CLINICAL PROFILE OF PATENT DUCTUS ARTERIOSUS IN

NEONATES

A Dissertation Submitted for the Degree of M.D

(Pediatrics)

Examination of Bharati Vidyapeeth Deemed University,

Pune.

May- June 2013.

 CONTENTS:

Sr. No. Particulars Page No.

1. Introduction

2. Review of Literature

3. Aims and Objectives

4. Materials and Methods

5. Proforma

6. Results

7. Discussion

8. Conclusion

9. List of Abbreviations

10. References
 INTRODUCTION

Patent ductus arteriosus (PDA) is one of the more common congenital

heart diseases. The incidence of PDA is inversely proportional to the
gestational age and birth weight. It can cause significant morbidity in the
neonatal period especially in the preterm infants. Medical and surgical
modalities have been used in the prevention and treatment of PDA.

Pathophysiology:
During fetal life ductus arteriosus (DA) serves to divert blood from
the fluid filled lungs to the descending aorta and placenta. After birth closure
of the DA has to take place to result in the separation between pulmonary
and systemic circulation. The closure of DA occurs in two phases, the
functional closure occurring in the first few hours after birth and anatomic
closure occurring over the next several days. The closure depends on the
balance between dilating and constricting forces. Lower oxygen
concentrations in utero, and high circulating levels of prostaglandin E 2
(PGE2), Prostaglandin I2(PGI2)1 and nitric oxide (NO) like vasodilators help
in keeping the ductus patent. After birth the increase in arterial Po2, decrease
in blood pressure in the ductus lumen (due to decrease in pulmonary
vascular resistance), decrease in circulating PGE2 and PGE2 receptors 2
result in the constriction of the ductus. The constriction of the DA produces
ductus wall hypoxia which leads to remodeling 3 and thus anatomical closure
takes place. PDA in term infants is because the wall of ductus is deficient in
both mucoid endothelial layer and muscular media. In contrast with the full
term infants the premature ductus is less likely to close due to decreased
intrinsic tone, decreased sensitivity to oxygen and increased sensitivity to
PGE2 and nitric oxide4. Even when the premature ductus does constrict, it
fails to produce profound hypoxia and to undergo remodeling and thus
susceptible to vessel reopening.

RISK FACTORS:
The incidence of PDA is inversely proportional to gestational age and
birth weight. The incidence of PDA in term infants has been estimated to be
57 per 1,00,000 live births5, whereas every third preterm infant with a birth
weight of 500 to 1500 grams can be expected to have a PDA 6. Female to
male ratio is 2:1. Approximately 20% of children with respiratory distress
syndrome have PDA. Exogenous surfactant therapy, lack of antenatal
steroids, presence of sepsis, liberal fluid therapy, congenital rubella,
maternal drug intake (like phenytoin and amphetamine), alcohol use and
exposure to radiation in mother and familial causes are other risk factors for
PDA.

HAEMODYNAMIC AND CLINICAL CONSEQUENCES:

The hemodynamic consequences are due to the shunting of blood from
the systemic to pulmonary circulation. A small shunt may be completely
asymptomatic whereas a large shunt results in congestive cardiac failure
(CCF). Blood flow to kidney, gastrointestinal tract and brain may be
compromised resulting in renal failure, necrotizing entrocolitis (NEC) and
intraventricular hemorrhage (IVH). A persistent PDA can lead to pulmonary
edema, pulmonary hemorrhage loss of lung compliance, which ultimately
leads to chronic lung disease. PDA causes deterioration of respiratory status,
increased ventilatory requirements and failure to wean from ventilation.
DIAGNOSIS:
Clinically PDA may present with signs of congestive cardiac failure.
Clinical signs like continuous murmur, hyperactive left ventricular impulse
are specific whereas the persistent need for ventilatory support is a sensitive
criterion for diagnosis. The appearance the appearance of 3 or more of the
following clinical signs-systolic murmur, hyperdynamic precordial impulse,
full pulses, widened pulse pressure, and/or worsening respiratory status
correlate well with morbidity. Echocardiography is an essential tool in the
diagnosis of PDA7. 2D ECHO in combination with either pulse wave,
continuous wave or colour Doppler is both sensitive and specific.
Echocardiographic evidence of PDA is known to precede the development
of signs and symptoms by 2 days 8. However, clinical features have better
correlation with long term morbidity.

TREATMENT:
Treatment of PDA is either conservative or by pharmacotherapy or
surgery. Indomethacin a non selective cyclooxygenase 1 (COX1) and
cyclooxygenase 2 (COX2) inhibitor has been used in the treatment of PDA.
Three doses of indomethacin are given as there are chances of spontaneous
opening with a single dose 9. The drugs ability to produce ductus closure is
inversely proportional to the post natal age at the time of treatment 10.
However indomethacin has been associated with several side effects like
bleeding tendencies, NEC and alterations in renal function. These effects
have led to the search for other alternatives. Ibuprofen also a nonselective
COX inhibitor has been found to have an equal efficacy with fewer side
effects11. PDA in preterm not responding to medical treatment and in term
infants requires surgical ligation by thoracotomy, video assisted
thoracoscopy or device closure.

The present study aims at analysing the risk factors, the clinical
features, the complications, the efficacy of various modalities of treatment
and the outcome at discharge.
 METHODS AND MATERIALS

 Study type: Cross sectional observational study.

 Sample size: 50.
 Setting: Neonatal intensive care unit and post natal wards of a Tertiary care
hospital.
 Age group: All neonates irrespective of weight/maturity.
 The enrollment period was 24 months (between August 2010 to July 2012).
 Inclusion criteria: Preterm and term neonates diagnosed with PDA by
echocardiography.
 Informed written consent was taken from the parents of neonates included in
the study.
 History of the patient and detailed examination was as per the proforma.
 Investigations were done as per the protocol of the neonatal care unit.
Echocardiography was done in all neonates.
 All data collected were analyzed using relevant statistical methods with
respect to risk factors, complications, treatment methods, response to
therapy and outcome at discharge.
 In our study with respect to gestational age, the gestational age in weeks
mentioned refers to the weeks of gestation + up to 6 days. For example, a
gestational age of 36 weeks meant, from 36 weeks up to 36 weeks + 6 days.
 The study was purely observational; the treatment was decided as per
discretion of the treating physician and as per the protocol of the unit.
Following terms were used if they met the defined criteria:
 Acute renal failure (ARF): Neonatal acute renal failure was defined by
serum creatinine greater than 1.5mg/dl regardless of urine output. ARF was
suspected in a newborn when serum creatinine failed to decline below
maternal levels by 5th day post-natally or was rising by 0.3mg/dl/day.

 Sepsis: Sepsis was suspected when there was presence of two of the
following four parameters: Total leukocyte less than 5000 cells/ mm 3, band
to total neutrophil ratio of more than 0.2, C-reactive protein more than
10ng/ml and micro-ESR of greater than 10 mm in one hour.
Sepsis was proven when there was isolation of pathogens either from blood,
cerebrospinal fluid, urine or trachea.

 Respiratory distress syndrome: Premature infants who shortly after birth

had tachypnoea, retractions, nasal flaring, grunting and cyanosis with
radiographic appearance of low volume lungs with a diffuse
reticulogranular pattern and air bronchogram were suspected to have
respiratory distress syndrome.

 Congestive cardiac failure (CCF): Neonates with tachycardia, tachypnoea,

increased respiratory efforts, rales, hepatomegaly and delayed capillary refill
time were suspected to have CCF.

 Intraventricular hemorrhage (IVH): IVH was identified by

ultrasonographic examination through the anterior fontanel.
 Bronchopulmonary dysplasia (BPD): BPD was diagnosed when the
neonate continued to remain oxygen dependent after the first 28 days of life.

