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Heterotaxy syndrome and intestinal rotational anomalies: Impact of the Ladd procedure
Journal of Pediatric Surgery 50 (2015) 1695–1700
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Heterotaxy syndrome and intestinal rotational anomalies: Impact of the Ladd procedure☆ Arash Salavitabar a, Brett R. Anderson b,⁎, Gudrun Aspelund c, Thomas J. Starc b, Wyman W. Lai b a b c
Department of Pediatrics, NewYork-Presbyterian/Morgan Stanley Children's Hospital, Columbia University Medical Center, 630 W 168th St.—VC 507, New York, NY 10032, USA Division of Pediatric Cardiology, Columbia University Medical Center, 3959 Broadway, CH 2N, New York, NY 10032, USA Division of Pediatric Surgery, Columbia University Medical Center, 3959 Broadway, CH 2N, New York, NY 10032, USA
a r t i c l e
i n f o
Article history: Received 1 December 2014 Received in revised form 16 February 2015 Accepted 21 February 2015 Key words: Heterotaxy syndrome Intestinal rotational anomalies Intestinal malrotation Small bowel obstruction Ladd procedure
a b s t r a c t Background: Children with heterotaxy syndrome and intestinal rotational anomalies (IRA) are at risk for midgut volvulus and ischemia. Controversy exists regarding risks and benefits of prophylactic Ladd procedures. The purpose of this study is to assess the impact of Ladd procedures on adverse events for children with heterotaxy and IRA. Methods: A retrospective cohort study using the Pediatric Health Information System (PHIS) database was performed. All children with heterotaxy and IRA admitted at age ≤30 days and discharged between 1/1/2004 and 1/1/2011 were included with a minimum 2-year follow-up period. The primary outcome was major morbidity, defined as a composite variable for intestinal obstruction/volvulus, ischemia, or resection, or inhospital mortality. Univariable and multivariable analyses were performed. Results: There were 325 patients who met the inclusion criteria, including 92 (28%) patients with single ventricles. Mean gestational age was 38.0 ± 2.1 weeks and birth weight was 3.1 ± 0.6 kg. Ladd procedure was performed during initial hospitalization on 188 (58%) children. In multivariable analyses, Ladd procedure on initial hospitalization was associated with a 2.2 times increased odds of adverse events on subsequent admissions (95% CI 1.3–4.0, p = 0.007). Conclusions: Ladd procedure is associated with increased odds of adverse events for children with heterotaxy and IRA. © 2015 Elsevier Inc. All rights reserved.
Heterotaxy syndrome refers to an array of abnormal anatomical configurations of the thoracoabdominal viscera. It ranges from, but does not include, complete situs solitus with levocardia and a D-cardiac loop to situs inversus totalis with dextrocardia and an L-cardiac loop [1,2]. It is a rare disorder that occurs in approximately 1 per 10,000 births [3]. There is a known association between heterotaxy syndrome and congenital heart disease (CHD). The severity runs the spectrum from isolated simple lesions, such as atrial septal defects, to complex single ventricle variants, with variations of systemic and pulmonary venous drainage, including interrupted inferior vena cava, bilateral superior venae cavae, and anomalous pulmonary venous connections [2,4]. Heterotaxy syndrome is also associated with various gastrointestinal abnormalities, the most clinically significant of which are intestinal rotational anomalies (IRA), a failure of normal rotation and fixation of any portion of the intestinal tract during embryonic development [4–11]. This arrest in development can predispose children to develop
☆ All authors are without conflicts of interest to disclose. ⁎ Corresponding author. Tel.: +1 212 305 4432. E-mail addresses: [email protected] (A. Salavitabar), [email protected] (B.R. Anderson), [email protected] (G. Aspelund), [email protected] (T.J. Starc), [email protected] (W.W. Lai). http://dx.doi.org/10.1016/j.jpedsurg.2015.02.065 0022-3468/© 2015 Elsevier Inc. All rights reserved.
a malfixated midgut with a narrow small bowel mesentery, which is a risk factor for volvulus and significant morbidity and mortality [2,12,13]. IRA are reported to occur in approximately 1 in 500 live births overall, but have been found to be present in a substantially large proportion (32-89%) of children and adults with heterotaxy syndrome [2,14–16]. Although a previously undiagnosed patient with IRA may theoretically present at any juncture of life with an acute volvulus, approximately 66%–80% of patients who present with volvulus will do so in the first month of life and 90% in the first year of life [11,14]. The surgical approach to correction of IRA typically involves performance of the Ladd procedure, including derotation of the bowel in cases of volvulus, lysis of peritoneal adhesive bands with broadening of the mesentery, and repositioning of the intestines [9,16]. There is lack of consensus between institutions regarding the appropriateness of prophylactic Ladd procedures in asymptomatic patients with heterotaxy syndrome and IRA, and all of the published studies to date have relied on relatively small populations from single-center studies [1,2,4,11,12,16]. We hypothesized that the Ladd procedure was associated with worse outcomes in children with heterotaxy syndrome and intestinal rotational anomalies. A retrospective study, using a multiinstitutional database, was performed to determine the impact of the Ladd procedure in heterotaxy patients across multiple centers.
