Medical and surgical options for induced abortion in first trimester

Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 503e516

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Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn

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Medical and surgical options for induced abortion in first trimester Haitham Hamoda, MD MRCOG, Subspecialist SpR in Reproductive Medicine and Surgery a, *, Allan Templeton, CBE, MD, FRCOG, FRCP, FMedSci, Professor in Obstetrics and Gynaecology b a b

Assisted Conception Unit, Level 11 Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, United Kingdom University of Aberdeen, Maternity Hospital, Foresterhill, Aberdeen AB9 2ZD, United Kingdom

Keywords: medical abortion mifepristone misoprostol MVA surgical termination of pregnancy

Medical abortion has been shown to be an effective alternative to surgery for termination of pregnancy in the late as well as the early first trimester of pregnancy. This review discusses the development, application and the current issues with medical and surgical abortion in the first trimester. Studies comparing the two approaches are also assessed as well as potential research directions in this area. Ó 2010 Elsevier Ltd. All rights reserved.

Introduction Surgical termination of pregnancy by vacuum aspiration was established as the method of choice for abortion in the 1960s. However, since the introduction of mifepristone in the 1980s, the uptake of medical abortion has been steadily increasing in countries where it has been available for routine use, and this has probably been one of the most significant developments in fertility control in recent years.

Medical termination of pregnancy In the early 1970s, studies reported the successful use of natural prostaglandins (PGs) in inducing abortion in early pregnancy. Subsequently, PG analogues were used for this purpose. However, the doses required with PG-only regimens were associated with a high frequency of side effects. Pretreatment with mifepristone was shown to shorten the induction to abortion interval, improve the * Corresponding author. Tel.: þ44 7958791622; Fax: þ44 2088404237. E-mail address: [email protected] (H. Hamoda). 1521-6934/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpobgyn.2010.02.006

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efficacy of the regimen and reduce the amount of pain experienced. A more effective application was found with PG in lower doses given in combination with mifepristone, and this forms the mainstay of most current regimens used in clinical practice.1 However, in many parts of the world, mifepristone might not be available due to cost or licensing implications and, in such situations, a misoprostol-only regimen could offer an alternative. Uterotonic compounds: PGs PGs are naturally occurring fatty acids that are produced by virtually all tissues in the body and function as local hormones. They are synthesised from essential fatty acids and are not normally stored in the tissues. A problem with the naturally occurring PG is their rapid breakdown by the enzyme 15-hydroxyprostaglandin dehydrogenase. It was noted that the incorporation of methyl groups protected from destruction by this enzyme, and this was the concept used in the PG analogues: carboprost, (PGF2a), gemeprost (PGE1), sulprostone (PGE2) and misoprostol (PGE1). Misoprostol was discovered in 1973 by scientists at Searle Pharmaceuticals and was licensed for the management of peptic ulcers. It exerts an anti-secretory activity, inhibiting the secretion of acid and pepsin in the stomach. The PG analogues are more stable, have a longer half-life and a more selective uterotonic effect compared to the parent compounds.2 Absorption pharmacokinetics for the different routes of misoprostol administration Tang et al.3 reported on the absorption kinetics of misoprostol 400 mg administered sublingually, orally and vaginally. The study showed significantly higher peak serum concentrations of misoprostol acid with sublingual administration. The time to peak concentration was shorter in the sublingual group and oral groups, while the area under the misoprostol acid concentration versus time curve was significantly greater for the sublingual group. The results suggested that the systemic bioavailability for the sublingual route is comparable to that with the vaginal route of misoprostol administration. The higher peak levels and shorter time to peak concentration may explain the increased prevalence of side effects noted with oral and sublingual administration. More recently, the same group reported on the absorption kinetics of five repeated doses of misoprostol 400 mg given sublingually or vaginally at 3-hourly intervals.4 The peak plasma levels of misoprostol acid decreased with repeated vaginal doses, but remained the same with sublingual administration. The area under the misoprostol acid concentration versus time curve was higher in the sublingual group, although subgroup analysis showed the reduction in plasma levels with vaginal administration only occurred in women with significant vaginal bleeding. Aronsson et al.5 assessed uterine contractility with the oral, sublingual and vaginal administration of misoprostol. Regular uterine contractions were noted in all women in the sublingual and vaginal groups, but not after oral administration. The increase in the uterine activity was significantly higher from 2 h onwards with sublingual and vaginal administration. These findings are consistent with the absorption kinetics reported by Tang et al.3 Misoprostol-only regimens for abortion in the first trimester Moreno-Ruiz et al.6 reported a systematic review of 13 studies between 1997 and 2003 that assessed a misoprostol-only regimen for medical termination of pregnancy up to 63 days of gestation. In most of these studies, misoprostol was given vaginally in a dose of 800 mg and repeated every 24 h, up to three doses. The complete abortion rate ranged from 84% to 96%, and the median induction to abortion interval was 6e9 h. Surgical intervention for excessive bleeding was required in 0.3e3.3%. In a randomised study on medical abortion up to 56 days gestation, a misoprostol-only regimen following placebo administration was compared to a combined regimen of mifepristone followed by misoprostol 48 h later. Misoprostol 800 mg was given vaginally followed by two further doses of 800 mg at 24-h intervals. The complete abortion rate was higher in the mifepristone and misoprostol group (95.7%) compared with 88% for the placebo and misoprostol group.7 These reports show that abortion could be successfully induced with PG alone, but the doses required were associated with a high frequency of side effects, suggesting that PG would be less suitable for use as sole agents to induce abortion.

