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PEDIATRICS Vol. 102 No. 5 November 1998, p. e56
,, and
From the Departments of * Neonatology and Cardiology, Shaare
Zedek Medical Center, Jerusalem, Israel.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
References
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Postnatally, therapeutic indomethacin administration is usually effective in mediating patent ductus arteriosus (PDA) constriction in premature infants. There are infants, however, who remain resistant to indomethacin and require more aggressive surgical intervention to facilitate ductal closure.
Indomethacin tocolysis has been reported to increase the incidence of persistent PDA in premature infants. It was our impression that infants exposed to antenatal indomethacin not only suffered from an increased incidence of PDA, but that they were more symptomatic from PDA and that for them, PDA was more resistant to medical closure. It is this observation that we sought to examine in this study.
Methods. Medical records of all mothers and
premature neonates with birth weight 
1500 g, admitted to the neonatal
intensive care unit of the Shaare Zedek Medical Center during 1996 and
1997, who survived for at least 1 week, were reviewed retrospectively. Data on maternal indomethacin and steroid exposure, birth weight and
gestational age, and ductus status and treatment were analyzed. In our
obstetrics department, indomethacin is the medication of choice to
inhibit premature labor. Mothers who arrive in premature labor are
started on indomethacin therapy, if delivery is not imminent.
All infants 1500 g were studied by a pediatric cardiologist between
24 and 72 hours of life using two-dimensional echocardiography with
color flow mapping to assess ductal patency. Decisions to treat were
based on echocardiographic evidence of PDA, along with any of the
following clinical signs: bounding pulses, diastolic pressure of 25
mm Hg, pulmonary plethora and/or cardiomegaly on chest x-ray, or
increasing oxygen requirement with no other explanation. Initial
treatment is with indomethacin, if there are no contraindications. Our
general approach is to begin therapy with a continuous indomethacin
infusion, followed by a course of bolus indomethacin if the infant does
not respond. However, each attending neonatologist may treat according
to his/her preference (ie, bolus vs continuous). All infants with PDA
are followed with serial echocardiographic examinations until the
ductus is closed.
Results. A total of 105 premature infants met the above criteria. Thirty-six of these 105 infants had echocardiographic signs of a PDA (34.3%). Those with PDA were less mature (gestational age, 28.9 ± 2.6 vs 30.3 ± 2.6 weeks, respectively) and tended to be smaller (1060 ± 270 vs 1166 ± 261 g). Of the 36 infants with PDA, 15 (42%) resolved spontaneously and 21 (58%) were symptomatic and required treatment with indomethacin. There were no differences in gestational age or birth weight between infants whose PDA resolved spontaneously and those requiring indomethacin therapy. Four of the 21 (19%) treated infants remained unresponsive to indomethacin and required ductal ligation.
Of 17 infants with PDA who responded to indomethacin therapy, 1 (6%) was treated with a single course of bolus indomethacin, to which he responded, and 16 (94%) were treated with continuous indomethacin and responded promptly. The differences in therapeutic responsiveness to initial treatment with continuous vs bolus indomethacin were not significant.
Of the 105 infants, 29 were exposed to indomethacin tocolysis. Those who were exposed to antenatal indomethacin and those who were not were well-matched with respect to birth weight and gestational age. Fifteen (52%) of the 29 exposed infants versus 18 (24%) of the 76 infants not exposed to antenatal indomethacin developed a PDA postnatally (relative risk = 2.1; 95% confidence interval: 1.22-3.74), and 45% of the antenatally exposed infants versus 12% of the nonexposed infants were symptomatic and required indomethacin (relative risk = 1.9; 95% confidence interval: 1.17-3.20). Four of the exposed infants versus none of the unexposed infants required surgical ligation.
Among the indomethacin-exposed infants, the nonresponsive and responsive infants were well-matched with regard to birth weight, gestational age, antenatal steroid exposure, and day of life on which indomethacin therapy was initiated. Multiple regression analyses found prenatal indomethacin exposure to be the most significant antecedent variable associated with both the incidence and the severity of PDA, as indicated by the need for indomethacin treatment.
Conclusions. We have demonstrated that prenatal indomethacin exposure increases both the incidence and the clinical severity of postnatal PDA, as manifested by increased need for therapeutic indomethacin and surgical ligation. Furthermore, we have shown it to be a more significant risk factor than gestational age, birth weight, or antenatal steroid exposure in both the development and the severity of postnatal PDA. These data should be considered in considerations as to choice of tocolytic therapy.
Key words: indomethacin, patent ductus arteriosus (PDA), tocolysis surgical ligation, premature neonate.
