The use of imaging methods with or without contrast agent administration in pregnant and breastfeeding women has been increasing in the past decades ^[1]. In this subset of patients, it is mandatory to consider both maternal and fetal effects deriving from the use of a contrast media. The use of contrast media is generally avoided by physicians and patients, mainly because of the lack of wide prospective studies on humans concerning this issue and because the effects on a human embryo and fetus are not completely known. In ouresearchers' opinion, it is important to be aware of the high value of such diagnostic methods in specific cases and of the actual low incidence of adverse effects during pregnancy if properly used, following the International Associations’ guidelines, in order to guarantee the safe and effective use of such instruments.

2. Classification of Contrast Agents

Contrast agents can be defined as any substance introduced into the body during imaging examinations, to improve the visualization and detection rate of internal structures. Medical imaging includes methods that use ionizing and non-ionizing radiation. Ionizing radiation consists of either particulate or electromagnetic energy such as alpha particles and beta particles, which have moderate penetrating power and can ionize tissues changing their normal structure and causing two types of effects: deterministic and stochastic ^[2]. Deterministic effects involve the loss of tissue function. If the radiation dose is distributed over time, the cellular repair mechanisms permit the tissue to recover from the damage. This implies a threshold dose above which the tissue will exhibit permanent damage since the radiation dose exceeds the capabilities of innate cellular repair mechanisms. Pregnancy loss, fetal malformations, neurodevelopment abnormalities, and fetal growth retardation, have a deterministic effect whereby a threshold or No-Adverse-Effect Level (NOAEL) exists ^[3]. On the other hand, stochastic effects have no threshold dose and can occur at any radiation dose. Nonionizing radiation (such as ultrasound waves, visible light, microwaves, and magnetic resonance imaging) “has enough energy to move around atoms in a molecule or cause them to vibrate, but not enough to remove electrons”. A fetus is partly protected from radiation effects by the mother’s surrounding soft tissues and uterus, both of which could stop alpha and beta particles from penetration. Nevertheless, if alpha and beta particles are ingested, injected, or inhaled severe adverse effects on the fetus could develop: radioactive material could accumulate in the pregnant woman’s bladder, causing internal radiation exposure ^[3]. Conversely, gamma and x-rays directed toward the abdomen of a pregnant woman not appropriately shielded can reach the fetus. Medical imaging based on ionizing radiation includes the following: computerized tomography (CT), positron emission tomography (PET), and X-ray imaging. Non-ionizing imaging is represented by magnetic resonance imaging (MRI) and ultrasound (US). Iodinated and gadolinium-based contrast agents (GBCA) are the most frequently used, as CT and MRI, respectively, are the imaging modalities mainly used in daily practice [4,5]^[4][5].

