PACE REVIEW Medical management of first-trimester induced abortion and miscarriage

Shamim Amis Jonathon Evans-Jones MRCOG FKCOG

urgical evacuation is the mainstay of treatment in the effects of bleeding per vaginum, diarrhoea and vomiting. In UK for first-trimester termination of pregnancy and a randomised trial, where 1 mg versus 0.5 mg of gemeprost Smiscarriage and, although a niinor procedure, it has an was compared, the complete abortion rate was similar for associated considerable morbidity and mortality.' Induced the two groups (98-100%), although the incidence of abortion in the UK is now a safe procedure but on a global adverse effects was significantly lower in the latter group.'O scale continues to be a major cause of maternal mortality.2 Misoprosto1 is a synthetic analogue of prostaglandin E, and Medical management would provide a safe and effective causes increased uterine contractility with a low incidence of alternative. Many women would prefer to be given the other unwanted effects." The main advantages over choice and avoid the risks associated with anaesthesia and gemeprost are that it does not require refngeration, is cheaper surgery.l Recent studies have confirmed high acceptability and can be administered orally or vaginally. One gemeprost rates, showing that 8496% of women would choose pessary costs &22, whereas the equivalent dose of misoprostol medical treatment for a subsequent abortion." is just over The uterotonic properties are enkanced if women are pretreated with rmfepristone, reflecting the effect BACKGROUND of antiprogesterones in increasing sensitivity to prostaglandins. The drugs used for medically induced abortion in the UK When misoprostol is used in combination with mifepristone, include an antiprogesterone,mifepristone, and several prost- the vaginal route has been shown to be superior to the onl aglandin analogues, including gemeprost and misoprostol. route (95% versus 87%, respe~tively).'~The incidence of Mifepristone is the 11P-dimethyl-amino-phenyl derivative of adverse effects was also reduced in the former group. %s is norethindrone and has a high affinity for progesterone and an unlicensed use of misoprostol and should be emphasised glucocorticoid receptors5 Receptor binding in the placenta is to the patient prior to its administration.'* followed by inefficient transcription of progesterone genes, so that mifepristone effectively blocks the progesterone recep- GUIDELINES FOR MEDICAL TERMINATION tors in the decidua, myometrium and cervix. This usually Details relating to orgarhtional, clinical and supportive results in termination of the pregnancy. When mifepristone aspects of abortion care are given in the evidence-based is used alone, the success rate is variable and never greater guidehe produced by the RCOG.'j The earlier the termination than 8896.6.7This is increased to 9496% when mifepristone is performed, the more effective is the procedure, with a lower is combined with a prostaglandin such as gemeprost or risk of complications. At six to seven weeks, medical termin- misoprostol. The recommended dose of oral mifepristone is ation is the method of choice and is effedive in 97.5% of cases. 600 mg followed by 1 mg of gemeprost given 48 hours later. The effectiveness falls to 93% for gemeprost and 89.1% for However, subsequent studies have shown that a lower dose misoprostol at between seven and nine weeks. The latter of nlifepristone (200 mg) is equally effective."9 induces less powerful uterine contrac7ions at th~~ Gemeprost is a prostaglandin El analogue and is effective An ultrasound determination of gestational age will help in 95% of cases in combination with mifepristone at less than improve efficacy and confirm that the pregnancy is intra- 63 days of amenorrhoea. Initial studies were with a dose of uterine. If the fetus is found to be non-viable, this might help 1 mg. The high efficacy is associated with increased adverse to allay some of the guilt and anxiety felt by women

The Ohstetn'ciun G Gynaecologist April 2002 Vol. 3 No. 2 Medicul munugement offirst-trimester induced abortion and miscam’age PA- mw