 Necrotizing enterocolitis: NEC was suspected when child had feed

intolerance, vomiting, abdominal distention, blood in stools, and when
abdominal radiographic findings revealed bowel wall edema, fixed position
of loop on serial radiographs, appearance of a mass, pneumatosis intestinalis,
portal or hepatic venous air, pneumobilia or pneumoperitoneum.
 PROFORMA

Baby’s Name:

I.P.D. Reg. No.: Sr.No.:

Mother’s Age: Father’s Age:

Date of Admission: Date of Discharge:

Birth weight: Sex:

Gestational Age: SGA/AGA/LGA

Provisional Diagnosis:

Final Diagnosis:

Presentation:

Respiratory distress: Yes/No

Apnoea: Yes/No
Feeding intolerance: Yes/No

Failure to wean from ventilation: Yes/No

Others:

Family History:

Family h/o congenital heart disease: Yes/No

Family h/o other genetic disorders: Yes/No

Consanguineous/ Non consanguineous marriage:

Antenatal History:

Maternal age:

Registered/unregistered:

GTT: HIV:

VDRL: TORCH titers:

Antenatal ultrasonography:

Past Obstetric History:

G P L A Abortion/still birth/LBW/Neonatal death

Pregnancy related problems:

TORCH infections: Yes/No

Diabetes mellitus: Yes/No

Hypertension: Yes/No

Medications (anticonvulsants/NSAID’s/antibiotics/antenatal steroids/others):

Exposure to radiation: ` Yes/No

Smoking: Yes/No

Alcohol use: Yes/No

Others:

Labour and Delivery:

Liqour:
Fetal distress:

APGAR scores: 1min: 5min: 10min:

Physical stimulation: Yes/No Oxygen: Yes/No

Bag and mask ventilation: Yes/No Duration:

Medications given:

Fluid Therapy (ml/kg/day):

Neonatal Assessment:

Sigleton/twin/triplet:

Head circumference: Length:

Chest circumference:

Risk factors:

Sepsis: Yes/No
Presence of hyaline membrane disease: Yes/No

Mechanical ventilation: Yes/No

Surfactant therapy: Yes/No

Intraventricular haemorrhage: Yes/No

Pulmonary haemorrhage: Yes/No

Bronchopulmonary dysplasia: Yes/No

General Examination:

Cardiovascular System:

Heart Rate:

Pulse:

Pulse pressure:

Hyperactive Precordium: Yes/No

Auscultation:
Murmur (Systolic/ Continuous):

Respiratory System:

Respiratory Rate:

Crepts: Yes/No

Abdomen:

Central nervous system:

Congenital Anomaly/ Dysmorphism:

Complication:

Congestive cardiac failure: Yes/No

Acute renal failure: Yes/No

Necrotizing enterocolitis: Yes/No

Intraventricular haemorrhage: Yes/No

Pulmonary hemorrhage: Yes/No

Pulmonary edema: Yes/No

Others:

Death: Yes/No

Investigations:

Hemoglobin:

Total leucocyte count:

Differential leucocyte count:

Serum sodium:

Serum potassium:

Blood urea:

Serum creatinine:

Chest X-ray:
E.C.G:

Echocardiography:

Others:

Treatment Given:

Fluids: ml/kg/day

Conservative Management: Yes/No

Medical Management:

Indomethacin: Yes/No (one course/two course)

Ibupofen: Yes/No (one course/two course)

Medication followed by Surgical Closure: Yes/No

Surgical Closure/Device Closure: Yes/No

Outcome:
Discharge/Death

Completely closed: Yes/No

Patent ductus arteriosus asymptomatic: Yes/No

Patent ductus arteriosus in failure and : Yes/No

Patent ductus arteriosus in failure medically controlled: Yes/No

Patent ductus arteriosus in failure not medically controlled: Yes/No

REVIEW OF LITERATURE- CLINICAL PROFILE OF PATENT DUCTUS
ARTERIOSUS IN NEONATES.

In utero the DA serves to divert ventricular output away from the lungs and
towards the placenta by connecting the main pulmonary artery to the descending
aorta. A PDA in the first 3 days of life is a physiological shunt in both term and
preterm newborn infants.

The incidence of PDA in term infants has been estimated to be 57 per 1, 00, 000
live births5. Also every third preterm infant with a birth weight between 501 to
1500 grams have a persistent PDA6. Left to right shunting through the PDA causes
an increased risk for IVH, NEC and death. In a retrospective study done by Noori
et al it was observed that persistent PDA was a risk factor for increased mortality 12.

Currently it is still not known when a conservative, pharmacological or surgical

closure would help. Also, it is unclear when a prophylactic or symptomatic PDA
closure would help.

Historical background:

Historically ductus was mentioned in the writings of Gallen as early as second

century A.D. He had dissected and described about the first DA. In 1900 Gibson
described the classic machinery murmur and also had recognized PDA a separate
clinical entity13. In 1907 Munro described the first surgical approach but it was not
until 1938 that PDA was successfully closed by Gross14.
EMBRYOLOGY:

The DA is a normal and essential structure in the fetus. Persistence of the ductus to
close after birth becomes abnormal. In the fetus the proximal portion of the sixth
pair of embryonic aortic arches become the proximal branch pulmonary arteries.
The distal portion of the left sixth arch persists as the DA which connects the left
pulmonary artery with left dorsal aorta. The distal right sixth aortic arch loses its
connection to the dorsal aorta and degenerates. This is usually complete by 8
weeks of gestation.

Incidence:

The incidence of PDA is inversely proportional to gestational age and birth weight.
The incidence of PDA in term infants has been estimated to be 57 per 1,00,000 live
births5, whereas every third preterm infant with a birth weight of 500 to 1500
grams can be expected to have a PDA 6. In a study by Kapoor and Gupta they
analyzed the diagnosis of children suffering from congenital heart disease and
PDA constituted 14.6% of all congenital heart diseases15.

Physiology of fetal circulation:

Of the 65% of the fetal cardiac output that reaches the right ventricle, only about 5
to 10% of it passes through the lungs 16,17. Majority of the right ventricular output
passes through the DA into the descending aorta. Thus DA is an important
structure in normal fetal development as it helps in the diversion of right
ventricular output away from the high resistance pulmonary circulation.
Intrauterine closure of the ductus will lead to fetal hyrops due to right heart
failure18.

Histology and mechanism of closure of ductus arteriosus:

Grossly the fetal ductus appears to be similar to the main pulmonary and
descending aorta. However there are important histological differences. The media
of surrounding aorta and pulmonary artery are composed of circumferentially
arranged layers of elastic fibres. The media of the ductus has longitudinally and
spirally arranged layers of smooth muscle fibres with loose, concentric layers of
elastic tissue19. The intima of the ductus is thickened and irregular with abundant
mucoid material which is also known as intimal cushions3.

The ductus arteriosus smooth muscle cell (DASMC) is an oxygen sensing site. The
endothelium releases vasoactive substances which are important in modulating the
tone of DA. Fetal patency is maintained by low oxygen tension and prostanoids
mainly PGE2 and PGI2. Due to the placental production and diminished clearance,
PGE2 and PGI2 levels are high in the fetus 19. After birth the post natal increase in
PaO2 and the decrease in circulating vasodialtors such as PGE 2 and PGI2 induce
the constriction of DASMC and eventually the functional closure of the ductus
arteriosus. The mechanism by which oxygen constricts the ductus needs more
investigation. Oxygen sensing mechanism in the DAMSC causes cell membrane
depolarization, which allows calcium influx and contraction. Developmentally
regulated potassium channels allow voltage gated potassium channels to open and
cause calcium influx20. Studies in preterm rabbits have shown that immaturity of
both potassium and calcium channels leads to ineffective oxygen mediated
constriction20.
Rho/Rho-kinase pathways induce calcium sensitization which causes sustained
vasoconstriction due to myosin light-chain phosphorylation 21. Rho/Rho-kinase
signaling depends on mitochondrial derived reactive oxygen species which may be
decreased in the preterm21. Oxygen induces release of endothelin-1 by the ductus,
which is a potent vasoconstrictor. It acts by increasing intracellular calcium
through G-protein coupling, though its role in closure of the ductus is
controversial21.

Successful contraction of the ductus causes “hypoxic zones” locally which triggers
cell death and production of growth factors such as transforming growth factor b
and vascular endothelial growth factor (VEGF). These result in vascular
remodeling and thus anatomical closure of the ductus. In preterm infants there is
failure to cause hypoxic zones and thus true anatomic closure doesn’t take place.

Echtler et al22 recently demonstrated that platelets are recruited to the luminal
aspect of the murine DA after birth. Persistent ductus arteriosus has been noticed in
those with induced platelet adhesion dysfunction or transgenic defects of platelet
biosynthesis. It has also been noted that non steroidal anti inflammatory drugs
increase platelet mediated thrombosis rather than decreasing it 23. Indomethacin also
promotes platelet accumulation after endothelial injury 22. Lower platelet counts are
associated with higher failure rate of indomethacin induced PDA closure 24. In a
retrospective study involving newborns between 24 to 30 weeks of gestation it was
found that thrombocytopenia to be an independent predictor of PDA 22. Infection
associated inflammatory mediators such as tumor necrosis factor is associated with
patency of DA. A temporary infection increases the chance of failure of closure of
the ductus. Possibly the proinflammatory cytokines affect platelet function and
thus inhibit thrombotic sealing of the constricted ductus 22. In preterm infants,
oxygen sensitivity is reduced but the sensitivity to PGE 2, NO and endothelin 1 is
increased4. PGE2 acts through G protein coupled receptors that activate adenyl
cyclase and therby making cyclic adenosine monophosphate (cAMP) to relax
vascular smooth muscle layers. Nitric oxide activates guanyl cyclase to produce
cyclic guanosine monophospahte (cGMP). It has been observed in fetal sheep that
the more immature sheep have decreased ability to degarade cAMP or cGMP and
thus more sensitivity to PGE2 and NO25. It has been shown that administration of
cortisol in fetal lambs in utero will result in ductus that respond similar to oxygen
and prostaglandin inhibition similar to mature fetus 26. This explains the decreased
incidence of PDA in preterms born to mothers who have received antenatal
steroids4.

