Low risk: if no missing data were reported or if appropriate methods were used to impute missing data, or if the reason for missing data is unlikely to be related to the true outcome. As such, we rated risk of bias in these domains as unclear. Before treatment, individuals with ASD may undergo preliminary tests with the chelating substance to evoke a response, followed by timed urine collection to determine the levels of heavy metals in the body (Bradstreet 2003; Adams 2009). Repeated up to 6 times For children in the control group who completed phase two of the trial, the mean (SD) score on the ATEC sociability subscale decreased from 14.9 (6.8) at the beginning of phase one, to 11.2 (6.5) at the end of phase two. Interventions were eligible for inclusion if they involved chelating substances of any type and dose, regardless of administration frequency or method, compared with placebo.
It is therefore unlikely that institutional review boards will approve future trials for chelation for ASD unless safety in children can be assured through the current approach to research. We also searched relevant websites, including Autism Speaks (www.autismspeaks.org/), Research Autism (https://researchautism.net/) and the US Department of Health and Human Services (www.hhs.gov/). #9childhood next schizophreni*:ti,ab 28 25 not 27 #8kanner*:ti,ab In addition we checked references lists and contacted experts. 3 pervasive development$ disorder$.tw. The significance of the between‐group difference was not reported.
Cochrane reviews typically avoid making recommendations for practice; however, given that harm resulting from the use of chelation therapy has been reported, and that no proven benefits have been found, it seems reasonable to conclude that use of chelation for the treatment of individuals with ASD symptoms should not be recommended. HTA 2014, Issue 4, searched 6 November 2014. DARE 2013, Issue 4 , searched 5 December 2013 (no records) Forty‐nine children who excreted high levels of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. #16[mh ferrozine] or [mh "pentetic acid"] or [mh deferoxamine] or [mh enterobactin] or [mh Fursultiamin] After receiving the glutathione or placebo lotion for seven days, all children received one round of oral DMSA, administered in a 10 mg/kg dose, three times per day for three days. For example, the unstandardised b‐weight signs suggest that increased excretion of As9 is associated with differential change patterns in PDD‐BI, ADOS and ATEC scores (although it is unclear how trialists created the change scores).
The significance of the between‐group difference was not reported. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Unclear risk: if the method of allocation concealment was not described.
We reported the searches in detail in Appendix 1. Unclear risk: if lack of information prohibits judgement of low or high risk of bias, or if the study did not address this outcome. Autism and chelation 30% to 49% may represent moderate heterogeneity (tw:(autis* OR asperger* OR "pdd‐nos" OR asd OR asds) OR mh:("Autistic Disorder" OR "Asperger Syndrome" OR "Child Development Disorders, Pervasive")) AND (mh:("Chelating Agents" OR "Chelation Therapy" OR "Iron Chelating Agents" OR "Siderophores") OR tw:(chelating OR chelate* OR chelator* OR complexon* or DMSA)) This underlying theory needs to be tested and confirmed before future trials that assess chelation for ASD symptoms are implemented. #10Rett*:ti,ab Unclear risk: if lack of information prohibits judgement of low or high risk of bias, or if the study did not address this outcome. S19 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 No results were reported with regard to potential differences between the experimental group and the control group in excretion levels of toxic metals during or after phase two. CBC: complete blood count. Urine was collected at the beginning of phase one, after the first dose of oral DMSA in phase one, after the ninth dose in phase one and at the end of the second round in phase two.
Only outcomes that were available at the beginning of phase one and at the completion of phase two, or were available at the beginning and end of phase two, could assist with answering this question. 1967 to November Week 4 2013, searched 5 December 2013 (143 records) 5 asperger$.tw. Science Citation Index (Web of Science), 1970 to 5 November 2014. #25
Katrina Williams received a salary through support of the APEX Australia Chair of Developmental Medicine, University of Melbourne. Novel therapies are used frequently by individuals with ASD (Hanson 2007). Despite their increasing use, most types of CAM for ASD lack a robust evidence base (Nye 2005; Millward 2008; Cheuk 2011; James 2011; Sinha 2011; Geretsegger 2014). Chelation therapy is one CAM that continues to be used and promoted as efficacious, despite reports of harm, withdrawal of a trial before recruitment because of safety concerns (Mitka 2008) and discouragement by physicians (Golnik 2009). Do repeated doses of oral DMSA decrease core features of ASD in children who have previously received a three‐day course of oral DMSA and are known to be high excreters? #7asperger*:ti,ab Conference Proceedings Citation Index ‐ Science and Conference Proceedings Citation Index ‐ Social Science & Humanities, 1990 to 5 November 2014, searched 6 November 2014. Quality of life for individual or family.
