Julie Craik1 and Louise Melvin1
(1)
Sandyford Sexual Health Service, NHS Greater Glasgow and Clyde, 2-6 Sandyford Place, Glasgow, G3 7NB, UK
Julie Craik
Email: mail@fsrh.org
Introduction
There are two main types of oral contraceptives, combined oral contraceptives (COCs) that contain both synthetic estrogen and progestogen, and progestogen-only pills (POPs), also known as ‘mini-pills’. Despite the availability of longer acting reversible methods of contraception, which are more effective with typical use than oral contraceptives, oral contraceptives remain one of the most commonly used hormonal contraceptives worldwide (United Nations. Department of Economic and Social Affairs. Population Division 2013).
In the early 1960s, the COC or ‘the pill’, as it is often referred to, was first approved for use in countries such as the US, UK and Australia with the POP becoming available later that decade. However, in Japan, it wasn’t until 1999 that the COC became available as a contraceptive medicine for women.
In the 1960s and 1970s COC formulations contained doses of estrogen and progestogen that were far higher than those administered in COCs today. The first COC marketed in the USA contained 150 mg of mestranol (Enovid®), which is roughly equivalent to 100 μg of ethinylestradiol. In Australia, the first marketed pill contained 50 μg of ethinylestradiol (Anovlar®). Ethinylestradiol and mestranol have been the principal synthetic estrogens used in COCs since the pill’s inception. It is only in recent years that COCs have been introduced onto the market which utilise estradiol either as estradiol valerate or as estradiol hemihydrate (e.g. Qlaira® and Zoely®).
Whereas the type of synthetic estrogen has remained fairly constant until recently, in contrast, a variety of progestogens have been used within COCs during the past 50 or so years. Progestogens can be classified by their structure, or often they are categorised by their ‘generation’ which reflects the timing of their launch onto the market. These different progestogens have been used in an attempt to combat some of the side effects experienced by women when using COCs. Examples of oral contraceptives using the different progestogens are shown in Table 5.1.
Table 5.1
Examples of progestogens contained in COCs and POPs by generation
|
Generation of progestogen |
Progestogen |
Examples of COCs a |
Examples of POPs b |
|
First generation |
Norithisterone (norethindrone), norethisterone acetate, norethynodrel acetate, ethynodiol diacetate, lynestrenol |
Brevinor® |
Micronor® |
|
Loestrin® |
|||
|
Second generation |
Levonorgestrel, norgestrel |
Microgynon® |
Norgeston® |
|
Third generation |
Desogestrel, gestodene, norgestimate |
Cilest® |
Cerazette® |
|
Gedarel® |
Cerelle® |
||
|
Mercilon® |
|||
|
Fourth generation |
Drospirenone, dienogest, nomegesterol acetate |
Qlaira® |
n/a |
|
Yasmin® |
|||
|
Zoely® |
Notes
aCombined oral contraceptives
bProgestogen only pills
Examples listed are UK products. Trade names may vary between countries and may not be available in all countries
Currently marketed COC formulations contain between 15 and 50 μg of ethinylestradiol or 50 μg of mestranol (equivalent to 35 μg of ethinylestradiol). In the UK, there are currently no monophasic ethinylestradiol pills containing more than 35 μg (Joint Formulary Committee. British National Formulary 2014).
Soon after their introduction, concerns were raised about an observed increased risk of venous thromboembolism (VTE) amongst ‘pill’ users compared to non-users (Anon 1967) which resulted in lower dose formulations. Current formulations have also been found to be associated with an increased risk of VTE (de Bastos et al. 2014; European Medicines 2014a) and there is continuing debate about the role of progestogens in mediating this risk (see Chap. 6).
Because of the COC’s impact on cardiovascular health, it has periodically attracted negative press and the issues around ‘pill scares’ are discussed further in Chap. 19. However, there are many benefits in the use of oral contraceptives which tend to be understated. An overview of the risks and benefits of oral contraceptives will be explored throughout this chapter.
Mechanism of Action and Effectiveness
Mechanism of Action: COCs
Combined oral contraceptives have several mechanisms of action which contribute to their effectiveness (Faculty of Sexual and Reproductive Healthcare 2011a). Their main mechanism of action is to prevent fertilisation via inhibition of ovulation (Rivera et al. 1999; Faculty of Sexual and Reproductive Healthcare 2011a). Suppression of ovulation occurs via a negative feedback system whereby the action of the hormones on the hypothalamic pituitary axis reduces the availability of luteinising hormone and follicle stimulating hormone, particularly mid cycle (Killick et al. 1987).
Traditionally COC regimens have involved taking 21 days of ‘active pills’ followed by a 7-day hormone-free interval. The estrogen and progestogen within the ‘active pills’ is delivered either steadily throughout the cycle (monophasic pills) or at differing doses (phasic pills). The first seven pills are used to suppress ovulation, with the remaining pills maintaining this suppression (Faculty of Sexual and Reproductive Healthcare 2011a). The hormone free interval involves no pill taking or taking a number of inactive/placebo pills, which in turn usually induces endometrial shedding and a so-called ‘withdrawal bleed’, thus mimicking the natural menstrual cycle. The withdrawal bleed tends to be lighter than the woman’s period and occasionally women may remain amenorrhoeic during the hormone-free interval, particularly if it is shorter than 7 days – increasingly COCs are being marketed with a shortened hormone free interval or fewer placebo pills, for example 24/4 or 26/2 regimems. (Bayer PLC 2013; Merck Sharp and Dohme Limited 2014a). While these shorter interval regimens are available, women can also be advised to use 21/7 monophasic pills with a shortened free interval or as part of an extended regimens such as tricycling (Faculty of Sexual and Reproductive Healthcare 2011a) – such use may be outside the product licence.
Mechanism of Action: POPs
The production of ‘hostile’ mucus that is impenetrable to sperm is one of several mechanisms by which POPs exert their effect (McCann and Potter 1994). It is the first line of defence, with the effect observed quickly after ingestion of a POP (McCann and Potter 1994). Some guidance advises that women starting a POP only need 2 days of pill taking to have contraceptive protection (Faculty of Sexual and Reproductive Healthcare 2015; World Health Organization 2004)- however, such advice may be outside the terms some product licences which advocate 7 days (Merck Sharp and Dohme Limited 2014b; Pfizer Limited 2010). POPs need to be taken daily, ideally at the same time each day, as the cervical mucus effect is quickly lost (McCann and Potter 1994).
In terms of their effect on ovulation, the ability to suppress ovulation is variable, with the desogestrel POP having been shown to do so more consistently than other pills such as the levonorgestrel pill (Rice et al. 1999).
Other documented mechanisms of action of POPs include reduction of cilia activity within the fallopian tube, suppression of mid-cycle peaks of the pituitary hormones, and, alterations to the endometrium which could hinder implantation (McCann and Potter 1994).
Efficacy and Effectiveness of Oral Contraceptives
The efficacy of oral contraception is a measure of its therapeutic effect i.e. how successfully it prevents pregnancy within a clinical trial setting. Effectiveness on the other hand is a measure of its effect in clinical practice or ‘real life’ use.
When used consistently and correctly i.e. perfect use, oral contraceptives are effective methods of contraception. For the COC, a gross 1 year cumulative failure rate based on clinical trial data has been calculated as being between 0.2 and 2.3 per 100 women (Mansour et al. 2010). However, to a greater extent than with some other methods, such as the progestogen-only implant or intrauterine methods (see Chap. 8), the effectiveness of oral contraceptives is largely dependent on the user. Human error is inevitable and missed pills are common amongst users of these methods (Aubeny et al. 2002; Potter et al. 1996). Trussell et al. reported that based on data from the National Survey of Family Growth within the USA, 9 % of women using oral contraceptives (COCs and POPs) will experience an unintended pregnancy in the first year (Trussell 2011).
In terms of what is the most effective oral contraceptive, data are often inadequate but no difference has been observed in contraceptive efficacy between 20 and 30 μg ethinylestradiol pills (Gallo et al. 2013) or different types and strengths of COCs. Similarly, there is insufficient evidence insufficient evidence to say if one POP is more effective than another or compare the efficacy of POPs to COCs (Grimes et al. 2013). In light of its greater potential for ovarian suppression, in theory it might be expected that the efficacy of the desogestrel pill would be higher than ‘traditional’ POPs. However, in the only comparative trial comparing a levonorgestrel pill to the desogestrel pill, no significant difference was noted in the rate ratio of pregnancy, even after excluding those who were breastfeeding (Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill 1998).
