- Email: [email protected]
Impact of Intrauterine Growth Restriction on Cardiac Surgical Outcomes and Resource Use
Impact of Intrauterine Growth Restriction on Cardiac Surgical Outcomes and Resource Use Ryan Graf, MS, Nancy S. Ghanayem, MD, Raymond Hoffmann, PhD, Mahua Dasgupta, MS, Maryanne Kessel, RN, MBA, Michael E. Mitchell, MD, James S. Tweddell, MD, and Ronald K. Woods, MD, PhD Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin and Herma Heart Center, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
stay (56.3 days versus 28.0 days for controls; p < 0.0001), postoperative days of mechanical ventilation (25.8 days versus 5.4 days for controls; p [ 0.002), postoperative cardiopulmonary arrest (7 of 41 cases [17.1%] versus 4 of 82 cases [4.9%] for controls; p [ 0.03), and postoperative infection (13 of 41 cases [31.7%] versus 13 of 81 cases [16.1%] for controls; p [ 0.04). The mean charge for the study group was considerably higher than that for the control group: $493,915 versus $175,144; p < 0.0001. Conclusions. IUGR is associated with a substantially increased length of hospital stay, postoperative morbidity, and resource use. These findings are relevant to risk stratification, prognosis, and potentially to contracting and reimbursement. IUGR merits further attention as an important risk factor in congenital heart operations.
I
documenting low birth weight as a significant risk factor for mortality and morbidity in congenital heart operations is based on cohorts defined solely by a maximum absolute weight, typically 2 or 2.5 kg, and comprised of varying percentages of premature infants [5–9]. Although these cohorts likely included certain percentages of patients with IUGR, IUGR status per se and any relationship with outcomes were not reported. We acknowledge the invariable overlap of weight, prematurity, and IUGR regardless of how the cohort is defined and the complexity of discerning specific effects of each regarding surgical outcomes. Our goal was to assess a cohort defined exclusively by IUGR status and document any relationship with surgical outcomes and resource use, because this has heretofore remained undocumented in the literature.
ntrauterine growth restriction (IUGR) occurs in as many as 1 in 5 infants with major cardiac anomalies [1]. Given that perinatal mortality for all infants with IUGR is 5 to 30 times higher than that of their non-IUGR counterparts, IUGR status may be an important prognostic factor for outcomes in congenital heart operations [2]. IUGR is an obstetric diagnosis based on a negative deviation of the intrauterine growth curve for various size measurements and gestational age [3]. This differs from small for gestational age (SGA), which is a postnatal diagnosis typically defined as less than 10% normal body weight for gestational age [3]. Although many newborns with SGA may have IUGR, it can exist in the absence of SGA. The important point is that IUGR does not necessarily equate with low absolute weight. It is estimated that one fourth to one third of patients weighing less than 2500 g at birth demonstrate IUGR [4]. The literature
(Ann Thorac Surg 2015;100:1411–5) Ó 2015 by The Society of Thoracic Surgeons
Patients and Methods Accepted for publication May 14, 2015.
Patients and Data Collection
Address correspondence to Dr Woods, Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Pediatric Cardiothoracic Surgery, Herma Heart Center and Children’s Hospital of Wisconsin, MS BS 730, 9000 W Wisconsin Ave, Milwaukee, WI 53226; e-mail: [email protected].
This was a retrospective matched case-control analysis of a study cohort matched 1:2 to a control group. The study group of 41 patients included all patients with IUGR who underwent cardiac operations at less than
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.05.064
CONGENITAL HEART
Background. We sought to evaluate outcomes of congenital heart operations and resource use in patients with intrauterine growth restriction (IUGR). Methods. This was a retrospective matched casecontrol study of 41 consecutive patients with IUGR matched 1:2 with a comparison cohort of 82 contemporaneous patients without IUGR who underwent congenital heart operations during the interval from January 1, 2000 to January 1, 2012. Matching was based on the Risk Adjustment for Congenital Heart Surgery (RACHS)-1 risk category, diagnostic category, age at operation, and gestational age. Results. Operative mortality (6 of 41 cases [14.6%] for the study group versus 5 of 82 cases [6.1%] for controls) and any major adverse event (14 of 41 cases [34.2%] for the study group versus 23 of 82 cases [28%] for controls) occurred in a higher percentage of study patients, with insignificant p values. Important differences in secondary outcomes included the following: mean total length of
CONGENITAL HEART
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Ann Thorac Surg 2015;100:1411–5