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The anti-progesterones (mifepristone) Development of mifepristone In 1980, the scientists at Rousel-Uclaf (Romainville-France), while investigating glucocorticoid antagonists, discovered a C-19 derivative of norethindrone with high affinity for the progesterone receptor. The company’s code for this drug was RU 38486 (subsequently shortened to RU 486) and the generic name, mifepristone. This discovery began a new era in fertility control and has shaped much of our current practice. In 1988, France became the first country to license the use of mifepristone in combination with a PG analogue for termination of pregnancy up to 49 days of gestation. Recent figures show that mifepristone is now licensed in 40 countries worldwide for use in the context of medical abortion.1,8 Mechanism of action in pregnancy termination Mifepristone blocks the progesterone receptors within the decidua, leading to ultra-structural changes in the endothelium of the decidual capillaries, vascular damage followed by decidual necrosis and detachment of the conceptus. Mifepristone has also been reported to result in an increase in uterine contractility 24e36 h after its administration. It also increases the myometrial sensitivity to exogenous PG.9 The effect of mifepristone administration on uterine contractility is shown in Fig. 1. Mifepristone was initially assessed for use as a single agent for termination of pregnancy, with varied success rates of 60e80%.1 Subsequently, a more effective application was found in combination with PG, and this forms the mainstay of most current regimens used in clinical practice.

Fig. 1. The effect of mifepristone administration on uterine contractility (J. Norman & D. Baird 2000, used with permission from the authors).

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Safety and side effects Worldwide, millions of women are reported to have used mifepristone, with seven reported deaths in the US related to medical abortion: one ruptured ectopic pregnancy and six related to infection (five caused by Clostridium sordellii). This gives a case-fatality rate of 1 per 100 000 medical abortions and is comparable to that associated with spontaneous miscarriage (0.7 per 100 000) or induced abortion overall, medical and surgical (0.7 per 100 000).10 There have been no deaths from infection for women taking mifepristone in Europe. As mifepristone crosses the placental barrier, this raises concerns about the possible teratogenic effects on the foetus in cases where the pregnancy continues. The long-term safety data are limited, but animal data are largely reassuring. A report on 21 women who continued their pregnancy following mifepristone administration included one case with sirenomelia and cleft palate. In a further report, multiple foetal abnormalities were noted following mifepristone administration for termination of pregnancy at 18 weeks of gestation for severe oligohydramnios. It remains difficult to ascertain whether this was related to mifepristone or co-incidental. However, there have been reports of normal development in human foetuses exposed to mifepristone.11,12 Combined regimens of mifepristone followed by PG analogues - Medical abortion up to 9 weeks of gestation Type of PG Currently, the two commonly used PGs are the PGE1 analogues gemeprost and misoprostol. The conventional PG analogue used for medical abortion is gemeprost. A 1-mg pessary costs w£20 and is unstable at room temperature. Studies have demonstrated that the PGE1 analogue misoprostol is an effective alternative to gemeprost.13,14 Misoprostol is cheap (£1 per dose) and, unlike gemeprost, does not require specific storage conditions. In Table 1, a summary of randomised trials that have evaluated the use of the combined regimen is presented. The study by Baird et al.13 showed no significant difference in efficacy between the two regimens, although the continuing pregnancy rate was significantly higher in the misoprostol group (2.3%) compared with the gemeprost group (0.2%). The study by Bartley et al.14 showed the complete abortion rate was significantly higher with misoprostol (98.7%) compared with gemeprost (96.2%), and the continuing pregnancy rates significantly lower (0.2%) compared with gemeprost (1.8%). The former study13 adopted a lower dose of misoprostol (600 mg) and used the oral route of administration and this might explain the lower efficacy noted in the misoprostol group. The manufacturer’s recommended regimen continues to be gemeprost 1 mg given in combination with mifepristone 600 mg, while the use of misoprostol constitutes an out-of-license use.16 The Royal