Factors Affecting the Effectiveness of OCs
Missed Pills
As indicated previously, missed pills are common with oral contraceptives. With COCs ovulation remains suppressed during the hormone free interval but there is evidence of follicular activity during longer hormone-free intervals (Baerwald et al. 2004; Hedon et al. 1992; Killick 1989; Killick et al. 1990). Consequently, there is greater potential for ovulation and method failure when women forget to take pills before or after the 7 day break by effectively extending the hormone-free interval. The World Health Organization (WHO) advises that efficacy may be diminished if three or more 30–35 μg pills or two or more 20 μg pills are missed (World Health Organization 2004). In the UK and USA, the Faculty of Sexual and Reproductive Healthcare (FSRH) and the Centre for Disease Control (CDC) respectively, advise when two or more pills (of 20 or 30 μg) are missed (Centre for Disease Control and Prevention 2013; Faculty of Sexual and Reproductive Healthcare 2011a). The UK applies this advice only to monophasic pills and advises that for phasic pills the advice in the summary of product characteristics should be followed (Faculty of Sexual and Reproductive Healthcare 2011a). A missed pill is regarded by the WHO, FSRH and CDC as being one that is more than 24 h late (Centre for Disease Control and Prevention 2013; Faculty of Sexual and Reproductive Healthcare 2011a; World Health Organization 2004). Reducing the hormone free interval, either via COCs with a shorter hormone free interval, or via extended regimens, has the potential to reduce the risk of follicular activity, and subsequent risk of ovulation (Spona et al. 1996; Willis et al. 2006).
In contrast to COCs, when POPs are missed there is less of a potential safety margin. For most POPs which have not been shown to consistently suppress ovulation, women are advised that contraceptive efficacy may be reduced if the pill is more than 3 h late i.e. 27 h since the last pill was taken (Faculty of Sexual and Reproductive Healthcare 2015; World Health Organization 2004). However, with the desogestrel POP, suppression of ovulation is reported to be maintained even when there is a 12-h delay in tablet taking (Korver et al. 2005). Women can therefore take the desogestrel POP up to 12 h late (36 h after the last pill was taken) without an impact on contraceptive efficacy (Faculty of Sexual and Reproductive Health Care 2015). This longer window period presents the desogestrel pill with an advantage over other POPs.
Factors Affecting Metabolism and Absorption
Factors that affect the metabolism or absorption of oral contraceptives also have the potential to affect their efficacy by reducing the bioavailability of estrogen and/or progestogen. Examples of such factors are vomiting and diarrhoea (resulting in reduced absorption of OCs), or taking concomitant medicines that induce cytochrome P-450 enzymes (resulting in increased metabolism of estrogen/progesterone and therefore reduced bioavailability). Some examples of drugs known to be strong inducers of cytochrome P450 are listed in Table 5.2.
Table 5.2
Examples of medicines which strongly induce cytochrome P450 (Faculty of Sexual and Reproductive Health Care 2011b)
|
Name of drug |
Classification |
|
Rifampicin |
Antibiotic |
|
Carbamazepine |
Antiepileptic |
|
Eslicarbazepine |
|
|
Oxcarbazepine |
|
|
Phenobarbital |
|
|
Phenytoin |
|
|
Primidone |
|
|
Ritonavir |
Protease inhibitor |
It is generally advised that if a woman has vomited within 2 h of taking an oral contraceptive, she should take another pill (Faculty of Sexual and Reproductive Healthcare 2011a; World Health Organization 2004). If a woman has severe diarrhoea or vomiting for more than 2 days, the advice for missed pills should be followed (Faculty of Sexual and Reproductive Healthcare 2011a; Faculty of Sexual and Reproductive Health Care 2015; World Health Organization 2004).
Women regularly taking medicines such as those listed in Table 5.2 would generally be advised to switch to a method which is unaffected by such drugs, for example an intrauterine method (see Chap. 8). For shorter term coverage, doubling the dose of COC or using condoms in addition to an oral method during treatment and for 28 days afterwards are suggested alternatives (Faculty of Sexual and Reproductive Health Care 2011b). The FSRH within the UK has published guidance entitled Drug Interactions with Hormonal Contraceptives designed to help practitioners give advice to women using such medications (Faculty of Sexual and Reproductive Health Care 2011b).
As oral contraceptives are absorbed via the small intestine and undergo extensive first pass metabolism before reaching the systemic circulation, factors that limit absorption may also impact on efficacy. With the increasing number of women being classified as obese, there has been interest in the effect surgical procedures designed to help with weight loss might have on absorption of oral contraceptives. There is unfortunately a lack of data on this issue, but it would not appear to impact significantly (Paulen et al. 2010). In the US, advice is that use of oral contraceptives is appropriate in those who have undergone surgery to reduce the storage capacity of their stomach, but for those who have undergone a procedure which limits a woman’s ability to absorb nutrients and calories, the potential risks are thought to outweigh any potential benefit (Centre for Disease Control 2010).
A European evidence-based consensus on reproduction in inflammatory bowel disease (van der Woude et al. 2010) indicates that there are no studies investigating the efficacy of oral contraceptives in women with inflammatory bowel disease, although in theory efficacy may be reduced in those with small bowel disease and malabsorption e.g. Crohns disease. The theoretical risk should be highlighted to women with Crohn’s disease (Faculty of Sexual and Reproductive Healthcare 2009c).
Effectiveness of OCs in Overweight and Obese Women
Women with a body mass index (BMI) that would classify them as obese (≥30 kg/m2) or of heavier weight (for example, women over 70 kg) have been included in some trials of oral contraceptives, but there is a lack of prospective studies specifically examining the effectiveness of OCs in these women and which use clinically determined measures rather than self-reported indicators. A Cochrane review reported that based on low quality evidence there does not appear to be an association between BMI and the effectiveness of hormonal contraceptives generally, but that data for individual methods are limited (Lopez et al. 2013b).
The issue of weight and efficacy has been raised in relation to other methods such as the progestogen-only implant (see Chap. 8), the combined transdermal patch (Janssen-Cilag Ltd 2014) and recently there has been discussion internationally about the effect body mass or weight has on the effectiveness of oral emergency contraception (European Medicines Agency 2014).
It has been suggested from pharmacokinetic data, that on starting combined oral contraceptives, women who are classified as obese may take longer to reach the required steady state for ovulation suppression, than women who are not (Edelman et al. 2009). This pharmacokinetic difference may in turn create potential for follicular activity and consequently, pregnancy (Edelman et al. 2009). Another small pharmacokinetic study reported lower peak levels of hormone amongst women with a BMI of over 30 kg/m2, although follicular activity was not increased (Westhoff et al. 2010).
In terms of what has been observed in ‘real life’ the findings are mixed. A population based case-control study reported a statistically significant increased risk of pregnancy amongst women with a BMI greater than 27.3 kg/m2 using COCs than for those with a BMI less than that (Holt et al. 2005). A criticism of the paper was its dependence on recall in relation to pill taking behaviour (Creinin and Roberts 2005). Similarly, a retrospective cohort study reported an increased risk in women weighing over 70.5 kg compared with women of lower weight (RR 1.6 95 % CI 1.1–2.4) (Holt et al. 2002). However, other studies have not reported statistically significant increases by body weight or BMI (Brunner and Hogue 2005; Burkman et al. 2009; Dinger et al. 2009; Vessey and Painter 2001).
In the past it has been advised that women, who are classified as obese, take two POPs per day instead of one. While evidence to disprove reduced effectiveness of POPs is lacking in these women, so too is evidence to support doubling the dose of POP (Faculty of Sexual and Reproductive Health Care 2015).
In the UK, COCs tend to be more cautiously prescribed to women with a high body mass index, not because of concerns about efficacy but more in relation to vascular health. Obesity in itself is not a contraindication to use of COCs. However, some women who are classified as obese may be advised to use other methods, if they have other risk factors such as older age and or hypertension. WHO Medical Eligibility Criteria for Contraceptive Use (World Health Organization 2010), suggests that the benefits outweigh the risks in women with a BMI of over 30 kg/m2, whereas, the UK document indicates that for those with a BMI of 35 kg/m2 or more, the risks outweigh the benefits (Faculty of Sexual and Reproductive Healthcare 2009b).
