Medical management of early pregnancy failure

Early pregnancy failure (EPF; that is, pregnancy failure in the first trimester) can be devastating for women and their partners. The diagnosis may be preceded by days or weeks of cramping, bleeding, and hoping. Once the diagnosis is made, women are most satisfied when they are given management options and can choose the one that best fits their needs (Table 1).¹ Medical management of EPF is a safe and desirable option for some women.

Epidemiology of EPF

EPF is an inclusive term that comprises incomplete, complete, or inevitable spontaneous abortion; anembryonic gestation (blighted ovum); and embryonic demise (missed abortion) at less than 14 weeks.²

Approximately 15% to 20% of clinically recognized pregnancies end in EPF.^2,3 Many EPFs occur before pregnancies have been clinically recognized (that is, women mistake them for “late cycles”). It is estimated that up to 60% of all conceptions end in early losses.⁴ Chromosomal abnormalities, most commonly translocations and aneuploidy, are responsible for more than half of all spontaneous EPFs.⁵ Other genetic defects that are currently impossible to discern by simple karyotype may be the cause of many spontaneous losses.

Diagnosis of EPF

The diagnosis of EPF may be suspected on signs and symptoms (vaginal bleeding, lower abdominal cramping, dilation of cervix) but is usually made by transvaginal ultrasound (U/S) and/or symptoms and serial beta human chorionic gonadotropin (BhCG) levels. Women with EPF may also be asymptomatic.

The term “spontaneous abortion” includes complete abortion, incomplete abortion, inevitable abortion, anembryonic pregnancy, and embryonic or fetal demise. In the case of a complete abortion, the patient has had a positive pregnancy test, has experienced vaginal bleeding with passage of tissue, and has a closed cervical os.⁶  In the case of incomplete abortion, the patient has had a positive pregnancy test, vaginal bleeding, and may have a closed or open cervical os. An endometrial thickness measurement distinguishing incomplete from complete abortion has not been established.^2,6,7

An EPF that is characterized by a history of a positive pregnancy test, vaginal bleeding without passage of tissue, and an open cervical os is termed an inevitable abortion.⁸  Anembryonic pregnancy, which was previously termed “blighted ovum,”⁶ describes the  absence of a visible yolk sac with a mean sac diameter (MSD) of 13 mm, the absence of an embryonic pole with MSD of 20 mm, or the presence of an empty amnion. Embryonic or fetal demise, previously termed “missed abortion,” describes the failure of a previously identified embryo to grow or show cardiac activity, or the absence of cardiac motion in embryos ≥5 mm.^6,9

Management options for EPF

In general, there are 3 options for management of EPF: expectant, medical, and surgical management (Table 1).¹ Expectant management consists of no intervention and awaiting natural passage of tissue. Medical management uses medication to expel uterine tissue. Surgical management is defined by mechanical removal of tissue from the uterus.

Successful management of EPF entails complete evacuation of the uterus. The success of each of these approaches depends on several factors including the type of loss (eg, with or without symptoms such as bleeding and cramping) and the gestational age.

Medical management of EPF

Medical management is a safe and effective alternative to expectant management or surgical management of EPF.¹ Medical management allows patients to avoid surgery and anesthesia. Patients may also feel that medical management is more “natural,” private, and under their control. Several medications have been studied for medical management.

Mifepristone is an antiprogestin that causes weakening of the uterine attachment of a pregnancy, resulting in capillary breakdown and synthesis of prostaglandins. Trials of mifepristone added to misoprostol have had conflicting results.^10,11

Misoprostol, a prostaglandin E1 analogue, is a uterotonic that results in cervical softening and contractions that expel the products of conception. It may be administered vaginally, orally, buccally, or sublingually. Adverse effects vary based on route of administration.^9,12

Misoprostol: route, dose, and safety

There is published literature on a wide range of therapeutic misoprostol regimens.^2,13,14 Optimal dose and route of administration of misoprostol have not been determined by randomized trials. Overall, misoprostol is safe and well-tolerated.⁹

Route: Patients receiving misoprostol vaginally rather than orally have decreased adverse gastrointestinal effects and prolonged duration of action.⁹ Oral misoprostol is less effective than vaginal misoprostol in emptying the uterus. Sublingual misoprostol is equivalent to vaginal misoprostol in inducing complete uterine emptying but is associated with more frequent diarrhea. There is no advantage to “wet” preparation (moistened with water) versus “dry” preparation of vaginal misoprostol.

Dosage: When compared with lower dosages, a dose of 800 mcg vaginal misoprostol is more effective at completing uterine emptying, although it results in a similar incidence of nausea.⁹ Based on international trials in settings with limited resources, WHO recommends a single oral dose of 600 mcg misoprostol for medical management of incomplete abortion and a single vaginal dose of 800 mcg misoprostol for medical management of anembryonic pregnancy and embryonic/fetal demise.^15,16 A single dose of misoprosotol 600 mcg administered sublingually is an alternative regimen.¹⁶ However, it is well proven that the success of medical management of EPF increases with multiple-dose regimens.¹⁷ Misoprostol 800 mcg administered vaginally is the most studied regimen for medical management of EPF.

