1 Department of Obstetrics and Gynecology, Columbia University, 630 West 168th Street, New York, NY 10032, 2 Clinical Trials and Surveys Corporation, 2 Hamill Road, Suite 350 West Quadrangle, Baltimore, MD 21210-1874 and 3 Epidemiology Branch, National Institute of Child Health and Human Development, National Institute of Health, 6100 Executive Blvd, Room 7B03, Rockville, MD 20852, USA
4 To whom correspondence should be addressed. e-mail: ard4{at}columbia.edu)
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Abstract |
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Key words: bleeding/early pregnancy failure/misoprostol
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Introduction |
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Both women and health care providers will benefit from information regarding bleeding patterns after medical management of EPF. Information about the duration and quantity of bleeding will aid in counselling regarding medical versus surgical options. In a study using 6 weeks of diary data, participants reported more bleeding and spotting days after voluntary medical abortion (mean 24 days) than after voluntary surgical abortion (mean 19 days) (Davis et al., 2000). Bleeding data from voluntary abortion studies may not be generalizable to EPF. Physiological differences between ongoing pregnancies and early pregnancy failures may result in different bleeding patterns after management with prostaglandins.
Little detailed information regarding bleeding after medical management of miscarriage has been published. For subjective bleeding outcomes, most studies rely on retrospective reporting rather than diary data, and do not distinguish heavy from light bleeding. No study has included data on sanitary product use, which might guide clinical management of bleeding. Most studies include objective outcomes such as haemoglobin changes after treatment. No study, however, has related subjective bleeding reports to changes in haemoglobin.
The objective of the current analysis was to describe bleeding patterns, sanitary product use and changes in haemoglobin following vaginal misoprostol for EPF.
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Materials and methods |
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Healthy women diagnosed with EPF were offered enrolment when ultrasound documented at least one of the following: (i) crownrump length between 5 and 40 mm without cardiac activity (fetal demise); (ii) gestational sac between 16 and 45 mm mean diameter without an embryonic pole (anembryonic gestation); (iii) no growth of the gestational sac or embryonic pole over 1 week; or (iv) abnormal rise in serum HCG level of <15% over 2 days with a yolk sac present. Other inclusion criteria included willingness to accept randomization and comply with the study protocol, access to a telephone, venous access and age
18 years. We excluded women with orthostatic hypotension, recent use of ovulation stimulation drugs, contraindication to non-steroidal anti-inflammatory drugs (NSAIDs), use of medication to induce miscarriage, known or suspected ectopic pregnancy, haemoglobin <9.5 mg/dl, current clotting disorder or use of anticoagulants, cardiovascular disease, current breast feeding, or karyotyping required.
At enrolment, all women underwent a transvaginal ultrasound to confirm non-viability as well as a pelvic exam and medical history. Laboratory tests included a baseline and 14 day haemoglobin level. After obtaining informed consent, participants were randomized to receive 800 µg of moistened (2 ml of saline) or dry misoprostol (Searle, Chicago, IL). A speculum was inserted and four, 200 µg tablets of misoprostol were placed into the posterior fornix with or without 2 ml of saline.
Each woman received a daily diary to record bleeding for 2 weeks. For each 24 h period, participants indicated if bleeding was (i) none; (ii) spotting; (iii) light; (iv) moderate; (v) heavy; and (vi) more than two pads/h. Participants selected the category of bleeding without guidance or definition by study staff. Participants also indicated the number of sanitary pads or tampons used daily. Haemoglobin measurement was repeated at 2 weeks at the local laboratory.
Success was defined as complete expulsion of the gestational sac without D&C for any reason. As per the study protocol, the success rate was calculated at 30 days after misoprostol treatment (Gilles et al., 2004). By day 30, 10 women underwent D&C for a success rate of 85%. Additionally, three D&Cs occurred after day 30. There was no difference in success rates between participants who received dry versus moistened misoprostol. The bleeding patterns were similar in the dry and moistened misoprostol groups (data not shown). Therefore, the groups are combined and results of the bleeding analyses are presented as one cohort.
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Results |
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At enrolment, 55% of the women reported cramping and 53% reported bleeding during the 24 h prior to treatment. The most common pattern was some bleeding or spotting every day for 14 days. The median number of bleeding or spotting days after treatment was 12. In this analysis, heavy bleeding included the following categories: moderate, heavy or more than two pads/h. Heavy bleeding was much less frequent than light bleeding or spotting. Participants reported a median of 3 days of heavy bleeding (10th percentile 1 day, 90th percentile 9 days).
The pattern of bleeding over time is presented in Figure 1 by the proportion of participants reporting any bleeding or heavy bleeding by study day. In this figure, days with missing diary data are excluded. Since some participants stopped diary entry when bleeding stopped, this may be an overestimate of the true proportion with bleeding. Almost all participants bled throughout the first week, with a modest decline during the second week. Heavy bleeding usually occurred during the first few days after treatment and declined sharply thereafter. The data were similar after participants undergoing D&C were excluded.