Table 1 Selected randomised trials assessing the combined medical regimen of mifepristone in combination with prostaglandin analogues. Study

Gestation (days)

Regimen

Numbers

Complete abortion (%)

p-value

Baird et al.13

63

Mifepristone 200 mg Misoprostol 600 mgm orally Mifepristone 200 mg Gemeprost 0.5 mg vaginally Mifepristone 200 mg Misoprostol 800 mgm vaginally Mifepristone 200 mg Gemeprost 0.5 mg vaginally Mifepristone 600 mg Misoprostol 800 mgm orally Mifepristone 600 mg Misoprostol 800 mgm vaginally

386

94.6

>0.05

391

96.7

500

98.7

499

96.2

130

87.0

133

95.0

Bartley et al.14

El Refaey et al.

63

15

63

0.02

0.02

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College of Obstetricians and Gynaecologists (RCOG) Guideline on induced abortion, however, states that misoprostol is a cost-effective alternative to gemeprost in this context.17 Dose and interval of mifepristone/dose of PG A Cochrane review reported a meta-analysis of four randomised trials comparing mifepristone in doses of 200e600 mg.18 Similar efficacy was reported and the review concluded that the dose of mifepristone can be lowered to 200 mg without significantly decreasing efficacy. A more recent systematic review of four randomised trials comparing mifepristone 200 and 600 mg again showed similar efficacy, but a 1%-higher continuing pregnancy rate with mifepristone 200 mg compared with 600 mg of mifepristone.19 However, the interpretation of these data has been questioned as the type, dose and interval of administration of PG varied in these studies, with two administering misoprostol orally. Furthermore, the complete abortion rates (88e94%) was lower, and the continuing pregnancy rates (0.3e2.8%) were considerably higher than those in large case series administering mifepristone in doses of 200 mg (complete abortion 97.7% and continuing pregnancy 0.3% in a series of 4132 women20). The manufacturer’s summary of product characteristics recommends an interval of 36e48 h between administering mifepristone and the PG analogue. Studies have reported high efficacy with shorter intervals of 24 h, 6e8 h and even the simultaneous administration of mifepristone and misoprostol, although one study carried out in Scotland showed reduced efficacy with a shorter interval of 6 h compared to a 36e48-h interval.21,22 Misoprostol has been used in doses of 400e800 mg in combination with mifepristone. Ashok et al.20 reported a review of the outcomes of medical abortion up to 63 days gestation in 4132 women. The initial 2000 cases received mifepristone 200 mg followed by a single dose of misoprostol 800 mg administered vaginally. They had a complete abortion rate of 97.5%, and efficacy significantly decreased at gestations >49 days. The regimen was subsequently modified to offer a second dose of misoprostol 400 mg to women who had not aborted within 4 h of the initial dose. There was no difference in efficacy with the modified two-dose regimen compared to the initial regimen (97.9% and 97.5%, respectively). However, there was a significant reduction in the continuing pregnancy rates from 0.6% to 0.1%. In 2004, the RCOG Guideline for induced abortion17, recommended a regimen of mifepristone 200 mg followed by misoprostol 800 mg given vaginally 1e3 days later for women up to 49 days of gestation, and a second dose of misoprostol 400 mg (vaginally or orally) 4 h later for women who had not aborted. Route of misoprostol administration Earlier medical termination of pregnancy protocols used misoprostol in doses of 400 mg administered orally. El Refaey et al.15 reported a randomised trial that compared the vaginal administration with the oral administration of misoprostol 800 mg following mifepristone 600 mg with medical abortion up to 63 days of gestation. This showed superior efficacy and lower side effects with vaginal administration (complete abortion rate of 95% compared to 87% for the oral group). It has, however, been suggested that women preferred the oral route of administration and valued having additional choice. Studies from Hong Kong and Aberdeen have since evaluated the feasibility of sublingual misoprostol administration in this context.23,24 Tang et al.23 reported a randomised trial that compared the sublingual and vaginal routes of misoprostol administration using a single dose of 800 mg for medical abortion up to 9 weeks of gestation following mifepristone administration. In the sublingual group, 98.2% had complete abortion. There was no significant difference between the two groups, although more side effects were noted in the sublingual group. Winikoff et al.25 reported a randomised study of 966 women undergoing medical abortion up to 63 days of gestation comparing buccal with oral administration of misoprostol 800 mg 24e36 h after mifepristone 200 mg. A total of 96.2% of patients in the buccal group had a complete abortion compared to 91.3% in the oral group. Efficacy decreased in the oral group as gestation increased, while side effects were higher with buccal administration. Medical abortion at 9e13 weeks of gestation To date, the medical regimen is not licensed for use at 9e13 weeks of gestations, and the majority of these cases are undertaken surgically.26

