Comment

See Comment page 1668

*Paul Bissell, Claire AndersonCentre for Pharmacy, Health and Society, School of Pharmacy,University of Nottingham, Nottingham NG7 2RD, UK Paul.Bissell@nottingham.ac.uk

We declare that we have no conflict of interest.

1 Stammers T. Emergency contraception from pharmacists missesopportunity. BMJ 2001; 322: 1245.

2 Marsh B, Finney S. Morning after pill fuels the epidemic of sexual diseases.Daily Mail Oct 18, 2003.

3 Ziebland S. Emergency contraception: an anomalous position in the familyplanning repertoire? Soc Sci Med 1999; 49: 1409–17.

4 Raine TR, Harper CC, Rocca CH, et al. Direct access to emergencycontraception through pharmacies and effect on unintended pregnancyand STIs: a randomised controlled trial. JAMA 2005; 293: 54–62.

The UK Faculty of Family Planning and ReproductiveHealth Care has just issued new guidance on what toadvise when combined oral contraceptive pills aremissed.1 This new guidance is part of a continuing seriesproduced by the Faculty’s Clinical Effectiveness Unit andis based on WHO publications. These publicationsinclude Medical Eligibility Criteria for Contraceptive Useand Selected Practice Recommendations for ContraceptiveUse.2,3

The WHO recommendations were produced by anexpert working group who reviewed all availableevidence. The Clinical Effectiveness Unit has adaptedthem for practice in a developed country, in this case theUK. Health professionals have generally welcomed theseclear and simplified messages,2,3 as a means of ensuringuniformity and quality in contraceptive provision. Itmust be remembered, however, that the initial WHOrecommendations were developed to improve andextend contraceptive provision in developing countries,where maternal and perinatal mortality and morbidityare high and the balance of contraceptive risk might bequite different.4 Reducing unplanned pregnancies isalso important in affluent countries, but the ClinicalEffectiveness Unit has followed WHO guidance inrelaxing some of the more cautious rules, resulting in apotential increased risk of pregnancy for a small numberof women. Has the Unit gone too far this time?

The new recommendations for missed contraceptivepills aim to simplify the previous rules that wereovercautious in their advice about use of back-upcontraception, such as condoms, for much of thecontraceptive pill cycle.5 The previous rules were also

confusing, contradictory, and fairly complex for somewomen. What do the new recommendations say? Thereare several consensus principles agreed by the authors(panel).1 All health professionals will concur with thestatements that pill dose does indeed matter, cycleregimen is important, and the key to oral contraceptivesuccess hinges on the pill-free interval.

So why is there controversy with these new rules thatstate no back-up contraception or emergency contra-ception is required until three or more 30–35 �gethinyloestradiol pills have been forgotten or two ormore 20 �g or less ethinyloestradiol pills? And whatabout triphasic regimens?

Women often report that they are taking a minior low-dose contraceptive pill but are unsure if itcontains oestrogen and rarely know the amount of

Missed contraceptive pills and the critical pill-free interval

1670 www.thelancet.com Vol 365 May 14, 2005

Panel: Clinical Effectiveness Unit consensus principlesabout missed contraceptive pills1

It is important to take an active (hormonal) pill as soon aspossible when pills have been missed.

If pills are missed, the chance that pregnancy will occurdepends not only on how many pills were missed but alsowhen the pills were missed.

Evidence for recommendations about missed pills ismainly derived from studies of women using 30–35 �gethinyloestradiol pills. Limited evidence on 20 �gethinyloestradiol pills suggests there could be a higher riskof pregnancy when missing such pills than when missing30–35 �g pills. A more cautious approach is recommendedafter missing 20 �g ethinyloestradiol pills.

Field experience highlights the need for simple guidelinesabout missed pills.

5 Litt IF. Placing emergency contraception in the hands of women. JAMA2005; 293: 98–99.

6 Ziebland S, Wyke S, Seaman P, et al. What happened when Scottishwomen were given advance supplies of emergency contraception?A survey and qualitative study of women’s views and experiences. Soc Sci Med 2005; 60: 1767–79.

7 McLeod A. Changing patterns of teenage pregnancy: population basedstudy of small areas. BMJ 2001; 323: 199–203.

8 Bissell P, Anderson C. Supplying emergency contraception via communitypharmacies in the UK: reflections on the experiences of users andproviders. Soc Sci Med 2003; 57: 428–33.

9 Anderson C, Bissell P, Sahram S, Sharma R. Manchester, Salford andTrafford Health Action Zone: report into the provision of emergencyhormonal contraception by community pharmacies via patient groupdirections. Nottingham, University of Nottingham, 2001.

10 Independent Advisory Group For Sexual Health and HIV. Annual report2003/2004. London: Department of Health, 2004.

Comment

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ethinyloestradiol in their pill. Therefore can theycorrectly apply these new rules about missing theircontraceptive pill? Careful teaching might rectify thispoint, but confusion will continue for some women.Health professionals who are already aware of theforthcoming new rules have expressed concern. Theywonder why there are two rules, one for 30–35 �gpills and another for those containing 20 �g or lessethinyloestradiol. One rule for all would be better.

