Studies employing Doppler echocardiogram and color flow mapping
have indicated that functional closure of the ductus arteriosus
in full term infants takes place in practically all newborns at
around 72 hours of life ( ).
In preterm newborns (PT-NB), the ductus arteriosus closes a little
later, taking place in the majority of those with gestational ages
of more than 30 weeks by 96 hours of life ( ).
In contrast, PT-NB with gestational ages less than 30 weeks and,
in particular, those who exhibit hyaline membrane disease have an
increased frequency of patent ductus arteriosus (PDA) ( ).
The ever greater use of exogenous surfactant has increased this
incidence and has also seen a significant increase in left-right
shunt through the ductus arteriosus. This being so, PDA can severely
aggravate the clinical conditions of NB, increasing ventilation
requirements and encouraging heart failure in addition to other
consequences which together worsen the prognosis of PT-NB.
In recent years, innumerable studies have been undertaken with
the objective of assessing the influence of PDA on the progress
of PT-NB. Doppler echocardiogram with color flow mapping has become
a fundamental tool for these assessments, allowing the early detection
of this defect and also evaluation of its hemodynamic repercussions.
It is clear that the global assessment of these repercussions should
also be made based on clinical criteria as well, such as, for example,
the presence of heart murmur, increased precordial activity or bounding
pulses. Associations between clinical and echocardiographic parameters
in a given group of PT-NB can provide fundamental elements for the
detection of PDA and also permits more appropriate treatment ().
All of these factors lead us to postulate that the presence of
PDA may cause echocardiographic alterations that would precede the
clinical manifestations. The present study was therefore designed
with the objective of analyzing the relationship between the echocardiographic
findings in patent ductus arteriosus and the presence of clinical
signs in PT-NB.
Study population and methods
This was a single center study of a longitudinal and prospective
cohort, undertaken at the Nursery Annex at the Maternity Unit at
the Hospital das Clínicas (FMUSP), part of the Pediatria
Neonatal and Intensive Pediatric Service of the Instituto da Criança
Professor Pedro de Alcântara at FMUSP.
The study population consisted of consecutive PT-NB with gestational
ages of less than or equal to 34 weeks, born between 01 July 2000
and 03 August 2001. Informed consent was obtained from parents and
the study was approved by the institution's Committee for Ethics
Infants were excluded if they exhibited a five minute Apgar score
less than or equal to five or congenital heart disease (except patent
foramen ovale or ductus arteriosus) or if they were the children
of diabetic mothers.
The NB were classed according to birth weight as appropriate for
gestational age (AGA) or small for gestational age (SGA). Newborns
were defined as AGA if their birth weights were between the 10th
and 90th percentiles of the intrauterine growth curves created by
Ramos6 and SGA if their birth weights were below percentile 10 of
the same reference standard. The definitive gestational age (GA)
for each NB was determined based on the date of last menstruation
or by the New Ballard method (
The NB underwent clinical and echocardiographic examination on
the third and seventh days of life and, then every week or 15 days,
until reaching term, i.e., between the 38th and 40th weeks of postconceptional
gestational age, or earlier if the patient was discharged or had
The physical examination of the PT-NB was performed by a neonatologist,
a member of the nursery's own treatment team, who was unaware of
the echocardiogram results. The clinical variables investigated
were : weight (grams); systemic arterial pressure in mmHg, measured
with an oscillometric, noninvasive method at the upper right arm,
pulse pressure in mmHg, defined as the difference between systolic
and diastolic pressures; the presence of heart murmur or increased
visible or palpable precordial activity. Clinical signs of PDA were
defined as the presence of one or more of the following:
- heart murmur;
- pulse pressure above 30 mmHg;
- visibly increased precordial activity.
The echocardiographic examinations were carried out using a TOSHIBA®
SSH-140-A ultrasound machine with 5 and 7.5 MHz electronic sector
transducer. All of the examinations were carried out at the bedside
and the specialist operating the echocardiograph was unaware of
the newborns' clinical status.
nterobserver variation was eliminated by the use of a single examiner
who was not involved in treating the NB (J.Y.A). Intraobserver variation
was evaluated and did not exceed 4% of the echocardiographic measurements
performed. All measurements were taken three times and averaged.
An anatomic analysis was performed by sequential segmentation, defining
the general cardiac anatomy and attempting to rule out all cardiac
Echocardiographic measurements in M mode were taken in accordance
with recommendations made by the American Society of Echocardiography,
published in 1980 (
and adapted for preterm newborn by Silverman in 1993 ( ).