Medical Eligibility Criteria for Contraceptive Use
The WHO first developed a Medical Eligibility Criteria (MEC) for Contraceptive Use in 1996; a fifth edition is due in 2015. It was designed to help policy makers and other specialists develop national guidelines on contraceptive service delivery rather than to be used as an actual guideline itself (World Health Organization 2010).
The FSRH within the UK and the CDC in the USA have both undertaken formal processes to adapt the WHO’s document for the UK (Faculty of Sexual and Reproductive Health Care 2009b) and US (Centre for Disease Control 2010) respectively. The UK (Faculty of Sexual and Reproductive Health Care 2009b) and US (Centre for Disease Control 2010) Medical Eligibility Criteria for Contraceptive Use are designed to help guide individual practitioners when counselling individuals and couples about contraceptive use. All three documents (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010) are available online and are a useful reference for practitioners. These documents are designed to give a sense of where the balance of risk lies for each method in the presence of a particular medical condition, risk factor or specific characteristic.
Each condition listed is assigned a category which ranges from there being no restriction on the use of the contraceptive, to the use of the contraceptive method presenting an unacceptable health risk. The categories are a guide and there are no rules for taking into account co-morbidities. The decision to prescribe or not prescribe when the balance of risk seemingly outweighs the benefits will be a matter of clinical judgement in conjunction with patient preference and availability/suitability of alternative options. While it is acknowledged that hormonal contraceptives may confer some non-contraceptive benefits, the MECs have been designed for use in contraceptive prescribing rather than the prescription of contraceptives for other purposes, as the benefit to risk ratio may differ (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Table 5.3 highlights some examples of conditions where it is suggested that COCs or POPs should not be used. These are examples and the list is not exhaustive. Practitioners should refer to the individual medical eligibility criteria for detailed information and updates as criteria may change and sometimes differ across the MECs.
Table 5.3
Examples of conditions where concomitant use COCs or POPs presents an unacceptable level of risk (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010)
|
COC |
POP |
|
Current thrombosis |
Current breast cancer |
|
History of thrombosis |
|
|
Known thrombogenic mutations |
|
|
Current/History ischaemic heart disease |
|
|
Stroke |
|
|
Current breast cancer |
|
|
Malignant liver tumours |
|
|
Aged over 35 and smoking more than 15 cigarettes per day |
Benefits and Risks of Oral Contraceptives
In this chapter we aim to provide an overview of the issues that are often of concern to women. It should be borne in mind that evidence often comes from observational studies and therefore may be limited by bias and confounding such as: being unable to control for women’s use of several different contraceptive formulations; the limited number of different formulations included within studies; or long-term studies starting before modern formulations were available.
Overall Risk of Mortality and Cancer
Data largely support the view that use of oral contraceptives does not increase a woman’s risk of death as compared with non-use (Colditz 1994; Hannaford et al. 2010; Vessey et al. 2010).
In the late 1960s a large prospective study was initiated in the UK (the RCGP oral contraceptive study) to investigate the health effects of oral contraceptives. By 2010, 39 years of follow-up and more than one million women-years of observation did not demonstrate any association between an increased risk of any cause mortality and oral contraceptive use compared with non-use, with a slightly protective effect reported (adjusted relative risk 0.88, 95 % confidence interval 0.82–0.93) (Hannaford et al. 2010).
Similarly, another large cohort study from the UK (Oxford Family Planning Association contraceptive study) with 602,700 woman-years of observation, found that compared to never users of oral contraceptives, the rate ratio for overall mortality was 0.87 (CI 0.79–0.96) (Vessey et al. 2010). While the ability to generalise from the findings may be limited by country specifications and changes in formulation over time (Hannaford et al. 2010), the findings are generally reassuring.
In terms of cancer risk, the International Agency for Research on Cancer (IARC), indicates that there is sufficient evidence from studies to demonstrate that COCs are carcinogenic in humans (group 1 classification), predominantly in relation to the breast, cervix and liver, although acknowledges that they may offer protection against certain other cancers (International Agency for Cancer 2012). These benefits and risks are discussed further in the sections below. Progestogen-only contraceptives are given an IARC group 2b classification, indicating the possibility of carcinogenicity (International Agency for Cancer 1999). Observational studies have reported no specific increased risk of mortality from all cancers as a result of COC use and no overall increased risk of cancer (Cibula et al. 2010; Hannaford et al. 2007, 2010).
Benefits Associated with Oral Contraceptive Use
Reduced Risk of Ovarian, Endometrial and Colorectal Cancer
Observational studies have consistently demonstrated a reduced risk of ovarian cancer amongst those who use COC for contraception (Collaborative Group on Epidemiological Studies of Ovarian Cancer 2008; Hannaford et al. 2007; Havrilesky et al. 2013; International Agency for Cancer 1999; Jick et al. 1993; Lurie et al. 2007, 2008; Ness et al. 2000; Poole et al. 2013; The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development 1987; Tsilidis et al. 2011; Tworoger et al. 2007; Vessey et al. 2003, 2010; Vessey and Painter 2006; Vessey and Yeates 2013; Weiderpass et al. 1999).
The duration of COC use has been shown to influence the level of protection against ovarian cancer such that women who have been using the COC for 10 years or more have half the risk of those who have never used a COC (Havrilesky et al. 2013). This non-contraceptive benefit has also been observed in women who are inherently at increased risk of ovarian cancer due to a BRCA gene mutation (Antoniou et al. 2009; Havrilesky et al. 2013; McGuire et al. 2004; McLaughlin et al. 2007; Narod et al. 2002; Whittemore et al. 2004).
The protective effect is provided not only whilst the woman is taking the pill but evidence shows that even after discontinuing a COC, women continue to experience a reduced risk of ovarian cancer for several decades; although the protective effect gradually lessens with time (Havrilesky et al. 2013; Lurie et al. 2008; Moorman et al. 2008).
In addition to offering a protective effect against ovarian cancer, data from observational studies suggest that COCs confer protection against endometrial cancer (Jick et al. 1993; Vessey and Painter 1995; Weiderpass et al. 1999; Cancer and Steroid Hormones (CASH) 1987) and possibly colorectal cancer (Bosetti et al. 2009; Campbell et al. 2007; Fernandez et al. 2001; Hannaford and Elliot 2005; Nichols et al. 2005; Troisi et al. 1997; Tsilidis et al. 2010). As with ovarian cancer, the protection against endometrial cancer afforded by COC use lasts for several years after stopping. However, less is known about the impact of duration of use on colorectal cancer risk with no apparent relationship evident from the available data.
While there is a well-documented benefit to use in terms of protection against ovarian cancer, available evidence does not yet allow recommendations to be drawn on the use of COCs for primary cancer prevention (Havrilesky et al. 2013).
Management of Acne
Acne is a common skin condition affecting women of reproductive age. A systematic review of randomised trials reported that there was evidence to demonstrate that COCs could result in a reduction in both inflammatory and non-inflammatory lesions and therefore should be considered for women with acne who also require contraception (Arowojolu et al. 2012). While some studies have shown benefits for particular pill types over others (see section on polycystic ovarian syndrome), the findings are often inconsistent and their clinical relevance undetermined. There is also a lack of data on which to draw conclusions about the effectiveness of COCs compared to other treatments (Arowojolu et al. 2012). An advantage over some medications such as isotretinoin is that COCs are not known to be teratogenic.
There is no evidence to advocate the use of progestogen-only pills for the management of acne and indeed acne can be a side effect of these pills (Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill 1998).
The use of co-cyprindiol tablets (Dianette®, Diane 35®, Clairette®) solely for contraceptive purposes is not advised (Faculty of Sexual and Reproductive Healthcare 2011a). These tablets, which contain ethinylestradiol and cyproterone acetate are licensed (in most countries) primarily for the treatment of acne and their use as a contraceptive should be reserved for women with acne that has not responded to antibiotics (European Medicines Agency Pharmacovigilance Risk Assessment Committee 2013).