Participants in the included study (Adams 2009) were reported to be randomly assigned, but no details were available on sequence generation or allocation concealment. The between‐group difference was reported to be non‐significant. Two review authors (SJ and SS) independently screened the titles and abstracts of citations identified by the search. Searched 6 December 2013 (9 records) We searched multiple databases to find studies that examined pharmaceutical chelating agents as treatment for ASD symptoms. Deaths have also been reported (Brown 2006).
We excluded nine studies because they were non‐randomised trials or were withdrawn before enrolment. #1 [mh ^"child development disorders, pervasive"] 17 or/9‐15 15 (Fursultiamin$ or TTFD or thiamine tetrahydrofurfuryl disulfide).tw. Science Citation Index ‐ expanded: 1970 to 5 November 2014, searched 6 November 2014. Finally, we are extremely grateful for invaluable feedback provided by external reviewers and statisticians.
5 autis$.tw. We would like to thank Laura MacDonald, Geraldine Macdonald and Joanne Wilson for feedback and guidance, and Margaret Anderson for assistance with the development of our search strategy. Changes in autism symptoms were assessed at the end of phase two using the Parental Global Impressions (PGI) questionnaire. Red blood cell (RBC) glutathione 1 pervasive development$ disorder$.tw. 6 autis$.tw.
Janssen‐Cilag had no control over the contents of the talk, and the speaker’s fee was paid to the University that employs her. 24 (edetate or Edetic Acid or Egtazic Acid or Fura‐2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).mp. (77430) 9 complexon$.tw. 7 asperger$.tw. Limited to ed=20131101‐20141106 (6 records) #25
Trialists did not report if these two children were included in the experimental group or in the control group. Searched 7 November 2014 (no records) 1980 to Week 48, searched 5 December 2013 (252 records) We included one study, which was conducted in two phases. The theoretical basis for mercury or other heavy metals as a cause of ASD draws on a wide variety of hypotheses, none yet confirmed. Each daily dosage contained ˜ 180 mg of “reduced 1‐glutathione in a lotion of isopropyl myristate, mineral oil, caprylic/capric triglyceride, and vitamin E acetate” (Adams 2009, p 5). We searched the following databases with no language or date restrictions.
Blinding of outcome assessment. S15 ("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown N1 (compoundor ether)) or cyclodextrin or cyclophane or cuprizone) The University provided IT, office and library facilities during the time of this protocol. (toxnet.nlm.nih.gov/) t1/2: time until maximum concentration drops in half. For children in the experimental group who completed phase two of the trial, the mean (standard deviation (SD)) score on the ATEC sociability subscale decreased from 16.6 (8.5) at the beginning of phase one, to 12.1 (6.5) at the end of phase two. Unclear risk: if the sequence generation process was not described.
The Davis 2013 review did not limit inclusion criteria to randomised controlled trials; whereas we included one trial, Davis 2013 included five trials. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three‐day course of oral DMSA. #24 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin) Conference Proceedings Citation Index ‐ Science and Conference Proceedings Citation Index ‐ Social Science & Humanities, 1990 to 4 December 2013, searched 5 December 2013 (3 records) Phase 2 ‐ up to 6 rounds of placebo: methyl cellulose "packed in identical pills and bottles as the DMSA. #2[mh "Developmental Disabilities"] sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide) As such, we rated risk of reporting bias as high. Katrina Williams: contributed to the write‐up of the protocol and the review, reviewed the included study and assessed risk of bias.
