Abnormal early pregnancy is a common experience for women. Approximately 1 in 4 women will experience a miscarriage during her lifetime.1 Between 15% and 20% of clinically recognized pregnancies are diagnosed as abnormal in the first or early second trimester.2 For more than 50 years, the standard management of early pregnancy failure has been a dilation and curettage (D&C). Typically, the procedure is performed in an operating room, which significantly increases cost. In recent years, the medical community began to question whether immediate evacuation by surgical intervention is truly necessary for most cases of early pregnancy failure.3–5
Misoprostol, a prostaglandin E1 analogue, has garnered attention over the past few decades, both in regimens for medical abortion and by itself for early pregnancy failure.6 Overall, comparison of trials using misoprostol for early pregnancy failure is difficult because the studies included various patient populations and dosing regimens (for example, repeat dosing every 3–4 hours or every 24 hours), different routes of administration (oral or vaginal), varying definitions of success (the time allowed until dilation and curettage was performed),7 and a misunderstanding of how to use ultrasonography to define both inclusion and success.8–10 Additionally, most of the large studies involve inpatient admission for medical management, a scenario that would be unlikely in the United States.11,12
To address these weaknesses, we conducted a multicenter randomized trial including 491 women treated with misoprostol 800 μg vaginally and 161 women who had a vacuum aspiration procedure for early pregnancy failure.13 Misoprostol treatment success was 71% (95% confidence interval [CI] 67–75%) after one dose and 84% (95% CI 81–87%) overall. Although this overall success was statistically equivalent to the 97% (95% CI 94–100%) for vacuum aspiration, the rates are clinically quite different. There may be easily identifiable subgroups for whom misoprostol treatment will be more or less effective and, ideally, some women for whom the success rates may more closely approximate those of vacuum aspiration. This report details the findings of a planned substudy of this multicenter trial to evaluate factors related to success with misoprostol treatment.
MATERIALS AND METHODS
This multicenter study was performed at Columbia University, the University of Miami, the University of Pennsylvania, and the University of Pittsburgh. This trial was designed to compare the efficacy and safety of misoprostol and vacuum aspiration for the treatment of early pregnancy failure. The study design included the prospective collection of data to allow a planned analysis of the predictors of successful treatment with misoprostol. The study was approved by the institutional review boards of the respective institutions, Clinical Trials and Surveys Corporation, and the National Institute of Child Health and Human Development.
The study protocol, population demographics, and treatment outcomes have been previously described.13 Women who had an anembryonic gestation or embryonic/fetal demise were eligible for inclusion if they had an ultrasound examination demonstrating an embryonic pole or crown-rump length between 5 and 40 mm without cardiac activity14, an anembryonic gestational sac with a mean diameter between 16 and 45 mm15, growth of gestational sac less than 2 mm over 5 days or less than 3 mm over 7 days,16 or an increase in human chorionic gonadotropin by less than 15% over 2 days with a yolk sac visualized by ultrasound examination. Women who had incomplete or inevitable abortions were also included. Incomplete spontaneous abortion was defined as passage of some products of conception with the residual anterior-posterior endometrial lining greater than 30 mm by transvaginal ultrasonography and uterine size less than 13 weeks. This cutoff was based on evidence from prior studies of women treated with misoprostol for medical abortion17 or early pregnancy failure.9 Inevitable abortion was defined as an intrauterine gestational sac less than 45 mm or embryonic pole less than 40 mm and an open internal cervical os to digital examination with active vaginal bleeding. Women were excluded from the primary study if they were anemic (hemoglobin level below 9.5 mg/dL), were hemodynamically unstable, had a history of a clotting disorder or were using anticoagulants, were allergic to prostaglandins or nonsteroidal anti-inflammatory drugs, or had previously undergone surgical or medical abortion, either self-induced or by other physicians during the current pregnancy. All subjects provided written informed consent.
Women who enrolled were randomized in a 3:1 ratio to medical treatment or vacuum aspiration. Randomization was stratified by study sites and type of pregnancy failure (anembryonic gestation or fetal demise versus incomplete and inevitable spontaneous abortion) using randomly permutated blocks. The day of randomization was considered study day 1. Women randomized to medical treatment had four 200 μg tablets (800 μg) of misoprostol (Cytotec, Searle Pharmaceuticals, Chicago, IL) inserted into the posterior fornix through a speculum. Rh-immune globulin was administered if the subject was Rh-negative and had not already received Rh-immune globulin. The subjects returned on day 3 (range: days 2–5) for a follow-up evaluation including transvaginal ultrasonography. If the ultrasound examination demonstrated a gestational sac or the endometrial lining was greater than 30 mm, a second dose of 800 μg of vaginal misoprostol was administered. On day 8 (range: days 6–10), if the expulsion of products of conception was still not completed, vacuum aspiration was offered. The subjects returned for a follow-up visit on day 15. A telephone interview was conducted on day 30 (range: days 25–35) to determine whether any subject underwent additional treatment. Women with symptoms potentially related to the study treatment were followed until they were resolved.