Pathophysiology:
The magnitude of shunting determines the hemodynamic effects of PDA. This
largely depends on the flow resistance. Resistance is determined by the length, the
narrowest diameter, overall shape and configuration of the DA. Also as the flow in
the ductus in dynamic and pulsatile, the elasticity of the ductal wall may affect the
impedance of flow27. The magnitude of shunting also depends on the pressure
gradient between aorta and pulmonary artery. This pressure gradient is dynamic
with systolic and diastolic components. This largely depends on systemic vascular
resistance, pulmonary vascular resistance and cardiac output. The impact of
changes in systemic and pulmonary vascular resistance is more in larger ductus
which have less flow resistance.
Pulmonary overcirculation and left heart volume overload develop as a result of
left to right shunting through the DA. Increased pulmonary blood flow due to the
ductal shunting causes increased pulmonary fluid volume. In patients with
moderate to large shunts this causes decreased lung compliance, which can result
in increased work of breathing. Pulmonary edema is usually uncommon but can
occur in patients with congestive cardiac failure.

Increased flow returning to the left heart leads to increased left atrial and left
ventricular end diastolic pressures. The left ventricle thus compensates by
increasing stroke volume and will eventually hypertrophy to normalize stress on
the wall. Neuroendocrine adaptation takes place in the form of increased
sympathetic activity and circulating catecholamines. These result in increased
contractility and heart rate. Due to diastolic “runoff” through the patent ductus the
diastolic pressure in the aorta decreases. This coupled with shorter diastolic time as
a result of tachycardia, increased intramyocardial tension from left ventricular
dilatation and increased myocardial oxygen demand can result in subendocardial
ischemia28.

With long-standing left to right shunts, progressive morphological changes in the

pulmonary vasculature takes place due to exposure of the pulmonary artery to high
pressure and increased flow through the ductus. These changes include arteriolar
medial hypertrophy, intimal proliferation, fibrosis and eventually obliteration of
pulmonary arterioles and capillaries. These result in progressive increase in
pulmonary vascular resistance. Gradually as the pulmonary vascular resistance
approaches and exceeds systemic vascular resistance, shunt reversal through the
ductus takes place and the shunt now becomes right to left. The exact
pathophysiological mechanisms for this is still unclear but there is evidence that
microvascular injury stimulates production of growth factors and enzymes that
eventually result in intimal proliferation and medial hypertrophy 29. Platelet
activation and endothelial dysfunction play a role in the obliteration of pulmonary
arterioles30.

Risk factors:
The incidence of PDA is inversely proportional to the gestational age. Every third
infant born with a birth weight of 501 to 1500 grams have a persistent PDA 6. Also
55% of infants born extremely low birth weight (<1000 grams) have been shown to
have persistent PDA that will ultimately require medical treatment 31. 60 to 70 % of
infants born <28 weeks of gestational age require medical or surgical therapy for
PDA4. In a study done by SI Omokhodion et al 32 it was shown that around 81% of
both preterm and term infants had suspected sepsis. Confirmed septicemia was
seen in 7.9% and 3.4% of term and preterm infants respectively. In the same study
it was shown than 5 out of 7 infants with respiratory distress had PDA. Also it was
observed that 40% of preterm and 25% of term infants who had birth asphyxia had
developed PDA. In a study by Echtler et al it was shown that lower platelets were
associated with decreased chance of closure of the DA 22. Gonzalez et al33 in their
study showed that infection associated inflammatory mediators such as tumor
necrosis factor (TNF) are associated with late patency of DA. A temporally related
infection increases the odds for failure of closure of the DA. Also it is possible that
other proinflammatory cytokines affect platelet function and thus inhibit
thrombotic sealing. Requirement of mechanical ventilation has been shown to
cause delayed closure of PDA. Nemerofsky et al 34 reported that spontaneous ductal
closure at 2 weeks of age occurred only in 50% of ventilated compared with 80%
of nonventilated very low birth weight infants. Bell et al 35 in their study had
compared the occurrence of PDA with restricted a liberal fluid intake. They had
observed that liberal fluid intake was associated with higher incidence of PDA.
Clinical features:
The clinical features of PDA vary greatly from those who are completely
asymptomatic to those with severe congestive cardiac failure and
Eissenmegerisation. Many infants are detected due to the murmur or incidentally
by echocardiogram.

Small PDA’s are usually asymptomatic. Physical signs of PDA may appear soon
after birth. They may present as failure to wean from ventilator, feed intolerance,
hepatomegaly, systolic murmur beast heard at left second parasternal area radiating
toward the back, increased precordial impulses and bounding peripheral pulses
(pulse pressure > 25 mm Hg). These signs have been described as the classical
physical signs of PDA. They usually appear on day of life 5 onwards 36. The
accuracy of these signs in diagnosis is not high. Also indicators of ductal opening
in a ventilated child have been studied. Metabolic acidosis not attributable to
hypoperfusion or sepsis, deteriorating respiratory status on day 3 or 4 after a period
of relative stability, increasing ventilatory requirement on day 3 or 4 unexplained
CO2 retention, fluctuating FiO2, requirements and recurrent apneas in a ventilated
baby should raise the suspicion of PDA.
Kupferschmid et al compared37 clinical and echocardiographic findings in infants
with PDA. They found that bounding pulses and murmur were absent in 15% and
20% of patients respectively. They suggested hyperdynamic precordium to be the
most sensitive sign which was found in 95% of the patients.
In a study by Davis et al 38 a high percentage of patients with PDA had no murmur.
Bounding pulses were also a poor indicator for the presence of PDA. They found
that bounding pulses and murmur had a sensitivity of 43% and 42% respectively.
Also specificity was 87% for murmur and 74% for bounding pulses. The
combination of bounding pulses and murmur had a positive predictive value of
77%.
Skelton et al39 examined a cohort of preterm infants daily for the first week after
birth with independent and blinded clinical and echocardiographic examinations.
On day 1, it was found that all infants had silent shunts though they had significant
shunts on ECHO. In the next 3 to 4 days, each of the signs of bounding pulses,
active precordium and systolic murmur were of reasonable specificity but of low
sensitivity for the diagnosis of PDA that was confirmed by echocardiography. The
presence of signs often correlated with the presence of PDA but most significant
PDA’s had no clinical signs. This study demonstrated that relying on clinical signs
led to a delay in diagnosis by a mean of about 2 days with a range of 1 to 4 days.
Evans and Moorcraft40 in their study found that there was no difference in pulse
pressure between babies who did and did not have significant PDAs. They found a
reduced systolic and diastolic pressure particularly among infants whose birth
weights were less than 1000 grams. Similar findings were seen in a prospective
study done by Ratner et al41. They found that PDA associated with reduced systolic
and diastolic pressures.

The importance of clinical diagnosis is that it has a better correlation with long
term morbidity. Also available evidence does not recommend routine screening
with echocardiography for at risk neonates42.
Investigations:
Chest Radiograph:
Radiographic findings are non specific for the diagnosis of PDA. Depending on the
size of the shunt, the chest radiograph may be completely normal or may
demonstrate cardiomegaly. There are signs of left atrial and left ventricular
enlargement with increased pulmonary vasculature. Upturned left bronchus may be
seen due to left atrial enlargement. Main pulmonary artery is frequently enlarged.
When pulmonary vascular obstructive disease develops, the heart size becomes
normal and there is marked prominence of the pulmonary artery segment and hilar
vessels.

Electeocardiogram:
The electrocardiographic findings in PDA vary depending on the size of the lesion.
In a small to moderated PDA the electrocardiogram may be completely normal or
features of left ventricular hypertrophy may be seen. With a large PDA, combined
ventricular hypertrophy is usually seen. Right ventricular hypertrophy is seen when
pulmonary vascular obstructive disease develops.

