Topiramate for migraine prevention in fertile women: Reproductive counseling is warranted

Clinical vignette

A 21-year-old woman with migraine without aura was seen in a headache center in Northern Italy. She had been taking low-dose (levonorgestrel (LNG) 0.1 mg and ethinyl estradiol (EE) 0.02 mg) combined oral contraception (COC) for five years, because of acne vulgaris and menstrual abnormalities, without any significant side effects. As the frequency of her migraine attacks was eight days per month, she was prescribed preventive treatment: topiramate 25 mg per day to titrate to a dosage of 50 mg twice daily. She was informed by the neurologist of possible adverse events, such as paresthesias, fatigue, nausea, anorexia and word-finding difficulties, and rare sudden visual loss. A possible interaction with the COC was not mentioned. After two months, while the frequency of her migraine attacks was decreasing, she experienced breakthrough bleeding: unusual bleeding between periods induced by the seven-day hormone-free interval. She was then referred urgently to the gynecologist, who found two functional follicular cysts at ultrasound suggesting insufficient ovarian suppression, in spite of the long-term treatment with COC.

The need to inform patients of relevant side effects

This young patient had an adverse event likely due to the interaction between topiramate and COC, which resulted in reversible consequences, without causing unplanned pregnancy. However, a re-evaluation of the endocrine and clinical profile was performed in this woman to resolve the functional ovarian cysts and the intra-menstrual bleeding. Indeed, the effect of COC on follicular activity is mainly dependent on the dose of EE (3), and previous studies have shown that follicles >10 mm diameter may be found with pills containing 0.02 mg EE in combination with 0.1 mg LNG (4). As with many antiepileptic drugs (AEDs), topiramate induces the metabolism of the estrogenic and/or progestenic component of COC (5). Even though the decrease of circulating concentrations of exogenous hormones is modest (6), it may be sufficient to compromise contraceptive efficacy and cycle control (7). In our case, topiramate use accelerated the hepatic elimination of COC by inducing the CYP 3A4 isoenzyme, and lowered the suppressive effect of COC on ovarian activity (8). A higher-dose COC (containing 30 mcg EE) was prescribed in the attempt to obtain a stronger inhibition of ovarian function and to prevent the formation of new functional follicles interfering with bleeding control. Alternatively, in line with the literature, an extended COC use, without a pill-free interval, could have been suggested to suppress effectively ovarian function (9).

It can be argued that the effect size of the interaction between topiramate and COC is higher during antiepileptic treatment, where topiramate is used at higher dosage, usually at least 200 mg daily (10), where there is a clear indication to use additional birth control methods. However, it can be seen with dosages used in migraine prevention, as reported in product prescribing information (11), such that patients should always be reminded to report any breakthrough bleeding even on conventional migraine-prevention doses (12). In addition, it is noteworthy that the study reporting data indicating that topiramate did not significantly change the area under the curve (AUC) of exogenous hormones (13) refers to the particular combination of 35 mcg EE and 1 mg norethindrone. This dose is less common in standard contraceptive practice for safety concerns, especially in patients with additional vascular risk factors, such as migraine with aura (14). Given the evidence that low-dose (15-20-30 mcg EE and less than 1 mg progestogen per day) COC has become the method of choice in modern contraception, the modest interaction of topiramate with COC may become clinically relevant both in terms of reducing contraceptive efficacy and inducing menstrual bleeding abnormalities. Moreover, it is quite common to miss at least one pill per cycle in typical use, further lowering contraceptive effect (15). This is the main reason why, in line with the latest medical Eligibility Criteria for Contraceptive Use (16), in every package of any COC, including the contraceptive patch and the vaginal ring, it is clearly reported to avoid the concomitant use of topiramate with COC without taking additional contraceptive methods.

These considerations underscore the importance of good communication between headache physicians, general practitioners and patients. There is a paucity of data on the attitudes toward counseling women on contraceptive safety and teratogenic risk in psychiatric practice with AEDs (17). We are under the impression that, even in headache practice, reproductive counseling regarding topiramate is quite uncommon in Europe, with potential medico-legal consequences, such as an unwanted pregnancy with a higher risk of birth defects (18).

In conclusion, we suggest headache experts routinely advise migraine sufferers taking topiramate and low-dose COC to take additional precautions for optimal reproductive planning and to report to their appropriate physician any potential effect of topiramate on their menstrual bleeding profile. Gynecologists should be well informed on the interaction between topiramate and COC in order to tailor effective contraceptive options and to understand potential reproductive side effects in the individual woman.

Clinical relevance summary

Even doses of topiramate (TPM) less than 200 mg may affect Combined Oral Contraceptives (COCs) efficacy and bleeding control.