Management of Heavy Menstrual Bleeding and Dysmenorrhoea
COCs are regarded as a viable non-surgical intervention for women experiencing heavy menstrual bleeding (National Institute for Health and Clinical Excellence 2007; The American College of Obstetricians and Gynecologists 2013). Their use has been shown to result in up to a 69 % reduction in bleeding amongst women with dysfunctional uterine bleeding (Matteson et al. 2013). The estradiolvalerate/dienogest COC (Qlaira®, Natazia®) is licensed in the UK for the management of heavy menstrual bleeding in those who wish to use oral contraceptives and for whom no pathology has been identified (Bayer PLC 2013). A pooled analysis of two randomised double-blind, placebo-controlled trials reported that following 6 months of treatment with the estradiolvalerate/dienogest COC the median menstrual blood loss in women with heavy and/or prolonged menstrual bleeding was reduced by 88 % from baseline, with most of the improvement being observed soon after starting and then maintained: for the placebo arm, the corresponding figure was 24 % (Fraser et al. 2011). Data comparing this product to other COCs is lacking and guidelines on the management of heavy menstrual bleeding do not, at present, advise the use of any one particular COC over another (National Institute for Health and Clinical Excellence 2007; The American College of Obstetricians and Gynecologists 2013). Continuous regimens may offer some benefits over cyclical regimens (Edelman et al. 2014).
Wong and colleagues (2009), following a review of randomised controlled trials, concluded that COCs may be more effective than placebo at treating primary dysmenorrhoea, although they cautioned about the interpretation of their findings given the limitations of the included studies. In a small randomised controlled trial comparing continuous to cyclic oral contraceptive use for the treatment of primary dysmenorrhoea, the continuous regimen appeared to be superior in reducing pain in the first 3 months of use, but by 6 months there was no observed difference (Dmitrovic et al. 2012).
Similarly, Davis and colleagues (2007) in reviewing the evidence assessing the effects of oral contraceptives in comparison to other treatments for endometriosis-associated pain, found only one study which met their inclusion criteria. While this study showed the COC studied to be as effective as a Gonadotrophin-Releasing Hormone (GnRH) analogue, the authors of the Cochrane review could not fully evaluate the effects of COCs on endometriosis-associated pain due to the limited available evidence.
A subsequent systematic review and meta-analysis by Davis et al. (2007) reported that compared to surgery alone, the postoperative use of oral contraceptives had a statistically significant higher total remission (no renewed pelvic pain or identification of endometriosis by ultrasound, laparoscope or laparotomy) and recurrence rate of endometriosis (reappearance of pain or endometrial cysts). Oral contraceptives did not differ significantly from other postoperative hormonal treatments such as danazol and GnRH analogues, although had fewer side effects Wu et al. (2013b).
The European Society for Human Reproduction and Embryology advocate both cyclical and continuous COC use for the management of women with endometriosis and pain associated with endometriosis (Dunselman et al. 2014).
Whereas for most POPs their effect on ovulation is variable and thus their impact on ovulatory associated pain would be expected to be less, the desogestrel POP, which reliably suppresses ovulation has been found to confer some benefits (Ahrendt et al. 2007; Razzi et al. 2007). While it may offer some benefit in women who have these symptoms and are requiring contraception, it is not currently documented specifically as a recommended hormonal therapy for endometriosis associated pain within European Guidelines on the management of this condition (Dunselman et al. 2014).
Benign Breast Disease
Benign breast disease is common, with the peak incidence occurring in women in their 40s and 50s (Rungruang and Kelley 2011). Studies are largely supportive that oral contraceptives do not increase a woman’s risk of developing benign breast diseases and in women with fibroadenomas, their use, particularly at higher doses, may actually offer women some protection (Canny et al. 1988; Sitruk-Ware et al. 1989; Vessey and Yeates 2007).
Medical eligibility criteria do not suggest that the use of oral contraceptives need to be restricted in women with benign breast disease (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010). When women have an undiagnosed mass, oral contraceptives do not necessarily have to be stopped; although it may of course be a woman’s preference to do so. Undiagnosed masses should be evaluated as soon as possible (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Use in Women with Polycystic Ovarian Syndrome
Women with polycystic ovarian syndrome commonly experience anovulatory cycles, oligomenorrhoea and hyperandrogenic symptoms such as hirsutism and acne. The lack of bleeding and increased estrogen levels may predispose women to an increased risk of endometrial hyperplasia and possibly endometrial cancer (Royal College of Obstetricians and Gynaecologists 2007a). To protect against this, in women with oligomenorrhoea or amenorrhoea, the UK Royal College of Obstetricians and Gynaecologists (RCOG) advises that oligomenorrhoeic women with PCOS use hormonal treatment such as oral contraceptives to protect the endometrium (Royal College of Obstetricians and Gynaecologists 2007a). Other guidelines similarly advocate the use of oral contraceptives (COC or POP) for endometrial protection in women with PCOS, although note that POPs may be associated with unpredictable bleeding patterns (Anon 2009).
There is currently insufficient evidence to say whether COCs are more effective than the insulin sensitizing drug metformin in the treatment of hirsutism and acne in women with PCOS (Costello et al. 2007). Guidelines (Anon 2009; Royal College of Obstetricians and Gynaecologists 2007a) currently do not recommend one COC formulation over another for the management of PCOS symptoms. However, in theory, COCs containing a progestogen with low androgenicity (e.g. some third generation progestogens) or anti-androgenic activity (e.g. drospirenone) may be more effective in treating symptoms than COCs that contain a mildly androgenic progestogen (e.g. levonorgestrel). The strength of a COC preparation may also make a difference as the higher the dose of ethinylestradiol the more hepatic production of SHBG is increased, which in turn reduces the activity of endogenous androgens (Layton 2010).
COCs containing cyproterone acetate are licensed for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhoea) and/or hirsutism (Bayer PLC 2014), in women of reproductive age. There has been particular controversy about their use in recent years due to fears about the associated risk of venous thromboembolism (see Chap. 6), which resulted in the European Medicines Agency (EMA) undertaking an evidence review in 2013 (European Medicines Agency Pharmacovigilance Risk Assessment Committee 2013). As indicated earlier in this chapter such COCs are not advised solely for contraceptive purposes or for use in conjunction with other hormonal contraceptives (Bayer PLC 2014; European Medicines Agency Pharmacovigilance Risk Assessment Committee 2013).
Risks Associated With Oral Contraceptive Use
Breast and Cervical Cancer
Breast Cancer
Breast cancer is known to be influenced by endogenous hormone levels (Endogenous Hormones and Breast Cancer Collaborative Group et al. 2013) and it is important to consider potential effects of exogenous hormones on breast cancer risk. Over the years, many studies have attempted to quantify the risk associated with oral contraceptives: the findings of which are often conflicting.
A statistically significant increased risk of breast cancer amongst current users as compared with never users has been observed in several studies (Collaborative Group on Hormonal Factors in Breast Cancer 1996; Hunter et al. 2010; Kahlenborn et al. 2006; Rosenberg et al. 2009). Yet, other published studies have not reported this (Gill et al. 2006; Hannaford et al. 2007; Marchbanks et al. 2002; Nichols et al. 2007; Shapiro et al. 2000; Vessey et al. 2010; Vessey and Painter 2006; Vessey and Yeates 2013). In one of the largest studies demonstrating an increased risk amongst current users compared with non-users (RR 1.24 (1.15–1.33)), the authors also found that the excess risk declined with time after stopping, with no significant difference noted between user and never users 10 or more years after stopping (RR 1.01 (0.96–1.05)) (Collaborative Group on Hormonal Factors in Breast Cancer 1996).
For women who have an increased risk of breast cancer due to an inherited BRCA gene mutation, the findings have varied (Brohet et al. 2007; Lee et al. 2008; Milne et al. 2005); (Narod et al. 2002). Meta-analyses report that recent formulations of COC do not appear to be associated with a further increasing of breast cancer risk in BRCA 1/2 carriers (Cibula et al. 2011; Iodice et al. 2010). Similarly, the available evidence does not currently support the notion that, women with a family history of breast cancer, should be more cautious about use of COCs due to them further increasing their risk (Gaffield et al. 2009).