Echocardiography:
Echocardiogram is the procedure of choice to confirm the diagnosis and to
characterize PDA. Echocardiogram helps in classifying PDA into silent, small,
moderate or large. Also it can determine the presence of other associated cardiac
diseases. M-mode echocardiography is used to determine cardiac chamber sizes
and quantitate left ventricular systolic function.
Assessment of ductal patency, determination of ductal shunt direction and
measurement of ductal pressure gradient are important. PDA can be visualized
from subxiphoid, modified left parasternal windows in infants using standard high
frequency ultrasound probes. Ductal size is usually measured by 2D imaging at
the narrowest point, which is usually towards the pulmonary end of the duct, where
it constricts first. Color Doppler mapping facilitates visualization of PDA and
allows evaluation of the direction of flow through the shunt. Shunt direction
reflects the difference between aortic and systemic circulation. Normally a left to
right shunt is present which will cause diastolic retrograde flow in the abdominal
aorta. The degree of flow reversal in the descending aorta provides information on
the amount of diastolic left to right shunting through the duct 43. If pulmonary artery
pressures are super systemic, right to left shunting will occur during systole and
rarely in diastole if the pulmonary artery diastolic pressure exceeds aortic diastolic
pressure. Hence, the duration of right to left shunt and the presence or absence of
retrograde flow in the descending aorta at the level of diaphragm provides
information on the degree of pulmonary hypertension and can be assessed during
follow up and treatment. For calculation of gradient pressure, pulse wave or
continuous wave Doppler interrogation is performed parallel to the direction of the
ductal flow jet as seen on color Doppler mapping. This Doppler gradient can be
used to assess pulmonary artery pressures, by comparing peak and mean Doppler
gradients to simultaneous systemic and arterial systolic and mean arterial blood
pressures. PDA gradient may require the use of continuous wave Doppler, whereas
information regarding the location of narrowing is better evaluated by pulsed-wave
Doppler.
Assessment of hemodynamic significance of the duct becomes important. This can
be performed by combining the folowing echocardiographic measurements 44. A
minimal ductal diameter greater than 1.5 to 2 mm is considered a
hemodynamically significant ductus. The direction of transductal shunt is
dependent on the transductal gradient, which is influenced by difference between
systemic and pulmonary vascular resistance and ductal size. Assessing shunt
direction and gradient becomes important. The quantification of left heart size
reflects the chronic effect of LV volume loading due to left to right shunt through
the ductus. Left ventricular end diastolic volumes can be measured on the basis of
M-mode or 2D measurements. A dilated left ventricle indicates the presence of
large shunt. The left atrial/aorta ratio can be used as an indicator of shunt size, with
a ratio >1.4 indicating a significant left to right shunt. In the presence of a ductal
left to right shunt, pulmonary venous flow increases and the rise in left atrial
pressure will result increased transmitral flow. Thus, an increase in early mitral
flow velocities reflects the amount of ductal shunting, assuming the absence of
atrial shunt, mitral valve stenosis or significant mitral regurgitation. In neonates
with large left to right shunts, the increased early transmitral flow can result in an
E/A ratio >1.0. The tracing reverts to typical preterm E/A ratio < 1.0 after ligation.
A large ductus with left to right shunting will result in significant retrograde flow
from the thoracic and abdominal aorta. The amount of retrograde flow may be
>50% of total aortic flow in neonates with a large ductus. The presence of
holodiastolic retrograde flow suggests at least a moderate amount of left to right
ductal shunting. A ductal diameter of >1.4 mm/kg of body weight Suggests a
hemodynamically significant shunt. Pulse-wave Doppler interrogation of the main
pulmonary artery in neonates with a hemodynamically significant DA
demonstrates turbulent systolic and diastolic flows and abnormally high antegrade
diastolic flow (>0.5 m/second).
Magnetic Resonance imaging and computed tomography:
Magnetic resonance imaging and computed tomography may be useful in defining
the anatomy in patients with unusual PDA geometry and in patients with
associated abnormalities of aortic arch 45. These include ductus arteriosus
aneurysm, PDA associated with vascular rings, with right aortic arch and with
cervical arch. A set of coronal spin-echo images is used to localize the ascending
aorta and pulmonary trunk. Flow is calculated as a product of the area of the great
vessels and the net mean velocity within it. The mean flow rate over the cardiac
cycle is calculated over the mean R-R interval, determined from the image
software for the calculation of blood volume per heart cycle to assess left and right
ventricular stroke volume.
Radionuclide scanning:
Techneticum-99m is injected via a cannula into a peripheral vein. Data analyses
assume exponential indicator clearance from normal cardiac chambers by
dilatation. The late prolongation of tracer disappearance compared with the initial
clearance rate indicates an abnormally early return of the indicator to the cardiac
chamber. Patients with left-to-right shunts demonstrate prolonged clearance of
radioactivity from all cardiac chambers distal to the site of the shunt. The
magnitude of curve distortion is quantitatively related to the size of the shunt and
counts recorded from the right lung are used for shunt quantization.

Cardiac Catheterization:
Therapeutic catheterization is the treatment of choice for most children and adults.
Cardiac catheterization allows to fully evaluating pulmonary vascular resistance
and degree of shunting. In patients with elevated pulmonary artery pressure,
assessment of pulmonary vascular resistance and its response to vasodilating
agents may be helpful in determining advisability of ductal closure. Assessment of
hemodynamics during temporary test occlusion with a balloon catheter also
provides information regarding advisability of closure. Angiography defines the
anatomy of the ductus arteriosus. Detailed anatomy of the ductus is essential for
transcatheter closure. Important features include minimal diameter, the largest
diameter, the length and the relationship of the ductus to the anterior border of the
tracheal shadow which helps in device positioning.

B-Type Natriuretic Peptide, N-terminal -pro-BNP, and Cardiac Troponin T:

There is increasing evidence that B-type natriuretic peptide (BNP) or N-terminal-
pro-BNP (NT-pro-BNP) levels can be used to indicate a symptomatic PDA and
guide in treatment46. In a study involving small series of preterm infants at <28
weeks47 or 25 to 34 weeks gestation48, plasma BNP levels correlated with
magnitude of ductal shunt (ductal size, left atrium to aortic root ratio and diastolic
flow velocity of the pulmonary artery). In neonates <28 weeks gestational age,
BNP levels of >550pg/ml on the second day of life were suggested to predict PDA
intervention with a sensitivity and specificity of 83% and 86% respectively 47. In
neonates born at 25 to 34 weeks the best cut off BNP concentration on day of life 3
for the diagnosis of symptomatic PDA was found to be 110 pg/ml with a
sensitivity of 100% and specificity of 95.3% 48. Similarly it was found that plasma
NT-pro-BNP levels obtained in infants born less than 33 or 34 weeks of gestation
were a good indicator of hemodynamically significant PDA 49. Suggested cut off
levels were 10,180 pg/ml on day of life 2 (sensitivity 100%, specificity 91%) and
11,395 pg/ml on day of life 3 (sensitivity 100%, specificity 95%)50.
BNP concentrations also decreased during the course of indomethacin therapy for
PDA. BNP- guided therapy (no indomethacin administration if the bNP level is
<100 pg/ml 12 or 24 hous after the first dose) reduced the number of indomethacin
doses during the course of the treatment and therby comorbidities associate with
indomethacin use51. Also it has been noted that plasma NT-pro-BNP and cardiac
troponin T (cTnT) are higher in preterm infants (VLBW or <32 weeks gestation)
with a PDA who subsequently develop IVH grade III/IV or death compared with
those with a PDA and without complications52.

Complications:
A left to right shunt through the ductus will cause increased pulmonary blood flow.
In the case of preterm preterm, respiratory distress with low plasma oncotic
pressure and increased plasma capillary permeability can result in interstitial and
pulmonary alveolar edema and also decreased lung compliance. This will inturn
lead to increased ventilatory settings, prolonged ventilation, high oxygen load 53 and
probably to chronic lung disease. In very low birth weight and extremely low birth
infants, lung injury is usually associated with myocardial dysfunction due to left-
side volume overload. This together with ductal steal phenomenon will worsen
systemic perfusion. Thus, infants born less than 1500 grams are susceptible to
hypoperfusion of vital organs and resultant additional comorbidities such as IVH,
periventricular leukomalacia, NEC and renal failure. In a retrospective study by
Noori S, McCoy M, Friedlich P, et al it was shown that a persistent PDA was a risk
factor for increased mortality12.
In a study by Marshal DD et al 54 and Oh w et al55 PDA has been shown to be a risk
factor for chronic lung disease (CLD). Also preterm baboons exposed to PDA have
arrested alveolar development, which is characteristic of BPD. However,
prophylactic PDA ligation within 24 hours did not decrease the rates of CLD56.
The complication of PDA to cause IVH is still unclear. In a study which assessed
prophylactic PDA ligation it was found that there was no significant reduction in
the occurrence of IVH but the study wasn’t sufficiently powered. However
prophylactic indomethacin use has shown to reduce IVH and improve long term
neurological outcome56. The effect of PDA on periventricular leukomalacia is still
unknown.
Preterm infants with PDA have decreased intestinal and renal blood flow and also
blood-flow velocity on ultrasound when compared to gestational age matched
infants without PDA57. These values normalize after ductal closure. In a systemic
review of PDA it was shown that the incidence of NEC has been decreased
significantly in those infants born less than 1000 grams who were treated early as
compared to the group that delayed treatment for 6 days 58. Also in a study it has
been shown that prophylactic ligation within 24 hours of life significantly reduced
the incidence of NEC56.
The incidence of infective arteritis associated with PDA has been decreased due to
the use of prophylaxis for infective endocarditis. Vegetations usually occur on the
pulmonary artery end of the ductus and embolic events are usually of the lung
rather than the systemic circulation. Aneurysm of the ductus is an entity reported
with an incidence as high as 8%. Ductal aneurysm most commonly presents in
infancy.

