Early pregnancy exposure to anti–calcitonin gene-related peptide (CGRP) monoclonal antibodies was associated with a 42% higher adjusted hazard of spontaneous abortion among patients with migraine in a retrospective cohort study. Propranolol exposure was not associated with an increased hazard compared with unexposed person-time.
Researchers analyzed 7,579 singleton pregnancies among 7,119 patients aged 15 to 45 years with pregestational migraine using the American Pregnancy Mother-Child cohort, derived from the MerativeMarketScan Commercial Database. Pregnancies were recorded between November 2018 and December 2021.
Pregestational migraine was identified through diagnostic codes or prescriptions for triptans or ergotswithin 6 months prior to the last menstrual period. Exposure to anti–CGRP monoclonal antibodies, including erenumab, fremanezumab, galcanezumab, and eptinezumab, or propranolol was determined from prescription and procedure claims.
The primary outcome was clinically detected spontaneous abortion at or before 20 weeks of gestation, identified using administrative claims. Researchers classified medication exposure as time-varying and used Cox proportional hazards models adjusted for maternal age, comorbidities, concomitant medications, and health care utilization. Additional analyses estimated absolute risk differences and assessed potential confounding by migraine severity.
Among the 7,579 pregnancies, 1,862 spontaneous abortions occurred (24.6%). A total of 350 pregnancies contributed anti-CGRP monoclonal antibody–exposed person-time, during which 100 spontaneous abortions occurred (28.6%). Another 283 pregnancies contributed propranolol-exposed person-time without anti-CGRP monoclonal antibodies, during which 37 spontaneous abortions occurred (12.8%). Because exposure was modeled as time-varying, pregnancies could contribute observation time to more than 1 exposure category.
The adjusted estimated risk of spontaneous abortion by 20 weeks was 28.7% under a hypothetical scenario in which all pregnancies were exposed to anti-CGRP monoclonal antibodies, compared with 24.5% without exposure.
The association persisted across sensitivity analyses that varied the duration of anti-CGRP exposure. A probabilistic bias analysis accounting for potential confounding by migraine severity modestly attenuated the association, although the estimated hazard remained elevated. No increased hazard was observed with propranolol following bias adjustment.
Patients exposed to anti-CGRP monoclonal antibodies had greater health care utilization before pregnancy and more frequent markers of migraine severity, including use of triptans, nonsteroidal anti-inflammatory drugs, and other preventive medications. Depression and concomitant antidepressant use were also more common among exposed patients, suggesting greater disease burden and treatment complexity.
Among pregnancies contributing anti-CGRP monoclonal antibody–exposed person-time, 49.1% involved exposure both before and during pregnancy, 42% involved treatment before pregnancy with residual exposure extending into gestation, and 8.9% involved exposure during pregnancy only. Because of their long half-lives, exposure could persist after treatment stopped. These patterns suggested that the findings primarily reflected medication exposure around conception and early pregnancy rather than treatment initiated during pregnancy.
Administrative claims did not directly capture migraine frequency or severity, leaving the possibility of residual confounding by indication. The relatively small number of anti-CGRP–exposed pregnancies limited statistical precision, and prescription claims could not confirm actual medication administration. Very early pregnancy losses that were not clinically recognized may have been missed, and gestational age was imputed for many losses. The commercially insured US population limited generalizability, while differences in pregnancy intention and treatment history could also have influenced the findings.
Although the observational design could not establish causality, the researchers called for further research into the pregnancy safety of anti-CGRP monoclonal antibodies, including longer-term offspring outcomes.
"Until more evidence is available, clinicians should consider the limited evidence on pregnancy safety when discussing anti-CGRPmAb treatment with individuals who may become pregnant," wrote lead study author Leah K. Flatman, PhD, of the Centre de Recherche Azrieli at Centre HospitalierUniversitaireSainte-Justine in Montréal, and colleagues.
The study was funded by the Canadian Foundation for Innovation. Flatman reported fellowship support; Leroux and Lipton disclosed pharmaceutical industry relationships; and Bérard reported research and Canada Research Chair support. No other disclosures were reported.
Source: JAMA Neurology
