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Abstract

Objective

To assess the safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation.

Methods

Safety reports of suspected adverse drug reactions were retrieved from VigiBase as of 31 December 2019, for a case-by-case assessment and disproportionality analysis using the reporting odds ratio (ROR).

Results

There were 94 safety reports: 50 (53.2%) on erenumab, 31 (33.0%) on galcanezumab, and 13 (13.8%) on fremanezumab. In five (5.3%) safety reports, drug exposure occurred prior to pregnancy, in 85 (90.4%) during pregnancy, in one (1.1%) during lactation, in one (1.1%) via paternal exposure, and in two (2.1%) the exposure time was unknown. Out of 94 safety reports, 51 (54.3%) consisted only of drug exposure, while 43 (45.7%) additionally reported 47 adverse drug reactions including maternal toxicities (n = 18), poor breastfeeding (n = 1), spontaneous abortion (n = 23), preterm birth/prematurity (n = 3), and birth defects (n = 2). There was no signal of disproportionate reporting for spontaneous abortion compared to the full database (reporting odds ratio 1.46, 95% confidence interval 0.97–2.20). When triptans were used as a comparator group, a signal of disproportionate reporting for spontaneous abortion was detected in association with erenumab, galcanezumab, and fremanezumab (reporting odds ratio 1.86, 95% confidence interval 1.12–3.13), which was not statistically significant after excluding confounded safety reports (reporting odds ratio 1.21, 95% confidence interval 0.67–2.21).

Conclusions

No specific maternal toxicities, patterns of major birth defects, or increased reporting of spontaneous abortion were found. However, because of the relatively limited number of adverse drug reactions reported and the lack of long-term safety data, continuous surveillance is required in pregnant and lactating women exposed to these drugs.

Keywords

Calcitonin gene-related peptide migraine VigiBase adverse drug reaction

Introduction

Erenumab, galcanezumab and fremanezumab are new monoclonal antibodies targeting either calcitonin gene-related peptide (CGRP) or its receptor (CGRP-R). They were recently approved for the prevention of episodic and chronic migraine (1). These molecules are administered by subcutaneous injections monthly or quarterly owing to their long half-life (3–6 weeks), thus providing potential adherence benefits over the other oral drugs more commonly used for migraine prevention (2). However, the long half-life could result in foetal exposure in women of childbearing potential who have unintended pregnancies while using these drugs (2). Indeed, as immunoglobulin G antibodies, erenumab, galcanezumab, and fremanezumab cross the placenta through the neonatal Fc receptor that appears after the first 20–22 weeks of pregnancy and allows for placental transport (3). Additionally, according to animal studies, CGRP is involved in the regulation of utero-placental blood flow and uterine relaxation, and may regulate gestational blood pressure, preventing hypertension and eclampsia (2).

In animal studies, these antibodies were not associated with reproductive toxicity (4). However, preclinical data cannot be fully translated to humans, and the safety data from clinical trials during pregnancy and lactation are scarce and uncertain (5,6). Therefore, unless deemed clinically necessary, the use of these drugs is not recommended during pregnancy according to the drug label (4).

Against this background, drug safety evaluations in the post-marketing setting represent an important source of information. We used VigiBase, the World Health Organization (WHO) pharmacovigilance database of safety reports of suspected adverse drug reactions (ADRs), to characterise the safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation in terms of temporal plausibility of drug-event pairs, presence of comorbidities increasing the risk for complications in pregnancy and lactation, and the use of concurrent drugs with potential foetal/maternal toxicity. We subsequently performed a disproportionality analysis (7) to investigate whether there was a disproportion of safety reports on specific pregnancy-related ADRs in association with erenumab, galcanezumab or fremanezumab, compared to VigiBase safety reports associated with all other drugs.

