Clinical Impacts of Delayed Diagnosis of Hirschsprung’s Disease in Newborn Infants

Background:Asian infants are at a higher risk of having Hirschsprung’s disease (HD). AlthoughHD is surgically correctable, serious and even lethal complications such as Hirschsprung’sassociated enterocolitis (HAEC) can still occur. The aim of this study was to investigate the riskfactors of HAEC, and the clinical impacts of delayed diagnosis of HD in newborn infants.Patients and methods:By review of medical charts in a medical center in Taiwan, 51 cases ofneonates with HD between 2002 and 2009 were collected. Patients were divided into twogroups based on the time of initial diagnosis: Group I, diagnosis made within 1 week after birth,and Group II after 1 week. Clinical features including demographic distribution, presentingfeatures of HD, short-term and long-term complications related to HD were compared betweenthe two groups of patients.

Results:There were 25 patients in Group I and 19 in Group II. Group II patients had more severeclinical signs and symptoms of HAEC than Group I patients. The incidence of preoperative HAECwas 12% in Group I and 63% in Group II (adjusted odds ratioZ12.81, confidenceinterval=2.60-62.97). Patients with preoperative HAEC were more likely to develop adhesive bowel obstruction after operation (33% vs. 3%,p=0.013) and failure to thrive (33% vs.3%,p=0.013). Also, patients with long-segment or total colonic aganglionosis were at riskof developing both postoperative HAEC (85% vs. 29%,p=0.001) and failure to thrive (39%vs. 3%,p=0.002).

Conclusion:In our study, we found that delayed diagnosis of HD beyond 1 week after birthsignificantly increases the risk of serious complications in neonatal patients. Patients withlong-segment or total colonic aganglionosis have higher risk of postoperative HAEC and failure to thrive. Patients with preoperative HAEC are more likely to have adhesive bowel obstructionand failure to thrive.

Copyright©2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rightsreserved.

1. Introduction

Hirschsprung’s disease (HD) is a congenital bowel motilitydisorder which occurs in approximately one of every 5000live births. It appears to have a complex genetic predisposition, and the incidence of HD has been reported to behigher in Asian infants as compared to infants from otherethnic origin.1,2Hirschsprung disease’s is caused by arrestof craniocaudal migration of neural crest cells (precursorsof colonic ganglion cells) during the fifth to 12thweeks ofgestation.3Unlike other congenital structural anomalies,HD does not cause any recognizable clinical featuresprenatally. With timely diagnosis, most affected childrennow can lead a normal and productive life with recentadvances in understanding of its pathogenesis andimprovement in surgical management. However, patientswho have HD can still develop life-threatening bowelobstruction, colonic perforation, sepsis, or severe diarrheaand dehydration before surgery. These complications werefirst recognized by Swenson and Fisher in 1956, and laterdescribed in detail by Bill and Chapman in 1962.4Caneiroand coworkers further defined Hirschsprung’s-associatedenterocolitis (HAEC) as a distinct clinical syndrome offever, diarrhea, abdominal distension, colicky pain, lethargy and passage of bloody stool.5Even today, HAECremains the major cause of serious morbidity and mortalityin HD.

Although HD typically presents in the newborn period, itcan occasionally be diagnosed in older children or adults.Those presenting beyond neonatal period usually are ofmilder forms. Previous studies have suggested that HAECoccurs more often in patients whose diagnosis of HD isdelayed2and that delayed diagnosis is also associated withpoorer long-term outcomes.6,7However, these studiesinvolved only older children. Correlation of timely diagnosisand disease outcome has not been studied in newborninfants with HD and bowel obstruction. The purpose of thepresent study aimed to investigate clinical impact ofdelayed diagnosis in newborn infants with HD and how itwould affect their outcome.

2. Methods

2.1. Patients and clinical characteristics

This was a study of case series performed by retrospectivechart review. We enrolled those patients who wereadmitted to the neonatal intensive care unit of Chang GungChildren’s Hospital with the diagnosis of HD by 60 days afterbirth during the period from January 2002 to December2009. Patients who declined treatment in this hospital orhad additional gastrointestinal anomalies were excluded.

The patients were divided into two groups based on thetime of diagnosis. In this report, the term “time of diagnosis” refers to the time of the patient being recognized ashaving or at which was diagnosed presumptively andmanaged accordingly. Those who were diagnosed within 1week of age were categorized as Group I, and those diagnosed beyond 1 week of age as Group II. Relevant clinicalfeatures including demographic data, age of diagnosis,level of aganglionosis segment, family history of HD, association with trisomy 21, history of delayed passage ofmeconium (beyond 48 hours of age) or constipation(subjective complaint from care taker), as well as symptoms related to HAEC, including foul-smelling diarrhea,bloody stool, abdominal distention, fever, vomiting, shock,dehydration (body weight loss more than 10% of birthweight), leukocytosis (>20,000 cells/mm3), elevated Creactive protein (CRP) level (>14 mg/dL) and colonicperforation8were reviewed.

