Medical management of miscarriage
- Miscarriage is a common event in women of reproductive age, with an incidence of 10–20%.
- Traditionally, surgical evacuation of the uterus was the gold standard for the management of miscarriage.
- Medical management of miscarriage using a suitable prostaglandin analogue is a safe and effective alternative with high efficacy and patient acceptability.
- Medical management can be routinely offered as an alternative option, thereby increasing women's choice.
- To understand the indications, efficacy and adverse effects of medical treatment.
- To learn about the various treatment regimens of medical management for different types of miscarriage at varying gestations.
- To understand the need for analgesia and psychological support during treatment.
- Prescribing misoprostol for unlicensed indication: where do we stand?
- Can medical management be offered to women where geographical barriers exist?
- Given the analgesia requirement and psychological sequelae associated with pregnancy loss, is medical management at home a feasible option?
The incidence of clinically recognised miscarriage remains around 10–20%, though post-implantation and biochemical pregnancy loss rates appear to be in the order of 30%. The majority of miscarriages occur early, before 12 weeks of pregnancy. Second trimester pregnancy loss contributes to less than 4% of pregnancy losses and less than 5% of miscarriages occur after identification of fetal heart activity. In the UK, miscarriage is defined as the loss of an intrauterine pregnancy before 24 completed weeks of gestation.
Non-viable pregnancies may be further classified as a ‘missed miscarriage’, if an embryo or fetus is present but is dead, or ‘anembryonic pregnancy’, if no embryo has developed within the gestation sac. Depending on whether or not tissue is expelled completely, it may be subdivided into complete and incomplete miscarriage. The term inevitable miscarriage is used if the pregnancy is in the uterus but the cervical os is open implying that it would not be possible to salvage the pregnancy.
Bleeding in early pregnancy is the most common reason for women to present to the gynaecology emergency department and miscarriage alone accounts for 50 000 of inpatient admissions to hospitals in the UK annually. Moreover, the widespread use of ultrasound in early pregnancy, either for specific reasons (such as bleeding) or as a routine procedure has resulted in early identification of non-viable pregnancies that are destined to miscarry.
Traditionally, surgical curettage was the gold standard for the management of miscarriage. The introduction of medical and expectant management of miscarriage has increased options for women as well as clinicians alike for the management of this common condition. Surgery is the method of choice for excessive bleeding, if vital signs are unstable or the woman has either suspected infection or gestational trophoblastic disease. In stable patients, surgical management can be performed as an office procedure. However, where suitable, patient's choice should be taken into consideration for the management of miscarriage.
In this review the authors focus on the medical management of miscarriage up to 20 weeks of gestation.
Medical management of miscarriage
Various types of medical treatments could be used as suitable alternatives to expectant or surgical treatment. It is only over the past two decades that the medical methods have become popular and most of the initial studies were done for termination of pregnancy.
The chief pharmacological agents include prostaglandins (misoprostol, gemeprost) used alone or in combination with the anti-progestogen mifepristone. The use of mifepristone in management of early pregnancy loss is debatable. Increasingly, newer evidence suggests that misoprostol alone has equivalent efficacy and is more cost-effective than use of mifepristone and misoprostol.
Mifepristone: is it indicated in miscarriage?
Mifepristone (RU486), an anti-progestogen was discovered in 1980 by chemists at Roussel-Uclaf, France. By competitive inhibition of natural progesterone, this C19 steroid increases the sensitivity of the myometrium to prostaglandins by 5 times with maximal effect on uterine contractility and cervical ripening at 36–48 hours following treatment.
This therefore forms the basis for the combination of the two drugs (mifepristone and prostaglandin analogues).
Choice of prostaglandin analogue: gemeprost or misoprostol
Prostaglandins F2α, E1 and E2 are naturally acting uterotonics which have a very short half life due to rapid deactivation in tissues. Their synthetic analogues that are used in clinical practice, including gemeprost and misoprostol, are more potent and have a longer half-life due to modification of their chemical structure. When used alone in high doses the prostaglandin analogues will induce expulsion of products of conception but have a high incidence of gastrointestinal side effects. The prostaglandin E1 analogue, gemeprost was licensed for early medical termination of pregnancy in 1991 at a dose of 1 mg administered vaginally. There is now a large body of evidence to show that misoprostol, a prostaglandin E1 analogue, has a similar efficacy and safety profile at all gestations[10, 11] although it is not licensed for this purpose. Misoprostol 200 microgram tablets are formulated for the treatment of peptic ulcer. Unlike the gemeprost pessary, misoprostol is stable at room temperature and therefore does not require stringent storage conditions and is also considerably cheaper, thus providing a cost-effective alternative to gemeprost. The cost of 200 mg mifepristone and up to five doses of gemeprost is £203.94, while an equivalent misoprostol regimen costs only £14.74 as (1 mg gemeprost pessary costs £20, whereas a single tablet of misoprostol costs as little as £1).
