Emergency contraception

Transcription

1 Abacus Services for Sexual and Reproductive Healthcare, Liverpool Community Health, Liverpool L2 5SF, UK Correspondence to: I Prabakar iprabakar@nhs.net Cite this as: BMJ 2012;344:e1492 doi: /bmj.e1492 This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Philip Routledge, professor of clinical pharmacology, Cardiff University. To suggest a topic for this series, please us at practice@bmj.com bmj.com Previous articles in this series ЖЖHormone replacement therapy (BMJ 2012;344:e763) ЖЖNewer drugs for focal epilepsy in adults (BMJ 2012;344:e345) ЖЖNewer antidepressants for the treatment of depression in adults (BMJ 2012;344:d8300) ЖЖProtease inhibitors for treatment of genotype 1 hepatitis C virus infection (BMJ 2011;343:d6972) THERAPEUTICS Emergency contraception I Prabakar, A Webb A woman aged 22 requests the morning after pill for unprotected sexual intercourse 36 hours ago. You offer her a copper intrauterine device (IUD), ulipristal acetate, or l evonorgestrel (table 1). She looks surprised and says she has never been offered a choice before: Can t I just have the pill I have taken before? What is emergency contraception? Emergency contraception refers to contraception taken to prevent pregnancy after unprotected sexual intercourse or a potential contraceptive failure. The Omnibus survey from the Office for National Statistics showed that 7% of women in the United Kingdom had used emergency contraception in the previous year. 1 This update focuses on the currently available choices for women requesting postcoital contraception. Available methods Women in the UK currently have three choices (table 1) 2 : Levonorgestrel (a progestogen) 1.5 mg, which is licensed up to three days (72 hours) after unprotected sexual intercourse Ulipristal acetate (a progesterone receptor modulator) 30 mg, which is licensed for use up to five days (120 hours) after unprotected sexual intercourse 3 A copper IUD fitted up to five days after unprotected sexual intercourse or ovulation, whichever is longer. The Yuzpe method, a combined oestrogen and progestogen emergency contraceptive, has more side effects and is no longer used when a progestogen only alternative is available. Mifepristone has been studied but is currently available only in China and Vietnam. There is no evidence to support the use of a levonorgestrel intrauterine system as an emergency contraceptive. How does it work? IUDs work by being toxic to the ovum and sperm and preventing fertilisation when used as ongoing contraception, but when fitted after fertilisation they also have an anti-implantation effect (table 2; fig 1). 2 4 Levonorgestrel Ovulation Ulipristal acetate Highest risk Luteinising hormone Follicle stimulating hormone Luteinising hormone surge Fig 1 Window of action of different emergency contraceptive methods in relation to ovulation Day Both these drugs work mainly by inhibiting ovulation. Whereas ulipristal suppresses lead follicles when given just before ovulation, including during the luteinising hormone surge, 5 levonorgestrel inhibits ovulation only if given before this surge. 6 Therefore, because the risk of pregnancy is highest in the two days leading up to ovulation, ulipristal acetate is probably more effective than levonorgestrel. Levonorgestrel is not effective after fertilisation, 7 and it is unclear whether ulipristal acetate has any effect after ovulation. How effective is it? The risk of pregnancy after one episode of unprotected sex varies throughout the menstrual cycle, increasing to 20-30% in the days leading up to and including ovulation. 8 Although estimating conception rates by day of the menstrual cycle has inherent errors, it is the best way to derive effectiveness data (fig 2) The copper IUD is always the most effective method of emergency contraception, with a Cochrane review identifying a collective failure rate of 0.09% from non-randomised studies. 11 Table 1 Available formulations in the United Kingdom Preparation Active ingredient Licensed up to Cost* Levonelle 1500 Levonorgestrel 1.5 mg 72 hours after UPSI 5.20 ( 6.2; $8.2) per tablet Prescription regulations Prescription only drug Levonelle One Step Levonorgestrel 1.5 mg 72 hours after UPSI per tablet Pharmacy drug EllaOne Ulipristal acetate 30 mg 120 hours after UPSI per tablet Prescription only drug Copper IUD Copper 120 hours after UPSI or 5 days after ovulation, whichever is longer (TT 380 Slimline) (Neosafe T380 Should be inserted by a trained clinician *As cited in the BNF 61 (March 2011). Most IUDs are not specifically licensed for emergency contraception but the World Health Organization supports their use if inserted before implantation of pregnancy. 