Methods

Data retrieval

For this pharmacovigilance study, we used VigiBase (http://www.vigiaccess.org/), the global database of safety reports of suspected ADRs developed and maintained by the WHO – Uppsala Monitoring Centre (WHO-UMC). Aims and structure of VigiBase are summarised in the Supplementary Methods. We retrieved de-duplicated safety reports collected in VigiBase from its inception through 31 December 2019. Within this timeframe, we selected safety reports reporting ADRs classified in the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) “Pregnancy and neonatal topics” (MedDRA version 22.1), associated with erenumab, galcanezumab and fremanezumab (anatomical, therapeutic and chemical (ACT), ATC codes N02CD01, N02CD02, and N02CD03, respectively). The SMQ “Pregnancy and neonatal topics” contains the subordinate SMQs “Congenital, familial and genetic disorders”, “Foetal disorders”, “Lactation related topics (including neonatal exposure through breast-milk)”, “Neonatal disorders”, “Normal pregnancy conditions and outcomes”, “Pregnancy labour and delivery complications and risk factors (excluding abortions and stillbirth)”, and “Termination of pregnancy and risk of abortion”. From this group of safety reports, we extracted the final dataset comprised of safety reports for which we could ascertain a plausible temporal correlation between exposure to erenumab, galcanezumab or fremanezumab and a pregnancy- or lactation-related adverse event. To achieve this aim, we considered safety reports enlisting any of the following ADRs (MedDRA preferred terms, PTs): “Drug exposure during pregnancy”, “Drug exposure in pregnancy”, “Exposure during pregnancy”, “Foetal exposure during pregnancy”, “Maternal exposure during pregnancy”, “Maternal exposure during pregnancy, first trimester”, “Foetal exposure during pregnancy, first trimester”, “Drug exposure via mother”, “Exposure via breast milk”, “Maternal exposure before pregnancy”, “Maternal drugs affecting foetus”, “Pregnancy”, “Pregnancy on contraceptive”, “Pregnancy test positive”, and “Paternal exposure during pregnancy”. Concerning “Maternal exposure before pregnancy”, based on FDA approval dates (May 2018 for erenumab, September 2018 for fremanezumab, and June 2019 for galcanezumab), and the date of data retrieval from VigiBase (31 December 2019), we defined a temporal plausible correlation when drug exposure occurred at the latest 1 year before spontaneous reporting. Moreover, we manually reviewed safety reports lacking any of the aforementioned ADRs and included in the final dataset two additional safety reports associated with erenumab and reporting premature birth and spontaneous abortion, respectively. Supplementary Table 1 shows safety reports excluded because of the impossibility of ascertaining drug exposure prior to or during pregnancy, involving patients of implausible or unknown sex and/or age, and/or reporting general ADRs not exclusively related to pregnancy. According to the exclusion criteria, four safety reports of reversible cerebral vasoconstriction syndrome were excluded because they either involved women of advanced age (n = 2) or patients of unknown sex (beyond unknown age, n = 2).

To perform the disproportionality analysis, we retrieved from VigiBase safety reports for all other drugs (excluding erenumab, galcanezumab, and fremanezumab), collected between database inception and 31 December 2019, and involving females aged between 14 and 46 years (as the latter was the oldest age recorded among the 94 safety reports included in the study). We applied the same inclusion criteria to the dataset of safety reports associated with erenumab, galcanezumab or fremanezumab reporting ADRs other than the specific one related to pregnancy (i.e. spontaneous abortion) investigated in the disproportionality analysis.

Case-by-case assessment

For the whole dataset of safety reports, we described the baseline characteristics, which included patient sex, patient age at ADR onset, suspected drug amongst erenumab, galcanezumab and fremanezumab, drug indication, country of origin of the safety report, reporting year, and type of reporter. Subsequently, we performed a case-by-case assessment of the reported ADRs and the co-reported drugs. For the co-reported drugs, we assessed their potential role in ADR onset and evaluated whether underlying diseases for which these were prescribed were per se risk factors for complications in pregnancy and lactation by screening the scientific literature (MEDLINE). To this aim, for each safety report, all drugs mentioned (as active ingredients) and underlying diseases (for which the drugs were administered) were searched in combination with specific pregnancy-related ADR(s) by using query boxes in PubMed. Case-by-case assessment was done independently in triplicate and disagreements were handled on a majority basis.

Disproportionality analysis

VigiBase allows for disproportionality analysis (or case-non-case analysis), which we used to assess whether suspected ADRs in pregnancy (at the level of MedDRA PTs) were differentially reported with erenumab, galcanezumab, or fremanezumab as compared with the full database.

