Abstract
The practice of extending combined oral contraceptive use (COC) and eliminating or reducing the hormone free interval has been in use for many years. More recently a range of products with new dosing options has been developed and marketed. Women and physicians in developed countries are comfortable with and many prefer the use of extended COC regimens which provide an option to eliminate or reduce the frequency of regular withdrawal bleeding. The extension of active pill taking and the reduction or elimination of the hormone-free interval have been shown to be beneficial for women who experience menstrual cycle-related problems such as heavy bleeding or dysmenorrhoea. The hormone-free interval of less than seven days has additional benefits in managing hormone withdrawal symptoms and efficacy may be improved in situations where pills are inadvertently missed or in women who are perceived as ‘poor’ pill takers. This paper provides a descriptive review highlighting the development of new dosing options that alter the traditional 21/7 COC regimen. The rationale for and the acceptability of COCs developed with alternative dosing regimens is examined.
INTRODUCTION
In the 50 years since the first oral contraceptive (OC) was marketed, it has undergone important changes. A wide range of other effective and reversible hormonal contraceptive products has been developed. Aside from the pill, combined hormonal contraceptive options now include a transdermal patch, subdermal implants, injections, and a vaginal ring. In addition, there are progestogen-only methods available as contraceptive pills as well as long-acting reversible contraceptives, including implants, injections, and hormonal intrauterine systems.
In the developed world, combined oral contraceptives (COCs) remain a popular choice for women. Data from randomly selected European women aged 15–49 years in 2006 showed the highest usage rates in France (49%) and the Czech Republic (44%) with the lowest use in Russia, the Baltic States, and Spain (15–18%)Citation1. In 2006–2008, 17% of women aged 15–44 years in the United States who reported that they were using contraception, were taking OCs and 34% of a representative survey of Australian women aged 16–59 years, using contraception in 2001, reported using this method of contraceptionCitation2,Citation3.
The development of new dosing regimens
In the early 1960s, the most serious adverse effect associated with COC use, thromboembolism, became evident; it was attributed to the high dose of oestrogen in the formulationCitation4,Citation5. The first modification to dosing was, thus, a decrease in the oestrogen dose. This occurred fairly quickly: COCs with 30 μg ethinylestradiol (EE) were released in the early 1970sCitation6. Attempts were also made to reduce the overall dose of steroids being consumed by developing phasic pillsCitation6,Citation7. At the same time, efforts were made to reduce progestogen-influenced side effects and androgenic effects on lipid and glucose metabolismCitation8. New progestogens, the so-called ‘third generation’ progestogens, including gestodene, norgestimate and desogestrel (DSG), were released in the mid 1990s.
Although extended-cycle use of COCs has been practised for decades by physicians and women, until recently, all COCs have been manufactured and licensed in a regimen of 21 days of active treatment followed by a seven-day hormone-free interval, when a withdrawal bleed usually occurs. A number of reasons for the original choice of this dosing regimen have been advanced, including: a desire to mimic the normal ovulatory cycle to facilitate general community acceptance; to bring the pill regimen into line with the Catholic Church's approach in approving the use of the ‘safe’ period for birth control; and concerns that not having a bleed on a monthly basis may be harmful.
In the past decade, the development of the COC has included the licensing of extended regimens of three or more months of continuous active-pill taking as well as regimens that shorten the hormone free interval or supplement with low-dose oestrogen ( and ).
Table 1 Extended cycle regimens
Table 2 Regimens with hormone-free intervals of less than seven days
The rationale for the development and marketing of these alternative regimens recognises that the existence of the seven-day hormone-free interval is not without problems:
When COCS are taken correctly, their contraceptive efficacy is mainly due to suppression of ovarian activity and prevention of ovulation. A lessening of ovarian suppression occurs with a decrease in oestrogen dose and also with time since the last active pill was ingested. While sufficient suppression to maintain contraceptive efficacy is present during the traditional seven-day pill-free interval in 30 μg EE COCs, there is an increased risk of escape from suppression with low dose (20 μg EE) pills. Schlaff et al. compared three different regimens of administration of low-dose pills with regard to the follicular suppression they achieved. The first regimen consisted of the intake, according to the conventional pattern, of 20 μg EE/100 μg levonorgestrel (LNG) during 21 days followed by a seven-day hormone-free interval. In the second regimen, pills containing 20 μg EE/150 μg DSG were taken continuously, with no hormone-free interval. The third regimen consisted of the intake of 21 active pills of the same kind (20 μg EE/150 μg DSG) followed by a shortened pill-free interval of two days and the administration of oestrogen alone (10 μg EE) for five days. The authors reported less follicular suppression in the traditional regimen than in either of the two other regimensCitation9. The ‘missed’ or ‘late start’ of a new cycle of pills, particularly low oestrogen pills, is therefore a potential problem. One in eight users of COCs can experience a contraceptive failure in the first year due to incorrect and inconsistent useCitation10. The importance of managing the ‘missed pill’ close to the hormone-free interval and the delay in restarting the intake of active pills after the break have led to the development of international protocols for ‘missed and late start’ pillsCitation11.
