Article In Brief
An analysis of data on fetal outcomes for women who took onabotulinumtoxinA before and/or during pregnancy found that the prevalence of major fetal defects in their children was consistent with those of the general population.
OnabotulinumintoxinA may be a safe therapeutic choice for pregnant women who have migraine, suggests a 29-year retrospective study published May 3 ahead of print in Neurology.
The analysis, which culled data from a safety database on fetal outcomes for pregnant women who took onabotulinumtoxinA before and/or during their pregnancy, found that the prevalence rate of major fetal defects in children born to those women was consistent with rates in the general population.
“A significant strength of this analysis is the large number of pregnancies within the Allergan Global Safety Database,” said the study's corresponding author, Mitchell Brin, MD, FAAN, FANA, FAHS, senior vice president of research and development and chief scientific officer of Botox and neurotoxins at AbbVie, which sponsored the study. (AbbVie acquired Allergan in 2020.)
The study authors noted that limited data have been available on the safety of onabotulinumtoxinA during pregnancy. Approximately 45 percent of pregnancies are unintended, they wrote, so onabotulinumtoxinA exposure may inadvertently occur prior to conception or during the early stages of pregnancy in women undergoing routine treatment.
Methodology and Results
To provide a cumulative 29-year update, investigators culled data from the database from Jan. 1, 1990, through Dec. 31, 2018. The database includes data on prospective pregnancies (where fetal outcomes were not known at initial reporting) and retrospective outcomes, in which the fetal outcomes of patients exposed to the drug were known. They evaluated data from women treated with onabotulinumtoxinA treated three months or less preceding conception. From this data, they estimated birth defect prevalence rates of live births from prospective pregnancies.
In nearly 95 percent of 318 pregnancies, women took onabotulinumtoxinA before conception or during the first trimester.
Approximately 77 percent of 195 prospective pregnancies resulted in live births, and 22.8 percent resulted in fetal losses (32 spontaneous and 13 elective).
Of 152 live births, 148 (97.4 percent) had normal outcomes and four had abnormal outcomes, including one major birth defect, two minor fetal defects, and one birth complication.
The prevalence rate for overall fetal defects was 2.6 percent and 0.7 percent for major fetal defects; in the general population, the rates were 3 to 6 percent. The researchers found that, among live births and known determinable exposure times, one birth defect occurred with preconception exposure and two with exposure in the first trimester.
“No discernible patterns in characteristics were observed in the 13 observed fetal defects, which were reported for prospective and retrospective pregnancies, cases of live birth and fetal loss, and patients treated for a variety of indications,” Dr. Brin told Neurology Today. In addition, “no consistent types of malformation by organ were observed.”
Neurologists who specialize in headache management told Neurology Today that the findings of this 29-year cumulative analysis are significant since many migraine therapies are not safe for pregnant women.
This extended analysis with a large sample size “will likely be reassuring to patients and clinicians who decide together to continue such a therapy for a neurologic condition during pregnancy, or for unintended pregnancies that may happen shortly after onabotulinumtoxinA administration,” said Matthew S. Robbins, MD, FAAN, FAHS, associate professor of neurology and director of the neurology residency program at Weill Cornell Medicine and New York-Presbyterian Hospital.
“It is important to understand the safety of onabotulinumtoxinA, given its role as an effective treatment for chronic migraine and the very high prevalence of chronic migraine in women of childbearing age,” Dr. Robbins added.
He pointed out that while migraine without aura generally improves during pregnancy in the majority of women, research tracking the prognosis of chronic migraine during pregnancy has been limited. Clinicians recommend that women avoid many other migraine preventive therapies during pregnancy, including those that target calcitonin gene-related peptide, he said.
The study, the largest of its kind, provides more evidence that use of onabotulinumtoxinA during early pregnancy is likely safe, said Teshamae Monteith, MD, FAAN, FAHS, associate professor of clinical neurology and chief of the headache division at the University of Miami Miller School of Medicine.