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1. Methods 1.1. Study design We performed a retrospective cohort study, using the Pediatric Health Information System (PHIS) database, to determine the impact of the Ladd procedure on major morbidity and mortality in children with heterotaxy syndrome and IRA. This study was classified by the Columbia University Medical Center Institutional Review Board as non-human subjects research and was exempted from further review. 1.2. Data source Data for this study were obtained from the PHIS database, an administrative database that contains in-patient, emergency department, ambulatory surgery, and observational data from 45 not-forprofit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Children's Hospital Association (Overland Park, KS). Data quality and reliability are assured through a joint effort between the Children's Hospital Association and participating hospitals. The data warehouse function for the PHIS database is managed by Truven Health Analytics (Ann Arbor, MI). For the purposes of external benchmarking, participating hospitals provide discharge/encounter data including demographics, diagnoses, and procedures. All data are de-identified at the time of data submission, and data are subjected to a number of reliability and validity checks before being included in the database. 1.3. Study population We included all children with heterotaxy syndrome and IRA initially admitted to a PHIS institution at less than or equal to 30 days of age and discharged between January 1, 2004 and January 1, 2011. The database was surveyed for subsequent admissions through 1/1/2013, to ensure a minimum 2-year follow-up period. Subjects were considered to have had heterotaxy and IRA based on the following codes from the International Classification of Disease, 9th revision, Clinical Modification (ICD9): 746.87 (malposition of the heart and cardiac apex) or 759.3 (situs inversus) to classify cardiac anomalies, and 751.4 (anomalies of intestinal fixation) to classify IRA. In order to include only asymptomatic children at the time of enrollment, those who experienced either a major morbidity (as defined by intestinal obstruction or volvulus, gut ischemia, or intestinal resection) or mortality on initial hospitalization were excluded. Patients were also excluded if they were coded for congenital atresia or stenosis of small intestine (751.1 and 751.2, respectively). 1.4. Predictor variables The primary predictor of interest was the performance of the Ladd procedure on the initial hospitalization (ICD-9 code 54.95). Covariates included birth weight, sex, gestational age, admit year, Risk Adjusted Congenital Heart Surgery (RACHS-1) score, and coding for hypoplastic left heart syndrome (HLHS)/common ventricle (746.7, 745.3), and total anomalous pulmonary venous return (TAPVR) (747.41). Missing data for birth weight and gestational age were common (25% and 31%, respectively). Since there was no significant difference in composite outcome or in the frequency of Ladd procedure between those with and without missing data for birth weight (p = 0.189 and p = 0.184, respectively) or for gestational age (p = 0.442 and p = 0.234, respectively), subjects with missing values were included in univariable analyses. The RACHS-1 methodology is a consensus-based ranking system for congenital heart surgery procedures. It was originally designed to allow for risk adjustment by baseline casemix, and it has been previously described and validated elsewhere [17]. In order to appropriately categorize the entire
study cohort, those children who underwent a cardiac surgical procedure not included in the original RACHS-1 methodology were labeled as category “Other” and those children who did not undergo any cardiac surgery were labeled as category “None”. RACHS-1 was included in all models as a series of seven dummy variables. 1.5. Outcome variables The primary outcome was major morbidity or mortality on admissions subsequent to the initial hospitalization in which the subjects were enrolled. Major morbidity was defined as intestinal obstruction including volvulus (560.2, 560.8, 560.81, 560.89, 560.90), gut ischemia (557.0, 557.9), and intestinal resection (procedure codes 45.6, 45.6145.63; 45.7, 45.71-45.79; 45.8, 45.81-45.8.3; 45.9, 45.90-45.95) on any subsequent admission. Mortality was defined as in-hospital death on any subsequent admission. Secondary outcomes included placement of a permanent feeding tube (procedure codes 43.1, 43.11; 46.32, 43.19, 44.39), median number of hospitalizations per patient-year, and median number of days admitted per patient-year. 1.6. Data analysis All statistical analyses were conducted in Stata software, version 13 (StataCorp, College Station, TX). Clinical and demographic variables were described with standard summary statistics, including means with standard deviations or medians with interquartile ranges (IQR) for continuous variables, as well as frequencies and percents for categorical variables. Univariable analyses were performed for all primary and secondary outcomes using chi-squared or Fisher's exact tests for categorical variables, and t-tests or Wilcoxon rank sum tests for continuous variables. Multivariable analyses were performed for primary outcomes only, and generalized estimating equations were used to account for clustering of standard errors by institution. Logistic regressions were performed, using forward stepwise procedure, where variables were entered in the final model if p values were b 0.10, and kept in the model if p b 0.05 or if inclusion changed the magnitude of the coefficient for the Ladd procedure by greater than 10%. 2. Results 2.1. Patient characteristics/study population A total of 347 children from 41 institutions were identified with heterotaxy syndrome and IRA. Of these, 325 met inclusion criteria, with a median follow-up time of 4.9 years (IQR 3.5–6.7). In total, the Ladd procedure was performed in 188 children (58%) (Fig. 1), with no significant differences in the rate of Ladd procedure over time (p = 0.494). Practices varied markedly between institutions, with some hospitals performing the Ladd procedure in all children with heterotaxy syndrome and IRA and some hospitals performing the Ladd procedure in none. Nearly one-third of children had single ventricles (28%, n = 92) and nearly one-third had TAPVR (27%, n = 87). Detailed characteristics of the study population are described in Table 1. For the patients who underwent cardiac surgery, the majority of procedures were classified as RACHS-1 categories three or four. There were no significant differences in the proportion of children who underwent Ladd procedure within each RACHS-1 category, although, patients who had cardiac surgery of any kind were less likely to have the Ladd procedure performed when compared to those who did not have cardiac surgery performed (51% vs. 66%, p = 0.009). Fig. 2 describes in detail the distribution of RACHS-1 scores and effects of congenital heart surgery and congenital heart surgery severity on the likelihood of the Ladd procedure being performed. The analyses show that children who did not undergo congenital heart surgery were significantly more likely to undergo the Ladd procedure than those who did undergo congenital heart surgery. However, there is no significant difference in the
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Children with Heterotaxy & Intestinal Rotational Anomalies n=347
Excluded
Adverse outcomea & Ladd on 1st hospitalization
Yes
No
n=22
Included
n=325 Laddb
No Laddc
n=188 (58%)
n=137 (42%)
Fig. 1. Patient characteristics. aMajor morbidity or mortality. bLadd procedure performed on initial hospitalization. cLadd procedure not performed on initial hospitalization.
probability of the Ladd procedure being performed by cardiac surgery severity.
2.2. Primary outcomes In total, 78 patients (24%) experienced a major morbidity or mortality. The Ladd procedure was significantly associated with the composite variable of major morbidity or mortality in both univariable and multivariable analyses. There were 28 deaths (8.6%) in the overall study group, with no difference in mortality for patients who did or did not undergo the Ladd procedure (8.5% vs. 8.8%, p = 0.937). Fig. 3 displays the proportions of patients with each of the specific major morbidities assessed. In multivariable analyses, Ladd procedure on initial hospitalization was associated with a 2.2 times increase in the odds of major morbidity or mortality (95% CI 1.3–4.0, p = 0.007), after considering the effects of birth weight, sex, gestational age, admit year, cardiac surgery, RACHS-1 score, single ventricle, and TAPVR, and controlling for clustering by institution. In both univariable and multivariable analyses, the only other variable that was significantly associated with major morbidity or mortality was birth weight (Table 2). For every additional kilogram a subject weighed at birth, the odds of major morbidity or mortality decreased by 60%.
