(2024) 22:329
Qu et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03537-2

BMC Medicine

RESEARCH ARTICLE

Open Access

Differences in hypersensitivity reactions
and gadolinium deposition disease/symptoms
associated with gadolinium exposure
to gadolinium-based contrast agents: new
insights based on global databases VigiBase,FAERS, and IQVIA-MIDAS
Han Qu1,2,3, Wenjing Li3, Zhenghua Wu2,3, Yuanyuan Wang2, Tingting Feng2, Nianyun Li4, Chendong Qi2,
Xiang Li3, Taishan Wei3, Guorong Fan2,3* and Yuefen Lou1*

Abstract
Background Hypersensitivity reactions (HSRs) can occur unexpectedly and be life-threatening when gadoliniumbased contrast agents (GBCAs) are used. Gadolinium deposition disease (GDD) and symptoms associated with gadolinium exposure (SAGE) have been controversial for a long time. However, similar studies are currently incomplete
or outdated. Therefore, comparing the safety of different GBCAs in terms of HSRs and GDD/SAGE using the latest
post-marketing safety data should yield further insights into safely using GBCAs.
Methods The safety differences between all GBCAs to GDD and the spectrum of GBCA-related HSRs were all compared and analyzed by using the World Health Organization database VigiBase and the FDA Adverse Event Reporting
System (FAERS) database in this study. A further analysis of SAGE was also conducted using FAERS data. The lower
limit of the reporting odds ratio (ROR) 95% confidence interval was used for signal detection. Moreover, the frequency
of HSRs was calculated by dividing the number of reports in VigiBase by the total sales volume (measured in millions)from 2008 to 2022 in the IQVIA Multinational Integrated Data Analysis System. All adverse events were standardizedusing the Medical Dictionary for Drug Regulatory Activities (MedDRA) 26.0.
Results This study shows that all GBCAs have the potential to induce HSRs, with nonionic linear GBCAs exhibiting a comparatively lower signal. According to standardized MedDRA query stratification analysis, gadobutrol had
a greater ­ROR025 for angioedema. The ­ROR025 of gadobenate dimeglumine and gadoteridol is larger for anaphylactic/
anaphylactoid shock conditions. Regarding severe cutaneous adverse reactions, only gadoversetamide and gadodiamide showed signals in FAERS and VigiBase. There were also differences in the frequency of HSRs between regions.
Regarding GDD, gadoterate meglumine, and gadoteridol had a lower ­ROR025. An analysis of the 29 preferred*Correspondence:
Guorong Fan
guorfan@163.com
Yuefen Lou
louyuefen@sina.cn
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Qu et al. BMC Medicine(2024) 22:329

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terms linked to SAGE indicated that special consideration should be given to the risk of skin induration associatedwith gadoversetamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadodiamide, and gadoteridol. Additionally, gadodiamide and gadoteridol pose a greater risk of skin tightness compared to other GBCAs.
Conclusions The risk differences among GBCAs using data from several sources were compared in this study. However, as a hypothesis-generating method, a clear causal relationship would require further research and validation.
Keywords Gadolinium-based contrast agents, VigiBase, FAERS, IQVIA-MIDAS, Hypersensitivity reactions, Gadolinium
deposition disease, Symptoms associated with gadolinium exposure

Background
Gadolinium-based contrast agents (GBCAs) are chelatesof gadolinium (Gd), a paramagnetic metal that induces
a magnetic field to enhance tissue contrast to characterize lesions and assess perfusion and flow-related abnormalities [1, 2]. From 1988, when the first GBCA wasintroduced to the market, to date, there are nine GBCAs
widely used in clinical practice. GBCAs can be classified
into linear and macrocyclic chelates according to theirchemical structure and ionic and nonionic according to
the Gd ionic state [3].
As the use of GBCAs increases, understanding more
specific symptomatic differences in the occurrence of
HSRs across GBCAs can provide guidance for clinicaluse. According to an 8-year cohort study [4], the incidence of HSR was 0.4%, which is lower than iodinatedcontrast media, but concerns remain. However, it ismainly clinical studies [5–7] and case reports [8–10]
that focus on HSRs to GBCAs. There are fewer studies
of more specific responses to HSRs due to some limitations; only one pharmacovigilance study analyzed dataon anaphylaxis from 1988 to 2012 [11]. In addition, it
has been shown that in patients who have been treatedwith GBCAs, Gd may be retained sites, mainly in thebones and skin, with only a small amount present in thebrain [12, 13]. The term “gadolinium deposition disease”(GDD) was first proposed by Semelka and colleagues in2016 to describe symptoms reported by patients withnormal renal function after exposure to GBCAs [14].
Although there is still much controversy regarding GDD,
the Uppsala Monitoring Centre (UMC) and the FDA
have been using GDD as a preferred term (PT) for thecollection of reports since the term GDD emerged. However, members of the American College of Radiology’s
Committee on Drugs and Contrast Agents in 2022 proposed a new term to describe symptoms reported after
intravascular exposure to GBCAs—symptoms associated with gadolinium exposure (SAGE) [15]. This term
was used in place of other nomenclatures that assumed
causation but had not been scientifically proven, whereas
according to the current study, SAGE is a combinationthat contains multiple PTs. Therefore, combining GDDand SAGE data may provide a more complete picture of

