Reversal

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Reversal

  1. 1. ORIGINAL ARTICLE Reversal of fetal ductal constriction after maternal restriction of polyphenol-rich foods: an open clinical trial P Zielinsky, AL Piccoli Jr, JLL Manica, LH Nicoloso, I Vian, L Bender, P Pizzato, M Pizzato, F Swarowsky, C Barbisan, A Mello and SC Garcia Fetal Cardiology Unit, Instituto de Cardiologia do Rio Grande do Sul/ FUC (IC/FUC), Porto Alegre, Brazil Objective: To test the hypothesis that maternal restriction of polyphenol- rich foods (PRF), which, like non-steroidal anti-inflammatory drugs (NSAID), inhibit prostaglandin synthesis in the third trimester, reverse fetal ductal constriction (DC). Study Design: An open clinical trial of 51 third trimester fetuses with DC with no history of NSAID intake was designed. All mothers were submitted to a food frequency questionnaire and were oriented to withdrawl PRF, being reassessed after 3 weeks. Doppler parameters were assessed before and after discontinuation of these substances. A control group of 26 third trimester normal fetuses, with no ductus arteriosus (DA) constriction, in which no dietary intervention was offered, was reviewed after 3 weeks. Student’s t-test and Wilcoxon’s test were used. Result: Mean gestational age was 32±3 weeks (28 to 37 weeks). After discontinuation of PRF (X3 weeks), 48/51 fetuses (96%) showed complete reversal of DC, with decrease in mean ductal systolic velocity (1.74±0.20 m sÀ1 to 1.31±0.34 m sÀ1 , P<0.001), mean diastolic velocity (0.33±0.09 m sÀ1 to 0.21±0.07 m sÀ1 , P<0.001) and mean right to left ventricular dimension ratio (1.37±0.26 to 1.12±0.17, P<0.001) and increase in mean ductal pulsatility index (PI) (1.98±0.36 to 2.46±0.23, P<0.001). Median daily maternal consumption of PRF was 286 mg per day and decreased after orientation to 0 mg per day, P<0.001. In the control group, with GA of 32±4 w (29–37 w), there was no significant differences in median daily maternal consumption of PRF, mean ductal systolic velocitiy, diastolic velocity, PI and right ventricular to left ventricular diameter ratio (RV/LV) ratio. Conclusion: Reduction of maternal PRF intake during pregnancy, especially in the third trimester, is followed by complete reversal of DC (wide open DA), which may influence maternal dietary habits in late pregnancy. Journal of Perinatology (2012) 32, 574–579; doi:10.1038/jp.2011.153; published online 3 November 2011 Keywords: fetal ductal constriction; prostaglandins; pulmonary hyper- tension; polyphenol-rich foods Introduction Ductal constriction (DC) has long been related to inhibition of the prostaglandin synthesis pathway, mainly as a result of maternal intake of non-steroidal anti-inflammatory drugs (NSAID) in the third trimester of pregnancy.1–5 Constriction of fetal ductus arteriosus (DA) is a risk factor for pulmonary hypertension in the newborn period, with its known severe consequences.6–11 For several years, many reports have been discussing the high prevalence of DC in the absence of a known trigger effect.11 It has been discussed that other extrinsic factors, in addition to NSAID, could be involved in the genesis of this important clinical situation.1,12,13 We and others have already suggested that maternal ingestion of polyphenol-rich foods (PRF) in late pregnancy, such as herbal teas, grape juice, dark chocolate and others, could be associated to fetal DC.14–18 Experimental studies in fetal lambs have supported this hypothesis, showing a cause and effect relationship of maternal consumption of green tea and other polyphenol-rich substances with constriction of fetal DA in the animal model.19 In the human setting, we have demonstrated that fetuses exposed to a maternal diet rich in polyphenols in the third trimester show higher ductal velocities and lower pulsatility indexes (PIs), as well as larger right ventricles, than those exposed to minimal amounts of these substances.15,16 The rationale for understanding the behavior of fetal ductal arteriosus flow dynamics after maternal ingestion of PRF in late pregnancy is that these substances have definite anti-inflammatory and antioxidant effects, largely reported in the literature,20–29 based on the inhibition of cyclooxygenase-2 or other components of the metabolic cascade resulting in prostaglandins