2.3. Secondary outcomes In total, 83 (26%) of all children underwent placement of permanent feeding tubes and were admitted a median of 0.7 times per year (IQR 0.3–1.2), with a median of 11 days admitted each year (IQR 6–22). Children who underwent the Ladd procedure were more likely to also undergo permanent placement of a feeding tube (30% vs 20%, p = 0.040) but were admitted to the hospital fewer times each year (median 0.6 vs. 0.8, p = 0.007). There was no difference in the median number of days admitted each year. The median follow-up time was 4.9 years (IQR 3.5–6.7); this was similar between the two groups. 3. Discussion In this retrospective, multicenter study of over 300 patients with heterotaxy syndrome and intestinal rotational anomalies, we found that performance of the Ladd procedure was associated with a 120% increase in the odds of major morbidity or mortality, even after considering the effects of birth weight, sex, gestational age, admit year, cardiac surgery, RACHS-1 score, single ventricle, and TAPVR, and controlling for clustering by institution. Subject characteristics, including severity of cardiac disease, were similar between those who did and did not have the Ladd procedure. However, physicians performed the Ladd procedure less often in
Table 1 Patient characteristics.
Female sex, number (%) Birth weight, mean (SD), kilograms Gestational age, mean (SD), weeks Age at initial admission, median (IQR), days Single ventricle, number (%) TAPVR, number (%)
Total
Ladda
No Laddb
p Value
188 (55%) 3.1 (0.6) 38.0 (2.1) 0 (0–2) 92 (28%) 87 (27%)
116 (55%) 3.1 (0.6) 38.1 (2.0) 0 (0–3) 48 (26%) 43 (23%)
72 (55%) 3.0 (0.7) 38.0 (2.3) 0 (0–2) 44 (32%) 44 (32%)
0.624 0.201 0.108 0.293 0.193 0.063
p Values represent differences in values between patients who did and did not have the Ladd procedure on initial hospitalization. IQR, interquartile range; SD, standard deviation; TAPVR, total anomalous pulmonary venous return. a Ladd procedure performed on initial hospitalization. b Ladd procedure not performed on initial hospitalization.
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1
2
3
4
5
6
Fig. 2. The relationship between cardiac surgery complexity and performance of the Ladd procedure among patients with heterotaxy syndrome. This graph displays the proportion of patients undergoing Ladd procedure by Risk Adjustment for Congenital Heart Surgery (RACHS-1) categories. “None” denotes no cardiac surgery performed. “Other” denotes a cardiac surgery not captured by the RACHS-1 system. ap Value compares the difference in the likelihood of the Ladd procedure being performed in subjects who did not undergo cardiac surgery. bp Values compare the differences in the likelihood of the Ladd procedure being performed for each RACHS-1 category versus all other categories. * denotes p b 0.05.
subjects who had cardiac surgery than in those who did not have cardiac surgery. The number of subsequent hospitalizations was higher in subjects who did not have the Ladd procedure, but with no significant difference found in the median number of days admitted per year. Interestingly, feeding tubes, in contrast, were placed more often in subjects who had a Ladd procedure, the causality of which could not be concluded given the retrospective nature of our study and the potential for variability in surgeon preference with regard to the placement of gastrostomy tubes at the time of operation. The management of patients with heterotaxy syndrome and IRA remains a controversial topic. The Ladd procedure, as with any surgical procedure, is not without its consequences, which can be potentially amplified in patients with congenital heart disease. However, there are also significant morbidities and mortalities associated with both acute decompensation of volvulus as well as the long-term effects of short-gut syndrome that can result [16]. The practice patterns by
some physicians and institutions are that the benefits of the Ladd procedure greatly outweigh the risks of performing this “elective” abdominal surgery and the risk of eventually developing midgut volvulus [1–4,15,16]. For these physicians, the timing of referral for the Ladd procedure depends largely on patient age, cardiac physiology, and personal preference. Furthermore, there has been recent interest in the utilization of a laparoscopic Ladd procedure, as opposed to laparotomy, for certain groups of pediatric patients with IRA [18]. While the outcomes of each approach are of interest, the PHIS database does not consider the Current Procedural Terminology (CPT) coding that distinguishes these approaches reliable, and thus we cannot differentiate between the Ladd procedures performed laparoscopically and those performed via laparotomy. Others argue that a prophylactic Ladd procedure is not warranted in children with heterotaxy and IRA, noting the relatively low potential for morbidity or mortality from the natural course of IRA, and emphasizing
n=35
0.2
Proportion of Subjects with Heterotaxy and Intestinal Rotational Anomalies
0.18 0.16 0.14 0.12 0.1 0.08
n=17
Ladd
n=9
No Ladd
n=8
0.06
n=7 0.04
n=2 0.02 0 Obstruction/Volvulus
Gut Ischemia
Intestinal resection
Fig. 3. Major morbidity in patients with heterotaxy syndrome. This graph displays the breakdown of major morbidities for patients who did and did not undergo the Ladd procedure on initial hospitalization.
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Table 2 Predictors of major morbidity or mortality. Univariable analyses
Ladd procedurea Birth weight Sex Gestational age Admit year RACHS-1 Heart surgery Single ventricle TAPVR
Multivariable analyses
OR (95% CI)
p Value
Adjusted OR (95% CI)
p Value
1.9 (1.3–4.0) 0.5 (0.3–0.7) 1.2 (0.7–2.1) 0.9 (0.8–1.0) 0.4 (0.2–1.1) 0.7 (0.4–1.2) 0.7 (0.4–1.2) 0.9 (0.5–1.6) 0.8 (0.5–1.5)
0.025⁎ 0.001⁎ 0.435 0.045 0.789 0.082 0.180 0.756 0.582
2.2 (1.3–4.0) 0.4 (0.3–0.7) – – – – – – –
0.007⁎ b0.001⁎ – – – – – – –
All variables with p b 0.1 on univariable analyses were considered in multivariable analyses. OR, odds ratio; CI, confidence interval; RACHS-1, Risk Adjusted Congenital Heart Surgery category. a Ladd procedure designates that a Ladd procedure was performed on initial hospitalization. ⁎ p b 0.05.
