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Significant Risks of Oral Contraceptives (Dec 2010)

Significant Risks of Oral Contraceptives (OCPs):

Why This Drug Class Should NOT Be Included In a Preventative Care Mandate

By Rebecca Peck, M.D., CCD

    Primary Care physicians spend a substantial part of their clinical time counseling patients on preventative care.  Some examples of these items include: providing information on diet and exercise ; giving smoking cessation counseling, performing diabetes and cholesterol screenings; obtaining mammograms, Pap smears, bone densitometry and administering immunizations.

The rationale behind such preventative screenings  is to reduce  morbidity and mortality by changing risky behaviors and by catching disease in its earliest stages.     

Currently, there are several entities that want to include oral contraceptive counseling and medications within a preventative care platform.

This proposal is ill-advised for several reasons.

Firstly, oral contraceptives (OCPs) have their own significant risks, namely an increase in cardiovascular events (such as an increase in venous thromboembolism, pulmonary embolism, myocardial infarction, and stroke) especially in older women and smokers (1,29-38). 

Secondly, OCPs increase the risk of the world’s most frequently occurring cancer, namely breast cancer (1-28).

Thirdly, OCP use leads to an increase in Human Papilloma Virus (HPV) infection and an increase in cervical cancer, which is the 2nd most common worldwide cancer (2,39-57).  

Therefore, OCPs fail the most important test of preventative medicine: they increase risk of disease instead of decreasing it.   

This paper will provide evidence of each of the above stated areas of risk: (1) increased cardiovascular events, (2) increased breast cancer rates, and (3) increased HPV and cervical cancer rates. 

This paper will not explore the various side effects of the pill, such as depression, migraine headache,  and weight gain, although these very real concerns may be one of the reasons why the number of women continuing OCPs is only 68% at 1 year (1, 2, 58).

There are also other serious risks of OCPs, such as an increase in liver tumors (14), especially in women with concomitant hepatitis infection,  which will not be further explored in this paper.

Increased Cardiovascular Morbidity and Mortality    Cardiovascular morbidity and mortality reported in OC users have been related firstly to the ethinylestradiol (EE) and as a first step, the estrogen dose has been reduced since the OCs were first introduced in the 60s. Later on, cardiovascular risk has been correlated to lipid profile changes and progestins with androgenic properties have been made responsible for cardiovascular events reported in OC users.

In order to minimize the incidence of adverse drug reactions and to induce beneficial changes in lipid patterns, new progestational molecules devoid of androgenic properties have been recently synthesized.

These compounds are the so called “third generation” progestins and were thought to have lower cardiovascular risks when they first came out (60). Unfortunately, there are some well-known class action lawsuits currently ensuing for yaz, just one example of such third generation compounds which caught media attention recently.

And, according to research (cited below), risk is NOT significantly lower regarding the cardiovascular risks; in fact, some studies show HIGHER risk.

The incidence of venous thromboembolism (VTE) among healthy women is low but increases with age (2).

OCPs are associated with a three-fold to five-fold higher risk of VTE (2, 38). The risk appears to be proportional to the estrogen dose and the type of progestin used. 

According to a recent large Danish study, over 2,000 women were studied for 6 years, (10.4 million woman years were recorded), and the researchers studied the venous thrombotic events  per type of progestin used.

Compared with OCPs containing levonorgesterl and with the same dose of estrogen and length of use, the rate ratio for OCPs with norethisterone was 0.98, with norgestimate 1.19, with desogestrel 1.82, with gestodene 1.86, with dropirenone 1.64 and with cyproterone 1.88. 

They concluded that for the same dose of estrogen and the same length of use, OCPs with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than OCPs with levonorgestrel. In a separate study published in Lancet, researchers determined that the excess risk for nonfatal venous thromboembolism (VTE) linked to this new generation of OCs to be 16/100,000 woman years. In contrast, the older generation OCs had rates of around 4.3/100,000.

Pulmonary embolism (PE) risks are also higher in patients that use OCPS. This is, in fact, because  VTE and PEs are similar phenomenon,  whereby clots can break off from the existing clot in the leg (which is defined as a VTE) and subsequently travel  to and become lodged in the lungs. As stated above, PE is related to the estrogen dose and type of progestin. 

A Lancet study noted that OCs containing desogestrel or gestodene are associated with higher risks of fatal PE than are those containing levonorgestrel. This is consistent with most previous studies comparing the effects of second-generation progestens on VTE (37). 

