Neurosensory Impairment after Surgical Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms

Article Outline

• Abstract
• Methods
  • Patients
  • Management of PDA
  • Outcomes
  • Statistical Analysis
• Results
  • Study Cohort and Status at First Diagnosis of PDA
  • Use of Indomethacin for Closure of PDA and Timing of PDA Ligation
  • Risks of Adverse Outcomes after Surgical Closure of PDA
  • Incidence of Surgical PDA Closure in Study Centers and its Association with Center-Specific Risks of Neurosensory Impairment
• Discussion
• Appendix. 
  • The TIPP Investigators
    • Canada
    • Australia
    • New Zealand
    • Hong Kong
• References
• Copyright

Objectives

To determine whether surgical closure of a patent ductus arteriosus (PDA) is a risk factor for bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP), and neurosensory impairment in extremely low birth weight (ELBW) infants.

Study design

We studied 426 infants with a symptomatic PDA, 110 of whom underwent PDA ligation and 316 of whom received medical therapy only. All infants participated in the multicenter Trial of Indomethacin Prophylaxis in Preterms (TIPP) and were observed to a corrected age of 18 months.

Results

Of the 95 infants who survived after PDA ligation, 50 (53%) had neurosensory impairment, compared with 84 of the 245 infants (34%) who survived after receiving only medical therapy (adjusted odds ratio, 1.98; 95% CI, 1.18-3.30; P = .0093). BPD (adjusted odds ratio, 1.81; 95% CI, 1.09-3.03; P = .023) and severe ROP (adjusted odds ratio, 2.20; 95% CI, 1.19-4.07; P = .012) were also more common after surgical PDA closure.

Conclusions

PDA ligation may be associated with increased risks of BPD, severe ROP, and neurosensory impairment in ELBW infants.

Abbreviations: BPD, Bronchopulmonary dysplasia, ELBW, Extremely low birth weight, PDA, Patent ductus arteriosus, ROP, Retinopathy of prematurity, TIPP, Trial of Indomethacin Prophylaxis in Preterms

Ligation of a patent ductus arteriosus (PDA) is one of the most common types of surgery in preterm babies. The Victorian Infant Collaborative Study Group reported that surgery with general anesthesia during the initial hospitalization increases the risk of neurologic and developmental disability in extremely low birth weight (ELBW) and extremely preterm infants.¹, ²

We undertook this study to determine whether surgical PDA closure was a risk factor for neurosensory impairment at 18 months in children who were enrolled in the Trial of Indomethacin Prophylaxis in Preterms (TIPP).³ We also examined the impact of PDA ligation on bronchopulmonary dysplasia (BPD) and on severe retinopathy of prematurity (ROP). We chose these 2 morbidities because their incidence may be altered by surgical PDA closure and because they typically develop well after the diagnosis and treatment of a PDA. Both BPD and severe ROP are also independently associated with later death or neurosensory impairment.⁴ The tendency to resort to PDA ligation reflects local clinical practice and likely varies between hospitals. Our third goal was to estimate how much the frequencies of surgical PDA closures in participating centers contributed to the variation between centers in the incidence of neurosensory impairment.

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Methods 

Patients 

Infants with birth weights between 500 and 999 g were enrolled in the TIPP study between January 1996 and March 1998.³ The research ethics boards of all clinical centers in Canada, the United States, Australia, New Zealand, and Hong Kong approved the trial protocol, and written informed consent was obtained from a parent or guardian of each infant. Participating neonatal intensive care units were located either in tertiary care maternity hospitals or in tertiary care children’s hospitals. Because surgical closure of a PDA is rarely performed immediately after birth, only infants who survived beyond their calendar day of birth were eligible for this study.

Management of PDA 

PDA was diagnosed with echocardiography and Doppler ultrasound scanning flow studies, which were requested when there was clinical suspicion of the condition. Left-to-right ductal shunting was confirmed with Doppler ultrasound scanning flow echocardiography before drug or surgical therapy.³ All other management decisions were at the discretion of the local clinicians. Indomethacin was the only drug used for PDA closure.