2.1. Iodinate Contrast Agents

CT represents the imaging modality used the most often in clinical practice, especially chest CT, as trauma and suspected pulmonary emboli represent the principal indications for imaging examinations ^[1]. CT employs ionizing electromagnetic radiations (X-rays) to create cross-sectional slice pictures inside selected areas of the body from different angles, creating a three-dimensional picture. Ionizing radiation, including X-ray, has moderate penetrating power and can ionize tissues, changing their normal structure and causing two types of effects: deterministic and stochastic ^[3]. There is evidence that shows that some adverse effects could occur at lower doses, too. As the Radiation Effects Research Foundation has demonstrated, radiation exposure during organogenesis and fetal development may lead to neurobehavioral changes, adverse effects on the central nervous system, malformations, low birth weight, and growth restriction ^[6]. Iodinate agents are used in CT to improve the detection rate of imaging. The Food and Drug Administration (FDA) classifies the iodinated contrast agents as pregnancy category B drugs as they are considered safe for pregnant women and lactating mothers, except for diatrizoate meglumine and diatrizoate meglumine sodium, which are classified as category C drugs: “Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in human beings, but potential benefits may justify the use of the drug in pregnant women despite the potential risks” ^[7]. The American College of Obstetricians and Gynecologists recommends their use in cases of effective need for additional diagnostic information which could affect maternal or fetal care and outcome ^[8]. Iodinate contrast media can be classified according to osmolarity, ionicity, and the number of benzene rings ^[9]. Ionic iodinate contrast media have one benzene ring monomer containing three iodine atoms and a side chain with a carboxylic acid (–COOH) group ^[9]. Their osmolality is 5–7 times that of normal serum, so they have been classified as hypertonic and high-osmolar iodinate contrast media. Non-ionic iodinate contrast media have one benzene ring monomer with various side chains containing polar alcohol (–OH) groups, but no –COOH groups. Due to its non-ionic characteristics, the osmolality is decreased to 2–3 times that of normal serum, but its radiopacity remains similar. Compared to the osmolality of ionic iodinate contrast media, monomeric non-ionic iodinate contrast media are classified as hypotonic or low-osmolar iodinate contrast media. The incidence of mild and moderate contrast reactions is higher for high-osmolar contrast media (6–8%) than for low-osmolar contrast media (0.2%). Nonionic contrast agents, characterized by a lower osmolality, cause less adverse reactions compared to ionic agents, therefore the formers have mostly been used in X-ray-related studies in recent years ^[10]. Adverse effects in pregnant women are the same as those of the general population: the most common being hypersensitivity, thyroid dysfunction, and nephropathy. There is no evidence regarding teratogenic effects in humans, but studies on animals suggest no teratogenic or mutagenic effects if used during pregnancy ^[9]. The transplacental passage of ionic agents has been demonstrated by experimental studies on animals: after entering the fetal bloodstream, they are excreted in fetal urine in the amniotic fluid and then swallowed by the fetus. There is no clear evidence of the transplacental passage of nonionic agents. Cohort studies suggest that exposure to iodinate contrast agents during pregnancy may cause thyroid dysfunction in offspring, including transient hypothyroidism and goiter. The fetal thyroid starts to become active and produces hormones from the beginning of the second trimester, with an increase in iodine uptake. It is highly sensitive to fluctuations in maternal iodine concentration in this period ^[11]. Actually, the major side effects are reported when ionic contrast agents are administrated during pregnancy and even in the preconceptional phase: the use of liposoluble ionic agents in hysterosalpingography in infertile women seems to correlate with a higher risk of thyroid dysfunction (2.4% vs. 0.7% in non-exposed fetuses) ^[12]. Contrarily, nonionic iodine media agents do not affect TSH and T4 levels in offspring, as their presence in fetal blood is transient ^[13]. The European Society of Urogenital Radiology recommended that neonatal thyroid function should be checked during the 1st week after birth if iodinated contrast media was given during pregnancy ^[14]. Iopamidol (Isovue) is a nonionic, low osmolarity, monomeric iodine agent which passes the placenta barrier. It has been demonstrated to be safe for fetal thyroid function, reproductive outcomes, and teratogenic effects in animals [15,16]^[15][16]. Iopromide (Ultravist) is the most used iodine contrast agent in CT: it is a nonionic, low osmolarity, and hydrosoluble agent with a transplacental passage. It is safe for teratogenic and mutagenic effects. One case report noted a transient TSH level increase in newborns when exposed during pregnancy, without thyroid hormone dysregulation ^[13]. The safety of such media agents is widely evident. Nevertheless, the lack of clinical studies on humans favors the doubts about their use in pregnant women, as this has been described only in a few case reports. As far as concerns breastfeeding, the iodinated contrast agents are completely cleared from the mother’s bloodstream in 24 h and their half-life in blood is 2 h. Less than 1% of the administrated iodine agent is excreted in milk and less than 1% of it is assumed by the breastfed baby ^[9]. Consequently, the median dose absorbed by the baby is 0.05% of the recommended safe dose to administrate if the infant needs a diagnostic imaging examination ^[17]. In conclusion, mothers can safely breastfeed their babies after exposure to iodine contrast agents; they can however stop breastfeeding for 12–24 h if they are still concerned regarding this ^[18].

