The Journal of Maternal-Fetal and Neonatal Medicine, 2012; Early Online: 1–7

© 2012 Informa UK, Ltd.

ISSN 1476-7058 print/ISSN 1476-4954 online
DOI: 10.3109/14767058.2012.733775

ORIGINAL ARTICLE

 reatment of patent ductus arteriosus (PDA) using ibuprofen: renal

T
side-effects in VLBW and ELBW newborns
Franco Bagnoli1, Annalisa Rossetti1, Gabriele Messina2, Annalisa Mori1, Martina Casucci1 & Barbara Tomasini1
1Department of Pediatrics, Obstetrics and Reproductive Medicine, Neonatal Intensive Care, University of Siena, Siena, Italy and
2Department of Physiopathology, Experimental Medicine and Public Health, University of Siena, Siena, Italy

surgical ligation. Surgical ligation is usually reserved for preterm

Objectives: This study aims to determine whether or not
treatment of preterm neonates with PDA using IV ibuprofen
can impair renal function and in what range of birth weights
and gestational ages the risk of major renal side-effects due to
ibuprofen is highest. Methods: 134 preterm newborns with PDA
were enrolled and randomized to receive either placebo or a
3-day-course (10, 5 and 5 mg/kg) of IV ibuprofen. 67 newborns
(mGA: 27+3 w and mBW: 989 g) with PDA received ibuprofen.
Results: Subdividing the infants according to BW and to GA,
the values of creatinine and BUN were only significantly higher
than initial values at the end of the therapy in newborns with a
BW ≤1000 g and/or GA ≤26 weeks. Renal impairment is greater
the lower the weight and gestational age of the infant at birth.
Conclusions: Ibuprofen significantly impairs renal function in
preterm infants with a GA ≤26 weeks and/or in ELBW neonates,
while it may be considered safe for infants with a BW >1000 g
and/or GA >26 weeks. Thus, before starting therapy with IV
ibuprofen, it is essential to take into account the BW and GA of
newborns and the effective need for treatment from the point of
view of the ratio of risks to benefits, due to its substantial renal
side-effects.
Keywords:  ELBW, ibuprofen, newborn, patent ductus arteriosus,
PDA, renal failure, VLBW
Introduction
Patent ductus arteriosus (PDA) is a common complication of
prematurity. Its incidence is inversely related to gestational age
and birth weight [1], affecting 40% of the preterm population; this
percentage rises to 80% of ELBW infants and 70% of infants born
at less than 28 weeks [2]. Failed closure of the PDA in infants can
result in potentially life-threatening sequelae, such as hemody-
namically significant left-to-right shunting of blood, and unde-
sirable pulmonary, renal and gastrointestinal effects, including
congestive heart failure, intraventricular hemorrhage (IVH),
necrotizing enterocolitis (NEC), bronchopulmonary dysplasia
(BPD) and death [3]. Because of the association between PDA
and a number of diseases and mortality in preterm infants, thera-
peutic closure of the PDA is current practice [4]. In addition to
clinical diagnosis, echocardiography remains the gold standard
both to establish the diagnosis and to follow therapy.
Once the diagnosis is confirmed, the treatment options include
conservative medical management, pharmacological therapy and
infants who present contraindications to non-steroidal anti-
inflammatory drugs (NSAIDs) and those in whom these drugs
are ineffective [4]. Pharmacotherapy of PDA involves the use of
COX-inhibitors, which have been demonstrated safe and effective
in the majority of infants treated [5].
Ibuprofen is effective in closing the ductus [6,7] and has fewer
side-effects than indomethacin, particularly concerning renal
hemodynamics [5,7]. Compared to indomethacin, ibuprofen
reduces the risk of oliguria and is associated with lower serum
creatinine levels following therapy [8]. Therefore, ibuprofen and
indomethacin are equally effective for ductal closure in the treat-
ment of symptomatic PDA, while ibuprofen has a more favor-
able renal safety profile and no effect upon cerebral blood flow
[7,9–11].
However, while some studies have found no renal side-effects
of ibuprofen [12], others maintain that renal side-effects remain
an issue with this drug [13]. The widespread use of ibuprofen has
brought to light its possible renal impact during therapy or imme-
diately after therapy withdrawal, being associated with increased
serum creatinine and blood urea nitrogen and/or decreased GFR
(glomerular filtration rate) and urine output [11,14]. In fact, a
recent study [15] on the use of ibuprofen in very preterm infants
shows significantly lower GFR (by almost 30%) on day 7 in infants
exposed to i.v. ibuprofen for PDA than in infants who were not.
Ibuprofen can induce clinically relevant nephrotoxic effects in
newborns, especially in preterm infants, because of its inhibition
of the COX-mediated synthesis of prostaglandins.
This study aims to determine whether or not early treatment
of preterm neonates with PDA using intravenous ibuprofen can
impair renal function and, in particular, in what range of birth
weights and gestational ages the risk of major renal side-effects
due to ibuprofen is highest.
Methods
This trial was a randomized, placebo-controlled, double-blind
parallel design study evaluation of intravenous ibuprofen using
an intent-to-treat analysis to evaluate the renal side effects of this
drug in preterm newborns with PDA.
It was conducted in the Neonatal Intensive Care Unit at Siena
University Hospital (Italy) between January 2006 and December
2010.
Neonates admitted to the unit were eligible for participation
in the study when they satisfied the following criteria: gestational