1 year of age at Children’s Hospital of Wisconsin from January 1, 2000 to January 1, 2012. The control group of 82 patients without IUGR undergoing cardiac operations at Children’s Hospital of Wisconsin during this same interval were matched according to Risk Adjustment for Congenital Heart Surgery (RACHS)-1 risk category, diagnostic category, age at procedure, and gestational age. The study and control groups were selected by carefully screening our institution’s administrative coding database as well as the clinical critical care and cardiac surgery databases. The diagnosis of IUGR was confirmed based on documentation provided by neonatal or cardiac intensive care attending physicians, which were in turn based on the obstetric history. Many patients also
demonstrated SGA; however, only those patients with documented IUGR were selected for this cohort. Diagnoses were categorized according to general management strategies as follows: biventricular acyanotic, biventricular cyanotic, single-ventricle with non– duct-dependent systemic output (non-Norwood type repair), single-ventricle with duct-dependent systemic output (Norwood type repair), and other. To facilitate matching, age at procedure and gestational age were each divided into 3 categories (Table 1). Patient information was obtained by extensive chart review and then deidentified. A database was created using the web-based Research Electronic Data Capture (REDCap) application. The Institutional Review Board at the Children’s Hospital of Wisconsin authorized the
Table 1. Comparison of Preoperative Characteristics of the IUGR Group and Controls Cases (N ¼ 41)
Matched Variables RACHS-1a 1 2 3 4 5/6 NC NE Diagnostic group Biventricular acyanotic Biventricular cyanotic Single-ventricle Norwood Single-ventricle non-Norwood Other Gestational age (1) 32 wk (2) 32–36 wk (3) 37 wk Age at procedure (1) Neonate 0–31 d
Weight at operation (kg) mean (SD)
Preoperative Preoperative Preoperative Preoperative Preoperative Preoperative Preoperative a
p Value 0.55
(2) Infant 1–6mo (3) Infant 6 mo–1 y Nonmatched Variables
Controls (N ¼ 82)
4 10 14 2 3 1 7
(9.8%) (24.4%) (34.2%) (4.9%) (7.3%) (2.4%) (17.1%)
9 19 29 5 7 1 12
(11.0%) (23.2%) (35.4%) (6.1%) (8.5%) (1.2%) (14.6%)
24 8 4 4 1
(58.5%) (19.5%) (9.8%) (9.8%) (2.4%)
50 17 9 5 1
(61%) (20.7%) (11.0%) (6.1%) (1.2%)
>0.9 >0.9 >0.9 >0.9 ...
10 (24.4%) 10 (24.4%) 21 (51.2%)
13 (16.1%) 25 (30.9%) 43 (53.1%)
(1) versus (3) ➔ p > 0.9 (2) versus (3) ➔ p ¼ 0.77
20 (48.8%)
43 (53.8%)
(1) versus (2) ➔ p ¼ 0.26 (1) versus (3) ➔ p > 0.9
19 (46.3%) 2 (4.9%)
27 (33.8%) 10 (12.5%)
Cases (N ¼ 41)
Controls (N ¼ 82)
D (Case Control)a
D 95% CI
p Value
2.7 (1.4)
3.8 (1.7)
2.22
2.71 to –1.73
<0.0001
total parenteral nutrition mechanical ventilation shock/acidosis renal failure seizure sepsis intracranial hemorrhage
19 18 3 1 1 3 2
(46.3%) (43.9%) (7.3%) (2.4%) (2.4%) (7.3%) (4.9%)
20 28 4 4 3 5 4
Odds Ratio (OR)
95% CI (OR)
p Value
4.26 2.00 1.82 0.50 0.67 1.20 w 1.00
1.51–12.05 0.73–5.42 0.28–12.00 0.06–4.50 0.07–6.35 0.29–5.01 0.18–5.47
0.007 0.18 0.53 0.54 0.72 0.80 >0.9
(24.4%) (34.2%) (4.9%) (4.9%) (3.7%) (6.1%) (4.9%)
Estimated difference obtained from the generalized linear model using matching.
CI ¼ confidence interval; Surgery.
NC ¼ not categorized;
NE ¼ not eligible;
OR ¼ odds ratio;
RACHS-1 ¼ Risk Adjustment for Congenital Heart
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generalized linear model, the corresponding analyses used the nonparametric Friedman test for the matched data and the Mann-Whitney test for the unmatched data.
collection of data from existing medical records under a waiver of the Health Insurance Portability and Accountability Act (HIPAA) for this retrospective study.
Outcomes
Results
Primary outcomes for this study included (1) operative mortality and (2) any major adverse event of operative mortality, cardiac arrest, postoperative use of extracorporeal life support or mechanical circulatory support, renal failure, intracranial hemorrhage, stroke, seizure, surgical reintervention, or a combination of events. Secondary outcomes included resource use defined by various lengths of stay and total hospital charges for the index surgical admission. Charges were obtained from the Office of Financial Services in the Department of Pediatrics at Children’s Hospital of Wisconsin. Other secondary outcomes included various measures of morbidity analyzed individually (Table 2 lists measures of morbidity). Although not considered morbidity per se, duration of mechanical ventilation was also recorded.
Table 1 provides the matched and nonmatched preoperative clinical characteristics of the groups. Both RACHS-1 risk category and diagnostic group appeared to be well matched. A somewhat lower percentage of study patients underwent surgical intervention between 6 months and 1 year of age, and a somewhat higher percentage of study patients were born at less than 32 weeks’ gestational age; however, these differences were not statistically significant. In general, nonmatched characteristics were similar between groups, with the exception of the study group demonstrating lower weight and a higher percentage of patients in this group receiving preoperative parenteral nutrition.