21 For example, one with a letter of competence in intrauterine techniques (certified by the Faculty of Sexual and Reproductive Healthcare). IUD=intrauterine device; UPSI=unprotected sexual intercourse. Table 2 Mechanism of action of emergency contraceptives Method of emergency contraception Copper intrauterine device Levonorgestrel 1.5 mg Ulipristal acetate 30 mg or delays ovulation fertilisation implantation No Yes Yes when used as emergency contraception 2 Only if before No No effects luteinising shown 6 7 hormone surge 5 6 Up to and No Unknown 2 including luteinising hormone surge 5 BMJ 24 MARCH 2012 VOLUME

2 Copper IUD Ulipristal Levonorgestrel None Fig 2 Comparative predicted estimates of the number of pregnancies expected if 1000 women at risk used various forms of emergency contraception or nothing Clinical trials and mode of action studies show that levonorgestrel is more effective than nothing, with an estimated % of pregnancies being prevented. 12 This large variation has been attributed to the inherent difficulties in calculating the effectiveness of contraceptive methods, such as uncertainty about the timing of intercourse. Levonorgestrel is licensed for use within 72 hours of unprotected sexual intercourse, and recent combined data from four World Health Organization randomised controlled trials suggest that it may be effective up to 96 hours. However, it is not certain whether administration of levonorgestrel on day 5 after unprotected intercourse protects against unintended pregnancy. 13 Evidence from two randomised trials has shown that ulipristal is at least as effective as levonorgestrel A metaanalysis concluded that the pregnancy rate was significantly lower with ulipristal than with levonorgestrel, with an odds ratio of 0.58 (95% confidence interval 0.33 to 0.99) at 0-72 hours and 0.55 (0.32 to 0.93) at hours. 15 Higher failure rates were seen for both methods when taken just before ovulation and when women had further unprotected intercourse. 16 How safe is it? No deaths or serious complications have been causally linked to emergency contraception. The IUD is safe for most women if fitted by an appropriately trained person. There is a small risk of uterine perforation (about 1/1000). A woman at higher risk of infection may wish to consider antibiotic cover for the most prevalent sexually transmitted infections. 4 Clinicians who lack training for IUD insertion should have a clear referral pathway so that women can access the most effective method in a timely manner. No serious complications have been reported for levonorgestrel. One case of dizziness was reported as an adverse event with ulipristal. 15 What are the precautions? For women with certain conditions, use of an IUD for both emergency and interval contraception poses an 62 BMJ 24 MARCH 2012 VOLUME 344

3 unacceptable health risk (WHO category 4; box) or is not recommended unless other more appropriate methods are unavailable or unacceptable (WHO category 3; box). 17 Between 5% and 10% of IUDs are spontaneously expelled while being used for long term contraception and so women must be encouraged to check the threads periodically. WHO does not identify any medical condition that limits the use of levonorgestrel. Although this method is not indicated for a woman with a suspected pregnancy, there is no known harm to the patient, the course of her pregnancy, or the fetus if levonorgestrel is accidentally used. 17 WHO has not yet made a statement on ulipristal. Because its safety has not been widely evaluated, the manufacturer advises avoidance if there is any risk of an implanted pregnancy or hepatic dysfunction; it also advises caution in women with asthma that is inadequately controlled with oral glucocorticoids and in those who have hereditary problems with lactose metabolism. It is not yet known whether ulipristal is excreted in breast milk so breast feeding is not recommended for up to 36 hours. 