biosynthesis. These actions are similar to that involved in prostaglandin inhibition caused by NSAID. The purpose of this study was to test the hypothesis that fetuses with constriction of DA and no history of maternal ingestion of NSAID, but whose mothers have used PRF in the third trimester, Received 14 July 2011; revised 27 September 2011; accepted 27 September 2011; published online 3 November 2011 Correspondence: Dr P Zielinsky, Fetal Cardiology Unit, Instituto de Cardiologia do Rio Grande do Sul/ Fundac¸a˜o Universita´iria de Cardiologia (IC/FUC), Avenue Princesa Isabel, 395, Porto Alegre, RS, 90620-001, Brazil. E-mail: zielinsky@cardiol.br Journal of Perinatology (2012) 32, 574–579 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp
  2. 2. show complete reversal of ductal constrictive effect and its hemodynamics consequences after maternal dietary intervention aimed at restriction of these substances. Methods Study design An open clinical trial was designed, in order to assess the effect of maternal dietary intervention on fetuses with diagnosis of DC whose mothers reported intake of PRF in the third trimester. The sample size was established considering a priori an alpha error of 5% and a beta type error of 10%. Patients Since November 2005 we started at the Fetal Cardiology Unit of the Institute of Cardiology of Rio Grande do Sul, Porto Alegre, Brazil, a structured program aimed at assessing with detail the flow dynamics of fetal DA on a routine basis. Third trimester fetuses with or without risk factors for cardiac abnormalities were routinely examined by Doppler echocardiography with this purpose. Over the period of November 2005 to June 2010, a total of 127 cases of fetal DCs were diagnosed. In all, 21 of the mothers have used pharmacological products containing NSAID or steroids during the third trimester and were excluded from the study. Other 55 fetuses were excluded because the protocol could not be completed as a result of loss of follow-up or delivery or else did not agree to participate after informed consent. We excluded pregnant women with a history of smoking, with chronic diseases or in use of drug treatment. The study group, therefore, was made up by 51 fetuses with DC whose mothers have used PRF after 28 weeks of pregnancy and who signed the informed consent. A control group of 26 third trimester normal fetuses from mothers without any abnormality, in which no dietary intervention was offered, was used as comparison. DA flow was laminar in the control group, with no DA constriction. Dietary assessment and intervention All the pregnant women were submitted, after informed consent, to a detailed food frequency questionnaire adapted from Block et al.30,31 The total maternal daily consumption of flavonoids was calculated from the USDA Database for the Flavonoid Content of Selected Foods and expressed in mg per day.32 After the application of the questionnaire, the mothers were oriented to withdrawl from the daily diet the 27 substances with higher concentrations of polyphenols (more than 30 mg per 100 g of food)Fgreen and black tea, mate tea, camomile tea, boldine tea, grape derivatives, dark chocolate, orange juice, fruit teas, olive oil, soy beans, berries, tomato, apples, spinach, peanuts and others, and asked to return for reassessment after a minimum interval of 3 weeks. Biological activity and bioavailability of the different polyphenols were considered in the dietary orientation.33,34 A new nutritional interview was then performed using the same instrument30 and the daily maternal intake of polyphenols was again calculated. The 26 mothers of the control group, in which no dietary intervention was offered, answered the same questionnaire at the time of their first fetal echocardiogram and again after 3 weeks, at the time of the control Doppler echocardiographic examination. Diagnosis of DC A comprehensive fetal echocardiogram with Doppler and color flow mapping was performed in every patient, according to techniques already described. Fetuses were considered to have DC only if the three following criteria were fulfilled: Doppler peak systolic ductal velocity of 1.4 m sÀ1 or above, peak diastolic ductal velocity of 0.30 m sÀ1 or above and ductal PI 2.2 or lower.35,36 The use of the PI in the assessment of ductal flow is useful, because