She noted that “chronic migraine can be disabling, and discontinuation of treatment may have devastating consequences for some women who become pregnant.”
However, Dr. Monteith added that she prefers to prescribe nonpharmaceutical interventions rather than onabotulinumtoxinA for her pregnant patients with migraine. She also consults with an obstetrician/gynecologist as needed.
Because of the large percentage of unintended pregnancies, Dr. Monteith would advise clinicians to obtain a history of preconception planning as well as birth control when considering treatment options. If a patient is either contemplating pregnancy or does not use adequate birth control, she noted, onabotuliniumtoxinA may not be an option in some cases.
“Migraine treatment during pregnancy can present significant challenges due to lack of controlled clinical trials and risks associated with specific medications,” said Brian M. Grosberg, MD, FAHS, director of the Hartford HealthCare Headache Center in West Hartford, CT, and program director of the headache and facial pain fellowship at the Ayer Neuroscience Institute at Hartford HealthCare and the University of Connecticut School of Medicine in Farmington, CT.
“Optimal management of migraine typically involves both pharmacologic and nonpharmacologic treatment approaches,” he said. While nonpharmacologic treatments alone may adequately manage migraine in some patients, uncontrolled migraine in pregnancy may pose risks that may require pharmacologic interventions, Dr. Grosberg said.
Clinicians must weigh the risks and benefits of pharmacologic treatments during pregnancy, he said. In 2022, the American College of Obstetricians and Gynecologists updated and published its evidence-based recommendations in Obstetrics & Gynecology. They suggested that physicians discuss the risks and benefits of using onabotulinumtoxinA during pregnancy and postpartum for prevention of chronic migraine.
“Clinical practice around onabotulinumtoxinA use for chronic migraine prevention during pregnancy is variable, with some clinicians stopping onabotulinumtoxinA preconception, others continuing until a positive pregnancy test, and still others continuing treatment through pregnancy,” said Addie Peretz, MD, clinical assistant professor of neurology and neurological sciences at Stanford School of Medicine. “Diving deeper into the safety of medications in pregnancy is imperative.”
Dr. Peretz added that “this study builds upon a prior study of over 200 eligible pregnancies to nearly 400 eligible pregnancies. While this is certainly a substantial increase, the amount of available data is still insufficient to determine that onabotulinumtoxinA is definitively safe in pregnancy.”
Nevertheless, it helps to have additional attention and research devoted to this issue. “In light of the paucity of safety data for most treatments in pregnancy, it is beneficial to be able to share the data we do have with our patients for shared decision making,” she said.
Dr. Grosberg would advise practitioners considering use of onabotulinumtoxinA to prevent chronic migraine during pregnancy to discuss the available literature, such as the findings of this study, and to examine the risks versus benefits with each patient and in consultation with colleagues in maternal-fetal medicine. He added that it is vital for treating providers to develop a plan for preconception counseling and migraine treatment during pregnancy.
An American Headache Society members' survey published in 2020 in Headache: The Journal of Head and Face Pain found that nearly two-thirds of health care providers would counsel women on migraine treatment during pregnancy before they even considered getting pregnant, Dr. Grosberg said.
However, he noted that another study published earlier this year in Headache reported that only 26 percent of health care providers would counsel patients on migraine treatment prior to pregnancy planning. More than one-third (35 percent) of respondents said they would wait until the patient became pregnant before broaching the topic of migraine treatment during pregnancy.
In addition, 90 percent of respondents reported that they would not feel comfortable recommending/prescribing or continuing onabotulinumtoxinA. By comparison, 66.7 percent of neurologists reported being somewhat or very uncomfortable using onabotulinumtoxinA for migraine prevention during pregnancy.
“Treating providers still feel that the safety of onabotulinumtoxinA during pregnancy is uncertain,” Dr. Grosberg said. That is why, in the current study published in Neurology, “information on the timing of preconception counseling becomes very important since the vast majority of pregnancy exposures to onabotulinumtoxinA occurred within three months prior to conception or during the first trimester of pregnancy.”