3 Drug interactions There are no drug interactions with the IUD. Liver enzyme inducing drugs (some anticonvulsants, drugs for tuberculosis and HIV, and herbal remedies such as St John s wort) reduce concentrations of levonorgestrel and ulipristal during use and for up to 28 days afterwards. Some professional groups recommend that the dose of levonorgestrel in women taking such drugs should be doubled if an IUD is unacceptable. Ulipristal should not be used in women taking drugs that can reduce its absorption (drugs that increase gastric ph: antacids, H 2 receptor antagonists, and proton pump Conditions that may be a health risk if an intrauterine device (IUD) is used (based on WHO eligibility criteria) 17 WHO MEC 4 A condition that represents an unacceptable health risk if the contraceptive method is used: Pregnancy Puerperal sepsis Immediately after septic abortion Unexplained vaginal bleeding before evaluation Persistently raised β human chorionic gonadotrophin concentrations or gestational trophoblastic cancer Cervical cancer Endometrial cancer Uterine fibroids with distortion of the uterine cavity Any congenital or acquired abnormality that distorts the uterine cavity in a manner that is incompatible with insertion of an IUD Current pelvic inflammatory disease Current purulent cervicitis, gonorrhoea, or infection with Chlamydia trachomatis Pelvic tuberculosis AIDS if not well controlled by antiretroviral treatment WHO MEC 3 A condition in which risks outweigh the advantages of using an IUD. Careful clinical judgment and access to clinical services will be needed, and IUDs are not usually recommended unless other methods are not available or acceptable. Conditions include: Fewer than four weeks postpartum (but longer than 48 hours) Ovarian carcinoma Severe thrombocytopenia inhibitors) or reduce its systemic concentration by inducing liver enzymes. 3 How cost effective is it? An analysis of the cost effectiveness of oral emergency contraception stated that ulipristal is a cost effective alternative to levonorgestrel for all women presenting for emergency contraception. 18 Studies based on economic models have shown that emergency contraception is nearly always cost effective. However, at a population level, provision of emergency contraceptives has not been shown to reduce the rate of unintended pregnancies or abortions, because many complex factors contribute towards unintended pregnancy rates. 19 How is it taken and monitored? Provide the woman with enough information to make an informed choice. Take a clinical history to exclude an implanted pregnancy; assess her need and eligibility for emergency contraception; and present the different methods available, evidence of their effectiveness, and possible interactions. 2 Discuss her need for ongoing contraception and facilitate a prompt start of a regular method. 20 Women who do not wish to retain an IUD for long term contraception can switch to an alternative method after a pregnancy has been reliably excluded. One episode of unprotected sex less than 72 hours ago The IUD is the most effective option. However, it may be unacceptable to some women because it is an invasive procedure and often requires onward referral. Both ulipristal and levonorgestrel have been shown to be effective, with a metaanalysis suggesting that ulipristal is superior to levonorgestrel. However, levonorgestrel is currently more widely available in pharmacies in the UK and other parts of the world. One episode of unprotected sex hours ago The IUD remains the most effective method, and ulipristal is both licensed and effective. Between 72 and 96 hours levonorgestrel may have some effect, but this use is outside the product licence. One episode of unprotected sex more than 120 hours ago If sexual intercourse occurred more than 120 hours ago, but the expected ovulation date was five days or fewer than five days ago, an IUD can still be fitted because of its postfertilisation but preimplantation effect. More than one episode of unprotected sex An IUD is the most effective method but should not be used if there is any risk of an implanted pregnancy. Use ulipristal only if all episodes were within five days of presentation. Levonorgestrel will not disrupt a preimplanted pregnancy, so if this is a possibility, a woman who has had unprotected sex in the past four days can still use this drug. Use of emergency contraception more than once in a single cycle WHO supports the use of levonorgestrel more than once in the same cycle. 17 WHO has not yet made a statement on ulipristal, but UK guidance does not support the repeated use of ulipristal owing to insufficient data on safety and efficacy. 2 BMJ 24 MARCH 2012 VOLUME