it is independent of the angle of ultrasound and is independent of gestational age.36 The presences of turbulent flow in the DA at color flow mapping, tricuspid regurgitation, interventricular septum bowing into the left ventricle from RV hypertension from DC, right ventricular to left ventricular diameter ratio (RV/LV) of 1.3 or higher or a larger pulmonary artery to aorta diameter ratio were noted but not considered essential diagnostic features of DC. The RV/LV ratio was obtained by the measurement of the maximal end diastolic transversal diameter just below the tip of the open atrioventricular valves. A control Doppler fetal echocardiogram was performed on the same day of the nutritional reevaluation (after a minimum of 3 weeks), to assess the effect of maternal dietary intervention upon the dynamics of fetal DA flow and RV/LV ratio. The examiners were blinded to the previous echo results. In the 26 mothers of the control group, a fetal Doppler echocardiogram was performed at the time of the first nutritional interview and after 3 weeks, in the same day of the second dietary assessment. Fetal echocardiographical examinations used General Electric equipments models Vivid III Expert or Vivid 5S, with a convex probe C 4–8 or a setorial multifrequencial transducer. All Doppler echocardiographic examinations were performed by experienced fetal cardiologists. Statistical analysis Data are expressed as mean±s.d. For comparison between fetal mean peak systolic and diastolic flow velocities, PI and RV/LV ratios before and after discontinuation of polyphenol-rich substances, a two-tailed Student’s t-test for paired samples was used. For comparison of the amount of maternal ingestion of polyphenols the Wilcoxon test was applied. Bland–Altman plots assessed inter-observer and intra-observer reproducibility of the variables. Alpha level was set at 0.05 for all statistical tests. Polyphenols and fetal ductal constriction P Zielinsky et al 575 Journal of Perinatology
  3. 3. Ethical aspects The study was approved by the Research Ethics Committee of the Institute of Cardiology of Rio Grande do Sul. The patients signed an informed consent before being enrolled in the protocol, which assured confidentiality of identity and data. Results Maternal consumption of PRF was documented in all cases, without history of NSAID intake. Mean maternal age was 28.36±6.5 years (15 to 42 years) and mean gestational age was 32±3 weeks (28 to 37 weeks). After discontinuation of PRF Figure 1 Doppler echocardiographic images of a 29-week fetus with severe ductal constriction (DC) secondary to a high daily maternal intake of polyphenol-rich foods, before and after dietary intervention. (a1) Two-dimensional echocardiographic imaging of the constricted ductus arteriosus, with color flow mapping showing ductal turbulence. (a2) Control study 3 weeks after maternal dietary intervention showing normalization of ductal flow. (b1) Pulsed Doppler spectrum of the ductal flow, showing increased systolic (1.9 m sÀ1 ) and diastolic (0.45 m sÀ1 ) velocities and decreased pulsatility index (1.5). (b2) Control study 3 weeks after suspension of PRF from the daily diet, depicting now normal systolic (0.84 m sÀ1 ) and diastolic (0.10 m sÀ1 ) velocities, as well as normal ductal PI (2.4). (c1) Two-dimensional imaging of the ventricles showing a dilated and hypertrophic right ventricle and increased right to left ventricular dimension ratio, with interventricular septum bowing into the left ventricle from RV hypertension from DC (arrow). (c2) Normalization of the RV/LV ratio 3 weeks after dietary intervention. LV, left ventricle; RV, right ventricle; PA, pulmonary artery; AO, aorta; DA, ductus arteriosus. Polyphenols and fetal ductal constriction P Zielinsky et al 576 Journal of Perinatology