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A randomised trial that compared medical abortion and surgical vacuum aspiration at 10e13 weeks of gestation, showed a complete abortion rate of 94.6% in the medical group and 97.9% in the surgical group.27 A subsequent review reported on the outcomes of medical abortion at 64e91 days of gestation in 1076 consecutive cases. The complete abortion rate for the medical regimen was 95.8%. Efficacy decreased and the continuing pregnancy rates increased as the gestational age increased, particularly for women with >12 weeks of gestation.28 Furthermore, a randomised trial in Aberdeen24 compared the sublingual route of misoprostol administration to the vaginal route of administration in the context of medical abortion at all gestations up to 13 weeks in 340 women. Complete abortion occurred in 98.1% of women in the sublingual group compared to 97.4% in the vaginal group. Over two-thirds of women in each group expressed satisfaction with the method, although more side effects were experienced by women in the sublingual group. A prospective series reported on medical abortion at 64e84 days of gestation in 321 women. Mifepristone 200 mg was followed by misoprostol 800 mg given vaginally followed by two further doses of 400 mg at 3-hourly intervals. The complete abortion rate was 89% with high reported acceptability (93%).29 The RCOG Guideline on induced abortion states that the medical regimen using mifepristone in combination with misoprostol would be a safe and effective alternative to surgery for women undergoing abortion at 9e13 weeks gestation.17 Anti-metabolites (methotrexate) Methotrexate inhibits dihydrofolate reductase, the enzyme necessary for purine and pyrimidine synthesis. Its effect on pregnancy appears to be predominantly on the rapidly dividing cytotrophoblast and has been shown to be effective for the treatment of gestational trophoblastic disease. It has also been used in the context of termination of pregnancy. A regimen of methotrexate and misoprostol 800 mg given vaginally was compared to a regimen of mifepristone and oral misoprostol 400 mg in a randomised trial. A total of 75% of women in the methotrexate group aborted by day 8 compared with 91% in the latter group. However, the overall complete abortion rate was comparable (surgical evacuation: 4.0% and 3.9%, respectively).30 Methotrexate is potentially teratogenic and there have been several reports of limb-reduction defects in foetuses following its use. The toxicity of methotrexate is dose dependent, although serious complications have been reported with low-dose methotrexate. Methotrexate is no longer seen as an alternative to the combined mifepristone/PG-analogue regimen and its use is now restricted to places where mifepristone is unavailable. Side effects and complications of medical termination of pregnancy Clinical trials on patients with peptic ulcers treated with misoprostol in daily doses of 400e800 mg have reported gastrointestinal side effects, abdominal pain and fever as the most frequent side effects. Side effects experienced by women using a regimen of 800 mg in three doses included nausea (24%), vomiting (23%), diarrhoea (50%), dizziness (15%), headache (11%), pyrexia (18%), chills (50%) and pelvic pain (96%). These did not differ significantly when misoprostol was given at 48-h intervals compared with 24-h intervals.31 It is not known whether the active metabolite of misoprostol (misoprostol acid) is secreted in the breast milk or not. This could potentially cause diarrhoea in nursing infants and, hence this has been given as a contraindication for its use by the manufacturer.2 However, it has been suggested that avoiding breast feeding for 4 h after oral administration of misoprostol and 6 h after vaginal administration would allow sufficient time for misoprostol levels in the breast milk to fall.32 Shannon et al.33 reported a systematic review of 65 studies and showed that the frequency of diagnosed or treated infection after medical abortion was estimated to be 0.92%. The RCOG Guideline on induced abortion recommends testing for lower genital tract infection, providing antibiotic prophylaxis or both.17 More recently, Fjerstad et al.34 reported on the infection rates after the joint change to buccal misoprostol from vaginal misoprostol and routine provision of antibiotics with medical abortion. Serious infections declined by 73%, from 0.93/1000 abortions to 0.25/1000, while the subsequent change to routine provision of antibiotics led to a further significant reduction in the rate of serious infection by 76%, from 0.25/1000 abortions to 0.06/1000. The rate of serious infections declined

