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.

Polyphenol-rich food general and on pregnancy effects: a review.

This review aimed to investigate possible protective or deleterious effects of polyphenol-rich foods (PRF) on chronic diseases, e.g. cardiovascular, and in pregnant women, along with their antioxidant and anti-inflammatory action. A great variety of foods and beverages, such as herbal teas, grape and orange derivatives, dark chocolate, and many others contain high concentrations of flavonoids and are freely consumed by the general population. In humans, PRF consumption reduces lipid peroxidation, and several studies have shown a positive correlation between an increased consumption of PRF and a decrease in the incidence of cardiovascular disease. On the other hand, current studies have suggested that maternal ingestion of PRF, especially during the third trimester of pregnancy, could be associated to fetal ductal constriction (DC). Fetuses exposed to this type of diet show higher ductal velocities and lower pulsatility indexes, as well as larger right ventricles than those exposed to minimal amounts of these substances. The underlying mechanism involved in these conditions has not been entirely elucidated, but it seems to be a result of the antioxidant and anti-inflammatory effects of polyphenols by some pathway. Furthermore, taking into account the deleterious effect in late-pregnancy against the numerous positive effects associated to polyphenols, this dual behavior deserves attention particularly to control the dietary ingestion of PRF during gestation. In this line, same PRF, natural constituents of human diet, may represent risk to fetal in late pregnancy compared to the use of nonsteroidal anti-inflammatory drugs.

Restricción del ductus arterioso fetal en gestante del tercer trimestre por consumo de paracetamol / Fetal ductus arteriosus constriction in the final third of pregnancy due to paracetamol comsumption

El ductus arterioso es una derivación que conecta la arteria pulmonar con el arco aórtico el que permite la descarga del ventrículo derecho sin pasar por la alta resistencia de los pulmones. La permeabilidad del conducto arterioso se mantiene durante la gestación por las prostaglandinas producidas especialmente PGE2, que circulan a nivel local, especialmente PGE2, y la baja saturación de oxígeno fetal. Se trata de una paciente que desde la semana 20 de gestación es diagnosticada de cólico renal con la necesidad de varios ingresos y colocación de catéter doble J por parte de Urología y la cual recibió tratamiento con paracetamol intravenoso y oral. Los controles ecográficos obstétricos a los largo de la gestación fueron normales hasta que en semana 32, cuando ingresa de nuevo por cuadro sospechoso de cólico renal tratado con Paracetamol, se objetivan en ecografía hallazgos compatibles con restricción precoz del ductus arterioso. Se indicó suspender el paracetamol y los cambios se redujeron en las 48 horas posteriores y casi desaparecieron por completo una semana tras la retirada de la medicación. La gestación llegó a término y el recién nacido presentó un ecocardiograma postnatal normal. Recomendamos la restricción de los analgésicos no opiáceos en el tercer trimestre y el seguimiento con Doppler del conducto arterioso en los casos en que se requiriera usarlos(AU)

Ductus arteriosus is a derivation that connects the pulmonary artery with the aortic arch and allows the discharge from the right ventricle without passing the high resistance of lungs. Permeability of the ductus arteriosus is kept during gestation because of the production of prostaglandins, particularly PGE2, which circulates locally, and the low fetal oxygen saturation. Here is a pregnant woman who, since her 20th week of gestation was diagnosed as a renal colic case. She required several admissions to hospital and placement of double J stent in the urology service and she was treated with intravenous and oral paracetamol. Obstetric ultrasound scans throughout gestation were normal until week 32, when she was admitted to hospital again for suspected renal colic and treated again with paracetamol. At that moment, findings compatible with early ductus arteriosus constriction were observed in ultrasound. It was then decided to stop the paracetamol treatment, the changes declined in the following 48 hours and they almost disappeared completely after one week after the medication withdrawal. It was finally a term pregnancy and the postnatal echocardiogram of the newborn was normal. Restricting non-opioid analgesics in the third pregnancy trimester and the follow up of the ductus arteriosus with Doppler technique when required(AU)

Nitric oxide and reactive species are modulated in the polyphenol-induced ductus arteriosus constriction in pregnant sheep.

