Migraine antibody drugs in early pregnancy linked to higher miscarriage rate in US claims study

A newer group of migraine prevention drugs works by blocking a signaling molecule called CGRP. Migraine is most common in women of childbearing age, so some pregnancies begin while these drugs are in use. A study of US insurance records has now compared those pregnancies with others. Miscarriage was more common when a pregnancy was exposed to the antibody form of the drugs in the first 20 weeks. It was no more common with propranolol, an older preventive.

The study, published on October 12 in JAMA Neurology, is observational and cannot show that the drugs caused the losses. Miscarriage is common in any group of pregnancies. People prescribed these drugs may have more severe migraine than those who are not. Insurance claims record that a prescription was filled, which is a step short of knowing it was used. The authors ask for further evaluation and stop short of a verdict.

Why migraine drugs in pregnancy are an open question

The paper begins with a familiar problem. Migraine affects individuals of reproductive age, but treatment options during pregnancy are limited due to safety concerns. An earlier study described how widespread the condition is at that stage of life: migraine is common among females of reproductive age, with an estimated prevalence of 17% to 24%.

CGRP stands for calcitonin gene-related peptide, a small protein released by nerves that plays a part in migraine pain. Since 2018, drugs that block it have been available to prevent attacks. The ones studied here are monoclonal antibodies. A monoclonal antibody is a laboratory-made protein built to latch on to one target in the body. There are four: erenumab, fremanezumab, galcanezumab and eptinezumab.

The concern in pregnancy comes from what else CGRP does. In the new paper’s words, CGRP is important in placental development. A laboratory study in 2007 found the molecule and its receptor at the human implantation site during early pregnancy, the place where the embryo attaches to the womb. Its authors concluded that CGRP there could modify placental angiogenesis and neovascularization. Both words refer to the growth of new blood vessels. A later paper summed up the molecule’s role in pregnancy as one which increases utero-placental blood flow and decreases uterine vascular resistance. In plain terms, it helps blood reach the placenta.

A drug that blocks CGRP might therefore matter to an early pregnancy. And these drugs linger. Half-life is the time the body takes to clear half of a dose. The team running a pregnancy safety study of one of them put it this way: due to the long half-life of galcanezumab and the prevalence of migraine in women of childbearing age, galcanezumab exposure may occur during pregnancy.

Until now there was little to go on. A review published in September judged that pregnancy data are limited to pharmacovigilance analyses and case reports of unintended exposures. Pharmacovigilance means the monitoring of a medicine’s safety after it reaches the market.

How the study tracked migraine drugs and miscarriage

The new work lists Leah Flatman as first author and Anick Bérard as senior author. This retrospective cohort study used data from the AM-PREGNANT cohort, derived from the Merative MarketScan Commercial Database, from 2018 to 2021. A retrospective cohort study means that researchers look back through existing records of a group of people and compare what happened to those who were and were not exposed to something. The database holds claims submitted to commercial health insurers in the United States.

The team started with 7,991,200 pregnancies and narrowed them down. In the end, 7119 individuals contributing 7579 singleton pregnancies met the predefined eligibility criteria. A singleton pregnancy is one with a single baby. Those included were aged 15 to 45, had continuous insurance, and had migraine before pregnancy. The paper defines that as a migraine diagnosis or triptan or ergot prescription within 6 months before the last menstrual period. Triptans and ergots are medicines taken to stop a migraine attack once it starts. The average age was 31.6 years.

Two kinds of preventive were examined. One was the four antibodies. The other was propranolol, a beta-blocker, which is a type of heart and blood pressure medicine long used to prevent migraine. Including propranolol gave the researchers a second comparison: people on a different preventive, who also had migraine that called for one.

Exposure meant 1 or more filled prescription or injection procedure claim during follow-up. It was treated as time-varying, so a pregnancy counted as unexposed until the first such claim and as exposed from then on.

The outcome was miscarriage at 20 weeks of pregnancy or earlier, which the paper calls spontaneous abortion. The statistical models adjusted for comorbidities and concomitant medications, meaning other illnesses and other medicines taken at the same time.

What the study found about miscarriage

Across all 7,579 pregnancies, 1862 spontaneous abortions occurred. That is about one in four.

The paper gives two raw counts. There were 100 miscarriages during time exposed to the antibodies, which it reports as 28.6%. There were 37 during time exposed to propranolol without the antibodies, reported as 12.8%.

Those two percentages are not a like-for-like measure of anyone’s chances. Each is calculated on time spent exposed, so neither is a simple share of a counted group of pregnancies. They are not adjusted for differences between the groups, and they depend on when in pregnancy exposure began. The adjusted analysis is the paper’s main comparison.

After adjustment, the rate of miscarriage during antibody-exposed time was 42% higher than during unexposed time, with a range from 12% to 80%. The authors then ran what they call bias-adjusted analyses, which simulate how errors in the records might have shifted the answer. The estimate remained similar in bias-adjusted analyses: 33% higher, with a range from 23% to 45%. That second range comes from the simulations. It measures a different kind of uncertainty from the first, so the narrower span does not mean a firmer result.