As an aside, the Ortho Evra patch is another form of hormone delivered by transdermal patch and has been associated with increased rates of P.E.  This patch has also made the headlines lately. The presumed mechanism is that the patch delivers a higher dose of estrogen into the circulatory system by avoiding the “first-pass” metabolism of the liver.

The risk of VTE associated with hereditary thrombophilias (such as Factor V Ledien mutation, hereditary deficiencies of antithrombin III, protein C, protein S, plasmingoen, factor X11 and dysfibrinogenemia) is further increased with OC use.

The risk of VTE in women who have Factor V Leidin and use OCs is 35-fold higher than in women who don’t have the mutation and who don’t use OCs.

Factor V Leiden and some of these other hereditary deficiencies are like “ticking timebombs”.

The women may not know that they carry the mutation until they take OCPs.  Due to the extreme cost of screening for these mutations, it would not be feasible in a cost-restricted healthcare environment to screen every patient for this possible mutation. Currently when there is a VTE on OCPs, the recommended blood tests for hereditary thrombophilias  is carried out.

Physicians should perform a detailed family history on every patient presenting for OCPs and if there is a history of multiple family members with VTE, such hereditary conditions should be suspected. Unfortunately, in the current rushed healthcare environment, complete family histories (and informed consent) are often lacking (61).

The risk of myocardial infarction (MI)  is extremely rare among reproductive-aged women.

Use of low dose OCPs increases the risk of MI by two-fold.

However the risk in OCP users who smoke (under 35)  is increased 10-fold over that of nonsmokers. For women over age 35 who smoke, the risk is increased even higher (2, 29). 

According to the WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception,  current use of OCPs is associated with an increased risk of MI among women with known cardiovascular risk factors and among those who have not been effectively screened, particularly for blood pressure (35).

Older women who smoke have excess risk associated with OCPS (400 per 100,000 woman-years). Another study showed that hypertensive OCP users were at higher risk for stroke and MI than hypertensive non-OCP users (32).

The risk of idiopathic cardiovascular death of women using OCPs was examined by researchers using two separate studies analyzed from the UK General Practice Research Database. They found that there were 15 unexpected idiopathic cardiovascular deaths: 4.3/100,000 for levonorgestrel OCs, 1.5/100,000 for desogestrel OCs, and 4.8/100,000 for gestodene OCs (36). In a separate study, the Oxford Family Planning Association Study, death from all causes was more than twice as high in smokers and users of OCPs compared to nonsmokers (29).

The risk of stroke in young women is rare, but substantially increased in users of OCPs.

Risk is associated with higher estrogen doses, advanced age, and smoking.  The risk of stroke in women with migraines who use OCPs is also increased significantly by smoking (2). The risk of hemorrhagic stroke in 35 and older women who smoked with OCPs was 2.2-fold higher than non-users (2, 36). The estimated risk of stroke with higher-estrogen dose OCs was associated with an 8-fold risk of stroke (36).

Increased Breast Cancer Risk
    According to the National Cancer Institute Surveillance Epidemiology and End Results, breast cancer is the most common female cancer in the U.S. and world-wide.  According to rates obtained from 2005-2007, the lifetime risk that a woman will develop breast cancer is 12.15% (or 1 in 8 women).  Another way to look at the data is to say that 122.9 per 100,000 women will develop breast cancer per year (across all races).

The next most frequent cancer worldwide is cervical cancer. According to the SEER data, in the U.S., 8.1 per 100,000 women will develop cervical cancer. For blacks, this rate increases to 10.1 per 100,000 women and for Hispanics, 12.0 per 100,000 women.  Worldwide, the International Agency for Research on Cancer (IARC)  estimates that 15.3 women per 100,000 women will develop cervical cancer worldwide per year.  In Africa, the rate increases to 25.2 women per 100,000 women.

Uterine and ovarian cancers occur at higher rates in the U.S. than they do worldwide, but they still lag way behind breast cancer, which is by far, the most frequently occurring cancer in the U.S. and worldwide.  The incidence of uterine cancer is 23.5 per 100,000 women. The lifetime risk of developing uterine cancer is 2.58% (or 1 in 39 women).  Ovarian cancer incident rates are 23.5 per 100,000 women. The lifetime risk of developing ovarian cancer is 1 in 39 (or 2.58%).