A similar level of risk was reported for the POP as for COCs in a large collaborative reanalysis of epidemiological studies (Collaborative Group on Hormonal Factors in Breast Cancer 1996). However, there is far less evidence relating to the POP and breast cancer, making it difficult to draw conclusions about any association. For women with current breast cancer, neither COCs or POPs are advised (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Cervical Cancer
Data from observational studies have been consistent in showing an increased risk of developing cervical cancer in women who have used COCs long-term, even after adjustment for confounders. A large meta-analysis of data undertaken in 2007 demonstrated that compared with never users, women who had used the COC for 5 or more years had a relative risk of 1.9 (95 % CI 1.69–2.13) for the development of invasive cervical cancer (International Collaboration of Epidemiological Studies of Cervical Cancer 2007). The relative risk of cervical cancer was found to increase by a factor of 1 · 38 (95 % CI 1 · 30–1 · 46) per 5 years of use (International Collaboration of Epidemiological Studies of Cervical Cancer 2007).
Cross sectional data published in 2013, indicated that use of COCs for 10 or more years may have a role in the progression of HPV to pre-cancer (OR 1.97 95 % CI 1.12–3.46) (Luhn et al. 2013). However, studies have also been consistent in demonstrating that any risk declines with time after stopping; and that a user’s risk of cervical cancer is not statistically different to that of a never user, 10 or more years after stopping (International Collaboration of Epidemiological Studies of Cervical Cancer 2007).
Cardiovascular Disease and Stroke
Myocardial Infarction
Myocardial infarction is a rare event in women of reproductive age. However, given their widespread use, there is much interest in whether use of oral contraceptives increases a woman’s risk of such cardiovascular events. A pooled analysis of data from 11 observational studies, published in 2013, concluded there was a small statistically significant increased risk of MI associated with current use of COCs (pooled OR 1.7 95 % CI 1.2–2.3) (Plu-Bureau et al. 2013). An increased risk has also been noted in other reviews (Baillargeon 2005).
A meta-analysis and systematic review also published in 2013 (Peragallo et al. 2013), suggested that current use of oral contraceptives was not, as compared with non-current users (past or never users), associated with a statistically significant increased risk of MI (eight studies; OR 1.34, 95 % CI 0.87–2.08) (Peragallo et al. 2013). The authors however note that their meta-analysis was possibly underpowered because of the limited number of studies eligible for inclusion and that more evidence is required to provide clarity on the effect of oral contraceptives on risk of MI (Peragallo et al. 2013). The included studies differed between the two meta-analyses, which may explain the differing findings.
Observed differences in study findings related to the risk of MI with COCs may be a consequence of the inability to control for all lifestyle factors that may influence cardiovascular health, such as physical activity levels. As smoking and hypertension are significant risk factors for cardiovascular disease, it is unsurprising that the risk of MI has been found to be greater amongst current COC users who smoke compared to those who do not (Croft and Hannaford 1989; Dunn et al. 1999; Khader et al. 2003; Vessey et al. 2003) and higher amongst users with hypertension compared to those with ‘normal’ blood pressure (Croft and Hannaford 1989; Curtis et al. 2006; Khader et al. 2003). Caution should be advised when considering prescribing COCs to women with multiple risk factors for cardiovascular disease as the risks may outweigh the benefits of use, or indeed be unacceptable depending on the factors involved (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
With so many different oral contraceptives available, women may wish to know if certain formulations are associated with more cardiovascular risk than others, particularly if they already have underlying health considerations which may put them at higher risk of cardiovascular complications. Therefore, as with VTE studies, researchers have sought to establish what (if any) influence the dose of estrogen and/or the dose of progestogen has on mediating risk of MI. Data are inconsistent (Lidegaard et al. 2012; Plu-Bureau et al. 2013; Wu et al. 2013a).
In light of ongoing concerns about the influence of progestogens within COCs on VTE, in 2013, the European Medicines Agency (EMA) completed a review of the risk of VTE associated with use of COCs. Their published findings indicate that there is an increased risk of MI associated with COCs and that while it was suggested that the progestogen type does influence the risk of VTE (see Chap. 6), the findings did not confirm a difference between progestogens in arterial thrombosis risk (European Medicines Agency 2014b).
There are limited data available on the risk of MI associated with use of POPs but an increased risk amongst users has not been demonstrated (Chakhtoura et al. 2011; Lidegaard et al. 2012). Therefore medical eligibility criteria indicate that the benefits of using the POP for contraception in women with multiple risk factors for cardiovascular disease generally outweigh any potential or theoretical risks (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Stroke and Migraine
There are global variations in the prevalence of stroke and mortality rates arising from stroke, but it remains one of the leading causes of death and adult disability (Feigin et al. 2014). Although in some countries there are trends towards an increased incidence of stroke amongst young adults (Feigin et al. 2014), as with MI, stroke is rare in women of reproductive age.
Migraine is an independent risk factor for stroke (Etminan et al. 2005). In one meta-analyses, the association with ischaemic stroke was only significant for those with migraine with aura (Schurks et al. 2009). In the meta-analyses investigating the link between migraine and haemorrhagic stroke, the association was not statistically significant in those with migraine with aura, but the authors noted the data were too few to be able to prove an association by type of migraine (Sacco et al. 2013).
The evidence as to the modifying effect of COCs is varied, with evidence generally suggesting that it may increase a woman’s risk of ischaemic (Baillargeon et al. 2005; Peragallo et al. 2013; Plu-Bureau et al. 2013) but not haemorrhagic stroke (Peragallo et al. 2013; Plu-Bureau et al. 2013; WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception 1996; Yang et al. 2009).
COC use in women with migraine has been found to slightly increase a woman’s risk of stroke compared to non-users with migraine (Chang et al. 1999; Lidegaard 1993; Schurks et al. 2009; Tzourio et al. 1995; WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception 1996). For women with migraine with aura, the use of a COC is therefore not advised as it is considered to present an unacceptable health risk (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010). For women with migraine but no aura, the advice varies – the WHO and CDC Medical Eligibility Criteria indicate that if a woman is aged over 35 when she starts the COC, the risks may outweigh the benefits, but for those under 35 years, the reverse is likely to apply (Centre for Disease Control 2010; World Health Organization 2010). Conversely in the UK, no age limit is applied to the advice for women who experience migraine without aura, and the benefits from starting a COC would generally be considered to outweigh any risks (Faculty of Sexual and Reproductive Health Care 2009b). Women who develop migraine while using the COC would generally be advised to consider an alternative method (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Similarly, COC use in women with hypertension, as compared to hypertensive non-users, has been found to adversely influence stroke risk (Curtis et al. 2006) and therefore should be restricted in women found to have hypertension. The use of combined hormonal contraceptives is generally not advised for women with hypertension, particularly in those with very high (systolic ≥160 mm Hg or diastolic ≥100 mm Hg) uncontrolled blood pressure or vascular disease (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
As with MI, there are limited data available, but it does not appear that the risk of ischaemic or haemorrhagic stroke is increased amongst users of POPs (Chakhtoura et al. 2009; Lidegaard et al. 2012). A meta-analysis (Chakhtoura et al. 2009) of six case control studies reported a combined odds ratio of 0.96 (95 % confidence interval: 0.70–1.31) for progestogen-only contraceptives and risk of stroke. The authors reported that the results were similar for progestogen methods regardless of their mode of administration. As POPs do not appear to increase the risk of stroke, medical eligibility criteria suggest that in women with hypertension who use POPs, the balance of risk is more favourable than with COCs (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Bone Health
The available evidence on the effect of OCs on bone health has limitations owing to factors such as: the lack of randomised controlled trials; different study designs; variations in the formulations of COCs used; different sites used for measuring bone mineral density (BMD), and confounders such as smoking habits, BMI, parity and previous exposure to hormones.
There are certain groups for whom it is important to know the consequences of hormonal contraception on bone health, for example adolescents and menopausal women. For the general population, use of COCs does not appear to negatively affect bone health and has not been shown to increase fracture risk (Lopez et al. 2014; Martins et al. 2006). It has however been suggested that COCs containing less than 30 μg of ethinylestradiol may have a negative impact on peak bone acquisition and that compared to never users, adolescents who use COCs containing 20 μg have lower bone mineral density (Nappi et al. 2012). In contrast, for peri-menopausal women, COC use may actually confer some benefits in terms of bone mineral density, even at low doses (Nappi et al. 2012), although the benefit has yet to be confirmed via randomised controlled trials. Use in the peri-menopause solely to assist bone health would need to be considered in the context of other age-related risks associated with COCs. Similarly, evidence is lacking a protective effect on bone loss in women at risk of osteoporosis e.g. women with dietary deficiency (Bergstrom et al. 2013).
