Optimal Timing for Soave Primary Pull-through in Short-Segment Hirschsprung Disease: A Meta-Analysis

Abstract

BACKGROUND:

The optimal age for endorectal pull-through (ERPT) surgery in infants with short-segment Hirschsprung disease varies, with a trend toward earlier surgery. However, it is unclear if the timing of surgery impacts functional outcomes. We undertook the present study to determine the optimal timing of ERPT in infants with short-segment Hirschsprung disease.

METHODS:

The NCBI PubMed database was searched for English-language manuscripts published between 2000–2019 analyzing functional outcomes for patient following the initial Soave ERPT for short-segment Hirschsprung disease. Raw data from these studies was obtained from the corresponding author for each manuscript. We combined data from these papers with our own institutional data and performed a meta-analysis.

RESULTS:

A total of 780 infants were included in our meta-analysis. Constipation occurred in 1.0–31.7%, soiling 1.3–26.0%, anastomotic stricture 0.0–14.6%, and anastomotic leak 0.0–3.4%. Regarding age at ERPT, younger infants at the time of initial corrective surgery had higher rates of soiling, stricture, and leak. On sub-group analysis, patients <2.5 months at their initial corrective surgery had higher rates of soiling (25.9% vs. 11.4%, p<0.01), as well as stricture (10.0% vs 1.7%, p<0.01) and leak (5.5% vs 1.3%, p<0.01).

CONCLUSION:

While age at Soave endorectal pull-through for short-segment Hirschsprung disease has decreased over time, functional outcomes associated with this trend have only recently been examined. Our findings suggest that patients <2.5 months old at the time of endorectal pull-through may have worse functional outcomes, emphasizing the need to consider further study of the timing of surgery in this population.

LEVEL OF EVIDENCE:

III

Hirschsprung disease (HSCR), which is characterized by the congenital absence of enteric ganglia along variable lengths of distal bowel, is treated by resection of the aganglionic segment. In his seminal report, Swenson described initial colostomy followed by proctocolectomy with coloanal anastomosis to treat short-segment HSCR (SS-HSCR), the most common form of the disease [1]. Later, Swenson recommended delaying the definitive surgery beyond four months of life based on his extensive experience and the high mortality associated with performing a pull-through procedure in younger infants [2]. Based on these recommendations, surgeons continued to defer the pull-through operation until the child was older, recommending repair at the age of 12–18 months [3] or at a weight of 20–30 pounds [4]. With increasingly earlier diagnosis of HSCR in infants [5], single-stage ERPTs began to be performed without a diverting enterostomy. So et al [6] described an experience with a primary Soave endorectal procedure in 20 neonates with SS-HSCR over a 10-year period and reported no mortality and good early outcomes. Carcassonne et al [7,8] treated neonates with daily irrigations at home and had them return for a single-stage pull-through procedure by the age of 3 months.

With heightened awareness of the disease, earlier diagnosis is established in the neonatal period in 80–90% of patients [9], and with improvements in surgery and anesthesia, ERPTs began to be performed at a younger age without a preliminary colostomy. Huang et al report that the median age of ERPT went from 6 months in 1997 to 1 month in 2006 [10]. Many surgeons currently perform ERPT surgery soon after diagnosis in order to increase the likelihood of a one-stage ERPT, and several studies report this approach is safe in newborns [11–13].

Unfortunately, bowel function after the pull-through procedure remains problematic for many patients with HSCR, with multiple studies showing high rates of impaired continence [14–16], increased stooling frequency [15], and diminished quality of life [15–18]. Despite these known complications, the evolution to early definitive surgery for SS-HSCR occurred without assessing long-term bowel function. It remains unknown whether the transition from a delayed to an early definitive operation has been associated with changes in functional outcomes.

Several recent studies have aimed to address the question of whether the timing of primary ERPT surgery for SS-HSCR is associated with functional outcomes. The results have varied, with some studies showing inferior outcomes in younger infants [19–21], others showing no association between outcomes with age at surgery [22,23], and one showing improved outcomes with younger age at ERPT [24]. With the goal of identifying an optimal age for ERPT surgery in infants with SS-HSCR, we performed a systematic review of the current literature and meta-analysis of the relevant studies with the addition of our institutional data to determine whether age at primary ERPT influences clinical outcomes.