Why are these rates important? Because many studies promoting the benefits of OCPs in the literature tout lowered risks of uterine and ovarian cancers, yet minimize the increase in risk of breast and cervical cancers caused by these same OCPs. 

Since the incident rate of breast cancer is 6 times higher than that of both uterine and ovarian cancers, it is important to highlight this point.

Even small increases in the relative risk of breast cancer caused by OCPs translate into much larger increases in absolute risk of breast cancer.

In 1972, a series of animal research studies showed that an oral contraceptive appeared to cause metastatic breast cancer in monkeys, which rarely develop breast cancer (61).

A study in 1981 found that women who took OCPs for 4 years prior to their first full term pregnancy (FFTP) had a 125% increased risk of breast cancer before age 32.

In 1993, the Cancer and Steroid Hormone study (CASH) showed a 40%  increased risk in women taking OCPs before their FFTP.

Dr. Chris Kahlenborn’s meta-analysis in Mayo Clinical Proceedings analyzed 34 case-control studies of OCPs and premenopausal breast cancer and found that the use of OCPs was associated with an increased risk of premenopausal breast cancer in general (OR 1.19), but when OCPs were used before FFTP, the risk went up to 1.44 (23).

The association between OCP use and breast cancer risk was greatest for women who had used OCPS for more than 4 years (OR 1.52) (19).

In a very recent study at Harvard, 116,60

8 patients were enrolled in a  prospective cohort study which found that current use of OCPs carries an excess risk of breast cancer with levonorgestrel accounting for much of the risk (3). 

Another population-based case control study examined the relationship between use of OCPs and breast cancer and among women in a cohort younger than 45 years old, they found that OCP use for 6 months or longer was associated with a relative risk (RR) of 1.3 with the RR risking to 2.2 for users of 10 or more years (4).

In another case control study (the Case Control Surveillance Study), the relative risk of breast cancer for OCP use over 1 year or more was 1.5.

The famous “triple negative breast cancer (TNBC)” study which came out last year (2009) showed that OCP use greater than 1 year was associated with a 2.5 fold increased risk of TNBC. Among women less than 40 years, the RR of TNBC associated with OCP use greater than 1 year was 4.2 (8).

The largest meta-analysis comprised of 54 epidemiological studies (Collaborative Group on Hormonal Factors in Breast Cancer) included 53,297 women with breast cancer and 100,239 controls. Women who were currently using OCPs had an increased RR of breast cancer (RR 1.24) and women who had used OCPs before the age of 20 had an elevated risk for breast cancer over subsequent years (RR 1.95) (25).

The Black Women’s Health Study from 1995 to 2007 results indicated that OCPs increased the RR 1.65 with a greater effect for estrogen negative than estrogen positive cancer (11). Another retrospective case control of African American women showed that OCPs also conferred a significantly increased risk of breast cancer (20).

Regarding risk of breast cancer based upon the hormonal content,  a U.S. based case-control study evaluated rates of breast cancer and estrogen and progesterone formulations. They found that women who recently used OCPs containing more than 35mcg of ethinyl estradiol were at higher risk than users of lower dose preparations (RR=1.99 and 1.27 respectively). They also found that this relationship was more marked among women less than 35 years of age. They also found significant trends of increasing breast cancer risk for pills with higher progestin and estrogen potencies (27).

There are several studies which show an increased rate of breast cancer for women who have used both OCPs as younger women and then are re-exposed as older women when they take hormone replacement therapy (HRT) (12, 16).  The risk of common exposure to both OCPs and HRT increases in women with other risk factors (RR 2.77).

There are now several randomized control trials that show the use of hormone therapy (HRT) increases the risk of breast cancer for postmenopausal women (10, 62, 63).

An important point to note is that the compounds that comprise HRT (estrogen and progesterone derivatives) are similar to compounds found in OCPs.

However, the postmenopausal dosages of these hormones are less potent, and are used by these women after their breast tissue has already fully matured. (Breast tissue matures after the first full term pregnancy). 

The HRT data showed an increase in postmenopausal breast cancer after just 5 years of use.  Young women, with susceptible breast tissue (those who have not had their first full term pregnancy yet), are exposed to stronger estrogen and progesterone derivatives for much longer periods of time. 

All of the case control studies cited in this paper showed an increased relative risk of breast cancer in younger women who used OCPs before their first full term pregnancy, and for those that used OCPs for 4 or more years.