An important issue for women is the effect of the hormone-free interval in allowing withdrawal symptoms, such as headache, acne and premenstrual symptoms, managed by the active pills, to reoccurCitation12,Citation13. The brief escape from ovarian suppression and the resulting change in hormonal activity is postulated as the reason for withdrawal symptoms in the pill-free interval.
A monthly menstrual bleed is not always appropriate; there are good reasons for either delaying or abolishing the withdrawal bleed altogether in case of dysmenorrhoea or menorrhagia, or for avoidance of the social or occupational disadvantages of menstruationCitation14 , Citation15.
The objective of this review is to outline the development of, rationale for and acceptability of COCs with alternative dosing regimens.
METHODOLOGY
A literature search for relevant articles in the English language was conducted using the search engines Pubmed and Google. There was no limit on years of publication and historic papers were specifically sought for a descriptive review of the topic. Key words were: continuous oral contraceptive, shortened hormone free interval, attitudes to monthly bleeding, hormone withdrawal symptoms, and oral contraceptive efficacy. The Cochrane database was searched for reviews relating to extended cycle contraception. References in reviews and in papers found were also accessed. Papers were selected on the basis of their clinical and historical relevance in the genesis and development of the practice and product development related to extended cycle contraception as well as those that illustrated the specific outcomes of improving contraceptive efficacy, analysis of bleeding patterns and effect on hormone withdrawal symptoms.
DISCUSSION
Is there a medical need for a hormone free interval?
The natural menstrual cycle and the cycle driven by combined hormonal contraception are completely different entities. The former is ovulatory, potentially fertile, and ends with the shedding of the endometrium when fertilisation has not occurred. During the administration of combined hormonal contraceptives ovulation is suppressed and the ‘bleed’ only occurs as a result of the withdrawal of exogenous hormones. We now have a good understanding of the safety of COCs utilised in the traditional dosing regimen. Is there evidence that extended use of COCs is also a safe practice?
While physicians have long been convinced that fertility promptly and fully recovers following discontinuation of OC use, many women still express concerns about infertility associated with the suppression of ovarian activity and the resultant changes in the menstrual cycleCitation16,Citation17.
As discussed earlier, research on the effect of COCs on ovarian, specifically follicular function, has demonstrated that there is sufficient follicular suppression during the days that active pills are being taken. But there is, particularly with low dose (20 μg EE) pills, a potential ‘escape’ from suppression as measured by increases in follicle stimulating hormone (FSH) and oestradiol as well as an increase in follicular development which occurs fairly quickly during the hormone-free intervalCitation9,Citation18–20. This shows that there is no ongoing interference with endocrine control mechanisms associated with the pharmacological suppression of ovarian function; indeed it demonstrates the extremely rapid reversibility of the aforementioned interference.
Another concern is that related to carcinogenesis from exposure to COCs over an extended period. Recent epidemiological studies into outcomes over the past 50 years of COC use have been reassuring in this regard: they demonstrated reduced rates of gynaecological cancers and indeed, of overall mortalityCitation21–23. Epidemiological studies can, however, be challenged, as they do not necessarily demonstrate a causal relationship. So, are these findings valid?
The reduction in ovarian cancer rates is plausible. It has been attributed to the prevention of ovulation, resulting in less injury to and subsequent repair of the ovarian epitheliumCitation24. Endogenous follicular oestrogen secretion is markedly suppressed in COC users and during ‘active’-pill taking target tissues are simultaneously exposed to the action of both an oestrogen and a progestogen, resulting in a reduction of the potential for endometrial hyperplasia and progression to cancer.
Endometrial safety was specifically studied in 50 women applying an extended cycle regimen of 84 active 30 μg EE /150 μg LNG pills followed by seven placebo pills over one year. On endometrial biopsy no significant pathology was identified and after study completion, endometrial histology showed a rapid return to normalCitation25.