Statistical Analysis
Clinical Outcomes
The major outcomes were compared using 1:2 IUGR to non-IUGR matching criteria for maximum power. A discrete Cox model in SAS, version 9.2 (SAS Institute, Cary, NC), was used to create a conditional logistic regression model for the categorical outcomes from the matched data. Generalized linear models with blocking on the individual matched sets were used for the continuous outcomes. Because some of the outcomes were skewed (eg, cost) in a manner that could not be accounted for by a
Table 2 summarizes the clinical outcomes. The primary outcomes of operative mortality or any major adverse event occurred in a higher percentage of study patients, albeit with insignificant p values. Likewise, important secondary clinical outcomes (eg, extracorporeal or mechanical circulatory support, reoperation for bleeding, and catheter-based reintervention) occurred in at least twice as many study patients, with differences that did not reach statistical significance. Despite these potentially clinically relevant differences, the only clinical outcomes
Assessment of Matching
Outcome Operative mortality Major adverse event 6-mo mortalitya Cardiopulmonary arrest ECLS/MCS Surgical reintervention (not bleeding) Surgical reintervention for bleeding Renal failure Infection ICH/stroke/seizure Gastrojejunostomy feeding tube Catheter-based reintervention Renal failure Bacteremia
Cases (N ¼ 41) 6 14 7 7 5 3 6 3 13 4 15 3 3 3
Controls (N ¼ 82)
(14.6%) (34.2%) (17.1%) (17.1%) (12.2%) (7.3%) (14.6%) (7.3%) (31.7%) (9.8%) (36.6%) (7.3%) (7.3%) (7.3%)
Duration mechanical ventilation (d) mean (SD) Duration of open sternal management (d) mean (SD)
5 23 7 4 5 7 4 4 13 5 18 1 4 8
25.8 (62.53) 1.3 (3.5)
a Includes operative mortality and mortality within 6 mo of operation. matching.
b
(6.1%) (28.0%) (8.5%) (4.9%) (6.1%) (8.5%) (4.9%) (4.9%) (16.1%) (6.1%) (22.0%) (1.2%) (4.9%) (9.9%)
OR
95% CI
p Value
2.68 1.39 2.32 5.62 3.06 1.12 4.76 1.62 2.83 1.88 2.08 6.00 1.62 0.73
0.75–9.62 0.58–3.36 0.71–7.51 1.13–28.14 0.56–16.86 0.27–4.58 0.90–25.18 0.31–8.38 1.04–7.69 0.39–9.01 0.89–4.82 0.63–57.05 0.31–8.38 0.18–2.95
0.13 0.46 0.16 0.03 0.20 0.87 0.07 0.57 0.04 0.43 0.09 0.12 0.57 0.66
D (Case – Control)b
95% CI for D
p Value
2.66 0.95
1.22–5.54 0.91–0.98
0.002 0.95
5.4 (7.9) 1.0 (2.5)
Estimated difference obtained from the generalized linear model using
CI ¼ confidence interval; ECLS/MCS ¼ extracorporeal life support/mechanical circulatory support; intrauterine growth restriction; OR ¼ odds ratio.
ICH ¼ intracranial hemorrhage;
IUGR ¼
CONGENITAL HEART
Table 2. Comparison of Postoperative Clinical Outcomes for the IUGR Group and Controls
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Ann Thorac Surg 2015;100:1411–5
reaching statistical significance were postoperative cardiopulmonary arrest, postoperative infection, and duration of postoperative mechanical ventilation. Outcomes were similar between groups regarding postoperative bacteremia, neurologic complications (hemorrhage, stroke, seizure, or a combination of these events), renal failure, and days of open sternal management.
CONGENITAL HEART
Resource Use The IUGR group demonstrated substantially increased resource use (Table 3). Postoperative length of stay for patients with IUGR exceeded the mean and median stays of the control group by 25 days and 10 days, respectively, which approximates a doubling of length of stay (p < 0.0001). For both groups, the postoperative stay accounted for the majority of inpatient days, which in turn occurred predominantly in an intensive care unit setting. Accordingly, the mean and median total hospital charges for the study group were at least double those of the control group.