14 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).af. S3 pervasive development* disorder* For children in the experimental group who completed phase two of the trial, the mean score on the ADOS sociability subscale decreased from 9.3 at the beginning of phase two, to 8.3 at the end of phase two. 9 (pervasive adj3 child$).tw. For children in the experimental group who completed phase two of the trial, the mean (SD) score on the ATEC speech/language communication subscale decreased from 13.4 (7.7) at the beginning of phase one, to 10.6 (7.0) at the end of phase two. Each daily dosage contained ˜ 180 Mercedes-benz c250 2015 in kenya mg of “reduced 1‐glutathione in a lotion of isopropyl myristate, mineral oil, caprylic/capric triglyceride, and vitamin E acetate” (p 5) Blood was collected at the beginning of phase one, at the beginning of phase two, after the third round of oral DMSA/placebo in phase two and after the sixth round of oral DMSA/placebo in phase two.
However, the latest edition of the DSM (DSM‐5) (APA 2013) has replaced these diagnostic labels with one umbrella term: autism spectrum disorder (ASD). A systematic review that examines potential beneficial and harmful effects of chelation for symptoms of ASD is urgently needed. Searched 7 November 2014 (1 record) #10 Rett* Limited to Date of registration, between: 01/12/2013 and 7/11/2014 (no new records) 18 Fursultiamin/ or (Fursultiamin$ or TTFD or thiamine tetrahydrofurfuryl disulfide).tw. Quality of the evidence Chelation for autism spectrum disorder (ASD) S17 (edetate or Edetic Acid or Egtazic Acid or Fura‐2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or Unapproved uses of chelation therapy, for example, when used as an intervention for ASD, may involve practitioners using various chelating substances and unlicensed routes of administration (such as through the rectum or the skin) to remove reported excess levels of mercury, other heavy metals or both (Semple 2011). Although the total number of children randomly assigned (and the number randomly assigned to each group) is not explicitly stated, it appears as though randomisation occurred after the initial blood collection (i.e. for the 77 children).
1946 to October Week 5 2014, searced 6 November 2014. 7 childhood schizophreni$.tw. DocType=All document types; Language=All languages; Furthermore, use of adjusted R² instead of R² appears to be a less‐than‐satisfactory approach to the handling of sample uniqueness, which likely artificially inflated model effect size. At the present time, the theory that heavy metals may cause autism or might worsen symptoms has not been established.
Additionally in phase two, one child dropped out as a result of elevated liver enzymes (reported to be due to psychiatric medication) and one child withdrew because of the death of a family member. Limited to EM>=2013120 (1 record) It is not related to autism or to chelation. The study included in this review was reported to be randomised and double‐blind (Adams 2009). Each round consisted of a 10 mg/kg dose, administered three times per day for three days, followed by 11 days of no DMSA. Two review authors (SJ and SS) independently assessed risk of bias of the included study using the tool described in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011, section 8.5.a). #7 asperger* 29 27 not 28 Shawn W Stevenson: contributed to the write‐up of the protocol and the review, screened records, reviewed the included study and assessed risk of bias.
Autis* AND (chelat* OR DMSA) Examples of CAM used for ASD include exclusion diets, essential fatty acids, multi‐vitamins, acupuncture, auditory integration training and chelation therapy. To date, no consistent evidence indicates that CAM is an effective intervention for the core features and associated behaviours of ASD (Nye 2005; Millward 2008; Cheuk 2011; James 2011; Sinha 2011; Geretsegger 2014). Since oral DMSA has a strong smell, each bottle included a small slotted container that contained oral DMSA, so that the medication smell was present in the container” (p 5). #20 (metal near/3 antagonist*) #17(Fursultiamin* or TTFD or "thiamine tetrahydrofurfuryl disulfide"):ti,ab 1937 to current, searched 5 December 2013 (57 records) High risk: if no blinding or incomplete blinding was reported and the outcome was likely influenced by lack of blinding, or if blinding of study participants and personnel was attempted but it is likely that blinding could have been broken and the outcome influenced by lack of blinding. All children (69 male and eight female; mean age 6.3 years) were Arizona residents who had been diagnosed with autism spectrum disorder (autism 95%, pervasive developmental disorder not otherwise specified (PDD NOS) 3%, Asperger’s 3%) by a psychiatrist, a psychologist or a developmental paediatrician.
