hemorrhage, and pregnancy termination. Although the use of misoprostol for these indications has become increasingly common worldwide, such uses have remained "off label," and the pharmaceutical industry has largely looked the other way in matters of drug development and product registration for these potential uses. As a result, many studies have been limited by small numbers of subjects, as well as by the use of idiosyncratic regimens and nonstandard or vague definitions of cases and outcomes.
In this issue of the Journal, Zhang et al. report the results among 652 women with early pregnancy failure who were randomly assigned (in a 3:1 ratio) either to receive misoprostol (one or two 800-μg doses vaginally) or to undergo vacuum aspiration5; women assigned to misoprostol underwent vacuum aspiration if medical therapy was unsuccessful. The results convincingly demonstrate the efficacy, safety, and acceptability of misoprostol to treat pregnancy failure (mostly missed abortion and anembryonic gestations) and show that this treatment may be an option that is preferable to surgery for some women. Indeed, in this series, over 80 percent of women given medical treatment needed no surgical intervention. Overall, the medically and surgically treated groups had similar and highly favorable ratings of their treatments.
The results of this report, together with those of earlier reports,6,7,8,9,10,11,12 provide clinicians with information they need to use this medication responsibly for the management of early pregnancy failure. However, some questions remain.
Existing studies demonstrate that the use of misoprostol is more effective than expectant management (nonintervention) for early pregnancy failure, the other main alternative to immediate surgical treatment.6,7,8 Missed abortion appears to be slightly less easily and less successfully resolved with the use of misoprostol therapy than is incomplete abortion.5,13 This finding suggests that whereas surgery is more of a "one size fits all" proposition for treating early pregnancy failure, medical treatment may not be. In addition, the lowest effective dose of misoprostol for each condition for which it is used is not yet clear, and this dose may turn out to be different for different categories of pregnancy loss.5,7 We also do not know whether repeated doses of misoprostol consistently result in greater efficacy than a single dose followed by sufficient time for it to work.9
Questions also remain about the route of administration, with almost every imaginable variant having been used. (Oral, vaginal, rectal, buccal, and sublingual use have all been reported.) Some studies suggest that vaginal application of misoprostol increases the success rate and reduces side effects as compared with oral or other routes, whereas the results of other studies indicate that the various routes are equally efficacious and have similar rates of side effects.10,11,12 Many studies of vaginal administration have used misoprostol tablets developed and registered for oral use. But the normal procedures of drug registration will make it impossible for a pharmaceutical company to register an oral tablet for vaginal use without considerable additional expenditure on studies and, possibly, reformulation of the tablet. So far, no company has made such an investment, in part because it would be almost impossible for such a product to compete successfully with the inexpensive misoprostol tablets currently available.
Although the study by Zhang et al. was conducted in the United States, the development of nonsurgical treatments for early pregnancy failure may have the most importance outside our country. In resource-constrained environments, high-quality surgical care is not readily available to all. The consequences of unsafe abortion are estimated to account for about 13 percent of all maternal deaths worldwide, almost all of which occur in developing countries.14 Misoprostol therapy as an alternative to surgery appears to be highly acceptable to women wherever it has been tested,5,10 and recent evidence shows clearly that using misoprostol instead of aspiration in an outpatient setting reduces the cost of services.15 It is likely that women offered misoprostol can be treated and discharged more promptly than those who undergo surgery.5 In addition, treatment with pills does not require the immediate availability of sterilized equipment, operating rooms, or surgically skilled personnel.
Despite its promise, the use of misoprostol for early pregnancy failure in resource-poor countries may face substantial obstacles. Where norms for the delivery of medical services are set by governments, off-label use of medications is frequently not allowed. In other cases, physicians may worry that off-label use of medication will result in sanctions or lack of reimbursement. Governments may also be hesitant to adopt a treatment officially that has not been registered or approved by their own or any internationally recognized regulatory agency.
For the future, both public and private sectors can work toward increasing the availability of dedicated misoprostol products for women's health indications. For now, clinicians have the opportunity to improve care for women by substituting a nonsurgical treatment for curettage or aspiration procedures, but they must be willing to make this transition in the context of the off-label use of a medication. That said, the report by Zhang et al., along with earlier peer-reviewed literature and wide community backing, provides support for such a transition.
Dr. Winikoff is president of Gynuity Health Projects, an organization that conducts research and other initiatives related to reproductive health techniques independent of support from the pharmaceutical industry.
Source Information
From Gynuity Health Projects, New York.
References
Mckee M, Priest P, Ginzler M, Black N. Can out-of-hours operating in gynaecology be reduced? Arch Emerg Med 1992;9:290-298.
Lanham JT, Kohl SG, Bedell JH. Changes in pregnancy outcome after liberalization of the New York State abortion law. Am J Obstet Gynecol 1974;118:485-492.
Johnston WR. Historical Abortion statistics, Romania. Johnston's archive. April 2005. (Accessed August 4, 2005, at http://www.johnstonsarchive.net/policy/abortion/ab-romania.html.)
Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:38-47.
Zhang J, Gilles JM, Barnhart K, Creinin MD, Westhoff C, Frederick MM. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med 2005;353:761-769.
Chung TKH, Cheung LP, Leung TY, Haines CJ, Chang AMZ. Misoprostol in the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102:832-835.
Bagratee JS, Khullar V, Regan L, Moodley J, Kagoro H. A randomized controlled trial comparing medical and expectant management of first trimester miscarriage. Hum Reprod 2004;19:266-271.
Ngai SW, Chan YM, Tang OS, Ho PC. Vaginal misoprostol as medical treatment for first trimester spontaneous miscarriage. Hum Reprod 2001;16:1493-1496.
Blanchard K, Taneepanichskul S, Kiriwat O, et al. Two regimens of misoprostol for treatment of incomplete abortion. Obstet Gynecol 2004;102:860-865.
Ngoc NTN, Blum J, Westheimer E, Quan TTV, Winikoff B. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet 2004;87:138-142.
Pang MW, Lee TS, Chung TKH. Incomplete miscarriage: a randomized controlled trial comparing oral with vaginal misoprostol for medical evacuation. Hum Reprod 2001;16:2283-2287.
Tang OS, Lau WNT, Ng EHY, Lee SWH, Ho PC. A prospective randomized study to compare the use of repeated doses of vaginal and sublingual misoprostol in the management of first trimester silent miscarriages. Hum Reprod 2003;18:176-181.
Demetroulis C, Saridogan E, Kunde D, Naftalin AA. A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure. Hum Reprod 2001;16:365-369.
Unsafe abortion: global and regional estimates of the incidence of unsafe abortion and associated mortality in 2000. 4th ed. Geneva: World Health Organization, 2004.
Graziosi GCM, van der Steeg JW, Reuwer PHW, Drogtrop AP, Bruinse HW, Mol BWJ. Economic evaluation of misoprostol in the treatment of early pregnancy failure compared to curettage after an expectant management. Hum Reprod 2005;20:1067-1071.(Beverly Winikoff, M.D., M)