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by 93% after a change from vaginal to buccal administration of misoprostol combined with routine administration of antibiotics. Excessive bleeding at the time of abortion is rare. However, there is more observed blood loss with medical abortion when compared with surgical abortion.18 Blood transfusion has been reported to occur in 0.1e0.2% of women undergoing medical abortion up to 63 days of gestation.20,35 Medical regimens carry a small risk of failure to terminate the pregnancy, and in such cases surgical intervention is needed. Ashok et al.20 reported a surgical evacuation rate of 2.3% with a regimen of mifepristone in combination with misoprostol for termination of pregnancy up to 63 days of gestation. Indications for surgery included continuing pregnancy (0.3%), missed abortion (0.3%) and incomplete abortion (1.6%). Bartley et al.35 reported a surgical evacuation rate of 3.6% using a regimen of mifepristone and gemeprost for termination of pregnancy up to 63 days of gestation. Of these, 1.4% had continuing pregnancy while 2.2% had incomplete abortion. For termination of pregnancy at 64e91 days of gestation, a review of 1076 cases showed that 4.2% of women required surgical evacuation. Of these, 16 (1.5%) had a continuing pregnancy, five (0.5%) had missed abortion, 20 (1.9%) had incomplete abortion, while four (0.4%) required emergency evacuation for bleeding.28 Serious complications including uterine rupture, cervical lacerations and major haemorrhage are rare. Exposure to misoprostol in early pregnancy has been associated with multiple congenital defects including skull defects, cranial nerve palsies, facial malformations, constriction rings, equinovarus, erythrogryposis and congenital transverse limb defects. These are thought to be secondary to uterine contractions leading to vasoconstriction and distal ischaemia. Much of this evidence has come from Brazil where misoprostol had been available over the counter in pharmacies and used in an illegal manner to selfinduce abortion. Several reports have suggested an association between misoprostol exposure in early pregnancy and the Mobius syndrome (congenital facial paralysis, with or without limb defects). This may be due to vascular disruption of the subclavian artery during the fourth to sixth weeks of embryonic development.36 The absolute risk of these abnormalities following exposure to misoprostol, however, could not be evaluated from these reports, and would be difficult to estimate due to the illegal nature of using misoprostol in the context of abortion in these countries and the likely underreporting of use. Both anti-progesterones and PG have contraindications to their use including: allergy to mifepristone or PG, adrenal insufficiency, severe asthma, long-term treatment with corticosteroids, haemorrhagic disorders or treatment with anticoagulants, porphyria, history of cardiovascular disease and women >35 years of age who are heavy smokers.1 Acceptability of medical abortion The provision of medical abortion offers additional choice to women. In a review on the acceptability of medical abortion in early pregnancy, Winikoff37 reported that, in most trials that offered women a choice between medical and surgical methods, 60e70% of women chose medical methods, with high reported acceptability of 88e97%. Furthermore, a multi-centre study in the UK assessed the perceived acceptability of home medical abortion in women undergoing conventional hospital-based early medical abortion. The majority of women (75.7%) said they could have managed the pain at home with oral analgesia, and 78.9% said they would have coped with the bleeding at home. Approximately one-third of women (36.0%) said they would have preferred to have the abortion at home.38 Analgesia requirements with medical abortion Abdominal pain is one of the most common adverse effects of medical abortion. Analgesia use and, hence presumably, the perception of pain is higher in women of younger age, higher gestation, those who had a longer induction to abortion interval and with an increased number of misoprostol doses, while women with a previous live birth require less analgesia.39 The majority of women undergoing medical abortion require oral analgesia or no analgesia and only a small proportion use intramuscular opiates. Westhoff et al.40 also reported on the use of advance analgesia use with medical abortion. Women who were given analgesia supplies were more likely to use it compared to those given a prescription. In turn, the latter group had higher analgesia use compared to those asked to use analgesia only as required.