Research has produced contradictory findings with regard to levels of heavy metals in individuals with ASD. Yashwant Sinha for pharmacological advice about topical glutathione and dimercaptosuccinic acid (DMSA). 9 childhood schizophrenia.tw. For the second phase of the included study, all children had received a three‐day course of oral DMSA before randomisation. #6autis*:ti,ab Limited to year= 2013 to 2014 (2 records) 4 (pervasive adj3 child$).tw. Phase 1 ‐ placebo lotion: administered 1 ×/d for 7 days: “The placebo was identical in packaging and formulation except it did not contain glutathione” (p 5) We searched reference lists from the retrieved articles for studies not already identified, and we contacted known experts in the field to enquire about other sources of information. # Query Limiters/Expanders Last Run Via Results Action #14[mh "Iron Chelating Agents"] Provoked urine will be examined cautiously (as provocation testing elevates urine heavy metal levels).
Finally, most of the secondary outcomes presented in the protocol of this review (James 2013) were not investigated in the included study. 25 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).mp. (kw:autis* OR kw:asperger* OR kw:ASD OR kw:ASDs) AND (kw:chelation OR kw:chelator OR kw:DMSA) #15 [mh siderophores] To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms. Results from this systematic review will help families with ASD make well‐informed decisions about the use of chelation therapy and will assist relevant services and guide other organisations in making decisions about best practice.
We discussed at length whether the study should be included, as all children entering phase two had already received a chelating agent. Analysis methods that we will use in updates of this review can be found in Table 2 and in our protocol (James 2013). According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5), autism spectrum disorder (ASD) is defined as a set of pervasive neurodevelopmental conditions that are characterised by difficulties in social interaction and communication, and by the presence of restricted, repetitive behaviours (i.e. stereotypies) (APA 2013). One of the more commonly used chelating substances, oral dimercaptosuccinic acid (DMSA; also called succimer), is given on a cyclical basis at doses of 10 mg/kg/d every eight hours for three days, followed by 11 days with no DMSA (Bradstreet 2003; Adams 2009).
Phase 1 ‐ 1 round of oral DMSA: 10 mg/kg dose, 3 ×/d, for 3 days 1967 to November Week 1 2014, searched 6 November 2014. #4(pervasive near/3 child*):ti,ab Limited to year= 2013 to 2014 (2 records) 21 (metal adj3 antagonist$).tw. #26#11 and #25 27 25 and 26 S10 (MH "Chelation Therapy") Urinary excretion of toxic metals and essential minerals 26 human/ or normal human/ or human cell/ SAS: Severity of Autism Scale. #10 Ts=(siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin) 13 (dimercaprol or dimercaptosuccinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).mp. ) She does not have an ongoing relationship with Janssen‐Cilag. Database content last updated 5 November 2014. Moreover, external validity is limited, given that the included study involved children from only one state (Arizona) in the United States of America, and given that only one chelating agent (DMSA) was assessed.
1 exp child development disorders, pervasive/ S5 (PDD or PDDs or PDD‐NOS or ASD or ASDs) 11 exp chelation/ For children in the control group who completed phase two of the trial, the mean (SD) score on the ATEC speech/language communication subscale decreased from 12.0 (8.4) at the beginning of phase one, to 10.5 (8.9) at the end of phase two. 14 (edetate or Edetic Acid or Egtazic Acid or Fura‐2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).mp. Length of follow‐up (e.g. ≤ 3 months vs > 3 months) However, before further trials are conducted, more evidence is needed to show that heavy metals cause or worsen the severity of autism, and the safety of pharmaceutical chelating agents for participants must be established.
Knowledge that all children received at least one round of chelation or awareness of who was in the high excreter group would likely yield high risk of bias in the second phase. The significance of the between‐group difference was not reported. No differences of opinions arose. Another smaller study from Italy (N = 37) found no difference in mercury, or in other heavy metals, between individuals with ASD and a group recruited from a neuropsychiatric service who did not have ASD (Albizzati 2012).
1 exp autism/ We did not conduct a meta‐analysis, given that only one study was included in this review. The between‐group difference was reported to be non‐significant. RBC: red blood cell.
