Medical treatment for early fetal death (less than 24 weeks): Cochrane systematic review

Abstract

Background

In most pregnancies that miscarry, arrest of embryonic or fetal development occurs some time (often weeks) before the miscarriage occurs. Ultrasound examination can reveal abnormal findings during this phase by demonstrating anembryonic pregnancies or embryonic or fetal death. Treatment has traditionally been surgical but medical treatments may be effective, safe, and acceptable, as may be waiting for spontaneous miscarriage. This is an update of a review first published in 2006.

Objectives

To assess, from clinical trials, the effectiveness and safety of different medical treatments for the termination of non-viable pregnancies.

Search methods

For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (24 October 2018) and reference lists of retrieved studies.

Selection criteria

Randomised trials comparing medical treatment with another treatment (e.g. surgical evacuation), or placebo, or no treatment for early pregnancy failure. Quasi-randomised studies were excluded. Cluster-randomised trials were eligible for inclusion, as were studies reported in abstract form, if sufficient information was available to assess eligibility.

Data collection and analysis

Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach.

Main results

Forty-three studies (4966 women) were included. The main interventions examined were vaginal, sublingual, oral and buccal misoprostol, mifepristone and vaginal gemeprost. These were compared with surgical management, expectant management, placebo, or different types of medical interventions were compared with each other. The review includes a wide variety of different interventions which have been analysed across 23 different comparisons. Many of the comparisons consist of single studies. We limited the grading of the quality of evidence to two main comparisons: vaginal misoprostol versus placebo and vaginal misoprostol versus surgical evacuation of the uterus. Risk of bias varied widely among the included trials. The quality of the evidence varied between the different comparisons, but was mainly found to be very-low or low quality.

Vaginal misoprostol versus placebo

Vaginal misoprostol may hasten miscarriage when compared with placebo: e.g. complete miscarriage (5 trials, 305 women, risk ratio (RR) 4.23, 95% confidence interval (CI) 3.01 to 5.94; low-quality evidence). No trial reported on pelvic infection rate for this comparison. Vaginal misoprostol made little difference to rates of nausea (2 trials, 88 women, RR 1.38, 95% CI 0.43 to 4.40; low-quality evidence), diarrhoea (2 trials, 88 women, RR 2.21, 95% CI 0.35 to 14.06; low-quality evidence) or to whether women were satisfied with the acceptability of the method (1 trial, 32 women, RR 1.17, 95% CI 0.83 to 1.64; low-quality evidence). It is uncertain whether vaginal misoprostol reduces blood loss (haemoglobin difference > 10 g/L) (1 trial, 50 women, RR 1.25, 95% CI 0.38 to 4.12; very-low quality) or pain (opiate use) (1 trial, 84 women, RR 5.00, 95% CI 0.25 to 101.11; very-low quality), because the quality of the evidence for these outcomes was found to be very low.

Vaginal misoprostol versus surgical evacuation

Vaginal misoprostol may be less effective in accomplishing a complete miscarriage compared to surgical management (6 trials, 943 women, average RR 0.40, 95% CI 0.32 to 0.50; Heterogeneity: Tau² = 0.03, I² = 46%; low-quality evidence) and may be associated with more nausea (1 trial, 154 women, RR 21.85, 95% CI 1.31 to 364.37; low-quality evidence) and diarrhoea (1 trial, 154 women, RR 40.85, 95% CI 2.52 to 662.57; low-quality evidence). There may be little or no difference between vaginal misoprostol and surgical evacuation for pelvic infection (1 trial, 618 women, RR 0.73, 95% CI 0.39 to 1.37; low-quality evidence), blood loss (post-treatment haematocrit (%) (1 trial, 50 women, mean difference (MD) 1.40%, 95% CI -3.51 to 0.71; low-quality evidence), pain relief (1 trial, 154 women, RR 1.42, 95% CI 0.82 to 2.46; low-quality evidence) or women's satisfaction/acceptability of method (1 trial, 45 women, RR 0.67, 95% CI 0.40 to 1.11; low-quality evidence).

Other comparisons

Based on findings from a single trial, vaginal misoprostol was more effective at accomplishing complete miscarriage than expectant management (614 women, RR 1.25, 95% CI 1.09 to 1.45). There was little difference between vaginal misoprostol and sublingual misoprostol (5 trials, 513 women, average RR 0.84, 95% CI 0.61 to 1.16; Heterogeneity: Tau² = 0.10, I² = 871%; or between oral and vaginal misoprostol in terms of complete miscarriage at less than 13 weeks (4 trials, 418 women), average RR 0.68, 95% CI 0.45 to 1.03; Heterogeneity: Tau² = 0.13, I² = 90%). However, there was less abdominal pain with vaginal misoprostol in comparison to sublingual (3 trials, 392 women, RR 0.58, 95% CI 0.46 to 0.74). A single study (46 women) found mifepristone to be more effective than placebo: miscarriage complete by day five after treatment (46 women, RR 9.50, 95% CI 2.49 to 36.19). However the quality of this evidence is very low: there is a very serious risk of bias with signs of incomplete data and no proper intention-to-treat analysis in the included study; and serious imprecision with wide confidence intervals. Mifepristone did not appear to further hasten miscarriage when added to a misoprostol regimen (3 trials, 447 women, RR 1.18, 95% CI 0.95 to 1.47).

