ABC | Volume 112, Nº5, May 2019

Guideline Brazilian Fetal Cardiology Guidelines – 2019 Arq Bras Cardiol. 2019; 112(5):600-648 inhibit PG, their use interruption reduces systolic and diastolic ductal velocities, with improvements of the abnormal hemodynamics. 89 There are no reports of important spontaneous reversal of ductal constriction without the removal of the causal factor. In more severe cases, preterm delivery may be necessary, with immediate neonatal cardiopulmonary resuscitation measures. Although the relationship between the duration of the prenatal condition of ductal constriction and the prevalence and severity of neonatal pulmonary hypertension has yet to be defined, ideally it should be as short as possible. The moment of preterm delivery, thus, takes into account fetal pulmonary maturity, the severity of the of ductal constriction presentation and its progressive nature. 62 To allow for recovery and early resolution of the process, it is obviously crucial to remove the cause immediately. 6.2. The Role of Anti-Inflammatory Substances in the Genesis of Fetal Ductal Constriction The action of non-steroidal anti-inflammatory drugs (NSAID) results from PG synthesis inhibition caused by the inactivation of the cyclooxygenase 1 (COX-1) and 2 (COX-2) enzymes. 96 This inhibitory effect reduces the formation of PGG2 and PGF2. 97,98 The use of this class of medication for treating premature birth, preeclampsia, and restricted growth in utero has made it possible to evaluate its effects on COX and ductal constriction. Indomethacin is the most studied NSAIDmedication. Its effect on COX is reversible after excretion. 99,100 It crosses the placental barrier freely, as early as in the second gestational trimester. 101 Fetal response to indomethacin, however, is individual, varying in studies with twin fetuses. 102 Reports of constrictions before 27 weeks gestation are rare; however, they have occurred as early as week 22 nd . 83 Other PG synthesis inhibitors are involved in fetal ductal constriction, with well documented dose-dependent effects, for example, in dipyrone, paracetamol, scopolamine, fluoxetine, paroxetine and sertraline. 66,91,103-111 Glucocorticoids also affect ductal patency. Their effects occur through the reduction of PG formation and ductal sensitivity to PGE2, with dose-dependent effects. 112,113 Concomitant use with indomethacin has a synergetic effect that duplicates the incidence of fetal ductal constriction. 114 6.3. Anti-Inflammatory and Antioxidant Action of Polyphenols The main action of phenolic compounds or polyphenols is described in the literature as anti- inflammatory and antioxidant, demonstrating positive effects on cardiovascular health, cancer, diabetes, and neurodegenerative diseases. 115-117 The antioxidant capacity of these compounds is essential to the organism in neutralizing the action of oxygen-reactive species, 118 which, when produced excessively and not destroyed by endogenous defense, may interact with DNA, proteins, and lipids, culminating in the development of diseases such as cancer. 119,120 Polyphenols play an important role in inhibiting the inflammatory cascade, with actions similar to that of NSAID, and are able to interfere with PG synthesis. The inflammatory cascade is initiated by the activation of phospholipase A2 (PLA2), stimulated, for example, by compounds such as thrombin, bradykinin, or epinephrine, upon membrane receptor binding. Activated PLA2 hydrolizes arachidonic acid (AA), or other similar polyunsaturated fatty acids, from membrane phospholipids. AA, in its turn, through the action of the COX-2 enzyme, initiates the formation cascade of PG and thromboxane (TX). Some NSAID, such as indomethacin, for example, inhibit the inflammatory cascade via inhibitory action of COX-2, a mechanism that has been studied in order to explain the similar effect of polyphenols in this process. Polyphenols have their anti-inflammatory effects through a variety of molecular targets, which may be divided into 2 pathways: AA-dependent and AA- independent. COX, lipoxigenase, and PLA2 are AA- dependent inflammatory mediators. The activation of these proteins leads to the release of AA (a starting point for general inflammatory response) which promotes the release of pro-inflammatory molecules. 114 On the other hand, nitric oxide synthase (NOS) nuclear factor- kappa B (NF-kB), and peroxisome proliferator activated receptor (PPAR) promote inflammation through AA- independent pathways. 6.4. Summary of Evidence for Ductal Constriction Management A cornerstone of treating and preventing ductal constriction during fetal life is the reduction of fetal exposure to agents that interfere with the biosynthesis of PGE1, and PGE2. The metabolic chain of PG production can be inhibited on different levels, such as in the decrease of AA production from phospholipids, by PLA2 inhibition, as is the case with corticosteroids, in the reduction of the transformation of AA to PGG2, measured by inhibition of COX-1 and COX-2, by maternal use of NSAID or consumption of polyphenol-rich foods, and by the inhibition of isomerase, which is responsible for the synthesis of PG, TX, and prostacyclin. 621