Maternal supplementation with docosahexaenoic acid does not cause constriction of fetal ductus arteriosus: randomized controlled trial.

OBJECTIVE: Docosahexaenoic acid (DHA) is recommended routinely in pregnancy to promote fetal development. DHA has anti-inflammatory activity, but its effects on the fetal heart and circulation are unknown. This study aimed to investigate whether maternal DHA supplementation in the third trimester affects maternal prostaglandin levels and fetal ductus arteriosus flow dynamics. METHODS: This was a double-blind randomized controlled trial with parallel groups conducted between 2018 and 2021. Pregnant women aged over 18 years with a normal fetus at 27-28 weeks' gestation showing no cardiac/extracardiac anomalies or ductal constriction were eligible for the trial. Women consuming substances with a known inhibitory effect on prostaglandin metabolism, such as non-steroidal anti-inflammatory drugs and polyphenol-rich foods, were excluded. The intervention group received oral supplementation of omega-3 with 450 mg/day of DHA for 8 weeks and the placebo group received capsules of soy lecithin for 8 weeks. Anthropometric measurements, assessment of polyphenol and omega-3 consumption, fetal morphological ultrasound examination, fetal Doppler echocardiographic examination and blood sample collection were performed at the start of the study and the latter two were repeated at follow-up. Prostaglandin E2 (PGE2) level and echocardiographic parameters were compared between the intervention and placebo groups and between baseline and follow-up. RESULTS: A total of 24 participants were included in each group. After 8 weeks, there were no significant differences between the intervention and placebo groups in maternal serum PGE2 level or Doppler echocardiographic parameters of ductal flow. No case of ductus arteriosus constriction was observed. The expected intragroup changes in cardiac morphology, as a result of advancing gestation, were present. CONCLUSIONS: Maternal DHA supplementation in the third trimester at a clinically recommended dose did not result in inhibition of PGE2 or constriction of the ductus arteriosus. These findings should be confirmed in postmarket surveillance studies with larger patient numbers in order to test the full safety profile of DHA and provide robust clinical reassurance. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Improvement in fetal pulmonary hypertension and maturity after reversal of ductal constriction: prospective cohort study.

OBJECTIVES: To test the hypotheses that estimated mean pulmonary arterial pressure (MPAP) decreases and pulmonary vascular maturation, assessed by the ratio of pulmonary arterial flow acceleration time to ejection time (AT/ET ratio), increases after reversal of fetal ductus arteriosus constriction by reducing maternal intake of the causal agent (prostaglandin inhibitors, such as polyphenol-rich foods or non-steroidal anti-inflammatory drugs), and that these effects are independent of gestational age, which are inferences not yet demonstrated in the clinical setting. METHODS: This was a prospective cohort study comparing Doppler echocardiographic ductal flow dynamics, MPAP and pulmonary arterial flow AT/ET ratio in third-trimester fetuses (≥ 28 weeks' gestation) with ductus arteriosus constriction, at the time of diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors either by suspending the use of pharmacological agents with potential for prostaglandin inhibition or by restricting the consumption of polyphenol-rich foods. MPAP was estimated using the Dabestani equation (MPAP = 90 - (0.62 × AT)), and pulmonary vascular maturity was assessed using the AT/ET ratio, according to reported validation studies. Student's t-test was used for comparison of variables at diagnosis with those after reversal of ductal constriction. Change in MPAP and pulmonary AT/ET ratio between the two assessments was compared with the expected change in the same gestational period in normal fetuses based on reference curves of MPAP and pulmonary AT/ET ratio constructed in normal fetuses from healthy pregnant women at 19-37 weeks' gestation, encompassing the same gestational age range as the study group (28-37 weeks). RESULTS: Seventy pregnancies with fetal ductus arteriosus constriction were included in the study. After 2 weeks of reduced maternal intake of prostaglandin inhibitors, normalization of mean systolic (change from 1.86 ± 0.34 m/s at diagnosis to 1.38 ± 0.41 m/s; P < 0.001) and diastolic (change from 0.41 ± 0.11 m/s to 0.21 ± 0.065 m/s; P < 0.001) ductal velocities and of mean pulsatility index (change from 1.99 ± 0.20 to 2.55 ± 0.42; P < 0.001) was demonstrated. MPAP decreased between the assessments (change from 66.7 ± 6.90 mmHg at diagnosis to 54.5 ± 6.70 mmHg after 2 weeks; P < 0.001) and mean pulmonary AT/ET ratio increased (change from 0.20 ± 0.06 to 0.33 ± 0.07; P < 0.001). Change in MPAP between diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors was -12.2 ± 0.30 mmHg, which was 5.3-times higher than that in 305 normal fetuses over 2 weeks during the same gestational period (-2.3 ± 0.19 mmHg) (P < 0.001), and change in pulmonary AT/ET ratio between the two assessments was 0.13 ± 0.08, which was 8.7-times higher than that in normal fetuses in the same gestational period (0.015 ± 0.08) (P < 0.001). CONCLUSIONS: Resolution of fetal ductal constriction is followed by a fall in MPAP and by an increase in pulmonary vascular maturity, to a significantly greater degree than is observed in normal fetuses in the same gestational-age period. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Increase of prostaglandin E2 in the reversal of fetal ductal constriction after polyphenol restriction.