2.2. Preoperative and postoperative complications

We investigated occurrence of preoperative and postoperative complications between the two groups. Patientswith HD who developed any one of the symptoms of foulsmelling diarrhea, bloody stool or fever were thought tohave enterocolitis (HAEC).9-11Preoperative complicationsincluded blood culture-proven sepsis, preoperative HAECand perforation. Postoperative complications includedpostoperative HAEC, adhesive bowel obstruction, anastosmosis leakage, anal stenosis due to stricture formation,anal excoriation, enterocutaneous fistula, constipation thatneeded treatment with laxatives and failure to thrive(weight for age less than third percentile). We also lookedinto the existence of risk factors that have been linked toHAEC, such as trisomy 215,7,9,12-14and HD with long segment(long-segment or total colonic) of aganglionosis.6,8,15-17Correlation between preoperative HAEC, level of aganglionosis, and development of postoperative complicationswere also examined.

2.3. Statistical analysis

The unpaired Studentttest was performed to examine thedifferences between demographic and clinical characteristics in the groups. Significance of differences in categorical values was analyzed using theX2test. Fisher’s exactprobability test was applied when examining variables oflow incidence. The logistic regression and odds ratio wasused to estimate possible correlations between analyzedfactors and the incidence of complications. All statisticalanalyses were completed using Predictive Analytics Software (PASW) Statistics 18 (IBM, Armonk, NY, United States),andp<0.05 was considered statistically significant.

3. Results

3.1. Demographic data and clinical characteristicsof patients

There were a total of 51 infants diagnosed with HD duringthe study period. However, the families of five patientsdeclined treatment in this hospital and these patients weredischarged without intervention. Two infants had othergastrointestinal anomalies (one had ileal atresia, and theother had intestinal malrotation and imperforate anus).Among the remaining 44 patients, 25 had HD diagnosedwithin 1 week of age in Group I, and 19 were diagnosedbeyond 1 week of age in Group II. Demographic distributions of the two groups were similar (Table 1). In bothgroups of HD patients, there was a higher proportion (88% inGroup I, 80% in Group II) of male than female. Meangestational age at birth was 38.4
1.4 weeks in Group I and38.0
2.7 weeks in Group II. Mean birth weight was3194
304 g in Group I and 3066613 g in Group II. Twopatients had trisomy 21, one in each group. None of thepatients had family history of previous HD. The distributionof levels of aganglionosis was similar: 76% rectosigmoid,12% long segment and 12% total colonic aganglionosis inGroup I, and 63% rectosigmoid, 11% long segment and 26%total colonic aganglionosis in Group II (pZ0.475). Only 28%of patients in Group I and 32% in Group II had the clinicalsymptom of delayed passage of meconium after birth. Theincidence of constipation before diagnosis of the diseasewas similar in Groups I and II (52% vs. 53%).

Table 2 shows the clinical presentations of preoperativeHAEC. The most common presentations of HAEC wereelevated CRP level, foul-smelling diarrhea, bilious vomiting, fever, and dehydration. Comparing Group I with GroupII patients, those in Group II (with delayed diagnosis of HD)were more likely to present with serious systemic symptomswhen they developed HAEC: shock, 0% versus 25%; dehydration, 0% versus 58%; leukocytosis, 0% versus 25%; andelevated CRP levels, 67% versus 92%. No infants with early diagnosis in Group I were in shock, and none in either group had colonic perforation.

3.2. Diagnosis of HD

In this study, 36 patients received contrast enema (lowergastrointestinal, LGI) study. However, LGI studies failed tomake the diagnosis of HD in nine of the 36 (25%) patients. Inthese nine patients, six were diagnosed as meconium plugsyndrome and three were diagnosed as ileus. Forty patientsreceived rectal suction biopsy before surgery. Five of thebiopsies (13%) failed in making a diagnosis of HD because ofinadequate sampling of the specimen and needed secondbiopsy to confirm HD.

3.3. Preoperative and postoperative complications

Comparison of the risks of developing preoperative andpostoperative complications between the two groups isshown inTable 3. Risk of preoperative sepsis was 4% inGroup I and 16% in Group II (pZ0.3), and risk of preoperative HAEC was 12% in Group I and 63% in Group II(pZ0.000). Although the chance of having various postoperative complications seemed higher in Group II, thedifference did not reach statistical significance. Whenexamining the risk factors associated with preoperativeHAEC, impacts from other possible confounding elements,i.e., trisomy 21 and level of aganglionosis, were adjusted.The adjusted odds ratio of having preoperative HAEC inGroup II infants (HD diagnosed beyond 1 week of age) was12.81 (confidence interval: 2.60-62.97).

Table 4depicts the association of preoperative HAECwith various postoperative complications. In the presenceof preoperative HAEC, there were increased risks forpostoperative adhesion bowel obstruction (33% vs. 3%,p=0.013) and failure to thrive (33% vs. 3%,p=0.013). Inregard to the impact of length of the aganglionosis segmenton the postoperative complications, longer length of thediseased segment (long-segment or total colonic HD) wasassociated with increased risk of postoperative HAEC (85%vs. 29%,p=0.001) and failure to thrive (39% vs. 3%,p=0.002), when compared to short-segment HD.