Treatment:

Different treatment strategies have been tried for the treatment of PDA. Treatment
may be conservative, with drugs or surgery. Also prophylactic treatment for PDA
has been tried.

Conservative Management:
Vanhaesebrouck et al59 studied 30 neonates <30 weeks of age in a prospective
study. As soon as a hemodynamically important PDA was made the infants were
treated conservatively. Conservative treatment involved fluid restriction
(maximum of 130 ml/Kg per day beyond day 3) and adjustment of ventilator
settings which included lowering inspiratory time and higher positive end-
expiratory pressure. No medication for PDA either therapeutic or prophylactic was
given. Also it was decided that those who didn’t show clinical improvement will
undergo surgical ligation. In their study ten neonates developed a clinically
important PDA. After conservative management the ductus in all neonates closed,
and none required surgical intervention. Also the rates of major complications
were the same as other studies. Hence it has been suggested that for a selective
group of very low birth weight preterm infants, conservative management
consisting fluid restriction and ventilator adjustment may be an alternative
treatment, though it requires larger studies to prove its efficacy.

Medical Management:

In 1976 it was first shown that nonselective cyclooxygenase (COX) inhibitors such
as indomethacin or ibuprofen inhibit prostaglandin synthesis 60. The efficacy of
COX inhibitors depends on gestational age and they are less effective in severely
preterm infants60. This has been frequently attributed to inadequate contraction of
DAMSC and also a failure of intimal cushion formation. Intimal cushion formation
involves nitric oxide mediated fibronectin synthesis 61 and chronic activation of the
prostaglandin receptor that promotes hyaluronic acid synthesis 62. Thus the
blockade of prostaglandin by COX inhibitors prevents effective closure in
immature infants. Also it has been observed that COX inhibitors are much less
effective in term infants versus preterm infants63.
The rate of primary ductal closure is similar in both ibuprofen and indomethacin
that is around 60 to 80% of premature infants with decreasing efficacy and high
recurrence rates in extremely preterm infants 11. After primary treatment failure in
infants born <1000 grams or <28 weeks gestation, successful PDA closure after a
second course of either indomethacin or ibuprofen was found in 44% 64 and 40%65
respectively.

Ibuprofen does not seem to be a potent vasoconstrictor on the mesenteric, renal and
cerebral vascular beds compared to indomethacin. In a study comparing both drugs
there was no statistically significant differences in the adverse events of pulmonary
hemorrhage, CLD and NEC between the two drugs. However NEC was found
twice often with indomethacin treatment and chronic lung disease occurred more
frequently with ibuprofen11.

Prophylactic trials with COX inhibitors have shown a decreased need for surgical
ligation, decreased incidence of pulmonary hemorrhage and serious
intraventricular hemorrhage58. However there is high incidence of spontaneous
ductal closure that many infants are unnecessarily exposed to drugs with pontential
adverse effects66. On the basis of current data, there is no role of ibuprofen in
VLBW infants who are at risk for PDA66.

Renal failure can occur with both indomethacin and ibuprofen. It has been
observed that renal failure or oliguria are more frequent with ibuprofen than
indomethacin, though it is reversible. Indomethacin in conjugation with postnatal
corticosteroids has shown to increase the risk of intestinal perforation 67. In a
clinical trial it was observed that prophylactic ibuprofen use is associated with
severe pulmonary hypertension66. However in a larger trial such association was
not noted.
Surgical management:

Surgical ligation is performed when either treatment with COX inhibitors fail or
are contraindicated. Beyond the fourth week of life, the successful closure with
pharmacological therapy decreases rapidly as the ductal tissue become more
mature and less regulated by prostaglandins. There is low morbidity and mortality
associated with PDA closure in experienced centers. However there are adverse
effects that have been reported. Recurrent laryngeal nerve palsy, chylothorax,
pneumothorax, a period of left ventricular dysfunction immediately after ligation
and concerns over development of scoliosis have been reported 68. A retrospective
study of 446 preterm infants revealed that surgical ligation was associated with
chronic lung disease69. In a study a trial of prophylactic ligation in the first 24
hours reduced the incidence of NEC 56. However there are no recent prospective
studies comparing surgical versus medical versus no treatment. Hence the risks and
benefits of surgical ligation compared with other modalities are still unknown.

If the neonates with PDA are managed appropriately with fluid restriction and
medications it may decrease the need for surgical intervention.

Results
We studied the clinical profile and outcome of 50 neonates with PDA over a period
of 2 years. The results are presented below.

Table 1: Distribution of gestational age in infants with PDA.

GESTATIONAL NUMBER OF PERCENTAGE

AGE IN MONTHS BABIES (n=50)

25-29 12 24%

30-34 26 52%

35-39 6 12%

40-44 6 12%

Figure 1: Distribution of gestational age in infants with PDA.

Gestational age (weeks)

30
26
25
Number of babies

20
Number of
babies
15
12
10
6 6
5

0
25-29 30-34 35-39 40-44

GA (weeks)
 This data suggests that 24% (n=12) of the neonates were less than 30 weeks of
gestation, 52% (n=26) were between 30 to 34 weeks while 12% (n=6) were
between 35 to 39 weeks. 12% (n=6) were between 40 to 44 weeks.

Table 2: Distribution of weight in infants with PDA.

WEIGHT in Kgs NUMBER OF BABIES PERCENTAGE

(n=50)

0.500-0.999 9 18%

1.000-1.499 23 46%

1.500-1.999 11 22%

2.000-2.499 2 4%

2.500-2.999 3 6%

3.000-3.499 2 4%

3.500-3.599 0 0%

Figure 2: Distribution of weight in infants with PDA.

 Weight (kg)
25 23

20
Number of babies

15
11
Number of babies
10 9

5 3
2 2
0
0
0.500- 1.000- 1.500- 2.000- 2.500- 3.000- 3.500-
0.999 1.499 1.999 2.499 2.999 3.499 3.599

Weight (kg)

The median birth weight was observed to be 1.308 kgs. 18% (n=9) of neonates
were between 0.500 to 0.999 kgs (Extremely low birth weight). 46% (n=23) were
between 1 to 1.499 kgs (very low birth weight). 22% (n=11) were between 1.5 to
1.999 kgs. 4% (n=2) of neonates were between 2 to 2.499 kgs. 6% (n=3) were
between 2.5 to 2.999 kgs. 4% (n=2) of the neonates were between 3 to 3.499 kgs.

Distribution of gender in infants with PDA.

It was observed that 33 neonates (66%) were male and 17 (34%) were female
(Figure 3).

Figure 3: Distribution of gender in infants with PDA.

Gender

34%
MALE
FEMALE

66%

Figure 4: Distribution of maturity with infants of PDA.

AGA/SGA

30%
SGA
AGA

70%

70% (n=35) of the infants were appropriate for gestational age while 30% (n=15)
of the infants were born small for gestational age. None were large for gestational
age.

Table 3: Presenting features of infants with PDA:

 Presenting complaints Number of babies(n=50) Percentage

Respiratory distress 44 88%

Hyperactive precordium 37 74%

Failure to wean from 33 66%

ventilation

Increased pulse pressure 32 64%

Murmur 27 54%

Apnoea 23 46%

Feed Intolerance 20 40%

44 (88%) of our neonates with PDA had respiratory distress as their presenting
complaints. 37 neonates (74%) had presented with hyperactive precordium. Failure
to wean from ventilation and increased pulse pressure were seen in 66% (n=33)
and 62 % (n=32) of our infants respectively. Other presenting complaints were
murmur (54%), apnoea (46%) and feed intolerance (40%).