Disproportionality analysis compares the proportion of specific ADRs reported for a single drug or a group of drugs (e.g. erenumab, galcanezumab, or fremanezumab), with the proportion of the same ADRs for a control group of drugs (e.g. the full database). The denominator in these analyses is the total number of ADRs reported for each group of drugs. If the proportion of a specific ADR is greater in patients exposed to a certain drug (cases) than in patients not exposed to this drug (non-cases), then an association can be hypothesized between the specific drug and the ADR of interest, and this is deemed a potential safety signal. We calculated disproportionality by Reporting Odds Ratio (ROR), considering as threshold for signal detection a number of safety reports ≥ 5 and a ROR lower limit of the 95% confidence interval (CI) > 1, to reduce the likelihood of false positives (7). After using the full database as the comparator group, we performed sensitivity analysis selecting only data from 2018 onwards, thus considering the effective period on the market of erenumab, galcanezumab and fremanezumab. Moreover, to mitigate confounding by indication, we performed disproportionality analysis by therapeutic area (without temporal restrictions), and selected safety reports where triptans (ATC class N02CC) were recorded as suspected drugs, as a proxy of migraine. All disproportionality analyses were planned a priori.

Characteristics of the safety reports were described as medians and interquartile ranges for quantitative variables and as counts and percentages for qualitative ones. Missing data were omitted from the description of the corresponding variables. Data management and analysis were performed using RStudio (version 1.2.5019, ©2009–2019 RStudio, Inc, Boston, MA).

Ethical approval by the local Ethical Committee was not required and sought for this study, according to the Human Research Act 810.30 (status as of 1 January 2020), from the Federal Assembly of the Swiss Confederation (Art. 2: “It does not apply to research which involves anonymously collected or anonymised health-related data”).

Results

From a total of 21,149,392 safety reports gathered in VigiBase as of 31 December 2019, we selected 94 safety reports associated with erenumab (n = 50, 53.2%), galcanezumab (n = 31, 33.0%), or fremanezumab (n = 13, 13.8%), concerning pregnancy and lactation (Figure 1). The characteristics of safety reports included in the study are shown in Table 1.

Figure 1.

Consort diagram showing the selection process of safety reports included in the study. Abbreviations: ADR: adverse drug reaction; SMQ: Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query.

Table 1.

Characteristics of safety reports included in the study.

Characteristic	n (%), N = 94
Patient sex
Female	92 (97.9)
Male*	2 (2.1)
Patient age at ADR onset
Reported (all females)	33 (35.1)
Median [IQR], years	28 [24–36]
Not reported	61 (64.9)
Suspected drug
Erenumab	50 (53.2)
Galcanezumab	31 (33.0)
Fremanezumab	13 (13.8)
Drug indication
Migraine	25 (26.6)
Migraine prophylaxis	7 (7.4)
Migraine without aura	2 (2.1)
Migraine with aura	1 (1.1)
Chronic migraine	1 (1.1)
Not reported	58 (61.7)
Country of origin
US	74 (78.7)
Germany	4 (4.3)
Switzerland	4 (4.3)
Australia	3 (3.2)
UK	3 (3.2)
Sweden	2 (2.1)
Czechia	1 (1.1)
Italy	1 (1.1)
Poland	1 (1.1)
Portugal	1 (1.1)
Reporting year
2019 (as of 31 December 2019)	94 (100.0)
Type of reporter
Physician	35 (37.2)
Pharmacist	3 (3.2)
Other health professional	11 (11.7)
Patient/consumer	45 (47.9)

*One child-mother safety report on fremanezumab (describing the child), and one safety report concerning paternal exposure to galcanezumab during pregnancy of the female partner.

ADR: adverse drug reaction; IQR: interquartile range.

In five (5.3%) safety reports, drug exposure (to either erenumab, galcanezumab or fremanezumab) occurred prior to pregnancy, in 85 (90.4%) during pregnancy, in one (1.1%) during lactation, in one (1.1%) via paternal exposure, and in two (2.1%) the exposure time was unknown (Table 2). Given that safety reports can report solely drug exposure or mention one or multiple ADRs, out of 94 safety reports we observed that 51 (54.3%) reported only drug exposure and 43 (45.7%) reported a total of 47 ADRs affecting either the mother and/or the foetus (Table 3).

Table 2.

Assessment of drug exposure in the safety reports included in the study.

	Safety reports on erenumab, n = 50 (53.2%)		Safety reports on galcanezumab, n = 31 (33.0%)		Safety reports on fremanezumab, n = 13 (13.8%)
Drug exposure,N = 94	Safety reports reporting only drug exposure	Safety reports reporting additional ADRs	Safety reports reporting only drug exposure	Safety reports reporting additional ADRs	Safety reports reporting only drug exposure	Safety reports reporting additional ADRs
Prior to pregnancy	–	1 (1.1)	1 (1.1)	–	2 (2.1)	1 (1.1)
During pregnancy	14 (14.9)	32 (34.0)	26 (27.7)	3 (3.2)	7 (7.4)	3 (3.2)
Paternal exposure	–	–	1 (1.1)	–	–	–
During lactation	–	1 (1.1)	–	–	–	–
Unknown*	–	2 (2.1)	–	–	–	–

Note: Data are presented as n (%) out of the total number of safety reports included in the study.

