Long‐term gastrointestinal outcomes in pediatric intestinal malrotation patients following operative treatment

Intestinal malrotation (IM) is a rare congenital birth defect that occurs in utero due to failure of intestinal rotation and fixation into the normal anatomic position.1 Generally, IM is diagnosed once a patient experiences a life-threatening complication (e.g., midgut volvulus) or as part of the workup for gastrointestinal symptoms. For those with symptomatic IM and for some who are asymptomatic, operative treatment, typically the Ladd procedure, is often performed to reduce the likelihood of a future volvulus.2 Previous studies investigating outcomes after the Ladd procedure typically have focused only on short-term operative outcomes3-6 with only a few identifying ongoing gastrointestinal symptoms.4, 7-9 In this study, we used TriNetX, a large multi-institutional aggregated database of electronic medical records (EMRs), to estimate the rates of diagnosed gastrointestinal symptoms several years postoperative treatment for pediatric IM patients compared to a general pediatric cohort. West Virginia University's Institutional Review Board determined that this study does not meet the definition of human subjects research. Data were extracted on August 1st, 2024 from the TriNetX Research Network, which provides access to aggregated deidentified EMR for over 130 million patients from 92 healthcare organizations (HCOs) across the world. We conducted a retrospective matched cohort study of postoperative gastrointestinal outcomes in pediatric IM patients across 32 HCOs. The control group for comparison also came from TriNetX data and consisted of a general pediatric cohort from 92 HCOs, including the HCOs in the pediatric IM cohort. TriNetX maps International Classification of Diseases (ICD), Ninth Revision, Clinical Modification (CM) codes (ICD-9-CM) to ICD, Tenth Revision, CM codes (ICD-10-CM) and ICD-9-CM procedure codes (PCS) to ICD-10-PCS codes using General Equivalence Mappings.10 TriNetX presents medical outcomes for periods of time after a defined index event, such as a diagnosis or procedure. Table 1 provides the inclusion and exclusion criteria for determining the cohorts. Cohorts were matched using propensity score matching (1:1) based on sex, current age, race, and ethnicity. To measure gastrointestinal symptoms, ICD-10-CM codes for constipation, abdominal pain, nausea and vomiting, diarrhea, and gastro-esophageal reflux disease (GERD) were queried (see Table S1C for ICD-10 codes). We present descriptive statistics of demographic data before and after matching. Cells with fewer than 10 cases but more than 0 cases are automatically rounded up to 10. Mean is displayed for the current age. Percentages are displayed for categorical variables. Data analysis was performed at two time intervals after the index event to evaluate overall (from Years 1 to 5) and longer-term outcomes (from Years 3 to 5). Follow-up began at 1 year after operation to exclude symptoms that could be related to operative intervention and recovery. The cohorts are the same for both follow-up periods. The former identifies whether the patient had one or more of the gastrointestinal outcomes in the 1–5 years after the index event, whereas the latter captures whether the patient had one or more of the gastrointestinal outcomes 3–5 years after the index event. Rates of the gastrointestinal outcomes for those follow-up periods were compared between cohorts. Risk ratios (RRs) with 95% confidence intervals were calculated. Three hundred fifty-four pediatric patients with IM met the inclusion criteria; these patients were matched 1:1 to 354 general pediatric patients. Table S2 provides cohort demographic data before and after matching. Before matching, the cohorts differed in current age, race, and sex. After matching, there were no significant differences in socio-demographic variables between the cohorts. Table 2 compares the cohorts in terms of the gastrointestinal outcomes for different follow-up periods. Compared to the pediatric general cohort, the pediatric IM cohort was at a higher risk of all gastrointestinal outcomes for both follow-up periods. Between 1 and 5 years post-index event, 147 (41.5%) patients in the pediatric IM cohort had a diagnosis of constipation compared to 26 (7.3%) patients in the pediatric general cohort (RR, 95% confidence interval: 5.65, 3.83–8.35), 96 (27.1%) IM patients had a diagnosis of abdominal pain compared to 24 (6.8%) in the general cohort (4.00, 2.62–6.10), and 145 (41.0%) IM patients had a diagnosis of nausea and vomiting compared to 41 (11.6%) patients in the general cohort (3.54, 2.58–4.84). Between 1 and 5 years post-index event, 80 (22.6%) IM patients had a diagnosis of diarrhea compared to 17 (4.8%) patients in the general cohort (4.71, 2.85–7.78) and 123 (34.7%) IM patients had a diagnosis of GERD compared to 10 (2.8%) patients in the general cohort (12.3, 6.57–23.04). Between 3 and 5 years post-index event, 104 (29.4%) IM patients had a diagnosis of constipation compared to 14 (4.0%) patients in the general cohort (7.43, 4.34–12.72), 58 (16.4%) IM patients had a diagnosis of abdominal pain compared to 15 (4.2%) patients in the general cohort (3.87, 2.23–6.69), and 75 (21.2%) IM patients had a diagnosis of nausea and vomiting compared to 25 (6.8%) patients in the general cohort (3.12, 2.02–4.83). Between 3 and 5 years post-index event, 34 (9.6%) IM patients had a diagnosis of diarrhea compared to 10 (2.8%) patients in the general cohort (3.4, 1.71–6.77) and 