the symptoms involved. Currently, similar studies are notcomprehensive enough or out of date [16–18], so analyzing GBCA-associated adverse events (AEs) using the latest post-marketing data may provide the most up-to-date
data to inform the safe clinical use of GBCAs.
This study aimed to compare the risk of HSRs, andGDD/SAGE of all GBCAs using disproportionality analysis, namely gadopentetate dimeglumine, gadobenate
dimeglumine, gadoxetate disodium, gadoterate meglumine, gadodiamide, gadoversetamide, gadoteridol, andgadobutrol (gadofosveset was excluded because of too
little data) in clinical practice by using two of the world’s
largest databases of AEs, the World Health Organization
database VigiBase or the FDA Adverse Event Reporting
System (FAERS). However, it is important to emphasize that disproportionality analysis is a hypothesisgenerating activity and represents potential statisticalassociations alone without causality [19]; explicit causality requires further research and verification. We additionally approximated the frequency of HSRs from 2008
to 2022 based on the VigiBase and the IQVIA Multinational Integrated Data Analysis System (IQVIA-MIDAS)
to compensate for the two safety databases’ incapacity to
do so without having the whole number of uses.

Methods
Data sources

This study extracted data from VigiBase (from inception
to July 3, 2023) and FAERS (from inception to March 31,2023) for GBCAs. VigiBase is the unique WHO global
database of reported potential side effects of medicinal products, developed and maintained by UMC. With
more than 30 million reports of suspected AEs of medications filed by the WHO Programme for International
Drug Monitoring member nations since 1968, it is thelargest database of its kind in the world. The FAERS isa database that contains AE reports, medication error
reports and product quality complaints resulting in AEs
that were submitted to the FDA. The FDA’s post-marketing safety surveillance program for drugs and therapeutic biologic products is intended to be supported by
the database. We mined and cleaned pharmacovigilancedata from FAERS using the open tool OpenVigil 2.1 [20].

Qu et al. BMC Medicine(2024) 22:329

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In addition, we extracted the total sales volume of each
GBCA from the IQVIA-MIDAS [21] from 2008 to 2022,with sales volume in standardized units. IQVIA-MIDAS
is internally validated through other sales data sources
and shows a high level of data accuracy [22].
Study design

This study included all HSR-related AEs categorized bygroup queries according to the Medical Dictionary for
Drug Regulatory Activities (MedDRA) 26.0. The narrow
version of the standardized MedDRA query (SMQ) wasused to define HSRs because it provides better predictability while retaining comparable sensitivity to the broad
version [23]. Based on allergic symptoms, we defined
HSRs in the following three SMQ levels: angioedema,
severe cutaneous adverse reactions (SCARs), and anaphylactic/anaphylactoid shock conditions (ASCs). PTs
in hypersensitivity or anaphylactic reactions but notincluded in the three SMQ levels were regarded as
anaphylactic reactions, others. In addition, GDD was
retrieved at the PT level in the FAERS and VigiBase.
Based on a study [24], we categorized the symptoms
included in SAGE into 29 PTs under 6 system organclasses and further analyzed SAGE using the FAERS
database.
Four patterns of drugs were identified: primary suspect drug, secondary suspect drug, interacting drug, andconcomitant drug. According to the procedure used by
the UMC, concomitant-related records were eliminatedto improve signal strength [25]. Since GDD and SAGE
are rare and still controversial, we only estimate the frequency of HSRs of GBCAs from 2008 to 2022 based on
VigiBase and IQVIA-MIDAS. The United Nations listof geographical divisions was used for the division ofregions or countries. Active ingredient names were used
when searching in the VigiBase, FAERS, and IQVIAMIDAS databases.
Statistical analysis

Reporting odds ratio (ROR) was employed to showwhether risk signals were present. The signal of disproportionate reporting was defined as ­ROR025 greater than
one and at least three cases. We used Microsoft Office
Excel 2016 (Los Angeles, CA, USA) to calculate demographic information and disproportionality analysis
results. Calculations of ROR and 95%CI were based on
2 × 2 contingency tables. The formulas are:Drug category

Event of Allinterest othereventsTarget drugsab

All other drugs in the databasecd

ROR = ad/bc; 95%CI = eln(ROR)±1.96

1 1 1 1
a+b+c+d

The frequency of HSRs was obtained by dividing
the number of reports in VigiBase by the total sales
volume (measured in millions) over 2008–2022 in
IQVIA-MIDAS.