OBJECTIVE: Because we have previously demonstrated the relation between polyphenol-rich foods (PRF) consumption and ductus arteriosus constriction, in this work, pregnant sheep were submitted to oral PRF intake for 14 days to understand how this process occurs. Fetal Doppler echocardiography, oxidative and inflammatory biomarkers and total polyphenol excretion were evaluated. RESULTS: The high polyphenol intake induced ductus arteriosus constriction by 71.6% increase in systolic (P = 0.001) and 57.8% in diastolic velocities (P = 0.002), and 18.9% decrease in pulsatility index (P = 0.033), along with 1.7-fold increase in total polyphenol excretion, 2.3-fold decrease in inflammatory mediator nitric oxide and following redox status changes (mean ± standard deviation): higher protein carbonyls (1.09 ± 0.09 and 1.49 ± 0.31), catalase (0.69 ± 0.39 and 1.44 ± 0.33) and glutathione peroxidase (37.23 ± 11.19 and 62.96 ± 15.03) in addition to lower lipid damage (17.22 ± 2.05 and 12.53 ± 2.11) and nonprotein thiols (0.11 ± 0.04 and 0.04 ± 0.01) found before and after treatment, respectively. Ductal parameters correlated to NOx , catalase, glutathione peroxidase and protein carbonyl. CONCLUSION: Our results highlight the need to reduce maternal PRF intake in late pregnancy to prevent fetal duct constriction through NO-mediated vasoconstrictive action of polyphenols.

Prenatal effects of maternal consumption of polyphenol-rich foods in late pregnancy upon fetal ductus arteriosus.

Fetal circulation has characteristic features, being morphologically and functionally different from extrauterine circulation. The ductus arteriosus plays a fundamental role in directing the blood flow to fetal inferior body parts. Basically, the ductus arteriosus directs 80-85% of the right ventricular output arising from the superior vena cava, coronary sinus, and a small part from the inferior vena cava to descending aorta. Its histological structure is made up predominantly by a thick muscular layer, differently from the aorta and the pulmonary artery, which increases with gestational age. The fibers have a circumferential orientation, especially at the external layers, facilitating and making effective ductal constriction. These factors may generate lumen alterations which may cause fetal and neonatal complications, such as heart failure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternal administration of indomethacin and/or other antiinflammatory drugs interfere in prostaglandins metabolism, causing ductal constriction. However, many cases of fetal ductal constriction, as well as of persistent neonatal pulmonary artery hypertension, remain without an established etiology, being referred as "idiopathic." In recent years, a growing body of evidence has shown that herbs, fruits, nuts, and a wide diversity of substances commonly used in daily diets have definitive effects upon the metabolic pathway of inflammation, with consequent inhibition of prostaglandins synthesis. This antiinflammatory action, especially of polyphenols, when ingested during the third trimester of pregnancy, may influence the dynamics of fetal ductus arteriosus flow. The goal of this review is to present these new observations and findings, which may influence dietary orientation during pregnancy.

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.

Relationship between circulating platelet counts and ductus arteriosus patency after indomethacin treatment.

OBJECTIVE: To determine whether low platelet counts are related to the incidence of patent ductus arteriosus (PDA) after indomethacin treatment in preterm human infants. STUDY DESIGN: Multivariable logistic regression modeling was used for a cohort of 497 infants, who received indomethacin (within 15 hours of birth). RESULTS: Platelet counts were not related to the incidence of permanent closure after indomethacin constriction. There was a relationship between platelet counts and the initial degree of constriction; however, this relationship appeared to be primarily influenced by the high end of the platelet distribution curve. PDA incidence was similar in infants with platelet counts < 50 × 109/L and those with platelet counts above this range. Only when platelet counts were consistently >230 ×109/L was there a decrease in PDA incidence. CONCLUSION: In contrast to the evidence in mice, low circulating platelet counts do not affect permanent ductus closure (or ductus reopening) in human preterm infants.

New insights on fetal ductal constriction: role of maternal ingestion of polyphenol-rich foods.

