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. 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. 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. (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. 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.
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