Diagnostic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: 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
Gadopentetate dimeglumine, a paramagnetic agent, is a complex formed between a chelating agent and a paramagnetic ion, gadolinium. It is in the same subclass of gadolinium-based contrast agents as gadobenate dimeglumine, gadodiamide, gadoversetamide, and gadoteridol. Gadopentetate dimeglumine is indicated for use with magnetic resonance imaging (MRI) in adults, and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine, and associated tissues. It also is indicated for use with MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the head, neck, and body (excluding the heart). Neither metabolism nor plasma protein binding has been detected. The mean elimination half-life is 1.6 hours (6).
Reproduction studies have been conducted in rats and rabbits. Although no congenital malformations were observed, daily IV doses in these species that were 7.5–12.5 times the human dose based on body weight (HD) resulted in slight retardation of development. Doses that were 2.5 times the HD did not cause this effect (6). The contrast agent crosses the placenta to the fetus in rabbits (7).
Long-term studies for carcinogenicity potential have not been conducted. The drug was not mutagenic or clastogenic in several assays. High doses impaired fertility in male and female rats, including dose-related irreversible toxicity of male rat reproductive organs (6).
In a 1997 report, 11 women at 16–37 weeks’ gestation underwent gadolinium-enhanced MRI for suspected uterine or placental abnormalities (8). The placentas were rapidly and intensely enhanced immediately after administration of the contrast agent. Three patients were in the 2nd trimester and eight were in the 3rd trimester. All infants were healthy at birth (8).
A 1992 case report described the inadvertent IV bolus administration of gadopentetate dimeglumine (0.2 mmol/kg) to a woman with multiple sclerosis shortly after conception (9). Her last menstrual period had occurred 23 days before the MRI procedure, thus giving her an estimated gestational length of 9 days. Because this was before the period of organogenesis, the authors of the report concluded that the most likely adverse effect would have been an early spontaneous abortion, rather than congenital malformations. A normal pregnancy occurred, however, terminating in the delivery of a healthy baby girl at 39 weeks’ gestation. The infant was developing normally at 3 months of age (9).
A 1993 report described two women at 3 and 5 months’ gestation, respectively, who were given the contrast agent for MRI diagnosis of Crohn’s disease (10). Both patients delivered healthy infants at term.
Eleven women with symptomatic hydronephrosis at 19–34 weeks’ underwent gadolinium-enhanced (gadopentetate dimeglumine) MRI excretory urography (11). There were no adverse effects of the procedure in the pregnancies. All of the infants had good Apgar scores, none had a birth weight below the third centile adjusted for gestational age and sex, and one had an umbilical hernia.
A prospective cohort study, conducted by a teratology information service in Italy, described the outcomes of 26 women who had an MRI with gadopentetate dimeglumine immediately before or after conception (12). Two cases were exposed preconceptional (4 and 12 days after the last menstrual period) and 24 were exposed at about a mean 30 days after the last menstrual period. Because of the short half-life of the agent, all of the exposures occurred before organogenesis. The outcomes were two spontaneous abortions (SABs), one elective abortion (mother taking valproic acid), two infants with low birth weight, and one infant with a congenital anomaly (hemangiomas; mother exposed at 31 days). No information was available on the two SABs. The 23 live births were all at term (12).
BREASTFEEDING SUMMARY
Gadopentetate dimeglumine is excreted into breast milk. A woman breastfeeding her infant was given the contrast agent 13 weeks after birth (13). Small amounts of the drug were found in her milk at 2, 11, 17, and 24 hours with a cumulative amount of 1.60 mcg-mols (0.023% of the administered dose).
A 2000 study described the excretion of gadopentetate dimeglumine into the breast milk of 19 women (14). One woman who was undergoing MRI received 0.2 mmol/kg IV (15 mmol), but the other 18 women received 0.1 mmol/kg (mean 5.9 mmol). Breastfeeding was stopped for at least 24 hours. The cumulative amount of drug excreted into milk over 24 hours was 0.57 µmol (range 0.05–3.0 µmol). This amount was a mean 0.009% (range 0.001% to 0.04%) of the mother’s dose. Because the amount excreted into milk would be far less than the recommended IV dose for neonates (200 µmol/kg), and because very little of orally administered gadopentetate dimeglumine is absorbed systemically, the authors concluded that waiting 24 hours to resume breastfeeding was not warranted (14). An editorial also concluded that waiting 24 hours was not required because of the small amounts in milk and the safety profile of the contrast agent in infants and children (15). The American Academy of Pediatrics classifies gadopentetate dimeglumine as compatible with breastfeeding (16), as do other reviewers (2–4).
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. Magnevist. Bayer HealthCare Pharmaceuticals, 2009.
7.Novak Z, Thurmond AS, Ross PL, Jones MK, Thornburg KL, Katzberg RW. Gadolinium-DTPA transplacental transfer and distribution in fetal tissue in rabbits. Invest Radiol 1993;28:828–30.
8.Marcos HB, Semelka RC, Worawattanakul S. Normal placenta: gadolinium-enhanced dynamic MR imaging. Radiology 1997;205:493–6.
9.Barkhof F, Heijboer RJJ, Algra PR. Inadvertent IV administration of gadopentetate dimeglumine during early pregnancy. AJR Am J Roentgenol 1992;158:1171.
10.Shoenut JP, Semelka RC, Silverman R, Yaffe CS, Micflikier AB. MRI in the diagnosis of Crohn’s disease in two pregnant women. J Clin Gastroenterol 1993;17:244–7.
11.Spencer JA, Tomlinson AJ, Weston MJ, Lloyd SN. Early report: comparison of breath-hold MR excretory urography, Doppler ultrasound and isotope renography in evaluation of symptomatic hydronephrosis in pregnancy. Clin Radiol 2000;55:446–53.
12.De Santis M, Straface G, Cavaliere AF, Carducci B, Caruso A. Gadolinium periconceptional exposure: pregnancy and neonatal outcome. Acta Obstet Gynecol 2007;86:99–101.
13.Rofsky NM, Weinreb JC, Litt AW. Quantitative analysis of gadopentetate dimeglumine excreted in breast milk. J Magn Reson Imaging 1993;3:131–2.
14.Kubik-Huch RA, Gottstein-Aalame NM, Frenzel T, Seifert B, Puchert E, Wittek S, Debatin JF. Gadopentetate dimeglumine excretion into human breast milk during lactation. Radiology 2000;216:555–8.
15.Hylton NM. Suspension of breast-feeding following gadopentetate dimeglumine administration. Radiology 2000;216:325–6.
16.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;106:776–89.