Why are we, the medical community, warning older women of the risks of HRT but NOT cautioning the younger women about these hormones? 

Some young women start OCPs right after menarche, while their breast tissue is highly susceptible to the effects of carcinogens (63). 

The IARC classified estrogen and progesterone as Class I carcinogens in 2005 (1). 

According to Dr. Angela Lafranchi, M.D., breast surgeon, the breast goes through a series of phases whereby tissue matures and develops.  It is not until the women has her first full term pregnancy and her milk develops, that those breast cells become fully matured.  After the breast cells have matured to this level, they are “protected” to some extent against carcinogenic influences. 

Therefore, exposing our young women’s breasts to years of carcinogenic hormones, before they have their babies is VERY harmful.

This important issue will need to be clarified with randomized control  trials.

Why have no randomized control trials been performed to date? 

One reason may be that it would not be in the pharmaceutical industry’s best interest to perform such expensive studies, especially if we examine what happened with the HRT experience.  Up until 2002, physicians mistakenly recommended HRT to postmenopausal women for cardiovascular health benefits and cancer protection.

Once the results of the Women’s Health Initiative were publicized in the mainstream media, prescriptions for HRT dropped by half in just a couple of months. 

There are currently over 100 million birth control prescriptions filled worldwide.

Certain entities may assume that the fallout of such studies would prove too great. 

Increased Rates of Human Papilloma Virus (HPV) and Cervical Cancer
    The use of OCPs has been associated with an increased risk of cervical intra-epithelial neoplasia (CIN) and cervical cancer (2, 39-57).  OCPs most likely act as a co-factor in the development of this disease.  OCPs are classified by the IARC as a cause of cervical cancer (39). 

There are many possible reasons why OCPs increase the rates of cervical cancer. 

Although HPV appears to be the strongest factor in the causation of the disease, not all women with

HPV develop cervical cancer.

OCPs have been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. The OCPs may bind to HPV DNA to either increase or suppress transcription of certain genes (40).

Other studies show that OCPS (and other factors such as smoking) may accelerate the cervical maturation process, representing increased cell proliferation and thus a possible greater vulnerability to HPV (41).  Still other studies show that longterm use of OCPs may lead to a more frequent persistence of HPV (42).

In  a 2007 meta-analysis that appeared in the Lancet, 16,473 women with cervical cancer and 35,509 without cervical cancer were reanalyzed centrally. The relative risk of cervical cancer is increased in current users of OCPs and declines after use ceases. 10 years’ use of OCPS from around age 20 to 30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7.3 to 8.3 per 1000 in less developed countries and from 3.8 to 4.5 per 1000 in more developed countries (39). Another earlier meta-analysis showed that long duration use of OCPs is associated with an increased risk of cervical cancer also (44). Still another large prospective cohort study of 47,000 women showed that those who had used OCPs had a significantly higher rate of cervical cancer than never-users (56).

A population-based cohort study of over 10,000 women showed positive correlation of HPV prevalence with older age and current use of OCPs. This study occurred in South Africa where cervical cancer rates are about the highest in the world (46).

Data from a hospital-based case-control study collected between 1979 and 1988 in 10 participating hospitals in 8 countries were analyzed to determine whether OCPs alters the risk of cervical cancer. Risk increased with duration of OCP use, was highest in recent and current users, and declined with time since cessation of use (51). Other studies confirmed that the risk of HPV infection was strongly and independently associated with increasing numbers of sexual partners in a lifetime, use of OCPs, younger age and black race (52-54).

    Preventative medicine is the backbone of any medical system. Patients must have confidence that the measures physicians are recommending are going to be beneficial for their health.  Oral contraceptives increase rates of cardiovascular morbidity and mortality, as well as increase rates of breast and cervical cancers. Patients need complete informed consent on all of the possible risks of OCPs. Complete personal and family histories need to be ascertained by health care providers  to ensure that adverse events do not occur. Patients incur substantial health risks when choosing  oral contraceptives. They should not be misled or confused into believing that what they are taking is “good for them” and is of the same beneficial effect as other evidence-based preventative measures.

Grateful acknowledgement  to Dr. Benjamin Peck, M.D., Dr. Chris Kahlenborn, M.D. and Dr. Richard Fehring, PhD    
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(16 Dec 2010, [Significant Risks of OCPs: Why This Drug Class Should Not Be Included in a Preventative Care Mandate] Rebecca Peck, M.D., CCD)