A Systematic Review of Secretin for Children With Autism Spectrum Disorders

Abstract

CONTEXT:

As many as 1 in every 110 children in the United States has an autism spectrum disorder (ASD). Secretin is 1 of many medical treatments studied for treating the symptoms of ASDs, but there is currently no consensus regarding which interventions are most effective.

OBJECTIVE:

To systematically review evidence regarding the use of secretin in children with ASDs who are aged 12 years and younger.

METHODS:

We searched the Medline, PsycINFO, and ERIC (Education Resources Information Center) databases from 2000 to May 2010 and reference lists of included articles. Two reviewers independently assessed each study against predetermined inclusion/exclusion criteria. Two reviewers independently extracted data regarding participant and intervention characteristics, assessment techniques, and outcomes and assigned overall quality and strength-of-evidence ratings on the basis of predetermined criteria.

RESULTS:

Evidence from 7 randomized controlled trials supports a lack of effectiveness of secretin for the treatment of ASD symptoms including language and communication impairment, symptom severity, and cognitive and social skill deficits. No studies have resulted in significantly greater improvements in measures of language, cognition, or autistic symptoms when compared with placebo; study authors who reported improvement over time did so equally for both the intervention and placebo groups.

CONCLUSIONS:

Secretin has been studied extensively in multiple randomized controlled trials, and there is clear evidence that it lacks benefit. The studies of secretin included in this review uniformly point to a lack of significant impact of secretin in the treatment of ASD symptoms. Given the high strength of evidence for a lack of effectiveness, secretin as a treatment approach for ASDs warrants no further study.

Secretin is a gastrointestinal polypeptide used to treat peptic ulcers and in the evaluation of pancreatic function.^1,2 Results of animal studies have suggested that secretin affects the central nervous system and may function as a neurotransmitter.^3,4 Interest in secretin for the treatment of symptoms of autism spectrum disorders (ASDs) stemmed from a nonblinded, uncontrolled case series of 3 children with ASDs who received synthetic intravenous secretin during a routine endoscopy evaluation for gastrointestinal problems.⁵ The report noted social, cognitive, and communicative gains after the first infusion and after a second infusion given weeks later.⁵

As part of an Agency for Healthcare Research and Quality–commissioned comparative effectiveness review, we assessed recent research on the use of secretin to treat ASD symptoms in children between the ages of 2 and 12 years with ASDs.⁶ Information on other interventions addressed in the full review can be found at www.effectivehealthcare.ahrq.gov.

METHODS

Search Strategy

We searched Medline via the PubMed interface, PsycINFO (psychology and psychiatry literature), and ERIC (Education Resources Information Center) (educational literature) from 2000 to May 2010 using relevant controlled vocabulary terms and key terms related to ASDs (eg, autistic disorder) and therapy-related terms (eg, therapeutics, secretin). We also hand-searched the reference lists of all included articles to identify additional studies and reviewed clinical trials related to therapies for ASDs to identify corresponding articles.

Study Selection

We developed study inclusion and exclusion criteria in consultation with an expert panel of clinicians and educators involved in the care of children with ASDs. We included all study designs and required that studies of secretin include at least 30 participants younger than the age of 12 years with ASDs. We also required that studies be published in the year 2000 or later, after the publication of the Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition (DSM-IV)⁷ and the widespread implementation of gold-standard ASD-assessment tools including the Autism Diagnostic Observation Schedule,⁸ and the Autism Diagnostic Interview-Revised.⁹

Data Extraction

Using standardized forms, 2 investigators independently extracted data regarding study design; descriptions of the study populations, intervention, and comparison groups; and baseline and outcome data, as well as data about harms or adverse effects. We also captured data on the conduct and timing of assessments to inform the assessment of quality. Principal outcomes of interest included effects on core symptoms of ASDs or common comorbid symptoms including sleep, anxiety, hyperactivity, and challenging behavior (eg, irritability/agitation).