the significance of potential postoperative complications [10–12]. Choi et al. [12] reported that, from a sample size of 177 patients with heterotaxy syndrome, only five developed symptomatic classic volvulus when initially managed non-surgically and concluded that the 0.6% incidence of volvulus in this population is lower than the rates of small bowel obstruction published elsewhere. Highlighting the lack of consensus within the field, this study shows that within the 41 institutions captured by the PHIS database, approximately half of children with heterotaxy syndrome and IRA undergo the Ladd procedure on initial hospitalization and that half do not, with no significant changes over time. Until this time, the reliance on relatively small, single-center studies has made it difficult for many institutions to apply the existing literature to their own patient populations, fueling the continued debate. This study, in contrast, involves over 300 children from 41 tertiary care children's hospitals. The significantly higher rate of adverse events found in children who underwent the Ladd procedure when compared to those managed by cautious observation raises concerns about the continued use of the Ladd procedure in asymptomatic children. This study suggests that, for the average, asymptomatic child with heterotaxy syndrome and IRA, the safest approach might be cautious observation. There are certain inherent limitations to this study. First, the study is retrospective, which limits our ability to imply causality. Second, administrative databases rely on diagnostic and procedure billing codes and lack other clinical details. This invariably results in misclassification of some patients. For example, a patient who undergoes intestinal resection for obstruction with volvulus could be coded for intestinal resection alone, obstruction/volvulus, or both. The bias introduced by misclassification can either strengthen the association between a prophylactic Ladd procedure with subsequent morbidity or weaken it. We attempted to mitigate the effects of this bias by using a composite variable for major morbidity, rather than performing statistical analyses on the individual subcomponents of that variable. This composite variable also allowed for subjects to be counted only once as having a major morbidity. We also used conservative inclusion criteria, which likely eliminated some children who were truly asymptomatic at the time of the Ladd procedure and who had in-hospital complications related to the procedure itself. This would result in an underestimation of the magnitude of the association between Ladd procedure and adverse events. It remains possible that other systematic differences in coding exist. For example, it is possible that children with mild symptoms undergoing the Ladd procedure (or not) might be more often coded for morbidities. This could lead to either an increase or a decrease in the magnitude of the effect observed.
In addition, this study does not capture all potential confounders. It is possible that the risk–benefit ratio for the Ladd procedure differs in certain subpopulations. For example, this study does not consider the effects of the distances that patients live from medical care. While it might be true that, for children living near a hospital, the Ladd procedure is associated with higher morbidity or mortality than unrepaired IRA, for children living in remote areas, the risks of unrepaired IRA might be more severe. Future studies, using similarly large, multicenter datasets, with more clinical granularity, are needed to confirm these findings as well as to explore questions pertaining to both reoperative rates in patients who had the Ladd procedure performed on initial hospitalization and rates and timing of late volvulus resulting in the need for a Ladd procedure in patients who did not initially have the Ladd procedure. 4. Conclusions For the average child with heterotaxy syndrome and intestinal rotational anomalies, the Ladd procedure is associated with increased odds of major morbidity or mortality. Close observation and follow-up, without elective or prophylactic Ladd procedure, might reduce the odds of future complications in asymptomatic children. References [1] Chang J, Brueckner M, Touloukian RJ. Intestinal rotation and fixation abnormalities in heterotaxia: early detection and management. J Pediatr Surg 1993;28(10): 1281–5. [2] Tashjian DB, Weeks B, Brueckner M, et al. Outcomes after a Ladd procedure for intestinal malrotation with heterotaxia. J Pediatr Surg 2007;42(3):528–31. [3] Lin AE, Ticho BS, Houde K, et al. Heterotaxy: associated conditions and hospitalbased prevalence in newborns. Genet Med 2000;2(3):157–72. [4] Yu DC, Thiagarajan RR, Laussen BC, et al. Outcomes after the Ladd procedure in patients with heterotaxy syndrome, congenital heart disease, and intestinal malrotation. J Pediatr Surg 2009;44(6):1089–95. [5] Moller JH, Amplatz K, Wolfson J. Malrotation of the bowel in patients with congenital heart disease associated with splenic anomalies. Radiology 1971;99(2):393–8. [6] Nakada K, Kawaguchi F, Wakisaka M, et al. Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg 1997;32(1):91–4. [7] Paddock RJ, Arensman RM. Polysplenia syndrome: spectrum of gastrointestinal congenital anomalies. J Pediatr Surg 1982;17(5):563–6. [8] Applegate KE, Goske MJ, Pierce G, et al. Situs revisited: imaging of the heterotaxy syndrome. Radiographics 1999;19(4):837–52. [9] Lampl B, Levin TL, Berdon WE, et al. Malrotation and midgut volvulus: a historical review and current controversies in diagnosis and management. Pediatr Radiol 2009;39(4):359–66. [10] Prendiville TW, Barton LL, Thompson WR, et al. Heterotaxy syndrome: defining contemporary disease trends. Pediatr Cardiol 2010;31(7):1052–8. [11] Pockett CR, Dicken B, Rebeyka IM, et al. Heterotaxy syndrome: is a prophylactic Ladd procedure necessary in asymptomatic patients? Pediatr Cardiol 2013; 34(1):59–63.
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[12] Choi M, Borenstein SH, Hornberger L, et al. Heterotaxia syndrome: the role of screening for intestinal rotation abnormalities. Arch Dis Child 2005;90(8): 813–5. [13] Borenstein SH, Langer JC. Heterotaxia syndromes and their abdominal manifestations. Curr Opin Pediatr 2006;18(3):294–7. [14] Strouse PJ. Disorders of intestinal rotation and fixation (“malrotation”). Pediatr Radiol 2004;34(11):837–51. [15] Ditchfield MR, Hutson JM. Intestinal rotational abnormalities in polysplenia and asplenia syndromes. Pediatr Radiol 1998;28(5):303–6.