Few studies have examined the effect of POPs on bone mineral density meaning that reviews evaluating the effect of contraception on fracture risk have failed to include the POP (Lopez et al. 2012, 2014). While there have been concerns about some non-oral progestogen-only methods reducing BMD (see Chap. 8), a negative effect with use of the POP is not expected (McCann and Potter 1994).
Glaucoma
In 2013 an increased risk of glaucoma associated with the use of oral contraceptives was reported via a range of media outlets (internet, press). These reports were based on findings from a cross sectional study presented at the annual meeting of the American Academy of Ophthalmology (2013). The reported findings suggested that self-reported glaucoma (not confirmed by diagnostics) was twice as likely amongst women who had used oral contraceptives for 3 years or more American Academy of Ophthalmology (2013).
Previous studies have differed in their findings regarding the risk of glaucoma, with earlier data from two UK cohorts suggesting no increased risk with ever use (RR 1.0 95 % CI 0.7–1.4) and RR 1.6 (95 % CI 0.9–2.0) respectively (Vessey et al. 1998). Another study suggested that although ever use of oral contraceptives did not appear to increase the risk of primary open-angle glaucoma, there was perhaps a modest increased risk with use of oral contraceptives for 5 or more years (Pasquale and Kang 2011). The authors of this latter study however, did suggest the findings required further consideration (Pasquale and Kang 2011). A statement published by the Faculty of Sexual and Reproductive Healthcare in 2013 advised they were unable to comment on the findings reported at the 2013 annual meeting until the results had been published in a journal publication. The FSRH advised, that women need not stop their pill but that anyone who had particular concerns should seek further advice from their GP or optician (Faculty of Sexual and Reproductive Healthcare 2013).
Gastrointestinal Disorders
There are data to suggest a possible association between oral contraceptive use and the development of inflammatory bowel disease (IBD), in particular Crohn’s disease (Cornish et al. 2008; Halfvarson et al. 2006; Khalili et al. 2013), although the limited available evidence does not suggest it affect disease flare-ups (Zapata et al. 2010). More research is required in this area to confirm the role of oral contraceptives in IBD development as studies have been limited by failure to control for family history and a lack of information about included formulations.
A European evidence-based consensus on reproduction in inflammatory bowel disease has highlighted that as a thrombophilic condition, use of oral contraceptives may increase the risk of thromboembolism in women with inflammatory bowel disease and therefore the decision to prescribe should be made on an individual basis (van der Woude et al. 2010). In the UK, medical eligibility criteria suggest the benefits of using oral contraceptives in women with IBD outweigh the risks (Faculty of Sexual and Reproductive Health Care 2009b). The CDC however suggest that the balance of benefits versus risks will depend on whether there are other risk factors for thromboembolism such as active/extensive disease or immobilisation (Centre for Disease Control 2010).
Teratogenicity
For some women, where a pregnancy is not planned, inadvertent use of oral contraceptives in early pregnancy may occur. Although pregnancy is listed as a contraindication to use of oral contraceptives within licensing information, a teratogenic effect has not been demonstrated (Waller et al. 2010). Concerns have been raised about fetal exposure to cyproterone acetate. Animal studies have revealed that feminisation of male fetuses may occur if cyproterone acetate is administered during the phase of embryogenesis at which differentiation of the external genitalia occurs. The SPC for Dianette (Bayer PLC 2014) advises that pregnancy must be excluded before treatment is begun, and while it acknowledges the fact that results of animal studies may not necessarily apply to humans, the possibility that administration of Dianette to women after the 45th day of pregnancy could cause feminisation of male fetuses needs to be considered.
Breastfeeding
The World Health Organization (WHO) advises that to reduce the risk of negative maternal and infant outcomes, there should be at least 24 months between pregnancies; although there are also concerns about intervals of more than 5 years (Conde-Agudelo et al. 2007; World Health Organization 2005). Whilst postpartum contraception is therefore important, women who are breastfeeding may be concerned about the impact of hormonal contraceptives on breastfeeding both in terms of exposure of infants to hormones and on breastfeeding outcomes such as breast milk volume.
There is limited evidence on which to draw conclusions about the effect of hormonal contraception has on breastfeeding outcomes including duration, success, milk quantity and quality, and that which exists is often inadequate and inconsistent (Kapp and Curtis 2010; Truitt et al. 2003). A randomised controlled trial published in 2012 found no difference in breastfeeding duration or infant growth between women started on a COC or POP 2 weeks postpartum, although there were some study limitations and the authors themselves highlighted the need for a larger equivalence study to clarify their findings (Espey et al. 2012).
Despite the lack of good quality data, there is general consensus that prior to 6 weeks postpartum, use of combined hormonal contraceptives is considered inappropriate for women who are breastfeeding because of concerns about the impact on breast milk volume (World Health Organization 2010; Faculty of Sexual and Reproductive Healthcare 2009b; Centre for Disease Control 2010). In women who are fully or almost fully breastfeeding i.e. able to use lactational amenorrhoea method, the risks of prescribing COC are likely to outweigh any benefit (Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Advice however differs in relation to the eligibility of breastfeeding women to use POPs. In the UK and the US the use of POPs in breastfeeding women prior to 6 weeks is generally supported (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b): the WHO’s medical eligibility criteria is slightly more cautious in the first 6 weeks in its interpretation of where it considers the balance of risk to lie- suggesting that the theoretical or proven risks still outweigh the benefits (World Health Organization 2010).
The WHO acknowledges that direct evidence does not generally support a negative effect of either the COC or the POP on infant health outcomes (World Health Organization 2009). However, they express concern about the limitations of the data (e.g. short duration of follow-up). The WHO’s more restrictive view on the use of POPs prior to 6 weeks postpartum is due, they indicate, to theoretical concerns about the impact of progestogens on infant brain development and the possible existence of negative unmeasured effects (World Health Organization 2009).
For postpartum non-breastfeeding women, as POPs are not thought to be associated with an increased risk of thrombosis, POPs can be used without restriction from delivery (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010). However because of the risk of thrombosis associated with COC use (see Chap. 6), each of these organisations advise a delay in initiating COCs until the risk of thrombosis associated with pregnancy and the postpartum period has reduced – the durations differ within each of the documents (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Interactions with Other Medicines
As mentioned earlier in this chapter, the efficacy of oral contraceptives has the potential to be reduced by enzyme-inducing medications (see Table 5.1). Oral contraceptives themselves also have the potential to impact on the efficacy of other drugs, for example COCs have been shown to increase the clearance of the antiepileptic medication lamotrigine, via the process of glucuronidation (Christensen et al. 2007; Sabers et al. 2001, 2003). The dose of lamotrigine may therefore need to be adjusted when starting or stopping COCs (GlaxoSmithKline UK 2014). It is important for health professionals to regularly check product information and other sources of information when considering co-prescribing medications with hormonal contraceptives.
Reported Adverse Effects
With regards adverse events/side effects related to OCs, establishing causation can be difficult due to the observational nature of studies and the number of other potential influencing factors. To establish causality, factors such as plausibility, dose-response effect, temporal relationships and any possible bias and confounding must be considered. While individual studies may suggest that certain pills may be better than other in terms of different side effects, collectively there is currently insufficient evidence from randomised controlled trials to suggest that any one pill or generation of progestogen is associated with a better side effect profile than others (Lawrie et al. 2011).
Irregular Bleeding and Cycle Control
Irregular bleeding or menstrual disturbances are common with POPs (Ahrendt et al. 2010; Faculty of Sexual and Reproductive Health Care 2009a). In the first 3 months around a third of women will experience a change in bleeding, with about 1 in 10 experiencing bleeding that is frequent i.e. more than five episodes of bleeding over a 90 day reference period (Faculty of Sexual and Reproductive Health Care 2009a). Longer-term, it is suggested that up to 40 % of women may experience erratic bleeding with use of the POP (Faculty of Sexual and Reproductive Health Care 2009a). While irregular bleeding can settle within the first few months of use (Faculty of Sexual and Reproductive Health Care 2009a; Lumsden et al. 2013), for some women bleeding patterns often remain irregular.
