Diagnostic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Available gadolinium-based contrast agents are complexes with chelating agents that lower the potential toxicity in patients receiving the agents by preventing the cellular uptake of free gadolinium. The complexes cross the placenta to the fetus and are excreted by the fetal kidneys into the amniotic fluid, where they remain for long periods. The complexes themselves are relatively nontoxic, but dissociation may occur to release free gadolinium into the amniotic fluid, where it could expose fetal lungs and gut. Presently, the risk of gadolinium-induced toxicity in the fetus is unknown but may be harmful (1–3). A concern has been raised for a risk of gadolinium-induced nephrogenic systemic fibrosis (3). The American College of Radiology recommends that these agents should not be routinely used in pregnancy and, if such use is indicated, a written informed consent be obtained from the patient (1). In addition, the guidelines of the Contrast Media Safety Committee of the European Society of Urogenital Radiology and a review article recommend that gadolinium-based contrast media may be used in pregnancy if such use is important to the mother’s health (4,5).
FETAL RISK SUMMARY
Gadoversetamide, a paramagnetic agent, is a complex formed between a chelating agent (versetamide) and a paramagnetic ion (gadolinium). It is in the same subclass of gadolinium-based contrast agents as gadobenate dimeglumine, gadodiamide, gadofosveset trisodium, gadopentetate dimeglumine, and gadoteridol. Gadoversetamide is indicated for use with magnetic resonance imaging (MRI) in patients with abnormal blood–brain barrier or abnormal vascularity of the brain, spine, and associated tissues. The agent also is indicated for use with MRI to provide contrast enhancement and facilitate visualization of lesions with abnormal vascularity in the liver in patients who are highly suspect for structural abnormalities of liver on computed tomography. Neither metabolites nor plasma protein binding has been detected. The mean elimination half-life is about 104 ± 20 minutes (6).
Reproduction studies have been conducted in rats and rabbits. In rats, daily IV doses given for 5 weeks (including gestation) that were equal to the human dose based on BSA (HD) reduced neonatal weights from birth through weaning. A dose 0.2 times the HD did not cause the effect. Neither dose was maternal toxic. A daily IV dose given on gestational days 7–17 that was 10 times the HD did cause maternal toxicity, as well as reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development (startle reflex and air rights reflex). These effects were not observed with doses that were equal to the HD. In rabbits, daily IV doses given during gestational days 6–18 that were 1 and 4 times the HD caused forelimb flexures and cardiovascular changes (malformed thoracic arteries, a septal defect, and abnormal ventricle) in fetuses. These effects were not observed at doses that were 0.3 times the HD. Maternal toxicity was not observed at any dose (6).
Long-term studies to evaluate the potential for carcinogenicity have not been conducted. Genotoxicity assays were negative but a chromosome aberration assay was positive. In fertility studies, daily IV doses given for 4 and 7 weeks that were 6 and 4 times the HD, respectively, caused irreversible toxicity in male rat reproductive organs and impaired fertility. These effects were not observed with a dose equal to the HD, nor were they observed in similar studies conducted in dogs. In a rat single-dose study, no adverse effects were seen on the male reproductive system 24 hours and 14 days after doses that were 1–25 times the HD (6).
BREASTFEEDING SUMMARY
Although no reports describing the administration of gadoversetamide during human lactation have been located, reviewers consider gadolinium contrast media to be compatible with breastfeeding because of the very small amounts excreted into milk and potentially being absorbed by a nursing infant (2–4). The American Academy of Pediatrics classifies gadopentetate dimeglumine as compatible with breastfeeding (7) (see Gadopentetate Dimeglumine).
References
1.Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG Jr, Froelich JW, Gilk T, Gimbel JR, Gosbee J, Kuhni-Kaminski E, Lester JW Jr, Nyenhuis J, Parag Y, Schaefer DJ, Sebek-Scoumis EA, Weinreb J, Zaremba LA, Wilcox P, Lucey L, Sass N, for the ACR Blue Ribbon Panel on MR Safety. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol 2007;188:1447–74.
2.Lin SP, Brown JJ. MR contrast agents: physical and pharmacologic basics. J Magn Reson Imaging 2007;25:884–99.
3.Chen MM, Coakley FV, Kaimal A, Laros RK Jr. Guidelines for computed tomography and magnetic resonance imaging use during pregnancy and lactation. Obstet Gynecol 2008;112:333–40.
4.Webb JAW, Thomsen HS, Morcos SK, and members of Contrast Media Safety Committee of European Society of Urogenital Radiology (ESUR). The use of iodinated and gadolinium contrast media during pregnancy and lactation. Eur Radiol 2005;15:1234–40.
5.Garcia-Bournissen F, Shrim A, Koren G. Safety of gadolinium during pregnancy. Can Fam Physician 2006;52:309–10.
6.Product information. OptiMARK. Mallinckrodt, 2009.
7.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;106:776–89.