Extended Use Of Combined Oral Contraceptive Pills

Extended Use of Combined Oral Contraceptive Pills
Dr Hamed Ellakwa
Associate Professor of Obsterics and Gynecology
Menoufiya University, Egypt
drhamedellakwa@yahoo.com

Introduction
• In 1957, the Food and Drug Administration (FDA) approved Enovid 10 mg (9.85 mg norethynodrel and 150 μg mestranol) for management of menstrual disorders; then in 1960 the (FDA) approved it as the first oral contraceptive.

Introduction
• Obvious advances in contraceptive technology are documented.
• In the last 15 years, we have seen modifications of oral contraceptives such as extended cycle regimens, lower doses, and novel delivery systems.

Introduction
• Combined Oral contraceptive pill (COCP) formulations have included a standard 21-day active regimen followed by a 7-day placebo or hormone-free week.
• Both physicians and women faced off-label manipulation of this regimen for years, for example, to minimize days of bleeding or to treat other medical conditions.

Non Oral Forms of Extended Cycle Methods
• 1 – Vaginal Ring: Nuva Ring
• 2 – Contraceptive patch's have been studied for extended cycle use.
• 3 – Monthly combined injectable contraceptives may similarly eliminate bleeding.

History
• Seasonale was first developed by Barr Pharmaceuticals, in collaboration with Eastern Virginia Medical School.
• The (FDA) approved Seasonale in the United States on 5^th September, 2003.
• It contains ethinyl estradiol/levonorgestrel for 84 consecutive days followed by 7 inert tablets.

History
• The FDA approved Lybrel for human consumption on May 22, 2007. Lybrel is currently available at pharmacies by prescription only.
• Health Canada approved Seasonale in July 2007, and Paladin Labs began distributing it in Canada on 4^th January, 2008.

Indications
Extended use of COCPs has been used for many years to treat:
• 1 – Endometriosis
• 2 – Dysmenorrhea
• 3 – Menstruation–associated symptoms¹³

Premenstrual tension
Menstrual headache
Bloating & cramping
Breast tenderness, mastalgia

Indications
• 4 – Menorrhagia
• 5 – Simple Ovarian cysts
• 6 – Androgen excess conditions: reduction in acne lesions and hirsutism
• 7 – Prevent Non Chlamydial pelvic inflammatory disease
• 8 – Reduced risk or slower progression of rheumatoid arthritis
• 9 – Reduced conditions appearing during menses, seizures, and asthma
• 10 – Personal preference (most common)

Acceptability
• Is it acceptable and desirable to women to decrease the frequency of menstruation?
• Many studies and publications argue for and against modifying the menstrual cycle.

Publications Argue Against Modifying the Menstrual Cycle
• The Iron Hypothesis, Stefan Kiechl and his colleagues in Austria over 13 ago, postulate that higher hematocrits and body iron stores may contribute to heart disease, supporting a protective benefit of menstruation.⁽²⁴⁾

Factors that Affect Acceptability of Extended Cycle OCP:
• 1 – Location
• 2 – Ethnicity
• 3 – Associated medical conditions
• 4 – Woman's career
• 5 – Health care provider

1 – Location
• An international acceptability study by Glasier and colleagues (2003) was conducted in family planning clinics in 4 different countries China, Nigeria, South Africa, and Scotland. It involved 200 menstruating women at each site. Attitudes about regular menstruation and amenorrhea differed among sites.⁽⁴⁾

• 81% of women in Nigeria said they liked having periods "to get rid of bad blood" and to reassure them that they were not pregnant.
• One third of women in Scotland preferred never to menstruate.
• In all centers, the most common reason for liking periods was because they were perceived as natural.

2 – Ethnicity
• Andrist and colleagues (2004) have looked at acceptability of amenorrhea in the United States by studying six sites selected for their diverse populations.⁽²⁷⁾

• More African American and Hispanic women felt it was necessary to have a period every month than white women.
• 59% of the women surveyed indicated that menstruating less than monthly would be acceptable.
• One third indicated that amenorrhea would be acceptable.

Associated Medical Conditions
Although no studies have looked at acceptability in these specific populations, one would assume high acceptability given the improvement in quality of life.⁽²⁸⁾

Women's Careers
• In 1999 National Health Interview Survey, Cote and colleagues found that women who had heavy flow were less likely to be working (62%) than women who have low/normal flow (74%).
• Heavy bleeders were estimated to work approximately 6.9% or 3.6 weeks less per year than normal bleeders.⁽²⁹⁾

Women's Careers
• For some careers, the cessation of menses is advantageous for women. Any job which limits hygiene, such as active-duty military, may be simplified by reducing menses. More than 60% of active-duty military women state that menstrual symptoms adversely affect their work.⁽¹¹⁾

Health Care providers
Sulak and colleagues in 2006 surveyed a sample of practitioners in the United States including medical doctors in obstetrics and gynecology, family medicine, nurse practitioners, and midwives.
• 551 health care professionals participated. Obstetrics and gynecology providers were significantly more likely than non obstetrics and non gynecology providers to agree that "extended oral contraceptive regimens should be rountinely offered to patients who wanted the option of eliminating monthly bleeding and other associated problems"⁽³⁰⁾

• Multivariate analysis looked at obstetrics and gynecology training, physician training, and female sex. Only obstetrics and gynecology specialty training was associated with more response in recommending extended oral contraceptive cycle regimens.
• Extended cycles make up greater than 10% of their total OCP prescriptions.