Route of misoprostol administration
Routes of misoprostol administration include oral, vaginal, sublingual, buccal, or rectal. The pharmacokinetic properties can be described using peak concentration (Cmax) indicating how well the drug is absorbed, time to peak concentration (Tmax) representing how rapidly the drug is absorbed and the area under the serum concentration versus time curve (AUC) which denotes bioavailability or the total exposure to the drug.
Pharmacokinetics studies comparing oral and vaginal administration have shown that vaginal misoprostol is associated with slower absorption, lower peak plasma levels, and slower clearance, similar to an extended-release preparation.[14, 15] Vaginal misoprostol is also associated with a greater overall exposure to the drug (area under the curve [AUC]) and greater local effects on the cervix and uterus. There is, however, a wide variation in the absorption of misoprostol through the vaginal epithelium among different women. There is no clinically significant difference between vaginal misoprostol that is administered dry and vaginal misoprostol moistened with water, saline, or acetic acid.[14, 16-18]
The rectal route of administration shows a similar pattern to vaginal administration, but has a lower AUC, including a significantly lower maximum peak concentration.
The sublingual route of administration has an AUC similar to that of vaginal administration, but more rapid absorption (higher Tmax) and higher peak levels (Cmax) than either vaginal or oral administration. This translates into higher rates of gastrointestinal side effects. Nevertheless, the sublingual route causes uterine contractions at a rate equivalent to vaginal administration and has less variation in absorption.
The buccal route is another mode of administration, which is less widely studied, in clinical trials. The drug is placed between the teeth and the cheek and absorbed through the buccal mucosa. The absorption rate (Tmax) after the buccal administration is the same as after vaginal administration but the serum drug levels attained are much lower with the AUC being half that of the vaginal route. A study comparing buccal to sublingual administration has also shown that the AUC of sublingual misoprostol is four times that of buccal administration. The sublingual route, however, had a higher incidence of gastrointestinal adverse effects when compared to the buccal route owing to a higher peak plasma concentration. In this study, the buccal route was more acceptable to women. However, more studies are required to compare the buccal route with other modes of administration.
When studying pharmacokinetics of repeated doses, vaginal bleeding can adversely affect the absorption of misoprostol. In a recent study by Tang et al. the peak plasma level and the bioavailability were higher after each dose of misoprostol following sublingual administration when compared with vaginal administration of repeated doses. The difference was probably due to a reduction in absorption of vaginal misoprostol in the presence of significant vaginal bleeding. Effectiveness and patient acceptability of the sublingual route has now been proven at all gestations in the context of randomised control trials comparing sublingual and vaginal route of administration as reported by Hamoda et al. Both sublingual and buccal routes avoid the inconvenience of vaginal administration and also the first pass effect of the liver and thus offer women an additional choice.
Mode of action and adverse effects with misoprostol
Misoprostol has uterotonic and cervical softening effects. Tang et al. reported that various studies on uterine contractility so far have demonstrated that a sustained level, rather than a high serum level, is required for the development of regular uterine contractions though they fail to define the threshold serum level for uterine contractility. While a single dose increases uterine tonus, repeated doses are required to maintain sustained contractions. These regular uterine contractions are sustained for a longer period after vaginal than after sublingual administration, with decreased activity occurring only after 4 hours (compared to 3 hours with sublingual).
Misoprostol also leads to cervical ripening. It has been proposed that that this action of misoprostol appears to be mainly on the connective tissue stroma with evidence of disintegration and dissolution of collagen.
The administration of non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief does not alter the efficacy of misoprostol. There are no known drug interactions with misoprostol.
