The use of calcitonin-gene related peptide antagonists in pregnancy and lactation – a brief safety review

INTRODUCTION:

Migraine headaches impose a substantial level of pain and disruption to a person’s quality of life. (Malmberg-Ceder, Soinila et al. 2022) Common triggers for migraine included physical activity, poor sleep hygiene, physical and mental fatigue, and emotional anxiety and stress. (Aderinto, Olatunji et al. 2024)

The age-adjusted prevalence of migraine is observed to be 21% in women, which is twice the rate of 10.7% seen in men (Burch, Rizzoli et al. 2021) and the economic burden is substantial. Starting from 2020 as a baseline, over the next 10 years migraine is predicted to have a in health-care costs of AU$1.67 billion, or AU$1313 per person. There could also be AU$68.13 billion loss to the GDP.(Tu, Liew et al. 2020)

Historically, acute migraine treatment has involved triptans as the leading clinical option. Preventive treatments include propranolol, metoprolol, amitriptyline and anti-epileptics such as sodium valproate and topiramate (Zobdeh, Ben Kraiem et al. 2021) as well as botulinum toxin.  (Kępczyńska and Domitrz 2022).

More recently a new class of drugs, the calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs), have become available as an effective preventative treatment for chronic migraine. (Ray, Dalic et al. 2024) In Australia eptinezumab, fremanezumab, galcanezumab and erenumab are available. The first three act directly against CGRP whilst erenumab acts against the CGRP receptor. (de Vries, Villalón et al. 2020). They are collectively referred to as CGRP antagonists. (AMH, 2025).

Briefly, the pathophysiology of migraine involves the triggering of the trigeminovascular system. Divisions of the trigeminal nerve innervate the face and as well as the meninges, which also includes intracranial blood vessels and the dura. These nerve branches release calcitonin-gene related peptide (CGRP), which acts as a potent vasodilator of cerebral and dural vessels, leading to neurogenic inflammation, and CGRP facilitates pain transmission from trigeminal vessels to the CNS.(Pescador Ruschel and De Jesus 2025)

Proof of concept for the role of CGRP has been demonstrated by the venous infusions of CGRP which results in migraine-like headaches. (de Vries, Villalón et al. 2020). Calcitonin gene-related peptide is reported to be most potent known vasodilator of both cerebral and peripheral blood vessels. (ACOG. 2022)

It is important to note that CGRP monoclonal antibodies (mAbs), due to their molecular size, exhibit only 0.1% presence in the brain as they are unable to cross the blood-brain barrier. Therefore, their mechanism of action primarily involves the trigeminal network located outside the brain. (Edvinsson and Warfvinge 2019). Two studies using radiolabelled mAbs have confirmed that these drugs act mainly peripherally, due to their large size.(Labastida-Ramírez, Caronna et al. 2023)

USE IN LACTATION:

For lactating mother’s, the current approved product information for erenumab (Aimovig) in eMIMS (2025) states:

“It is not known whether Aimovig is present in human milk. There are no data on the effects of Aimovig on the breastfed child or the effects of Aimovig on milk production. Because drugs are excreted in human milk and because of the potential for adverse effects in nursing infants from Aimovig, a decision should be made whether to discontinue nursing or discontinue Aimovig, taking into account the potential benefit of Aimovig to the mother and the potential benefit of breast feeding to the infant.”

However, a more forensic analysis of the pharmacokinetics of CGRP drugs, understood as the timeline of the drug’s absorption, bioavailability, distribution, metabolism and excretion, is important in assessing the suitability of administering these drugs to pregnant and lactating mothers. (Ernstmeyer and Christman 2023)

THE RESEARCH:

Erenumab (Aimovig), a biosynthetic immunoglobulin G monoclonal antibody (mAb), is a large protein molecule with a weight of 150,000 Da. (Bussiere, Davies et al. 2019, Kothari, Wanjari et al. 2024).

Because of the size of erenumab, presentation via maternal milk to a newborn infant faces a number of physical barriers.

First, erenumab (and other mAbs) must cross the mammary epithelium from maternal blood into milk. A review of the research by LaHue, Anderson et al. (2020) of 155 women using the mAbs certolizumab, rituximab or natalizumab across 30 studies reported that “a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.”

These researchers applied the relative infant dose (RID), a metric comparing the infant and maternal drug dose, where <10% is generally considered safe, and found that certolizumab and rituximab were present in maternal milk at <1%.