4. Discussion

Clinical presentations of HAEC range widely, from mildlyabdominal distension with no systemic manifestations; tolife-threatening conditions such as severe dehydration,shock and sepsis. Our study showed that infants with HDhave high risk of presenting with the most severe symptomsof HAEC during neonatal period, and HAEC is more likely tooccur in infants whose diagnosis of HD is made beyond 1week of age. In our study, compared to diagnosis madewithin 7 days after birth, delayed diagnosis put neonatalpatients with HD at a 13-fold increased risk for HAEC beforesurgery. Our findings demonstrated an overall incidence ofpreoperative HAEC of 34%, while 47% of the neonates presented with severe dehydration, 27% with sepsis, and 20%with shock.

When Teitelbaum et al. defined the term Hirschsprung’sassociated enterocolitis (HAEC), they also identifieddelayed diagnosis beyond 1 week, and the presence oftrisomy 21 as significant risk factors for HAEC.9In our study,delayed diagnosis of HD was shown to be an independentrisk factor for the development of HAEC in the preoperativeperiod. Two of the 51 patients (4%) with HD had trisomy 21in this case series. With the small case number in this study,we were unable to distinguish if trisomy 21 was a risk factorto HAEC, as some other earlier studies had also suggested.7,13,18However, it reiterates the fact that infantswith intestinal stenosis have high likelihood of havingtrisomy 21.

As for the correlation to postoperative complications,although we did not find direct associations betweendelayed diagnosis of HD and the postoperative complications, our results revealed that postoperative complications, specifically adhesive bowel obstruction and failure tothrive, are associated with the presence of preoperativeHAEC. Our study also showed that long-segment or totalcolonic aganglionosis are independent risk factors to postoperative HAEC and failure to thrive, as previous studieshad demonstrated.

So far, the pathogenesis of HAEC is still unclear, and itsetiology could be multifactorial. Mechanical obstruction,abnormal mucin production, decreased secretion ofimmunoglobulin A (IgA), and dysfunction in white bloodcells have all been proposed to explain the development ofHAEC.19For example, the longer aganglionosis impliesa greater proximal obstruction and a more extensiveimpairment of the bowel immune system, which in turnleads to higher susceptibility of intestinal stasis andbacterial production, whereas early recognition or diagnosis of this condition with prompt rectal or stomydecompression can relieve intestinal stasis and reducebacterial overgrowth with time.

The 34% incidence of preoperative HAEC in this study ishigher than those of other previous reports.10,19This mightbe attributed to the fact that the majority of our neonatalintensive care unit patients were referred from local clinicsor regional hospitals, and in the cases of HD, usually afterthey developed significant signs and symptoms of HAEC. Infact, all but two of our 15 patients with severe preoperativeHAEC were referred to this medical center under theimpression of sepsis, shock, or severe enterocolitis withdehydration. This unfortunate phenomenon attested to ourconcern about lack of awareness of HD among today’spediatricians. Advances in fetal ultrasonographic examination have aided in the precisein uterodiagnosis of many

major congenital surgical diseases. As a result, clinicianscaring for newborn infants have gradually relied more onthe obstetrician’s prenatal findings and lost vigilance in therecognition of those congenital surgical conditions.However, distal bowel obstruction from ganglion celldisorder seldom causes any features that could be identi-fied by fetal sonogram. In addition, patients with HD mayonly have subtle symptoms and develop enterocolitis asinitial presentation.

“Delayed passage of meconium” has been emphasized asan early sign indicating presence of HD in newborn infants.However, although nearly all neonates pass meconiumwithin 48 hours of life, only 60e90% of neonates with HDfail to pass meconium in that time period.Furthermore,neonates with HD may also pass meconium within 48 hoursafter birth. We noted that only 30% of patients with HD hadhistory of delayed meconium passage in our study. As forthe presentation of constipation, another symptom thatshould arouse clinicians to the diagnosis of HD, is just asdifficult to perceive or define during the neonatal period.

The current gold standard in the diagnostic confirmationof HD is histopathologic findings based on rectal suctionbiopsy,22although contrast enema study (LGI series) isusually performed to decide whether a suction biopsy isindicated. The sensitivity and specificity of rectal suctionbiopsy are reported to be 97-100% and 99-100%, and ofcontrast enema study 65-80% and 66-100%, respectively.There are pitfalls in both studies leading to false-negativeresults. Inadequate biopsy sites or tissue amounts impairthe reliability of rectal suction biopsy, whereas the contrastenema study might be misleading if patients with HD alsohad meconium plug in colon. Scott et al. reported 10-38%incidence in the association of meconium plug syndromewith HD. In this study, 12 out of 44 patients (29%) with HDwere found to have meconium plug in their colon, and six ofthese 12 infants failed to be recognized as having HDradiographically. It needs to be reemphasized that oneshould be careful in interpretation of LGI study results,since the the presence of meconium plug may mask theradiologic features of HD, and HD may be the cause ofmeconium plug.

In conclusion, our study showed delayed diagnosis of HDin newborn infants not only increases serious morbidities inthe neonatal period, but also indirectly affects their longterm outcome. Clinicians need to be vigilant in the recognition of HD in newborn infants and provide appropriatecare accordingly, to prevent the detrimental complications.