4 TIPS FOR HEALTHCARE PROFESSIONALS Consider implanted pregnancy Is there any chance that the woman could already have an implanted pregnancy? Were there any other episodes of unprotected sex in the current menstrual cycle as well as the index event for which emergency contraception is requested? Consider risk of pregnancy with the index episode of unprotected sex Has she had a risk of pregnancy, if so, when was that? Has she been using any other contraception and, if so, what was the nature of potential contraceptive failure (for example, a split condom, missed pills)? Provision of emergency contraception Does she have any serious medical conditions? Is she receiving any drugs that may make oral emergency contraception less effective? Does she have a high risk of sexually transmitted infections? Have I offered all possible choices and explained their relative effectiveness? Sexual health What is she going to use for ongoing contraception? Can she start it now? Is she at risk of sexually transmitted infections and how soon could she be tested? TIPS FOR PATIENTS You now have the choice of a copper intrauterine device (copper IUD); oral levonorgestrel (Levonelle); and the new oral tablet, ulipristal (ellaone), for emergency contraception This acts by preventing fertilisation and, to some extent, by preventing implantation of a fertilised egg It is the most effective method of emergency contraception and is not affected by any drugs that you may take It can be fitted up to five days after unprotected sex or up to five days after your predicted ovulation date; your doctor will be able to advise you on this It can also be retained for continuing contraception until it is due for expiry, usually five or 10 years Levonorgestrel and ulipristal These drugs act by interfering with ovulation, but ulipristal works further into the highest risk time in your cycle Levonorgestrel can be taken up to three days after unprotected sex and ulipristal can be used up to five days after sex Because some drugs reduce the effectiveness of ulipristal and levonorgestrel, you need to tell your doctor about any medical conditions that you have and drugs that you take These drugs cause vomiting in 1% of women; if it happens within two to three hours of taking the tablets speak to your doctor because you may need a further dose These drugs work only as emergency contraception and do not provide protection if you have further unprotected sex; talk to your doctor about continuing contraception If you have been using hormonal contraception but missed some pills ask your doctor what additional contraceptive precautions may be needed for the next two weeks after oral emergency contraception Oral emergency contraceptives can alter your bleeding pattern and it is important to do a pregnancy test three weeks after the unprotected sex if you do not have a normal period Common adverse effects IUD insertion may be uncomfortable, with about half of women experiencing some pain during the procedure. Menstrual irregularities, such as heavier or longer periods, are common in the first three to six months after insertion but usually decrease with time. 4 Encourage women to check the threads periodically. Levonorgestrel and ulipristal Nausea and headache are common adverse effects (20-25%) but are usually mild and self limiting. 2 3 Vomiting occurs in 1% of women, and if it happens within two to three hours, a further dose of the drug is recommended. Both levonorgestrel and ulipristal can affect the timing of the next bleed and a pregnancy test is advised three weeks after the episode of unprotected intercourse in any woman who has not had an entirely normal period. Failure of emergency contraception If a woman conceives after oral emergency contraception her choices should not be affected by the fact that she has taken emergency contraception. Because ulipristal is newly licensed, report any pregnancies that still occur with this drug to the relevant regulatory body, such as the Medicines and Healthcare Products Regulatory Authority in the UK. Failures of an IUD inserted for emergency contraception are rare, but any that do occur should be managed like other IUD failures. 