Although many studies have sought to investigate how best to prevent or treat the irregular bleeding, to date there is little evidence to suggest that any of the tested interventions work long-term (Abdel-Aleem et al. 2013). It is generally advised that women wait around 3 months to see if bleeding patterns settle before trying another method or switching to a different POP (Faculty of Sexual and Reproductive Healthcare 2009a). It is important to consider other factors that could cause irregular bleeding, for example sexually transmitted infections, pregnancy and abnormal cervical cytology and to exclude these either via a clinical history and/or examination (Faculty of Sexual and Reproductive Health Care 2009a).
Around 20 % of women using a COC will experience irregular bleeding in the first 3 months (Faculty of Sexual and Reproductive Health Care 2009a), which usually settles with time. Women will differ in their views as to what represents an acceptable bleeding pattern and it is difficult to compare between different preparations (Thorneycroft 1999) but COCs are considered generally to provide good cycle control. A Cochrane review reported that findings from comparative trials tended to suggest that COCs containing 20 μg of ethinylestradiol were associated with more bleeding disruptions than those with 30–35 μg (Gallo et al. 2013). However, these bleeding disruptions included lack of bleeding also and the authors called for more standardisation in the collection of bleeding data and highlighted there was insufficient evidence to exclude the role of progestogens in their findings (Gallo et al. 2013). Women using continuous or extended dosing regimens may experience a reduced number of bleeding days compared with cyclical regimens (Edelman et al. 2014).
Lawrie et al. (2011) suggested that on the basis of one double blind RCT of 456 women (Loudon et al. 1990), COCs containing third generation progestogens may offer favourable bleeding profiles to those containing second generation progestogens (RR 0.71, 95 % CI 0.55–0.91). However, when considering which pill to prescribe, the benefits of higher dose COCs and newer progestogens in terms of bleeding control should be considered in the context of their possible increased risk of thrombosis compared to those containing lower doses of ethinylestradiol or older progestogens (see Chap. 6).
Weight Changes
Two Cochrane reviews have sought to establish whether there is an association between oral contraceptive use and weight gain (Gallo et al. 2014; Lopez LM et al. 2013b). The Cochrane review examining combined hormonal contraceptives reported that from four trials which compared combined hormonal methods (3 COC trials and 1 combined transdermal patch) to either placebo or no intervention, no association with weight gain was found (Gallo et al. 2014). The authors did however caution that the findings are limited by the small number of studies and that given the wide variety of methods available, they could not completely exclude the possibility that an association may be present for some methods (Gallo et al. 2014).
The review also included a number of trials comparing combined methods to one another, but the authors reported that any differences were not substantial and that discontinuation rates did not tend to differ in these trials (Gallo et al. 2014). Claims that the anti-mineralocorticoid activity of drospirenone may counteract weight gain or fluid retention are largely unsubstantiated.
It has been reported that with use of progestogen-only contraceptives generally, after 12 months of use, the typical weight gain experienced is less than 2 kg (Lopez et al. 2013b). However, few data on the POP were included, which makes it difficult to directly apply the findings to this method. Although the evidence does not suggest a causal relationship between weight gain and oral contraceptive use, an effect cannot be entirely excluded due to the limitations of the available evidence.
Nausea
Gastrointestinal disorders such as nausea and vomiting are listed in the product information of different oral contraceptives as having occurred in varying frequencies within clinical trials. However, causation has not been established.
Headache
Headaches are a commonly listed undesirable effect possibly associated with use of oral contraceptives. A systematic review published in 2005 (Loder et al. 2005) examined the evidence as to whether the use of COCs resulted in or aggravated headaches. The review included a range of reasonable quality cohort studies and concluded that the available evidence did not appear to suggest a strong relationship between headaches and COC use (Loder et al. 2005). The review suggested that some women might possibly have a higher risk of developing headaches with COC use and that these women tended to be those with a strong personal or family history of problematic headaches (Loder et al. 2005). The authors noted that there did not appear to be any evidence to suggest that the dose or type of progestogen would influence headache in COC users or that switching between COCs would help to treat headaches. It was postulated that, based on the belief headaches may be associated with estrogen withdrawal during the pill free interval, that shortening or manipulating this may provide some benefit (Loder et al. 2005).
A Cochrane review comparing continuous or extended COC use to cyclical use suggested that from few included studies which examined menstrual symptoms, those who used longer regimens tended to experience less frequent headaches (Edelman et al. 2014). Women experiencing headaches during their hormone free interval may potentially benefit from omitting or shortening it, either by using a regimen designed to be taken this way or by running packets together.
Evidence directly relating to the influence of progestogen-only methods on the development of headaches is lacking (MacGregor 2013). Use of the 75 μg desogestrel pill may confer some benefit to women with migraines (Huber et al. 2000; Merki-Feld et al. 2013a, b; Nappi et al. 2011), decreasing the frequency and intensity of episodes, although the data comes from small observational studies and more large prospective trials are required to confirm any potential observed benefit.
Mood Changes/Depression
Mood change is often cited as a reason for discontinuation of oral contraceptives (Davis et al. 2005) and whilst a causal association has not been demonstrated, the possibility of mood changes (both improved and worsened) can be highlighted to women.
A randomised controlled trial in which 76 adolescents with dysmenorrhoea were given either a COC or placebo for 3 months found that upon exiting the study there were few differences in the mean Centre for Epidemiologic Studies Depression Scale (CES-D) scores for the two groups (Davis et al. 2005). Similarly Duke and colleagues (2007) reported no significant difference in the odds of depression in users of oral contraceptives compared to non-users, although they did find that compared to women who used oral contraceptives for contraceptive purposes, women who used them for other reasons were at increased risk of experiencing depressive symptoms (RR 1.32, 95 % CI = 1.07–1.62). Analysis from a national longitudinal study of women aged 25–34 suggested that use of hormonal contraceptives (combined as well as progestogen-only), may be be protective against depressive symptoms with reported lower mean levels of concurrent depressive symptoms amongst hormonal contraceptive users than users of low efficacy contraception or no contraception (Keyes et al. 2013).
While Jofee et al. (2003) in their study investigating the impact of oral contraceptive use on premenstrual mood found that amongst 658 women using oral contraceptives, the only significant predictor of mood deterioration was previous depression; Young and colleagues reported that women with depression do not appear to have worsening of their symptoms with use of combined hormonal contraceptives, indeed depression symptoms lessened (Young et al. 2007). Analysis from a national longitudinal study of women aged 25–34 suggested lower mean levels of concurrent depressive symptoms amongst hormonal contraceptive users (combined as well as progestogen-only) than non-users (Keyes et al. 2013).
For women with dysmenorrhoea COC use may help to improve premenstrual mood, although for most women it may have little impact (Joffe et al. 2003). Women with premenstrual syndrome (PMS) may wish to consider using the COC continuously rather than cyclically (Royal College of Obstetricians and Gynaecologists 2007b).
Large scale studies investigating any association between mood change, depression and oral contraceptive use, including studies which compare the influence of different pill types, are lacking. Therefore it is difficult to draw any conclusions about the effects of the different pill types on mood, including premenstrual syndrome and whether any pill is more effective than another. Medical eligibility criteria for contraceptive use do not suggest that there is any reason to restrict use of oral contraceptives in those who are depressed (Centre for Disease Control 2010; Faculty of Sexual and Reproductive Health Care 2009b; World Health Organization 2010).
Sexual Interest
Decreased libido is often reported to health professionals in clinical practice. Given that a decreased libido has the potential to impact on an individual’s quality of life and relationship; it is perhaps no surprise that a number of studies have sought to investigate whether an association between OCs and libido exists. Undertaking such studies and drawing any clear conclusions is challenging given the subjective nature of the outcome, inter-individual variability and the number of possible biological, social and psychological factors that could impact, for example, the quality of the person’s sexual relationship.
Reviews on the topic have tended to suggest no effect, whilst recognising the inherent difficulties associated with this research. Pastor and colleagues (2013) reported that while although a decline of free testosterone and an increase in sex hormone binding globulin was observed in those studies examining plasma levels; only 15 % of the 8422 COC users from the included studies, reported a decrease in sexual interest. The decrease in sexual interest tended to be amongst users of very low dose pills i.e. those containing 15 μg of ethinylestradiol (Pastor et al. 2013).
An earlier non-systematic review (Schaffir 2006) similarly suggested no effect for COCs and reported that, although there were limited studies on the topic, a major impact on sexual desire with use of POPs was unlikely.