During the transition from intrauterine to extrauterine
existence, the ductus arteriosus is transformed from a vital component of the fetal circulation into an unnecessary and even deleterious appendage to the neonatal circulation. As such, it is normally programmed physiologically to constrict automatically shortly after
birth. In premature infants, however, spontaneous closure often is
delayed, resulting in persistent patency of the ductus arteriosus
(PDA), which may require medical intervention to promote closure. To
date, the most widely used pharmacologic agent for this purpose is
indomethacin. Postnatally, therapeutic indomethacin administration is
usually effective in mediating PDA constriction in premature infants.
There are infants, however, who remain resistant to indomethacin and
require more aggressive surgical intervention to facilitate ductal
closure.
Indomethacin tocolysis has been reported to increase the incidence of
persistent PDA in premature infants.1 It was our
impression that infants exposed to antenatal indomethacin not only
suffered from an increased incidence of PDA, as reported, but that they
were more symptomatic from PDA and that for them, PDA was more
resistant to medical closure. It is this observation that we sought to
examine in this study.
Medical records of all mothers and premature neonates with birth
weight All of our infants weighing Analysis of Data
A total of 105 premature infants met the above criteria. Of these,
36 (34.3%) had echocardiographic signs of a PDA. Those with PDAs were
less mature (gestational age, 28.9 ± 2.6 vs 30.3 ± 2.6 weeks, respectively; P = .01) and tended to be smaller
(1060 ± 270 vs 1166 ± 261 g; P = .053). Of the 36 infants with PDA, 15 (42%) resolved spontaneously and
21 (58%) were symptomatic and required treatment with indomethacin.
There were no differences in either gestational age or birth weight
between those infants whose PDA resolved spontaneously and those
requiring indomethacin therapy. Four (19%) of the 21 treated infants
remained unresponsive to indomethacin and required ductal ligation.
Of 17 infants with PDA who responded to indomethacin therapy, 1 (6%)
was treated with a single course of bolus indomethacin to which he
responded, and 16 (94%) were treated with continuous indomethacin and
responded promptly. Of the treatment failures who proceeded to
ligation, 1 was treated initially with bolus indomethacin followed by a
second course of continuous indomethacin, and 3 were treated initially
with continuous indomethacin, followed by a second course with bolus
indomethacin. The differences in therapeutic responsiveness to initial
treatment with continuous versus bolus indomethacin were not
significant (P = Influence of Prenatal Indomethacin
Of the 105 infants, 29 were exposed to indomethacin tocolysis.
Those who were exposed to antenatal indomethacin and those who were not
were well-matched with respect to birth weight and gestational age
(Table 1). Fifteen (52%) of the 29 exposed infants versus 18 (24%) of the 76 (P = .012) infants not exposed to antenatal indomethacin developed a PDA
postnatally (relative risk = 2.1; 95% confidence interval [CI]:
1.22-3.74) (Fig 1). Forty-five percent of
the antenatally exposed infants versus 12% (P = .0006) of the nonexposed were symptomatic and required indomethacin therapy (relative risk, 1.9; 95% CI: 1.17-3.20). Four of the exposed infants versus none of the unexposed infants (P = .006) required surgical ligation.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
References
1500 g, admitted to the neonatal intensive care unit of the
Shaare Zedek Medical Center during 1996 and 1997, who survived for at
least 1 week, were reviewed retrospectively. Data on maternal indomethacin and steroid exposure, birth weight and gestational age,
and ductus status and treatment were analyzed. In our obstetrics department, indomethacin is the medication of choice to inhibit premature labor. Our obstetrics protocol for antenatal indomethacin is
one dose of 100 mg per rectum followed by 25 mg, po, four times per
day. Mothers who arrive in premature labor are started on indomethacin
therapy, if delivery is not imminent.
1500 g studied by a pediatric
cardiologist between 24 and 72 hours of life using two-dimensional echocardiography with color flow mapping to assess ductal patency. Decisions to treat are based on echocardiographic evidence of PDA,
along with any of the following clinical signs: bounding pulses,
diastolic pressure of 25 mm Hg, pulmonary plethora and/or cardiomegaly on chest x-ray, or increasing oxygen requirement with no
other explanation. Initial treatment is with indomethacin, if there are
no contraindications. Our general approach is to begin therapy with a
continuous indomethacin infusion,9 followed by a
course of bolus indomethacin if the infant does not respond with
closure of the ductus. However, each attending neonatologist may treat
according to his/her preference (ie, bolus vs continuous). All infants
with PDA are followed with serial echocardiography until the ductus is
closed.
2 analyses were used to examine independence
between categorical variables (eg, incidence of PDA, percent treated
with indomethacin). Then multivariate analysis was performed using
multiple logistic regression models constructed alternatively using
presence or absence of PDA and the need for indomethacin treatment as
dependent variables and other measured variables, including gestational age, birth weight, antenatal indomethacin administration, and antenatal
steroid treatment, as independent variables. Correlation coefficients
and P values were calculated and used to estimate the
relative contribution of the variables.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
.45).