The following were evaluated: diameters of the aorta and left atrium
and the left atrium-aorta ratio; systolic and diastolic diameters
of the left ventricle; diastolic thickness of the interventricular
septum and posterior left ventricle wall. By means of pulse Doppler,
the aortic cardiac output in the left ventricle exit channel ( ).
The effects of PDA on each of these echocardiographic parameters
The diameter of the ductus arteriosus was determined using color
flow mapping , as described by Roberson & Silverman (
Ductus arteriosus diameter was defined as the smallest internal
diameter observed by color flow mapping , closest to the pulmonary
extremity of the ductus arteriosus.
Those NB with PDA on the third day of postnatal life were divided
into two groups according to the postnatal evolution of their ductus
arteriosus: Group A: NB who exhibited spontaneous ductus arteriosus
closure by the seventh day of life and Group B: NB who had not exhibited
spontaneous ductus arteriosus closure by the seventh day of life.
The patient sample was described using percentages, measures of
central tendency (means) and of dispersal (standard deviation).
The effect that PDA had on the echocardiographic parameters investigated
was gauged by means of the application of regression models, using
techniques for the analysis of longitudinal data, using the presence/absence
of PDA as co-variable. Significance was defined as a p value of
less than 0.05.
Student's t test was employed to compare the mean diameter of ductus
arteriosus in group A with that in group B. Furthermore, a ROC curve
was constructed with the objective of evaluating whether the diameter
of the ductus arteriosus predicts its spontaneous closure and to
identify cutoff points for differentiating these patients.
One possible association between the existence of clinical signs
of PDA and failure to spontaneously close the ductus arteriosus
was investigated by means of homogeneity tests (Pearson's chi-square)
The statistical software package SPSS-10.0 was used for data analysis.
Sixty-nine NB with GA at birth less than or equal to 34 weeks were
selected for the study. Eight of them were excluded, four because
their mothers had been given corticosteroids, three because they
presented congenital heart disease (intraventricular communication
in two and transposition of the great arteries in one) and the last
due to severe perinatal asphyxia.
The characteristics of the newborn infants evaluated in this study
are described in Table 1.
Table 1 -
Characteristics of preterm newborns assessed in the study
The clinical assessment performed on the third day of life detected
heart murmur in eleven NB (18.0%), visibly increased precordial
activity in eight (13.1%) and increased pulse pressure in just two
NB (3.3%). All of these NB had patent ductus arteriosus detected
by echocardiographic examination.
On the third day of postnatal life PDA was detected in 21 NB (34.4%).
If the subset of NB with weights below 1,000 g is taken alone, PDA
was observed in 58.8% (10/17), while among those weighing more than
1,000 g, this incidence was 25% (11/44), which is a statistically
significant difference (p = 0.0001). The presence of PDA was observed
in 52.2% (12/23) of those NB with GA of less than 30 weeks, while
for the subset of NB with GA above 30 weeks, the incidence was 23.7%
(9/38), which is also a statistically significant difference(p <
The echocardiographic measurements were compared according to the
presence or absence of PDA and investigate the difference between
measurements for the two outcomes. It was observed that the presence
of PDA significantly increased the diameter of the left atrium,
diastolic and systolic left ventricle diameters, interventricular
septum thickness and the posterior wall of the left ventricle in
addition to aortic cardiac output measurements. The magnitudes of
these increases for each variable are shown in Table 2. The presence
of PDA had no significant impact on the measurements of the aorta
or the left atrium-aorta ratio.
Table 2 -
Effects of the presence of patent ductus arteriosus (PDA) on the
Seven (33.3%) of the 21 NB with PDA on the third day of life had
exhibited spontaneous ductus arteriosus closure by the seventh day
(Group A) and in 14 NB (66.6%) this spontaneous closure did not
take place (Group B). The mean diameter of the ductus arteriosus
was significantly greater in group B (2.6±0.7 mm) than in
group A (1.5±0.5 mm; p = 0.003). The area under the ROC curve
for no spontaneous ductus arteriosus closure was 0.93 (95%IC = 0.81-1.04;
p = 0.003). The cutoff point that gave greatest sensitivity (100%)
for the identification of NB with no spontaneous closure was a 1.7
mm diameter ductus arteriosus. The point that gave the greatest
specificity (100%) was at 2 mm diameter.