S6 kanner* 5 (PDD or PDDs or PDD‐NOS or ASD or ASDs).tw. Blood was collected to assess CBC and RBC glutathione. #5 TS= (complexon* or Fursultiamin* or TTFD or "thiamine tetrahydrofurfuryl disulfide") 12 chelation therapy/ Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data. 11 (metal adj3 antagonist$).tw. In phase two, two children (one in each treatment group) withdrew because of perceived lack of benefit, and four children dropped out as the result of adverse effects (two children in the control group for worsening of behaviours, and two children in the experimental group ‐ one for sleep problems and one for worsening of behaviours and skills). Limited to year=2013 to 2014 (7 records) Autism Data (www.autism.org.uk/autismdata).
She is not involved in any funded work relevant to chelation therapy. Shawn is currently employed by the University of Melbourne and has received no personal funds. 13 exp chelating agent/ High risk: if other sources of bias exist. See below for more detailed information on risk of bias. #15[mh siderophores] Heatlh Technology Assessment Database 2014, Issue 4, part of the Cochrane Library.
#16 [mh ferrozine] or [mh "pentetic acid"] or [mh deferoxamine] or [mh enterobactin] or [mh Fursultiamin] Conference Proceedings Citation Index – Science (Web of Science), 1990 to 5 November 2014. SJ and SS then obtained and reviewed the full text of studies that met, or seemed likely to meet, the inclusion criteria. #21("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown next (compound or ether)) or cyclodextrin or cyclophane or cuprizone):ti,ab Instead, the included study was conducted in two phases: During the first phase, participants were randomly assigned to receive seven days of glutathione lotion (experimental group) or placebo lotion (control group) followed by three days of oral dimercaptosuccinic acid (DMSA) (for all children). DocType=All document types; Language=All languages; #2 Ts=("childhood schizophren*") #13 #4 AND #3 The quality of the evidence is poor. 17 (chelation or chelating or chelator$).tw. This review included data from only one study, which had methodological limitations.
Three studies (Cohen 1976; Cohen 1982; Adams 2013) (N = 34, N = 93 and N = 99, respectively), all from the USA, found higher levels of lead in individuals with ASD compared with individuals without ASD, with overlapping levels observed between diagnostic groups. #3 pervasive next development* next disorder* #20(metal next/3 antagonist*):ti,ab Limited to 2013 to 2014 (no records) For the current version of this review, meta‐analysis was not possible, as only one study was included. For the included study, we judged the risk of bias to be low, high or unclear for each of the following domains. #12 [mh "Chelation Therapy"] 13 (edetate or Edetic Acid or Egtazic Acid or Fura‐2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).af. Stephen James is employed by Southwest Autism Research and Resource Center. For the first phase of the included study, children in the experimental group initially received glutathione lotion, which was administered once per day for seven days. #24(siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin):ti,ab #9 childhood next schizophreni* We would also like to thank Dr. Each round consisted of 3 days on placebo, followed by 11 days off autism AND chleation 13 Chelating Agents/ For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD‐BI ritualism/resistance to change subscale decreased from 15.0 (8.5) at the beginning of phase two, to 11.5 (8.2) at the end of phase two.
8 Rett$.tw. Participant details, including age, gender, sample size and diagnosis. Study methods and setting, including study duration, design and location. Social Sciences Citation Index: 1970 to 5 November 2014, searched 6 November 2014. The evidence is current to November 2014.
Nonetheless, all of the trials included in the Davis 2013 review were reported to have substantial methodological limitations, and the results of our review support the findings reported by Davis 2013; we agree that no available evidence supports the use of chelation to treat individuals with ASD symptoms. Two studies ‐ one from the USA (N = 452) and one from Jamaica (N = 130) ‐ exploring differences in mercury level in blood reported no association between ASD and higher levels of mercury when analyses were adjusted for fish eating and other relevant factors (Hertz‐Picciotto 2010; Rahbar 2013). Two additional children in the experimental group withdrew from the study as the result of low excretion of metals and worsening of symptoms, including sleep problems (n = 1) and sleep problems plus increased tantrums (n = 1).