[16] Ferdman B, States L, Gaynor JL, et al. Abnormalities of intestinal rotation in patients with congenital heart disease and the heterotaxy syndrome. Congenit Heart Dis 2007;2(1):12–8. [17] Jenkins KJ, Gauvreau K, Newburger JW, et al. Consensus-based method for risk adjustment for congenital heart surgery. J Thorac Cardiovasc Surg 2002; 123(1):110–8. [18] Hsiao M, Langer JC. Surgery for suspected rotation abnormality: selection of open vs laparoscopic surgery using a rational approach. J Pediatr Surg 2012; 47(s):904–10.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Heterotaxy syndrome and intestinal rotational anomalies: Impact of the Ladd procedure☆ Arash Salavitabar a, Brett R. Anderson b,⁎, Gudrun Aspelund c, Thomas J. Starc b, Wyman W. Lai b a b c
Department of Pediatrics, NewYork-Presbyterian/Morgan Stanley Children's Hospital, Columbia University Medical Center, 630 W 168th St.—VC 507, New York, NY 10032, USA Division of Pediatric Cardiology, Columbia University Medical Center, 3959 Broadway, CH 2N, New York, NY 10032, USA Division of Pediatric Surgery, Columbia University Medical Center, 3959 Broadway, CH 2N, New York, NY 10032, USA
a r t i c l e
i n f o
Article history: Received 1 December 2014 Received in revised form 16 February 2015 Accepted 21 February 2015 Key words: Heterotaxy syndrome Intestinal rotational anomalies Intestinal malrotation Small bowel obstruction Ladd procedure
a b s t r a c t Background: Children with heterotaxy syndrome and intestinal rotational anomalies (IRA) are at risk for midgut volvulus and ischemia. Controversy exists regarding risks and benefits of prophylactic Ladd procedures. The purpose of this study is to assess the impact of Ladd procedures on adverse events for children with heterotaxy and IRA. Methods: A retrospective cohort study using the Pediatric Health Information System (PHIS) database was performed. All children with heterotaxy and IRA admitted at age ≤30 days and discharged between 1/1/2004 and 1/1/2011 were included with a minimum 2-year follow-up period. The primary outcome was major morbidity, defined as a composite variable for intestinal obstruction/volvulus, ischemia, or resection, or inhospital mortality. Univariable and multivariable analyses were performed. Results: There were 325 patients who met the inclusion criteria, including 92 (28%) patients with single ventricles. Mean gestational age was 38.0 ± 2.1 weeks and birth weight was 3.1 ± 0.6 kg. Ladd procedure was performed during initial hospitalization on 188 (58%) children. In multivariable analyses, Ladd procedure on initial hospitalization was associated with a 2.2 times increased odds of adverse events on subsequent admissions (95% CI 1.3–4.0, p = 0.007). Conclusions: Ladd procedure is associated with increased odds of adverse events for children with heterotaxy and IRA. © 2015 Elsevier Inc. All rights reserved.
Heterotaxy syndrome refers to an array of abnormal anatomical configurations of the thoracoabdominal viscera. It ranges from, but does not include, complete situs solitus with levocardia and a D-cardiac loop to situs inversus totalis with dextrocardia and an L-cardiac loop [1,2]. It is a rare disorder that occurs in approximately 1 per 10,000 births [3]. There is a known association between heterotaxy syndrome and congenital heart disease (CHD). The severity runs the spectrum from isolated simple lesions, such as atrial septal defects, to complex single ventricle variants, with variations of systemic and pulmonary venous drainage, including interrupted inferior vena cava, bilateral superior venae cavae, and anomalous pulmonary venous connections [2,4]. Heterotaxy syndrome is also associated with various gastrointestinal abnormalities, the most clinically significant of which are intestinal rotational anomalies (IRA), a failure of normal rotation and fixation of any portion of the intestinal tract during embryonic development [4–11]. This arrest in development can predispose children to develop
☆ All authors are without conflicts of interest to disclose. ⁎ Corresponding author. Tel.: +1 212 305 4432. E-mail addresses: [email protected] (A. Salavitabar), [email protected] (B.R. Anderson), [email protected] (G. Aspelund), [email protected] (T.J. Starc), [email protected] (W.W. Lai). http://dx.doi.org/10.1016/j.jpedsurg.2015.02.065 0022-3468/© 2015 Elsevier Inc. All rights reserved.
a malfixated midgut with a narrow small bowel mesentery, which is a risk factor for volvulus and significant morbidity and mortality [2,12,13]. IRA are reported to occur in approximately 1 in 500 live births overall, but have been found to be present in a substantially large proportion (32-89%) of children and adults with heterotaxy syndrome [2,14–16]. Although a previously undiagnosed patient with IRA may theoretically present at any juncture of life with an acute volvulus, approximately 66%–80% of patients who present with volvulus will do so in the first month of life and 90% in the first year of life [11,14]. The surgical approach to correction of IRA typically involves performance of the Ladd procedure, including derotation of the bowel in cases of volvulus, lysis of peritoneal adhesive bands with broadening of the mesentery, and repositioning of the intestines [9,16]. There is lack of consensus between institutions regarding the appropriateness of prophylactic Ladd procedures in asymptomatic patients with heterotaxy syndrome and IRA, and all of the published studies to date have relied on relatively small populations from single-center studies [1,2,4,11,12,16]. We hypothesized that the Ladd procedure was associated with worse outcomes in children with heterotaxy syndrome and intestinal rotational anomalies. A retrospective study, using a multiinstitutional database, was performed to determine the impact of the Ladd procedure in heterotaxy patients across multiple centers.