21 Contributors: IP wrote the initial draft and revised subsequent versions of the manuscript. IP sought expert advice from AW, who contributed to final revisions. Competing interests: Both authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. Provenance and peer review: Commissioned; externally peer reviewed. Patient consent not required (patient anonymised, dead, or hypothetical). 1 Lader D. Opinions survey report no 41. Contraception and sexual health, Office for National Statistics, lifestyles/contraception-and-sexual-health/ /index.html. 2 Faculty of Sexual and Reproductive Healthcare. Clinical guidance. Emergency Contraception CEUguidanceEmergencyContraception11.pdf. 3 HRA Pharma UK. EllaOne: summary of product characteristics www. medicines.org.uk/emc/medicine/22280/spc/ellaone+30+mg/. 4 Faculty of Sexual and Reproductive Healthcare. FSRH clinical guidance. Intrauterine contraception Brache V, Cochon L, Jesam C, Maldonado R, Salvatierra AM, Levy DP, et al. Immediate pre-ovulatory administration of 30mg ulipristal acetate significantly delays follicular rupture. Hum Reprod 2010;25: Croxatto HB, Brache V, Pavez M, Cochon L, Forcellodo ML, Alvarez F, et al. Pituitary ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.5 mg dose given on the days preceding ovulation. Contraception 2004;70: Noé G, Croxatto HB, Salvatierra AM, Reyes V, Villaroel C, Muňoz C, et al. Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation. Contraception 2010;81: Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation: effects on the probability of conception, survival of the pregnancy and sex of the baby. N Engl J Med 1995;333: Stirling A, Glasier A. Estimating the efficacy of emergency contraception how good are the data? Contraception 2002;66: Espinos JJ, Rodriguez-Espinosa J, Senosiain R, Aura M, Vanrell C, Gispert M, et al. The role of matching menstrual data with hormonal measurements in evaluating effectiveness of post coital contraception. Contraception 1999;60: Cheng L, Gülmezoglu AM, Piaggio G, Ezcurra E, Van Look PF. Interventions for emergency contraception. Cochrane Database Syst Rev 2008;2: Trussell J, Raymond EG. Emergency contraception: a last chance to prevent unintended pregnancy questions/ec-review.pdf. 13 Piaggio G, Kapp N, von Hertzen H. Effect on pregnancy rates of the delay in administration of levonorgestrel for emergency contraception: a combined analysis of four WHO trials. Contraception 2011;84: Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol 2006;108: Glasier AF, Cameron ST, Logan SJS, Casale W, Van Horn J, Sagar L, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized non-inferiority trial and meta-analysis. Lancet 2010;375: Glasier A, Cameron ST, Blithe D, Scherrer B, Mathe H, Levy D, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception 2011;84: WHO. Medical eligibility criteria for contraceptive use whqlibdoc.who.int/publications/2010/ _eng.pdf. 18 Thomas CM, Schmid R, Cameron S. Is it worth paying more for emergency hormonal contraception? The cost effectiveness of ulipristal acetate versus levonorgestrel 1.5 mg. J Fam Plann Reprod Health Care 2010;36: Raymond EG, Trussell J, Polis CB. Population effect of increased access to emergency contraceptive pills. Obstet Gynecol 2007;109: Faculty of Sexual and Reproductive Healthcare, Clinical Guidance. Quick starting contraception CEUGuidanceQuickStartingContraception.pdf. 21 WHO. Selected practice recommendations for contraceptive use BMJ 24 MARCH 2012 VOLUME 344

5 10-MINUTE CONSULTATION Epistaxis Omar Mulla, 1 Simon Prowse, 1 Tim Sanders, 2 Paul Nix 1 1 Ear, Nose, and Throat Department, Leeds General Infirmary, Leeds LS1 3EX, UK 2 The Shap Medical Practice, Penrith CA10 3LW, UK Correspondence to: O Mulla omarmulla@doctors.org.uk Cite this as: BMJ 2012;344:e1097 doi: /bmj.e1097 This is part of a series of occasional articles on common problems in primary care. The BMJ welcomes contributions from GPs. bmj.com Previous articles in this series ЖЖVaricose veins (BMJ 2012;344:e667) ЖЖReviewing a patient with coeliac disease (BMJ 2012;344:d8152) ЖЖDyspepsia (BMJ 2011;343:d6234) ЖЖThe Hajj (BMJ 2011;343:d5593) A 52 year old man presents with recurrent epistaxis. It usually settles after 10 minutes. What you should cover Ask about Initial