Results
Descriptive analysis of HSRs in VigiBase

In VigiBase, regarding HSRs, the number of cases ofdifferent GBCAs in descending order was gadobutrol(n = 9454), gadoterate meglumine (n = 6489), gadopentetate dimeglumine (n = 5160), gadobenate dimeglumine (n = 3653), gadoteridol (n = 2997), gadoxetate
disodium (n = 1250), gadodiamide (n = 1064), and gadoversetamide (n = 323). Except for gadoxetate disodium,
all GBCAs were reported more by females than males.
The reports were mainly concentrated among patients
aged 18–64 years. The primary reporting regions for thedifferent GBCAs varied, with gadopentetate dimeglumine, gadobenate dimeglumine, gadodiamide, and gadoversetamide reported predominantly from the Americas;
gadoxetate disodium and gadobutrol reported mainly
from Asia; and gadoterate meglumine and gadoteridol
reported primarily from Europe. The annual reporting
rates for individual GBCAs were unstable from 2008 to
2022. The lowest reported rate of serious events (including death, life-threatening, disability, and hospitalization)
was gadoxetate disodium (4.0%), while the highest was
gadobenate dimeglumine (22.91%) (Table 1).
Disproportionality analysis results of suspected AEs
in FAERS and VigiBase

As shown in Tables 2 and 3, all GBCAs showed significant
signals of HSRs in both FAERS and VigiBase. For nonionic GBCAs, the results of both databases indicated thatthe two linear GBCAs had the lowest probability of HSRs
among all GBCAs, with gadodiamide (­ROR025 = 2.24
and 1.44 (in VigiBase and FAERS, respectively)) having alower ­ROR025 than gadoversetamide (­ROR025 = 3.56 and1.76). For ionic GBCAs, the FAERS results showed that
all linear GBCAs had lower R­ OR025 than the macrocyclic
type, whereas the VigiBase results showed that only theother two linear GBCAs, except for gadobenate dimeglumine, had lower ­ROR025 than the macrocyclic GBCAs.
Figure 1a and 1b display the results of disproportionality analysis for three SMQ levels in VigiBase andFAERS. For ASCs, in both databases, it was shown thatthe ­ROR025 was greater for gadobenate dimeglumine­(ROR025 = 10.45 and 18.35 (in VigiBase and FAERS,
respectively)) and gadoteridol ­(ROR025 = 6.92 and 20.17),
with no significant signal for gadoversetamide. For
SCARs, both databases indicated that gadoversetamideQu et al. BMC Medicine(2024) 22:329

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Table 1 Characteristics of reports with suspected HSRs sourced from VigiBase
Gadopentetate
dimeglumine
Total
GenderAge

UN Continent

Yearsof reporting

OutcomeF

Gadobenate
dimeglumine

Gadoxetate
disodium

Gadoteratemeglumine

Gadodiamide

Gadoversetamide

Gadoteridol

Gadobutrol

5160

3653

1250

6489

1064

323

2997

9454

3005 (58.24%)

2202 (60.28%)

521 (41.68%)

4123 (63.54%)579 (54.42%)

120 (37.15%)

1842 (61.46%)

5737 (60.68%)

M

1800 (34.88%)

1275 (34.90%)

551 (44.08%)

2188 (33.72%)

336 (31.58%)

70 (21.67%)

1046 (34.90%)

3202 (33.87%)

Unknown

3556.88%)

176 (4.82%)

178 (14.24%)

178 (2.74%)

149 (14.00%)

133 (41.18%)

109 (3.64%)

515 (5.45%)

0–27 days

1 (0.02%)3 (0.08%)

0 (0%)

5 (0.08%)

0 (0%)

0 (0%)

3 (0.10%)13 (0.14%)

28 days–
23 months

8 (0.16%)1 (0.03%)

0 (0%)

11 (0.17%)

2 (0.19%)

0 (0%)

1 (0.03%)7 (0.07%)

2–11 years

85 (1.65%)

12 (0·33%)

2 (0.16%)130 (2.00%)

7 (0.66%)

1 (0.31%)23 (0.77%)

65 (0.69%)

12–17 years

138 (2.67%)

60 (1.64%)

2 (0.16%)199 (3.07%)

27 (2.54%)

1 (0.31%)58 (1.94%)

205 (2.17%)

18–44 years

1852 (35.89%)

1097 (30.03%)

198 (15.84%)

2251 (34.69%)

319 (29.98%)

55 (17.03%)

991 (33.07%)2903 (30.71%)

45–64 years

1680 (32.56%)

1331 (36.44%)584 (46.72%)

2386 (36.77%)

323 (30.36%)

57 (17.65%)

1144 (38.17%)3725 (39.40%)

65–74 years

461 (8.93%)452 (12.37%)

188 (15.04%)

638 (9.83%)

91 (8.55%)

11 (3.41%)

348 (11.61%)

1119 (11.84%)≥ 75 years

214 (4.15%)

207 (5.67%)

66 (5.28%)

248 (3.82%)

39 (3.67%)

6 (1.86%)

155 (5.17%)409 (4.33%)

Unknown

721 (13.97%)

490 (13.41%)

210 (16.80%)

621 (9.57%)

256 (24.06%)

192 (59.44%)274 (9.14%)

1008 (10.66%)

Americas3404 (65.97%)

1678 (45.93%)

227 (18.16%)

787 (12.13%)590 (55.45%)

312 (96.59%)

674 (22.49%)

2321 (24.55%)

Asia

761 (14.75%)

466 (12.76%)

870 (69.60%)

2217 (34.17%)

149 (14.00%)

8 (2.48%)820 (27.36%)

4152 (43.92%)

Europe899 (17.42%)1460 (39.97%)