undergoing a termination of pregnancy. l8 century has interest in this field been rekindled.2’ As well as Within the UK, mifepristone must be administered on avoiding complications of surgery, it is also less expensive licensed premises or in a hospital. Prostaglandins are then than surgery) with a saving of A50 per case.26 administered 3648 hours later, with the patient being kept Various effjcacy rates for medical treatment of miscar- under observation for four to six hours. Facilities for riages have been cited. Factors determining success are the immediate suction curettage should be available in the event type of miscarriage, the gestation, the type, dose and route of excessive vaginal bleeding. A two-week follow-up is of administration of medication and whether an ultrasound important, with a repeat pregnancy test and an ultrasound scan is used to assess completion. scan if products of conception have not been identified. The efficacy of medical treatment for silent miscarriage Women who are rhesus (D) negative should be given anti- varies from 52% to 929’6, depending on the doses of D rhesus immunoglobulin simultaneously. Contraindications mifepristone and misoprostol.2’z28Nielsen et al.27used lower to medical termination are shown in Tuble 1. oral doses of both and defined success objectively using transvaginal ultrasound to detect retained products. Vaginal misoprostol is effective in 88% of cases.‘‘) In silent miscarriage A bvoi u te the progesterone level is already low and therefore the Pregnancy of more than 63 days antiprogesterone may be omitted. This has important implic- 0 Suspected ectopic pregnancy ations in countries where mifepristone is unavailabk. Further 0 Adrenal insufficiency studies in the UK indicate that the success rate with 0 Long-term glucocorticoid therapy 0 Haemoglobinopathies or anticoagulant therapy mifepristone and vaginal misoprostol is similar to that seen in 0 Anaemia induced abortion. 0 Known allergy to mifepristone or prostaglandin In the case of incomplete miscarriage, use of either oral 0 Smokers over 35 years of age 0 Potphyria misoprostol (400 mg) alone or intramuscular sulprostone Re1RelativeRtive (0.5mg) has been shown to be effective in 95% of cases. a.0 Hypertension Sulprostone was withdrawn after three cases of myocardial Ia Severe asthmaI infar~tion.~~Subsequent studies have shown a lower success rate of misoprostol in incomplete nliscaniages ADVERSE EFJ3CTS AND COMPLICATIONS ([email protected]%).31~3’The discrepancy between these two studies The most common adverse effects are gastrointestinal and (de Jonge et al.jl and Cliung et aZ.jz)can be explained by the are mainly related to the prostaglandins. Besides nausea and difference in the mean duration of amenorrhoea (80 and 66 vomiting, headaches, dizziness and tiredness can occur. days, respectively) and the use of pelvic ultrasound. The Haemorrhage requiring transfusion is a recognised complic- morbidity in those treated medically was lower than in those ation of both surgical and medical treatment and the risk requiring surgery (1.7% versus 6.6%),3 increases with gestational age. Blood loss before nine weeks In the only published patient-centred partdly randomised of gestation is similar for both methods.I8 Significant blood controlled trial comparing the medical method with surgd loss necessitating a transfusion occurs in 0.7-1% of evacuation, dlferent regimens of misoprostol and mife- Abdominal pain requiring analgesia, and in particular pristone were used for silent and incomplete parented analgesia, is greater with medical abortion than Complete evacuation of the utetus was assessed by history with surgical abortion (28.5-350/0).~~~’~This is not surprising and clinical examination, without resorting to pelvic ultra- as the woman is fully conscious during medical treatment. sound. The overall success rate was 93% for the medical Approximately 5% of women require surgical curettage method and 98% for surgery (P=0.004). In the case of silent following medical treatment. l9 The continuing pregnancy misamage, the efficacy was greatest for those pregnancies of rate after rnifepristone and gemeprost is 0.3%. If oral miso- less than ten weeks or with a sac diameter of less than 24 mm prostol is used, the risk can be as high as 7%.13 Although (92-94%) and was not statistically signiticantly different from there has been no reported fetal abnormality with mife- that of surgery. In women with incomplete miscarriage, the pristone, misoprnstol has been associated with defective success rate for both methods was 100%. formation of the frontal and temporal regions of the skull Gemeprost used alone for miscarriage is effective in 77% and limbs, due to vascular disr~iptioii.~~,~*In view of this, it of cases at gestations of less than 13 weeks.33 The dis- is recommended that unsuccessful medical termination advantages of using gemeprost rather than misoprostol should be followed by surgical evacuation. have already been mentioned. The proportion of women requesting medical treatment MEDICAL MANAGEMENT for miscarriage is the Same as the proportion requesting Miscarriage commonly occurs in 15-209’6 of pregnancies medical termination (20%),3,2i although with experience within the first trimester. The routine management of such this is likely to increase. The main reasons stated were cases is still surgical evacuation. Although medical manage- avoidance of general anaesthesia or surgery (57%) and ment of miscarriage with herbal remedies was known feeling ’more natural’ and ‘in control’ of the process (36%). before the 13th century, only in the last decade of the 20th The acceptability of medical treatment over surgery was the