2.2. Gadolinium-Based Contrast Agents

MRI does not involve radiation: it employs strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body ^[19]. MRI during pregnancy is generally considered safe for the fetus, especially in the second or third trimester. The main advantage of MRI compared to US and CT is the ability to visualize the soft tissue structures without the use of ionizing radiation and without depending on an operator’s skills. Currently, the risks concerning the process of deposition of energy in the body in the form of heat, quantified by the specific absorption ratio (SAR) and measured in units of watts per kilogram (W/kg), are only theoretical. In animal models, tissue heating caused by elevated SAR during pregnancy, resulting in a rise in maternal body temperature of more than 2–2.5 °C for at least 30–60 min, has been shown to cause fetal harm. Thus, the FDA and the International Electrotechnical Commission (IEC) recommend not exceeding the maximum SAR of 4 W/kg for the whole body, which is capable of increasing the body temperature by 0.6 °C for 30 min of MRI exposure [19,20]^[19][20]. The main theoretical risks for the fetus exposed to MRI during pregnancy consist of potential teratogenesis, heating of the tissues, which may cause miscarriage and/or injury to organ systems in the first trimester, and acoustic damage resulting from exposure to the magnetic field, but there is currently no evidence of actual damage in animal studies. The main limitations of the studies conducted on humans which are currently available are their retrospective nature and the lack of long-term outcome data [21,22]^[21][22]. According to the guidelines of the American College of Radiology (ACR) and ACOG, MRI, performed with scanners of 3.0T or less, is not associated with any adverse effects on the fetus and no specific precautions are recommended in the first trimester, but it should be used with caution at any gestational age when it is not possible to obtain an accurate diagnosis with other methods and when the information provided may impact on the medical treatment [23,24]^[23][24]. The technique is commonly used in pregnant women to assess acute abdominal and pelvic pain, neurological abnormalities, fetal anomalies (central nervous system, face and neck abnormalities, evaluation of chest, abdominal pelvic masses), localization or abnormally invasive placenta (AIP), myomas, neoplasms, infections, and/or cardiovascular abnormalities. GBCAs are intravenous drugs used to enhance the quality of MRI or magnetic resonance angiography. The FDA classifies GBCA as category C agents: their use in animals showed some adverse effects, but studies in humans are lacking. Their use is recommended when the potential benefits overcome the risks as outlined by the American College of Radiology ^[9]. GBCAs are classified according to their ionicity, the chelating ligand (macrocyclic or linear), their pharmacokinetics, and their risk of causing nephrogenic systemic fibrosis (NSF). The ionic macrocyclic agents represent the safest ones, as they have the highest stability. Contrarily, nonionic linear ones are the least stable, therefore the most dangerous, as Gadolinium in its free form is toxic for humans ^[25]. The incidence of adverse reactions to GBCAs is low. Most reactions are mild and transient, with skin reactions being the most frequent [26,27]^[26][27]. GBCAs are assumed to cross the placenta in humans since they have been shown to cross the primate’s placenta. These agents accumulate in the amniotic fluid and are not effectively removed from the fetal environment. However, no adverse effects in humans have been reported when clinically recommended doses of GBCAs have been used in pregnant patients. Gadolinium exposure during early pregnancy has been reported in a small number of cases without apparent adverse effects. De Santis et al. investigated if the administration of GBCAs during the first trimester led to teratogenesis or mutagenesis: no effects on newborns were found ^[28]. Marcos et al. analyzed the impact of exposure to GBCAs during the second and third trimesters of pregnancy in 11 newborns: none of them showed adverse effects at birth ^[29]. Concerning the breastfeeding period, a small percentage of GBCAs is excreted in breast milk and absorbed by the child ^[17]. A study revealed that the maximum cumulative amount of gadolinium excreted in breast milk over 24 h was less than 0.04% of the maternal dose and that only 1–2% of such amount was absorbed by the fetus and passed into the bloodstream ^[30]. There are no reports of adverse effects in newborns breastfed after GBCA administration. Scientific societies agree that it is not necessary to stop breastfeeding, nevertheless, mothers can choose to discard breast milk for 12–24 h after injection of contrast agents as a prevention ^[31]. Long-term risks linked to the GBCA administration include nephrogenic systemic fibrosis (NSF) and retained intracranial gadolinium. NSF is a rare and severe disease characterized by fibrosing skin lesions and organ failure, observed in patients with impaired renal function. To date, no cases of NSF have been reported in a pregnant patient or newborn after intrauterine exposure ^[32]. The retained intracranial gadolinium, first described as observed T1 shortening predominantly in the globus pallidus and dentate nucleus, and also observed in patients with normal renal function, has been mainly related to multiple administrations of GBCA during life [21,32]^[21][32]. No evidence is available about the safety during pregnancy of gadoxetic acid, a GBCA used in enhanced MRI to assess liver function useful to detect and characterize liver lesions in patients with known or suspected focal liver disease and to assess the risk stratification of chronic liver disease ^[33]. As it shows a similar safety profile to other GBCAs for hypersensitivity reactions and NSF but there is incomplete information documenting intracranial gadolinium retention in patients administered gadoxetic acid, its use during pregnancy should be carefully evaluated.