*Safety reports of premature birth and spontaneous abortion, respectively.

ADRs: adverse drug reactions.

Table 3.

Adverse drug reactions in pregnancy and lactation reported for erenumab, galcanezumab and fremanezumab as of 31 December 2019.

	Safety reports on erenumab, n = 36^a^,b		Safety reports on galcanezumab, n = 3^a		Safety reports on fremanezumab, n = 4^a
	Without confounders	With confounders	Without confounders	With confounders	Without confounders	With confounders
Spontaneous abortion	13	6	1	–	1	2
Birth defects	1	–	–	–	–	1
Preterm delivery/prematurity	2	1	–	–	–	–
Maternal ADRs	13	–	1	1	–	–
Lactation ADRs	1	–	–	–	–	–

^a Safety reports reporting only drug exposure prior to or during pregnancy, or during lactation, were excluded from this analysis.

^b With erenumab, some safety reports reported more than one adverse drug reaction.

ADRs: adverse drug reactions.

Maternal adverse drug reactions

There were 15 safety reports (16.0%) reporting 18 maternal ADRs, including 10 safety reports of ineffective anti-migraine treatment with erenumab, galcanezumab or fremanezumab, recorded as headache (n = 1), migraine (n = 5), incomplete therapeutic product effect (n = 2), ineffective drug (n = 1), and therapy non-responder (n = 1). Three safety reports reported nausea/vomiting, one hypothyroidism, one depression, one vaginal haemorrhage, one missed abortion and gestational trophoblastic detachment, and one dizziness. Confounders were present only in the last safety report with concurrent use of bupropion (Supplementary Table 2) (8).

Foetal adverse drug reactions

Out of 94 safety reports, two (2.1%) reported birth defects. There was one safety report of anencephaly with erenumab (in a woman of unknown age), and one safety report of renal aplasia and gastroesophageal reflux disease with fremanezumab. The latter involved a woman of unknown age also using contraceptives (at first ethinylestradiol, iron, norethisterone; then, ethinylestradiol, levonorgestrel), salbutamol, and the anti-migraine preparation acetylsalicylic acid/caffeine/paracetamol (9 –11).

Three (3.2%) safety reports reported preterm birth and prematurity in association with erenumab, of which one involved a 37-year-old woman who suffered from placental insufficiency and pre-eclampsia before delivery.

Spontaneous abortion occurred in 23 safety reports (24.5%), of which 15 (16.0%) were without confounders.

In three safety reports, maternal age over 35 years was the only confounder (12).

Two safety reports with maternal age over 35 years and additional confounders for spontaneous abortion were reported: a 41-year-old woman using dienogest-estradiol and ibuprofen (co-reported drugs as confounders) (12 –14), and a 36-year-old woman using vortioxetine, lisdexamfetamine, and valacyclovir (co-reported drugs and underlying diseases for which these were prescribed as confounders) (12,15 –18).

Three other safety reports of spontaneous abortion confounded by the use of other drugs occurred in younger women, two on erenumab and one on fremanezumab. The first reported the use of promethazine (as a confounder) (19); the second reported the use of sumatriptan, topiramate, ondansetron, metoclopramide, levothyroxine, norethisterone, cyclobenzaprine, diphenhydramine, and venlafaxine (co-reported drugs and underlying diseases for which these were prescribed as confounders) (5,13,20 –22); and the third reported the use of paracetamol, ondansetron, duloxetine and olanzapine (co-reported drugs and underlying diseases for which these were prescribed as confounders) (5,22 –24).

Supplementary Table 2 provides details on the abovementioned confounders.