onset, frequency, duration, and triggers (such as weather) How are the nose bleeds controlled? Distinguish between anterior (blood running out of the nose, usually one nostril) and posterior (blood running into the throat or from both nostrils) bleeds Trauma, including nose picking Previous nasal surgery Medical history, specifically checking for hypertension and clotting disorders in the patient or their family Medication check for aspirin, clopidogrel, warfarin, and any potential drug interactions that might have precipitated bleeding. If appropriate, test blood clotting. Also inquire about any homeopathic medicines Assess for symptoms and signs of anaemia if bleeding has been heavy or prolonged. If appropriate, carry out a full blood count Facial pain or deep otalgia with epistaxis may be the first sign of a nasopharyngeal tumour In young male patients consider juvenile nasopharyngeal angiofibroma and ask about nasal obstruction, headache, rhinorrhea, and anosmia. These are rare benign tumours that tend to bleed. They occur in the nasopharynx of prepubertal and adolescent males. Ninety five per cent of nose bleeds arise from Little s area, a region of the anteroinferior nasal septum. This area is extremely vascular, as terminal branches of the internal and external carotid arteries anastamose here. What you should do First aid Whether the patient is bleeding or not, assess their cardiovascular state pulse, blood pressure, and capillary refill. If the patient is actively bleeding, seat them and ask them to lean forward (to minimise the swallowing of blood) and apply pressure on to the soft cartilaginous part of the nose for 10 minutes. If bleeding does not stop, refer them to an ear, nose, and throat department and send them to hospital. The urgency and mode of transfer will depend on the clinical condition of the patient, but do not underestimate the amount of blood that can be lost Causes of epistaxis Idiopathic (85%) Trauma Drugs: aspirin, clopidogrel, warfarin Rhinitis: viral, allergic Neoplastic: tumours of the nose, sinuses, and nasopharynx Hereditary: Osler-Weber-Rendu disease, haemophilia, von Willebrand disease during epistaxis. Patients should not drive themselves to hospital because they may not be covered by their motor insurance in this situation. Treatment If the patient has stopped bleeding, use an otoscope or a torch and nasal speculum to look at the anterior nose and septum for evidence of a bleeding vessel, which will often appear as a red dot on pale mucosa. If a vessel is seen, chemical cautery may be attempted using a topical local anaesthetic such as lidocaine or co-phenylocaine (5% lignocaine with 0.5% phenylephrine) to help vasoconstriction, if bleeding is active, and a silver nitrate stick. If no facility for cautery is available refer to ear, nose, and throat; most departments have rapid access casualty clinics designed for this purpose. If the patient s history suggests anterior epistaxis and no vessel is seen, it is reasonable to discharge with a two week course of 0.1% chlorhexidine, 0.5% neomycin cream or petroleum jelly these help with drying of the nasal mucosa and can prevent further bleeding. Advise patients to return if bleeding persists. Simple pressure will not stop epistaxis from posteriorly placed vessels, so recurrent or heavy bleeds that appear posterior in origin need endoscopic assessment in an ear, nose, and throat clinic to help identify a bleeding point. Follow-up Always give patients advice about how to stop further bleeding: (1) Pinch the soft part of the nose and lean forward (2) Avoid hot foods and drinks (preventing vasodilatation) (3) Place ice packs on the nose (to promote vasoconstriction). If epistaxis is refractory or if you suspect any problem other than a simple bleed for example, a septal perforation or tumour seek an opinion from an ear, nose, and throat clinician. Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. Provenance and peer review: Not commissioned; externally peer reviewed. Accepted: 7 December 2011 USEFUL READING Kucik CJ, Clenney T. Management of epistaxis. Am Fam Physician 2005;71: Murthy P, Nilssen EL, Rao S, McClymont LG. A randomised clinical trial of antiseptic nasal carrier cream and silver nitrate cautery in the treatment of recurrent anterior epistaxis. Clin Otolaryngol Allied Sci 1999;24: BMJ 24 MARCH 2012 VOLUME