The risk of breast cancer, while taking the pill is less clear, as epidemiological studies have not provided clear clues to a causal relationshipCitation26,Citation27. However, the overall rise in breast cancer risk in COC users, if any, is likely to be small. The effect of the hormone-free interval on this risk is not known, but it could be postulated that increasing activity within the breast due to withdrawal from hormonal suppression may not be beneficial.
A further concern has been expressed about an increase in the risk of serious adverse events due to the extended exposure to oestrogen in extended COC and oestrogen-supplemented regimens. So far, studies comparing extended use with traditional regimens have not reported an increase in adverse events of this natureCitation28,Citation29. No serious adverse events were observed in five of the six randomised controlled trials comparing cyclic with continuous use examined in a Cochrane review, however overall trial numbers were found to be too small to rule out the occurrence of rare adverse eventsCitation30.
What about women's and physician's attitudes towards monthly menstruation?
Women's attitudes to menstruation have been examined in a number of studies internationally. When specifically asked about their preferences, women in developed countries are generally positive about bleeding less frequently than monthly and experiencing less menstrual loss.
A survey published in 2004 of 1,195 German women aged 15–49 years indicated that 26–35% of them preferred to bleed monthly, while 37–46% wished never to bleed. Reasons for preferring bleeding included: fear of pregnancy, infertility, adverse effects, and also the feeling that menstruation is natural. The women who preferred not to bleed cited as advantages: fewer cycle-related complaints, better hygiene, improved quality of life, and less blood lossCitation15. A 1999 Dutch telephone survey of more than 300 women in four age groups found that up to 80% of the women interviewed preferred changes that either would make bleeding less painful, of shorter duration, and less heavy, or would induce amenorrhoea. Younger women (age 15–19 years) preferred less pain and shorter duration, while older women (45–49 years) preferred amenorrhoea. The majority also indicated a preference for bleeding less than once a month or neverCitation31.
In the United States, a national sample of 1,470 women responded to a survey asking about menstrual suppression. Most (78%) of respondents had never heard of menstrual suppression with OCs. Fifty-nine percent indicated that they would be interested in not menstruating each month and a third would choose to never have a periodCitation32. But women's attitudes are culture-dependent. An international study found that a majority of African women in Cape Town and Nigeria (75–80%) liked to have periods. Their prime concern was related to the return of fertilityCitation17.
For almost as long as the pill has been available, physicians have been willing to prescribe extended regimens to their patients. German gynaecologists were found to prescribe extended cycles primarily for medical reasons such as dysmenorrhoea, hypermenorrhoea, endometriosis, and premenstrual dysphoric disorder. They indicated a preference for the uninterrupted intake of three packs of COCs, followed by a seven-day breakCitation16. A prospective survey of over 500 health care professionals in the United States (including primary care physicians, obstetrician/gynaecologists, nurse practitioners, and physician assistants), who prescribe OCs, revealed that 87% thought that extended use regimens should be offered routinely, with only 12% believing that withdrawal bleeding with the conventional seven-day hormone-free interval had ‘health benefits and is necessary’Citation33.
Adolescents may experience much distress due to troublesome menstrual cycles. A survey of North-American specialists managing adolescents (predominantly paediatricians and gynaecologists) found that nearly all (99% of 222 respondents) had prescribed extended cycles to young women and that 33% did this more than 10% of the time. Unlike the German gynaecologists, they were most commonly responding to patients' requests to delay the bleeding episode until after specific events (82%) and for fewer menses per year (72%), but they also used extended-cycle regimens for menstruation-related disorders or complaints such as menorrhagia, dysmenorrhoea, and endometriosis. In common with the German gynaecologists, they most commonly prescribed 84 days of active pills followed by a placebo breakCitation34.
Bleeding and the menstrual cycle; do extended-cycle regimens have a benefit?
Research was conducted as early as in the 1970s into extending cycle regimens. It recognised that the choice of the cyclical administration of steroids during 21 days, followed by a ‘pill-free’ interval of seven days, was purely arbitrary and there were likely to be benefits in a departure from monthly withdrawal bleeding. The first published study examined the attitudes to and outcomes of a regimen of 84 active pills followed by a six-day break in almost 200 women attending a family planning clinic in Edinburgh. The pill used in the study contained high doses of steroids by today's standards: 50 μg EE and 250 μg lynestrenol. The authors commented that ‘the majority of women (82%) welcomed the associated freedom from menstrual and premenstrual symptoms, and many found the tri-cycle regimen easier to follow’. Interestingly, the doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves, some citing a concern about ‘missing’ a pregnancyCitation35.