The medical community is unsure what WHO and theClinical Effectiveness Unit mean by “missed pills”. Thereis no definition in the recommendations, but it is likelyto refer to extending the dose regimen to more than36 h (taking a contraceptive pill more than 12 h latefrom the designated daily time). This point does,however, need clarifying because being 2 days latestarting the contraceptive pill after a pill-free intervalmight mean between 49 h and 71 h late, and as we shallsee, every extra hormone-free hour may matter.

There is no strong evidence stating it is safe to miss upto three 30–35 �g ethinyloestradiol pills at the start ofa new packet without advising back-up contraceptionor emergency contraception if unprotected sex hasoccurred. True method-failures can occur in users ofcombined oral contraceptive pills taking a standardpill-free break, indicating that 7 hormone-free days istoo long for a small number of women.6 Any extensionto the pill-free interval could be critical.7,8

Large ovarian follicles develop in a significant numberof users taking combined oral contraceptive pills, andaccurate detection of ovulation requires frequent anddetailed endocrine and ultrasonic evaluation. Only twostudies have used such technology to address thisproblem.7,8 Neither was cited by WHO or the ClinicalEffectiveness Unit, so we do not know if they wereconsidered. Follicular development during the pill-freeweek (with dominant follicles of 10 mm or more reportedin as many as 86% of users of low-dose combined oralcontraceptive pills) has been consistently reported withthe improved ability to monitor ovarian function withfrequent high-resolution transvaginal ultrasonography.7

Worryingly, one ultrasound paper suggested that theincidence of presumptive ovulation ranged from 12%to 28% when women correctly took a 20 �g ethinyl-oestradiol combined oral contraceptive pill.8

Ovulation after deliberate extension of the pill-freeinterval has been documented and is linked to the type

and dose of steroids used, the administration regimen,users’ adherence, and the individual responsiveness ofwomen taking the combined oral contraceptive pill.9–11

Studies with relatively small numbers of women (asquoted by the Clinical Effectiveness Unit) are notpowered to detect this wide individual variation, andbasing new guidance on such a paucity of data is unwiseand could lead to an increase in unintended pregnancies.

In conclusion, the work of the Clinical EffectivenessUnit is highly valued and is changing the face ofcontraceptive practice. Bringing leaders in the fieldtogether to develop consensus recommendations is tobe applauded, but careful consideration must be takenwhen rules are relaxed in litigious societies. With theavailable evidence, we suggest one rule for all—actionto be taken after missing two rather than three pills forall doses of combined oral contraceptive pills, but witha major educational exercise to highlight the risks ofextending the pill-free interval.

*Diana Mansour, Ian S FraserNewcastle Primary Care Trust, Newcastle upon Tyne NE4 6BE,UK (DM); and Department of Obstetrics and Gynaecology,University of Sydney, Sydney, New South Wales, Australia (ISF) diana.mansour@newcastle-pct.nhs.uk

We have both received honoraria and expenses for presentations and lecturesat symposia and for research projects sponsored by the drugs industry.

1 Faculty Statement for the CEU on a New Publication: WHO SelectedPractice Recommendations for Use Update. Missed pills: newrecommendations. J Fam Plann Reprod Health Care 2005; 31: 153–55.

2 WHO. Medical eligibility criteria for contraceptive use, 3rd edn. Geneva:World Health Organization, 2004.

3 WHO. Selected practice recommendations for contraceptive use, 2nd edn. Geneva: World Health Organization, 2004.

4 Costello A, Osrin D, Manandhar D. Reducing maternal and neonatalmortality in the poorest communities. BMJ 2004; 329: 1166–68.

5 Korver T, Goorissen E, Guillebaud J. The combined oral contraceptive pill:what advice should we give when tablets are missed? Br J Obstet Gynaecol1995: 102: 601–07.

6 Trussell J. Contraceptive failure in the United States. Contraception 2004;70: 89–96.

7 Baerwald A, Olatunbosun O, Pierson R. Ovarian follicular development isinitiated during the hormone-free interval of oral contraception use.Contraception 2004; 70: 371–77.

8 Pierson R, Archer D, Moreau M, Shangold G, Fisher A, Creasy G. OrthoEvra/Evra versus oral contraceptives: follicular development andovulation in normal cycles and after an intentional dosing error. Fertil Steril 2003; 80: 34–42.

9 Hamilton C, Hoogland H. Longitudinal ultrasonographic study of theovarian suppressive activity of a low-dose triphasic oral contraceptiveduring correct and incorrect pill intake. Am J Obstet Gynecol 1989;161: 1159–62.

10 Landgren B, Csemicsky G. The effect of follicular growth and lutealfunction of ‘missing the pill’: a comparison between a monophasic and a triphasic combined oral contraceptive. Contraception 1991;43: 149–59.

11 Creinin M, Lippman J, Eder S, Godwin A, Olson W. The effect of extendingthe pill-free interval on follicular activity: triphasic norgestimate/35 �gethinyl estradiol versus monophasic levonorgestrel/20 �g ethinylestradiol. Contraception 2002; 66: 147–52.