Congenital gastrointestinal malformations are more common in children with Down syndrome (DS) (prevalence 3-13%) than in children without Down syndrome (prevalence 15 per 10.000 live and still births) and are associated with serious morbidity and mortality (Bermudez 2019, Lagan 2020, Marilyn 2022). According to the European Prevalence charts and tables the overall prevalence of congenital gastrointestinal malformations is rather stable in the period 2005-2022. The most common disorders include esophageal atresia/tracheoesophageal fistula (0.3-0.8%), pyloric stenosis (0.3%), duodenal stenosis/web/atresia (1-5%), Hirschsprung’s Disease (HD) (1-3%), and anal stenosis/atresia (1-4%) (Ravel 2020). These conditions are surgically treated and are associated with several (post-surgical) complications, including feeding problems, obstipation, and enterocolitis. Because of the severe impact on the children’s health, it is important to map the risk of post-surgical complications, in order to better understand the consequences of gastrointestinal disorders and surgery in children with Down syndrome and improve awareness for clinicians.

1. Children who have undergone a gastrointestinal surgery for HD

Table 9. Summary of Findings – Down Syndrome versus no Down Syndrome with outcomes enterocolitis, mortality, toxic megacolon, other abdominal complications, constipation, incontinence, soiling, and feeding difficulties

Population: Children with Hirschsprung’s disease who have undergone a gastrointestinal surgery

Intervention: Down Syndrome

Comparator: No Down Syndrome

1. _{Risk of Bias: very serious (-2 levels). Inclusion criteria and exclusion criteria were not always clearly defined, demographic information was missing for some studies, loss to follow-up was not always clearly reported, the outcome was not always clearly and consistently defined, and confounders were not taken into account. Imprecision: serious (-1 level). Confidence interval crosses one border of clinical significance;}
2. _{Risk of Bias: very serious (-2 levels). Inclusion criteria and exclusion criteria were not always clearly described, demographic information was not always reported, loss to follow-up was not always clearly reported, and confounders were not assessed. Imprecision: serious (-1 level). The confidence interval is very wide;}
3. _{Imprecision: very serious (-2 levels). The confidence interval crosses overlaps both borders of clinical significance.}
4. _{Risk of Bias: very serious (-2 levels). Inclusion criteria and exclusion criteria were not always clearly described, loss to follow-up was not always clearly reported, outcome measures were not always clearly defined, and no confounders were assessed. Imprecision: serious (-1 level). The confidence interval crosses one border of clinical significance;}
5. _{Risk of Bias: very serious (-2 levels). Inclusion criteria and exclusion criteria were not always clearly described, loss to follow-up was not always clearly reported, outcome measures were not always clearly defined, and no confounders were assessed. Imprecision: serious (-1 level). Confidence interval crosses one border of clinical significance;}
6. _{Risk of Bias: very serious (-2 levels). Inclusion criteria and exclusion criteria were not clearly described, loss to follow-up was not clearly reported, outcome measures were not always clearly defined, and no confounders were assessed. Imprecision: serious (-1 level). The confidence interval is very wide;}

_{* Balela (2023) defined other abdominal complications as postoperative persistent obstructive symptoms: abdominal distension, bloating, borborygmi, vomiting, or severe constipation following pull-through}

2. Children who have undergone a gastrointestinal surgery for congenital duodenal obstruction

Table 10. Summary of Findings – Down Syndrome versus no Down Syndrome with outcomes mortality, enterocolitis, toxic megacolon, other abdominal complications, feeding difficulties, constipation, incontinence, and soiling

Population: Children with congenital duodenal obstruction who have undergone a gastrointestinal surgery

Intervention: Down Syndrome

Comparator: No Down Syndrome

1. _{Risk of Bias: very serious (-2 levels). Inclusion criteria and exclusion criteria were not always clearly described, loss to follow-up was not always clearly reported, and confounders were not always assessed;}
2. _{Risk of Bias: very serious (-2 levels). Complications were not clearly (pre-)defined, and no confounders were assessed. Imprecision: very serious (-2 levels). Confidence interval crosses both borders of clinical significance}
3. _{Risk of Bias: very serious (-2 levels). Loss to follow-up was not clearly reported, and no confounders were assessed.}

Description of studies

A total of 13 studies were included in the analysis of the literature. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables.

Hackam (2003) conducted an observational study in children with Hirschsprung’s disease (HD) undergoing surgery between 1 January 1995 and 31 December 2000. Children with a diagnosis of HD were included in this study. Exclusion criteria were having undergone surgery for HD at another institution or before the study period and having total colonic disease.

Morabito (2006) conducted an observational study in children with HD undergoing surgery between January 1990 and December 2006. Patients with confirmed Down syndrome and total colonic aganglionosis were included in this study. No exclusion criteria were defined.  

Travassos (2011) conducted an observational study in children with HD undergoing surgery between March 1987 and August 2008. No further inclusion criteria and exclusion criteria were defined.