With respect of clinical signs of PDA (heart murmur, increased
precordial activity or increased pulse pressure) on the third day
of postnatal life, a significantly greater frequency was observed
for group B (71.4%) than for group A (14.3%; p = 0.013) (Table 3).
Table 3 -
Characteristics of preterm newborns that had spontaneous closure
of the arterial canal (group A) versus those with no spontaneous
closure (group B)
None of the NB in group A exhibited reopened ductus arteriosus
during the follow-up period. Ten of the NB in group B received pharmacological
treatment with indomethacin, one NB underwent surgery, and the remaining
three NB suffered fatal outcomes on the fourth day of life without
having received treatment for ductus arteriosus.
Pharmacological treatment for ductus arteriosus was given by the
14th day of postnatal , with three doses of indomethacin (0.2 mg/kg/dose
given enterally) given at 12 hour intervals. Eight (80%) of these
NB exhibited complete ductal closure and none of them exhibited
reopened ductus arteriosus during the follow-up period. Two NB (20%)
exhibited partial closure after 1 cycle of indomethacin, one of
whom was given a second cycle, resulting in complete closure. In
one case the decision was taken to treat the ductus arteriosus with
surgery on the fifth day of postnatal life, since pharmacological
treatment was not attempted because of gastric hemorrhaging.
The three NB who presented PDA on day three and went on to die
on the fourth, suffered massive pulmonary hemorrhaging. These NB
had GA below 30 weeks, diagnoses of hyaline membrane disease, were
given exogenous surfactant on the first day of life and all had
a ductus arteriosus with a diameter of more than 2 mm. However,
none of them had presented clinical signs of PDA on the third day
The behavior of PDA in PT-NB has been the subject of innumerable
studies for almost 30 years (
There are, however, few in the published literature that have prospectively
assessed the behavior of PDA in PT-NB, correlating clinical data
with findings from echocardiography with Doppler and color flow
mapping ( ).
In this study we observed a 34.4% incidence of PDA on the third
day of life. This incidence was significantly higher among NB with
birth weights below 1,000 g (58.8%) and also among those with GA
at birth of less than 30 weeks (52.2%). These results are comparable
with findings by Reller et al. (
who reported an incidence of PDA, on the third day of postnatal
life, of around 50% of NB with GA at birth of less than 29 weeks,
and an even higher incidence among those with hyaline membrane disease
One of the most intriguing issues in the evolution of PDA in PT-NB
is the definition of the hemodynamic repercussions of ductus arteriosus,
which sometimes is not easy in clinical practice, as was described
by Evans (
This is why the association with echocardiographic assessment is
of fundamental importance. In this study, the effect of PDA was
assessed in relation to certain echocardiographic variables. It
was observed that ductus arteriosus significantly increased systolic
and diastolic left ventricle diameters, left atrium diameter, interventricular
septum and wall thickness and aortic cardiac output. These results
demonstrate a dilatation of the left-hand cardiac chambers, probably
as a result of excessive pulmonary flow and increased pulmonary
venous return to the left atrium. In this state left ventricular
systolic volume is increased and, finally, so is aortic cardiac
output. It was observed that the increase in cardiac output in the
presence of PDA reached approximately 40 ml/min/kg (±10 ml/min/kg),
which accounts for a mean increase on these NB's baseline cardiac
output of 30%. This result is in agreement with others in the literature,
such as findings described by Walther et al., who observed an increase
in the aortic cardiac output of NB with birth weights below 1,250
g of around 60 ml/min/kg, in the presence of ductus arteriosus and
with hemodynamic repercussions ( ).
Lindner et al. observed an increase in aortic cardiac output of
up to 50% against baseline and also observed that, after ductal
closure, the cardiac output level returned to baseline ( ).
One measurement that has always been much used in the literature
top assess the repercussions of ductus arteriosus is the left atrium/aorta
ratio, with a ratio of more than 1.5 exhibiting high sensitivity
and specificity for detecting ductus arteriosus, as reported by
Iyer & Evans (
In this study, however, we did not observe any effect of PDA on
this echocardiographic measurement, with no significant difference
demonstrated. This might be because in many PT-NB, the size of the
aorta is already enlarged and, even if the left atrium also increases,
the LA/AO ratio may not. Another motive may be the presence of a
patent foramen ovale, which may reduce the size of the left atrium,
by left-right interatrial shunting, even in the presence of a large
ductus arteriosus ( ).