Comment To our knowledge, this is the first study to assess cardiac surgical outcomes and resource use in young infants with IUGR. The predominant finding was that IUGR status was associated with substantially increased postoperative lengths of stay and hospital charges—nearly twice that of otherwise similar patients without IUGR. We also found significant associations between IUGR status and postoperative cardiopulmonary arrest and infection. Survival and other measures of morbidity also appeared to be worse in infants with IUGR; however, these trends were not statistically significant. IUGR, although complex and incompletely understood, likely shares many etiologic factors with prematurity and low-birth-weight non-IUGR status [3]. However, IUGR status is considered to confer unique risk based on comparisons of noncardiac cohorts of premature infants in whom IUGR status was associated with increased risk of mortality, necrotizing enterocolitis, and requirement of mechanical ventilatory support [10]. Previous reports have evaluated cardiac surgical outcomes in patients with low operative weights. Oppido and associates [8] reported a series of 60 patients with a mean operative weight of 2.1 kg. Only 8 patients were less than 32 weeks’ gestation, and IUGR status was not reported. Early mortality was 15% and reported to be
unrelated to prematurity status. Lechner and colleagues [7] reported a series of 46 patients with a median operative weight of 2.3 kg and a median gestational age of 35.5 weeks. Early mortality was 13% without controlling specifically for prematurity or documenting IUGR status. Median length of stay was 26 days and median duration of mechanical ventilation was 7 days. In the report by Azakie and colleagues [9], the cohort included 75 patients with a median weight of 2.1 kg and a median gestational age of 36 weeks. Discharge mortality was 7.5%, median length of stay was 19 days, and median duration of mechanical ventilation was 40 hours. Prematurity was not found to be a factor in early mortality; however, IUGR status was not reported. The remaining single-institution series by Reddy and associates [6] included 102 patients who weighed less than 2.5 kg. Median weight was 2.1 kg, and median gestational age was 34 weeks; IUGR status was not documented [6]. Early mortality was 10%. Median length of stay was 19 days and median duration of mechanical ventilation was 5 days. In a multiinstitutional report based on the Society of Thoracic Surgeons congenital database, Curzon and coworkers [5] compared outcomes in 517 patients weighing less than 2.5 kg to those of 2,505 patients weighing 2.5 to 4.0 kg. Overall, discharge mortality was significantly higher across all RACHS levels and in certain diagnostic/ procedural groups. For example, discharge mortalities in the lower versus higher weight groups were 11.8% and 2.6%, respectively, for the arterial switch procedure and were 22.7% and 12.9%, respectively, for systemic to pulmonary artery shunts for pulmonary atresia with an intact ventricular septum. This study did not report on prematurity, IUGR status, or other outcome measures. It is difficult to compare the results of our cohort with those of previous reports because the defining feature of our cohort was unique. Approximately half of our cohort had operative weights greater than 2.3 kg, and the range extended from 0.6 kg to 5.9 kg. We would therefore refrain from attempting any such comparisons. We did not design this study to discern various effects of absolute patient weight or gestational age. Because of practical considerations and the strong linkage between IUGR and weight, we did not attempt to match for operative weight. Our results nevertheless strongly suggest that IUGR is an important risk factor. Based on a subanalysis not reported because of low patient numbers and statistical constraints, we suspect that IUGR confers an important risk independent of both operative weight
Table 3. Comparison of Resource Use for the IUGR Group and Controls Variable a
Total charges ($) mean (SD) Total LOS (d) mean (SD) Postoperative LOS (d) mean (SD)
Controls
493,915 (687,396) 56.3 (72.0) 47.8 (66.2)
175,144 (174,982) 28.0 (28.6) 22.4 (23.3)
a Based on charges available for 34 study patients and 68 matched control patients. using matching.
IUGR ¼ intrauterine growth restriction;
LOS ¼ length of stay.
D (Case – Control)
95% CI for D
p Value
4.72 3.13 3.52
2.72–8.16 1.84–5.31 2.16–5.75
<0.0001 <0.0001 <0.0001
b
Cases
b
Estimated difference obtained from the generalized linear model
Ann Thorac Surg 2015;100:1411–5
and gestational age, with a likely diminishing impact at the lower extremes of weight and prematurity. However, confirmation of this suspicion would require a larger cohort and a more tailored study design. Our study was also not designed to address the issue of delayed versus early surgical correction in patients with IUGR. In general, our approach has been consistent with that reported by the previously cited authors of not delaying surgical intervention based on size alone. We would also agree that the expected risk/benefit and management should be individualized for each patient.
There was heterogeneity both within and between groups in our cohort. We attempted to address this by categorizing certain variables and matching for well-established risk factors. An apparently successful matching process does not eliminate the possibility of bias or confounding from other variables. Finally, this study is fully subject to all constraints typical of retrospective studies of relatively small numbers of patients.
Conclusions IUGR is associated with substantially increased lengths of stay, postoperative morbidity, and resource use. These findings are relevant to risk stratification, prognosis, and, potentially, contracting and reimbursement. IUGR merits further attention as an important risk factor in congenital heart operations.
This work received partial support from the American Association of Thoracic Surgery Summer Intern Scholarship.