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1. Methods 1.1. Study design We performed a retrospective cohort study, using the Pediatric Health Information System (PHIS) database, to determine the impact of the Ladd procedure on major morbidity and mortality in children with heterotaxy syndrome and IRA. This study was classified by the Columbia University Medical Center Institutional Review Board as non-human subjects research and was exempted from further review. 1.2. Data source Data for this study were obtained from the PHIS database, an administrative database that contains in-patient, emergency department, ambulatory surgery, and observational data from 45 not-forprofit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Children's Hospital Association (Overland Park, KS). Data quality and reliability are assured through a joint effort between the Children's Hospital Association and participating hospitals. The data warehouse function for the PHIS database is managed by Truven Health Analytics (Ann Arbor, MI). For the purposes of external benchmarking, participating hospitals provide discharge/encounter data including demographics, diagnoses, and procedures. All data are de-identified at the time of data submission, and data are subjected to a number of reliability and validity checks before being included in the database. 1.3. Study population We included all children with heterotaxy syndrome and IRA initially admitted to a PHIS institution at less than or equal to 30 days of age and discharged between January 1, 2004 and January 1, 2011. The database was surveyed for subsequent admissions through 1/1/2013, to ensure a minimum 2-year follow-up period. Subjects were considered to have had heterotaxy and IRA based on the following codes from the International Classification of Disease, 9th revision, Clinical Modification (ICD9): 746.87 (malposition of the heart and cardiac apex) or 759.3 (situs inversus) to classify cardiac anomalies, and 751.4 (anomalies of intestinal fixation) to classify IRA. In order to include only asymptomatic children at the time of enrollment, those who experienced either a major morbidity (as defined by intestinal obstruction or volvulus, gut ischemia, or intestinal resection) or mortality on initial hospitalization were excluded. Patients were also excluded if they were coded for congenital atresia or stenosis of small intestine (751.1 and 751.2, respectively). 1.4. Predictor variables The primary predictor of interest was the performance of the Ladd procedure on the initial hospitalization (ICD-9 code 54.95). Covariates included birth weight, sex, gestational age, admit year, Risk Adjusted Congenital Heart Surgery (RACHS-1) score, and coding for hypoplastic left heart syndrome (HLHS)/common ventricle (746.7, 745.3), and total anomalous pulmonary venous return (TAPVR) (747.41). Missing data for birth weight and gestational age were common (25% and 31%, respectively). Since there was no significant difference in composite outcome or in the frequency of Ladd procedure between those with and without missing data for birth weight (p = 0.189 and p = 0.184, respectively) or for gestational age (p = 0.442 and p = 0.234, respectively), subjects with missing values were included in univariable analyses. The RACHS-1 methodology is a consensus-based ranking system for congenital heart surgery procedures. It was originally designed to allow for risk adjustment by baseline casemix, and it has been previously described and validated elsewhere [17]. In order to appropriately categorize the entire
study cohort, those children who underwent a cardiac surgical procedure not included in the original RACHS-1 methodology were labeled as category “Other” and those children who did not undergo any cardiac surgery were labeled as category “None”. RACHS-1 was included in all models as a series of seven dummy variables. 1.5. Outcome variables The primary outcome was major morbidity or mortality on admissions subsequent to the initial hospitalization in which the subjects were enrolled. Major morbidity was defined as intestinal obstruction including volvulus (560.2, 560.8, 560.81, 560.89, 560.90), gut ischemia (557.0, 557.9), and intestinal resection (procedure codes 45.6, 45.6145.63; 45.7, 45.71-45.79; 45.8, 45.81-45.8.3; 45.9, 45.90-45.95) on any subsequent admission. Mortality was defined as in-hospital death on any subsequent admission. Secondary outcomes included placement of a permanent feeding tube (procedure codes 43.1, 43.11; 46.32, 43.19, 44.39), median number of hospitalizations per patient-year, and median number of days admitted per patient-year. 1.6. Data analysis All statistical analyses were conducted in Stata software, version 13 (StataCorp, College Station, TX). Clinical and demographic variables were described with standard summary statistics, including means with standard deviations or medians with interquartile ranges (IQR) for continuous variables, as well as frequencies and percents for categorical variables. Univariable analyses were performed for all primary and secondary outcomes using chi-squared or Fisher's exact tests for categorical variables, and t-tests or Wilcoxon rank sum tests for continuous variables. Multivariable analyses were performed for primary outcomes only, and generalized estimating equations were used to account for clustering of standard errors by institution. Logistic regressions were performed, using forward stepwise procedure, where variables were entered in the final model if p values were b 0.10, and kept in the model if p b 0.05 or if inclusion changed the magnitude of the coefficient for the Ladd procedure by greater than 10%. 2. Results 2.1. Patient characteristics/study population A total of 347 children from 41 institutions were identified with heterotaxy syndrome and IRA. Of these, 325 met inclusion criteria, with a median follow-up time of 4.9 years (IQR 3.5–6.7). In total, the Ladd procedure was performed in 188 children (58%) (Fig. 1), with no significant differences in the rate of Ladd procedure over time (p = 0.494). Practices varied markedly between institutions, with some hospitals performing the Ladd procedure in all children with heterotaxy syndrome and IRA and some hospitals performing the Ladd procedure in none. Nearly one-third of children had single ventricles (28%, n = 92) and nearly one-third had TAPVR (27%, n = 87). Detailed characteristics of the study population are described in Table 1. For the patients who underwent cardiac surgery, the majority of procedures were classified as RACHS-1 categories three or four. There were no significant differences in the proportion of children who underwent Ladd procedure within each RACHS-1 category, although, patients who had cardiac surgery of any kind were less likely to have the Ladd procedure performed when compared to those who did not have cardiac surgery performed (51% vs. 66%, p = 0.009). Fig. 2 describes in detail the distribution of RACHS-1 scores and effects of congenital heart surgery and congenital heart surgery severity on the likelihood of the Ladd procedure being performed. The analyses show that children who did not undergo congenital heart surgery were significantly more likely to undergo the Ladd procedure than those who did undergo congenital heart surgery. However, there is no significant difference in the
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Children with Heterotaxy & Intestinal Rotational Anomalies n=347
Excluded
Adverse outcomea & Ladd on 1st hospitalization
Yes
No
n=22
Included
n=325 Laddb
No Laddc
n=188 (58%)
n=137 (42%)
Fig. 1. Patient characteristics. aMajor morbidity or mortality. bLadd procedure performed on initial hospitalization. cLadd procedure not performed on initial hospitalization.
probability of the Ladd procedure being performed by cardiac surgery severity.
2.2. Primary outcomes In total, 78 patients (24%) experienced a major morbidity or mortality. The Ladd procedure was significantly associated with the composite variable of major morbidity or mortality in both univariable and multivariable analyses. There were 28 deaths (8.6%) in the overall study group, with no difference in mortality for patients who did or did not undergo the Ladd procedure (8.5% vs. 8.8%, p = 0.937). Fig. 3 displays the proportions of patients with each of the specific major morbidities assessed. In multivariable analyses, Ladd procedure on initial hospitalization was associated with a 2.2 times increase in the odds of major morbidity or mortality (95% CI 1.3–4.0, p = 0.007), after considering the effects of birth weight, sex, gestational age, admit year, cardiac surgery, RACHS-1 score, single ventricle, and TAPVR, and controlling for clustering by institution. In both univariable and multivariable analyses, the only other variable that was significantly associated with major morbidity or mortality was birth weight (Table 2). For every additional kilogram a subject weighed at birth, the odds of major morbidity or mortality decreased by 60%.