All children were given one round of oral DMSA for screening purposes to ensure that only high heavy metal excreters continued on to the second phase. #11
ID Search 7 (ASD or ASDs or PDD or PDDs).tw. DMSA dose of 10 mg/kg body weight administered 3 times per day vs higher doses) Low risk: if no blinding or incomplete blinding was reported but review authors judged the outcome as unlikely to have been influenced by lack of blinding, or if blinding of study participants and personnel was ensured and it is unlikely that blinding could have been broken. 29 24 not 28 Limited to year= 2013 to 2014 (no records) Of particular concern are the trialists’ questionable data analytical approach and interpretation of findings.
We searched the following databases on 6 November 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In‐Process, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including three trials registers. No disagreements arose. 27 11 and 26 We found only one randomised controlled trial that evaluated oral dimercaptosuccinic acid (DMSA) for ASD, but this trial did not use ideal methods for answering our question. 50% to 74% may represent substantial heterogeneity Trialists acknowledged that the effect of the phase one oral DMSA carried over into phase two: ". the single screening round of DMSA [in phase one] had an unexpectedly dramatic effect on improving abnormal glutathione and platelet levels, and the effect lasted until the end of phase two, so that phase two was not a placebo‐control‐led investigation" (Adams 2009, p 3). Types of pharmaceutical chelating substances used to reduce heavy metal poisoning are outlined in Table 1 . Although this study sheds light on the impact of using different quantities of DMSA rounds, it does not address completely the question of whether DMSA is effective in the first place.
Blinding of participants and personnel. During phase one, one child experienced an adverse event (lethargy and diminished appetite), causing the child to withdraw from the study (treatment group not specified). 9 Kanner$.tw.
This hypothesis is currently being explored (Deth 2008; Zecavati 2009; Garrecht 2011). Given prior reports of serious adverse events, such as changes to calcium levels in blood, kidney impairment and reported death, risks of using pharmaceutical chelating agents for ASD currently outweigh proven benefits. The excess of stored or circulating total body mercury or other heavy metals is thought to interfere with developmental processes implicated in ASD, and it has been suggested that symptoms of mercury poisoning and ASD share some characteristics (Bernard 2001). Mercury, through its ability to cross the blood‐brain barrier and the placental barrier, can affect the nervous system and disrupt normal development of the foetus (Aschner 1990; Liu 2008).
The inclusion of only one study, which had a relatively small sample size and a high likelihood of carry‐over effects and other biases, precludes confidence in the findings. 10 (chelation or chelating or chelator$).tw. Unclear risk: if lack of information permits judgement of whether other sources of bias exist.
Autism and chelation Searched 9 December 2013 (12 records) DocType=All document types; Language=All languages; During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Individuals with ASD also exhibit preoccupations and restricted, repetitive patterns of interest and behaviours, which may include strong adherence to routines and stereotyped speech and motor movements (Lecavalier 2006; APA 2013). Heavy metal levels in blood or non‐provoked urine.
Participant age (e.g. adult vs child, preschool vs school‐age) Allocation concealment or sequence generation was inadequate (selection bias) 10 Rett$.tw. S14 (chelation or chelating or chelator*) Social Sciences Citation Index (Web of Science), 1970 to 5 November 2014. PsycINFO (Ovid), 1967 to November Week 1 2014. Limited to year=2013 to 2014 (no records) Low risk: if a random component was used in the sequence generation process, such as coin‐tossing, computer‐generated random numbers or a table of random numbers. DocType=All document types; Language=All languages; International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).
These two‐weekly cycles are repeated up to six times, totalling approximately three months of treatment (Adams 2009). #5(PDD or PDDs or PDD next NOS or ASD or ASDs):ti,ab 28 exp animals/ not humans.sh. 12 (dimercaprol or dimercapto succinic acid or dimercaptosuccinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).af. Ultimately, however, we believed that we would not be deviating from protocol by including the study, because the second phase of the study was a randomised placebo‐controlled trial. In this context, it is thought that individuals with ASD have an impaired capacity to excrete heavy metals, and that the severity of autism symptoms is inversely correlated with excretion ability (Holmes 2003; Kern 2007). The level of urinary excretion of toxic metals was not reported for participants in the control group during or after phase two, and no results were reported with regard to potential differences between the experimental group and the control group in excretion levels of toxic metals during or after phase two.