Disproportionality analysis

In the disproportionality analysis for spontaneous abortion (as MedDRA PT), when considering females of fertile age within the full database as the comparator group, we did not find disproportionality for spontaneous abortion with erenumab, galcanezumab, or fremanezumab (ROR 1.46, 95% CI 0.97–2.20). Similar results were found when excluding safety reports with confounders (ROR 0.95, 95% CI 0.57–1.58). By restricting the analysis to safety reports reported since 2018 (when the first-in-class erenumab received FDA approval), we found a greater proportion of spontaneous abortion reporting on erenumab, galcanezumab, or fremanezumab, compared to all other drugs in VigiBase (ROR 1.88, 95% CI 1.24–2.83). When considering those safety reports without confounders, the disproportionality was not significant (ROR 1.22, 95% CI 0.73–2.03). Lastly, by using safety reports with triptans (without temporal restrictions) as the comparator group, we found a greater proportion of spontaneous abortion reporting on erenumab, galcanezumab, or fremanezumab (all safety reports, ROR 1.86, 95% CI 1.12–3.13), which was not statistically significant after excluding confounded safety reports (ROR 1.21, 95% CI 0.67–2.21). Table 4 provides the frequencies used to calculate RORs and 95% CI.

Table 4.

Contingency tables used to calculate reporting odds ratios and 95% confidence intervals.

	All safety reports		Safety reports without confounders
	Safety reports of spontaneous abortion	Safety reports with any other ADR	Safety reports of spontaneous abortion	Safety reports with any other ADR
Comparator: full database
Safety reports associated with erenumab, galcanezumab, and fremanezumab	23	4004	15	4012
Safety reports associated with any other drug	11,919	3,023,996	11,919	3,023,996
• Comparator: full database• Temporal restriction: starting 2018*
Safety reports associated with erenumab, galcanezumab, and fremanezumab	23	4004	15	4’012
Safety reports associated with any other drug	1887	616,391	1887	616,391
Comparator: triptans
Safety reports associated with erenumab, galcanezumab, and fremanezumab	23	4004	15	4012
Safety reports associated with any other drug	38	12,322	38	12,322

*Reporting of adverse drug reactions associated with erenumab, galcanezumab and fremanezumab started in 2018.

ADR: adverse drug reaction.

Discussion

We analysed 94 safety reports of ADRs affecting pregnancy and lactation spontaneously reported to VigiBase involving erenumab, galcanezumab and fremanezumab up to 31 December 2019. We observed that, over 1.5 years since the first-in-class erenumab was authorised by the FDA, no specific maternal toxicities, patterns of major birth defects, or spontaneous abortion have emerged as hallmarks of toxicity with erenumab, galcanezumab and fremanezumab.

Because of ethical restrictions on the inclusion of pregnant women in randomised clinical trials, the majority of information on drug safety in pregnancy and lactation either derives from observational studies in the post-marketing setting or relies on experts’ opinions (25). Expert-based guidelines from the European Headache Federation suggest avoiding the use of monoclonal antibodies acting on the CGRP system for migraine prevention in pregnant or nursing women (26).

In our study, we identified safety reports of maternal ADRs in association with the use of erenumab, galcanezumab and fremanezumab prior to or during pregnancy. Preclinical models and notions relating to the state of pregnancy per se provide reasons for expecting harmful effects when administering erenumab, galcanezumab or fremanezumab during pregnancy. In rats, circulating CGRP levels rise during pregnancy up to the time of delivery, increasing the responsiveness of various vascular beds and likely playing a role in regulating utero-placental blood flow and myometrium and utero relaxation (27). In humans, as in the animal models, systemic CGRP levels increase during pregnancy, peaking during the last trimester and dropping again after delivery, suggesting that CGRP might contribute to the vascular adaptations occurring during pregnancy (28). Moreover, as levels of CGRP are lower in women with pre-eclampsia than in women with normotensive pregnancies, CGRP may also play a role in maintaining normal gestational blood pressure (28 –30). Therefore, blocking the CGRP system during pregnancy may increase the potential for gestational hypertension, pre-eclampsia and eclampsia (2). Migraine per se has also been associated with an increased risk of hypertensive disorders (31). Nevertheless, in the present study, there was only one case of pre-eclampsia reported in association with erenumab, which resulted in a subsequent premature delivery. The other maternal ADRs were more frequently represented by a lack of efficacy of the drug to treat migraine, along with a few others ADRs (e.g. nausea and vomiting, hypothyroidism, and depression), likely related to the status of pregnancy (15). A single case of poor feeding was reported concerning safety reports on lactation.

Second, we assessed erenumab, galcanezumab, and fremanezumab safety reports of foetal ADRs. As immunoglobulin G antibodies, these monoclonal antibodies cross the placenta through the neonatal Fc receptor that appears after the first 20–22 weeks of pregnancy and allows for placental transport (3). Foetal exposure to erenumab, galcanezumab or fremanezumab may therefore occur; however, no data are available on the effect of CGRP blockade in a developing foetus.