713e Obstetriciun & Gynaecologist ilpril2001 Vol. 3 AO. 2 89 pkw;zm Shamim Amis, Jonathon Evansgones

same for both incomplete and silent miscarriages of less 11 Norman p.,Thong KJ, Haird u1’.Ulerine contractilily and induction (if than ten weeks. Both these trials (Henshaw et ~1.~and abortion in early pregnancy by rnisoprostol and mifepristone. lancet 1992;338:12356 Hinshaw et aLL5)were based on the Brewin and Bradley 12 Hinshaw K, El-Refaey H, Rispin K, TempleLon AA. Mid-trimester design, which allows the effect of patient choice on various termination for fetal abnormality: advantages of a ncw regimen using mifepristone and misoprostol. BrJ Obstet Gynaecol19!?5;102:i5960 outcomes to be assessed and yet maintains a randomised 13 El-Refaey H, Dhamnasekar R? Abdalla M, Calder L, Templeton A. group for comparing two interventions.j4 Induction of abortion with mifepristone (RrJ486) and oral or vaginal Medical management of miscarriage may be less suitable misoprostol. NEngl JMed 1995;332:983-7 14 Uritish Medical Society and Royal Pharmaceutical Society of Great for those women with heavy vaginal bleeding, anaemia Britain. British Mzirational Formtib?y 40. London; September 2000 (haenioglobin less than lOg/dl) or who are pyrexial and 15 Royal College of Obstctricians and Gynaecologists Clinical Effectiveness who have contraindications to medical therapy (Table I). In Support Unit. l%e Cure oJ Women Requesting Induced Abortion London: KCOG Press; 2000 (Evidence-based guideline no 7) those cases where the products of conception have not 16 McKinley C, Thong KJ, Baird I>T. The effect of mifepristone (RL486) been passed, an ectopic pregnancy must tie excluded. and gestation on the efficacy of medical abortion with rmfepristone and Expectant management appears to be a suitable altern- misoprvstvl. Hum Reprod 1993;S:1502-5 17 Creinin MD, Vitringnoff E, Galbraith T), Klaisle C. A randomized trial ative to medical management in cases of spontaneous comparing rnisoprostol three and seven days after methotrexate for miscarriage although, again, varying rates of efficacy have early abortion. Am,/ Ohstet G!~~.neco/1995;173:157M4 18 Rodger %W,Baird DT. Blood loss following induction of early abortion been qu0ted.3~3~ using mifepristone (RL1486) and a prostaglandin analogue (genieprost). Contraception 1989;40:43947 CONCLUSIONS 19 1JK blukicentre Study - find results. The efficacy and tolerance of mifepristonc and prostaglandin in termination of pregnancy of less than In these days of patient choice, the onus is on health profes- 63 days gestation. Contraception 1997: 51:1-5 sionals to provide the option of medical treatment for all 20 UK Multicentre Trial. Tlie efficzicy and tolennce of rmfepristone and indications for uterine evacuation, irrespective of gestation. prostaglandin in first trimester termination of pregnancy. UrJ Ohstet Gpaecol1990;974804 Both surgical and medical methods should be viewed as 21 El-Refaey €1. Templeton AA. Early induction of abortion by a having complementary rather than alternative roles. Further combination of oral mifepristone and misoprostol administered by the patient-centred randomised controlled trials are required to vaginal route. Contraception 1994;49:11 1-$ 22 Herishaw KC, Naji SA. Russell IT. Templeton M. Comparison of establish the optimal dose of mifepristone and which prosta- medical abortion (using mifepristone and gemeprost) with surgical glandin should be used. MCUU~aspiration. Efficacy and early medical sequelae. Hum Reprod 1994;9:2167-72 23 Fonseca W, Alencar AJ. hlota FS, Coelho IIL. Misoprostol and AUTHOR DETAILS congenital malformations [letter]. Luncet 1991;338:56 Shamim Amis MRCOG, Specialist Registrar in Obstetrics 24 Pastuszak AL, Schuler L, Speck-Martins C, Coclho K-E, Cordello SM. Vargas F, et ui. Use of misoprostol during pregnancy and Mobius and