Outcomes 

BPD and ROP were pre-specified secondary outcomes in the TIPP study.³ All data were collected prospectively in a standardized fashion. BPD was defined as the need for supplemental oxygen at a postmenstrual age of 36 weeks.⁵ Infants were screened for ROP by using local nursery protocols, and the diagnosis was made in accordance with the international classification.⁶, ⁷ Severe ROP included unilateral or bilateral disease stages 4 and 5. Infants were also classified as having severe ROP when they received cryotherapy or laser therapy in at least 1 eye.

The primary outcome in the TIPP study was a composite of death before a corrected age of 18 months or survival with ≥1 neurosensory impairments.³ Neurosensory impairments were defined by the presence of cerebral palsy, cognitive delay, hearing loss requiring amplification, or bilateral blindness. The same long-term outcomes were used in this study. Cerebral palsy was diagnosed when the child had non-progressive motor impairment characterized by abnormal muscle tone and decreased range or control of movements. Cognitive delay was defined as a Mental Development Index score <70 (2 SDs less than the mean of 100) on the Bayley Scales of Infant Development II.⁸ The score was assumed to be <70 when the child could not be tested because of severe developmental delay. Sound field audiometry was performed to determine the presence or absence of hearing loss.³ Infant blindness was defined as a corrected visual acuity <20/200. Follow-up was targeted for a corrected age of 18 months, but the protocol allowed a window of 18 to 21 months (12-21 months for audiometry). Efforts to conduct assessments continued beyond a corrected age of 21 months to maximize completeness. Home visits or assessments in non-study facilities were permitted when necessary.³

Statistical Analysis 

Infants with a symptomatic PDA were divided in 2 groups: infants who received medical therapy only (PDA-no surgery group) and infants who underwent PDA ligation (PDA-surgical closure group). The prevalence of qualitative baseline factors was compared between the 2 groups with a chi-square test. Means and medians for quantitative baseline factors were compared with the student t test or a non-parametric equivalent. Odds ratios and 95% CIs were calculated to estimate the differences in prognostic risk for infants who underwent PDA ligation, as compared with the infants who received only medical PDA therapy. Logistic function regression was used to compare the rates of poor outcomes with and without adjustment for a pre-specified set of potentially prognostic baseline factors (antenatal steroids, gestational age, sex, multiple births and mother’s education) and for the total dose of indomethacin received per kilogram bodyweight between birth and the time the child was discharged from the study center. Logistic regression was also used to determine whether the timing of surgery by week after birth influenced the risk of poor outcome. The relationship between the proportions of ducts closed by surgery and 18-month outcome was investigated by weighted least squares, with study center as the unit of analysis. All analyses were carried out with SAS software version 6.12 (SAS Institute, Cary, NC). All P values were 2-sided and not adjusted for multiple testing. A P value <.05 was considered to be significant.

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Results 

Study Cohort and Status at First Diagnosis of PDA 

Of the 1202 infants who were enrolled in the TIPP study, 9 infants died on their calendar day of birth. Adequate data for analysis of the composite outcome at 18 months were available for 1134 of the remaining 1193 infants (95%). There were 708 infants (62%) without a symptomatic PDA, 316 infants (28%) with PDA who were treated without surgery, and 110 infants (10%) who underwent PDA ligation. Table I shows the baseline characteristics of the infants and their mothers for the 2 subgroups of infants with PDA. The status of the infants was comparable in the 2 groups at the time of their first echocardiographically confirmed diagnosis of PDA (Table II).