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Home administration of misoprostol Studies from the United States have reported high efficacy and good acceptability for medical abortion carried out in home settings41 and home care is becoming the standard approach there. Studies have also reported the feasibility and high acceptability of the home regimen in Guadeloupe and, more recently, in the UK, Sweden, France, Vietnam and Tunisia with high efficacy and acceptability.42,43 The provision of medical abortion at home allows the procedure to be carried out in the privacy of a familiar environment and avoids the inconvenience of an additional visit to the hospital. It might also have major cost-saving implications for health-service provision. Research is needed to compare the acceptability and efficacy of home medical abortion with that carried out in hospital settings. Follow-up The main reason for follow-up after medical termination of pregnancy is to confirm successful abortion and to identify possible complications following the procedure. Abortion is usually confirmed through identifying the products of conception or by carrying out a transvaginal ultrasound of the uterus. Follow-up is usually offered within 2 weeks of abortion.17 It has been suggested, however, that giving women simple instructions and advice about detecting complications would be a suitable alternative, with little evidence that mandatory follow-up visits detect conditions that women could not learn to recognise themselves.32 Follow-up, however, remains essential for women who do not expel recognisable products of conception, to exclude the risk of continuing pregnancy. Licensing The use of misoprostol in the context of termination of pregnancy represents an out-of-licence use for the product, while administering it through the vaginal route also constitutes an unlicensed route of administration. The European Union (EU) Pharmaceutical Directive 65/65/EEC specifically permits doctors to use “licensed medicines for indications or in doses or by routes of administration outside the recommendations given in the product licence.” In the United Kingdom, the licensing authority working through the Medicines Control Agency and under the Medicines Act Regulations of 1968 can provide exemptions to prescribe unlicensed medicines or to use or advise the use of licensed medicines for indications, or in doses, or by routes of administration, outside the terms of the product licence. In each case, however, the doctor should be able to justify this use in accordance with a responsible body of professional opinion. The RCOG Guideline on induced abortion has indicated that misoprostol would be a cost-effective and acceptable alternative for all abortion procedures where the E1 analogue gemeprost is conventionally used. Patients should be properly informed that this represents an unlicensed indication for use of the product.17 Surgical termination of pregnancy Development of surgical abortion Historical reviews indicate that abortion was practiced in ancient civilisations and it has been described that dilators, curettes and even a rudimentary suction apparatus existed. The modern curette (from the French verb, curer, ‘to cleanse’) was developed in France in 1723. During the last quarter of the 19th century, the German physician Alfred Hegar developed the dilators that now bear his name, and dilatation and curettage or ‘D&C’ became widely practised as a method for evacuation of the uterus. This remained the principal abortion technique until the introduction of the vacuum-suctionaspiration machine in the mid-20th century. This was initially described by James Young Simpson in the 19th century. Vacuum aspiration was then refined and used in China, Japan and Eastern Europe before eventually being introduced into clinical practice in Britain and the US in the late 1960s. By the beginning of the following decade, vacuum aspiration gradually became established as the standard method for first trimester surgical termination of pregnancy in the developed world.44

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Safety and complications Surgical termination of pregnancy is a very safe procedure, especially when performed in the first trimester of pregnancy. In a review on the complications of legally induced abortion, the rate of uterine perforation was estimated to be 0.2%, cervical injury was estimated to occur in 0.18e0.96%, while the rate of retained products of conception was estimated to be 0.6%. Vacuum aspiration had the lowest major complication rate for all surgical methods. Sharp curettage had a major complication rate 2.3 times higher than vacuum aspiration.45 In a further review of various studies only using vacuum aspiration for first trimester termination of pregnancy, the rate of trauma to the uterus was reported to be 0e0.4%, trauma to the cervix 0e1.0%, haemorrhage 0e2.4% and infection 0.6e2.5, while the estimated mortality rate was 1:100 000.46 The RCOG guidelines on induced abortion state that conventional suction termination would be an appropriate method for gestations between 12 and 15 weeks.17 Anaesthesia for surgical abortion Performing surgical abortion under local anaesthesia could minimise the complications associated with general anaesthesia and increases the options available to women undergoing abortion. It is also associated with a faster recovery time, and a shorter stay in hospital. It also reduces the burden on theatre facilities and allows the procedure to be carried out on an outpatient basis. Surgical abortion under local anaesthesia is widely practised in the United States and is now the standard practice there. The acceptability of this approach has not been fully evaluated in the United Kingdom and the majority of surgical abortions are still carried out under general anaesthesia. A series of 17 725 women who had surgical termination of pregnancy under general anaesthetic and 36 430 women who received local anaesthetic had no difference in the rate of major complications, but the rates of haemorrhage, cervical injury and uterine perforation were all higher with general anaesthesia while febrile and convulsive morbidity was higher with local anaesthesia.47 A paracervical block is generally the standard technique used for the administration of local anaesthesia. A two-point block at 4 and 8 o’clock positions gave similar pain scores to a four-point block at 3, 5, 7 and 9 o’clock.48 The technique used, however, for administering the paracervical block is not standardised.17 It has been suggested that the effect produced relates to tissue distension rather than the agents used. However, studies have shown that the use of local anaesthesia was associated with less pain when compared to injecting saline or water. A randomised trial compared immediate surgery to that carried out 3e5 min after administration of local anaesthesia and reported no difference in the pain experienced or patient satisfaction.49 The Department of Health Expert Group Report in 2002 indicated that conscious sedation using intravenous opiates and sedatives would be an appropriate technique for the reduction of the pain and anxiety associated with surgical abortion and would be safer than general anaesthesia, as the patient could continue to breathe without assistance and have a faster recovery.50 Manual vacuum aspiration (MVA) Karman introduced the principal of MVA with the use of the Karman cannula; since then, the procedure had mainly been used in areas with limited resources where it has offered an option to provide safe, relatively cheap, effective abortion, and allowed the procedure to be performed in outpatient settings. Within the last decade, however, there has been increasing experience from the United States of surgical abortion under local anaesthesia and reports have suggested the safety and high efficacy of this method. Edward and Creinin51 reported their experience in early surgical abortion (<6 weeks gestation) using MVA under local anaesthetic in 2399 cases. The complete abortion rate was 99.2% while the continuing pregnancy rate was 1.3 per 1000 procedures. Abortion was confirmed by inspecting the products of conception under magnification to identify the gestational sac. If this was not seen, follow-up with serial human chorionic gonadotropin (hCG) measurements was arranged. A summary of 12 studies assessing MVA in 20 000 women reported efficacy rates ranging between 95% and >99%. The upper gestational limit for these studies ranged from 6 to 16 weeks. MVA was also