Correspondence: Annalisa Rossetti, Department of Pediatrics, Obstetrics and Reproductive Medicine, Neonatal Intensive Care, University of Siena, Siena,
Italy. E-mail: annalisa.rossetti1985@gmail.com

1
2   B. Franco et al.
age ≤32 weeks, birth weight ≤1500 g, PDA with evidence of ductal Table I.  Study population’s general characteristics before ibuprofen
shunting documented by echocardiography, postnatal age >72 h, treatment.
and informed consent signed by a parent/legal guardian. Local Total population 67 preterm newborns
ethical committee approved this study; 7% of newborns’ parents Male (female) n = 36 (31)
refused to participate to the study. Exclusion criteria included: AGA (SGA) n = 50 (17)
congenital heart malformation, major congenital malformations Mean birth weight (BW) 989 ± 326 g
and/or chromosomal anomalies, antenatal renal malformation   500–750 g n = 18
on fetal ultrasound, platelet count <75,000/mm3, clinical bleeding
mBW: 659 ± 60 g
tendency, renal failure, congenital bacterial infection, treatment
mGA: 25 ± 1.18 weeks
with a steroid at any time since birth. Echocardiograms were
  751–1000 g n = 26
performed in the first 72–96 h of life and the day after the end of
each cycle of therapy. The purpose of the echocardiograms was mBW: 898 ± 72 g
to evaluate the patency of the ductus and shunting. The criterion mGA: 27+1 ± 1.65 weeks
for hemodynamically significant PDA was the presence of at least   >1000 g n = 23
two of the following three parameters: (i) LA/AO ratio of ≥1.4:1; mBW: 1347 ± 146 g
(ii) LV/AO ratio of 2.1:1; and/or (iii) narrowest ductal diameter mGA: 29+6 ± 1.65 weeks
>1.5 mm, left-to-right shunting of blood and diastolic reversal of Mean gestational age (GA) 27+3 ± 2.5 weeks
blood flow in the aorta.   ≤26 weeks n = 32
Ibuprofen was given intravenously for 10  min using mBW: 763 ± 134 g
10 mg/kg loading doses, followed by 5 mg/kg/d on the second and mGA: 25+3 ± 1 weeks
third study days, using an umbilical venous catheter or periph-   >26 weeks n = 35
eral IV site. The indices of renal failure used were creatininemia, mBW: 1194 ± 213 g
azotemia (BUN) and glomerular filtration rate (GFR). Plasma
mGA: 29+4 ± 1.6 weeks
creatinine, urea and electrolytes were recorded before the begin-
Closure of ductus following a single cycle of 56.7%
ning of therapy and the dosages were repeated at the end of the ibuprofen
3-day course of IV ibuprofen. GFR was estimated on day 1 and at
Closure of ductus following two cycles of therapy 12%
the end of the 3-day course of IV ibuprofen using the Schwartz
Closure of ductus following three cycles of therapy 6%
formula with the specific k value for preterm infants (0.33) [16].
Surgical ligation of the duct (after at least one cycle 25.3%
From day 1 to day 7, the amount of fluid administered to the of ibuprofen)
population was 70–90–110–130–140–140–150 mg/kg.
134 preterm newborns with PDA were enrolled in our study confidence intervals. The data analysis was conducted using Stata,
and randomized to receive either placebo or a 3-day-course version 8.0 [17].
(10 mg/kg, 5 mg/kg and 5 mg/kg) of IV ibuprofen.
Placebo group was formed by 67 preterm newborns (39 males
and 28 females; 53 appropriate for gestational age and 14 small for Results