For this secondary analysis, only women who received misoprostol and were not lost to follow-up were included. Misoprostol success was defined as complete abortion without the need for a vacuum aspiration within 30 days of treatment. Univariable analysis was performed using χ2 analyses or 2-sample median tests as appropriate to evaluate all demographic, medical history, and outcome variables for prediction of misoprostol success. Variables with P ≤ .1 were considered for inclusion in the multivariable analysis. Two additional variables, clinical site and best estimate of gestational age, were forced into the multivariable analysis due to clinical relevance.
Logistic regression analyses were performed for both overall misoprostol success and first-dose success of misoprostol treatment. Success by day 30, defined as no surgical intervention by day 30, was the modeled event. A step-wise selection procedure was used, with entry significance 0.25 and stay significance of 0.1. After completing the predictor model, gestational age and clinical site were then inserted into the model. Additionally, pregnancy type was maintained in the first-dose success model to be comparable with the overall success model. All statistical analyses were performed with SAS 8.2 (SAS Institute, Cary, NC).
A total of 652 women were enrolled in the primary study between March 2002 and March 2004, of whom 491 were randomized to receive misoprostol, and 485 met the criteria for this secondary analysis. The 485 subjects included 177 (36.5%), 279 (57.5%), and 29 (6.0%) women with a diagnosis of anembryonic gestation, embryonic/fetal demise, and incomplete/inevitable abortion, respectively. Univariable predictors of treatment success are presented in Table 1. Multivariable analysis revealed that the presence of localized lower abdominal pain within the past 24 hours, vaginal bleeding within the last 24 hours, Rh-negative blood type, and nulliparity were predictive of a high probability of overall success (Table 2). However, only vaginal bleeding within the last 24 hours and parity of 0 or 1 were predictive of first-dose success (Table 3). Clinical sites, subtypes of early pregnancy failure, and gestational age at treatment did not affect treatment success. The outcomes in the multivariable model, when not including the forced-in variables (gestational age and clinical site), resulted in no significant changes from those in the full model.
Using these predictors, comparative rates were tabulated for women presenting with a combination of 2 or more of these symptoms or characteristics for overall success and single (first)–dose success. All of the tabulations for overall success resulted in efficacy rates of 92% or greater, but all except for two resulted in small numbers in the subgroups (n = 44 or less). The specifics from the two combinations of characteristics with significant numbers for overall success and the predictors of single-dose success are presented in Table 4.
Misoprostol treatment of women with early pregnancy failure provides an opportunity for women who desire active management to have a timed expulsion and avoid a vacuum aspiration procedure. This trial included 485 women, which allows unique opportunities for analyses unlike prior, smaller studies. We have demonstrated that successful treatment is significantly more likely in women who are nulliparous or have localized lower abdominal pain within the past 24 hours, vaginal bleeding within the last 24 hours, or Rh-negative blood type. These predictors of successful treatment demonstrate a relative gradient of efficacy. Specifically, the overall efficacy gradient of approximately 95–85–80% is evident for women who have pain and bleeding in the prior 24 hours, all subjects, and those with neither pain nor bleeding in the past 24 hours. A similar gradient is present for first-dose efficacy of approximately 80–70–60% for women who are nulliparous and have bleeding in the prior 24 hours, all subjects, and those who are not nulliparous and have not had bleeding in the past 24 hours.
The finding that Rh-negative blood type is highly associated with overall treatment success is surprising and not previously reported. One may hypothesize that Rh-mismatch could be an underlying reason for early pregnancy failure and create a situation in which misoprostol is more effective. Additionally, this finding may imply that women who are Rh-negative may have an underlying cause of early pregnancy failure that is different from Rh-positive women. However, because of the lack of an easily plausible explanation, we would recommend awaiting further trials before assuming this association is definitely true. Conversely, the findings of associations of recent bleeding and cramping with overall misoprostol success are expected. Low parity as a predictor suggests that the receptivity of the uterus to the effects of misoprostol changes with growth or stretching of the myometrium with past pregnancies.