1. Methods

1.1. Study Selection

We began this systematic review and meta-analysis by performing a review of the literature using PubMed and searched for the following keywords: age, Hirschsprung, and surgery. Articles from 2000–2019 were included. We excluded articles not related to HSCR and those in languages other than English. We selected both retrospective and prospective studies for which age at primary ERPT surgery and functional outcomes were available, while excluding case reports, non-clinical studies, and basic science articles. Relevant articles were reviewed by title, abstract, keywords, and then full text. Finally, we included only articles in which a Soave procedure was performed as the definitive procedure for SS-HSCR and for which functional outcomes were available (Fig. 1). The Soave operations included open, laparoscopic and mini sub-umbilical incisions for determining the level of aganglionosis and colorectal mobilization. We contacted the authors of the four studies that were included after the exclusions above. Each author provided the raw data for their patient cohort in a de-identified manner. The data from our institution, MassGeneral Hospital for Children (MGHfC), was added to the database.

Figure 1.

Flowchart of Inclusion and Exclusion Criteria.

1.2. Data Extraction

The following data were provided by each author for their respective study: year of publication, country, period of management, total number of patients who underwent ERPT surgery for SS-HSCR, surgical technique (open versus laparoscopic), age at ERPT surgery, age at follow-up, tools used to evaluate constipation and soiling, and outcomes of interest (constipation, soiling, post-ERPT Hirschsprung-associated enterocolitis (HAEC), anastomotic leak, and anastomotic stricture). Based on the data available from the prior studies and our series of patient, the age at ERPT and age at follow-up were categorized into subgroups for analysis. These included age at ERPT: 0–1.0 month, 1.1–2.4 months, 2.5–4.0 months, 4.1–8.0 months, 8.1–12.0 months; and age at follow-up: 0–12.0 months, 12.1–24.0 months, 24.1–36.0 months, 36.1–48.0 months, 48.1–60.0 months, 60.1–72.0 months, >72.0 months. Patients were then re-grouped into those younger and older than 2.5 months in order to analyze outcomes for constipation and soiling as well as rates of anastomotic stricture and leak across older and younger cohorts. The age of 2.5 months was determined based on the raw data received from all authors. This age cut-off is similar to other literature that used 2 months [25] and 3 months [26]. Finally, we excluded syndromic patients (Down Syndrome or other identified genetic syndromes) and patients who underwent ERPT surgery after 12 months of age, but not those who had an initial colostomy.

The variables of constipation, soiling, and postoperative HAEC were defined differently by each author. Miyano et al used a prospective questionnaire and caregiver interview records to assess postoperative bowel function. This included recording frequency of bowel movements, presence or absence of staining/soiling, frequency of perianal erosions, anal appearance, and medications required to assist in bowel movements. The authors do not discuss their definition of postoperative HAEC in their manuscript but were able to provide this data in their raw dataset [22]. Lu et al used the pediatric incontinence or constipation scoring system (PICSS) to assess for these outcomes between 33–36 months for all patients. Based on the PICSS, children who scored below the age-specific lower limit of the 95% confidence interval were considered to have incomplete continence or constipation. They defined postoperative HAEC according to the 2009 HAEC scoring system which consists of history, physical examination, radiologic and laboratory findings, with a total of 16 variables used for evaluation and scoring. Scores >10 were consistent with HAEC [20]. Chung et al [27] assessed their clinical outcomes using the seven-item bowel function score (BFS), a multivariate scoring system developed by Rintala et al [28] to assess several clinical outcomes including soiling and constipation. Soiling was scored by frequency and constipation was scored by management strategy (none, diet, laxatives, or enemas) [27]. Zhu et al. reported presence of constipation or soiling at 24 months after surgery. They defined postoperative HAEC as the presence of foul-smelling diarrhea, vomiting, or fever [19]. Finally, our institutional data was obtained by chart review. Constipation, soiling, and postoperative HAEC were recorded if their postoperative medical record included these diagnoses in the postoperative clinic visit and/or inpatient admission notes.

The collection of our institutional data was approved by the MGB Healthcare Institutional Review Board (IRB). The MGB IRB determined that our analysis of de-identified data from the other institutions did not qualify as human subjects research and was therefore deemed exempt.

1.3. Statistical Analysis

We performed a meta-analysis on all data from the four studies and the MGHfC patient database. Descriptive data were described as counts and percentages of total patients. Categorical variables were analyzed using the chi-square test and p<0.05 was statistically significant. All analyses were performed using Stata Statistical Software version 15.1 (StataCorp LP, College Station, TX).