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reported to be associated with less noise and to have shorter operating time compared to electric vacuum aspiration (EVA).52 A more recent systematic review of 10 randomised trials including 1660 women compared MVA with EVA and reported similar efficacy (97.9% MVA vs. 97.5%) and acceptability for the two methods. In women with 49 days of gestation, less blood loss and less severe pain perception was reported with MVA, while the operating time was shorter with EVA. The authors concluded that MVA was an effective alternative to EVA and might be safer than EVA.53 Surgical abortion under local anaesthesia using MVA offers additional choice to women, particularly those wishing to avoid general anaesthesia. Furthermore, it could be carried out on outpatient basis and this may have important implications for health-service provision. Research is needed to compare MVA with medical abortion in the early first trimester to compare the acceptability and efficacy of these two methods. Cervical priming Cervical priming has been shown to reduce the incidence of complications associated with surgical termination of pregnancy as uterine perforation, cervical injury, haemorrhage and incomplete abortion. It has also been shown to make the procedure quicker and easier to perform. Young age and higher gestational age have been reported as risk factors associated with an increased risk of uterine perforation and cervical laceration.54 The RCOG guideline on induced abortion recommends routine cervical priming for women younger than age 18 or at gestations of >10 weeks.17 The World Health Organisation also recommends routine priming for nulliparous women >9 weeks of gestation.54 Cervical priming has traditionally been carried out using either pharmacological agents as the PG analogues gemeprost and misoprostol or osmotic dilators. Pharmacological agents have been more popular in the United Kingdom, while osmotic dilators such as laminaria have been widely used in North America. PGs have been shown to result in ripening of the cervix and to increase the baseline cervical dilatation and reduce the mechanical force required to dilate the cervix. This action is believed to result mainly from a direct effect on the connective tissue stroma within the cervix. Studies have shown that misoprostol is an effective alternative to gemeprost in the context of cervical priming prior to surgical termination of pregnancy.55 A dose of misoprostol 400 mg administered vaginally has been reported to be the optimal dose for cervical priming prior to surgical abortion. This was significantly more effective than a dose of 200 mg and as effective as higher doses of 600e800 mg, although the latter two doses were associated with significantly more side effects. A priming interval of 3 h has been reported to be the optimal time interval for vaginal administration of misoprostol prior to first trimester surgical abortion. Studies show greater efficacy with this compared to shorter intervals of 2 h and similar efficacy to longer intervals of 4 h but with less side effects.56,57 These studies, however, used subjective measures and did not use a cervical tonometer to assess the force required for cervical dilatation. Achieving optimal priming intervals remains a practical problem even under strict study settings as most surgical abortions are performed on day-case operating lists with women being admitted on the morning prior to surgery. Oral or sublingual administration could be carried out by women before hospital admission, and could allow better priming intervals to be achieved. Several randomised trials have compared the oral with the vaginal routes of misoprostol administration. In the largest of these studies, higher efficacy was reported with vaginal administration of misoprostol 400 mg 4 h prior to surgery compared to oral administration of misoprostol 400 mg 8 h before surgery in a group of 900 women.58 The sublingual route of misoprostol administration has also been compared to the vaginal route of administration and noted to have similar efficacy, but with more number of side effects.59 Studies have also shown mifepristone to have similar or greater cervical priming effect prior to surgical termination of pregnancy compared to gemeprost. Greater cervical dilatation has also been reported for mifepristone compared to misoprostol. Despite its efficacy, cost implications may limit the clinical application of mifepristone in this context, but selective use could be considered.60 The regimens licensed within the manufacturers’ summaries of product characteristics include the following: - gemeprost 1 mg given vaginally 3 h before surgery and - mifepristone 600 mg given orally 36e48 h before surgery.16