  4. 4. (X3 weeks), 48/51 fetuses (96%) showed complete reversal of DC (wide open DA). A decrease in mean ductal peak systolic velocity (1.74±0.20 m sÀ1 (s.d.) to 1.31±0.34 m sÀ1 (s.d.), P<0.001) and mean peak diastolic velocity (0.33±0.09 m sÀ1 (s.d.) to 0.21±0.07 m sÀ1 (s.d.), P<0.001) was observed. Mean right to left ventricular dimension ratio decreased (1.37±0.26 (s.d.) to 1.12±0.17 (s.d.), P<0.001) and mean ductal PI increased (1.98± 0.36 (s.d.) to 2.46±0.23 (s.d.), P<0.001) (Figures 1 and 2). Median daily maternal consumption of polyphenol-rich substances was 286 mg per day (122.2 mg per day (25th percentile); 409.2 mg per day (75th percentile)) and decreased after dietary orientation to a median of 0 mg per day (0 mg per day (25th percentile); 0.12 mg per day (75th percentile)), P<0.001. Mean reduction in PRF consumption after intervention was 96%. Mean systolic and diastolic velocity reductions after dietary orientation were, respectively, 24.71 and 34.49% and mean increase in ductal PI was 28%. In the control group, with a gestational age of 32±4 weeks (29 to 37 weeks), there was no significant differences in median daily maternal consumption of PRF (189 vs 192 mg per day), mean ductal systolic velocitiy (1.04±0.3 vs 1.09±0.4 m sÀ1 ), diastolic velocity (0.19±0.11 vs 0.21±0.08 m sÀ1 ), PI (2.3±0.2 vs 2.3±0.4) and RV/LV ratio (1.1±0.3 vs 1.1±0.2). Bland–Altman test showed no significant inter-observer and intra-observed variability on the assessment of the Doppler variables and of the RV/LV ratios. Discussion This study shows that constriction of DA is reversed in the vast majority of fetuses whose mothers underwent dietary intervention aiming to decrease daily intake of PRF after a period of 3 weeks or more. This finding is consistent with the conceptual hypothesis that maternal consumption of substances with anti-inflammatory effects in late pregnancy may have a constrictive action upon the fetal ductus, as a result of prostaglandin biosynthesis inhibition.1–3,14,16–18 There are many evidences supporting this view, such as the demonstration that normal fetuses exposed to a maternal daily diet with higher content of polyphenol substances (above the 75th percentile) have higher ductal velocities and RV/LV ratios than fetuses exposed to lower amounts of PRF (below the 25th percentile).15,16 A cause and effect relationship between maternal ingestion of polyphenol-rich beverages and fetal DC in late pregnancy has been experimentally shown in an animal model using fetal lambs.19 Case reports in the recent literature have also described fetal DC in the human fetus following maternal consumption of camomile tea and antocyanins,17,18 with reversion of the effect after suspension of the flavonoid-rich beverages from the diet. As the early reports in the decade of 1980 that indomethacin and other NSAID, when taken by pregnant women in the third trimester, could lead to fetal DC,2,37–39 many reports have dealt with the pharmacological mechanism for this phenomenon, being c 3.0 2.5 2.0 1.5 1.0 0.5 Pulsatility index 01 Pulsatility index 02 2.5a b 0.7 0.6 0.5 0.4 0.3 0.2 0.1 2.0 1.5 1.0 0.5 Systolic velocity 01 Systolic velocity 02 Diastolic velocity 01 Diastolic velocity 02 Figure 2 Behavior of ductal flow velocities and pulsatility index in fetuses with ductal constriction secondary to maternal ingestion of polyphenol-rich foods before and after dietary intervention. (a) Blox-plot of mean systolic velocities before (01) and after (02) dietary intervention. (b) Blox-plot of mean diastolic velocities before (01) and after (02) dietary intervention. (c) Blox-plot of mean pulsatility indices before (01) and after (02) dietary intervention. Polyphenols and fetal ductal constriction P Zielinsky et al 577 Journal of Perinatology
  5. 5. a consensus that inhibition of the prostaglandin metabolic pathway, especially cyclooxygenase-2, was the most important.3,4,40,41 It was also shown that this effect was reversible after decreasing the dosage of these drugs or completely suspending its administration.3,42 From that time on, and based on this knowledge, utilization of NSAID in late pregnancy has been avoided whenever possible. As PRF are largely consumed in the general population, including during gestation,43–45 and their clinical effects as anti- inflammatory and antioxidants products are widely described, we sought the basic literature about their chemical properties, which describes unequivocally that they depend on inhibition of prostaglandin biosynthesis.20,22–27,29 The presumption that fetal DC unrelated to maternal ingestion of NSAID could be associated to maternal intake of PRF has been investigated and the results have corroborated the idea.8,11,14,16–18 We then designed the present open clinical trial in order to determine if restriction of these substances in fetuses