2. Results

2.1. Study Characteristics

A total of 780 patients were included across five studies. The distribution of age at ERPT and age at follow-up by study is shown in Table 1. Reviewing all 780 patients, most were 2.5–4.0 months old (48.0%) at the time of ERPT, followed by patients 0–1.0 months (22.2%), 4.1–8.0 months (11.9%), 8.1–12.0 months (11.2%), and 1.1–2.4 months (6.8%). In terms of age at follow-up, the majority of patients were 24.1–36.0 months old (59.1%), followed by 12.1–24.0 months (20.0%), >72.0 months (7.2%), 0–12.0 months (4.7%), 36.1–48.0 months (4.1%), 48.1–60.0 months (3.1%), and 60.1–72.0 months (1.8%).

Table 1.

Study characteristics

Author	Type of Article	Year		Country	Number of Patients (N)	Age at ERPT (months) N (%)	Age at Follow-Up (months) N (%)
Miyano	RSC	2017	1997–2015	Japan	76	0–1.0: 22 (29.0%)	0–12.0: 1 (1.3%)
						1.1–2.4: 6 (7.9%)	12.1–24.0: 16 (21.1%)
						2.5–4.0: 11 (14.5%)	24.1–36.0: 8 (10.5%)
						4.1–8.0: 16 (21.1%)	36.1–48.0: 6 (7.9%)
						8.1–12.0: 21 (27.6%)	48.1–60.0: 6 (7.9%)
							60.1–72.0: 8 (10.5%)
							>72.0: 31 (40.8%)
Lu	RMC	2017	2005–2012	China	415	0–1.0: 112 (27.0%)	0–12.0: 0 (0.0%)
						1.1–2.4: 0 (0.0%)	12.1–24.0: 0 (0.0%)
						2.5–4.0: 303 (73.0%)	24.1–36.0: 415 (100%)
						4.1–8.0: 0 (0.0%)	36.1–48.0: 0 (0.0%)
						8.1–12.0: 0 (0.0%)	48.1–60.0: 0 (0.0%)
							60.1–72.0: 0 (0.0%)
							>72.0: 0 (0.0%)
Chung	RMC	2017	2003–2016	China	50	0–1.0: 8 (16.0%)	0–12.0: 0 (0.0%)
						1.1–2.4: 17 (34.0%)	12.1–24.0: 0 (0.0%)
						2.5–4.0: 19 (38.0%)	24.1–36.0: 1 (2.0%)
						4.1–8.0: 3 (6.0%)	36.1–48.0: 16 (32.0%)
						8.1–12.0: 3 (6.0%)	48.1–60.0: 12 (24.0%)
							60.1–72.0: 4 (8.0%)
							>72.0: 17 (34.0%)
Zhu	RSC	2019	2010–2015	China	198	0–1.0: 20 (10.1%)	0–12.0: 26 (13.1%)
						1.1–2.4: 20 (10.1%)	12.1–24.0: 123 (62.1%)
						2.5–4.0: 32 (16.2%)	24.1–36.0: 8 (4.0%)
						4.1–8.0: 65 (32.8%)	36.1–48.0: 0 (0.0%)
						8.1–12.0: 61 (30.8%)	48.1–60.0: 0 (0.0%)
							60.1–72.0: 0 (0.0%)
							>72.0: 0 (0.0%)
MGHfC	RSC	N/A	1994–2019	USA	41	0–1.0: 11 (26.8%)	0–12.0: 8 (19.5%)
						1.1–2.4: 10 (24.4%)	12.1–24.0: 9 (22.0%)
						2.5–4.0: 9 (22.0%)	24.1–36.0: 5 (12.2%)
						4.1–8.0: 9 (22.0%)	36.1–48.0: 8 (19.5%)
						8.1–12.0: 2 (4.9%)	48.1–60.0: 5 (12.2%)
							60.1–72.0: 1 (2.4%)
							>72.0: 5 (12.2%)

RSC: retrospective single-center, RMC: retrospective multicenter

2.2. Functional Outcomes

Functional outcomes and specific postoperative complications for which data were available were examined in each of the five studies (Table 2). The rate of constipation ranged from 1.0–31.7%, soiling ranged from 1.3–26.0%, and post-ERPT HAEC occurred in 5.3–26.0%. Anastomotic stricture was present in 0.0–14.6% and anastomotic leak, which occurred within a week after surgery, occurred in 0.0–3.4%.