Antenatal Indomethacin and PDA
View larger version (17K):
[in a new window]
Fig. 1.
The top indicates the relative risk (vertical line) of developing a
postnatal PDA in indomethacin-exposed infants versus nonexposed
infants. Relative risk and 95% CIs (horizontal bar) were calculated by
multivariate linear regression. Results show that incidence is
increased significantly. The bottom indicates the relative risk
(vertical line) of a postnatal PDA being symptomatic and requiring
medical therapy for closure in indomethacin- exposed infants versus
nonexposed infants. Relative risk and 95% CIs (horizontal bar) were
calculated by multivariate linear regression. Results show that risk is
increased significantly.
Among the indomethacin-exposed, the nonresponsive and responsive infants were well-matched with regard to birth weight (889 ± 255 vs 1078 ± 351; P = .36), gestational age (25.7 ± 1.7 vs 28.7 ± 3.6; P = .15), antenatal steroid exposure (78% vs 100%; P = .86), and day of life on which indomethacin therapy was initiated (2.5 ± 1.3 vs 1.5 ± 0.5; P = .17).
Combined Analysis
Multiple regression analyses found prenatal indomethacin exposure to be the most significant antecedent variable associated with both the incidence of PDA and PDA severity, as indicated by the need for indomethacin treatment (Table 2).
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
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Indomethacin has been used for >20 years as a successful tocolytic agent. However, indomethacin does cross the placenta and, in most infants, causes in utero ductal constriction, increasingly significant at >31 weeks' gestation.2,3 This constriction generally is reversible, resolving after discontinuation of the indomethacin. Our data confirm the observations of Norton and associates1 that indomethacin tocolysis increased postnatal PDA incidence. These observations are, however, somewhat different from the findings of Eronen and co-workers,4 who noted no increased incidence of PDAs requiring indomethacin therapy among infants exposed to antenatal indomethacin. Although Eronen et al4 described a trend that did not reach statistical significance toward increased need for surgical ligation in these infants, our data now demonstrate definitively that indomethacin tocolysis also increases the clinical severity of the resulting PDAs, as manifested by increased need for therapeutic indomethacin. Furthermore, it is a more significant risk factor than gestational age, birth weight, or antenatal steroid exposure in both the development and the severity of postnatal PDA.
After in utero constriction, the subsequent ability of the ductus to recontract in response to oxygen or indomethacin appears to be limited, possibly reflecting early ischemic damage to the inner muscle wall.5 Gittenberger-de Groot described cytolytic necrosis in the media of the ductus after functional constriction, preceding full anatomic closure.6 Ductal necrosis also has been described in response to chronic hypoxia,7 with similar histologic changes observed in intrauterine growth-retarded fetuses.8 All of these infants have a diminished capacity for subsequent ductal constriction, manifesting clinically as a loss of ductal responsiveness and decreased sensitivity to indomethacin.
In 1995,9 our group introduced 36-hour continuous indomethacin infusion to treat PDA, and although each attending neonatologist may determine whether to treat with either bolus or continuous indomethacin, most do begin with the continuous infusion. As such, it is important to note that our overall 19% indomethacin failure rate is quite consistent with failure rates quoted in the medical literature,10,11 and that within our population, there was no difference in the responsiveness to continuous versus bolus indomethacin, implying that our approach is not associated with reduced therapeutic efficacy. Much larger numbers, however, would be needed to prove efficacy definitively.
In the current study, 1 responder and 1 nonresponder were treated initially with bolus indomethacin. To avoid possible bias and/or confusion associated with use of different therapeutic administration protocols, each of the statistical calculations cited above was repeated with these two infants removed from the study group. None of the results were affected adversely. Thus, we feel it is acceptable to analyze all of the infants in a single group. Clinical factors influencing therapeutic responsiveness and the pathophysiology thereof are likely to be qualitatively similar regardless of mode of administration. We believe, therefore, that these observations are relevant to all premature infants with PDA treated with indomethacin.
In summary, we have demonstrated that not only does prenatal indomethacin constitute a risk factor for PDA development, but also for PDA severity and resistance to therapy. Furthermore, it is the most significant risk factor among those studied in the development of these outcomes. These data should be considered in considerations of choice of tocolytic therapy.
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FOOTNOTES |
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Received for publication Mar 5, 1998; accepted Jun 3, 1998.
Reprint requests to (C.H.) Department of Neonatology, Shaare Zedek Medical Center, PO 3235, Jerusalem, Israel 91031.
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ABBREVIATIONS |
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PDA, patent ductus arteriosus.
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REFERENCES |
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This article has been cited by other articles:
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  M. Narayanan-Sankar and R. I. Clyman Pharmacology Review: Pharmacologic Closure of Patent Ductus Arteriosus in the Neonate NeoReviews, August 1, 2003; 4(8): e215 - 221. [Full Text] [PDF]
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