Propranolol looked different. Its adjusted estimate was 2% higher than no exposure, with a range from 29% lower to 47% higher, which is consistent with no effect but too wide to rule out a modest rise. The bias-adjusted figure showed no difference at all. The paper’s summary is that no association was observed with propranolol.

The authors do not claim to have shown harm. They call for further evaluation of the antibodies’ safety and write that their results emphasize counseling for individuals of childbearing potential. Counseling here means discussing the drugs and pregnancy with patients who could become pregnant.

What earlier monitoring of CGRP migraine drugs in pregnancy showed

Earlier evidence had not shown a problem, though it was a weaker kind of evidence.

One research team has twice searched the World Health Organization’s global database of safety reports, which collects accounts of suspected side effects from doctors and patients. Their 2023 paper opened by noting that safety data on the use of migraine preventive monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) system in pregnancy are limited. Up to the end of 2021, 286 safety reports were found. Sixty-three of them mentioned a miscarriage. Miscarriage was reported no more often with these drugs than across the database as a whole, or than with triptans.

An update in 2024 covered both the antibodies and newer CGRP-blocking pills known as gepants. It found 467 reports, mostly originating from the United States of America, and again no signal compared with triptans.

The team was candid about what such counts can do. In their words, disproportionality analysis is a hypothesis-generating method that does not allow definitive conclusions to be drawn on drug safety. Disproportionality analysis means checking whether a problem is reported more often with one drug than with others. Because nobody knows how many pregnancies were exposed in total, it cannot produce a rate.

The September review reached the same place. Sixteen studies met inclusion criteria. Its authors found that the reports and case studies have not identified specific patterns of maternal, fetal, or neonatal toxicity, and they called for pregnancy registries.

Gathering better data has been slow. One of two ongoing pregnancy safety studies of galcanezumab, an insurance-claims study designed to look at birth defects, reported in 2024 that it had identified 207 galcanezumab-exposed pregnancies in women with migraine over more than four years. It needs 430 with linked infant records. Its final report is planned for December 2027.

The new study is a different kind of evidence. It has a comparison group, and it can estimate a rate.

Migraine itself, other migraine drugs and miscarriage

Any study of this question has to reckon with how common miscarriage is. A Lancet review states that miscarriage is generally defined as the loss of a pregnancy before viability. It put the pooled risk at 15.3% of all recognized pregnancies and listed risk factors that include very young or older female age, previous miscarriages and smoking.

Migraine may carry a small risk of its own. A UK study published in January matched pregnancies by migraine status: 193,208 pregnancies of women with migraine were matched one-to-one to women without migraine. Miscarriage was recorded in 10.8% of the migraine group and 10% of the other.

The same study looked at medicines. Triptans, the antidepressant amitriptyline and anti-inflammatory painkillers were each tied to more miscarriages among women with migraine. One result matches the new paper: beta-blockers were not associated with a higher risk of miscarriage.

A North American study of 7,890 women who were planning a pregnancy adds a caution. There, a history of migraine before conception was not appreciably associated with miscarriage. The largest increase was among those taking prescription preventives, at 43% higher, but with a range from 28% lower to 184% higher, which is too wide to lean on. The authors’ reading was that migraine medication use patterns suggesting greater underlying migraine severity were associated with increased risk of miscarriage. In other words, the medicine may be a marker of how severe the migraine is.

Miscarriage rates in these studies run from 10% to about 25%. The spread may reflect how early a pregnancy is recognized and recorded in each data source.

What the migraine drug study cannot show about pregnancy

Cause. This was an observational study of insurance records. It shows that miscarriage was more frequent during exposed time. It cannot show that the antibodies were the reason.

Who is given these drugs. People prescribed an antibody for migraine may differ from those who are not, above all in how severe their migraine is. The propranolol comparison helps, since those patients also needed prevention, but the two groups may still differ.

What a claim records. A filled prescription shows that a drug was dispensed. Whether and when it was used is not recorded. Because the antibodies clear slowly, a dose given shortly before pregnancy could still be present in the body during a pregnancy counted as unexposed.

Which losses are counted. Claims capture a miscarriage only when it leads to medical care. Very early losses may be missed in both groups.

Small numbers. The antibody result rests on 100 miscarriages. Its range, from 12% to 80% higher, is wide.

One result for four drugs. The estimate is for the four antibodies taken together. The gepant pills were not part of the study.

Who was studied. These were commercially insured people in the United States between 2018 and 2021.

The study is about a pattern across thousands of pregnancies and says nothing about any single one. Do not stop or change a prescribed medicine without talking to your doctor.

Whether a migraine preventive is continued, changed or paused in a particular person who is pregnant or planning a pregnancy is assessed by their doctor.

For drugs that had only voluntary reports behind them in pregnancy, the study supplies a measured comparison, and its authors treat it as a reason to look harder.