Its half-life is 20 to 40 minutes when administered orally in a fasting patient. Side effects are generally limited to the gastrointestinal tract, including nausea, diarrhoea, vomiting, dizziness, fever and chills. Regardless of the administered route, side-effects are dose-related. Some women experience an unpleasant taste when it is taken sublingually or buccally. A sense of numbness over the mouth and throat has also been reported when it is taken sublingually.
Medical management of first trimester miscarriage
Various medical methods have been described using prostaglandin analogues (gemeprost or misoprostol) with or without antiprogesterone priming (mifepristone). However, there is lack of consensus as to whether the addition of the mifepristone confers any benefit for the treatment of miscarriage. The evidence from the larger studies has been summarised below.[28-33]
Wagaarachchi et al. proposed that although incomplete miscarriages may be managed with misoprostol alone, in the presence of an intact sac and a closed cervix (early fetal demise), priming with the antiprogesterone mifepristone makes the regimen more effective with success rate of above 80%.
A Cochrane review by Neilson et al. suggested that non-viable pregnancies may contain viable trophoblast (placental) tissue, which produces hormones, which may in theory make these pregnancies more susceptible to anti-hormone therapy and more resistant to uterotonic (stimulating uterine contractions) therapy than pregnancies in which (incomplete) miscarriages have already taken place.
However, more recent trials report that mifepristone may not be necessary for medical management of miscarriage as the pregnancy is non-viable and the progesterone level is already low. A recent randomised trial by Gronlund et al. showed that the addition of mifepristone did not improve the overall success rate compared with regimens using misoprostol alone and these results were subsequently confirmed by Stockhein. Mifepristone is expensive and not available in many countries. Regimens using prostaglandins or prostaglandin analogues alone would be a more practical approach to the problem.
According to NICE guidance on the management of miscarriage, there is a wide variation in efficacy rates ranging from 13% to 96%. The efficacy of medical management may be influenced by multiple factors such as the type of miscarriage, sac size and whether follow-up is clinical or involves ultrasound. Total dose, duration of use and route of administration of prostaglandin are also important factors. Higher success rates (70–96%) were associated with incomplete miscarriage, high-dose misoprostol (1200–1400 micrograms) with a repeat course if required, prostaglandins administered vaginally and clinical follow-up without routine ultrasound. Studies in which efficacy was assessed later show much higher success rate than when the efficacy was assessed on the same day of treatment.
The success rate of medical management is higher in women with incomplete miscarriage when compared to missed miscarriage. A recent meta-analysis of 13 randomised controlled trials by Graziosi et al. in 2004 confirms the findings with complete evacuation rates ranging between 60% and 83% for missed miscarriage and 99% for incomplete miscarriage.
Similarly, higher doses of misoprostol are associated with higher success rate. In a study by Chung et al. 225 women with spontaneous miscarriage and ultrasound diagnosis of retained products of conception (POC) were treated with up to 1200 micrograms of oral misoprostol in three divided doses followed by a repeat course the second day. The success rate with the first course of misoprostol was about 48% but increased to 70% after a repeat course of treatment the next day.
A success rate of 84% was reported by Wagaarachchi et al. who used 200 mg of mifepristone followed by 800 micrograms of misoprostol vaginally 36 to 48 hours later and a further two doses orally of 400 micrograms 3 hours apart. A repeat course of misoprostol alone was offered if the patients failed to pass POCs and success defined as complete evacuation within 3 days without the need of surgical curettage.
Many studies have been performed to investigate the best regimen for medical management of miscarriage. The optimal regimen is yet to be determined. Table S1[28, 31, 35, 38-42] gives an overview of various relatively large studies over the past 15 years with details of treatment regimens, success criteria and success rates for women with first trimester pregnancy loss.
Recent NICE guidance published in Dec 2012 evaluated randomised controlled trials comparing various regimens using misoprostol with or without mifepristone, route of administration, success rates and side effects. The guidance recommends that:
For women with missed miscarriage, a single dose of 800 micrograms (oral or vaginal) of misoprostol was the most effective overall. For women with an incomplete miscarriage, the evidence suggested that a single dose of 600 micrograms of misoprostol was effective.
For women with missed miscarriage, used at the same dose, both vaginal and oral routes of administration had similar effectiveness, and that both were more effective than sublingual administration. The majority of side-effects did not show a difference by route. For women with incomplete miscarriage the incidence of diarrhoea was lower with vaginal when compared to the oral route but there were no significant differences between oral and sublingual routes.