Figure 5: Presenting feature in neonates with PDA

 Presenting features
50 44
45
40 37
35 33 32
30 27
25 23
20
20
Number of patients

15
10
5 Number of babies
0
es
s m n e ur a ce
iu tio ur oe an
si tr or
d la ss r m n ler
y d
ec en
ti pr
e
M
u Ap to
to
r pr v lse In
ira ve ro
m pu ed
sp cti f ed Fe
Re ra an as
ype we cre
H to In
ure
il
Fa
Presenting feature

Table 4: Risk factors for PDA:

Risk factor Number of babies (n=50) Percentage

Not received antenatal 42 84%

steroids

Prematurity 41 82%

Sepsis 33 66%

Birth weight <1500 grams 32 64%

Hyaline membrane disease 25 50%

Not received surfactant 23 46%

Perinatal depression 18 36%

Maternal pregnancy induced 15 30%

hypertension

Maternal diabetes 2 4%

Exposure to radiation 2 4%
antenatally

Out of 50 neonates, 42 (84%) of neonates were born to mothers who had not
received antenatal steroids. 41 (82%) of the neonates had prematurity as a risk
factor. Sepsis was found in 33 neonates (66%). 25 neonates (50%) had hyaline
membrane disease. 18 (36%) babies had perinatal depression at birth. 15 (30%)
neonates were born to mothers who had pregnancy induced hypertension. 2
neonates (4%) were born to mothers who had gestational diabetes. Also 2 neonates
(4%) were born to mothers who were exposed to radiation antenatally.

Figure 6: Risk factors associated with PDA

Risk factors
45 42 41
40
35 33 32
30
25
25 23
20 18
15
15
Number of patients

10
5 2 2
Number of babies
0
ds rity is s e nt ion n s y
r oi u eps gm e as cta ss sio ete tall
t s a n b a
ste ma S 0
5 0 ne d
i rf re te ia n
tal r e <1 su dep p er al d ante
na P a d
t r e al hy tern on
n te eigh emb ceiv inat ed a ati
a w r e r c M i
ed h e m ot Pe ind
u
ra
d
ceiv B irt alin N y to
tr
e Hy nc re
o gna o su
N re p
lp Ex
na
er
at
M
Risk factor
Figure 7: Average fluid received per day (ml/kg/day)

Average fluid received

120

100

80
fluid received

60

40
Average fluid received

20

0
DAY 1 DAY 2 DAY 3 DAY 4
Average fluid received on

On an average the neonates had received 77.20 ml/kg of fluid on day 1. On day 2
they had received 87.2 ml/kg of fluids. The neonates received 97.75 ml/kg and
110.20 ml/kg of fluids on the third and fourth day respectively.

Table 5: Fluid therapy over 4 days:

 Fluids Days
Received
Day 1 Day 2 Day 3 Day 4
(ml/kg/day)
(n=50) (n=50) (n=49) (n=49)

50-69 9 (18%) 1 (2%) - -

70-89 39 (78%) 32 (64%) 11 (22.44%) 5 (12.2%)

90-109 2 (4%) 16 (32%) 30 (61.20%) 17 (34.69%)

110-129 - 1 (2%) 8 (16.3%) 23 (46.93%)

130-149 - - - 4 (8.16%)

The above table represents the daily distribution of fluids among the neonates.
Figure 8: Fluid therapy over 4 days:

Fluid therapy

45

40 39

35 50-69 ml
32
30 70-89 ml
30
Number of patients

90-109 ml
25 110-129 ml

20 130 - 149 ml
16 17
15
11
10 9
5 4
5
2 1
0 0 0 0 0
0
Day 1 Day 2 Day 3 Day 4
Fluid Therpy on
Figure 9: Average fluid received over 4 days.

Average fluid over 4 days

6%

32%

70-89 ml
90-109 ml
110-129 ml

62%

On an average 16 (32%) neonates who had PDA had received 70-89 ml/kg/day of
fluids over 4 days. 31 (62%) of neonates had received 90-109 ml/kg/day and 3
(6%) neonates had received 110-129 ml/kg/day of fluids on an average of 4 days.
Table 6: Complications of PDA.

Complication Number of babies(n=50) Percentage

Congestive cardiac failure 38 76%

Acute renal failure 10 20%

Intraventricular 8 16%
hemorrhage

Chronic lung disease 4 8%

Necrotizing entrocolitis 3 6%

Pulmonary hemorrhage 3 6%

Congestive cardiac failure was seen as a complication in 38 neonates (76%). 10

neonates (20%) had developed acute renal failure as complication. 8 neonates
(16%) had developed intraventricular hemorrhage. Chronic lung disease was seen
in 4 neonates (8%). Necrotizing enterocolitis and pulmonary hemorrhage were
seen as a complication in 3 neonates (6%) each.

Figure 10: Complications of PDA.

 Complications
40 38
35

30

25
Number of babies
20
Number of patients

15
10
10 8
5 4 3 3

0
re re e e s e
ag as liti ag
ia lu ia lu r h ise co r h
f f or d or
ac na
l
ng tro
di re em u en em
ca
r h cl g h
ut
e lar ni sin ry
ve Ac u r o
oti
a
sti ric Ch cr on
ng
e
ent Ne u lm
Co v P
tra
In
Complication

Table 7:Associated congenital anomalies with PDA.

ASSOSCIATED CONGENITAL NUMBER OF BABIES

 ANOMALY

Hypospadiasis 1

Midgut volvulus 1

Multicystic dysplastic kidney 1

Small left kidney 1

4 neonates (8%) had associated congenital anomalies. The associated anomalies

were hypospadiasis in 2% (n=1), midgut volvulus in 2% (n=1), multicystic
dysplastic kidney in 2% (n=1) and small left kidney in 2% (n=1).

Table 8:Associated heart disease with PDA.

Heart defect Number of babies (n=7)

PDA with VSD 3

PDA with ASD 2

PDA with VSD and ASD 1

PDA with PFO 1

3 of our neonates (6%) had an associated ventricular septal defect (VSD). Atrial
septal defect (ASD) was seen in association in 2 of our neonates (4%). 1 neonate
(2%) had ASD and VSD in association whereas 1 neonate (2%) had persistent
foramen ovale (PFO) as an association.

Diagram 1: Medications Received:

 PDA (n=50)

Conservative Medical
Management Management
(n=12) (n=38)
Indomethacin 1 Closed
(n=1)
Ibuprofen First
Closed (n=3) Not closed (n=) course (n=37)

Closed (n=24) Not closed 2 died

(n=13)

Ibuprofen
second course
(n=11)

Closed (n=5) Not closed 2 underwent

(n=6) surgery

Indomethacin
(n=4)

Closed (n=1) Not closed 1 died, 2

Figure 11: Medications received:
(n=3) underwent
surgery
 Medications received
30 26
25
20
15
10 7
Number of patients

5 4
1
0
se se cin cin Number of babies
our our tha tha
ec o
c e
m
e
on tw dom do
en en in In
r of r of by
up up we
d
Ib Ib ll o
fo
en
r of
up
Ib
Medications

12 of our neonates (24%) were managed conservatively. 26 neonates (52%)

received a single course of ibuprofen, 7 neonates (14%) went onto receive the
second course of ibuprofen. 4 neonates (8%) received indomethacin following 2
courses of ibuprofen. Only one neonate received indomethacin alone.

Figure 12: Medication received and outcome:

 Outcome

30

25 24

Closed
20
Number of patients

Not closed

15 13

10 9
6
5
5 4
3 3
1 1
0 0
0
Ibuprofen Ibuprofen Ibuprofen Indomethacin No treatment Medication
one course two course followed by followed by
indomethacin surgery
Medications

Out of 37 neonates who received ibuprofen, closure was observed in 24 neonates

(65%), while it remained patent in 13 neonates (35%). Out of the 13 neonates 2
(15%) were asymptomatic and 11 (85%) were symptomatic. The 11 neonates then
went onto receive second course of ibuprofen. PDA was closed in 5 (45%) of those
neonates whereas it remained patent and symptomatic in 6 (55%) of them. 4 of
these neonates received indomethacin following ibuprofen while in two PDA was
surgically closed. In the indomethacin group, PDA closed in 1 (25%), whereas
remained patent in 3 neonates (75%). Of them, 1 neonate (33%) died and 2
neonates (50%) were symptomatic and required surgical closure. One neonate
received indomethacin as a single drug and it was closed. Out of the 12 infants
who received conservative management, PDA was closed in 3 (25%) of the
neonates and remained patent in 9 (75%). Of those in whom PDA was patent, 8
neonates (66.67%) were asymptomatic and 1(8.33%) neonate was symptomatic. 4
neonates required surgery for PDA closure.

Table 9: Conservative Management:

Number of babies Closed Not closed

12 3 (25%) 9(75%)

12 of our babies were conservatively managed. PDA closed in 3 (25%) of them

and remained patent in 9 (75%) of them.