The concept of taking active pills during 12 weeks, followed by a seven-day hormone-free interval, often called ‘tricycling’ was further investigated in a study conducted in three Swedish centres in 1993. The 198 participants were randomised to either a standard (21/7) or a tricycle regimen (84/7) of 30 μg EE and 150 μg DSG. In spite of there being significantly more breakthrough bleeding and spotting in the group with the extended regimen, questionnaires completed at 12 months or after discontinuation indicated that 63% of the women preferred it, while 26% preferred the traditional regimen. The important factor in this preference may have been that both the breakthrough bleeding and the spotting decreased during the trial. Women in the extended use group also reported fewer headachesCitation36.
Extended cycle regimens have, more recently, been examined in some detail, and there is a clearer picture of the frequency and amount of bleeding that is likely to occur. It appears that extended regimens do induce amenorrhoea in most subjects, but there is a tendency for increased spotting and breakthrough bleeding, particularly in the early months of treatment. With time, the bleeding often improves and, despite the inconvenience, women are prepared to accept thisCitation15,Citation16,Citation37. This initial increased bleeding and spotting may be more pronounced in ‘new’ pill usersCitation16. On a practical level, there is a benefit in the reduced quantity of withdrawal bleeding in extended regimens with a significant difference in the amount of money spent on feminine hygiene productsCitation15.
In longer extended-use studies the results are similar. In a 12-month randomised controlled trial comparing continuous and cyclic use of a 20 μg EE/100 μg LNG pill, amenorrhoea or infrequent bleeding was present in 68% of continuous users during months one to three and increased to 88% during months ten to twelve. Spotting increased initially with continuous use but reduced over time. A small subset had an endometrial biopsy at entry and again at nine months, and no hyperplasia or neoplasia was reportedCitation36. A single-treatment, open-label study, examining the safety and efficacy of a 20 μg EE/90 μg LNG pill in continuous use over a year also showed amenorrhoea to have occurred in the majority of subjects at 13 months (59%), with 79% reporting absence of bleeding requiring sanitary protection. Safety profile and efficacy were reported to have been similar to those of the standard regimenCitation39.
A COC containing 30 μg EE and 3 mg drospirenone (DRSP) has also been examined in an open-label trial assessing the bleeding profile during an extended 126-day regimen. One hundred and seventy seven women recorded bleeding events, completed satisfaction questionnaires, and a subset of 30 had endometrial biopsies. Amenorrhoea was induced in 40%, a somewhat lower rate than that reported for the previously discussed EE/LNG extended regimens, but in 60% there was a shift to less intense bleeding; 68% were satisfied with the extended regimen and safety was comparable to that seen in a conventional regimenCitation40. A study from Israel compared the same formulation of EE and DRSP in a 21/7 regimen vs. an 84/7 regimen in 137 women; there was a significant reduction in the amount of bleeding in the extended-cycle regimen at six monthsCitation41.
A recent Cochrane review into the subject of extended-cycle regimens commented with regard to bleeding profiles that in five of the six studies reviewed it was reported that bleeding patterns were either no different or improved with extended-cycle regimens compared to the conventional cycle regimen. The authors of the review did comment that it was not possible to aggregate data from the randomised controlled trials included as they did not share a standard treatment (type of pill or duration of dosing)Citation30.
An interesting question for the practising clinician is whether the difference between the constituents of the various COCs affects bleeding outcomes.
A comparative study of four active treatments, namely, 20 μg EE/100 μg LNG, 30 μg EE/100 μg LNG, 20 μg EE/1000 μg norethindrone acetate (NETA), and 30 μg EE/1000 μg NETA for 180 days showed that the use of COCs containing NETA resulted in more days of amenorrhoea and fewer days of spotting than preparations containing LNGCitation42.
With regard to problem bleeding, while a decrease in dysmenorrhoea in the continuous- compared to standard regimen groups has been reported in the past, most studies did not address the issue of dysmenorrhoea and menorrhagiaCitation43. However, menstrual pain and heavy menstrual bleeding were specifically surveyed in the Israeli study discussed above: at six months, a significant improvement was observed among women applying extended use compared to those having the traditional 28-days pill-driven cyclesCitation41. Among a cohort of women in the United States entering a study examining patients' acceptance and continuation of a regimen extending the duration of intake of active COCs and shortening the hormone-free interval to 3–4 days, 40% reportedly did so for relief of dysmenorrhoea or pelvic pain, and 36% for heavy withdrawal bleedingCitation13.