138 (11.04%)

3381 (52.09%)

278 (26.13%)

2 (0.62%)1503 (50.15%)

2681 (28.36%)

Oceania89 (1.72%)

47 (1.29%)

14 (1.12%)

100 (1.54%)

41 (3.85%)

1 (0.31%)0 (0%)

289 (3.06%)

Africa7 (0.14%)2 (0.05%)

1 (0.08%)

5 (0.08%)

6 (0.56%)

0 (0%)

0 (0%)

11 (0.12%)2022

93 (1.80%)

89 (2.44%)

42 (3.36%)

523 (8.06%)

23 (2.16%)

0 (0%)

204 (6.81%)

599 (6.34%)

2021

101 (1.96%)

105 (2.87%)

95 (7.60%)

684 (10.54%)

13 (1.22%)

0 (0%)

316 (10.54%)882 (9.33%)

2020

93 (1.80%)

247 (6.76%)

137 (10.96%)

632 (9.74%)

20 (1.88%)

0 (0%)

408 (13.61%)

908 (9.60%)

2019

203 (3.93%)

286 (7.83%)

241 (19.28%)

794 (12.24%)

148 (13.91%)

4 (1.24%)362 (12.08%)

1002 (10.60%)

2018

71 (1.38)

173 (4.74%)

111 (8.88%)880 (13.56%)

23 (2.16%)

10 (3.10%)349 (11.64%)

1153 (12.20%)

2017

87 (1.69%)

242 (6.62%)

102 (8.16%)

540 (8.32%)

29 (2.73%)

3 (0.93%)187 (6.24%)

888 (9.39%)

2016

93 (1.80%)

276 (7.56%)

75 (6.00%)

373 (5.75%)

37 (3.48%)

8 (2.48%)

162 (5.41%)736 (7.79%)

2015

152 (2.95%)

291 (7.97%)

97 (7.76%)

403 (6.21%)

56 (5.26%)

12 (3.72%)

82 (2.74%)

773 (8.18%)

2014

214 (4.15%)

473 (12.95%)

105 (8.40%)429 (6.61%)

41 (3.85%)

5 (1.55%)

103 (3.44%)648 (6.85%)

2013

99 (1.92%)

113 (3.09%)

53 (4.24%)

140 (2.16%)

26 (2.44%)

2 (0.62%)70 (2.34%)

335 (3.54%)2012

276 (5.35%)

140 (3.83%)

48 (3.84%)

135 (2.08%)

42 (3.95%)

11 (3.41%)

55 (1.84%)

382 (4.04%)2011

360 (6.98%)

194 (5.31%)

31 (2.48%)

155 (2.39%)

86 (8.08%)

31 (9.60%)

66 (2.20%)

232 (2.45%)

2010

385 (7.46%)

174 (4.76%)

15 (1.20%)

79 (1.22%)

76 (7.14%)

39 (12.07%)

93 (3.10%)

117 (1.24%)

2009

557 (10.79%)

177 (4.85%)

8 (0.64%)32 (0.49%)

93 (8.74%)

59 (18.27%)

100 (3.34%)

49 (0.52%)

2008

295 (5.72%)

475 (13.00%)

1 (0.08%)70 (1.08%)

58 (5.45%)

10 (3.10%)

98 (3.27%)

42 (0.44%)

Death

55 (1.07%)

45 (1.23%)

0 (0.00%)

14 (0.22%)

32 (3.01%)

22 (6.81%)

30 (1.00%)

50 (0.53%)

Life-threatening

154 (2.98%)

268 (7.34%)

17 (1.36%)

241 (3.71%)

30 (2.82%)

3 (0.93%)186 (6.21%)

257 (2.72%)

Disability

24 (0.47%)

15 (0.41%)

1 (0.08%)13 (0.20%)

28 (2.63%)

13 (4.02%)

14 (0.47%)

27 (0.29%)

Hospitalization

231 (4.48%)

509 (13.93%)

32 (2.56%)

507 (7.81%)

50 (4.70%)

24 (7.43%)

330 (11.01%)

589 (6.23%)

Other4696 (91.01%)

2816 (77.09%)

1200 (96.00%)

5714 (88.06%)

924 (86.84%)

261 (80.80%)

2437 (81.31%)

8531 (90.24%)

Reported
rate of serious events

8.99%

22.91%

4.00%

11.94%

13.16%

19.2%

18.69%

9.26%

HSR hypersensitivity reactions, UN United Nations­(ROR025 = 3.80 and 3.06) had the most significant signal;
gadopentetate dimeglumine, gadobenate dimeglumine,gadoxetate disodium, and gadobutrol had no significant
signals. For angioedema, gadobutrol ­(ROR025 = 12.45

and 20.64) had the largest ­ROR025, gadodiamide had thesmallest ­ROR025 in VigiBase ­(ROR025 = 2.23), and no significant signal in FAERS, while gadoversetamide had no
significant signal in VigiBase and the smallest R­ OR025

Qu et al. BMC Medicine(2024) 22:329

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Table 2 Disproportionality analysis results of all suspected HSRs associated with GBCAs in VigiBase
Target GBCAs
Event (a)All other drugs
No event (b)Event (c)No event (d)ROR (95% CI)