gestational age); mean gestational age was 27+6 weeks (±4 weeks) In the placebo group, the medians of creatinine and blood urea
and mean birth weight was 1197 g (±835 g). nitrogen were 0.65 mg/dl and 23 mg/dl on day 1, and 0.6 mg/dl
Ibuprofen group was formed by 67 preterm infants (36 males and 38 mg/dl on day 7, respectively.
and 31 females; 50 AGA and 17 SGA); the mean gestational age In the Ibuprofen group, instead, the median of creatinine
was 27+3 weeks (±2.5 weeks), and the mean birth weight was 989 g and blood urea nitrogen were 0.6 mg/dl and 19.5 mg/dl on day
(±326 g) (Table I). 1, and 1 mg/dl and 84 mg/dl at the end of 3-day-course of IV
The subjects were stratified into three birth weight categories: ibuprofen, respectively – values were higher at the end of the
500–750 g (n = 18), 751–1000 g (n = 26), and >1000 g (n = 23), and 3-day course of IV ibuprofen compared to initial values, but this
subdivided into two gestational age categories: ≤26 weeks (n = 32) difference was only significant for the blood urea nitrogen (with
and >26 weeks (n = 35). p = 0.0008).
A descriptive analysis of the variables of the study population While on day 1, creatinine and blood urea nitrogen values
was performed. Creatinine and urea levels did not pass tests of were similar between placebo and ibuprofen groups (creatinine:
normality and homogeneity of variance, so a logarithmic trans- 0.65 mg/dl vs 0.6 mg/dl, p = 0.14; blood urea nitrogen: 23 mg/
formation was performed for both of them. Log creatinine values dl vs 19.5 mg/dl, p = 0.92, respectively), on day 7 (at the end of
were normally distributed, while log urea values were not. Log 3-day-course of IV ibuprofen in the treated group) creatinine
creatinine values were back-transformed using the exponential and blood urea nitrogen were statistically different between the
transformation to give means and standard errors (SE) in the two categories (creatinine: 0.6 mg/dl vs 1 mg/dl, p = 0.0003; blood
same unit as the original data. Log creatinine and urea levels at urea nitrogen: 38 mg/dl vs 84 mg/dl, p = 0.0000002), showing
day 1 and day 3 were comparatively analyzed using a paired t-test higher values in the ibuprofen group.
and the Wilcoxon matched pairs test, respectively. Comparisons Stratifying the placebo group into two weight ranges (≤ and
of creatinine and urea levels between patients with gestational age > 1000 g), the median of serum creatinine did not differ signifi-
≤26 weeks and those >26 weeks, and between patients weighing cantly between day 1 and day 7 in either group, though there
≤1000 g and those >1000 g, were performed using the unpaired was a slight decrease in preterm babies weighing >1000 g (from
t-test for log creatinine levels and the Mann–Whitney test for urea 0.7 mg/dl to 0.6 mg/dl) whereas babies weighing ≤1000 g showed
levels. Confidence intervals (CI) were calculated at 95% and the a slight increment (from 0.6 mg/dl to 0.7 mg/dl). Blood urea
significance level set at 0.05. Power analysis was not performed nitrogen (BUN) showed the same pattern.
because the difference was observed at prearranged significance In the Ibuprofen group, subdividing the infants according to
level sets and because the power is appropriately indicated by weight, it became apparent that in newborns with a birth weight