Menezes (2005) conducted an observational study in children with HD undergoing surgery between 1975 and 2003. No further inclusion criteria and exclusion criteria were defined.

Pini Prato (2019) conducted an observational study in children with HD undergoing surgery between January 1994 and December 2017. Inclusion criteria were HD diagnosis confirmed by an expert pathologist based on histochemistry on rectal suction biopsy or on histochemistry and histology on resected specimen, and Down syndrome confirmed at postnatal karyotype. Exclusion criteria were lack of data regarding extent of aganglionosis, surgery and/or outcome measures, and patients who are not being regularly followed up in the dedicated outpatient clinic.

Niramis (2010) conducted an observational study in children undergoing surgery for congenital intrinsic duodenal obstruction (CIDO) between 1997 and 2006. Additionally, they divided the groups of children with and without DS in children with and without congenital heart disease (CHD). No further inclusion criteria and exclusion criteria were defined.

Bethell (2020) conducted an observational study in children undergoing surgery for congenital duodenal obstruction (CDO) between 1 March 2016 and 1 March 2017. Inclusion criteria were live born cases of congenital occlusion or narrowing of the duodenum associated with atresia, stenosis, duodenal web, or annular pancreas, presenting prior to a post-conceptual age of 44 completed weeks, having undergone operative repair, and having a diagnosis of Down Syndrome or no other detected chromosomal abnormality. Exclusion criteria were cases of duodenal occlusion or narrowing caused by congenital bands associated with malrotation, intestinal volvulus, duplication cyst, or malignancy without an intrinsic duodenal abnormality.

Balela (2023) conducted an observational study in children with HD undergoing surgery between January 2017 and January 2022. Inclusion criteria were a diagnosis of HD, age <18 years, and undergoing a pull-through surgery at. Exclusion criteria were deceased patients and incomplete medical records.

Kwendakwema (2016) conducted an observational study in children with HD undergoing surgery between 2000 and 2015. A diagnosis of HD was the only inclusion criterion. Exclusion criteria were chromosomal anomalies other than trisomy 21 and patients with missing data.

Le-Nguyen (2019) conducted an observational study in children with HD undergoing surgery between January 1990 and December 2017. Exclusion criteria were children with early deaths owing to severe and complex malformations (mostly cardiac), patients with incomplete information about enterocolitis, and patients with missing data.

Surena (1994) conducted an observational study in children with HD undergoing surgery between 1975 and 1992. No further inclusion and exclusion criteria were defined.

Sakurai (2020) conducted an observational study in children with HD undergoing surgery between 2004 and 2018. Exclusion criteria were having undergone surgery in other hospitals, children on parenteral nutrition without radical surgery due to severe extensive aganglionosis, and children who underwent radical surgery at over one year of age.

Singh (2004) conducted an observational study in children with congenital duodenal obstruction who were diagnosed between January 1991 and April 2002 and underwent surgery. Exclusion criteria were patients with extrinsic duodenal obstruction caused by peritoneal bands or annular pancreas.

Results

1. Enterocolitis

Eight studies reported the outcome enterocolitis, all in children with HD. The results are presented in Table 3. A pooled RR of 1.42 (95% CI 1.01 to 1.99) was calculated, meaning that Down syndrome is associated with a higher risk of postoperative enterocolitis, when compared to no Down syndrome. This is considered a clinically relevant difference between the two groups. The results are also shown in Figure 1. 

Table 3. Postoperative enterocolitis in children with HD: DS versus no DS

_{1The difference between the groups is clinically relevant}

Figure 1. Forest plot of postoperative enterocolitis in children with HD: DS versus no DS

2. Mortality

Seven studies reported the outcome mortality, four in children with HD, and three in children with congenital duodenal obstruction. Cause of death was not always reported, but was often not directly related to surgery.

2.1. Children who have undergone a gastrointestinal surgery for HD

The results are presented in Table 4. A pooled RR of 9.68 (95% CI 3.06 to 30.60) was calculated, meaning that DS is associated with a higher risk of mortality, when compared to no DS. This is a clinically relevant difference between the two groups. The results are also shown in Figure 2.  

Table 4. Mortality in children with HD: DS versus no DS

_{1The difference between the groups is clinically relevant}

Figure 2. Forest plot of mortality in children with HD: DS versus no DS

2.2 Children who have undergone a gastrointestinal surgery for congenital duodenal obstruction

Niramis (2010), Bethell (2020), and Singh (2004) examined mortality in children with congenital duodenal obstruction. The results are presented in Table 5. A pooled RR of 3.05 (95% CI 1.85 to 5.01) was calculated, meaning that DS is associated with a higher risk of mortality, when compared to no DS. This is a clinically relevant difference between the two groups. The results are also shown in Figure 3.  