Gadopentetate dimeglumine

6414

5280

5,618,410

29,339,215

6.35 (6.12–6.58)

Gadobenate dimeglumine

4270

2503

5,476,204

29,486,344

9.19 (8.74–9.65)

Gadoxetate disodium

1371

1257

5,200,202

29,766,491

6.24 (5.78–6.74)

Gadoterate meglumine

7540

5371

5,598,164

29,358,246

7.36 (7.11–7.62)

Gadodiamide

1240

2882

5,327,434

29,637,765

2.39 (2.24–2.56)

Gadoversetamide

385

589

4,866,805

30,101,542

4.04 (3.56–4.60)

Gadoteridol

3546

2029

5,406,117

29,557,629

9.56 (9.05–10.09)

Gadobutrol

11,5076213

5,636,201

29,315,400

9.63 (9.34–9.94)

GBCAs gadolinium-based contrast agents, CI confidence interval, ROR reporting odds ratio, HSRs hypersensitivity reactions

Table 3 Disproportionality analysis results of all suspected HSRs associated with GBCAs in FAERS
Target GBCAs
Event (a)All other drugs
No event (b)Event (c)No event (d)ROR (95% CI)

Gadopentetate dimeglumine

2028

2571

870,039

10,280,468

9.32 (8.79–9.88)

Gadobenate dimeglumine

1052

1346

835,625

10,317,083

9.65 (8.90–10.46)

Gadoxetate disodium

109

151

736,957

10,417,889

10.20 (7.98–13.06)

Gadoterate meglumine

408

327

860,947

10,293,424

14.92 (12.90–17.25)

Gadodiamide

194

1556

773,622

10,379,734

1.67 (1.44–1.94)

Gadoversetamide

96

646

712,441

10,441,923

2.18 (1.76–2.70)

Gadoteridol

361

562

799,682

10,354,501

8.32 (7.29–9.49)

Gadobutrol

1443

1267

877,486

10,274,910

13.34 (12.37–14.38)

GBCAs gadolinium-based contrast agents, CI confidence interval, ROR reporting odds ratio, HSRs hypersensitivity reactions

Fig. 1 a Disproportionality analysis results of hypersensitivity-associated SMQ levels in VigiBase. b Disproportionality analysis resultsof hypersensitivity-associated SMQ levels in FAERS. SMQ, standardized MedDRA queryQu et al. BMC Medicine(2024) 22:329­(ROR025 = 1.36) in FAERS. Overall, the risk of angioedema with nonionic linear GBCAs was minimal.
We further analyzed the PTs under SMQ levels comparatively, and the differences are shown in Fig. 2a and2b, with specific values shown in the additional file (Additional file 1: Table S1-S2). Based on the results of the two
databases, the following results can be summarized:
gadopentetate dimeglumine had the highest likelihoodof eye swelling (­ ROR025 = 6.06 and 11.16 (in VigiBase andFAERS, respectively)), swollen tongue ­(ROR025 = 3.93 and6.35), and tracheal oedema (­ROR025 = 18.94 and 27.70);
gadobenate dimeglumine had the strongest signal regarding anaphylactic reaction (­ROR025 = 9.56 and 16.53) andanaphylactoid reaction ­(ROR025 = 10.63 and 163.81); forgadoterate meglumine, swelling of eyelid ­(ROR025 = 6.92
and 7.26) and type I hypersensitivity (­ROR025 = 77.72
and 24.82) were the highest signal; regarding gadoversetamide, the R­ OR025 of exfoliative rash ­(ROR025 = 110.98
and 125.14) and rash macular (­ROR025 = 9.3 and 10.95)
were the most significant; for gadoteridol, anaphylactoid shock ­(ROR025 = 56.22 and 58.05), circulatory collapse ­(ROR025 = 5.99 and 3.86), and shock (­ROR025 = 7.40
and 18.55) were the strongest signal; gadobutrol had
the highest signal about lip swelling (­ROR025 = 3.59 andPage 6 of 115.94), mouth swelling (­ROR025 = 1.84 and 1.52), urticaria ­(ROR025 = 18.91 and 41.76), and skin test positive­(ROR025 = 2.79 and 23.07).
The disproportionality analysis results of GDD are
shown in Table 4. According to the results of VigiBase, linear GBCAs had a higher risk than macrocyclic GBCAs. Gadobutrol and gadobenate dimeglumine
Table 4 Disproportionality analysis results for suspected GDDcases of GBCAs in FAERS and VigiBase
Subgroup

FAERSnVigiBase
ROR025n

ROR025Gadopentetate dimeglumine

38425.13168

1748.36

Gadobenate dimeglumine

481145.87174

3246.28

Gadoxetate disodium

1

31.65

127

5123.18

Gadoterate meglumine

17775.4220

89.38

Gadodiamide

27

707.39157

4525.03

Gadoversetamide

18981.19144

18,618.41

Gadoteridol

5134.0511

95.83

Gadobutrol

74

1995.0471

323.81

ROR reporting odds ratio, GBCAs gadolinium-based contrast
agents, GDD gadolinium deposition disease