A second “barrier’ is the digestion of a mAb in the infants GIT. A study of the IgG1 mAb palivizumab presence in neonatal intestinal fluid found a variably level of destruction of 50%. (Sah, Lueangsakulthai et al. 2020) As a guide to understanding the poor GI abruption, “native” IgG is only 0.01% absorbed intact from the GIT. (Anderson 2021)

Other “barriers” to infant exposure include the extent to which the drug is bound by maternal plasma proteins, the degree of drug ionisation, lipid solubility and most pertinently, the molecular weight of the drug, which for CGRP drugs is 150,000 Da. (Hotham and Hotham 2015).

Once a CRGP drug enters the infant GIT there are added impediments to the drug entering its bloodstream. These include the infant gut immune barrier (GIB) (Daneman and Rescigno 2009), as well as infant acidic denaturing. (Tashima 2021). 

The implications of this low rate of infant GI tract absorption of mAbs is readily demonstrated by another mAb, natalizumab, for which there is considerable pharmacokinetic data.

Natalizumab is given at a 300mg dose and, according to the official information, will achieve an average patient plasma concentration of 110mg/L. Applying the aforementioned 0.01% GIT absorption and an estimated volume of distribution of 0.25L (Anderson 2021), the infant would be exposed to a concentration of approximately 0.04% of the mother’s serum level.

This is a trivial level when measured against the WHO Working Group of experts of drug use during breastfeeding, who consider an infant: maternal ratio of less than 10% to be safe.

Indeed, many medicines enter breast milk, but usually the amount received by the infant is less than 10% of the maternal dose.(Amir, Pirotta et al. 2011)

In summary, Rayhill (2022) has noted: “The large size of monoclonal antibodies could theoretically reduce the degree that these medications are expressed in breast milk, although this has not been adequately studied.”

PREGNANCY IMPLICATIONS:

The positive implications associated with a putative low foetal concentration are supported by a 2021 analysis of WHO pharmacovigilance date for erenumab, galcanezumab and fremanezumab when given during pregnancy and lactation. (Noseda, Bedussi et al. 2021) The researchers reported that there were “no specific maternal toxicities, patterns of major birth defects or increased reporting of spontaneous abortion…”

There are various case reports of erenumab given during pregnancy. For example, Vig, Garza et al. (2022) referenced a case of a woman who used erenumab for migraine through her pregnancy with no harm to her child.

In another report of three pregnancies with gestational exposure to erenumab, two women ceased erenumab during the first trimester with no adverse sequalae for their babies.

One woman ceased erenumab 1 month before conception and experienced a first trimester spontaneous abortion due to gestational trophoblastic neoplasia, however a subsequent pregnancy was uneventful. No plausible drug-related explanation could be offered by the authors for the spontaneous abortion. (Bonifácio, de Carvalho et al. 2022)

An updated safety analysis on erenumab, galcanezumab, fremanezumab and eptinezumab use in pregnancy by  Noseda, Bedussi et al. (2023) “ showed no signals of foeto-maternal toxicity according to VigiBase® safety reports.”

A case series and literature review by Elosua-Bayes, Alpuente et al. (2024) focused on the periconceptional period of CGRP therapies that were ceased prior to conception. They reported that “database reviews revealed 63 spontaneous abortions, eight premature births, and seven birth defects among 286 World Health Organization and 65 European Medicines Agency cases. These rates align with untreated population rates.”

They concluded that “CGRP-mAbs use in the periconceptional period does not lead to clinically significant increase in pregnancy-related pathology or adverse effects on newborns within our case series and the literature reviewed.”

A reasonable explanation for foetal safety is that mAbs likely do not cross the blood brain barrier secondary to their molecule size. (de Vries, Villalón et al. 2020).

In contrast to these positive reports, Rayhill (2022) advise that CGRP mAbs should be ceased 5-6 months pre-conception due to their long half-life and a lack of safety data.

EFFICACY:

All four CGRP therapies have been reported to possess long-term safety, making them “effective and well-tolerated for the prevention of migraines.” (Muddam, Obajeun et al. 2023)

Summarising the current research, Oliveira, Gil-Gouveia et al. (2024) reported that “Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6–61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29–88% of the patients stopped medication overuse.”

CONCLUSION:

Based upon the preceding literature review, the use of erenumab and other CGRP medications in lactation is an option that can be positively considered by a clinician when balancing the maternal benefits against potential foetal harms. However caution is necessary because longer-term studies are still required, (Burch, Rizzoli et al. 2021) notably in its cardiovascular impact, since CGRP has protective properties in cardiovascular disease. (González-Hernández, Marichal-Cancino et al. 2016).

Their use in pregnancy currently has contradicting research findings.   (Elosua-Bayes, Alpuente et al. 2024) (Moisset, Demarquay et al. 2024)