Risk of intracranial hypertension with intrauterine levonorgestrel: reply

Dr Friedman raises some questions about our study (Etminan et al. 2015). She claims that the search term cerebral edema used in the disproportionality analysis should not have been used. Disproportionality analysis using the FDA’s FAERS database is intended to demonstrate whether there is a strong signal for a specific adverse event secondary to a drug that warrants further investigation. This type of analysis is used routinely by the FDA to issue warnings on specific safety concerns with prescription drugs (FDA.gov). Although cerebral edema was used as a search term in our study, the majority of events were cases of benign intracranial hypertension (BIH). In fact, when restricting the analysis to only cases of ‘benign intracranial hypertension’ in women with Mirena^™ in FAERS using OpenVigil (2.1) (Böhm et al. 2012), the disproportionality odds ratio (OR) was still 3.4 (95% CI: 2.59–4.45) (Böhm et al. 2012).

Dr Friedman questions the timing of Mirena™ used with respect to the pseudotumor cerebri (PTC) events in our cohort study. All events in our study were ascertained after the dispensation date for a Mirena™ prescription. We did not have the time of discontinuation but women had to be on a study drug for at least six months before experiencing an event. Given that levonorgestrel blood levels in women on intrauterine levonorgestrel can fluctuate at times equaling those of oral levonorgestrel formulations (Xiao et al. 1990), it is biologically plausible for a woman on Mirena™ to experience intracranial hypertension only after a few months of use. As we acknowledged in our paper, we did not have information on other covariates. Moreover, the objective of the study was not to compare the risk of PTC with nonusers of hormonal contraceptive, but only to compare the risk of intracranial hypertension or papilledema with two oral progestin-based contraceptives.

Dr Friedman claims that there are no epidemiologic studies linking hormonal contraceptives to intracranial hypertension. This statement is inaccurate. Most of the epidemiologic studies (Ireland et al. 1990; Radhakrishnan et al. 1993) that have attempted to answer this question lacked statistical power. The OR from the study by Ireland and colleagues that Dr Friedman cites was 2.5 (95% CI: 0.95–6.54) (Ireland et al. 1990), with an upper bound of the confidence interval that does not exclude a risk with hormonal contraceptives. In fact, one recent case-control study (Rai et al. 2015) of 473 women (18–55) with PTC found a statistically significant increase (OR = 7.7, 95% CI: 3.2–16.4) with intrauterine levonorgestrel use (IUL) compared to nonusers. This study does not seem to have adjusted for body mass index (BMI), a major confounder for this question. However, results of a sensitivity analysis with the extreme assumption of a 50% confounding among IUL users (50% having a high BMI) within IUL users compared to 10% in nonusers still yields an OR of 2.87 (Schneeweisse, 2006).

Finally, our study was an independent study prompted by our group’s interest on drug safety and ocular outcomes and was not in any way influenced by involvement as an expert in any litigation.