Abstract
Regulatory approval of new drugs, including subsequent new indications, requires that they have undergone preclinical and clinical testing which focuses on safety and efficacy. For contrast media these tests have never included pregnant and lactating women to investigate possible effects on the fetus and neonate. The summary of product characteristics or the package insert includes a statement about this lack of knowledge. Current practice is not based on formal testing, but on small series and case reports of pregnant and lactating women from the peer-reviewed literature, and on our understanding of the pharmacokinetics of contrast media in pregnant and lactating subjects based on animal data. Although no contrast media have been approved for use in pregnant and lactating women, this does not mean that they are contraindicated, but use of contrast media in these subjects will always be off-label.
Before 2006 most radiologists believed that gadolinium-based contrast media were safe and that they could be used when indicated in pregnant and lactating women. The documentation of a link between nephrogenic systemic fibrosis (NSF) and exposure to some gadolinium-based contrast media changed the situation. Now the most unstable agents (those most likely to release gadolinium) are absolutely contraindicated in pregnant women and in lactating women the milk produced within 24 h of administration must be discarded. The other more stable agents may be used in pregnant women if enhanced magnetic resonance imaging (MRI) is clinically indicated, and lactating women can continue breast feeding after enhanced MRI if they wish.
Gadolinium-based contrast media have not shown mutagenic or teratogenic effects in animal experimental studies (1). They can cross the placenta in both directions and although they are water soluble, their molecular weight (500–850 Da) means that relatively small amounts cross the single layer of chorionic epithelium which separates the maternal blood from fetal tissue. Pharmacokinetic studies have used mice and rats because murine and human placentas are structurally similar. The maximum fetal concentration was 0.07% of the injected dose when pregnant mice were given high doses of gadoterate meglumine (0.5 mmol per kg) (2), and the maximum fetal gadolinium concentration was only 0.01% of the injected dose when pregnant rats were given 0.3 mmol per kg of gadodiamide (3). Gadolinium contrast agents in the fetal blood are excreted by the fetal kidneys into the bladder which empties into the amniotic fluid. Reabsorption of amniotic fluid occurs both by fetal swallowing and across membranes into the fetal circulation, from which it can cross the chorionic epithelium back into the mother. The whole amniotic fluid volume turns over every 24 h (4). The half-lives of gadodiamide in mouse fetal tissues and the amniotic fluid were 4 h and 5 h, respectively, after a dose of 0.5 mmol per kg to the pregnant mother, with only tiny amounts of gadolinium detectable in the fetus and none detectable in the amniotic fluid at 48 h (2). Similarly, only traces of gadodiamide were detected in fetal tissue at 24 h when pregnant rats were given gadodiamide 0.3 mmol per kg (3). A total of 57 infants whose mothers were given gadopentetate dimeglumine (0.1–0.2 mmol per kg) showed no adverse effects (5–10).
Excretion of gadolinium contrast media into milk is limited because the molecules are water soluble and show minimal protein binding. When 20 lactating women were given 0.1–0.2 mmol per kg of gadopentetate, <0.04% of the dose given was excreted in the milk over 24 h (11). It was estimated that <1% of the recommended intravenous dose for an infant reaches the gut after a lactating mother is given gadolinium contrast agents intravenously (11). Doses of 0.1 to 0.2 mmol/kg of gadopentetate and gadodiamide are tolerated intravenously by neonates (12, 13). When gadolinium contrast agents are given orally, only tiny amounts are absorbed – <1% in a study of gadopentetate (14). Thus only a very small amount of gadolinium contrast media should reach the fetal blood when a lactating woman is given gadolinium contrast agents.
In gadolinium contrast media, the gadolinium is bound with a chelating agent to prevent exposure of the body to free gadolinium, which is toxic. The molecules of the non-ionic linear gadolinium agents gadodiamide and gadoversetamide are the least stable, so gadolinium is more likely to be released from them. Again, according to laboratory studies, ionic linear chelate molecules (gadopentetate dimeglumine, gadobenate dimeglumine and gadofosveset) have intermediate stability and the macrocyclic agents gadobutrol, gadoteridol, and gadoterate meglumine are the most stable.
The stability of gadolinium contrast agents affects the amounts of gadolinium which are retained in the tissues after administration. Tweedle et al. (15) described retention of gadolinium in the liver and bone of mice and rats 14 days after administration of gadolinium agents, with greater amounts retained with linear than macrocyclic agents. Sieber et al. (16) gave high doses of gadolinium agents to rats and found the highest gadolinium concentrations in skin, bone, and liver with gadodiamide. There was 10 times less gadolinium retention in the skin with gadopentetate and 30 times less with gadoterate and gadobutrol. In patients who had received gadolinium agents, four times more gadolinium was retained in the bone after gadodiamide than after gadoteridol (17). The amounts of gadolinium retained in the skin increased over time in patients with NSF (18), raising the suggestion that gadolinium stored in bone might be released over time.
NSF occurs in patients with impaired renal function and in neonates and infants, glomerular filtration rate (GFR) is low. At the age of 1 week, mean GFR is 40 mL/min/1.73m2, at 2 weeks it is 65 mL/min/1.73m2, and at 8 weeks it is 95 mL/min/1.73m2 (19). Neonates may therefore be at risk of NSF if they receive the less stable gadolinium agents. There are no data on fetal renal function, but precautions suitable for neonates are also likely to be desirable for the fetus.
The amounts of gadolinium reaching the fetus when the mother is given gadolinium agents are small, and the amounts of gadolinium reaching the milk when the lactating mother is given gadolinium agents are also small. Nonetheless, the potential for gadolinium retention in the tissues with the less stable agents, the lack of knowledge about its long-term effects, and the increased risk associated with immature renal function in the neonate are all causes of concern. The European Medicines Agency (EMA) has recommended restricting the use of high-risk gadolinium agents in neonates and infants, and discontinuing breast feeding for at least 24 h if the higher-risk gadolinium agents are given to lactating women (20). The EMA does not make a specific recommendation about pregnant women, but it would seem advisable to use the same precautions as for neonates.
Based on the data in the literature and the EMA recommendations, the European Society of Uroradiology Contrast Medium Safety Committee (ESUR CMSC) has modified its recommendations for the use of gadolinium contrast media in pregnant and lactating women as follows (21, 22):
Pregnant women. The highest risk gadolinium contrast media are contraindicated in pregnant women. The intermediate and lowest risk gadolinium contrast media may be given to pregnant women in the lowest dose required to provide essential diagnostic information; Lactating women. Lactating women who receive the highest risk gadolinium contrast media should stop breast feeding for 24 h and discard the expressed milk. Lactating women who receive the intermediate and lowest risk agents should discuss whether to discontinue breast feeding for 24 h with their doctor.
The new guidelines also state that the highest risk gadolinium agents are contraindicated in neonates up to 1 month of age and should be restricted to the minimum recommended dose in infants up to 1 year.
In conclusion, the regulatory statements and clinical practice for the use of contrast media in pregnancy and lactation differ. Clinical guidelines based on current clinical and experimental data indicate that pregnant and lactating women can undergo enhanced MRI provided that the high-risk gadolinium-based contrast agents are not used.