The Journal of Maternal-Fetal and Neonatal Medicine


≤1000 g, creatinine values before and after therapy showed a statis-
tically significant difference (median 0.93 mg/dl and 1.19 mg/dl,
respectively), with p = 0.01. In contrast, in newborns with a BW
>1000 g, creatinine values remained stable (p = 0.16) (Figure 1;
Table II). Moreover, while creatinine values were similar between
newborns ≤ and > 1000 g prior to therapy (median 0.93 mg/dl and
0.92 mg/dl, respectively; p = 0.95), at the end of the 3-day course of
IV ibuprofen creatinine levels were statistically different between
the two categories (p = 0.006, with a median of 1.19 mg/dl in
newborns with a BW ≤1000 g and 0.79 mg/dl in those >1000 g),
Figure 1.  Creatinine: comparison of its values between before and after the
therapy with iv ibuprofen in preterm newborns. Values of creatinine (mg/dl):
comparison between before and after the therapy with iv ibuprofen in preterm
newborns stratified into birth weight and gestational age categories. Blood
urea nitrogen shows the same behavior than creatinine.
Treatment of PDA using ibuprofen: renal alteration  3
showing that ibuprofen only had significant renal effects in infants
with a birth weight ≤1000 g (Table III).
Plasma urea showed the same behavior as creatinine. In fact,
in newborns with a birth weight >1000 g the median blood urea
nitrogen increased from 63 mg/dl to 71 mg/dl (p = 0.07), whereas
in newborns with a birth weight ≤1000 g, the median blood urea
nitrogen showed a statistically significant difference between
before and after therapy (median 54 mg/dl and 98 mg/dl, respec-
tively; p = 0.0002) (Table II). Besides, while blood urea nitrogen
values were similar between newborns ≤ and > 1000 g before the
start of therapy, at the end of the therapy blood urea nitrogen
values were statistically different between the two categories
(p = 0.04, with a median of 98 mg/dl in newborns with of birth
weight ≤1000 g and 71 mg/dl in those >1000 g) (Table III).
Subdividing the preterm population weighing ≤1000 g into
a further two groups (≤750 g and 751–1000 g) showed that
in neonates weighing 751–1000 g creatininemia increased by
0.87 mg/dl to 1.16 mg/dl (p = 0.018); in preterm infants weighing
≤750 g it increased from 0.95 mg/dl to 1.65 mg/dl (p = 0.02).
Azotemia behaved in the same way, increasing from 46 mg/dl to
95 mg/dl (p = 0.001) in the population weighing 751–1000 g, and
from 71 mg/dl to 114.5 mg/dl in the population ≤750 g (p = 0.026).
The infants were also stratified into two gestational age catego-
ries (≤26 weeks and >26 weeks), and we evaluated the behavior
of creatinine and blood urea nitrogen in these different popula-
tions. The values of both creatinine and blood urea nitrogen were
only significantly higher than initial values at the end of the 3-day
course of IV ibuprofen in newborns with a gestational age of
≤26 weeks, while in those with a gestational age >26 weeks the

Table II.  Values of creatinine and blood urea nitrogen (BUN) in preterm newborns stratified into birth weight (BW) and gestational age (GA) categories;
comparison of these values between before and after the therapy with iv ibuprofen.
Creatinine (mg/dl) Blood urea nitrogen (mg/dl)
Preterm newborns Before the therapy (A) After the therapy (B) p: A vs B Before the therapy (A) After the therapy (B) p: A vs B
Total population 0.93 1.03 NS 61 84 p = 0.0008
Birth weight (BW)
  >1000 g 0.92 0.79 NS 63 71 NS
  ≤1000 g 0.93 1.19 p = 0.01 54 98 p = 0.0002
  751–1000 g 0.87 1.16 p = 0.018 46 95 p = 0.001
  ≤750 g 0.95 1.65 p = 0.02 71 114.5 p = 0.026
Gestational age (GA)
  >26 weeks 0.92 0.92 NS 55 71 NS
  ≤26 weeks 0.72 1.38 p = 0.004 65 126 p = 0.00005
The values of both creatinine and BUN were only significantly higher than initial values at the end of the 3-day course of IV ibuprofen in newborns with a BW ≤1000 g and/or GA
≤26 weeks, while in those with BW >1000 g and/or GA >26 weeks the increases were not significant.
A, before the beginning of the therapy with IV ibuprofen; B, at the end of the 3-day course of IV ibuprofen. BUN, blood urea nitrogen; BW, birth weight; GA, gestational age.

Table III.  Values of creatinine and blood urea nitrogen (BUN) before the beginning and at the end of the 3-day course of IV ibuprofen in preterm newborns
stratified into birth weight (BW) and gestational age (GA) categories.
Birth weight Gestational age
p: ≤1000 g p: ≤26 weeks
≤1000 g >1000 g vs >1000 g ≤26 weeks >26 weeks vs >26 weeks
Before the therapy
(A)
  Creatinine (mg/dl) 0.93 0.92 NS 0.72 0.92 NS
  Urea (mg/dl) 54 63 NS 65 55 NS
After the therapy
(B)
  Creatinine (mg/dl) 1.19 0.79 p = 0.006 1.38 0.92 p = 0.0001
  Urea (mg/dl) 98 71 p = 0.04 126 71 p = 0.001
The differences between ≤ and >1000 g and/or ≤ and >26 weeks in creatinine and blood urea nitrogen (BUN) were recorded only at the end of the therapy and not at the beginning.
A, before the beginning of the therapy with IV ibuprofen; B, at the end of the 3-day course of IV ibuprofen.

© 2012 Informa UK, Ltd.