Table I. Baseline characteristics of the infants and their mothers

Characteristics	PDA-no surgery (N = 316)	PDA-surgical closure (N = 110)	P value
Mothers
Age (years)	29±7⁎	27±7⁎	.014
Ethnic background, n (%)
White	219(69)	72(65)	.36
Black	33(10)	18(16)
Asian	22(7)	5(5)
Other or unknown	42(13)	15(14)
Level of education, n (%)
Junior high school only	104(33)	30(27)	.17
Completed high school	85(27)	38(35)
Some college or university	105(33)	39(35)
Unknown	22(7)	3(3)
Single parent, n (%)	81(26)	36(33)	.17
Preeclampsia or eclampsia, n (%)	41(13)	9(8)	.23
Tocolysis, n (%)	70(22)	27(25)	.60
Antenatal glucocorticoid administration, n (%)	252(80)	87(79)	.89
Cesarean section, n (%)	155(49)	46(42)	.22
Infants
Birth weight (g)	771±126⁎	742±133⁎	.046
Gestational age (weeks)	25.6±1.8⁎	25.1±1.4⁎	.004
Female sex – no. (%)	147(47)	47(43)	.51
Birth weight <10th percentile – no. (%)†	58(18)	10(9)	.023
Born in study center – no. (%)	305(97)	103(94)	.27
Singleton birth	208(66)	78(71)	.060
Apgar score at 5 minutes
Median	7	7	.69
Interquartile range	6-8	6-8

Table II. Therapies and morbidities between birth and first diagnosis of patent ductus arteriosus

Therapies and morbidities	PDA-no surgery	PDA-surgical closure	P value
Supplemental oxygen (days)
Median	5	5
Interquartile range	3-7	3-7	.89
Positive pressure ventilation (days)
Median	5	5	.51
Interquartile range	3-7	3-7
Received surfactant on day 1, n (%)	257(81)	85(77)	.071
Randomized to prophylactic indomethacin, n (%)	97(31)	39(35)	.46
Serious⁎ pulmonary hemorrhage, n (%)	41(13)	9(8)	.23
Necrotizing enterocolitis, n (%)	4(1.3)	3(2.7)	.38
Culture-proven sepsis and/or meningitis, n (%)†	13(4.1)	5(4.5)	.79

Use of Indomethacin for Closure of PDA and Timing of PDA Ligation 

A total of 239 of 316 infants (76%) in the PDA-no surgery group and 91 of 110 infants (83%) in the PDA-surgical closure group received indomethacin to treat PDA. The total rates of exposure to indomethacin between birth and discharge from the study center were identical in the 2 groups: 89% of infants in both groups received doses of randomly assigned prophylactic indomethacin, open-label therapeutic indomethacin, or both. However, the median total drug dose per group—including any doses of prophylactic indomethacin—was higher in the PDA–surgical closure group than in the PDA-no surgery group: 0.64 mg/kg bodyweight (interquartile range, 0.37-0.91) versus 0.45 mg/kg bodyweight (interquartile range, 0.29-0.67; P = .0002).

Nine of the 110 infants (8%) who underwent PDA ligation had the procedure during the first week of life, 31 (28%) during the second week, 32 (29%) during week 3, 21 (19%) during week 4, and 17 (16%) during week 5 or later.

Risks of Adverse Outcomes after Surgical Closure of PDA 

BPD, severe ROP and neurosensory impairment at a corrected age of 18 months, particularly cognitive delay, were more likely to develop in infants whose PDA was closed surgically than in infants whose PDA was managed without surgery. This finding remained strong after adjustment for any differences in the groups for the use of antenatal steroids, gestational age at birth, sex, multiple births, mother’s education, and the total dose of indomethacin per kilogram bodyweight that infants in both groups received during their stay in the study center (Table III).