2.3. Secondary outcomes In total, 83 (26%) of all children underwent placement of permanent feeding tubes and were admitted a median of 0.7 times per year (IQR 0.3–1.2), with a median of 11 days admitted each year (IQR 6–22). Children who underwent the Ladd procedure were more likely to also undergo permanent placement of a feeding tube (30% vs 20%, p = 0.040) but were admitted to the hospital fewer times each year (median 0.6 vs. 0.8, p = 0.007). There was no difference in the median number of days admitted each year. The median follow-up time was 4.9 years (IQR 3.5–6.7); this was similar between the two groups. 3. Discussion In this retrospective, multicenter study of over 300 patients with heterotaxy syndrome and intestinal rotational anomalies, we found that performance of the Ladd procedure was associated with a 120% increase in the odds of major morbidity or mortality, even after considering the effects of birth weight, sex, gestational age, admit year, cardiac surgery, RACHS-1 score, single ventricle, and TAPVR, and controlling for clustering by institution. Subject characteristics, including severity of cardiac disease, were similar between those who did and did not have the Ladd procedure. However, physicians performed the Ladd procedure less often in
Table 1 Patient characteristics.
Female sex, number (%) Birth weight, mean (SD), kilograms Gestational age, mean (SD), weeks Age at initial admission, median (IQR), days Single ventricle, number (%) TAPVR, number (%)
Total
Ladda
No Laddb
p Value
188 (55%) 3.1 (0.6) 38.0 (2.1) 0 (0–2) 92 (28%) 87 (27%)
116 (55%) 3.1 (0.6) 38.1 (2.0) 0 (0–3) 48 (26%) 43 (23%)
72 (55%) 3.0 (0.7) 38.0 (2.3) 0 (0–2) 44 (32%) 44 (32%)
0.624 0.201 0.108 0.293 0.193 0.063
p Values represent differences in values between patients who did and did not have the Ladd procedure on initial hospitalization. IQR, interquartile range; SD, standard deviation; TAPVR, total anomalous pulmonary venous return. a Ladd procedure performed on initial hospitalization. b Ladd procedure not performed on initial hospitalization.
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1
2
3
4
5
6
Fig. 2. The relationship between cardiac surgery complexity and performance of the Ladd procedure among patients with heterotaxy syndrome. This graph displays the proportion of patients undergoing Ladd procedure by Risk Adjustment for Congenital Heart Surgery (RACHS-1) categories. “None” denotes no cardiac surgery performed. “Other” denotes a cardiac surgery not captured by the RACHS-1 system. ap Value compares the difference in the likelihood of the Ladd procedure being performed in subjects who did not undergo cardiac surgery. bp Values compare the differences in the likelihood of the Ladd procedure being performed for each RACHS-1 category versus all other categories. * denotes p b 0.05.
subjects who had cardiac surgery than in those who did not have cardiac surgery. The number of subsequent hospitalizations was higher in subjects who did not have the Ladd procedure, but with no significant difference found in the median number of days admitted per year. Interestingly, feeding tubes, in contrast, were placed more often in subjects who had a Ladd procedure, the causality of which could not be concluded given the retrospective nature of our study and the potential for variability in surgeon preference with regard to the placement of gastrostomy tubes at the time of operation. The management of patients with heterotaxy syndrome and IRA remains a controversial topic. The Ladd procedure, as with any surgical procedure, is not without its consequences, which can be potentially amplified in patients with congenital heart disease. However, there are also significant morbidities and mortalities associated with both acute decompensation of volvulus as well as the long-term effects of short-gut syndrome that can result [16]. The practice patterns by
some physicians and institutions are that the benefits of the Ladd procedure greatly outweigh the risks of performing this “elective” abdominal surgery and the risk of eventually developing midgut volvulus [1–4,15,16]. For these physicians, the timing of referral for the Ladd procedure depends largely on patient age, cardiac physiology, and personal preference. Furthermore, there has been recent interest in the utilization of a laparoscopic Ladd procedure, as opposed to laparotomy, for certain groups of pediatric patients with IRA [18]. While the outcomes of each approach are of interest, the PHIS database does not consider the Current Procedural Terminology (CPT) coding that distinguishes these approaches reliable, and thus we cannot differentiate between the Ladd procedures performed laparoscopically and those performed via laparotomy. Others argue that a prophylactic Ladd procedure is not warranted in children with heterotaxy and IRA, noting the relatively low potential for morbidity or mortality from the natural course of IRA, and emphasizing
n=35
0.2
Proportion of Subjects with Heterotaxy and Intestinal Rotational Anomalies
0.18 0.16 0.14 0.12 0.1 0.08
n=17
Ladd
n=9
No Ladd
n=8
0.06
n=7 0.04
n=2 0.02 0 Obstruction/Volvulus
Gut Ischemia
Intestinal resection
Fig. 3. Major morbidity in patients with heterotaxy syndrome. This graph displays the breakdown of major morbidities for patients who did and did not undergo the Ladd procedure on initial hospitalization.
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Table 2 Predictors of major morbidity or mortality. Univariable analyses
Ladd procedurea Birth weight Sex Gestational age Admit year RACHS-1 Heart surgery Single ventricle TAPVR
Multivariable analyses
OR (95% CI)
p Value
Adjusted OR (95% CI)
p Value
1.9 (1.3–4.0) 0.5 (0.3–0.7) 1.2 (0.7–2.1) 0.9 (0.8–1.0) 0.4 (0.2–1.1) 0.7 (0.4–1.2) 0.7 (0.4–1.2) 0.9 (0.5–1.6) 0.8 (0.5–1.5)
0.025⁎ 0.001⁎ 0.435 0.045 0.789 0.082 0.180 0.756 0.582
2.2 (1.3–4.0) 0.4 (0.3–0.7) – – – – – – –
0.007⁎ b0.001⁎ – – – – – – –
All variables with p b 0.1 on univariable analyses were considered in multivariable analyses. OR, odds ratio; CI, confidence interval; RACHS-1, Risk Adjusted Congenital Heart Surgery category. a Ladd procedure designates that a Ladd procedure was performed on initial hospitalization. ⁎ p b 0.05.