4   B. Franco et al.
increases were not significant (Figure 1; Table II). The differences
between ≤ and > 26 weeks in creatinine and blood urea nitrogen
were recorded at the end of the therapy (p = 0.0001 and p = 0.001,
respectively), and not at the beginning, showing that ibuprofen
only had significant renal effects in infants with a gestational age
≤26 weeks (Table III).
Ibuprofen therapy was associated with a significantly lower GFR
at the end of treatment. In fact, the mean GFR at the end of the 3-day
course of IV ibuprofen (GFR: 14.52 ml/min/1.73 m) [2] was nearly
10% lower than the mean GFR prior to treatment (GFR: 16.13 ml/
min/1.73 m) [2]. Ibuprofen therapy in very preterm infants with
PDA caused a reduction in GFR. Moreover, stratifying infants into
categories according to birth weight (≤ and > 1000 g) and gesta-
tional age (≤26 and >26 weeks) revealed that the reduction in GFR
was more evident in infants with a birth weight ≤1000 g (about
25%) and gestational age ≤26 weeks (nearly 37.50%). At the end
of therapy, the weight of preterm infants in the ibuprofen group
increased in 59.50% of cases, decreased in 32% and remained stable
in 8.5%. The median weight gain was +4.6% of initial weight; this
percentage rose especially in newborns with a birth weight ≤1000 g
(+5.56%) and gestational age ≤26 weeks (+5.56%). Stratifying
newborns into Small for Gestational Age (SGA) and appropriate
for gestational age (AGA) categories, 73.3% of SGA preterm infants
presented a body weight increase, in contrast to 53.1% of AGA
preterm infants.
Concerning the closure of Botallo’s duct, 56.7% of preterm
newborns showed closure following a single cycle of ibuprofen,
while 12% needed two cycles of therapy and 6% required three
cycles. 25.3% (n = 17) required surgical ligation of the duct after
at least one cycle of therapy (up to a maximum of three cycles);
of these, nine preterm infants weighed ≤750 g at birth and only
one neonate weighed >1000 g. 50% of the premature population
weighing ≤750 g at birth required surgical ligation of the duct.
None of the preterm infants died following the operation. Lastly,
90% of the infants who underwent surgical ligation of the duct
gained weight, with a mean of +5.5% initial weight.
Discussion
Many studies in the literature have shown that ibuprofen is as
effective as indomethacin in bringing about PDA closure [6,7,18],
and has fewer side-effects [5,6,8–11,19–21].
However, concerning the renal side-effects of ibuprofen,
studies in the literature have reported contrasting results. Some
authors found no renal side-effects of ibuprofen [11,12,21], but
did not focus on the renal side-effects of ibuprofen as the primary
outcome. Pezzati et al. [11] did not show any renal side-effects of
ibuprofen as they found no increase in plasma creatinine during
or after ibuprofen therapy in preterm neonates born at <33 weeks
gestation. In their Doppler ultrasound study, they found no
significant decreases in the peak-systolic velocity, mean velocity
or end-diastolic velocity of the superior mesenteric artery and
renal artery following ibuprofen therapy. Dani et al. [12], studying
prophylactic ibuprofen for the prevention of intraventricular
hemorrhage (IVH) in a population of gestational age (GA) <28
weeks (P: 832 ± 215 g and GA: 25.3 ± 1.2 weeks) found that serum
creatinine levels, urine outputs and rates of oliguria did not differ
between the ibuprofen and placebo group. In a recent study,
Katakam et al. [21] observed that creatininemia increased after
treatment with ibuprofen, although not in a statistically signifi-
cant manner (from 1.09 mg/dl to 1.32 mg/dl, p = 0.74).
Other authors have reported that renal damage ascribable to the
therapeutic use of ibuprofen was statistically significant but mild
The Journal of Maternal-Fetal and Neonatal Medicine
and transitory [5,7,22–24]. In fact, Fanos et al. [24] maintain that