Table III. Risk of adverse outcomes after surgical closure of PDA

Outcome	PDA subgroup	Event rate	Unadjusted		Adjusted analyses⁎
			Odds ratio	P value	Odds ratio (95% CI)	P value
BPD	PDA-no surgery	127/251(51%)
	PDA-surgical closure	67/100(67%)	1.98	.0057	1.81(1.09-3.03)	.023
Severe ROP	PDA-no surgery	32/251(13%)
	PDA-surgical closure	27/100(27%)	2.53	.0016	2.20(1.19-4.07)	.012
Death or neurosensory impairment at 18 months	PDA-no surgery	155/316(49%)
	PDA-surgical closure	65/110(59%)	1.50	.07	1.55(0.97-2.50)	.069
Death before 18 months	PDA-no surgery	71/316(22%)
	PDA-surgical closure	15/110(14%)	0.55	.049	0.56(0.29-1.10)	.095
Neurosensory impairment at 18 months	PDA-no surgery	84/245(34%)
	PDA-surgical closure	50/95(53%)	2.13	.0021	1.98(1.18-3.30)	.0093
Cognitive delay	PDA-no surgery	66/239(28%)
	PDA-surgical closure	41/92(45%)	2.11	.0034	1.96(1.14-3.35)	.015
Cerebral palsy	PDA-no surgery	35/245(14%)
	PDA-surgical closure	18/95(19%)	1.40	.29	1.22(0.64-2.33)	.55

Figure 1 shows the risk of death or impairment after PDA ligation for subgroups of infants who had the operation during weeks 1, 2, 3, 4, 5, or later after birth. Although we hypothesized that earlier surgery would lead to better outcomes than delayed surgery, we found little evidence that the timing of the surgery was an important determinant of poor long-term outcome (P [linear trend] = .37).

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• Figure 1. 

  Outcome of death or neurosensory impairment and age since birth at time of PDA ligation.

Incidence of Surgical PDA Closure in Study Centers and its Association with Center-Specific Risks of Neurosensory Impairment 

Figure 2 shows the relationships between the rates of surgical PDA closure in each of the 32 study hospitals and the rates of death, the composite of death or impairment, and neurosensory impairment. The incidence of PDA ligation varied greatly in centers, from 0 to >20%. In the analysis that was adjusted only for the number of infants who were enrolled in each center, we observed a significant relationship between the frequency of PDA ligation and the risk of neurosensory impairment at 18 months (Figure 2C). After additional adjustment for the use of antenatal steroids, gestational age at birth, sex, multiple births, and mother’s education, the same trend remained, but the relationship was no longer statistically significant. This suggests that differences in patient population partly explain the variation of PDA ligation rates in centers.

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• Figure 2. 

  Relationship between the rate of PDA ligation in study infants in individual centers and the outcomes of death (A), death or impairment (B), and neurosensory impairment (C). The circles represent the data of individual centers. The area of each circle is proportional to the number of patients enrolled in each center. The fitted weighted regression line is shown along with its P value. After adjustment for antenatal steroid use, gestational age at birth, sex, multiple births, and mother’s education, the P values for death, death or impairment, and neurosensory impairment were .47, .30, and .21, respectively.

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Discussion 

In this large international cohort of ELBW infants, surgical closure of a PDA was a strong risk factor for neurosensory impairment at 18 months. Compared with infants whose PDA was treated without surgery, infants who underwent PDA ligation also had increased risks of BPD and of severe ROP. Deaths appeared to be less common in infants who underwent PDA ligation than in infants in the comparison group. This may represent a true beneficial effect of surgical PDA closure on survival, in keeping with a recent report suggesting that the mortality rate is higher in infants whose ductus remains patent after medical treatment.⁹ Alternatively, the mortality rate in our ligation group may be spuriously low, because deaths could occur only after the surgery, whereas deaths in the comparison group could occur at any time after the first diagnosis of PDA. This bias may have affected our mortality data, but not our estimates of the risk of neurosensory impairment in survivors.

These findings question the commonly held view that surgical closure of a PDA is safe in ELBW infants.¹⁰, ¹¹, ¹², ¹³ Some authors have proposed that PDA ligation is preferable to drug therapy in very small and immature babies,¹⁰, ¹¹, ¹², ¹³ although others have not shared this opinion.¹⁴, ¹⁵, ¹⁶ Limited data are available from controlled clinical trials of surgical PDA closure to inform this debate. We have been able to find only 4 small studies in which preterm infants with PDA were randomly assigned to prophylactic¹⁷ or therapeutic PDA ligation.¹⁸, ¹⁹, ²⁰ Long-term outcomes for infants randomized to undergo surgery or medical therapy have not been published. However, Gersony et al observed a higher incidence of severe ROP in infants whose symptomatic PDA was closed surgically compared with infants who received indomethacin.²⁰ Although the authors of a recent systematic review of this trial were unable to offer any biologically plausible explanation for the adverse effect of PDA ligation on severe ROP,²¹ this observation is consistent with our finding of an increased risk of severe ROP after surgical PDA closure.