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The RCOG guideline on induced abortion states that misoprostol in a dose of 400 mg administered vaginally, would be an effective and acceptable regimen. This, however, would be an out-of-licence use for the product.17 Comparing medical and surgical methods for termination of pregnancy The provision of medical abortion as an alternative to surgery offers additional choice to women, and studies have shown that women value having the choice of abortion method.61 Reasons given by women in favour of medical abortion include autonomy, more privacy, less invasiveness and greater ‘naturalness’ when compared to surgery, while frequently mentioned drawbacks include abdominal pain, duration of bleeding, number of visits and the waiting period to know if the treatment has been successful. A patient-preference randomised trial compared a combined regimen of mifepristone and gemeprost 1 mg with surgical vacuum aspiration under general anaesthesia in 363 women undergoing abortion 63 days of gestation. Women were allocated to their preferred method, while those who did not have a strong preference for either method were randomised. Similar efficacy was noted for those with 49 days of gestation (complete abortion rate: 98% in both groups), while for those with >49 days and 63 days of gestation, medical abortion was less effective (complete abortion rate: 93%, compared with 98% with surgery). The overall efficacy was 94% for medical abortion compared with 98% with surgery. Medical abortion was reported to be more painful at increased gestations and the bleeding was heavier and had been judged to last longer. There were no significant differences between the women who preferred to undergo any particular intervention and those randomised to it.62,63 However, women in the medical arm only received a single dose of gemeprost and this explains the lower success rates, compared with those in more recent reports using a two-dose misoprostol regimen combined with mifepristone (complete abortion rate: 98%20). Most women who had a preference for a method accepted their chosen procedure. At gestations of 49 days, acceptability between the two randomly allocated groups was the same, while surgery was significantly more acceptable for women with 49 and 63 days of gestation. For women randomly allocated to medical abortion, gestational age was the only predictor of acceptability before abortion.63 Howie et al.61 reported a 2-year follow-up study on the same group of women and reported no significant differences in general, reproductive or psychological health between the two groups. Most women placed a high value on the provision of choice of method of abortion, with 86e90% indicating a willingness to pay for the provision of such choice. A further patient-preference randomised trial in the same centre compared medical abortion and surgical vacuum aspiration in 368 women at 10e13 weeks of gestation. A total of 94.6% medical group had complete abortion, compared with 97.9% in the surgical group (p ¼ 0.07). There was no significant difference in the acceptability of the method used between women in the two groups (p ¼ 0.26).27 Prior to abortion, 72% indicated a preference for medical abortion while 28% showed a preference for surgery. Despite having a preference for a particular method, women were content with alternatives. Women were more likely to choose the same abortion method again if they had shown a preference for that method prior to abortion.64 To our knowledge, no studies have compared surgical termination, under local anaesthesia using MVA, with medical abortion. In conclusion, studies show that medical abortion is an effective alternative to surgery in both the late, as well as early first trimester, and with high reported acceptability. Furthermore, these reports highlight the value women place on having a choice of abortion method. Medical abortion offers an alternative to those who wish to avoid surgery or anaesthesia and should be routinely available to women. Conclusion  Medical abortion is an effective alternative to surgical termination of pregnancy.  Misoprostol has been shown to be an effective alternative to gemeprost. Its use, however, remains an out-of-license application for the product.

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 MVA is an effective alternative to electric vacuum aspiration. Offering surgical abortion under local anaesthesia using MVA has numerous advantages. In addition to avoiding general anaesthesia and its associated risks, it also increases women’s choice.  Vaginal administration of misoprostol is more effective than oral administration both with medical abortion and cervical priming prior to surgical abortion.  More recently, sublingual administration of misoprostol has been reported as an effective alternative to vaginal administration.

Practice points  Medical abortion is an effective option for termination of pregnancy in the late as well as the early first trimester.  The dose of mifepristone can be reduced from 600 to 200 mg without loss of efficacy.  Cervical priming reduces the risks of complications with surgical abortion.  Patient counselling is essential to ensure informed choice of procedure, and to provide information on follow-up and post-abortion contraception.

Research agenda  Randomised trial comparing medical methods with MVA in the early first trimester.  Randomised trial to compare home medical abortion to medical abortion in hospital settings.  Assessment of the acceptability of self-administration of misoprostol for cervical priming prior to hospital admission and its effect on achieving optimal priming intervals.

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