79 (22.3%) IM patients had a diagnosis of GERD compared to 10 (2.8%) patients in the general cohort (7.98, 4.16–15.00). Few prior studies have examined gastrointestinal symptoms after operative treatment, although some smaller-scale studies have been conducted.4, 7-9 Two studies found that a large majority of patients were symptom-free after having a Ladd procedure.2, 3 However, the symptoms and follow-up considered in these studies were ambiguous. Recently, one multicenter study and two larger-scale studies identified persistent gastrointestinal symptoms following operative treatment.1, 11, 12 However, prior research did not compare pediatric IM patients to a general pediatric cohort to determine if their rates of gastrointestinal symptoms are higher than what one would expect if they did not have IM and operative intervention. In the current work, we utilized an EMR database and presented the first large-scale study comparing the long-term gastrointestinal outcomes of pediatric patients with IM following operative intervention to a general pediatric population. The findings demonstrate the presence of higher rates of gastrointestinal symptoms post-index event for pediatric IM patients compared to a matched general pediatric cohort. Consistent with other studies that call for long-term follow-up for IM patients after operative treatment, an automatic gastroenterology referral or a coordinated care model may be important in helping to manage and treat these ongoing symptoms in pediatric IM patients.1, 4, 9 As such, the current data can inform the management strategy of physicians taking care of pediatric IM patients who have had operative treatment. This study has several limitations. The data only include diagnosed symptoms, and we cannot identify if they were chronic symptoms. Individuals may have such symptoms and not seek medical care for them, which may be the case for those who have recurring symptoms for extended periods of time. The results may also potentially overrepresent gastrointestinal issues, as only patients who had at least one medical visit at least 5 years after the index event were included. Since the data comes from aggregated medical records, there is no way to assess if a patient has no medical records 5 years later due to having no medical visits or due to having dropped out of the system. It seems unlikely for it to be the former as one might expect the majority of patients within the health system to have at least one medical visit of any kind ≥5 years after the index event. Gastrointestinal symptoms may also be overrepresented if diagnosed symptoms are carried over into future medical records through duplication despite resolution of those symptoms. Additionally, the general pediatric cohort may reflect a sicker population than a true baseline for pediatric patients, since they are drawn from a sample of those who had at least one medical visit followed by one other medical visit at least 5 years later. Because we examined a long-term follow-up period (5 years), the IM cohort's sample size is not large enough to stratify by age at surgery, volvulus, or new versus persistent GI symptoms postoperatively. Another limitation is that TriNetX's aggregate-level data cannot identify individual-level factors associated with an increased risk of experiencing postoperative gastrointestinal symptoms. To protect patient privacy, TriNetX rounds up to 10 any cell with between 1 and 9 patients. The general cohort gastrointestinal rates with a frequency of 10 may thus overestimate the rates and underestimate the differences between cohorts. Our findings demonstrate that a large group of pediatric IM patients experience gastrointestinal symptoms several years after operative treatment for IM, and that these rates are significantly higher than those of a propensity-matched general pediatric cohort. Given the substantial risk of gastrointestinal symptoms, all pediatric IM patients who undergo operative treatment should have routine gastroenterology follow-up in addition to the already recommended postoperative follow-up.1, 4, 9 These results also suggest that IM should be considered a chronic disease. This study was guided by members of the Intestinal Malrotation Patient and Clinician Team (IMPACT), a patient-centered and multidisciplinary group of intestinal malrotation patients, caregivers, clinicians, and researchers. Formation of IMPACT was funded through a Patient-Centered Outcomes Research Institute® (PCORI®) Eugene Washington Engagement Award (EACB-30046). The statements in this publication are solely the responsibility of the authors and do not necessarily represent the views of PCORI®, its Board of Governors, or Methodology Committee. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5U54GM104942-08 and by the Presbyterian Health Foundation under their New Investigator Seed grant mechanism (#20230274). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Cortney Ballengee Menchini, MD (West Virginia University School of Medicine); Darren Bodkin, MD (University of Oklahoma Health Sciences, Oklahoma Children's Hospital at OU Health); Scott C. Fligor, MD (Vascular Biology Program and the Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston); Thomas Hirsch, MD (Vascular Biology Program and the Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston); Mark Puder, MD (Vascular Biology Program and the Department of Surgery, Boston Children's Hospital, Harvard Medical School). The authors declare no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.