In our analysis, birth defects included one case of anencephaly with erenumab and one case of renal aplasia and gastroesophageal reflux disease with fremanezumab. Indeed, in a population-based study, among chronic maternal diseases, migraine appeared to be associated with neural tube defects (particularly anencephaly), although that study had a major limitation of recall bias (32). In the case of renal aplasia and gastroesophageal reflux disease, oral contraceptives, salbutamol and the antimigraine preparation acetylsalicylic acid/caffeine/paracetamol recorded as concomitant drugs have not been associated with an increased risk of major birth defects so far (9 –11). Unfortunately, VigiBase lacks detailed information on the timing of drug exposure during pregnancy, making it impossible to ascertain if the exposure occurred in the first, second or third gestational trimester.

Spontaneous abortion was the most frequently reported foetal ADR and, in the majority of cases, without concomitant drugs or underlying diseases acting as confounders for the causal drug-ADR relationship.

When present, concomitant drugs were either other migraine prophylactic agents (e.g. antiepileptic medications, antidepressants, reuptake inhibitors of noradrenaline and serotonin) (6), or medications for the treatment of acute migraine attacks including paracetamol, NSAIDs, triptans, and antiemetics (21). Concerning triptans, the relatively numerous data, mainly on sumatriptan, have so far not suggested an increased risk of malformations or other adverse foetal effects (20). A meta-analysis of six studies found no increased risk of miscarriage in triptan-exposed compared to triptan-unexposed migraine patients, but an increased risk of miscarriage was found when the triptan-exposed migraine patients were compared with healthy controls without migraine (33). Maternal migraine has been associated with an increased risk of miscarriage (31). A population-based study on pregnant women with migraine showed that the risk of miscarriage in those receiving a migraine preventive drug was as high as that observed in untreated women (31).

In addition to concomitant drugs and migraine, certain comorbid conditions might have increased the risk of spontaneous abortion as well. Depression, for example, was present in three cases and is a common disorder during pregnancy that has been associated with an increased risk of miscarriage (34); however, the use of antidepressants by pregnant women has also been shown to increase the risk of spontaneous abortion (15).

Through a pharmacovigilance approach, we found that reporting of spontaneous abortion in association with erenumab, galcanezumab and fremanezumab was not disproportionally different from that in the full database. By either performing the analysis in a restricted time period (starting from the year of the first-in-class erenumab marketing authorisation), or choosing triptans as the comparator group to reduce confounding by indication, a signal of disproportionality for spontaneous abortion emerged in association with erenumab, galcanezumab and fremanezumab, which was not confirmed when only safety reports without confounders were selected. This could have been due to the small sample size of the present case series (compared to the larger amount of safety reports of comparative groups). On the other hand, the loss of signal that we observed in the absence of confounders might suggest that the aggravating condition promoting the onset of spontaneous abortion could be represented by the whole burden of migraine, comorbidities and medications characterising affected patients rather than monoclonal antibodies acting on the CGRP system per se.

Moreover, most of the safety reports included in this study were from the US because of the initial approval by the FDA, first of erenumab (explaining the higher number of associated safety reports), then of fremanezumab and galcanezumab. Because in disproportionality analysis lack of disproportionality should not to be interpreted as the drug of interest being potentially free of any specific adverse event, a signal of disproportionate reporting for spontaneous abortion in association with erenumab, galcanezumab, and fremanezumab might be detected on a larger sample. Spontaneous reporting will increase with the subsequent approval of these drugs worldwide. This is extremely relevant since signal detection depends on the number of safety reports and the present disproportionality analysis should be accordingly reassessed at regular intervals for confirmation or rejection. Importantly, we did not observe any cluster of ADRs affecting pregnancy and lactation related to erenumab, galcanezumab and fremanezumab use.