with third trimester DC without maternal intake of NSAID would be followed by reversal of the disorder. The results herein presented are consistent with this hypothesis. Adhesion to diet by the pregnant women who have participated in this study, decreasing daily ingestion of the 27 specific foods with the highest content of polyphenols after dietary orientation to a much lower amount,32 points toward the feasibility of establishing dietary habits with very low consumption of these substances. There are limitations to the present study. First, we acknowledge that a stronger level of evidence would have been achieved with a randomized clinical trial. However, the ethics of such delineation is debatable, as the present evidences strongly point toward the association between maternal ingestion of PRF and fetal DC. Probably the same reasoning have been used for now more than three decades with the clinical recommendation to avoid maternal administration of NSAID in late pregnancy, as there has never been published, to our knowledge, a randomized clinical trial to test the hypothesis that these drugs are harmful to the fetus, because of their ductal constrictive effect. Based on the knowledge already accumulated, how could the option of ‘no intervention’ in fetuses with overt DC be acceptable? Second, and for the same reason, we did not have a control group of fetuses with DC in which no dietary orientation was offered. Instead, we describe a control group made up of normal fetuses with no DA constriction, in order to show that when no dietary intervention is performed, the ductal flow dynamics does not change. The comparison of the results obtained in the present series with those depicted in historical cohorts studied before this hypothesis had been raised has not been performed. Moreover, this study did not address the issues of postnatal outcomes and of the potential maternal psychological impacts of nutritional intervention. An ongoing multicenter case–control study aims to assess the odds ratio of neonatal pulmonary hypertension resulting from fetal DC according to maternal ingestion of PRF in late pregnancy. A total ban on all foods containing polyphenols in pregnancy would seem a rather exaggerated conclusion to draw from this study. Before setting off a major health scare leading to complete mandatory polyphenol abstention, the facts must be put into proportion. Conclusion In conclusion, this study demonstrates that maternal dietary intervention in pregnancies with fetal DC not associated to NSAID usage in the third trimester, aiming to restrict the intake of PRF, results in complete reversal of DC (wide open DA) after a period of at least 3 weeks. This new knowledge may influence routine obstetrical surveillance of maternal dietary habits in late pregnancy. Conflict of interest The authors declare no conflict of interest. References 1 Luchese S, Manica JL, Zielinsky P. Intrauterine ductus arteriosus constriction: analysis of a historic cohort of 20 cases. Arq Bras Cardiol 2003; 81(4): 405–410, 399–404. 2 Momma K, Konishi T, Hagiwara H. Characteristic morphology of the constricted fetal ductus arteriosus following maternal administration of indomethacin. Pediatr Res 1985; 19(5): 493–500. 3 Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME. Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother 2006; 40(5): 824–829. 4 Toyoshima K, Takeda A, Imamura S, Nakanishi T, Momma K. Constriction of the ductus arteriosus by selective inhibition of cyclooxygenase-1 and -2 in near-term and preterm fetal rats. Prostaglandins Other Lipid Mediat 2006; 79(1–2): 34–42. 5 Takami T, Momma K, Imamura S. Increased constriction of the ductus arteriosus by dexamethasone, indomethacin, and rofecoxib in fetal rats. Circ J 2005; 69(3): 354–358. 6 Jaillard S, Elbaz F, Bresson-Just S, Riou Y, Houfflin-Debarge V, Rakza T et al. Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs. Br J Anaesth 2004; 93(6): 818–824. What is known on this subject K Fetal ductal constriction is related to inhibition of the prostaglandin synthesis as a result of NSAID exposition in late pregnancy. Third trimester maternal intake of polyphenol-rich foods, which also inhibit prostaglandins, may likewise trigger ductal constriction in the fetus. 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