Regimens and Efficacy of Extended use OCP
The high failure rate of 28-day cyclic, combined oral contraceptives of 5% to 8% is mostly due to the difficulty women experience remembering to take a pill every day.

• A large part of the failure rate is attributable to a delayed start with successive pills packs.
• At the end of the placebo week in traditionally packaged pills, up to 47% of women have developed an ovarian follicle large enough to ovulate unless it is immediately suppressed by hormones.

Modifying the regimens of CHC to shorten or delete the hormone-free week may decrease the likelihood of ovulation if pack initiation is delayed.

Option 1: Decrease the Number of Placebo Weeks or Withdrawal Weeks per Year
It administers 12 weeks (84 days) of active hormonefollowed by 1 week (7 days) of placebo. A woman taking this pill has only four scheduled withdrawals bleeds per year.

Anderson and Hait(2003) found in their large, randomized multicenter trial found that ethinyl estradiol levonorgestrel (.03/.15) had a failure rate of 0.60 per 100 woman-years, based on Pearl Index calculations.⁽³²⁾

Option 2: Decrease the Number of Placebo Days
• One modification of the traditional CHC regimen is to shorten the number of placebo days from 7 per cycle to 3 or 4.
• This Extended regimen has high efficacy, with a Pearl Index of up to 1.29 (1.29 pregnancies per 100 woman-years). ⁽³³⁾

Option 3: Continuous use with no withdrawal weeks
• Perhaps the most radical modification of the conventional pill regimen is to completely eliminate hormone-free days. This option has been studied for up to 1 year of continuous hormone use.
• Two small randomized trials compared oral continuous regimens with conventional regimens⁽³⁴⁾.

• Additional prospective clinical trials have evaluated the acceptability of continuous use for up to 168 days.
• Continuous use CHCs appear to be acceptable and well tolerated, but studies have been too small to evaluate efficacy.

Option 4: Continuous use until breakthrough bleeding, then hormone-free interval
• That this option may be particularly useful for women who have persistent bleeding on continuous regimens,
• but more studies are needed ⁽³⁵⁾.

Safety of Extended Cycle (OCP)
• Concerns have been expressed that extended cycle regimens migh allow proliferation of Endometrium resulting in hyperplasia with its consequences.
• Studies of extended cycle regimens have confirmed the lack of hyperplasia with pathologic examination of biopsies.^(36,37)

• 65% of women had inactive or atrophic endometrium, 10% had proliferative endometrium, 6% had secretory endometrium, and 5% had menstrual endometrium, with no cases of Atypia.⁽³⁸⁾

Concern About Possibility of Pregnancy
• In a (RCT) of cyclic versus continuous pills, only 5 of 40 women in the cyclic arm, and 4 of 39 in the continuous year-long arm expressed concerns about pregnancy.^[20]
• Women who are adherent to pill regimens are at low risk of pregnancy and can be reassured.

Long Term Effects
• There is no available data at this time concerning the long term effects of menstrual suppression on a woman's overall health. There exists concern in the medical field that increasing the amount of hormones typically taken by a woman may have an adverse effect on her long term health, but there is no data to confirm or disprove this. ^{(16, 37, 38, 39, 40)}

Evidence based Medicine
• In Cochrane review (2005) Edelman and colleagues[24] reviewed 6 (RCT) comparing 28-day cyclical with extended cycle (OCP).
• They concluded that there were no differences between the traditional and extended cycles in satisfaction, compliance, pregnancy rates, and safety. Subjects taking extended cycle (OCP) had 4 to 14 fewer days of bleeding than those using the traditional regimen.

Side effects
• Extended use of COCPs or non oral combined hormonal contraceptives carries the same risk of side effects and medical risks as traditional COCP use.
• loss of sex drive (libido), headaches, acne, weight gain, vaginal (fungal) infections, and depression.
• Serious risks of COCPs that can be life threatening include blood clots, stroke, and heart attack. These risks are increased in women who smoke cigarettes.⁽²¹⁾

Side effects
• With all extended-cycle COCPs, breakthrough bleeding is the most common side effect, especially in the first 3-6 months of use although it tends to decrease over time. In a 12-month study of a continuous COCP regimen, 59% of women experienced no bleeding in months six through twelve and 79% of women experienced no bleeding in month twleve (Archer et al, 2006).

Contraindications
• Combined oral contraceptives are generally accepted to be contraindicated in women with pre-existing cardiovascular disease, in women who have a familial tendency to form blood clots (such as familial factor V Leiden), women with severe obesity and / or hypercholesterolemia (high cholesterol level), and in smokers over age 35.
• COC are also contraindicated for women with liver tumors, hepatic adenoma or severe cirrhosis of the liver, and for those with known or suspected breast cancer.

Summary
• Extended cycle contraception is a safe, acceptable form of contraception and efficacious, especially for users of oral contraceptive pills.
• It results in fewer bleeding episodes, which are desired by many women.

Although not enough data to recommend one regimen over another, the use of these new regimens will provide women with more options, and almost certainly will improve the acceptability and efficacy of COCP.

References

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