Hormone withdrawal symptoms
Apart from bleeding issues, research has shown that some women suffer from withdrawal symptoms during the hormone-free interval. A seminal study asked 262 COC users to maintain records of hormone-related symptoms throughout the cycle, both when taking active pills and during the intervals. Participants included both new users, who kept diaries for three cycles, and current users, who kept diaries for two cycles. COCs used were primarily monophasic and the progestogen component included norethindrone, levonorgestrel, desogestrel and norgestimate. Although the dose of oestrogen is not stated, at the time of publication (2000) COCs commonly contained 35 μg or less of EE. Symptoms found to be significantly worse during the hormone-free interval were pelvic pain, bloating or swelling, breast tenderness, and headachesCitation12.
Patient satisfaction outcomes with regard to hormone withdrawal symptoms have been examined in extended-cycle regimens and are generally positive, with a number of studies reporting improvement in premenstrual symptoms and reduced headacheCitation13,Citation43–45. The Cochrane Review commented that extended-cycle regimens were better than traditional regimens in managing withdrawal headache, genital irritation, tiredness, bloating, and menstrual painCitation30.
Efforts to manage the withdrawal symptoms of the hormone-free interval apart from extended cycles and continuous use have more recently included shortening the hormone-free interval. One of the first interventions of this type was reported in a study of 20 μg EE plus 75 μg gestodene administered for 23 days compared to the usual 21 days, effectively shortening the placebo phase to five days instead of seven.
The study was designed as a double-blind, randomised, multicentre trial involving 60 women; it aimed primarily at demonstrating improved ovarian suppression and consequently a greater safety margin when pills were ‘missed’. The authors commented that shortening the hormone-free interval by extending the active pill phase might also benefit patients on long-term treatment with enzyme-inducing drugs, particularly those with epilepsy, and patients with headaches, non-focal migraine, breast tension, and bleeding problems attributable to fluctuating high endogenous oestrogen levelsCitation18.
In clinical practice the management of symptoms associated with fluctuating endogenous oestrogen levels in the seven-day hormone-free interval has sometimes been addressed by the ‘off-label’ use of low-dose oestrogen tablets, such as those used in hormone replacement therapy during the hormone-free interval. A product containing 20 μg EE and 150 μg DSG given for 21 days, followed by two days of placebo and then five days of 10 μg EE has been available in the United States since 1998. Comparison of this oestrogen-supplemented COC regimen with an extended regimen found similar suppression of ovarian activity, indicating support for this rationaleCitation9.
The further development of the reduction of the hormone-free interval, with a ‘short’ extended cycle has delivered some important new initiatives in the evolution of the COC and directly addresses issues raised by the use of ‘long’ extended-use regimens, such as the tricycling regimen. As previously discussed, the principal problem with extended cycles is the increase in unscheduled bleeding, and although this is generally less intense that that found in traditional cycles, its appearance can be problematic for women. Practising clinicians have, for some time, used the concept of a three day pill ‘holiday’ when this unscheduled bleeding occurs, allowing a withdrawal bleed which appears to stabilise the bleeding patternCitation46. A potential problem of this intervention, however, is the need to ensure that enough pills are taken prior to and between pill ‘holidays’, so that efficacy is not compromisedCitation46. The regimens with shortened hormone-free intervals do in effect utilise this pragmatic approach to provide scheduled bleeding and minimise the nuisance of breakthrough bleeding that tends to occur with extended regimens. They simultaneously aim at minimising the appearance of hormone-withdrawal symptoms, and maintaining or possibly improving efficacy. The marketed 24/4-day regimen containing 20 μg EE and 3 mg DRSP has been shown to have bleeding patterns comparable to traditional regimens and to be beneficial in managing hormone withdrawal symptoms; it has also been approved for treatment of the premenstrual dysphoric disorder (PMDD)Citation47.
Another development has been the oestradiol valerate (E2V)/dienogest (DNG) COC which has a shortened placebo phase of two days combined with oestrogen alone for two days before and after the placebo phase and a phasic dosing pattern described as a ‘dynamic dosing’ regimen where the oestrogen component is gradually reduced, while the progestogen component increases. A comparative study of this regimen with a 21/7 20 μg EE/100 μg LNG COC reported higher rates of amenorrhoea and reduced duration and intensity of withdrawal bleeding with the E2V/DNG COC. Rates of intracyclic bleeding were similar in both regimensCitation48.