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References 1. Wallenstein MB, Harper LM, Odibo AO, et al. Fetal congenital heart disease and intrauterine growth restriction: a retrospective cohort study. J Matern Fetal Neonatal Med 2012;25:662–5. 2. Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD, Tashiro M. Fetal growth and perinatal viability in California. Obstet Gynecol 1982;59:624–32. 3. Resnik R, Creasy RK. Intrauterine growth restriction. In: Resnik R, Iams JD, Lockwood CJ, Moore TR, Greene MF (eds). Creasy and Resnik’s maternal-fetal medicine principles and practice. Philadelphia, PA: Saunders; 2014:743–56. 4. Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull WHO 1987;65: 663–737. 5. Curzon CL, Milford-Beland S, Li JS, et al. Cardiac surgery in infants with low birth weight is associated with increased mortality: analysis of the Society of Thoracic Surgeons Congenital Heart Database. J Thorac Cardiovasc Surg 2008;135:546–51. 6. Reddy VM, McElhinney DB, Sagrado T, Parry AJ, Teitel DF, Hanley FL. Results of 102 cases of complete repair of congenital heart defects in patients weighing 700 to 2500 grams. J Thorac Cardiovasc Surg 1999;117:324–31. 7. Lechner E, Wiesinger-Eidenberger G, Weissensteiner M, et al. Open-heart surgery in premature and low-birth-weight infants—a single-centre experience. Eur J Cardiothor Surg 2009;36:986–91. 8. Oppido G, Napoleone CP, Formigari R, et al. Outcome of cardiac surgery in low birth weight and premature infants. Eur J Cardiothorac Surg 2004;26:44–53. 9. Azakie A, Johnson NC, Anagnostopoulos PV, Egrie GD, Lavrsen MJ, Sapru A. Cardiac surgery in low birth weight infants: current outcomes. Interact Cardiovasc Thorac Surg 2011;12:409–14. 10. Piper JM, Xenekais EJ, McFarland M, Elliot BD, Berkus MD, Langer O. Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants? Obstet Gynecol 1996;87:169–74.
CONGENITAL HEART
Limitations
GRAF ET AL CARDIAC OPERATIONS AND IUGR
stay (56.3 days versus 28.0 days for controls; p < 0.0001), postoperative days of mechanical ventilation (25.8 days versus 5.4 days for controls; p [ 0.002), postoperative cardiopulmonary arrest (7 of 41 cases [17.1%] versus 4 of 82 cases [4.9%] for controls; p [ 0.03), and postoperative infection (13 of 41 cases [31.7%] versus 13 of 81 cases [16.1%] for controls; p [ 0.04). The mean charge for the study group was considerably higher than that for the control group: $493,915 versus $175,144; p < 0.0001. Conclusions. IUGR is associated with a substantially increased length of hospital stay, postoperative morbidity, and resource use. These findings are relevant to risk stratification, prognosis, and potentially to contracting and reimbursement. IUGR merits further attention as an important risk factor in congenital heart operations.
I
documenting low birth weight as a significant risk factor for mortality and morbidity in congenital heart operations is based on cohorts defined solely by a maximum absolute weight, typically 2 or 2.5 kg, and comprised of varying percentages of premature infants [5–9]. Although these cohorts likely included certain percentages of patients with IUGR, IUGR status per se and any relationship with outcomes were not reported. We acknowledge the invariable overlap of weight, prematurity, and IUGR regardless of how the cohort is defined and the complexity of discerning specific effects of each regarding surgical outcomes. Our goal was to assess a cohort defined exclusively by IUGR status and document any relationship with surgical outcomes and resource use, because this has heretofore remained undocumented in the literature.
ntrauterine growth restriction (IUGR) occurs in as many as 1 in 5 infants with major cardiac anomalies [1]. Given that perinatal mortality for all infants with IUGR is 5 to 30 times higher than that of their non-IUGR counterparts, IUGR status may be an important prognostic factor for outcomes in congenital heart operations [2]. IUGR is an obstetric diagnosis based on a negative deviation of the intrauterine growth curve for various size measurements and gestational age [3]. This differs from small for gestational age (SGA), which is a postnatal diagnosis typically defined as less than 10% normal body weight for gestational age [3]. Although many newborns with SGA may have IUGR, it can exist in the absence of SGA. The important point is that IUGR does not necessarily equate with low absolute weight. It is estimated that one fourth to one third of patients weighing less than 2500 g at birth demonstrate IUGR [4]. The literature
(Ann Thorac Surg 2015;100:1411–5) Ó 2015 by The Society of Thoracic Surgeons
Patients and Methods Accepted for publication May 14, 2015.
Patients and Data Collection
Address correspondence to Dr Woods, Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Pediatric Cardiothoracic Surgery, Herma Heart Center and Children’s Hospital of Wisconsin, MS BS 730, 9000 W Wisconsin Ave, Milwaukee, WI 53226; e-mail: [email protected].