Fig. 2 a Disproportionality analysis results of hypersensitivity-associated PTs in VigiBase. b Disproportionality analysis resultsof hypersensitivity-associated PTs in FAERS. PT, preferred termQu et al. BMC Medicine(2024) 22:329

Page 7 of 11

had higher R­ OR025 based on FAERS results. For SAGE,
no GBCAs showed signals in psychiatric disorders; all
GBCAs prompted signals in ≥ 10 PTs except gadoxetate
disodium, which did not prompt signals at any of the PTs;
gadopentetate dimeglumine had a minimum number ofsignals at the PT level of only 10; gadodiamide and gadoversetamide prompted signals in 15 PTs, both prompted
the highest number of signals, and gadoversetamide
generated the strongest signal in 14 PTs. What is more,
except for gadoversetamide, the risk of gadopentetate
dimeglumine, gadobenate dimeglumine, gadodiamide,

and gadoteridol regarding skin induration requires extra
attention. Gadodiamide and gadoteridol have a higher
risk of skin tightness than other GBCAs. The specific values of the signals are shown in Table 5.
Time to onset analysis of suspected HSRs

Excluding reports with unknown onset times, the probability of HSRs within 1 day for individual GBCAs ranged
from 93.73 to 98.89%, with those greater than 1 day being
predominantly associated with SCARs.

Table 5 ROR025 of suspected SAGE-related PTs
Gadopentetate Gadobenate Gadoxetate Gadoterate Gadodiamide Gadoversetamide
dimeglumine
dimeglumine disodium
meglumine

Gadoteridol Gadobutrol

Skin and subcutaneous tissue disorders
Pain of skin10.90414.933/2.518

29.93449.28328.921/Skin burning
sensation

2.628

3.766

/

4.539

2.668

5.396

2.247

4.471

Skin discoloration

/

/

/

2.074

10.77817.82

13.6862.045

Skin induration

235.878

195.828//488.827655.195

400.833

7.906

Skin tightness

/

/

/

18.855233.292/

271.484

6.609

Musculoskeletal and connective tissue disorders
Arthralgia

1.12

1.093

/

/

2.31

2.19

1.049

/

Bone pain

/

/

/

4.21

3.953

6.304

3.016

2.177

Joint stiffness

/

/

/

/

/

40.73524.8/

Muscle fatigue

/

/

/

/

/

1.169

/

/

7.548

4.041

/

1.867

7.371

13.167

10.56

2.819

Muscle twitching

/

/

6.986

/

/

/

5.372

Muscular weak- 2.138
ness

2.069

/

1.602

4.929

6.085

4.456

/

Musculoskeletal /chest pain

1.903

/

/

/

/

/

/

Pain in extrem-

1.268

/

/

2.823

2.455

1.884

/

Muscle tightness

ity

2.057

General disorders and administration site conditions
Asthenia

/

/

/

/

1.195

1.319

1.175

/

Pain

4.519

6.109

/

/

11.63937.73618.065

/

1.215

/

1.757

1.471

2.588

/

2.283

Nervous system disorders
Cognitive
disorder/Headache

/

/

/

2.154

/

/

/

1.112

Paraesthesia

1.932

2.201

/

6.937

1.367

/

/

2.502

Neuralgia

/

/

/

1.415

/

/

/

/

Quality of life
decreased

9.895

6.255

/

/

17.87638.002

16.395

1.739

Number of signals at PT level

10

12

0

12

15

15

14

11

Investigations

ROR reporting odds ratio, SAGE symptoms associated with gadolinium exposure, PTs preferred terms

Qu et al. BMC Medicine(2024) 22:329

Estimation of the frequency of suspected HSRs

Based on data from the IQVIA-MIDAS database from2008 to 2022, the usage frequency of the different GBCAs
varied by region, with gadobutrol (24.92%) having thehighest rate of use in the Americas, gadopentetate dimeglumine (48.01%) in Asia, and gadoterate meglumine(48.98%) in Europe (Additional file 1: Fig. S1).
The total sales volumes for 2008–2022 are shown in
the additional file (Additional file 1: Table S3), and thehighest total frequency of the three SMQs was gadoxetate disodium (Fig. 3a). In addition, we estimated thefrequency of each SMQ level for the Americas, Asia, andEurope, and the results are shown in Fig. 3b–d, with sales
in the three regions for the years 2008–2022 also displayed (Additional file 1: Table S4). Concerning ASCs, inall three continents, the frequency of ASCs was highest
for gadobenate dimeglumine and lowest for gadoversetamide. In the Americas, Asia, and Europe, the highest frequency of angioedema was gadopentetate dimeglumine,
gadobutrol, and gadoterate meglumine, respectively; for
SCARs, the highest frequency was gadoversetamide, gadoteridol, and gadobenate dimeglumine, respectively.