Vaginal Discharge
The Summaries of Product Characteristics for many oral contraceptives list vaginal discharge as an undesirable effect noted within clinical trials. However, oral contraceptive use is not thought to alter vaginal flora or discharge considerably (Eschenbach et al. 2000). A change in vaginal discharge can be the result of sexually transmitted or non-sexually transmitted infection (e.g. vulvovaginal candidiasis (VVC) or bacterial vaginosis (BV)).
While it has been postulated that COCs may be associated with an increased risk of VVC because of the increased exposure to estrogen, an association has not been clearly demonstrated (Faculty of Sexual and Reproductive Healthcare 2012). It would not however be unreasonable to consider trying another form of contraception in a COC user who continues to experience recurrent VVC (Faculty of Sexual and Reproductive Healthcare 2012). With regards other causes of vaginal discharge COCs may reduce the risk of bacterial vaginosis (Calzolari et al. 2000; Riggs et al. 2007; Shoubnikova et al. 1997).
Fertility Return
When stopping contraception, a woman’s chance of becoming pregnant will be influenced by a number of factors including her background fertility and that of her partner. There is some documented evidence to suggest that women who have been using oral contraceptives may take slightly longer to conceive compared with other methods for example barrier methods (Doll et al. 2001; Hassan and Killick 2004; Mikkelsen et al. 2013; Vessey et al. 1986) and intrauterine devices (Doll et al. 2001) but that this effect is transient. A large prospective study (Cronin et al. 2009) of drospirenone and other progestogen containing COCs reported no initial delay with 79.4 % of women pregnant after 1 year – this study did not undertake a direct comparison to other non-oral methods.
Data are often limited by a lack of ability to control for factors such as frequency and timing of intercourse, fertility of the partner, age, and smoking history. Overall, the evidence does not suggest that oral contraceptive use has an impact on long-term fertility. A review of available studies, published in 2011 (Mansour et al. 2011) suggested that overall pregnancy rates after stopping oral contraceptives are similar at 1 year to those stopping barrier methods or who have used no method. The 1 year pregnancy rates were reported to be approximately between 80 % and 95 % (Mansour et al. 2011).
In a trial of the desogestrel POP, the average time to first post-treatment ovulation was 17.5 days with all women (n = 99) having ovulated 30 days after treatment: Six women (approximately 6 % (6/99)) ovulated 7 days post-treatment (Korver et al. 2005). Therefore after stopping oral contraceptives, if pregnancy is not desired, an alternative contraceptive method should be started immediately (Mansour et al. 2011; Faculty of Sexual and Reproductive Healthcare 2015, 2011a).
Factors to Consider When Prescribing Oral Contraceptives
Before prescribing contraception, potential benefits and risks should be identified through detailed history taking. These should be discussed with the patient and taken into account along with patient preferences, cultural and social factors. Key information to identify in the history should include:
· Medical conditions (past and present) including migraine with aura and thrombosis
· Family history of medical conditions including thrombosis
· Medication history (including prescription & non-prescription medicines, herbal remedies including St John’s Wort and any other supplements)
· Menstrual history including attitude to amenorrhoea if relevant
· Contraceptive history including any previous problems
· Gynaecological history including cervical screening and HPV immunisation
· Any relevant surgical procedures
· Obstetric history and plans for future pregnancies
· Social history including smoking
There is no need for routine pelvic examination or ultrasound before initiating oral contraception. It is good practice to consider screening for sexually transmitted infection and cervical cytology where clinically appropriate and as resources allow. When prescribing a COC blood pressure monitoring is generally advised to exclude hypertension (Centre for Disease Control and Prevention 2013; Faculty of Sexual and Reproductive Healthcare 2011a; World Health Organisation 2004).
Quick Starting OCs
In some countries there has been a move toward the practice of quick starting oral contraceptives at any time in the menstrual cycle even in some instances, when pregnancy cannot be excluded, such as when prescribing oral emergency contraceptives (Faculty of Sexual and Reproductive Healthcare CEU 2010). The exception being co-cyprindiol pills which the UK Faculty of Sexual and Reproductive Healthcare advises are not started until pregnancy can definitely be excluded (Faculty of Sexual and Reproductive Healthcare 2010).
The objective of quick starting practice is to reduce barriers for women who may continue to be at risk if they have to wait until pregnancy can be excluded before starting oral contraceptives. The Centres for Disease Control and Prevention in the U.S. advise pregnancy testing in this circumstance, if a woman does not experience a withdrawal bleed in 3 weeks (Centre for Disease Control and Prevention 2013). The UK’s Faculty of Sexual and Reproductive Healthcare advises that if oral contraceptives are initiated when there has been a risk of pregnancy, that women be advised to test for pregnancy no sooner than 3 weeks after the last episode of unprotected sexual intercourse, in case women misinterpret bleeding patterns and in order to limit any potential exposure should emergency contraception fail (Faculty of Sexual and Reproductive Healthcare 2010).
Conclusions
Oral contraceptives are effective methods of contraception. However, their effectiveness is largely dependent on the user, and when pills are missed there is potential for an unintended pregnancy to occur. Whereas several COCs can be missed before efficacy is affected, when a POP is more than 3 h late, additional precautions are required if a pregnancy is to be avoided: the exception being the desogestrel pill which suppresses ovulation and can be taken up to 12 h late.
When used consistently and correctly and when prescribed appropriately, the risk/benefit profile of oral contraceptive use is likely to be favourable for the majority of women. There is no evidence that use will affect risk of all-cause mortality. There are certain conditions such as a history of cardiovascular disease, stroke, migraine with aura, hypertension, or smoking more than 15 cigarettes per day when aged over 35, which may tip the balance of risk unfavourably when considering prescribing a COC, and indeed in some instances present an unacceptable health risk. Where the risks are considered to outweigh the benefits, but the risk is not classified as unacceptable, the decision to prescribe is largely a matter of clinical judgement and/or the preference of the woman, taking into account potential non-contraceptive benefits and the availability/acceptability of other methods. Consulting with a specialist, either in contraception and/or the condition in question is advisable in such instances.
While COCs have some drawbacks in terms of their risk profile (for example cardiovascular risks), the same concerns do not appear to apply to POPs. Whilst it could perhaps be argued that women requesting oral contraceptives should therefore, in the first instance, be offered POPs in preference to COCs, it should be borne in mind that POPs may be less effective in ‘real life’ use as they generally require more rigid schedules to ensure protection is not lost if pills are taken late. In addition, POPs are often associated with less acceptable bleeding patterns than COCs.
COCs have a number of non-contraceptive benefits that have yet to be adequately demonstrated in POP users: alleviation of dysmenorrhoea, reduced menstrual bleeding and management of acne. Whilst a number of adverse events/side effects are reported by users of oral contraceptives, for example, weight gain, headaches, decreased interest in sex, there is often a lack of data to prove an association. Establishing a causal association is often difficult because of the limited data and the observational design of many studies.
Take Home Messages
· Oral contraceptives (COCs and POPs) are effective methods of contraception when used consistently and correctly.
· Efficacy can be affected by user compliance and factors that affect absorption or metabolism; for example vomiting, or use of enzyme inducing medications.
· Although there are some risks associated with use of COCs, when prescribed appropriately, they have a favourable benefit to risk profile for the majority of women
· COC use has been found to offer protection against ovarian and endometrial cancer, which lasts for several decades after stopping. Evidence is currently insufficient to allow recommendations to be made about their use primarily for cancer prevention.
· There are a number of other non-contraceptive benefits associated with COC use such as control of heavy menstrual bleeding, alleviation of dysmenorrhoea and acne improvement.
· Conditions likely to present a less favourable benefit to risk profile when COCs are used include a past or current history of cardiovascular disease, stroke or having certain risk factors for these conditions, such as migraine with aura or hypertension.
· POPs have a lower risk than COCs with regards cardiovascular health and there are few medical conditions that would limit a woman’s eligibility to use POP.
· Current COC use may be associated with a small increase in risk of developing cervical cancer and possibly breast cancer. Any small increase in cancer risk reduces with time after stopping and women who use COCs have not been found to be at increased risk of death from cancer compared to those who have never used COCs.
· Weight gain, headaches and mood changes are often cited by women as concerns regarding side effects of COCs, but causal associations have not been established.
· Bleeding patterns may be irregular with use of POPs and there is little evidence of how best to manage irregular bleeding associated with use of POPs.
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