ABC | Volume 114, Nº5, May 2020

Statement Brazilian Cardiology Society Statement for Management of Pregnancy and Family Planning in Women with Heart Disease – 2020 Arq Bras Cardiol. 2020; 114(5):849-942 In its free form, the gadolinium ion is neurotoxic; its bond to a chelating agent, however, forms a stable complex, thus protecting the organism from adverse effects. Gadolinium chelates cross the placental barrier, and they may accumulate in the amniotic cavity; nonetheless, some studies have shown that only 0.01% of the dose is present in fetal circulation 4 hours after contrast administration, and only traces are detected after 24 hours. During lactation, both iodinated contrast agents and gadolinium have low lipid solubility, and their concentration in breast milk is lower than 1% and 0.04%, respectively. 46 For this reason, the American Academy of Pediatrics and the WHO recommend not suspending lactation. Obtaining patients’ informed consent and clarifying the inherent risks of tests that are necessary for medical practice are essential measures that should be part of the interdisciplinary decision to indicate radiation examination during gestation, which involves the obstetrician and the radiology team. 2.4.3. Key Points • Indication for a radiological examination should consider the real benefit for determining therapeutic practice during pregnancy and the impossibility of substitution with an alternative radiation-free method (ultrasound, echo, and magnetic resonance); • The radiologist is the professional who is most prepared to evaluate the best diagnostic option in a given clinical situation, ensuring the safety of the pregnant woman and the fetus; • Radiological examinations should be performed in institutions that are able to guarantee the adoption of effective protection measures and that have modern equipment that is regularly calibrated and measured; • CMR is a complementary examination for defining diagnosis of heart disease. It is safe during gestation. Nevertheless, the use of gadolinium should be avoided; • The need for an examination with radiation demands interdisciplinary discussion involving a radiologist, a cardiologist, and an obstetrician, in addition to the patient’s informed consent. 2.5. Cardiovascular Drugs during Pregnancy and Breastfeeding Requirement of pharmacological therapy is very frequent during pregnancy and lactation. 48 It is estimated 34% of pregnant women with heart disease use cardiovascular medications, with the following distribution: beta-blockers (22%), antiplatelet drugs (8%), diuretics (7%), ACEI (2.8%), and statins (0.5%). 49 In this series, the prevalence of adverse events to the fetus, especially IUGR, was twice as high when compared to the women who did not take medication. 50 It is estimated that 10% to 15% of women with heart disease present cardiac complications that lead to medication treatment during gestation like systemic arterial hypertension (SAH), cardiac arrhythmias, HF, and thromboembolism. 51,52 However, prescription drugs during pregnancy requires basic knowledge of pharmacokinetics and drug classification for maternal and fetal safety during pregnancy and lactation. The pharmacokinetics of medications are influenced by the physiological changes of pregnancy, often leading to a reduction in drug plasma concentration such that any dose adjustments should be considered to achieve therapeutic efficacy. 53 Table 7 summarizes 54 the aspects deserve the following considerations: • Absorption of orally administered drugs is reduced due to delayed intestinal motility. 55 Besides, the use of antacids and iron as a supplement appears to induce drug chelation at increased gastric pH, resulting in reduced drug bioavailability; 56 • The volume of drug distribution is increased during pregnancy due to plasma volume expansion contributing to a reduction in peak drug concentration; 57 • Liver metabolism is accelerated during pregnancy because liver perfusion is greater. This means that the fraction of the drug removed from the liver circulation is increased such that drugs such as propranolol, nitroglycerine, and verapamil are extracted faster from the systemic circulation. 54 Drugs such as warfarin, which do not depend on flow but on liver activity and plasma free fraction are not influenced their concentration during pregnancy. On the other hand, nifedipine and metoprolol plasma levels are reduced in pregnancy due to increased enzyme catalytic activity; 58 • 85% increase in renal blood flow compared to pre- gestational levels. 59,60 However, a tubular function is variable, with a reduction in uric acid excretion and glucose absorption, and an increase in protein excretion. 61 As for safety, most drug studies in pregnancy are performed on animals and have little applicability because the effects are generally species-specific. Human studies are almost always retrospective and include small series. Pregnant women, except in rare circumstances, are excluded from large clinical trials. Thus, the medical literature on drugs in pregnancy has, for the most part, questionable scientific evidence. In 1979, the Food and Drug Administration (FDA) 62 introduced the classification of drugs according to categories A through X, which are widely used in daily practice. 55 This classification labeled drugs according to animal and female studies in categories that they ranged from drugs that did not pose a risk to the fetus (category A) to teratogenic ones (category X). In 2015, the classification (A, B, C, D, and X) was replaced by the so-called Pregnancy and Lactation Labeling Rule (PLLR), 63 which is currently being accepted more. It provides a descriptive summary and detailed information on animal studies and clinical trials, as outlined in Table 8. 2.5.1. Antihypertensive Drugs (Table 9) Nifedipine : hypotensive and tocolytic action; not teratogenic. May require shortening of intake range or higher dose due to CYP3A4-mediated accelerated hepatic metabolism. Increased hypotension with concomitant magnesium sulfate use. 64-66 864