This was a retrospective matched case-control analysis of a study cohort matched 1:2 to a control group. The study group of 41 patients included all patients with IUGR who underwent cardiac operations at less than
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.05.064
CONGENITAL HEART
Background. We sought to evaluate outcomes of congenital heart operations and resource use in patients with intrauterine growth restriction (IUGR). Methods. This was a retrospective matched casecontrol study of 41 consecutive patients with IUGR matched 1:2 with a comparison cohort of 82 contemporaneous patients without IUGR who underwent congenital heart operations during the interval from January 1, 2000 to January 1, 2012. Matching was based on the Risk Adjustment for Congenital Heart Surgery (RACHS)-1 risk category, diagnostic category, age at operation, and gestational age. Results. Operative mortality (6 of 41 cases [14.6%] for the study group versus 5 of 82 cases [6.1%] for controls) and any major adverse event (14 of 41 cases [34.2%] for the study group versus 23 of 82 cases [28%] for controls) occurred in a higher percentage of study patients, with insignificant p values. Important differences in secondary outcomes included the following: mean total length of
CONGENITAL HEART
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Ann Thorac Surg 2015;100:1411–5
1 year of age at Children’s Hospital of Wisconsin from January 1, 2000 to January 1, 2012. The control group of 82 patients without IUGR undergoing cardiac operations at Children’s Hospital of Wisconsin during this same interval were matched according to Risk Adjustment for Congenital Heart Surgery (RACHS)-1 risk category, diagnostic category, age at procedure, and gestational age. The study and control groups were selected by carefully screening our institution’s administrative coding database as well as the clinical critical care and cardiac surgery databases. The diagnosis of IUGR was confirmed based on documentation provided by neonatal or cardiac intensive care attending physicians, which were in turn based on the obstetric history. Many patients also
demonstrated SGA; however, only those patients with documented IUGR were selected for this cohort. Diagnoses were categorized according to general management strategies as follows: biventricular acyanotic, biventricular cyanotic, single-ventricle with non– duct-dependent systemic output (non-Norwood type repair), single-ventricle with duct-dependent systemic output (Norwood type repair), and other. To facilitate matching, age at procedure and gestational age were each divided into 3 categories (Table 1). Patient information was obtained by extensive chart review and then deidentified. A database was created using the web-based Research Electronic Data Capture (REDCap) application. The Institutional Review Board at the Children’s Hospital of Wisconsin authorized the
Table 1. Comparison of Preoperative Characteristics of the IUGR Group and Controls Cases (N ¼ 41)
Matched Variables RACHS-1a 1 2 3 4 5/6 NC NE Diagnostic group Biventricular acyanotic Biventricular cyanotic Single-ventricle Norwood Single-ventricle non-Norwood Other Gestational age (1) 32 wk (2) 32–36 wk (3) 37 wk Age at procedure (1) Neonate 0–31 d
Weight at operation (kg) mean (SD)
Preoperative Preoperative Preoperative Preoperative Preoperative Preoperative Preoperative a
p Value 0.55
(2) Infant 1–6mo (3) Infant 6 mo–1 y Nonmatched Variables
Controls (N ¼ 82)
4 10 14 2 3 1 7
(9.8%) (24.4%) (34.2%) (4.9%) (7.3%) (2.4%) (17.1%)
9 19 29 5 7 1 12
(11.0%) (23.2%) (35.4%) (6.1%) (8.5%) (1.2%) (14.6%)
24 8 4 4 1
(58.5%) (19.5%) (9.8%) (9.8%) (2.4%)
50 17 9 5 1
(61%) (20.7%) (11.0%) (6.1%) (1.2%)
>0.9 >0.9 >0.9 >0.9 ...
10 (24.4%) 10 (24.4%) 21 (51.2%)
13 (16.1%) 25 (30.9%) 43 (53.1%)
(1) versus (3) ➔ p > 0.9 (2) versus (3) ➔ p ¼ 0.77
20 (48.8%)
43 (53.8%)
(1) versus (2) ➔ p ¼ 0.26 (1) versus (3) ➔ p > 0.9
19 (46.3%) 2 (4.9%)
27 (33.8%) 10 (12.5%)
Cases (N ¼ 41)
Controls (N ¼ 82)
D (Case Control)a
D 95% CI
p Value
2.7 (1.4)
3.8 (1.7)
2.22
2.71 to –1.73
<0.0001
total parenteral nutrition mechanical ventilation shock/acidosis renal failure seizure sepsis intracranial hemorrhage
19 18 3 1 1 3 2
(46.3%) (43.9%) (7.3%) (2.4%) (2.4%) (7.3%) (4.9%)
20 28 4 4 3 5 4
Odds Ratio (OR)
95% CI (OR)
p Value
4.26 2.00 1.82 0.50 0.67 1.20 w 1.00
1.51–12.05 0.73–5.42 0.28–12.00 0.06–4.50 0.07–6.35 0.29–5.01 0.18–5.47
0.007 0.18 0.53 0.54 0.72 0.80 >0.9
(24.4%) (34.2%) (4.9%) (4.9%) (3.7%) (6.1%) (4.9%)
Estimated difference obtained from the generalized linear model using matching.
CI ¼ confidence interval; Surgery.
NC ¼ not categorized;
NE ¼ not eligible;
OR ¼ odds ratio;
RACHS-1 ¼ Risk Adjustment for Congenital Heart
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generalized linear model, the corresponding analyses used the nonparametric Friedman test for the matched data and the Mann-Whitney test for the unmatched data.
collection of data from existing medical records under a waiver of the Health Insurance Portability and Accountability Act (HIPAA) for this retrospective study.