Our study is the first to describe an association between ligation of PDA and neurosensory impairment later in childhood. However, 2 previous reports by the Victorian Infant Collaborative Study Group have alerted the medical community to the possibility of an adverse relationship between surgery with general anesthesia during the initial hospitalization and sensorineural outcome at 5 years of age in extremely preterm or ELBW infants.¹, ² Ligation of PDA was the most common type of surgery in the Victorian cohort.¹

Doyle et al offered several possible explanations for the association between surgery and subsequent neurosensory impairment. First, brain injury may have preceded the surgery in some patients; second, infants who underwent surgery may have been sicker; third, perioperative or intraoperative events such as hypothermia, cardiorespiratory instability, or exposure to anesthetic drugs may directly contribute to poor outcome.¹ Anesthetic drugs that are routinely used during neonatal surgeries have been shown to cause apoptotic neurodegeneration in the developing rat brain.²²

Like Doyle et al, we can only speculate about the possible explanations for the association between surgical PDA closure and neurosensory impairment. The limitations of our study include the lack of information about surgical techniques, use of anesthetic drugs and adverse perioperative or intraoperative events in our database. Our observational study design does not permit us to determine whether the surgical closure of a PDA was a cause or just a marker of poor long-term outcome. However, the strong relationship between PDA ligation and BPD, severe ROP and neurosensory impairment remained after the adjustment for important prognostic baseline characteristics including gestational age and sex and after the adjustment for the differential use of indomethacin that we observed between the medical and surgical PDA groups. We suggest that this ancillary analysis of data from the TIPP study raises questions about the long-term safety of surgical PDA closure in ELBW infants. These questions should be examined in future randomized clinical trials that compare surgical with medical PDA therapy.

Trials are also needed to define when a PDA ligation is indicated and when it is not. In this study, the decision to refer a patient for PDA ligation was not prescribed by protocol for the TIPP study. The locally responsible clinicians decided if and when a PDA should be closed surgically. We were struck by the great variability in the rate of PDA ligation among individual study centers. Rates of surgical PDA closure ranged from 0 to >20%. This variation may be caused by differences in case mix, sampling variability, or differences in clinical practice.²³ Our adjusted analyses suggest that differences in case mix on admission contributed to the observed variability in the frequency of PDA ligations. However, differences in clinical practice may also have played a role.

What are the implications of our findings for the care of very preterm infants? Should clinicians prescribe prophylactic indomethacin to all ELBW infants because this approach has been shown to reduce the rates of surgical PDA closure?³ We do not recommend the liberal use of prophylactic indomethacin because further analyses of the entire TIPP study cohort have yielded these results: In the 2 subgroups of TIPP study infants who underwent PDA ligation, the incidence of death or neurosensory impairment was 55% (22 of 40 infants) after indomethacin prophylaxis and 61% (43 of 70) after placebo. In contrast, in the much larger subgroups of TIPP study infants who did not undergo PDA ligation, the incidence of death or neurosensory impairment was 47% (249 of 534) after indomethacin prophylaxis and 44% (218 of 499) after placebo. Therefore, any benefit derived from preventing PDA ligation in a minority of patients appears to be offset by a small adverse effect of prophylactic indomethacin on the long-term outcome of most infants who do not undergo PDA ligation.

In summary, PDA ligation is a risk factor for poor long-term outcome in ELBW infants. Universal indomethacin prophylaxis will prevent a few PDA ligations, but most ELBW infants will not benefit from prophylactic indomethacin and may even be harmed. Controlled trials with long-term follow up are urgently needed to better delineate the role of surgical closure of a PDA in the care of ELBW infants.