Gynaecology9Whipps Cross Hospital, Whipps Cross syndrome in infmls. NEngl,JMed 1998;338:1881-5 Road, London G11 lNR, LJK (corresponding author) 25 Hinshaw HE. Medical management of miscarriage. In: Grudzinkas G, Jonathon Evans-Jones FRCOG, Lead Clinician and O‘Brien PMS, editors. Problcnw in Ear@ Pregnancy Advances in Diugnosis and iWanagenmt. London: RCOG Press, 1997. p. 284-95 Consultant, Department of Obstetrics and Gynaecology, 26 Hughes I, Ryan M, Hinshaw K; Henshaw R, Rispin R. Templeton A. The Colchester General Hospital, Colchester, UK costs of treating miscarriage: a comparison of medical and surgical management. BY.^ Obstet Gpzaecoll996;103: 1217-21 References 27 Nielsen S, Hahlin M, Platkhristcnscn JJ. Unsuccessful treatment of 1 Drife J, Lewis G. lK%y Mothers Die. Report on Confidential Enquiries missed abortion with a combination of antiprogesterone and a prostaglandin El analogue. BrJ Obstel G~uecol1~997,104:lW!2~ into :Vatmu1 Urnfhs in lbe United Kiizgciom 19.9496 London: The Stationel-J.Office; 1998 28 El-ReFaey H, Hinshdw K, Henshaw R, Smith NC. Templeton A. Medical management of missed ahortion and anembryonic pregnancy. BilrJ 2 EWdrt WK, Winikoff B. Towards safe and effective medical abortion. Science 1998:281:52&1 1992;305:1399 29 Zalanyi S. Vaginal misoprostol alone is effective in the treatment of 3 Henshaw RC, Naji SA, Russel IT. Comparison of medical abortion with missed abortion. BY,/ Ohstet Gyizuecol1998105:1026-35 surgical vacuum: wonien’s preferences and acceptability of treatment. 30 Henshaw RC, Cooper K. El-Refaey H, Smith NC. Templeton AA. B@l loC)3;307714-17 Medical management of miscamage: uterine evacuation of incornplele it Newhall EP, K’iriikoff B. Aholtion with mirepristone and misoprostol: and inevitable and spontaneous abortion. B:MJ 1993;306:894-5 regimens, efficacy, acceptability and future directions. J Obstet Am 31 de Jonge EJM. Markm JD, Manefeldt E, De Wet GH, Pattison RC. Gjmecol2000;183 Suppl 2S4-53 Randomised clinical trial of medial evacuation and surgical curettage 5 Mahajan DK, London SN. Mifepristone (RU486): a review. Ferti/ Sten! for incomplete miscarriage. BMr 1995;311:662 1997;68:%7-76 32 Chung T, Leiing P, Cheung LP, Haines C, Chang AM. A medical 6 Couzinet B, Le Strat N. Ulmann A. Baulieu EE, Schaisong G. approach to the management of spontaneous abortion with Termination of early pregnancy by the progesterone antagonist misoprostol. Acta Obstel Gynecol Scand 1997;76:24%51 mifepristone (RU486). NEngl JMed 1986;315:1565-70 33 Egarter C, Lederhilger J, Kurz C. Gemeprost for first trimester missed 7 Grimes DA. Mishell DKJ, Shoupe D, Lacc-ma M. Ealy abortion with a abortion. Arch Gynecol Ohstet 1995;256:29-32 single dose of antiprogestin RU4S6. Ant Jobstet Gynccoll9SS;l58:1~~7-12 34 Brewin CR. Bradley C. Patient preferences and nndomised clinical 8 Penney GC, McKesstxk L, Rispin R, El-Refaey H, Templeton A. An trials. BMJ 1983;299:3155 effective low cost regimen for early medical abortion. Br JFam Plann 35 Nielsen S, Hahlin M, Platz-Christensen J. Randomised trial comparing loC%;21:54 expectant with medrcal management for first trimester iniscaniaga. Br 9 Baird DT, Suckchareon N. Thong KJ. Randomized trial of nlisoprostol J Obstet ~naecollW;106:8047 and cervagem in combination with a reduced dose of niifcpristone for 36 Jurkovic D: Ross JA. Nicholaides KH. Expectant managcment of missed induction of abortion. Hum Repd 1995:95:1521-7 miscarriage. BrJ Obstet Gynaecol1998;105:67C&l 10 Rodger Mw. Logan AF, Baird DT. Induction of ;hortion in early 37 Chipchase J, James D. Randomised trial of expectant versus surgical pregnancy with n~epristoneand two different doses of prostaglandin. managenlent of spontaneous miscarriage. Br ,J Ohstet ~yynmcol Contraception 1989;39:497-502 1937:104:84G1

90 The Obstelrician G Gynaecologist Apd ZOO1 Vol. 3 No. 2