Outcomes
Results
Primary outcomes for this study included (1) operative mortality and (2) any major adverse event of operative mortality, cardiac arrest, postoperative use of extracorporeal life support or mechanical circulatory support, renal failure, intracranial hemorrhage, stroke, seizure, surgical reintervention, or a combination of events. Secondary outcomes included resource use defined by various lengths of stay and total hospital charges for the index surgical admission. Charges were obtained from the Office of Financial Services in the Department of Pediatrics at Children’s Hospital of Wisconsin. Other secondary outcomes included various measures of morbidity analyzed individually (Table 2 lists measures of morbidity). Although not considered morbidity per se, duration of mechanical ventilation was also recorded.
Table 1 provides the matched and nonmatched preoperative clinical characteristics of the groups. Both RACHS-1 risk category and diagnostic group appeared to be well matched. A somewhat lower percentage of study patients underwent surgical intervention between 6 months and 1 year of age, and a somewhat higher percentage of study patients were born at less than 32 weeks’ gestational age; however, these differences were not statistically significant. In general, nonmatched characteristics were similar between groups, with the exception of the study group demonstrating lower weight and a higher percentage of patients in this group receiving preoperative parenteral nutrition.
Statistical Analysis
Clinical Outcomes
The major outcomes were compared using 1:2 IUGR to non-IUGR matching criteria for maximum power. A discrete Cox model in SAS, version 9.2 (SAS Institute, Cary, NC), was used to create a conditional logistic regression model for the categorical outcomes from the matched data. Generalized linear models with blocking on the individual matched sets were used for the continuous outcomes. Because some of the outcomes were skewed (eg, cost) in a manner that could not be accounted for by a
Table 2 summarizes the clinical outcomes. The primary outcomes of operative mortality or any major adverse event occurred in a higher percentage of study patients, albeit with insignificant p values. Likewise, important secondary clinical outcomes (eg, extracorporeal or mechanical circulatory support, reoperation for bleeding, and catheter-based reintervention) occurred in at least twice as many study patients, with differences that did not reach statistical significance. Despite these potentially clinically relevant differences, the only clinical outcomes
Assessment of Matching
Outcome Operative mortality Major adverse event 6-mo mortalitya Cardiopulmonary arrest ECLS/MCS Surgical reintervention (not bleeding) Surgical reintervention for bleeding Renal failure Infection ICH/stroke/seizure Gastrojejunostomy feeding tube Catheter-based reintervention Renal failure Bacteremia
Cases (N ¼ 41) 6 14 7 7 5 3 6 3 13 4 15 3 3 3
Controls (N ¼ 82)
(14.6%) (34.2%) (17.1%) (17.1%) (12.2%) (7.3%) (14.6%) (7.3%) (31.7%) (9.8%) (36.6%) (7.3%) (7.3%) (7.3%)
Duration mechanical ventilation (d) mean (SD) Duration of open sternal management (d) mean (SD)
5 23 7 4 5 7 4 4 13 5 18 1 4 8
25.8 (62.53) 1.3 (3.5)
a Includes operative mortality and mortality within 6 mo of operation. matching.
b
(6.1%) (28.0%) (8.5%) (4.9%) (6.1%) (8.5%) (4.9%) (4.9%) (16.1%) (6.1%) (22.0%) (1.2%) (4.9%) (9.9%)
OR
95% CI
p Value
2.68 1.39 2.32 5.62 3.06 1.12 4.76 1.62 2.83 1.88 2.08 6.00 1.62 0.73
0.75–9.62 0.58–3.36 0.71–7.51 1.13–28.14 0.56–16.86 0.27–4.58 0.90–25.18 0.31–8.38 1.04–7.69 0.39–9.01 0.89–4.82 0.63–57.05 0.31–8.38 0.18–2.95
0.13 0.46 0.16 0.03 0.20 0.87 0.07 0.57 0.04 0.43 0.09 0.12 0.57 0.66
D (Case – Control)b
95% CI for D
p Value
2.66 0.95
1.22–5.54 0.91–0.98
0.002 0.95
5.4 (7.9) 1.0 (2.5)
Estimated difference obtained from the generalized linear model using
CI ¼ confidence interval; ECLS/MCS ¼ extracorporeal life support/mechanical circulatory support; intrauterine growth restriction; OR ¼ odds ratio.
ICH ¼ intracranial hemorrhage;
IUGR ¼
CONGENITAL HEART
Table 2. Comparison of Postoperative Clinical Outcomes for the IUGR Group and Controls
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reaching statistical significance were postoperative cardiopulmonary arrest, postoperative infection, and duration of postoperative mechanical ventilation. Outcomes were similar between groups regarding postoperative bacteremia, neurologic complications (hemorrhage, stroke, seizure, or a combination of these events), renal failure, and days of open sternal management.
CONGENITAL HEART
Resource Use The IUGR group demonstrated substantially increased resource use (Table 3). Postoperative length of stay for patients with IUGR exceeded the mean and median stays of the control group by 25 days and 10 days, respectively, which approximates a doubling of length of stay (p < 0.0001). For both groups, the postoperative stay accounted for the majority of inpatient days, which in turn occurred predominantly in an intensive care unit setting. Accordingly, the mean and median total hospital charges for the study group were at least double those of the control group.