In cases where women vomit after administration of oral medication, it can be difficult to determine if the dose should be repeated. This is not an issue with the vaginal route of administration.
Medical management of second trimester miscarriage
The optimal method of second trimester miscarriage continues to be debated. Medical induction of labour in the second trimester is a safe and effective alternative to dilation and evacuation, particularly in situations where fetal autopsy is desirable, due to patient's preference, or more commonly, simply because of the lack of trained late dilation and evacuation providers.
Protocols using misoprostol with or without mifepristone appear to be safe and effective with minimal side effects. The optimal dose, schedule, and route of administration have not been determined. Gómez Ponce de León and Wing performed a review of 14 studies on the use of misoprostol for termination of pregnancy with intrauterine fetal demise in second and third trimesters. They concluded that misoprostol is highly effective in inducing delivery after 24 to 48 hours of administration.
Vaginal and oral misoprostol are equally effective although the oral regimen has higher gastrointestinal side-effects. Nynde et al. compared oral and vaginal administration of 200 micrograms of misoprostol given 6 hourly for up to four doses. The induction to delivery time was significantly shorter in the vaginal group by nearly 8 hours. However, the dose of misoprostol needs to be modified according to gestational age. This is due to the fact that the sensitivity of the uterus to prostaglandins increases with increasing gestation. During the second trimester therefore, due to increased sensitivity of the myometrium to prostaglandins, lower doses are sufficient when compared to the first trimester.
The existing data regarding timing of repeated dosing include intervals as frequently as 3 hours and as long as 24 hours. The reports that describe the shortest intervals from induction to delivery included regimens where repeated dosing occurred every 4 to 6 hours.[45, 46]
Although there is a large body of evidence on the use of misoprostol for first trimester miscarriage, the literature is scarce with regard to second trimester miscarriage. Moreover, the studies included in the systematic review above are small, and not comparable owing to use of different routes, doses, intervals of administration of misoprostol and varying gestational ages. Thus the optimal regimen for medical management of second trimester miscarriage is yet to be determined. The treatment regimens and outcomes evaluated are summarised in Table S2.[45, 47, 48]
The review by Gómez Ponce de León recommends the following regimen:
Fetal demise from 13 to 17 weeks
Vaginal misoprostol 200 micrograms every 6 to 12 hours for a total of four doses. If the first dose does not lead to effective contractions the subsequent dose could be doubled to 400 micrograms. The maximum daily dosing should not exceed 1600 micrograms.
Fetal demise from 18 to 26 weeks
Vaginal misoprostol 100 micrograms every 6 to 12 hours for a total of four doses. If the first dose does not lead to effective contractions the subsequent dose could be doubled to 200 micrograms. The maximum daily dosing should not exceed 800 micrograms.
Apart from use of misoprostol, other methods for the management of second trimester miscarriage include extra-amniotic instillation of ethacridinelactate, intracervical administration of PGE2 gel[50, 51] intravenous infusion of concentrated oxytocin[49, 51] or insertion of laminaria tents.
Yapar et al. compared five different methods for second trimester pregnancy termination including fetal deaths. They compared the use of extra-amniotic instillation of ethacridine lactate, intracervical PGE2 gel, intravenous infusion of concentrated oxytocin, intracervical balloon insertion and vaginal misoprostol in 340 patients. They reported both misoprostol and PGE2 were less effective than the other three methods in achieving successful expulsion of products within 24-48 hours. The finding was contradicted by Hou et al. in their systematic review. They concluded that compared to extra-amniotic instillation of ethacridine lactate, misoprostol has higher success rate with shorter time of labour but more gastrointestinal side effects for second trimester pregnancy termination.
Jain et al. compared use of misoprostol with PGE2 for second trimester pregnancy loss or termination for medical reasons. They concluded that misoprostol is at least as effective as PGE2 but it is less costly, easier to administer and associated with fewer adverse effects.
Traditionally, oxytocin has been the most commonly used induction agent at later gestational ages. However, oxytocin fails to induce labour effectively as a single-agent therapy at mid-trimester as the number of myometrial oxytocin receptors only increase significantly in the third trimester. Compared with misoprostol, oxytocin requires longer induction times and has higher rates of serious side effects, particularly water intoxication.
Other methods such as the use of intra-cervical placement of laminaria tents alone or in combination with misoprostol to improve the efficacy of the prostaglandin analogue in the second trimester induction have been reported. Jain et al. concluded that laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the efficacy of vaginal misoprostol in the second trimester of pregnancy.