Fetal ductus arteriosus constriction is a clinical disorder that occurs as a result of inhibition of the prostaglandin synthesis pathway, and has long been associated to maternal intake of nonsteroidal antiinflammatory drugs in late pregnancy. As a consequence of an increased right ventricular pressure, with tricuspid regurgitation and heart failure, there is a risk for the development of neonatal pulmonary artery hypertension. This article reviews the basic knowledge of the mechanisms involved in this important disorder. Clinical and experimental evidence that maternal consumption of polyphenol-rich substances, such as herbal teas, orange and grape juice, chocolate, and others, may interfere with fetal ductus arteriosus dynamics are discussed. Preventive measures to avoid fetal ductal constriction in the third trimester of pregnancy are discussed, including the possible need to change maternal dietary orientation, aiming to limit ingestion of foods with high concentrations of polyphenol-rich substances.

Intrauterine ductus arteriosus constriction: analysis of a historic cohort of 20 cases.

OBJECTIVE: To describe the relative incidence, presentation, and evolvement of fetuses with early ductus constriction. METHODS: Twenty fetal echocardiograms indicating ductus constriction were reviewed in a population of 7000 pregnants. RESULTS: The cases were divided into group A (related to maternal use of cyclooxygenase inhibitors [n=7] and group B (idiopathics [n=13]). Mean gestational age was 32.5 +/- 3.1 (27-38) weeks and maternal age was 28.2 +/- 8.5 (17-42) years. Mean systolic velocity in the ductus was 2.22 +/- 0.34 (1.66-2.81) m/s, diastolic velocity 0.79 +/- 0.28 (0.45-1.5) m/s, and pulsatility index 1.33 +/- 0.36 (0.52-1.83). Two cases of ductal occlusion were noted. In 65% of the cases, an increase occurred in the right cavities; in 90% of the cases, tricuspid or pulmonary regurgitation, or both, occurred, with functional pulmonary atresia in 1 case. Diastolic velocity was greater in group A (1.13 +/- 0.33) than in group B (0.68 +/- 0.15) (P=0.008). The other data were similar in the 2 groups. The evolvement was not favorable in 4 patients from group B, including 1 death and 2 cases of persistent pulmonary hypertension. CONCLUSION: The high incidence of idiopathic constriction of the ductus arteriosus suggests that its diagnosis is underestimated and that many cases of persistence of fetal circulation in newborns may be related to constriction of the ductus arteriosus not diagnosed during intrauterine life. Group B had a lower severity but a risk of an unfavorable evolvement, suggesting a distinct alteration.

Tratamiento con eritropoyetina humana recombinante en período neonatal: indicaciones y controversias / Treatment with recombinant human erythropoietin in the neonate: progress and controversies

La eritropoyetina recombinante (rHuEPO) se utiliza en dos patologías del neonato que se caracterizan por tener niveles inadecuadamente bajos de eritropoyetina circulante: la anemia del prematuro (AP) de muy bajo peso de nacimiento y la anemia hiporregenerativa tardía de la enfermedad hemolítica por incompatibilidad Rh (EHIRh). La experiencia recogida luego de 5 años de utilización en la AP ha demostrado que : a) parece no traer complicaciones; b) para ser efectiva, debe usarse a dosis no inferiores a 500 Ul/kg/semana; c) induce una marcada estimulación de la eritropoyesis, evidenciable por la importante respuesta reticulocitaria observada; d) disminuye significativamente los requerimientos transfuncionales cuando se administra a partir de la 2a. semana de vida; e) no está aún establecida la utilidad de su empleo desde las primeras horas de vida; f) el tratamiento debe durar de 6 a 8 semanas; g) el principal factor limitante de su eficacia terapéutica es la depleción de hierro, por lo que el mismo debe administrarse a dosis de 6 mg/kg/día o superiores mientras dure el tratamiento con rHuEPO. Por lo tanto, su utilización rutinaria parece estar justificada para disminuir la probabilidad de ocurrencia de complicaciones transfuncionales, aunque simultáneamente se deberán realizar los máximos esfuerzos para establecer criterios transfusionales estrictos y disminuir los volúmenes de sangre extraídos para análisis. En niños con EHIRh que han recibido transfusiones intrauterinas se produce una marcada inhibición de la eritropoyesis que demora 2 a 4 meses en recuperarse espontáneamente. El tratamiento con rHuEPO, en los casos comunicados, logró evitar la indicación de transfusiones adicionales. Se encuentran en marcha algunos estudios prospectivos

Factors determining reopening of the ductus arteriosus after successful clinical closure with indomethacin.