Comment To our knowledge, this is the first study to assess cardiac surgical outcomes and resource use in young infants with IUGR. The predominant finding was that IUGR status was associated with substantially increased postoperative lengths of stay and hospital charges—nearly twice that of otherwise similar patients without IUGR. We also found significant associations between IUGR status and postoperative cardiopulmonary arrest and infection. Survival and other measures of morbidity also appeared to be worse in infants with IUGR; however, these trends were not statistically significant. IUGR, although complex and incompletely understood, likely shares many etiologic factors with prematurity and low-birth-weight non-IUGR status [3]. However, IUGR status is considered to confer unique risk based on comparisons of noncardiac cohorts of premature infants in whom IUGR status was associated with increased risk of mortality, necrotizing enterocolitis, and requirement of mechanical ventilatory support [10]. Previous reports have evaluated cardiac surgical outcomes in patients with low operative weights. Oppido and associates [8] reported a series of 60 patients with a mean operative weight of 2.1 kg. Only 8 patients were less than 32 weeks’ gestation, and IUGR status was not reported. Early mortality was 15% and reported to be
unrelated to prematurity status. Lechner and colleagues [7] reported a series of 46 patients with a median operative weight of 2.3 kg and a median gestational age of 35.5 weeks. Early mortality was 13% without controlling specifically for prematurity or documenting IUGR status. Median length of stay was 26 days and median duration of mechanical ventilation was 7 days. In the report by Azakie and colleagues [9], the cohort included 75 patients with a median weight of 2.1 kg and a median gestational age of 36 weeks. Discharge mortality was 7.5%, median length of stay was 19 days, and median duration of mechanical ventilation was 40 hours. Prematurity was not found to be a factor in early mortality; however, IUGR status was not reported. The remaining single-institution series by Reddy and associates [6] included 102 patients who weighed less than 2.5 kg. Median weight was 2.1 kg, and median gestational age was 34 weeks; IUGR status was not documented [6]. Early mortality was 10%. Median length of stay was 19 days and median duration of mechanical ventilation was 5 days. In a multiinstitutional report based on the Society of Thoracic Surgeons congenital database, Curzon and coworkers [5] compared outcomes in 517 patients weighing less than 2.5 kg to those of 2,505 patients weighing 2.5 to 4.0 kg. Overall, discharge mortality was significantly higher across all RACHS levels and in certain diagnostic/ procedural groups. For example, discharge mortalities in the lower versus higher weight groups were 11.8% and 2.6%, respectively, for the arterial switch procedure and were 22.7% and 12.9%, respectively, for systemic to pulmonary artery shunts for pulmonary atresia with an intact ventricular septum. This study did not report on prematurity, IUGR status, or other outcome measures. It is difficult to compare the results of our cohort with those of previous reports because the defining feature of our cohort was unique. Approximately half of our cohort had operative weights greater than 2.3 kg, and the range extended from 0.6 kg to 5.9 kg. We would therefore refrain from attempting any such comparisons. We did not design this study to discern various effects of absolute patient weight or gestational age. Because of practical considerations and the strong linkage between IUGR and weight, we did not attempt to match for operative weight. Our results nevertheless strongly suggest that IUGR is an important risk factor. Based on a subanalysis not reported because of low patient numbers and statistical constraints, we suspect that IUGR confers an important risk independent of both operative weight
Table 3. Comparison of Resource Use for the IUGR Group and Controls Variable a
Total charges ($) mean (SD) Total LOS (d) mean (SD) Postoperative LOS (d) mean (SD)
Controls
493,915 (687,396) 56.3 (72.0) 47.8 (66.2)
175,144 (174,982) 28.0 (28.6) 22.4 (23.3)
a Based on charges available for 34 study patients and 68 matched control patients. using matching.
IUGR ¼ intrauterine growth restriction;
LOS ¼ length of stay.
D (Case – Control)
95% CI for D
p Value
4.72 3.13 3.52
2.72–8.16 1.84–5.31 2.16–5.75
<0.0001 <0.0001 <0.0001
b
Cases
b
Estimated difference obtained from the generalized linear model
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and gestational age, with a likely diminishing impact at the lower extremes of weight and prematurity. However, confirmation of this suspicion would require a larger cohort and a more tailored study design. Our study was also not designed to address the issue of delayed versus early surgical correction in patients with IUGR. In general, our approach has been consistent with that reported by the previously cited authors of not delaying surgical intervention based on size alone. We would also agree that the expected risk/benefit and management should be individualized for each patient.
There was heterogeneity both within and between groups in our cohort. We attempted to address this by categorizing certain variables and matching for well-established risk factors. An apparently successful matching process does not eliminate the possibility of bias or confounding from other variables. Finally, this study is fully subject to all constraints typical of retrospective studies of relatively small numbers of patients.
Conclusions IUGR is associated with substantially increased lengths of stay, postoperative morbidity, and resource use. These findings are relevant to risk stratification, prognosis, and, potentially, contracting and reimbursement. IUGR merits further attention as an important risk factor in congenital heart operations.
This work received partial support from the American Association of Thoracic Surgery Summer Intern Scholarship.
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Limitations
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