Authors' conclusions

Available evidence from randomised trials suggests that medical treatment with vaginal misoprostol may be an acceptable alternative to surgical evacuation or expectant management. In general, side effects of medical treatment were minor, consisting mainly of nausea and diarrhoea. There were no major differences in effectiveness between different routes of administration. Treatment satisfaction was addressed in only a few studies, in which the majority of women were satisfied with the received intervention. Since the quality of evidence is low or very low for several comparisons, mainly because they included only one or two (small) trials; further research is necessary to assess the effectiveness, safety and side effects, optimal route of administration and dose of different medical treatments for early fetal death.

Author(s)

Lemmers Marike, Verschoor Marianne AC, Kim Bobae Veronica, Hickey Martha, Vazquez Juan C, Mol Ben Willem J, Neilson James P

Summary

Medical treatment for early fetal death (less than 24 weeks)

What is the issue?

A miscarriage is the spontaneous death and/or expulsion of an embryo or fetus from the uterus before it is able to survive on its own. This natural death of an embryo or fetus ('non-viable pregnancy' or 'intrauterine fetal death', depending on the duration of pregnancy) can be identified by ultrasound before symptoms like blood loss and abdominal pain occur. Sometimes an embryo may not have even developed ('empty sac'). In the past, treatment for a deceived embryo/fetus, has usually been by dilatation and curettage (D&C) surgery, but drugs have now been developed to replace the need for surgery which may be helpful for the expulsion to happen. Misoprostol and gemeprost are synthetic prostaglandin E analogues that can stimulate expulsion of the embryo/fetus from the uterus. Mifepristone blocks the activity of progesterone, a hormone that supports pregnancy. These and similar drugs may be useful in bringing on expulsion in women with a non-viable pregnancy and can be used before 24 weeks' gestation.

Waiting for spontaneous expulsion is also possible. Women who retain the dead embryo/fetus can experience severe blood loss or develop an infection of the womb. These are rare complications. Gastro-intestinal side effects such as nausea and diarrhoea, cramping or abdominal pain and fever have been reported with misoprostol.

Why is this important?

Surgical treatment has the disadvantage of requiring anaesthesia. It carries risks of damage to the uterus or cervix and possible development of fibrous tissue in the inner lining of the uterus. These can be avoided if the non-viable pregnancy is treated with medication, or if the woman is able to wait for a spontaneous expulsion.

We set out to determine if medical treatment is as good as, or better than, surgical treatment or expectant management (waiting for the expulsion to happen). Furthermore, we compared different doses and administration routes in order to detect which regimen most often induces a complete miscarriage with the fewest side effects.

What evidence did we find?

For this updated review, 43 randomised clinical trials involving 4966 women with non-viable pregnancies at less than 24 weeks' gestation were included. The main interventions examined were vaginal, sublingual, oral and buccal misoprostol, mifepristone and vaginal gemeprost. These were compared with surgical management, expectant management, placebo, or different types of medical interventions were compared with each other. Fourteen comparisons had only one trial. The studies varied in risk of bias. The quality of the evidence ranged from very low or low for most comparisons.

Vaginal misoprostol may hasten miscarriage when compared with placebo but made little difference to rates of nausea, diarrhoea or to whether women were satisfied with the acceptability of the method. It is uncertain whether vaginal misoprostol when compared to placebo reduces blood loss or pain because the quality of the evidence for these outcomes was found to be very low.

Vaginal misoprostol was less effective in accomplishing a complete miscarriage compared to surgical management and may be associated with more nausea and diarrhoea. Vaginal misoprostol made little difference to pelvic infection, blood loss, pain or women's satisfaction/acceptability of method when compared to surgical management.

There was little difference between different routes of giving misoprostol when trials compared the vaginal route with placing it under the tongue or between oral and vaginal misoprostol. Single studies found mifepristone to be more effective than placebo and vaginal misoprostol to be more effective than expectant management. However the quality of this evidence was found to be very low and so we are not convinced of these findings. Mifepristone did not appear to provide any additional benefit when added to misoprostol.

What does this mean?

Using misoprostol as an alternative to surgical treatment may decrease the need for surgery for women with an early fetal death. The use of misoprostol can have some side effects such as nausea and diarrhoea, but risks of severe blood loss or pelvic infection were not higher compared to surgical treatment or expectant management. Further research is needed on drug doses, routes of administration and potential adverse effects, including future fertility, and also on women's views of drug treatment, surgery and waiting for spontaneous miscarriage.

Reviewer's Conclusions

Implications for practice

Available evidence from randomised trials supports the use of misoprostol as one possible option for the treatment of non-viable pregnancies before 24 weeks. In general, side effects of medical treatment were minor. There were no major differences in effectiveness between different routes of administration. Treatment satisfaction was addressed in only a few studies, in which the majority of women were satisfied with the received intervention.

There is intense interest in the reproductive uses of misoprostol because it appears a potent method for pregnancy interruption as well as being cheap and stable at room temperature. Using misoprostol as an alternative to surgical treatment for early fetal death could decrease the number of curettages, thus preventing women from the specific risks that are related to surgical intervention.

Implications for research

Ultrasound demonstration of early pregnancy failure before 14 weeks is a common problem that merits greater research effort than has occurred to date. Further research to assess the effectiveness, safety and side effects of misoprostol, including optimal route of administration and dose, should focus on the dose regimens that tend to be most effective according to our review results: vaginal or sublingual misoprostol in higher dosages. Women's views about the acceptability of medical treatment, surgical treatment and expectant management could be integral to future research protocols, as could economic assessments. Long-term outcomes, notably subsequent fertility, deserves further study in appropriately powered randomised controlled studies.

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