OBJECTIVE: Anti-inflammatory substances that inhibit the synthesis of prostaglandins, such as non-steroidal anti-inflammatory drugs (NSAIDs) and polyphenol-rich foods, can cause constriction of the fetal ductus arteriosus. This study aimed to test the hypothesis that reversal of fetal ductal constriction after maternal restriction of polyphenol-rich foods, in the third trimester of pregnancy, is accompanied by increased plasma levels of prostaglandin E2 (PGE2). METHODS: This was a controlled clinical trial of women with singleton pregnancy ≥ 28 weeks undergoing fetal echocardiography. The intervention group included pregnancies with diagnosis of fetal ductal constriction and not exposed to NSAIDs. The control group consisted of third-trimester normal pregnancies. Both groups answered a food frequency questionnaire to assess the amount of total polyphenols in their diet, underwent Doppler echocardiographic examination and had blood samples collected for analysis of plasma levels of PGE2. Intervention group participants received dietary guidance to restrict the intake of polyphenol-rich foods. The assessments were repeated after 2 weeks in both groups. RESULTS: Forty normal pregnancies were assessed in the control group and 35 with fetal ductal constriction in the intervention group. Mean maternal age (26.6 years) and mean body mass index (30.12 kg/m2 ) were similar between the two groups. Intragroup analysis showed that dietary guidance reduced the median consumption of polyphenols (from 1234.82 to 21.03 mg/day, P < 0.001), increasing significantly the plasma concentration of PGE2 (from 1091.80 to 1136.98 pg/mL, P < 0.05) in the intervention group after 2 weeks. In addition, Doppler echocardiography showed reversal of fetal ductal constriction in the intervention group. No significant changes were observed in the control group. CONCLUSIONS: Dietary intervention for maternal restriction of polyphenol-rich foods in the third trimester of pregnancy is accompanied by increase in plasma levels of PGE2 and reversal of fetal ductal constriction. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Polyphenol supplementation inhibits physiological increase of prostaglandin E2 during reproductive period - A randomized clinical trial.

Anti-inflammatory property of polyphenols and their effect on the metabolism of prostaglandins is not established in healthy humans. This study aimed to evaluate the effect of polyphenol supplementation in plasma levels of prostaglandin E2 and other markers of inflammation and oxidative stress in women using contraceptives. In this randomized double-blind clinical trial, women aged 25-35 years were selected. Participants received capsules containing polyphenols or placebo, to be consumed for fifteen days. From 40 women randomized, 28 completed the study. Control group showed a significant increase in the levels of PGE2 (p=0.01) while the polyphenols group showed no change in these levels (p=0.79). There was an increase in hs-CRP (p<0.01) and F2-isoprostane (p=0.04) in the control group. The GSSG to GSH ratio significantly reduced in the polyphenols group (p=0.02). Supplementation with polyphenol capsules inhibited the increase in markers of inflammation and oxidative stress in women of childbearing age using combined hormonal contraceptives.

Reversal of fetal ductal constriction after maternal restriction of polyphenol-rich foods: an open clinical trial.

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 (≥3 weeks), 48/51 fetuses (96%) showed complete reversal of DC, with decrease in mean ductal systolic velocity (1.74±0.20 m s(-1) to 1.31±0.34 m s(-1), P<0.001), mean diastolic velocity (0.33±0.09 m s(-1) to 0.21±0.07 m s(-1), 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.

Maternal consumption of polyphenol-rich foods in late pregnancy and fetal ductus arteriosus flow dynamics.

OBJECTIVE: To test the hypothesis that maternal consumption of polyphenol-rich foods during third trimester interferes with fetal ductal dynamics by inhibition of prostaglandin synthesis. STUDY DESIGN: In a prospective analysis, Doppler ductal velocities and right-to-left ventricular dimensions ratio of 102 fetuses exposed to polyphenol-rich foods (daily estimated maternal consumption >75th percentile, or 1089 mg) were compared with 41 unexposed fetuses (flavonoid ingestion <25th percentile, or 127 mg). RESULT: In the exposed fetuses, ductal velocities were higher (systolic: 0.96+/-0.23 m/s; diastolic: 0.17+/-0.05 m/s) and right-to-left ventricular ratio was higher (1.23+/-0.23) than in unexposed fetuses (systolic: 0.61+/-0.18 m/s, P<0.001; diastolic: 0.11+/-0.04 m/s, P=0.011; right-to-left ventricular ratio: 0.94+/-0.14, P<0.001). CONCLUSION: As maternal polyphenol-rich foods intake in late gestation may trigger alterations in fetal ductal dynamics, changes in perinatal dietary orientation are warranted.