Table 2.

Rates of outcomes by study

Author	Constipation N (%)	Soilirg N (%)	Post-ERPT HAEC N (%)	Anastomotic Stricture N (%)	Anastomotic Leak N (%)
Miyano	1 (1.3 %)	1 (1.3%)	4 (5.3%)	2 (2.6%)	0 (0.0%)
Lu	31 (7.5%)	85 (20.5%)	N/A	21 (5.1%)	14 (3.4%)
Chung	12 (24.0%)	13 (26.0%)	13 (26.0%)	N/A	N/A
Zhu	2 (1.0%)	10 (5.1%)	27 (13.6%)	0 (0.0%)	4 (2.0%)
MGHfC	3 (31.7%)	7 (17.1%)	9 (22.0%)	6 (14.6%)	0 (0.0%)

When comparing outcomes across age at ERPT, younger patients had higher rates of constipation, soiling, anastomotic stricture, and anastomotic leak (Table 3). Constipation occurred more frequently (18.4%) among patients who were 1.1–2.4 months old at the time of ERPT surgery (Fig. 2a). Soiling had a similar trend, with the highest rates occurring in the youngest cohorts: 27.5% in those 0–1.0 months old at time of ERPT and 20.4% in those 1.1–2.4 months old (Fig. 2b). Post-ERPT HAEC occurred at the highest rate among patients 1.1–2.4 months old (18.9%) at the time of their ERPT (Table 3). As shown in Table 3, anastomotic stricture and leak rates followed a similar trend, with younger patients experiencing both outcomes more often than older patients. Patients 0–1.0 months old had the highest rates of both stricture (10.4%) and leak (6.4%).

Table 3.

Analysis of outcomes across age groups

		Age at Endo-rectal Pullthrough
Outcome	0–1.0 Months (N=173) N (%)	1.1–2.4 Months (N=53) N (%)	2.5–4.0 Months (N=374) N (%)	4.1–8.0 Months (N=93) N (%)	8.1–12.0 Months (N=87) N (%)	p-value
Constipation	13 (7.6%)	9 (18.4%)	30 (8.2%)	5 (6.3%)	2 (2.7%)	0.04
Soiling	47 (27.5%)	10 (20.4%)	55 (15.0%)	1 (1.3%)	3 (4.1%)	< 0.01
Post-ERPT HAEC	5 (2.9%)	10 (18.9%)	17 (4.6%)	10 (10.8%)	11 (12.6%)	< 0.01
Anastomotic Stricture	18 (10.4%)	2 (3.7%)	7 (1.9%)	2 (2.2%)	0 (0.0%)	< 0.01
Anastomotic Leak	11 (6.4%)	0 (0.0%)	6 (1.6%)	1 (1.1%)	0 (0.0%)	< 0.01

Figure 2a.

Constipation Rates by Age at Endo-rectal Pullthrough. * denotes p<0.05

Figure 2b.

Soiling Rates by Age at Pull-through. * denotes p<0.05

2.3. Comparative Outcomes for Patients Younger and Older than 2.5 Months of Age

Following analysis of the data above, patients were divided into two cohorts based on whether they were younger or older than 2.5 months of age at the time of their ERPT surgery. Patients younger than 2.5 months old had a significantly higher rate of soiling (p<0.01) while the rate of constipation was not statistically different (Fig. 3a). The rates of anastomotic stricture and leak were both significantly higher in patients less than 2.5 months old (Fig. 3b).

Figure 3a.

Constipation and Soiling Rates in Patients Younger and Older than 2.5 Months of Age. * denotes p<0.05

Figure 3b.

Anastomotic Stricture and Leak Rates in Patients Younger and Older than 2.5 Months of Age. * denotes p<0.05

3. Discussion

Functional outcomes are problematic after pull-through surgery for HSCR. Numerous studies have examined long-term results and identified high rates of fecal soiling, constipation, and stooling frequency as compared to controls [14,15,18,29], with major associated impact on social morbidity [16]. Recent publications have investigated factors impacting functional outcomes and found that age at the time of ERPT surgery is one such factor. One study showed that age at ERPT was not correlated with inferior outcomes [22] while others concluded that patients undergoing ERPT as neonates had worse postoperative functional results than those undergoing surgery later in life [20,30]. Huang et al concluded that age <2 months at ERPT was a risk factor for early incontinence, late incontinence, and constipation, but was not a risk factor for HAEC or anastomotic stricture [25]. Sun et al compared outcomes between patients older and younger than 3 months of age at the time of ERPT and found that perianal erosion, enterocolitis, and soiling were more common in younger patients [26]. Interestingly, despite these findings, a survey of pediatric surgeons in Europe found that most respondents (87.5%) performed ERPT surgery before 3 months of age [31].