ibuprofen administration affects renal function in VLBW infants,
but these alterations are to be considered transient, as the values
return within the normal range one week after drug administra-
tion. Van Overmeire et al. [23] found that ibuprofen significantly
decreased urine production on day 1 and significantly increased
serum creatinine concentration on day 3 compared with placebo;
however, these effects were transient and the difference between
ibuprofen and placebo groups was no longer significant on day
3. Aranda et al. [22] found that although mean serum creatinine
was significantly higher in the ibuprofen group compared to the
placebo group, these differences disappeared when adjusted for
baseline, and blood urea nitrogen did not differ significantly
between the two groups; thus the author concludes with the affir-
mation that ibuprofen decreases PDA with a minimal effect on
renal function and does not unduly decrease the urine flow rate
(Table III).
In contrast, other authors, such as Gournay and Vieux, have
shown that ibuprofen can cause renal side-effects. Gournay
et al. [25] demonstrated that preventive therapy with ibuprofen
(received within 6 h of birth) significantly decreased urine output
during days 1–3 and significantly increased creatinine during
days 4–7. Vieux et al. [15] showed that ibuprofen therapy was
associated with a significantly lower GFR on day 7 (which lasted
until day 28) and a significantly decreased urine output.
Our study showed that the treatment of PDA with ibuprofen
was associated with renal alterations. In fact, ibuprofen signifi-
cantly impaired renal function in newborns with a birth weight
≤1000 g and/or gestational age ≤26 weeks, while in infants with
a BW >1000 g and/or GA >26 weeks this drug did not produce
substantial increases in serum creatinine and blood urea nitrogen
values or decreases in GFR and urine output. It is therefore clear
that renal impairment is greater the lower the weight and gesta-
tional age of the infant at birth. The fact that the values of renal
parameters were similar in infants of various weights and gesta-
tional ages prior to therapy with ibuprofen, while creatininemia
and azotemia were statistically different after a 3-day course of IV
ibuprofen, again demonstrates that ibuprofen significantly alters
renal function only in the categories ≤26 weeks and ≤1000 g.
Moreover, we also found episodes of oliguria or anuria in these
infants, especially in preterm infants with extremely low birth
weight and GA. Therefore, it is very important to evaluate the
potential renal side-effects of ibuprofen before starting treatment
and, consequently, the effective need for such therapy, bearing in
mind the ratio of risk-benefit based on birth weight and gesta-
tional age. In addition, ibuprofen therapy caused a weight gain in
about 59% of the population, due both to the reduction of urine
output and to the fact that ibuprofen antagonizes the effects of
diuretics. No studies in the literature have specifically evaluated
the renal side-effects of ibuprofen therapy on a large number of
premature neonates with BW ≤750 g and 751–1000 g and GA ≤26
and >26 weeks. In our opinion, the fact that other studies have
not divided the infants into classes according to GA explains why
some authors, including Aranda [22], Van Overmeire [23] and
Fanos [24], did not find significant alterations in renal function.
The lack of division into classes of BW and GA may have hidden
renal impairment in the population with lower BW and GA,
as demonstrated in our study, which has highlighted that such
infants are more susceptible to alterations in renal parameters.
No newborn has presented significant acidosis; all newborns
have parenteral nutrition during the study and, in particular,
proteic and glucidic intakes are comparable between all examined
subjects.

