by John Gever, Managing Editor, MedPage Today September 16, 2014

Action Points

BOSTON — Women using combined oral contraceptives containing norethindrone or levonorgestrel were substantially more likely to develop multiple sclerosis (MS) than those not on birth control pills, analysis of a large claims database indicated.

Among some 4,300 women in Kaiser Permanente’s Southern California system from 2008 to 2011, those whose most recent oral contraceptive contained norethindrone had a 57% higher risk of definite MS or clinically isolated syndrome (CIS) (odds ratio 1.57, 95% CI 1.16-2.12) compared with plan members who had no record of oral contraceptive use, said Annette Langer-Gould, MD, PhD, of Kaiser’s Southern California Los Angeles Medical Center.

Oral contraceptive users whose most recent product contained levonorgestrel showed a similar increase in risk, with an odds ratio of 1.75 (95% CI 1.29-2.37), Langer-Gould said during a poster session here at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, held jointly this year with its North American counterpart.

But those using contraceptives containing another progestin compound, drospirenone, did not show any increase in MS risk (OR 1.02, 95% 0.64-1.62), she said.

This pattern of results was the same, although the specific odds ratios changed somewhat, when the analysis examined the oral contraceptives that plan members had used the most — as opposed to just the ones they used most recently — recognizing that many women may switch from one type of product to another over time.

The findings shed new light on a previous Kaiser study that had found a 35% increase in MS risk with oral contraceptives generally, Langer-Gould said.

For the current study, she and colleagues constructed a nested case-control study from claims data in Kaiser’s Southern California system. They identified 400 cases of incident clinically definite MS or CIS (a first MS-like demyelinating event) in the records for female plan members 14 to 48 years old, and matched them to about 3,900 others on the basis of age, race/ethnicity, and membership characteristics.

There were 160 cases and 1,260 controls who had used combined oral contraceptives — that is, those with both estrogen and progestin hormones. As the earlier study had found, this was an imbalance: 40% of cases versus 32% of controls had used such products. Most of the women in both groups had used more than one type.

The statistical analysis adjusted for parity and miscarriages, smoking status, and body mass index category (obese, overweight, or normal/underweight).

Langer-Gould told MedPage Today that levonorgestrel and norethindrone are distinctive in one respect: they have androgenic effects. Moreover, levonorgestrel is powerfully androgenic whereas norethindrone is only moderately so, which could account for the higher point estimate of risk seen with levonorgestrel-containing products.

Drospirenone, on the other hand, is anti-androgenic, Langer-Gould said — thus, further supporting a hypothesis that androgenic effects contribute to MS development.

More broadly, she also suggested that “The Pill” may have played a role in the rising incidence of MS in women over the past 50 years. Norethindrone was used in the first oral contraceptive introduced in 1960, and levonorgestrel-containing products entered the market 10 years later. Incidence rates for MS among women have also climbed during this period.

Langer-Gould acknowledged that the associations found in the study could be spurious. It was a retrospective analysis of administrative records, and the available data did not cover all potential confounders, such as diet, vitamin D status, or lifestyle factors other than smoking.