Success of medical management for EPF

Success of medical management should be determined by expulsion of the gestational sac, rather than by endometrial thickness on transvaginal U/S. Studies that use an endometrial thickness of  >15 mm to define failure of medical management may underestimate success rates of expectant and medical management.²

Patients with symptoms such as cramping and bleeding, which are indicative of a clinical diagnosis of an incomplete or inevitable spontaneous abortion, experience greater success with medical management.^17,18 Success of medical management increases with multiple dose regimens.¹⁷ The most studied multiple-dose regimen of misoprostol is 800 mcg vaginal misoprostol, repeated on day 3 if there is incomplete expulsion, as diagnosed by a persistent gestational sac on transvaginal U/S.^17,19

Medical versus surgical management

In a Cochrane review (9 randomized controlled trials [RCTs], n=1766) with incomplete abortion before 13 weeks, where misoprostol was used orally or vaginally, there was no significant difference in success defined by complete miscarriage.¹⁸ Not surprisingly, women using misoprostol have fewer surgical procedures, and a higher risk of unplanned procedures.

The largest multicenter RCT (n=652) compared women with EPF (94% anembryonic gestation or embryonic/fetal demise, 6% incomplete/inevitable abortion) treated with 800 mcg vaginal misoprostol (n=491) or surgical management (n= 161).¹⁹ In the misoprostol arm, women received 800 mcg vaginal misoprostol, repeated on day 3 if expulsion was incomplete (diagnosed by persistence of gestational sac). Surgical aspiration was performed on day 8 if expulsion was incomplete. With one dose of misoprostol, there was 71% successful evacuation. Success increased with a second 800-mcg dose of vaginal misoprostol if the gestational sac was still present on U/S on day 3. The overall success was 84% with misoprostol and 97% with surgical management. Success of medical management did not vary by gestational age, but did differ by type of EPF: 93% for incomplete/inevitable abortion, 88% for embryonic/fetal demise, 81% for anembryonic pregnancy. There was no difference in hemorrhage or endometritis between the groups (<1%).

Since medical management with misoprostol is an acceptable alternative to surgical evacuation, patient preference should guide decision making.^18,19

Medical versus expectant management

In 24 RCTs (n=1888) comparing medical to expectant management for embryonic/fetal demise or anembryonic pregnancy, medical management was shown to be significantly more effective than expectant management.^9,18 Most studies investigated vaginal misoprostol.⁹

Compared with expectant management, vaginal misoprostol shortens the time to achieve complete uterine evacuation at less than 24 hours after treatment and at less than 48 hours after treatment.

Patient counseling

Patients choosing medical management of EPF should have appropriate counseling regarding expected symptoms. Bleeding with medical management is heavier and longer in duration than with surgical management, but rarely requires intervention.²⁰ Women report approximately 12 days of bleeding after medical management. Bleeding will most likely be heavy for about 3 to 4 days, followed by light bleeding or spotting for several weeks.¹⁵

Patients should be counseled to contact their physicians if they experience heavy vaginal bleeding (soaking through more than 2 extra large sanitary pads per hour for 2 consecutive hours) or signs of infection.¹⁵

Some women experience fever and/or chills during the first 24 hours after misoprostol use.¹⁵ Patients should call their doctors and be evaluated for infection if fever and/or chills persist beyond 24 hours. Nausea and vomiting may occur and will usually resolve 2 to 6 hours after taking misoprostol.

Contraindications and complications

Table 2 presents a list of contraindications to medical management.^13,15,19

Complications after medical management of EPF are rare. The incidence of gynecologic infection after surgical, expectant, or medical management of EPF is low (2%-3%). There is no evidence to show a differential risk of infection by management choice.²¹ In the largest RCT (n=652) comparing medical with surgical management, there were no differences in the following complications: hemorrhage requiring hospitalization with or without blood transfusion (1%); hospitalization for endometritis (<1%), fever (3%-4%); emergency visit to hospital within 24 hours of treatment (2%-3%), unscheduled hospital visits (17%-23%); decrease in hemoglobin ≥2 g/dL (4%-9%); and decrease in hemoglobin ≥3 g/dL (1%-5%).¹⁹

Failure of medical management

Failure of expectant or medical management results in the need for surgical evacuation.

Follow-up

No RCTs have assessed optimal follow up after EPF. We recommend a follow-up visit that includes a clinical history and bimanual exam 7 to 14 days after medication use.¹⁵ In general, BhCG levels do not need to be followed after either expectant or medical management.

Transvaginal U/S after medical management of EPF can be used to confirm successful expulsion of the gestational sac.¹⁵ Endometrial thickness after medical management should not be measured as it is not predictive of success.⁷ Endometrial thickness does not predict retained products of conception or need for surgical evacuation.