We used vaginal misoprostol in our study based on what we have learned from medical abortion studies. When used in regimens for medical abortion after either mifepristone18 or methotrexate19 treatment, vaginal misoprostol results in a higher rate of complete abortion than oral misoprostol, as well as a more rapid rate of pregnancy expulsion. A small, nonrandomized trial suggests the same is true when using misoprostol for early pregnancy failure.20
One of the primary problems with many published trials of medical treatment of early pregnancy failure is the definition of success. Some studies had used an endometrial thickness of 15 mm when assessed by transvaginal sonography as cutoff for “success.”21–27 However, mounting evidence from literature on medical abortion (Fox MC, Creinin MD, Meyn LA, Murthy AS, Harwood B. Ultrasound appearance of the endometrium after medical abortion [abstract]. Contraception 2004;70:261)17 and early pregnancy failure8–10 indicate that such a cutoff is too stringent. Interestingly, medical abortion studies, which commonly quote success rates exceeding 95%,28 do not use endometrial thickness to define success. In medical abortion studies, women who have sonographic disappearance of the gestational sac are highly likely not to need any further intervention, which accounts for the high success rate. Our current study confirms that almost all women with an endometrial thickness less than 30 mm after misoprostol treatment for early pregnancy failure also complete expulsion spontaneously and uneventfully.13 As such, women who failed treatment in this study truly required clinical intervention. Therefore, the predictors of success we present in this analysis realistically reflect clinical outcomes. Unfortunately, even in this study, when aspirations were only performed when clinically indicated (in other words, aspiration was not performed solely because the endometrial thickness exceeded 15 mm), misoprostol is still only 70–80% successful after one dose.13 Importantly, we have been able to define the most ideal candidates for medical treatment with misoprostol alone.
Health care providers should discuss the options for treatment of early pregnancy failure with a keen sense of what the patient strongly desires. It is highly likely that the first-dose success rate may be most important for women, especially when the option is a vacuum aspiration that could be performed in a relatively short period of time. Women who have vaginal bleeding within the last 24 hours and a parity of less than 2 are the women most likely to be treated successfully with a single dose of misoprostol. Interestingly, Rh-negative women and those who have had lower abdominal pain in the last 24 hours are more than 90% likely, based on those individual factors, to have overall success, but each of these factors is not important in increasing the likelihood of success with a single dose of misoprostol.
Because women generally prefer some treatment to no treatment,5,29 the success rate of vaginal misoprostol for early pregnancy failure appears to be an advance in medical treatment. However, this rate is significantly lower than the success rates for combination treatment with mifepristone and misoprostol for medical abortion. Multiple large trials have demonstrated more than 95% complete abortion rates using mifepristone 200 mg followed 6–24 hours later by misoprostol 800 μg vaginally through 63 days of gestation.30,31 As clinicians and researchers, we must ask why women with an undesired normal pregnancy can receive a treatment regimen that is more effective than that tested for women with a desired abnormal early pregnancy. The information presented in this analysis will allow us to better tailor misoprostol treatment for early pregnancy failure.
1. Warburton D, Fraser FC. Spontaneous abortion risks in man: data from reproductive histories collected in a medical genetics unit. Am J Hum Genet 1964;16:1–25.
2. Hemminki E. Treatment of miscarriage: current practice and rationale. Obstet Gynecol 1998;247–53.
3. Macrow P, Elistein M. Managing miscarriage medically. BMJ 1993;306:876.
4. Ballagh SA, Harris HA, Demasio K. Is curettage needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279–82.
5. Jurkovic D, Ross JA, Nicolaides KH. Expectant management of missed miscarriage. Br J Obstet Gynaecol 1998;105:670–1.
6. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:38–47.
7. Creinin MD, Schwartz JL, Guido RS, Pymar HC. Early pregnancy failure: current management concepts. Obstet Gynecol Surv 2001;56:105–13.
8. Luise C, Jermy K, Collons WP, Bourne TH. Expectant management of incomplete, spontaneous first-trimester miscarriage: outcome according to initial ultrasound criteria and value of follow-up visits. Ultrasound Obstet Gynecol 2002;19:580–2.
9. Creinin MD, Harwood B, Guido RS, Fox MC, Zhang J. Endometrial thickness after misoprostol use for early pregnancy failure. Int J Gynaecol Obstet 2004;86:22–6.
10. Reynolds A, Ayres-de-Campos D, Costa MA, Montenegro N. How should success be defined when attempting medical resolution of first-trimester missed abortion? Eur J Obstet Gynecol Reprod Biol 2005;118:71–6.