Page 8 of 11

Discussion
GBCAs have been used internationally for more than
35 years in hundreds of millions of patients. Although
GBCAs are relatively safe, several studies have reported
some AEs associated with GBCAs, including HSRs
and GDD/SAGE. This study compared the safety of all
GBCAs regarding HSRs and GDD/SAGE by analyzing
the global post-marketing data, providing data to support
a more rational clinical management of GBCA-associated AEs.
Based on demographic information, AE reports wereconcentrated in the 18–64 age group, with a predominance of those ≥ 45 age group, which may be because
middle-aged and older adults are the main population
using GBCAs. AE reports on females make up the majority of HSR reports. This may be related to the existence ofgenetic differences between the sexes. Regarding regions,the subject countries of reported AEs varied among
GBCAs, which in combination with sales data is mainly,
but not absolutely, related to the usage preference of eachregion. For example, Asia, which has the third highest
sales of gadobutrol among the three regions, reported

Fig. 3 a Total frequency of the three SMQ levels in three regions from 2008 to 2022. b Total frequency of the three SMQ levels in the Americas
from 2008 to 2022. c Total frequency of the three SMQ levels in Asia from 2008 to 2022. d Total frequency of the three SMQ levels in Europe
from 2008 to 2022. SMQ, standardized MedDRA query; ASCs, anaphylactic/anaphylactoid shock conditions; SCARs, severe cutaneous adverse
reactionsQu et al. BMC Medicine(2024) 22:329

more AEs regarding HSRs than the Americas andEurope, which may be related to genetic and ethnic factors. In our study, the frequency was lower than in previous studies, which may be due to the fact that VigiBase
and FAERS are spontaneous reporting systems (SRSs)
that do not cover all AEs during the course of the study as
in the clinical randomized trials.
Allergy is one of the triggers of angioedema [26]. In thegeneral population, the incidence of severe allergic reactions is 0.01–0.03% [27]. However, 46% of allergic reactions are accompanied by angioedema [28]. Angioedema
caused by GBCAs can occur in the face, eyes, lips, throat,etc., and has also been reported in the small intestine[29]. The results of this study showed that gadobutrol had
a greater ­ROR025 for angioedema. However, when considering the amount of use, gadobutrol had the highest frequency of angioedema in Asia, but its percentage of use
in Asia was only in the fourth place, which may be related
to reporting bias or racial differences. The site of occurrence of angioedema differs among drugs; therefore,
when using a particular GBCA, special attention needs tobe paid to its high-risk site.
AEs associated with ASCs have been reported in theliterature more frequently and sometimes fatally [30–32]. According to the results of FAERS and VigiBase,the ­ROR025 of gadobenate dimeglumine and gadoteridol
is larger. Among the three regions, gadobenate dimeglumine had the highest frequency of ASCs, followed
by gadoteridol. Shock is a more serious reaction, andpatients who experience shock may not have a history ofallergy. Therefore, preparation of resuscitation measures
is necessary before administering GBCAs. In addition,skin testing may be beneficial in patients with a history ofsystemic reactions to Gd [33].
SCARs were mainly urticaria, exfoliative rash, etc., andGBCAs were classified as drugs that could cause acutegeneralized exanthematous pustulosis [8]. Preclinicalresearch indicates that Gd compounds may activate dermal fibroblasts, encourage their proliferation, and aid in
the development of myofibroblasts, hence inducing profibrotic reactions in the skin in vitro. Moreover, Gd affects
the synthesis of collagen and the amount of collagen in
the skin [34]. In FAERS, only gadoversetamide and gadodiamide hinted the signal for SCARs, while in VigiBase,in addition to gadoversetamide and gadodiamide, gadoteridol and gadoterate meglumine also hinted the signal.
Although SCARs are rare, similar reactions may occur
multiple times in sensitive patients and may be delayed,so they should be evaluated with caution if reused andobserved for several days after use. The frequency of
SCARs varies by region, which may be related to regional
usage preferences or ethnicity.

Page 9 of 11

GDD was proposed in 2016 [35]; there are several
hypotheses about GDD but the mechanism of occurrence
and pathophysiology is still unclear. However, some studies have suggested that GDD is more likely to occur withlinear GBCAs [36], and the results of VigiBase reaffirm
this conclusion. SAGE was proposed in 2018 to describe
the symptoms associated with exposure to GBCAs and isused to help researchers report the associated symptoms
in a more standardized way to allow for a more coherent
interpretation of related studies. GDD can also be considered a subset under the symptoms associated with thegadolinium exposure rubric [35]. This study found differences in the risk of different GBCAs occurring in different symptoms by analyzing the data in FAERS, with
gadoversetamide having the strongest signal in all 14 PTs,
but in terms of sales volume, its use is now very low, andthe risk of associated ADEs is considerably lower. In contrast, gadoxetate disodium did not suggest a suspicious
signal. In addition, five GBCAs had a higher risk of skininduration; gadodiamide and gadoteridol also need more
attention regarding skin tightness. The AEs of GBCAs
involve multiple systems and can ultimately affect apatient’s quality of life, so it is important to prevent theassociated risks. The National Institutes of Health held ameeting in 2018 to clarify the direction of future researchon gadolinium retention [37]. It is hoped that the resultsof this study will provide data to support subsequent
research.
This study, like many studies of pharmacovigilance
databases, has certain limitations. Firstly, the FAERS
and VigiBase are SRSs with diverse, uncertain data
sources, and the number of reports for a given drug may
be affected by the extent of the product’s use, publicity,and the nature of the AEs, as well as underreporting or
overreporting. Therefore, even if the results of disproportionality analysis are significant, it is not possible toconfirm a causal relationship between the drug and theAEs. Secondly, we recognize that the estimation of AE
frequency is rough because not all patients use a single standard unit of GBCA. In addition, the extent ofreporting in different areas can affect the estimation of
frequency. Thirdly, the quality of relevant reports cannot be guaranteed as there is still a lot of controversy
and the understanding of GDD/SAGE is still limited, so
we did not estimate the frequency of GDD/SAGE, andthe results of disproportionality analysis are only a preliminary probe based on the current data; more researchneeds to be continued. Finally, the site of use of GBCAs
also affects the frequency of HSRs, and we were unable
to analyze site-specific frequency further due to missing
data. However, the inclusion of real-world data was ascomprehensive and systematic as possible to ensure theQu et al. BMC Medicine(2024) 22:329