Misoprostol is routinely used for medical management of second trimester loss in women with prior caesarean section without dose alteration as the risk of uterine scar dehiscence is low and has been reported as less than 0.4%.[53, 54]
Abdominal pain is one of the most common adverse effects of the medical methods of managing miscarriage. In routine clinical practice, analgesia should be offered to all women. The perception of pain and request for pain relief has wide individual and cultural variations. Services should make a range of oral and parenteral analgesics available to meet women's needs. Pain is most likely to be felt in the first few hours after prostaglandin analogue administration. Studies have shown that analgesic requirements and the perception of pain are significantly higher in women of younger age and those at a higher gestational age, with a longer induction-to-expulsion of products interval and with a greater number of misoprostol doses, whereas it is lower in older, parous women and those at lower gestations. Non-steroidal anti-inflammatory drugs (NSAIDs) are a potential first-line treatment. It should be noted that NSAIDs do not appear to mitigate the action of misoprostol or mifepristone in clinical trials, despite theoretical concerns and may decrease narcotic requirements. The role of advance or prophylactic analgesia, conscious sedation and para-cervical block and their effectiveness, as well as women's satisfaction and acceptance, need further research.
Psychological sequelae following miscarriage
There has been an increased awareness of the psychological consequences of miscarriage for women and their partners. Women experiencing miscarriage may be overwhelmed by the symptoms and suffer from a variety of psychological effects like anxiety and depression[57, 58] along with a feeling of emptiness, guilt and failure. Other reported consequences include sleep disturbance, social withdrawal, anger and marital disturbance. Fathers can also be affected emotionally. These and other feelings that women describe have been conceptualised by many as being part of a pattern of grief in response to the loss of a baby.
Evidence, however, is insufficient to demonstrate the superiority of either psychological support, such as counselling, or no intervention post-miscarriage. Given the equivocal evidence, women's preference should play a large role in the decision-making process.
Misoprostol is currently only approved by the Food and Drug Administration (FDA) for the prevention and treatment of gastric ulcers resulting from the chronic administration of NSAIDS.
Misoprostol has been extensively studied in reproductive health, and is widely recommended for the treatment of missed and incomplete miscarriages, the induction of abortion, and cervical preparation before uterine instrumentation and postpartum haemorrhage prophylaxis and treatment.
The use of drugs for off-label indications is legal, common practice, and not considered experimental if based on sound scientific evidence. Drug licensing is not proof of effectiveness and many drugs of proven efficacy are not licensed.
In all cases the evidence must be carefully considered and the benefit:risk ratio assessed before a drug is prescribed for an unlicensed indication. Patients and their carers should be properly informed if a doctor prescribes a licensed drug for an unlicensed indication.
The European community regulations permit doctors to prescribe unlicensed regimens and permit pharmacists to dispense and nurses to administer medicines prescribed.
Medical management may be undertaken successfully on an outpatient basis. In a recent UK-based study regarding choice of setting, if only medical methods were available, 67% of respondents would opt for hospital management with 33% choosing the home setting. Zhang et al. reported that complications with misoprostol treatment occur at a rate of less than 1 in 70 treated patients thus suggesting that hospitalisation of patients is unnecessary. Allowing women to go home soon after they have received misoprostol may therefore be a plausible option and be less costly to the NHS. However, it might not be feasible at an advanced gestational age where more than one dose of misoprostol and narcotic analgesics may be required.
Consideration should be given to offering this approach, depending on the clinical situation and patient choice.
Medical management with misoprostol carries a risk of heavy bleeding in a small proportion of women. Zhang et al. reported visits to the gynaecology emergency units by 3% of women within 24 hours after treatment with misoprostol. This highlights the fact that women should have quick and easy access to hospital in the event of heavy bleeding. In view of these findings, medical management should be offered with caution in remote and rural settings and where geographical barriers exist.
Medical management of miscarriage is a safe and effective means of miscarriage. Medical management is an alternative technique that complements but does not replace surgical management. Its availability has led to an improvement in choice for women who miscarry.
Disclosure of interests
Contribution to authorship
PA conceived the idea. LS and MM drafted the abstract. LS reviewed the literature and drafted the manuscript. MM provided comments on the manuscript. LS and MM prepared the CPD questions.