It is difficult to ascertain whether or not renal impairment
caused by ibuprofen is permanent or transient. Although creat-
ininemia and azotemia values may return to normal relatively
quickly, this does not mean that the drug has not caused damage
to the glomeruli which is hidden by the maturation and increasing
number of glomeruli in subsequent months. Nonetheless, the
detection of oliguria and even anuria in some of our preterm
neonates suggests that renal impairment caused by ibuprofen is
probably long-lasting. Dani et al. [12] found no significant altera-
tion in renal function parameters, probably because the aim of
their study was to assess the lower incidence of IVH in neonates
treated with preventive ibuprofen and they therefore only studied
creatininemia as an indicator of renal function (setting a cut-off
level of 1.5 mg/dl), without considering other indicators or any
decrease in diuresis. The study by Pezzati et al. [11], on the other
hand, considered only a small population (nine neonates) with
a relatively high mean GA (29.1±1,2 weeks); in this age group,
they found no relevant renal impairment, like our study. Our
results are in line with those of Vieux et al. [15], who show that
ibuprofen can alter renal function, causing significant alterations
in glomerular filtration rate (GFR) and fractional excretion of
Sodium (FENa). Antonucci et al. [13] also showed that ibuprofen
can cause renal impairment, demonstrating a decrease in urinary
prostaglandin E2 (uPGE2) excretion.
Renal prostaglandins, in particular prostaglandin E2 (PGE2),
play a homeostatic role in renal function through their hemo-
dynamic (vasodilatation) and tubular (salt and water excretion)
effects. They also protect renal perfusion and the glomerular
filtration rate under conditions in which vasoconstrictor forces
are activated, such as renal stress, especially in perinatal kidneys.
They protect the glomerular filtration rate by vasodilating the
afferent arterioles, and by contrasting the renal vasoconstrictor
effects of angiotensin II, endothelin and catecholamines [26].
The renal protective role played by vasodilatory prostaglandins is
particularly important during the neonatal period, when imma-
ture kidneys are perfused at very low pressure [13]. Immature
neonatal kidneys are considered prostaglandin-dependent organs
due to their susceptibility to a transient lack of prostaglandins
[27,28]. Perinatal kidneys are under a condition of permanent
stress because of high preglomerular and postglomerular vascular
resistance. At birth, the glomerular filtration rate is very low, espe-
cially in preterm neonates, and is regulated by a delicate balance of
intrarenal vasoconstrictor and vasodilator forces. In fact, neonates
have elevated levels of angiotensin II (which has a vasoconstric-
tive action), whose action is antagonized by PGE2 (which has a
protective vasodilatory action). Therefore, the immature kidneys
of preterm infants depend on the action of prostaglandins in the
perinatal and neonatal period. Although sufficient for growth
and development under normal conditions, the low glomerular
filtration rate of the newborn kidney limits postnatal renal func-
tional adaptation to stress; this adaptation becomes even more
problematic in preterm infants of lower gestational age, in whom
a combination of factors affect renal function.
The neonatal kidney is highly vulnerable to drug-induced
toxicity because of its specific anatomic and functional char-
acteristics. Manifestations of drug-induced renal toxicity are
strongly influenced by the stage of development of the kidney
[26]. Nephrotoxic damage in the newborn may result in deficits
of glomerular filtration and tubular function, such as renal failure
(with increased blood creatinine and urea), impaired ability
to concentrate urine and eliminate substances or regulate the
electrolyte balance, and changes in blood pressure. Ibuprofen, a
NSAID, inhibits cyclooxygenase (COX) activity and consequently
© 2012 Informa UK, Ltd.
Treatment of PDA using ibuprofen: renal alteration  5
prostaglandin synthesis. This decrease in renal prostaglandin
synthesis leads to unrestricted vasoconstriction, followed by
reduced renal perfusion and glomerular filtration rates [26].
Thus, ibuprofen can induce clinically relevant nephrotoxic effects
in the newborn (especially in preterm infants). Antonucci et al.
[13] studied the renal side-effects of ibuprofen in preterm infants
with PDA by measuring changes in urinary PGE2 and reported
a marked reduction (59.4%) in urinary levels of PGE2 after
ibuprofen therapy, underlining the strong inhibition exerted by
the drug on renal synthesis of PGE2, the most marked decreases
being associated with acute renal failure. Thus this author demon-
strated that ibuprofen administered during the first few days of
life causes a decrease in PGE2 synthesis by the immature kidney,
enhancing the physiological reduction in urinary excretion of
this prostanoid during the phase of adaptation to extra-uterine
life [13]. Moreover, a difference in serum creatinine behavior
over time was documented between preterm infants treated
with ibuprofen and controls, thus supporting the hypothesis of
a nephrotoxic effect of the drug. Cuzzolin et al. [14] divided a
population of 246 newborns (not necessarily affected by patency
of Botallo’s duct) into four categories of GA, from 22 to 36 weeks,
and analyzed serum creatinine levels and urine output for the first
month of life, demonstrating that the simultaneous administra-
tion of certain drugs (including ibuprofen) in preterm newborns
is an important risk factor for acute renal failure. Our data are
in line with Cuzzolin’s results, although the two studies are not
strictly comparable as Cuzzolin et al. did not consider exclusively
neonates with patent Botallo’s ducts. In fact, there were no differ-
ences in serum creatinine levels at birth among their four groups
of GA, probably because creatinine levels at birth reflect maternal
plasma concentrations; on the contrary, significant differences
among the four GA groups became evident from day 3 to day
21 of life. In the neonates with lower Gas, the decrease in creati-
nine was much slower and 56% of neonates had impaired renal
function (in contrast to only 15% in the group with higher gesta-
tional ages). Allegaert et al. [19,20,29,30] have conducted various
studies on the detrimental effects of ibuprofen on the glomerular