Table 5. Mortality in children with congenital duodenal obstruction: DS versus no DS

_{1The difference between the groups is clinically relevant}

Figure 3. Forest plot of mortality in children with congenital duodenal obstruction: DS versus no DS

Subgroup of children with congenital heart disease (CHD)

Niramis (2010) additionally examined mortality in a subgroup of children with CHD. 18 of 49 children (37%) of children with DS died during follow-up, compared to 11 of 25 children (44%) without DS, RR = 0.83 (95% CI 0.47 to 1.49). This is not a clinically relevant difference between the groups.

Subgroup of children without congenital heart disease (CHD)

Niramis (2010) also evaluated mortality in a subgroup of children without CHD. 10 of 37 children (27%) with DS died during follow-up, compared to 5 of 116 children (4%) without DS, RR = 6.27 (95% CI 2.29 to 17.18). This is a clinically relevant difference between the groups.

3. Toxic megacolon

No evidence was found for the outcome toxic megacolon.

4. Other abdominal complications
Two studies reported the outcome other abdominal complications. Balela (2023) assessed persistent obstructive symptoms in children with HD, and Singh (2004) evaluated complications in children with congenital duodenal obstruction. 

4.1 Children who have undergone a gastrointestinal surgery for HD

Balela (2023) reported that 2 of 5 children (40%) in the DS group experienced persistent obstructive symptoms, compared to 23 of 109 children (21%) in the no DS group, RR = 1.90 (95% CI 0.61 to 5.89) and OR = 2.49 (95% CI 0.39 to 15.81). After adjusting for type of surgery, sex, age at surgery, aganglionosis type, and global developmental delay, OR = 2.63 (95% CI 0.38 to 18.08). This is a clinically relevant difference.

4.2 Children who have undergone a gastrointestinal surgery for congenital duodenal obstruction

Singh (2004) reported that 2 of 28 children (7%) in the DS group experienced complications, compared to 5 of 48 children (10%) in the no DS group, RR = 0.69 (95% CI 0.14 to 3.30). This is considered a clinically relevant difference between the groups.

5. Constipation

Five studies reported the outcome constipation, all in children with HD. The results are presented in Table 6. A pooled RR of 1.44 (95% CI 1.13 to 1.82) was calculated, meaning that DS is associated with a higher risk of constipation, when compared to no DS. This is a clinically relevant difference between the two groups. The results are also shown in Figure 4.  

Table 6. Constipation in children with HD: DS versus no DS

_{1The difference between the groups is clinically relevant}

Figure 4. Forest plot of constipation in children with HD: DS versus no DS

6. Incontinence and soiling

Incontinence
Four studies reported the outcome incontinence, all in children with HD. The results are presented in Table 7. A pooled RR of 2.13 (95% CI 1.10 to 4.12) was calculated, meaning that DS is associated with a higher risk of incontinence, when compared to no DS. This is a clinically relevant difference between the two groups. The results are also shown in Figure 5.  

Table 7. Incontinence in children with HD: DS versus no DS

_{1The difference between the groups is clinically relevant}

Figure 5. Forest plot of incontinence in children with HD: DS versus no DS

Soiling
Two studies reported the outcome soiling, both in children with HD. The results are presented in Table 8. A pooled RR of 4.25 (95% CI 2.23 to 8.10) was calculated, meaning that DS is associated with a higher risk of incontinence, when compared to no DS. This is a clinically relevant difference between the two groups. The results are also shown in Figure 6.  

Table 8. Soiling in children with HD: DS versus no DS

_{1The difference between the groups is clinically relevant}

Figure 6. Forest plot of soiling in children with HD: DS versus no DS

7.  Feeding difficulties

Having achieved full enteral feeds

One study in children with congenital duodenal obstruction reported the outcome feeding difficulties. Bethell (2020) reported that 0 of 20 children (0%) in the DS group had not achieved full enteral feeds 1 year post-surgery, compared to 1 of 44 children (2%) in the no DS group, RR = 0.71 (95% CI 0.03 to 16.81). This is a clinically relevant difference between the groups.

A systematic review of the literature was performed to answer the following question(s):

What is the risk of complications in children with DS undergoing a gastrointestinal surgery?

Table 1. PICO

Relevant outcome measures

The guideline panel considered enterocolitis, mortality and toxic megacolon as critical outcome measures for decision making; and constipation, incontinence and soiling, feeding difficulties, and other abdominal complications as important outcome measures for decision making.

The guideline panel defined a difference of 25% (0.8 ≥ RR ≥ 1.25) as minimal clinically (patient) relevant difference.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 8 May 2024. The detailed search strategy is listed under the tab ‘Literature search strategy’. The systematic literature search resulted in 453 hits. Studies were selected based on the following criteria: fitting PICO, published in 1990 or later, systematic reviews and or meta-analyses, RCTs, comparative observational studies. 23 studies were initially selected based on title and abstract screening. After reading the full text, 13 studies were excluded (see the table of excluded studies), and 10 studies were included. Three studies included in the review of Zhang (2023) were additionally included (Le-Nguyen, 2019; Sakurai, 2020; Surena, 1994).