11. Chung T, Leung P, Cheung LP, Haines C, Chang AM. A medical approach to management of spontaneous abortion using misoprostol: extending misoprostol treatment to a maximum of 48 hours can further improve evacuation of retained products of conception in spontaneous abortion. Acta Obstet Gynecol Scand 1997;76:248–51.
12. Chung TK, Lee DT, Cheung LP, Haines CJ, Chang AM. Spontaneous abortion: a randomized, controlled trial comparing surgical evacuation with conservative management using misoprostol. Fertil Steril 1999;71:1054–9.
13. 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;353:761–9.
14. Goldstein SR. Significance of cardiac activity on endovaginal ultrasound in very early embryos. Obstet Gynecol 1992;80:670–2.
15. Rowling SE, Coleman BG, Langer JE, Arger PH, Nisenbaum HL, Horii SC. First trimester US parameters of failed pregnancy. Radiology 1997;203:211–7.
16. Nyberg DA, Mack LA, Laing FC, Patten RM. Distinguishing normal from abnormal gestational sac growth in early pregnancy. J Ultrasound Med 1987;6:23–7.
17. Harwood B, Meckstroth KR, Mishell DR, Jain JK. Serum beta-human chorionic gonadotropin levels and endometrial thickness after medical abortion. Contraception 2001;63:255–6.
18. el-Rafaey H, Rajasekar D, Abdalla M, Calder L, Templeton A. Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med 1995;332:983–7.
19. Creinin MD, Darney PD. Methotrexate and misoprostol for early abortion [published erratum appears in Contraception 1994;49:99]. Contraception 1993;48:339–48.
20. Creinin MD, Moyer R, Guido R. Misoprostol for medical evacuation of early pregnancy failure. Obstet Gynecol 1997;89:768–72.
21. Nielsen S, Hahlin M, Platz-Christensen Unsuccessful treatment of missed abortion with a combination of an antiprogesterone and a prostaglandin E1 analogue. Br J Obstet Gynaecol 1997;104:1094–6.
22. Zalányi S. Vaginal misoprostol alone is effective in the treatment of missed abortion. Br J Obstet Gynaecol 1998;105:1026–8.
23. Nielsen S, Hahlin M, Platz-Christensen Randomised trial comparing expectant with medical management for first trimester miscarriages. Br J Obstet Gynaecol 1999;106:804–7.
24. Gronlund L, Gronlund AL, Clevin L, Andersen B, Palmgren N, Lidegaard O. Spontaneous abortion: expectant management, medical treatment or surgical evacuation. Acta Obstet Gynecol Scand 2002;81:781–2.
25. Graziosi GCM, Mol BWJ, Reuwer PJH, Drogtrop A, Bruinse HW. Misoprostol versus curettage in women with early pregnancy failure after initial expectant management: a randomized trial. Hum Reprod 2004;19:1894–9.
26. Moodliar S, Bagratee JS, Moodley J. Medical vs surgical evacuation of first-trimester spontaneous abortion. Int J Gynaecol Obstet 2005;91:21–6.
27. Blohm F, Friden BE, Milsom I, Platz-Christensen Nielsen S. A randomised double blind trial comparing misoprostol or placebo in the management of early miscarriage. BJOG 2005;112:1090–5.
28. Schreiber C, Creinin M. Mifepristone in abortion care. Semin Reprod Med 2005;23:82–91.
29. Luise C, Jermy K, May C, Costello G, Collins WP, Bourne TH. Outcome of expectant management of spontaneous first trimester miscarriage: observational study. BMJ 2002;324:873–5.
30. Schaff EA, Fielding SL, Westhoff C. Randomized trial of oral versus vaginal misoprostol at one day after mifepristone for early medical abortion. Contraception 2001;64:81–5.
31. Creinin MD, Fox MC, Teal S, Chen A, Schaff EA, Meyn LA. A randomized comparison of misoprostol 6 to 8 hours versus 24 hours after mifepristone for abortion. MOD Study Trial Group. Obstet Gynecol 2004;103:851–9
The National Institute of Child Health and Human Development Management of Early Pregnancy Failure Trial (principal investigators are indicated by asterisks)
National Institute of Child Health and Human Development: J. Zhang*, T. Nansel; Columbia University: C. Westhoff*, A. Davis, C. Robilotto; University of Miami: J. Gilles*, M. Diro, F. Doyle, N. Vazquez; University of Pennsylvania: K. Barnhart*, J. Hollander, K. Timbers, A. Hummel, L. Martino; University of Pittsburgh: M. Creinin*, B. Harwood, R. Guido, A. Murthy, C. Schreiber, L. Reid; and Clinical Trials and Surveys Corporation: M. Frederick*, X. K. Huang.