Study-Quality Assessment

Two investigators independently assessed each study by using a quality-assessment form developed by the review team with input from experts in the field. We evaluated the following elements with a series of yes/no questions in each domain (eg, were outcomes coded and assessed by people blinded to the intervention status of the participants?):

• study design;

• diagnostic approach;

• participant ascertainment and characterization;

• intervention description;

• outcomes measurement; and

• statistical analysis.

Disagreements between assessors were resolved through discussion to reach consensus. Overall assessment of quality was determined by using a prespecified algorithm that is available in the full report.⁶

We assessed the strength of evidence of the current research by using methods established in the Evidence-Based Practice Centers' methods guide for effectiveness and comparative effectiveness reviews.¹⁰ Assessments are based on consideration of 4 domains: risk of bias; consistency in direction of the effect; directness in measuring intended outcomes; and precision of effect (Table 1). We determined the strength of evidence separately for major intervention-outcome pairs by using a prespecified approach that is described in detail in the full review.⁶

TABLE 1.

Domains Used to Assess Strength of Evidence

Risk of bias: Reflects issues in study design and conduct that could result in biased estimates of effect

Consistency: Reflects similarity of effect sizes seen across studies; consistency cannot be assessed when only 1 study is available

Directness: Reflects the relationship between the intervention and the ultimate health outcome of interest

Precision: Reflects the level of certainty around the effect observed

Data Synthesis

Given considerable heterogeneity in the interventions and outcome measures used in studies that met our inclusion criteria, we did not conduct any meta-analyses. We summarized characteristics of study populations and interventions and used descriptive statistics to report study outcomes.

RESULTS

Figure 1 shows the flow of articles retrieved for the review. Among 4120 articles located for the full review, 8 articles^11–18 met our inclusion criteria and addressed secretin use in 8 unique populations. Seven studies were randomized controlled trials,^11–17 and 1 was a prospective case series.¹⁸ We assessed 2 trials as being of good quality,^14,15 5 as being of fair quality,^{11–13,16–17} and the case series as being of poor quality.¹⁸

FIGURE 1.

Location of studies that addressed secretin use in children with ASDs.

^a The total number of articles in the exclusion categories exceeds the number of articles excluded, because most of the articles fit into multiple exclusion categories.

Of the 8 studies that evaluated the impact of secretin in the treatment of ASDs, 1 study¹⁵ was a repeated-dose intervention study. Two studies used synthetic human secretin,^11,12 3 used porcine secretin,^14,16,17 and 1 used biological secretin;¹³ 1 report did not specify the type of secretin used.¹⁸ All of the studies evaluated only short-term outcomes and had follow-up periods that ranged from 3 to 12 weeks. Outcomes assessed included measures of receptive and expressive language, gastrointestinal symptoms, adaptive behavior, cognitive impairments, social skills, and fine motor skills. Participant numbers in the treatment arms of the randomized controlled trials ranged from 21 subjects ¹² to 47 subjects.¹⁷

No studies revealed significantly greater improvements in measures of language, cognition, or autistic symptoms when compared with placebo. Study authors who reported improvement over time did so equally for both intervention and placebo groups. There also was no benefit demonstrated according to type of secretin (porcine or synthetic).

DISCUSSION

Overall, the studies of secretin included in our review uniformly point to a lack of significant impact of secretin in the treatment of autism symptoms. Similar to our study, a Cochrane review of 13 randomized studies revealed no evidence for the effectiveness of single- or multiple-dose intravenous secretin in children or adults with ASDs.¹⁹ Secretin has been studied exhaustively in multiple randomized controlled trials, and there is clear evidence that it lacks benefit for treating children with ASDs.

CONCLUSIONS

Previous studies have demonstrated that secretin is not effective for improving language, cognition, behavior, communication, autism symptom severity, or socialization skills. The strength of evidence for this lack of effectiveness is high. With 7 randomized controlled trials with fair- to good-quality scores and 1 case series that contributes to this evidence base, future studies are unlikely to change the estimate of effect for this treatment. Further studies of secretin in children with ASDs are not warranted.