filtration rate by measuring the clearance of amikacin and vanco-
mycin. They have emphasized a significant and clinically relevant
reduction in the clearance of these drugs; the decrease found in
GFR is consistent with a 21% lower amikacin clearance following
ibuprofen therapy.
We questioned whether other mechanisms are responsible
for water retention, in addition to the inhibition of prostaglan-
dins. Studies on animals and human adults have demonstrated
that PGE2 antagonizes the activation and insertion of aquaporin
2 (AQP2) into the apical membrane of collecting duct cells and,
consequently, the action of the hormone vasopressin AVP (which
has an antidiuretic effect); the administration of prostaglandin
inhibitors (such as ibuprofen) provokes an increase in urinary
excretion of AQP2 in both animals and adult humans, with a conse-
quent reduction of diuresis. We therefore questioned whether the
administration of ibuprofen to preterm neonates for the closure
of the PDA may have caused the water retention found in many
of the neonates in our study. In a study involving a population of
preterm neonates weighing 1056 ± 46 g and with mean GA 28.7
weeks, who were treated with ibuprofen to close the PDA, Li et al.
[31] demonstrated significantly decreased urinary levels of AQP2;
therefore water retention in preterm neonates is not caused by an
increase in levels of AQP2. The author explains the discordance
of this result with those obtained in animals and adult humans
as mainly being due to the immaturity of neonatal kidneys, as it
seems that the collecting duct may be relatively resistant to the
6   B. Franco et al.
action of the antidiuretic hormone, and there may be low expres-
sion of AQP2 and a poorly functioning mechanism transporting
AQP2 to the apical membrane of the main collecting duct cells.
Moreover, ibuprofen has a quantifiable impact on renal drug
clearance, as demonstrated by Allegaert et al. [19,20], who found
a significant decrease in the clearance of drugs such as amikacin.
In fact, the neonatal kidney is highly vulnerable to drug-induced
toxicity due to its specific anatomic and functional characteris-
tics; furthermore, critically ill newborns are frequently exposed
to nephrotoxic drugs, especially in the first days of life. The mani-
festations of drug-induced renal toxicity are strongly influenced
by the stage of development of the kidney [26]. Administration of
ibuprofen in neonates is associated with a reduction in glomerular
filtration, which is reflected in the reduced elimination of drugs
dependent on renal function for clearance. This is of great impor-
tance in preterm infants, who may receive several other nephro-
toxic drugs (such as amikacin and vancomycin) during their first
month of life, thus requiring dosage to be checked and adjusted
according to plasma levels. This needs to be taken into account
when other drugs which are primarily eliminated by glomerular
filtration are considered in such infants, either during or after
ibuprofen treatment. Long-term follow-up is required to ensure
that the alterations observed are the result of delayed maturation
and not of subtle lesions that could impact these subjects’ renal
function later in life.
The study has some limitations. The gold standard to deter-
mine GFR is insulin clearance. However, the need for voluntary
bladder voiding renders this impossible in newborns. Creatinine
clearance is an accepted and feasible measurement in the preterm
infant. The study population should be larger and Cystatin C,
uPGE2 and FENa should be evaluated as further parameters to
test renal functioning. Also the effects of genetic polymorphism
(CYP2C9 and CYP2C8) should be evaluated.
Conclusions
This study has shown that treating PDA with ibuprofen is
associated with renal alterations. Ibuprofen may be considered
safe for infants with a birth weight >1000 g and/or gestational
age >26 weeks, as it does not cause substantial increases in
serum creatinine and blood urea nitrogen values or signifi-
cant decreases in GFR and urine output in these patients. On
the contrary, ibuprofen significantly impairs renal function
in preterm infants with a gestational age ≤26 weeks and/or in
ELBW neonates. Moreover, we encountered episodes of oliguria
or anuria in these infants, especially in the preterm neonates
with extremely low birth weight or gestational age. Thus, before
starting therapy with IV ibuprofen it is essential to take into
account the birth weight and gestational age of newborns and
the effective need for treatment from the point of view of the
ratio of risks to benefits, due to its substantial renal side-effects.
Consequently, if there are no clinical and echocardiographical
signs of duct closure after the first course of ibuprofen, the
possibility of surgical ligation of the duct should be considered
instead of a second cycle of the drug.
Finally, ibuprofen has an impact on renal drug clearance; it
is associated with a reduction of glomerular filtration, reflected
the impaired elimination of drugs which depend on renal func-
tion for clearance. This is of upmost importance in preterm
infants, who may receive several other nephrotoxic drugs (such
as amikacin and vancomycin) during their first month of life,
thus requiring dose adaptation. Dosing needs to be checked and
adjusted to plasma levels, and long-term follow-up is required.
The Journal of Maternal-Fetal and Neonatal Medicine
The risk of ibuprofen-induced nephrotoxicity can be reduced by
adopting certain preventive measures, such as avoiding the use
of multiple nephrotoxic agents, ensuring adequate hydration,
and monitoring diuresis, serum levels of creatinine and urea,
and urinary PGE2 (as an index of renal synthesis of this prosta-
glandin) [26]. The optimal time to treat the PDA is when treat-
ment with COX inhibitors will be most effective, while seeking to
avoid treating infants who may have spontaneous closure of the
ductus. Therefore, prophylactic treatment is only indicated when
the risk of IVH is very high. The current trend is to treat early
pre-symptomatic PDA at 2–7 days of age, after echocardiographic
confirmation. This will minimize the exposure to COX inhibi-
tors of infants whose ductus will close spontaneously and at the
same time benefit those who will respond most favorably to COX
inhibitors.
Declaration of Interest: The authors report no conflict of interest.
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