the significance of potential postoperative complications [10–12]. Choi et al. [12] reported that, from a sample size of 177 patients with heterotaxy syndrome, only five developed symptomatic classic volvulus when initially managed non-surgically and concluded that the 0.6% incidence of volvulus in this population is lower than the rates of small bowel obstruction published elsewhere. Highlighting the lack of consensus within the field, this study shows that within the 41 institutions captured by the PHIS database, approximately half of children with heterotaxy syndrome and IRA undergo the Ladd procedure on initial hospitalization and that half do not, with no significant changes over time. Until this time, the reliance on relatively small, single-center studies has made it difficult for many institutions to apply the existing literature to their own patient populations, fueling the continued debate. This study, in contrast, involves over 300 children from 41 tertiary care children's hospitals. The significantly higher rate of adverse events found in children who underwent the Ladd procedure when compared to those managed by cautious observation raises concerns about the continued use of the Ladd procedure in asymptomatic children. This study suggests that, for the average, asymptomatic child with heterotaxy syndrome and IRA, the safest approach might be cautious observation. There are certain inherent limitations to this study. First, the study is retrospective, which limits our ability to imply causality. Second, administrative databases rely on diagnostic and procedure billing codes and lack other clinical details. This invariably results in misclassification of some patients. For example, a patient who undergoes intestinal resection for obstruction with volvulus could be coded for intestinal resection alone, obstruction/volvulus, or both. The bias introduced by misclassification can either strengthen the association between a prophylactic Ladd procedure with subsequent morbidity or weaken it. We attempted to mitigate the effects of this bias by using a composite variable for major morbidity, rather than performing statistical analyses on the individual subcomponents of that variable. This composite variable also allowed for subjects to be counted only once as having a major morbidity. We also used conservative inclusion criteria, which likely eliminated some children who were truly asymptomatic at the time of the Ladd procedure and who had in-hospital complications related to the procedure itself. This would result in an underestimation of the magnitude of the association between Ladd procedure and adverse events. It remains possible that other systematic differences in coding exist. For example, it is possible that children with mild symptoms undergoing the Ladd procedure (or not) might be more often coded for morbidities. This could lead to either an increase or a decrease in the magnitude of the effect observed.
In addition, this study does not capture all potential confounders. It is possible that the risk–benefit ratio for the Ladd procedure differs in certain subpopulations. For example, this study does not consider the effects of the distances that patients live from medical care. While it might be true that, for children living near a hospital, the Ladd procedure is associated with higher morbidity or mortality than unrepaired IRA, for children living in remote areas, the risks of unrepaired IRA might be more severe. Future studies, using similarly large, multicenter datasets, with more clinical granularity, are needed to confirm these findings as well as to explore questions pertaining to both reoperative rates in patients who had the Ladd procedure performed on initial hospitalization and rates and timing of late volvulus resulting in the need for a Ladd procedure in patients who did not initially have the Ladd procedure. 4. Conclusions For the average child with heterotaxy syndrome and intestinal rotational anomalies, the Ladd procedure is associated with increased odds of major morbidity or mortality. Close observation and follow-up, without elective or prophylactic Ladd procedure, might reduce the odds of future complications in asymptomatic children. References [1] Chang J, Brueckner M, Touloukian RJ. Intestinal rotation and fixation abnormalities in heterotaxia: early detection and management. J Pediatr Surg 1993;28(10): 1281–5. [2] Tashjian DB, Weeks B, Brueckner M, et al. Outcomes after a Ladd procedure for intestinal malrotation with heterotaxia. J Pediatr Surg 2007;42(3):528–31. [3] Lin AE, Ticho BS, Houde K, et al. Heterotaxy: associated conditions and hospitalbased prevalence in newborns. Genet Med 2000;2(3):157–72. [4] Yu DC, Thiagarajan RR, Laussen BC, et al. Outcomes after the Ladd procedure in patients with heterotaxy syndrome, congenital heart disease, and intestinal malrotation. J Pediatr Surg 2009;44(6):1089–95. [5] Moller JH, Amplatz K, Wolfson J. Malrotation of the bowel in patients with congenital heart disease associated with splenic anomalies. Radiology 1971;99(2):393–8. [6] Nakada K, Kawaguchi F, Wakisaka M, et al. Digestive tract disorders associated with asplenia/polysplenia syndrome. J Pediatr Surg 1997;32(1):91–4. [7] Paddock RJ, Arensman RM. Polysplenia syndrome: spectrum of gastrointestinal congenital anomalies. J Pediatr Surg 1982;17(5):563–6. [8] Applegate KE, Goske MJ, Pierce G, et al. Situs revisited: imaging of the heterotaxy syndrome. Radiographics 1999;19(4):837–52. [9] Lampl B, Levin TL, Berdon WE, et al. Malrotation and midgut volvulus: a historical review and current controversies in diagnosis and management. Pediatr Radiol 2009;39(4):359–66. [10] Prendiville TW, Barton LL, Thompson WR, et al. Heterotaxy syndrome: defining contemporary disease trends. Pediatr Cardiol 2010;31(7):1052–8. [11] Pockett CR, Dicken B, Rebeyka IM, et al. Heterotaxy syndrome: is a prophylactic Ladd procedure necessary in asymptomatic patients? Pediatr Cardiol 2013; 34(1):59–63.
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[12] Choi M, Borenstein SH, Hornberger L, et al. Heterotaxia syndrome: the role of screening for intestinal rotation abnormalities. Arch Dis Child 2005;90(8): 813–5. [13] Borenstein SH, Langer JC. Heterotaxia syndromes and their abdominal manifestations. Curr Opin Pediatr 2006;18(3):294–7. [14] Strouse PJ. Disorders of intestinal rotation and fixation (“malrotation”). Pediatr Radiol 2004;34(11):837–51. [15] Ditchfield MR, Hutson JM. Intestinal rotational abnormalities in polysplenia and asplenia syndromes. Pediatr Radiol 1998;28(5):303–6.
[16] Ferdman B, States L, Gaynor JL, et al. Abnormalities of intestinal rotation in patients with congenital heart disease and the heterotaxy syndrome. Congenit Heart Dis 2007;2(1):12–8. [17] Jenkins KJ, Gauvreau K, Newburger JW, et al. Consensus-based method for risk adjustment for congenital heart surgery. J Thorac Cardiovasc Surg 2002; 123(1):110–8. [18] Hsiao M, Langer JC. Surgery for suspected rotation abnormality: selection of open vs laparoscopic surgery using a rational approach. J Pediatr Surg 2012; 47(s):904–10.