Diagnostic (Radiopaque Agent)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use a gadobutrol in human pregnancy have been located. 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). 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
Gadobutrol, a gadolinium-based contrast agent, is a paramagnetic macrocyclic administered for magnetic resonance imaging (MRI). It is indicated for IV use in diagnostic MRI in adults and children 2 years of age or older to detect and visualize areas with disrupted blood–brain barrier and/or abnormal vascularity of the central nervous system. The agent does not display any particular protein binding and is not metabolized. The mean terminal half-life is 1.81 hours (6).
Reproduction studies have been conducted in rats, rabbits, and monkeys. In rats, maternally toxic doses that were 12 times the human equivalent dose based on BSA (HED) caused retardation of the embryo development and embryolethality. Similar toxicity, but without evidence of maternal toxicity, occurred in rabbits at doses that were 8 times the HED. In rabbits, the toxicity occurred despite minimal placental transfer (0.01% of the dose detected in the fetuses). In monkeys, gadobutrol was not teratogenic but was embryolethal when given IV during organogenesis in doses up to 8 times the recommended single human dose based on BSA. However, pregnant animals received repeated daily doses so their exposure was much higher than that obtained with the standard single dose in humans (6).
Studies for carcinogenicity have not been conducted. Multiple assays for mutagenicity were negative. No effect on fertility and general reproductive performance was observed in male and female rats (6).
It is not known if gadobutrol crosses the human placenta, However, other gadolinium-based contrast agents cross (see Gadobenate Dimeglumine and other agents in this subclass) and exposure of the embryo–fetus should be expected with gadobutrol. The molecular weight (about 605) and the terminal half-life are consistent with placenta transfer.
BREASTFEEDING SUMMARY
No reports describing the use of gadobutrol during human lactation have been located. However, the molecular weight (about 605) and terminal half-life (1.81 hours) suggest that the drug will be excreted into breast milk. Although there are no reports, 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. Gadavist. Bayer HealthCare Pharmaceuticals, 2011.
7.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;106:776–89.