reliability and authenticity of this study and provide data
support for further research.

Conclusions
Different GBCAs exhibited diverse profiles regarding
HSRs, which could be further affected by geographic
area. Our study provides additional data support for theprevention of HSRs. As for the differences of GBCAs in
GDD/SAGE, this study only analyzed the currently available post-marketing data as a preliminary exploration,and more unbiased studies are needed.
Abbreviations
Gd	Gadolinium
HSRs	Hypersensitivity reactions
GBCAs	Gadolinium-based contrast agents
SAGE	Symptoms associated with gadolinium exposure
GDD	Gadolinium deposition disease
FAERS	FDA Adverse Event Reporting System
ASCs	Anaphylactic/anaphylactoid shock conditions
SCARs	Severe cutaneous adverse reactions
AEs	Adverse events
IQVIA-MIDAS	IQVIA Multinational Integrated Data Analysis System
UMC	Uppsala Monitoring Centre
MedDRA	Medical Dictionary for Drug Regulatory Activities
SMQ	Standardized MedDRA queryPTs	Preferred terms
ROR	Reporting odds ratio
SRSs	Spontaneous reporting systems

Page 10 of 11

Availability of data and materials
Requests for access to VigiBase should be directed to CustomSearches@
who-umc.org. The data obtained from OpenVigil 2.1 can be found at https://​openv​igil.​sourc​eforge.​net/. The data of IQVIA-MIDAS are available from thecorresponding author upon reasonable request.

Declarations
Ethics approval and consent to participate
Since data in FAERS, VigiBase, and IQVIA-MIDAS are anonymized and publicly
available, the requirements for obtaining informed consent and institutional
review board approval were waived.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Pharmacy, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, No.1279 Sanmen Road, Shanghai 200434, People’s
Republic of China. 2 Department of Clinical Pharmacy, Shanghai General
Hospital, Shanghai Jiao Tong University School of Medicine, No.85 Wujin Road,
Shanghai 200080, People’s Republic of China. 3 School of Pharmacy, Shanghai
Jiao Tong University, No.800 Dongchuan Road, Shanghai 200240, People’s
Republic of China. 4 Department of Radiology, Shanghai General Hospital,
Shanghai Jiao Tong University School of Medicine, No.85 Wujin Road, Shanghai 200080, People’s Republic of China.
Received: 12 February 2024 Accepted: 22 July 2024

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03537-2.
Additional file 1: Table S1. Disproportionality analysis results of all PTs ofsuspected HSRs in VigiBase. Table S2. Disproportionality analysis resultsof all PTs of suspected HSRs in FAERS. Table S3. Sales volume of GBCAs
from 2008 to 2022. Table S4. Sales volume of GBCAs in Americas, Asia, andEurope from 2008 to 2022. Fig. S1. Sales volume share of each GBCA in different regions from 2008 to 2022. GBCA: gadolinium-based contrast agent.
Acknowledgements
The authors acknowledge the Uppsala Monitoring Centre (UMC) who manages and provides the data used in the present study. The views expressedin this study are the personal views of the authors and may not reflect theposition of the WHO.
Authors’ contributions
Conceptualization, Y.F.L., G.R.F., and H.Q.; resources, Y.F.L. and G.R.F.; data curation, H.Q., T.T.F., and W.J.L.; methodology, Y.F.L., G.R.F., and H.Q.; formal analysis,
H.Q., and N.Y.L.; data curation, H.Q., W.J.L., C.D.Q., and T.S.W.; writing—originaldraft, H.Q.; visualization, H.Q. and X.L.; writing—review and editing, Y.F.L., G.R.F.,
H.Q., Y.Y.W., and Z.H.W.; revision: H.Q., Y.Y.W. and Z.H.W.; supervision, Y.F.L., G.R.F.,
and Z.H.W.; funding acquisition: Y.F.L., G.R.F., and Z.H.W.; all authors read andapproved the final manuscript.
Funding
This work was supported by the National Natural Science Foundation ofChina (81973289), Shanghai Key Clinical Discipline Construction Project(02. DY11.03.19.03), Scientific and Innovative Action Plan of Shanghai(22S21902000 and 23S21900900), and Bethune Charitable Foundation(Z04JKM2023E040).

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