Table 10: Gestational age and PDA closure:

Gestational age
(weeks) Total PDA

Closed Not closed

25-29
12 9 (75%) 3 (25%)

30-34
26 22 (84.6%) 4 (15.4%)

35-39
6 5 (83.3%) 1 (16.7%)

40-44
6 1 (16.6%) 5 (83.4%)

PDA closed in 9 (75%) of neonates between 25-29 weeks of gestation, whereas

remained patent in 3 (25%) of them. Out of the 26 infants between 30-34 weeks of
gestation, PDA closed in 22 of them (84.6%) and remained patent in 4(15.4%) .
PDA closed in 5 neonates (83%) between 35-39 weeks of gestation whereas
remained patent in 1 (17%) neonate. PDA closed in only 1 (17%) neonate of the 6
who were between 40-44 weeks and remained patent in 5 (83%).

Figure 13: PDA closure and association with gestational age.

Gestational age vs PDA closure

25

20
Number of babies

15
Closed
10 Not closed

0
25-29 30-34 35-39 40-44
Gestational age (weeks)

Figure 14: Outcome:

Outcome
4%

Completely closed
22% PDA asymptomatic
PDA in failure not medically con-
trolled

74%
Out of the 50 babies who had PDA, it was closed in 37 (74%) of them and
remained patent in 13 (26%) of them. Out of those 13, it was asymptomatic in
11(22%) of neonates and symptomatic in 2 neonates (4%).

Figure 15: Mortality associated with PDA:

Outcome

8%
Discharge
Death

92%

4 of our neonates (8%) died whereas 46 neonates (92%) survived.

Discussion

We studied clinical profile of 50 neonates with patent ductus arteriosus over the
period of 2 years. The results of the patients are discussed below.

Gestational age and occurrence of PDA (Table 1):

The premature ductus is less likely to close due to decreased intrinsic tone,
decreased sensitivity to oxygen and increased sensitivity to PGE2 and nitric oxide 4.
In our study of 50 neonates with PDA, 76% (n=38) were below 34 weeks of
gestational age, whereas only 12% (n=6) each were between 35-39 weeks and
above 40 weeks of gestational age respectively.
Therefore as expected, our study also shows an inverse relationship between
occurrence of PDA and gestational age with the occurrence reducing with
increasing age.
Shanthala et al70 had studied 21 neonates with PDA. They found 70% (n=14)
neonates to be below 32 weeks of gestational age, while 20% (n=4) were between
33 to 36 weeks of gestational age. 10% of their neonates were above 37 weeks of
gestational age. These findings are similar to our study.

Reller et al71 did studied ductal patency in the premature infants. They found 40 to
55% of their infants born less than 29 weeks of gestation to have PDA.

Hence prematurity remains an important risk factor for the development of PDA.

Birth weight and occurrence of PDA (Table 2):

In our study of 50 neonates with PDA, 64% (n=32) were very low birth weight
(below 1500 grams). 26% (n=13) were low birth weight (between 1500 to 2500
grams) while only 10% (n=5) of all neonates were above 2500 grams.
This data suggests that the risk of having an established PDA is probably more in
neonates with lower birth weight. This can be possibly attributed to the relationship
of low birth weight with prematurity.
In the study by Shanthala et al 70 55% of neonates were less than 1500 grams, 25%
between 1500 to 2000 grams and 20% to be above 2000 grams. These findings
were similar to our study.
In a large multicentre study by Ellison et al 72, they reported that 42% of infants
born with birth weights between 500 to 999 grams had PDA and 21% of infants
born between 1000 to 1499 grams had PDA.
Presenting features in patients with PDA (Table 3):
Physical signs and symptoms of PDA appear typically 3 to 4 days after delivery
and are characterized by failure to wean ventilator pressures, a long systolic
murmur at the left upper sternal edge radiating to the back, increased precordial
impulses, and bounding peripheral pulses.
Our study revealed respiratory distress as the most common presenting feature
88% (n=44), followed by hyperactive precordium 74% (n=37) and failure to wean
from ventilation 66% (n=33). 64% (n=32) of the neonates were found to have
bounding pulses while a murmur was audible in 54% (n=27). Apnea and feed
intolerance were the other common symptoms found in 46% (n=23) and 40%
(n=20).
Shunting across the DA causes increased pulmonary blood flow leading to
respiratory distress. This when combined with low plasma oncotic pressure and
increased capillary permeability can result in interstitial and alveolar pulmonary
edema and decreased lung compliance. These in turn lead to higher ventilator
settings, prolonged ventilation and high oxygen load.
A small PDA is associated with normal peripheral pulses, whereas a large PDA
will result in bounding pulses and wide pulse pressure, due to runoff of blood into
pulmonary artery during diastole.
The heart is normal in size when the ductus is small, but moderately to grossly
enlarged when the ductus is large, which results in hyperactive precordium.
Murmur is seen due to the left to right shunting of blood through the ductus. PDA
results in altered intestinal perfusion and mucosal integrity, both of which result in
feed intolerance.
As most of our infants were premature 76% (n=38) and had sepsis 66% (n=33),
both of which predispose to feed intolerance, PDA cannot be attributed as the sole
cause of feed intolerance.
Similarly apnea being a manifestation of multiple etiologies including prematurity,
sepsis and metabolic abnormalities, its presence cannot be considered secondary to
PDA alone.
In a study done on 100 neonates with PDA in Iran, Saiedi et al 73 observed that
audible murmur was the commonest sign (n=89/100), followed by respiratory
distress (n=72/100) and bounding pulses (n=28/100). Apnea was the least common
sign found in only 21% (n=21) of the neonates.
In another study by Kupferschmid et al74, they had compared clinical and
echocardiographic findings of 29 neonates with PDA and found hyperdynamic
precordium to be the most sensitive diagnostic sign found in 95% (n=27) of the
infants. Bounding pulses and murmur were found in 85% (n=24) and 80% (n=23)
of the subjects.
These results suggest that whenever we find a neonate with respiratory distress,
failure to wean from ventilation, hyperactive precordium and bounding pulses it
would be prudent to do an echocardiography to rule out the presence of PDA.

Risk factors for PDA (Table 4):

Prematurity: In our study Prematurity, 82% (n=41) emerged as the single most
important risk factor for PDA the reason for which is explained earlier.
Sepsis: 66% (n=33) of our 50 neonates had sepsis, indicating sepsis itself
contributes to persistence of DA. Sepsis induces thrombocytopenia and release of
pro-inflammatory cytokines that affect platelet function and thus inhibit sealing of
the DA.
Hyaline membrane disease: Hyaline membrane disease also an important risk
factor for the persistence of DA as it increases pulmonary pressures and requires
mechanical ventilation as well. 25 out of 50 patients (50%) suffered from hyaline
membrane disease.
Fluid: Initial fluid management in a case of PDA is crucial as early volume
expansion directly impacts subsequent occurrence of persistent PDA and the need
for treatment. The average fluid received by all neonates was 77.2 ml/kg on day 1
followed by 87.2 ml/kg on day 2, 97.75 ml/kg on day 3 and 110.2 ml/kg on day 4
of life. As compared to other studies, the total fluid intake in our neonates was less
which is due to the restricted fluid policy with protocol based management in our
unit. Probably the incidence of PDA would have been higher if more fluids were
given.
Antenatal steroids: 84% (n=42) out of the 50 neonates had not received antenatal
steroids. Administration of antenatal steroids possibly enhances the response of the
ductus to oxygen and prostaglandin inhibition thus increasing the likelihood of
closure3,4.
Surfactant therapy: 46% (n=23) of our subjects had not received surfactant
therapy. Surfactant therapy reduces the need for mechanical ventilation and also
decreases the risk of developing hyaline membrane disease, thus indirectly
influencing the other risk factors for PDA. Hence it is possible that if these
neonates had received surfactant it would have decreased the incidence of PDA
either directly or by decreasing the incidence of hyaline membrane disease.
Pregnancy induced hypertension (PIH): 30% (n=15) of our neonates were born
to mothers who had PIH. The coexistence of PDA in babies of mothers with PIH
can probably be explained by their tendency to be premature with lower birth
weights. The drawback of the study remains that it was not designed to determine
the incidence of the risk factors in those with PDA’s as compared to a control
group.
Koch et al31 studied 122 neonates less than 1000 grams with PDA. They observed
that 64 neonates (52%) had not received antenatal steroids and 107 neonates (88%)
required mechanical ventilation. 85 (70%) of their subjects had hyaline membrane
disease. 41 (34%) of neonates had not received surfactant whereas 21(18%) of
neonates were born to mothers with PIH.
Chrone et al69 studied 446 infants less than 28 weeks who had PDA. They found
42.5% of their neonates had sepsis, 19.6% of them received fluid greater than
160ml/kg/day. 41.7 % of their infants had either not received antenatal steroids or
had received within 24 hours prior to delivery. Maternal PIH was a risk factor in
12.3% of the neonates, while maternal diabetes was seen in 6%.
We would possibly be able to reduce the incidence of PDA’s by administering
antenatal steroids if delivery of a premature child is expected, administering
surfactant in premature neonates and by controlling sepsis.