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Appendix. 

The TIPP Investigators 

British Columbia Children’s Hospital, Vancouver: A. Solimano, M. Whitfield, F. Germain, J. Tomlinson; Royal Alexandra Hospital, Edmonton: A. Peliowski, P. Etches, B. Young; Glenrose Rehabilitation Hospital, Edmonton: C.M.T. Robertson; Foothills Hospital and Alberta Children’s Hospital, Calgary: D. McMillan, R. Sauve, L. Bourcier, H. Christianson; Royal University Hospital, Saskatoon: K. Sankaran, B. Andreychuk; Health Sciences Centre, Winnipeg: M. Seshia, O. Casiro, V. Debooy, V. Cook; St. Boniface Hospital, Winnipeg: C.M.G. Cronin, D. Moddemann, N. Granke; The Salvation Army Grace Hospital, Windsor: C. Nwaesei, L. St. Aubin; St. Joseph’s Health Centre, London: D. Reid, D. Lee, C. Kenyon, L. Whitty, J. Farrell; Hamilton Health Sciences Corporation, Hamilton: B. Schmidt, S. Saigal, P. Gillie, J. Dix, B. Zhang; Women’s College Hospital, Toronto: A. Ohlsson, E. Asztalos, L. Wiley; The Hospital for Sick Children, Toronto: A. James; Kingston General Hospital, Kingston: K.F.W. Young Tai, M. Clarke; IWK Grace Health Centre, Halifax: M. Vincer, S. Stone.

King Edward Memorial Hospital for Women, Perth: R. Kohan, N. French, H. Benninger; Women’s and Children’s Hospital, Adelaide: C. Barnett, R. Haslam, J. Ramsay; Royal Women’s Hospital, Melbourne: P. Davis, L. Doyle, B. Faber, K. Callanan; Mercy Hospital for Women, Melbourne: S. Fraser; Westmead Hospital, Westmead, New South Wales: K. Lui, M. Rochefort, E. McAvoy; Royal Women’s Hospital, Brisbane: P. Colditz, M. Pritchard; Mater Mothers’ Hospital, Brisbane: P. Steer, D.I. Tudehope, V. Flenady, J. Hegarty.

National Women’s Hospital and Middlemore Hospital, Auckland: L. Mildenhall, W. Smith, L. McCarthy.

Prince of Wales Hospital, Shatin: T.F. Fok.

National Institute of Child Health and Human Development Neonatal Research Network, United States

Stanford University Medical Center, Palo Alto: D.K. Stevenson, B. Fleisher, B. Ball; University of New Mexico School of Medicine, Albuquerque: L.A. Papile, G. Laadt, C. Backstrom; University of Texas Southwestern Medical Center at Dallas: J.E. Tyson, S. Broyles, S. Madison; University of Alabama, Birmingham: W.A. Carlo, K. Nelson, M. Collins, S. Johnson; Children’s Hospital Michigan, Detroit: S. Shankaran, V. Delaney-Black, G. Muran, D. Driscoll; Emory University, Atlanta: B.J. Stoll, N. Simon, E. Hale; Case Western Reserve University, Cleveland: A.A. Fanaroff, D. Wilson, M. Hack, N. Newman; University of Miami, Miami: C.R. Bauer, A.M. Worth, W. Griffin; Brown University, Providence: W. Oh, B.R. Vohr, A. Hensman.

Steering Committee: B. Schmidt (Chair), P. Davis, D. Moddemann, A. Ohlsson, R.S. Roberts, S. Saigal, A. Solimano, M. Vincer, L. Wright.

External Safety Monitoring Committee: M. Gent, W. Fraser, M. Perlman.

BSID II Certification: R. Adkins.

Audiology Central Adjudication Committee: L. Elden, C.M.T. Robertson, B.R. Vohr.

Consultant Pharmacist: S. Gray.

Coordinating and Methods Center: Biostatisticians: R.S. Roberts, K. Thorpe; Trial Coordinator: N. LaPierre.

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