OBJECTIVE: To examine the role of ductus arteriosus (DA) constriction and loss of luminal blood flow in producing permanent closure of the DA in human infants. METHODS: We studied 77 newborn infants (gestational age, 23 to 33 weeks) with asymptomatic patent ductus arteriosus (PDA), who had "complete clinical closure" (defined as the disappearance of all PDA signs) after treatment with indomethacin (three doses within 36 hours). All infants had an echocardiogram 24 to 36 hours after the last dose of indomethacin. They were then followed for the development of ductus reopening. RESULTS: Despite the absence of clinical signs, 18 (23%) of 77 infants still had some residual luminal blood flow according to their echocardiograms. The failure to obliterate luminal blood flow completely was directly related to the infant's postnatal age when treatment was begun and to the amount of fluid administered before treatment. Subsequently the DA reopened in 16 (21%) of 77 infants. As predicted, infants with residual luminal blood flow after indomethacin treatment had a higher rate of subsequent clinical reopening than did those with no luminal flow. In addition, immature infants had a significantly higher reopening rate than did more mature infants. The increased risk of reopening in immature infants was seen even when indomethacin caused complete obliteration of ductus luminal blood flow. CONCLUSION: The DA of immature infants is resistant to the constriction-induced ischemic damage that is necessary for subsequent permanent closure of the vessel.

Effect of low intravaginal doses of prostaglandin E2 on the closure time of the ductus arteriosus in term newborn infants.

Seventeen term newborn infants (control subjects) and 17 whose mothers had been given intravaginal doses of prostaglandin E2 (PGE2) were examined serially by color Doppler echocardiography to determine whether maternal PGE2 prolonged ductal patency. No clinically relevant differences in closure times were found. Low-dose intravaginal PGE2 therapy was not associated with prolonged ductal patency in term infants.

Ductus arterioso en prematuros / Patent ductus arteriosus in premature infants

La mejoría de la terapia ventilatoria en prematuros con síndrome de dificultad respiratoria aumentó la incidencia del ductus arterioso persistente en esta población. La incidencia del ductus permeable es incierta y depende de la edad gestacional, sexo y stress perinatal; la permeabilidad en niños con peso de nacimiento inferior a 1.750 g es del 31% y en los menores de 1.000 g del 80% (Universidad de California, San Fracisco). La incidencia es mayor en los niños con síndrome de difucultad respiratoria por inmadurez pulmonar y en los tratados con surfactante artificial, en cambio, ha demostrado ser menor en prematuros con antecedentes de retardo del crecimiento intrauterino o administración de glucocorticoides a la madre. Las manifestaciones clínicas dependen de la magnitud del cortocircuito de izquierda a derecha a nivel del ductus, sumado a las características de inmadurez del miocardio, incapaz de tolerar sobrecargas de volumen. La disminución del flujo sistémico que se produce en el ductus hemodinámicamente significativo, altera la perfusión renal y gastrointestinal. La clínica del ductus en el prematuro ventilado con presión positiva es atípica. La ecocardiografía M y bidimensional y el estudio Doppler demostraron ser la principal metodología diagnóstica no invasiva, al evaluar relación AI/Ao, dimensión del ventrículo izquierdo e intervalos de tiempo sistólico de ventrículo izquierdo. El ductus sintomático es el que requiere tratamiento. Este consiste en el cierre farmacológico o quirúrgico. La digoxina no está indicada. La restricción hídrica, si bien altera las manifestaciones clínicas del ductus permeable, no modifica su indicencia (Green y colaboradores). Los diuréticos, si bien pueden controlar el fallo cardíaco congestivo, pueden ser causa de disbalances electrolíticos y contribuir a la persistencia del ductus permeable al aumentar la excreción renal de PGE2