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Some of the newest and most popular oral contraceptives -- including the drospirenone/ethinyl estradiol combo marketed as Yaz -- have been linked to a small, but significant risk of gallbladder disease, according to a large retrospective cohort study.

The study of nearly three million women taking ethinyl estradiol combined with one of seven progestins between 1997 and 2009 found a small, but statistically significant risk of having gallstones for drospirenone (adjusted RR 1.20, 95% CI 1.16 to 1.26), Mahyar Etminan, PharmD, MSc, of the University of British Columbia in Vancouver, and colleagues reported.

They also found a similar risk of gallbladder disease (defined as needing cholecystectomy) for desogestrel (adjusted RR 1.05, 95% CI 1.01 to 1.09) and for norethindrone (adjusted RR 1.10, 95% CI 1.06 to 1.14) compared with the older progestin levonorgestrel RR 1.00 (ref), they wrote in the CMAJ.

No statistically significant risks were associated with the other oral contraceptive formulations containing ethynodiol diacetate, norgestrel, and norgestimate, Etminan and co-authors wrote.

The drospirenone/ethinyl estradiol pill, marketed as Yaz and Yasmin in the U.S. and Canada, is one of the most prescribed oral contraceptives, with worldwide sales of $2 billion in 2009, the authors said in their background.

However, the researchers said the data showing an increased risk of gallstones for drospirenone is not clinically meaningful compared with other formulations of other contraceptives.

"The surge in the number of reported cases of gallbladder disease facilitated through the media may have contributed in making drospirenone appear to be associated with a higher risk of gallbladder disease compared with older contraceptives," Etminan and co-authors wrote.

Studies have associated long-term use of an oral contraceptive with an increased risk of gallbladder disease compared with no use, they noted.

The investigators cited several potential mechanisms for the association, including increased cholesterol production in the liver, with excess precipitated in bile leading to gallstone formation; progesterone has been shown to decrease gallbladder motility, impeding bile flow.

While the scientific evidence of gallbladder disease requiring cholecystectomy associated with drospirenone is mainly anecdotal, the authors noted recent concerns in the media over links between drospirenone and gallstones.

So Etminan and colleagues undertook a study using the IMS LifeLink Health Plan Claims Database, the largest of its kind in the U.S., with health information on about 78 million residents in all geographic areas of the country, with an average enrollment period of two years.

Data included information on demographics, specific prescription drugs, diagnoses (using ICD-9 data) and hospital admissions (including ED visits and surgical procedures).

Using the database, they identified 2,721,014 women in the cohort, ages 28 to 30, 27,087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period.

Cohort entry was defined as baseline (an index date) after 180 days of continuous exposure to a study drug.

The researchers found an adjusted rate ratio for the risk of cholecystectomy for six months of taking the newer progestins:

• Drospirenone: RR 1.20 (95% CI 1.16 to 1.26)
• Desogestrel: RR 1.05 (95% CI 1.01 to 1.09)
• Norethindrone: RR 1.10 (95% CI 1.06 to 1.14)
• Norgestrel: RR 1.06 (95% CI 0.99 to 1.12)
• Ethynodiol diacetate: RR 1.08 (95% CI 0.99 to 1.25)
• Norgestimate: RR 1.00 (95% CI 0.9 to 1.04)

The results were also consistent in the secondary analysis, in which the outcome was hospital admission secondary to gallbladder disease, they added.

Among the women who had surgical or laparoscopic cholecystectomy, the mean time to surgery was 330 days and the baseline characteristics were comparable no matter which of the progestins they took, Etminan and colleagues wrote.

More gallbladder disease was found among women who were reported smokers, who had diabetes, were older, and were obese, they noted, which is consistent with previous studies.

There are a number of different pills on the market with varying formulations that combine ethinyl estradiol and drospirenone, desogestrel, or norethindrone.

In December 2010, the FDA approved a form of Yaz enriched with folate, Beyaz, designed to prevent neural tube defects in women who are unaware of their pregnancy while on the pill.

A desogestrel combination oral contraceptive, Emoquette, was recently approved in generic form by the FDA.

While the LifeLink database was large, the investigators cited some limitations to their study, including a lack of data on body mass index (BMI) and ethnicity, as well as possible confounding factors such as diet.

BMI is a potential confounder because drospirenone has been marketed for having the least effect on weight, which may have led to more physicians prescribing the progestin to heavier women.

"Such bias (if present) would make it appear more harmful with respect to gallbladder disease," they stressed, since obesity is an established risk factor for gallstones.

"However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant," they concluded.

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