Limitations

This study suffers from some general limitations inherent to using VigiBase as a data source. Safety reports describe suspected ADRs for which, most of the time, a causal relationship with a specific drug cannot be proven given the presence of comorbidities and concomitant drugs. Since information comes from a variety of sources, the probability that the suspected adverse effect is drug related is not the same in all cases. No information is provided on the overall number of patients exposed to a certain drug, thus the incidence of a certain adverse event cannot be extrapolated. Even more so, post-marketing data may be influenced by biases such as selective reporting and underreporting, and, because data collection only involves spontaneous reporting, might be partial and incomplete. The ROR computation does not inform about the real risk of ADR but only shows an increased risk of ADR reporting. Spontaneous reporting could be characterised by high variability of event reporting resulting in notoriety bias (i.e. stimulated reporting in the case of media attention for a given drug/adverse event pair), and dilution bias (which occurs when new drugs, receiving media attention for a certain adverse event, hide older drugs from the same class in the generation of signals of disproportionate reporting) (7).

Further specific limitations concern the limited number of safety reports analysed and the fact that, although we considered erenumab, galcanezumab and fremanezumab as a whole, these drugs have different mechanisms targeting either the CGRP ligand or its receptor, and therefore might not share an identical safety profile. Notwithstanding these limitations, drug safety assessment based on the largest worldwide database of spontaneous ADR reporting can be used to detect and monitor ADRs of clinical relevance.

Conclusions

Through a qualitative and quantitative analysis of safety reports gathered in VigiBase concerning ADRs in pregnancy and lactation associated with erenumab, galcanezumab and fremanezumab, we did not identify specific maternal toxicities, patterns of major birth defects, or increased reporting of spontaneous abortion. However, because of the relatively limited number of ADRs reported, the lack of long-term safety data and the lack of reversal strategies for these antibodies and their clinical effects, continuous surveillance is required in pregnant and lactating women exposed to these drugs. More representative database analyses and pharmacoepidemiological studies are warranted prior to determining erenumab, galcanezumab, and fremanezumab safety in pregnancy.

Clinical implications

From VigiBase, no specific maternal toxicities, patterns of major birth defects, or increased reporting of spontaneous abortion, emerged as hallmarks of the safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation.

Because of the relatively limited number of ADRs reported to date in pregnant and lactating women, continuous surveillance of the safety profile of erenumab, galcanezumab and fremanezumab in real-world clinical practice in this susceptible population is necessary.

More representative database analyses and pharmacoepidemiological studies are warranted prior to determining erenumab, galcanezumab, and fremanezumab safety in pregnancy.

Supplemental Material

sj-pdf-1-cep-10.1177_0333102420983292 - Supplemental material for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Supplemental material, sj-pdf-1-cep-10.1177_0333102420983292 for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database by Roberta Noseda, Francesca Bedussi, Claudio Gobbi, Chiara Zecca and Alessandro Ceschi in Cephalalgia

Supplemental Material

sj-pdf-2-cep-10.1177_0333102420983292 - Supplemental material for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Supplemental material, sj-pdf-2-cep-10.1177_0333102420983292 for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database by Roberta Noseda, Francesca Bedussi, Claudio Gobbi, Chiara Zecca and Alessandro Ceschi in Cephalalgia

Supplemental Material

sj-pdf-3-cep-10.1177_0333102420983292 - Supplemental material for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Supplemental material, sj-pdf-3-cep-10.1177_0333102420983292 for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database by Roberta Noseda, Francesca Bedussi, Claudio Gobbi, Chiara Zecca and Alessandro Ceschi in Cephalalgia

Footnotes

Acknowledgements

The study results and conclusions are those of the authors and not necessarily those of the Uppsala Monitoring Centre (UMC), or World Health Organization (WHO). Information does not represent the opinion of the UMC or the WHO.

Author contributions

All authors contributed to the conception of the work. RN designed the study and analysed the data. All authors were involved in the interpretation of the data. RN drafted the manuscript, and FB, CZ, CG and AC revised it critically for intellectual content.

The dataset analysed during the current study is available from the corresponding author on reasonable request.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Roberta Noseda

Alessandro Ceschi

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Supplementary Material

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Safety profile of erenumab,galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Abstract

Objective

Methods

Results

Conclusions

Keywords

Introduction

Methods

Data retrieval

Case-by-case assessment

Disproportionality analysis

Results

Maternal adverse drug reactions

Foetal adverse drug reactions

Disproportionality analysis

Discussion

Limitations

Conclusions

Clinical implications

Supplemental Material

sj-pdf-1-cep-10.1177_0333102420983292 - Supplemental material for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Supplemental Material

sj-pdf-2-cep-10.1177_0333102420983292 - Supplemental material for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Supplemental Material

sj-pdf-3-cep-10.1177_0333102420983292 - Supplemental material for Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

ORCID iDs

References

Supplementary Material