With relation to clinical diagnosis of PDA, we observed that clinical
symptoms were present in 52% of the NB with PDA on the third day
of life, which is compatible with the literature, with heart murmur
being the most common clinical symptom. In other studies a hyperactive
precordium has been the most sensitive clinical sign for PDA diagnosis,
attaining a sensitivity of 95%, as reported by Kupferschmid et al.
However, their clinical assessment was performed at the end of the
first week of postnatal life, in contrast with our study, in which
assessments were made on day three. This could explain the differences
in the two studies' observations since on the third day it is possible
that a hyperactive precordium may not yet be detectable.
It is known that when PDA is diagnosed on the third day of life
there is always the possibility of its spontaneous closure. In their
study, Roberson & Silverman found an incidence of spontaneous
ductal closure after day three of 27.1% of the NB studied (
That result is similar to our study, in which spontaneous closure
of the ductus arteriosus took place in 33.3% of the NB studied.
This study employed a sample of convenience that consecutively
included all patients during the study period. Taking into account
the sample size (seven patients in group A and 14 in group B) and
the mean diameter of 1.4±0.5 mm,6 for the ductus arteriosus
in the general population, this study offered a power of 80% with
alpha at 5% for the detection of a difference of 60% between study
groups, which, in our opinion, is satisfactory, although it remains
a weak point of the study.
When a comparative analysis was performed of the subset of NB who
exhibited spontaneous ductal closure (group A) against the group
in which this did not occur (group B), it was observed that the
two groups were comparable in terms of birth weight, gestational
age at birth, incidence of hyaline membrane disease, use of surfactant
and need for mechanical ventilation. It was also observed, however,
that ductus arteriosus diameter was larger in group B (2.6±0.6
mm) than group A (1.4±0.6 mm), which is similar to results
observed by Roberson & Silverman, who reported ductus arteriosus
measurements of 2.6±0.7 mm and 1.8±0.8 mm, respectively
These results demonstrate that the larger the duct, the lower the
chance of spontaneous closure. So, from what size of diameter onwards
does closure fail to occur? In an attempt to answer this question
we constructed a ROC curve on which we could observe that the cutoff
point for duct diameter with greatest sensitivity (100%) was 1.7
mm and the diameter with greatest specificity (100%) was 2.2 mm.
In other words we can state that PDA smaller than 1.7 mm will probably
close spontaneously, while those above 2.2 mm will not close spontaneously.
In a similar study of PT-NB under 1,500 g, Kluckow & Evans found
that an internal ductus arteriosus diameter above 1.5 mm offered
a sensitivity of 81% and specificity of 85% for detecting PDA with
hemodynamic repercussions (
Pharmacological treatment of the ductus arteriosus was given to
10 patients in group B with indomethacin given enterally. This is
because when the study was carried out, intravenous indomethacin
was not available at the hospital where this study was performed.
Even so, treatment was successful for eight of these patients (80%).
Clinical signs of PDA were observed on the third day of life in
just 14.3% of the group in which there was spontaneous ductal closure
and in 71.4% of the other group, which is also similar to results
described by Roberson & Silverman (
This demonstrates that the presence of clinical signs on day three
should increase the risk of failure to close spontaneously.
It is well worth emphasizing that, in our study, three NB with
GA of less than 30 weeks and who presented PDA diameters greater
than 2.2 mm, but with no clinical signs on day three, suffered fulminating
deterioration with severe pulmonary hemorrhaging and death between
the third and fourth days of life, with no specific treatment for
ductus arteriosus having been attempted. This would appear to be
a special group of NB, who present a high risk of developing severe
and fatal complications, possibly due to the major left-right flow
through the ductus arteriosus which targets the lungs in the first
As a result of this, it becomes ever more necessary to attempt
to identify this group of NB as early as possible so that more aggressive
treatment can be employed, even before the third day of life. Some
international perinatology centers have observed that, in NB with
birth weights below 1,000 g who present PDA on the first day of
life, there is an 80% risk of developing persistent signs of ductus
In a prospective, randomized study carried out by Couser et al.,
indomethacin was used prophylactically during the first 24 hours
of the lives of PT-NB who had received surfactant in the delivery
room, observing a significant reduction in left-right shunt via
the ductus arteriosus ( ).
In conclusions, we can state that among PT-NB, and especially among
those with GA less than 30 weeks, the observation on the third day
of life of a persistent patent ductus arteriosus with a diameter
of more than 2.2 mm on echocardiogram with color flow mapping can
predict the need for treatment, especially when there is also at
least one clinical sign. Such NB should be given pharmacological
or surgical treatment to close the ductus arteriosus as quickly