The scarcity of data available for second- and third-trimester exposure to onabotulinumtoxinA, however, is a limitation of the study, Dr. Robbins noted, adding that only 17 exposures were tracked during those trimesters. For this reason, he said it is difficult to generalize these results to a common clinical scenario—timing onabotulinumtoxinA during the preconception phase so the treatment effect lasts into the first trimester, and then resuming it on schedule during pregnancy or only if there is a chronic migraine relapse during pregnancy, which typically occurs in the second and third trimesters.
“Given the black box warning for botulinum toxins for distant spread, it would be reassuring if reports could address maternal in addition to fetal outcomes, including rates of preterm labor,” Dr. Robbins said.
The study is also limited by the fact that the analysis was restricted to only reported pregnancies within the database, which indicates they may not have captured information on concomitant medication exposure, comorbidities, other potentially relevant factors, and other data during postnatal development.
“Conclusions about the safety of onabotulinumtoxinA during pregnancy should be made with caution and continued monitoring [should occur] in the absence of a comparative or controlled study,” Dr. Grosberg said.
Dr. Monteith concurred that the retrospective database has “substantial missing data.” In the analysis of 397 eligible pregnancies, only 49 percent were prospective, she noted.
“I would like to see a larger series of prospective cases throughout the course of pregnancy,” she said, “especially as there are providers who do not discontinue the use of onabotuliniumtoxinA for treatment of neurologic disorders during pregnancy.”
For clinicians who provide onabotulinumtoxinA injections to treat patients with migraine, this data provides some context for conversations with women considering pregnancy. It also sets the stage for what could happen in the case of accidental pregnancy or cessation of treatment immediately after becoming pregnant, said Jessica Ailani, MD, FAAN, FAHS, director of the Georgetown Headache Center and professor of clinical neurology at Medstar Georgetown University Hospital in Washington, D.C.
“Any data provided of used treatments in pregnancy and their safety is value added in the clinical space,” said Dr. Ailani, a board member of the American Headache Society. But like Drs. Grosberg and Monteith, she lamented that the data are limited to mainly the first trimester and that only 397 reports could be included for analysis. “This does not help provide information for patients who need to continue treatment through pregnancy,” she said.
Dr. Ailani added that this publication does not make it clear whether the manufacturer is maintaining an ongoing registry of people who become pregnant and are on onabotulinumtoxinA injections. It would be helpful, she said, if health care providers could document in a registry when their patients use onabotulinumtoxinA or decide to continue the injections while pregnant. “This is one way we can continue to grow the safety data in this area,” she said.
Dr. Monteith noted that there are opportunities to conduct a larger study. “More research is needed to improve the inclusivity of treatment guidelines,” she said. “We need to focus more on women of childbearing age given hormonal considerations, the potential of infertility, but also to investigate the safety of widely used therapeutics that are often restricted.”
For now, Dr. Robbins said, “a strategy that many neurologists and headache specialists use is to hold off on onabotulinumtoxinA during pregnancy and to instead use peripheral nerve blocks with local anesthetics, which may have a clearer safety track record given their widespread use.”
Dr. Brin is an employee of AbbVie and receives salary and stock/stock options as compensation. Drs. Robbins and Peretz had no disclosures. Dr. Monteith has received fees for serving on the advisory board for Abbvie, Teva, Novartis, and Linpharma. Her institution has received educational grants from Amgen and Abbvie. Dr. Ailani has received consulting fees from Abbvie, Amgen, Aeon (where she serves on the data monitoring board), Axsome, Biohaven, BioDelivery Scientific International (2022), Eli-Lilly, GlaxoSmithKline, Lundbeck, Linpharma, Impel, Miravio, Pfizer, Neurolief, Neso, Satsuma, Theranica, and Teva. She has received research grants from Abbvie, Biohaven, Eli-Lilly, Satsuma, and Zosano. Dr. Grosberg has received book royalties from Wiley and honoraria from MedLink Neurology and Theranica.