Combining raw data from four previously published studies and our own patient cohort allowed us to perform a meta-analysis of 780 children who underwent ERPT surgery as infants, representing the largest study yet to address this question. Our results suggest that performing ERPT in younger infants is associated with an increased rate of the postoperative complications examined, including soiling, anastomotic stricture, and leak. Choosing an age of 2.5 months as a cutoff, statistically significant differences were found in the outcomes of each of these endpoints, with the older group consistently doing better.

The observation of a potential relationship between age at ERPT and clinical outcomes raises the intriguing question of why younger infants may fare more poorly after ERPT surgery. Given the more delicate and smaller structures in neonates and young infants, the anal sphincter mechanism, pelvic floor, or pelvic nerve plexuses may be more prone to injury through transection or stretching. Other technical factors yet to be identified may also contribute. For example, Miyano et al, whose data are included in the current study, found no age-based difference in outcomes, possibly reflecting their technical approach. Miyano et al started their mucosal dissection just proximal to the anorectal line, rather than relative to the dentate line, in order to ensure preservation of the anal transitional zone [9,22]. Another possibility is that pathological identification of normal ganglion cells may be more challenging in younger infants, although this question has not been addressed in the literature.

While our findings suggest that waiting a few months before surgery may be beneficial when considering long-term bowel function, this requires either that the child be diverted or that the caregivers are able to successfully evacuate the colon by performing anal dilations and/or colonic irrigations daily. If the colon cannot be evacuated effectively, either ERPT or diversion is mandatory at a young age. Our present study does not address patients with long-segment HSCR, who often cannot be effectively evacuated by irrigation and thus cannot have surgery delayed.

While our findings raise important questions, we acknowledge several important limitations. These include the relatively short follow-up as well as the variable duration of follow-up, potentially biasing against children who had surgery at an earlier age and may therefore have been followed longer and thereby more likely to experience a complication. In addition, and like much of the current literature, the included studies vary in their definitions of constipation and soiling. Another challenge exists in assessing soiling prior to toilet training and in distinguishing frequent bowel movements from pathologic soiling in young children. Our inability to follow-up with patients after they completed toilet training is another limitation, given that the raw datasets we analyzed do not track age at toilet training. Additionally, we were unable to include HAEC in the final analysis due to the variable criteria used for its diagnosis, a common problem with studies on this condition and in this type of meta-analysis. We also do not know the exact age at diagnosis for each patient, and it is possible that a patient who presents earlier in life may have a different and/or more severe disease phenotype from one presenting later in infancy. Moreover, detailed pathology data, such as the precise length of aganglionosis, are not available to us. Future, large-scale studies should include pathological findings to compare outcomes based on this factor. Finally, while we limit the inclusion criteria to children undergoing Soave ERPT, surgical techniques vary among the included studies and these variations may impact outcomes.

Overall, multiple studies examining long-term outcomes after ERPT surgery for HSCR have confirmed that functional results are not optimal. Our current systematic literature review and meta-analysis suggests that the timing of ERPT surgery represents one factor that impacts outcomes. However, why younger age at time of surgery is associated with poorer outcomes is unknown. Surgeons should be aware of these results and be cautious when performing an ERPT operation in the neonatal period or in very early infancy. Further studies implementing a standardized assessment tool for postoperative outcomes after ERPT for SS-HSCR are warranted to validate our findings and to understand what other factors contribute to clinical outcomes.

4. Conclusions

Over the previous three decades the age at ERPT for SS-HSCR has decreased, but postoperative functional outcomes remain suboptimal, which is likely multifactorial. Our study suggests one factor may be performing the definitive procedure in infants younger than 2.5 months and that delaying primary ERPT until later in infancy may improve these outcomes. To validate our findings, multicenter prospective studies are needed to follow SS-HSCR patients after ERPT surgery with standardized bowel function assessment tools and rigorous long-term follow-up.