Another option in combined oral contraception to reduce unwanted, unscheduled bleeding, while maintaining the benefits associated with extended-use regimens, will be created by the likely marketing of extended-regimen COCs with a ‘woman-controlled’ approach to the withdrawal bleed. In such regimens, the breakthrough bleed will act as a signal to stop taking active hormone pills and have a designated hormone-free interval. This may not appeal to all women as a reasonably high level of health literacy may be required to manage a flexible regimen; however, it would provide some women with a sense of control in managing unscheduled bleeding episodes.
What about efficacy?
A vital question about whether continuous active treatment or shortened hormone-free intervals provide a benefit over the conventional cyclic regimen, is that of efficacy. Does a reduction in the number of inactive pills actually translate into significantly fewer contraceptive failures?
Most contraceptive methods operate within a range of efficacy values covering both perfect and typical use, primarily due to poor compliance or misuse. An estimated failure rate of 9% has been ascribed to the COC used over 12 months in the United StatesCitation49. It has been assumed that by using continuous regimens, which might improve compliance, efficacy would improve.
As discussed earlier, in research studies, a surrogate measure of contraceptive efficacy, the inhibition of ovarian activity, is commonly usedCitation9,Citation50. The Hoogland scoring system for assessing ovarian activity is frequently utilised; its development was based on the assumptions that ‘ovulation and possible pregnancy during pill intake can only occur in cases where residual ovarian activity is present’ and that ‘follicle growth during pill use complies with growth in spontaneous cycles’. This and other studies concluded that the degree of residual ovarian activity could be regarded as a useful measure of the effectiveness of oral contraceptivesCitation51. The scoring system combines ultrasound assessment of follicular size and appearance with the measurement of LH, FSH, oestradiol and progesterone levelsCitation9,Citation18,Citation45.
A fascinating study into the question of missed pills and poor compliance randomised women to either a 21/7- or a 24/4 days-regimen of pills containing 20 μg EE and 3mg DRSP. A test of real life efficacy was built into the trial by replacing the initial three pills in both groups with placebos in the third treatment cycle, mimicking a late pill start after the hormone-free interval. The 24/4 days-regimen was found to suppress ovarian activity to a greater degree than the conventional cycle; 88% of the subjects in the former group had no follicular development compared to 56% in the latterCitation52.
All of these studies with low-dose oestrogen COCs indicate reduced ovarian activity and potential improved efficacy by extending active pill taking and reducing the hormone-free interval. As yet there is no published evidence that this is the case, but the results of an ongoing post-marketing active surveillance study of a COC containing 20 μg EE and 3 mg DRSP in a 24/4 days-regimen compared with the same pill administered according to a 21/7 days-regimen is being undertaken with this objective.
conclusion
Women and physicians in developed countries are comfortable with and many prefer the use of extended COC regimens. The extension of active pill taking and the reduction, supplementation with low dose oestrogen or elimination of the hormone-free interval are advantageous for women who experience heavy menstrual bleeding or dysmenorrhoea. The hormone-free interval of less than seven days has additional benefits in managing withdrawal symptoms. Further trials are necessary to assess the impact of longer-term use of extended regimens on safety, cancer and cardiovascular disease. While efficacy is likely to be better in situations where pills are inadvertently missed or in women who are perceived as ‘poor’ pill takers, the proposition that reducing the opportunity for mistakes would result in improved efficacy has yet to be substantiated and ongoing research into this issue is needed.
ACKNOWLEDGEMENTS
The author would like to thank Dr Marco Serrani, Bayer Schering Pharma, for his assistance in reading and commenting on the manuscript drafts and Jenny Szkolar from inScience Communications, a Wolters Kluwer business, who provided editorial assistance. Funding for this assistance was provided by Bayer Schering Pharma AG.
Declaration of interest: Dr Read is an independent consultant in family planning and has provided expert opinion to pharmaceutical companies including Bayer Schering Pharma, MSD and Pfizer. She has received support to attend conferences from Bayer Schering Pharma and is a principal investigator for a MSD funded contraceptive trial. This paper was written solely by the author, with editorial assistance provided by Bayer Schering Pharma as detailed in the acknowledgements. Dr Read did not receive, nor does she expect to receive any payment in its preparation.
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