Future fertility

A long-term study of women who had had expectant, medical, or surgical management of EPF found that the method of management for EPF does not affect future fertility. In this RCT there was no significant difference in the live birth rate 5 years after miscarriage: 79% among women who had expectant management; 79% among women who had medical management; and 82% among women who had surgical management.²²

Cost-effectiveness

When accounting for multiple cost-associated variables, surgical management with office manual vacuum aspiration is generally more cost-effective than medical management. However, medical management is more cost-effective than surgical management in an operating room. For incomplete or inevitable abortion, medical management is the most cost-effective treatment method.²³

Patient acceptability

In a large RCT comparing medical and surgical management of EPF, women who had undergone medical management reported more symptoms such as cramping and bleeding. However they reported similar quality-of-life and acceptability measurements as women who had surgical management.²⁴ In another large RCT comparing medical and surgical management, 83% of women who underwent medical management with misoprostol reported that they would recommend medical management to others. Seventy-eight percent reported that they would “probably” or “absolutely” use medical management again.¹⁹

Patient preference

Preferences regarding management of EPF are diverse.²⁵ Women’s preferences may depend upon their desire for privacy, their reluctance to undergo surgery, and their expectations concerning EPF management options. Since all currently available options for treatment of EPF are similar in safety and efficacy, patient preference should guide physicians.

References

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2. Chen BA, Creinin MD. Medical management of early pregnancy failure: efficacy. Semin Reprod Med. 2008;26(5):411-422.

3. Hemminki E. Treatment of miscarriage: current practice and rationale. Obstet Gynecol. 1998;91(2):247-253.

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7. Reeves MF, Lohr PA, Harwood BJ, Creinin MD. Ultrasonographic endometrial thickness after medical and surgical management of early pregnancy failure. Obstet Gynecol. 2008;111(1):106-112.

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10. Stockheim D, Machtinger R, Wiser A, et al. A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure. Fertil Steril. 2006;86(4):956-960.

11. Kollitz KM, Meyn LA, Lohr PA, Creinin MD. Mifepristone and misoprostol for early pregnancy failure: a cohort analysis. Am J Obstet Gynecol. 2011;204(5):386.e1-386.e6.

12. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet. 2007;99(Suppl 2):S160-S167.

13. Royal College of Obstetricians and Gynaecologists (RCOG). Green-top guideline no. 25. The management of early pregnancy loss. http://www.rcog.org.uk/womens-health/clinical-guidance/management-early-pregnancy-loss-green-top-25. Published October 2006. Accessed April 17, 2013. 

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16. Gemzell-Danielsson K, Ho PC, Gómez Ponce de León R, Weeks A, Winikoff B. Misoprostol to treat missed abortion in the first trimester. Int J Gynaecol Obstet. 2007;99(Suppl 2):S182-S185. 

17. Creinin MD, Huang X, Westhoff C, et al; National Institute of Child Health and Human Development Management of Early Pregnancy Failure Trial. Factors related to successful misoprostol treatment for early pregnancy failure. Obstet Gynecol. 2006;107(4):901-907.  

18. Neilson JP, Gyte GM, Hickey M, Vazquez JC, Dou L. Medical treatments for incomplete miscarriage (less than 24 weeks). Cochrane Database Syst Rev. 2010;(1):CD007223. Update in: Cochrane Database Syst Rev. 2013;3:CD007223.

19. Zhang J, Gilles JM, Barnhart K, et al; National Institute of Child Health and Human Development (NICHD) Management of Early Pregnancy Failure Trial. A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med. 2005;353(8):761-769.

20. Davis AR, Hendlish SK, Westhoff C, et al; National Institute of Child Health and Human Development Management of Early Pregnancy Failure Trial. Bleeding patterns after misoprostol vs surgical treatment of early pregnancy failure: results from a randomized trial. Am J Obstet Gynecol. 2007;196(1):31.e1-31.e7.

21. Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment [MIST] trial). BMJ. 2006;332(7552):1235-1240.

22. Smith LF, Ewings PD, Quinlan C. Incidence of pregnancy after expectant, medical, or surgical management of spontaneous first trimester miscarriage: long term follow-up of miscarriage treatment (MIST) randomised controlled trial. BMJ. 2009;339:b3827. 

23. Rausch M, Lorch S, Chung K, Frederick M, Zhang J, Barnhart K. A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss. Fertil Steril. 2012;97(2):355-360.

24. Harwood B, Nansel T; National Institute of Child Health and Human Development Management of Early Pregnancy Failure Trial. Quality of life and acceptability of medical versus surgical management of early pregnancy failure. BJOG. 2008;115(4):501-508.

25. Wallace RR, Goodman S, Freedman LR, Dalton VK, Harris LH. Counseling women with early pregnancy failure: utilizing evidence, preserving preference. Patient Educ Couns. 2010;81(3):454-461. 

Dr. Gariepy is an assistant professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale University, New Haven, Connecticut.

Dr. Stanwood is an associate professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale University, New Haven.

The authors have no conflicts of interest to disclose with respect to the content of this article.