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Neither total days of bleeding nor pad counts was associated with change in haemoglobin (correlation days bleeding and change in haemoglobin r = 0.003, correlation total pads and change in haemoglobin r = 0.184). Reported days with moderate or greater bleeding was associated with a decrease in haemoglobin (r = 0.31, P = 0.014). Participants in the highest quartile of heavy bleeding days (>6 days) had a larger drop in haemoglobin (0.99 g/dl) than those reporting fewer heavy bleeding days (0.3 g/dl) (P = 0.045).
Thirteen subjects underwent D&C after misoprostol; one subject underwent two D&Cs. Of the 14 D&Cs, eight were performed as per the study protocol for a retained gestational sac after the second dose of misoprostol. One subject decided not to wait for expulsion after misoprostol and opted for a D&C on study day 2. Five D&Cs were performed for bleeding complaints, and Table II summarizes the clinical course for these subjects. Bleeding patterns reported in the 2 week diary were similar for subjects who underwent D&C for bleeding complaints and those who did not (data not shown). Detailed information on bleeding for subjects who underwent D&C after completion of their 2 week diary is unknown.
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Discussion |
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Overall, misoprostol treatment was safe. Clinically important changes in haemoglobin were very uncommon. Of the five women who underwent D&C for subjective prolonged or heavy bleeding, only one had a large decrease in haemoglobin. No participant required blood transfusion. This agrees with other reports using misoprostol for EPF (Muffley et al., 2002; Wood and Brain, 2002
), and large trials using misoprostol after mifepristone for voluntary abortion (Peyron et al., 1993
; El-Refaey et al., 1995
). A few women, however, will experience important blood loss which can be obscured in analyses of mean changes. This study lacked the power to identify risk factors for uncommon but clinically important decreases in haemoglobin. Since these events are rare, even a large study may fail to identify risk factors.
This study provides the most comprehensive analysis of bleeding after medical management of EPF to date. Daily bleeding for at least 2 weeks was the most often reported pattern. Heavy bleeding days were few and limited to the first few days after treatment. The duration of bleeding was longer than reported in studies using a similar regimen (El-Refaey et al., 1992; Chung et al., 1999
). The use of daily diaries, rather than retrospective recall, and a longer duration of observation could explain this difference. Davis reported a bleeding pattern very similar to our results in a prospective, 6 week diary study of bleeding after mifepristone and misoprostol for voluntary termination of pregnancy. Ninety-five percent of participants reported bleeding at 7 days and 60% reported bleeding at 2 weeks (Davis et al., 2000
). Since bleeding after 2 weeks cannot be determined from our data, we underestimate the total days of bleeding after treatment. Davis reported a mean of 24 days of bleeding or spotting during the 6 weeks after mifepristone and misoprostol (Davis et al., 2000
). To obtain a more comprehensive description of bleeding patterns, future studies should include a longer duration of follow-up.
Subjective measures of participant experience correlated poorly with objective measures of blood loss. Neither total days of bleeding nor use of sanitary pads was associated with changes in haemoglobin. There was a modest association between heavy bleeding days and decreases in haemoglobin. Clinically important changes were infrequent among participants reporting the most days of heavy bleeding. Ongoing heavy bleeding should alert clinicians to be vigilant, but surgical intervention is rarely necessary. Variable personal habits or insufficient detail could explain the lack of association between pad counts and changes in haemoglobin. Women can choose from many sanitary products with variable capacity. The study diary did not distinguish products designed for light flow from those for heavy flow.
Episodes of prolonged or delayed bleeding may occur following medical management of EPF and occasionally lead to D&C. While uncommon, four participants underwent D&C for bleeding complaints >2 weeks after treatment and apparent successful expulsion of the gestational sac. Our rate of late D&Cs may be an underestimate if subjects sought care from an outside institution after active surveillance had ended. Delayed treatment failures can also occur after medical regimens for voluntary abortion. In two large trials using mifepristone and misoprostol for medical abortion (n = 4393), 59 (1.3%) women underwent D&C for bleeding complaints and 41 of these occurred >2 weeks after treatment (Allen et al., 2001). In our study, late bleeding was associated with histological findings of degenerating products of conception at the time of D&C. While suggestive, we cannot determine if these retained tissues contributed to bleeding complaints. Future studies of bleeding which include longer durations of follow-up may identify predictors of late D&C. Such studies would need to be large since late D&C is uncommon.
Conclusion
Bleeding for 2 weeks after vaginal misoprostol for EPF is common. Heavy bleeding is usually limited to a few days after treatment. Clinically important changes in haemoglobin after misoprostol use are rare. Though uncommon, delayed episodes of prolonged or heavy bleeding requiring D&C can occur following medical management of EPF.
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Acknowledgements |
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References |
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Submitted on January 15, 2004; accepted on April 5, 2004.
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