Complications of PDA (Table 6):

Congestive cardiac failure: In our study, 76% neonates (n=38) developed
congestive cardiac failure. 37 out of these received medications for closure of PDA
while one expired before treatment could be initiated.
Acute renal failure: The second most common complication was acute renal
failure, seen in 20% (n=10) of our patients. Etiology of renal failure in a case of
PDA can be multifactorial. PDA causes decreased renal perfusion, while drugs
used in treatment of PDA (ibuprofen, indomethacin and diuretics) can precipitate
renal failure. Other risk factors like sepsis is a well documented cause of acute
renal failure.
Intraventricular haemorrhage: 8 out of the 50 (16%) developed IVH as a
complication. Most of our infants with PDA were premature and had low birth
weight, which by themselves were important risk factors for the development of
IVH.
Chronic lung disease (CLD): CLD developed in 4 neonates (8%) in our study.
This was probably due to prolonged ventilation required to treat the interstitial and
alveolar pulmonary edema and decreased lung compliance caused by PDA.
Necrotizing enterocolitis: NEC developed in 3 (6%) of our neonates. Preterm
infants with PDA have decreased intestinal blood flow as compared with age-
matched infants without PDA57. Drugs used in the closure of PDA (ibuprofen and
indomethacin) can potentially cause NEC as they alter mesenteric blood flow. All
the three neonates were premature and had received two courses of ibuprofen.
Overmiere et al11, studied 148 neonates between 24 to 32 weeks of age with PDA.
They found that 12% (n=19) had ARF while 23.6% (n=35) had developed IVH.
Chronic lung disease and NEC were seen in 45.9% (n=68) and 8% (12) of their
neonates. When compared to our study, the complication rates were probably more
due to their selection criteria which included only infants less than 32 weeks of
gestational age.
It would be of paramount importance to recognize and treat PDA as it would
reduce the risk of complications thereby decreasing morbidity and mortality.

Associated congenital anomalies and heart defects with PDA (Table 7,8) :
In our study we found that 8% (n=4) of our neonates had associated congenital
anomalies while 14% (n=7) had associated heart defects. The associated
anomalies were hypospadiasis in 2% (n=1), midgut volvulus in 2% (n=1),
multicystic dysplastic kidney 2% (n=1) and small left kidney 2% (n=1).
Associated cardiac anomalies were VSD in 6% (n=3), ASD 4% (n=2), PFO 2%
(n=1) and VSD with ASD 2% (n=1).

Treatment received and outcome (Diagram 1):

12 (24%) neonates were asymptomatic initially so were managed conservatively
while 38 (76%) presented as failure so required some form of treatment.
Of the 12 neonates who were managed conservatively, PDA closure occurred in 3
(n=25%) and remained patent in 9 (75%). 7 (58%) of these 12 babies were born at
term. These would however require surgical closure in future as these are unlikely
to close because of abnormal anatomy.
In the group that received treatment for closure of PDA, 37 out of the 38 neonates
had received ibuprofen whereas 1 neonate received indomethacin as initial
treatment.
In the 37 neonates who received first course of ibuprofen, PDA closure was
observed in 65% (n=24) while it remained patent in 35% (n=13). 2 of these 13
neonates however succumbed to sepsis before definitive management of PDA
could be done.
11 of those neonates who did not respond to first course of ibuprofen received the
second course of ibuprofen. Among those receiving the second course (n=11),
closure occurred in only 5 (45%) while the remaining 6 (55%) continued to have
PDA. In those whom the PDA did not close, two required surgical closure for
intractable failure.
The remaining four neonates went on to receive a course of indomethacin. It was
observed that PDA closed in only 1 (25%) out of the four who received
indomethacin and remained patent in the other 3 (75%). 2 of these 3 neonates
required surgery whereas one had died.
It is noted from the above findings that those neonates who required more than
one course of medication had a decreased probability of closure.
Richards et al65, studied 160 neonates with PDA who weighed less than 1000
grams treated with ibuprofen. The overall closure rate was 65%. PDA closed in
45% of those who received the first course of ibuprofen and closed in 40% of those
who received the second course. The lesser rate of closure compared to our study is
probably due to all their infants being extremely low birth weight.
In the study by Overmiere et al11 it was found that PDA closed in 70% and 66% of
those who had received first course of ibuprofen and indomethacin respectively.
But when a second course of these medications was given PDA closed in only 25%
of those who received ibuprofen and 33% of those who received indomethacin.
Association of gestational age with PDA closure (Table 10) :
The above data suggests a statistically significant association between gestational
age and closure of PDA.
In premature neonates, a linear relationship exists between gestational age and
probability of closure and that also that the chances of closure decreases
significantly if born at term.
These findings are similar to a study by Koch et al 31 who studied 122 neonates with
PDA. They found that for each week increase in gestational age above 23 weeks,
the odds of spontaneous closure increased by 1.5.
Once term anatomical changes take place and the chances of closure are poor.

Outcome (Figure 14,15):

PDA closure occurred in 74% (n=37) of which it occurred spontaneously in 3,
medically in 30, whereas it required to be closed surgically in 4. In the remaining
26% (n=13) of our neonates it continued to remain patent.
Of the 13 neonates in whom PDA was patent, 11 (84%) remained asymptomatic
(not in failure) while the other 2 (16%) had developed congestive cardiac failure
later..
4 (8%) out of our 50 neonates has a fatal outcome. The cause of death could be
attributed to refractory congestive cardiac failure in 1 baby (25%), sepsis in 2
babies (50%), and sepsis with acute renal failure in 1 baby (25%).
In the study by Shanthala et al70 8 (28%) of their 29 neonates died. All these
neonates expired due to complications of sepsis.

Conclusion

Prematurity and low birth weight were the major risk factors for PDA. 76% of the
neonates in the study were below 34 weeks of gestational age while 64% (n=32)
and 86% (n=43) were below 1500 grams and 2000 grams respectively.
Respiratory distress and failure to wean from ventilation were the most common
presenting features found in 88% and 74% of the neonates. Hyperactive
precordium, widened pulse pressure and murmur were the other common features.

Sepsis and hyaline membrane disease were also found to be important risk factors
for PDA accounting for 66% and 64% of the neonates respectively. 84% and 46%
of neonates had not received antenatal steroid and surfactant respectively.

PDA closure occurred in 65% of infants after only one course of ibuprofen,
whereas closure rate was only 45% when they went on to receive a second course.
4 children were given indomethacin after 2 courses of ibuprofen and closure rate
was found to be 25%.

PDA was closed surgically in 4 neonates (8%). 9 neonates in whom PDA had not
closed and remained asymptomatic would require closure at a later date.

Congestive cardiac failure and acute renal failure were the most common
complications observed seen in 76% and 20% of the neonates respectively.
Intraventricular hemorrhage, necrotizing enterocolitis, chronic lung disease were
the other complications observed.

Prematurity by itself predisposes to complications like sepsis, NEC, RDS and IVH.
In conjunction with PDA the morbidity and mortality increase significantly. Hence
it is prudent to initiate early treatment for its closure in a selected group of patients.
 List of Abbreviation:

ARF- Acute renal failure

ASD- Atrial septal defect

BNP- B-type natriuretic peptide

cAMP- Cyclic adenosine monophosphate

CCF- Congestive cardiac failure

cGMP- Cyclic guanosine monophosphate

CLD- Chronic lung disease

CLD- Chronic lung disease.

COX1- Cyclooxygenase 1

COX2- Cyclooxygenase 2

COX- Cyclooxygenase

cTnT- Cardiac troponin T

DA- Ductus arteriosus

DASMC- Ductus arteriosus smooth muscle cell

IVH- Intraventricular hemorrhage

NEC- Necrotising Enterocolitis

NO- Nitric oxide

NT-pro-BNP- N-terminal-pro-BNP

PDA- Patent ductus arteriosus

PFO- Patent foramen ovale

PGE2- Prostaglandin E2

PGI2- Prostaglandin I2

PIH- Pregnancy induced hypertension

TNF- Tumor necrosis factor

VEGF- Vascular endothelial growth factor

VSD- Venricular septal defect

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