Many interventions are available for ASD, and although some, such as early intensive intervention, are effective in improving communication, social interaction and behaviours, none are capable of producing complete remission of all symptoms. Pharmacological interventions are often prescribed for individuals with ASD, primarily to target specific associated symptoms or co‐occurring features. Currently, however, no pharmacological interventions target the core symptoms of ASD. Individuals with ASD often use complementary and alternative medicine (CAM) too; approximately 75% of children with ASD use CAM (Hanson 2007). 8 Rett$.tw. Conference Proceedings Citation Index – Social Science & Humanities (Web of Science), 1990 to 5 November 2014.
Low risk: if participants and trial investigators had no foreknowledge (i.e. before eligibility, decisions made and informed consent obtained) of intervention assignment through the use of, for example, central allocation or sequentially numbered envelopes that were opaque and sealed. DocType=All document types; Language=All languages; Unclear risk: if lack of information prohibits judgement of low or high risk of bias. Treatment dosage (e.g. Changes in the following core symptoms of ASD, using any measure (e.g. the Aberrant Behavior Checklist (ABC), CARS), as assessed separately.
Although it fulfilled criteria for inclusion, the methods, which we have outlined here, are not appropriate to allow testing of the hypothesis of interest in this review. Shawn W Stevenson was employed by Autism Victoria at the time of this review. Key results (scholar.google.com/) 10 or/1‐9 16 siderophores/ During the first phase, 77 children with ASD were assigned randomly to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral DMSA. (www.who.int/ictrp/en/) #22(dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb):ti,ab Trials were also eligible for inclusion if the chelating substances were provided alone or as adjunctive treatment compared with placebo (e.g. chelation in combination with a behavioural intervention vs placebo in combination with a behavioural intervention). #13 MeSH descriptor: [Chelating Agents] explode all trees 16 or/1‐8 Only one trial was included in this review, and we judged it to have high or uncertain risk of bias and methodological problems that limited the interpretation of outcomes presented. High risk: if a study has a protocol and one or more prespecified outcomes were not reported or were reported in a manner that was not prespecified, or if a study has no protocol and all expected outcomes have not been reported.
Treatment type (e.g. dimercaptosuccinic acid (DMSA) vs other agents) Incidentally, trialists did not report the b‐weight for SAS regressed on T19, although they reported on its statistical significance. Autism spectrum disorders (ASD) are types of disorders characterised by difficulties in social interaction and communication, and restricted and repetitive behaviours. We did not conduct a meta‐analysis, as only one study was included. #5 (PDD or PDDs or PDD next NOS or ASD or ASDs) Tmx: time until maximum concentration. We assessed and reported missing data and dropouts for the included study (see Characteristics of included studies).
DMSA: dimercaptosuccinic acid. Chelation therapy involves administering a chelating substance that binds to heavy metals, such as lead and mercury, which then is excreted in urine. (scielo.br/cgi‐bin/wxis.exe/iah/) CDSR 2013, Issue 12, searched 5 December 2013 (no records) A systematic review evaluating the effectiveness of chelation for ASD (Davis 2013) was published after the title for this review was registered. FDA: Food and Drug Administration. 2 pervasive development$ disorder$.tw. #18 complexon* Moreover, if these findings are in fact valid, they actually undermine the heavy metal toxicity theory and the rationale for chelation treatment, suggesting that it should not be used in the first place.
Low risk: if no blinding of outcome assessment was reported but review authors judged the outcome measurement as unlikely to have been influenced by lack of blinding, or if blinding of outcome assessment was ensured and it is unlikely that blinding could have been broken. Searched 9 December 2013 (no records) Patients with heavy metal poisoning, such as acute lead poisoning, require urgent hospitalisation and administration of chelating substances intravenously or by deep intramuscular injection for four hours. During treatment of patients with acute lead poisoning, blood and urine are monitored constantly, as significant shifts in the heavy metal can occur between the blood and the central nervous system with dire consequences. Edited (no change to conclusions) Searched 6 November 2014 (12 records) 18 (metal adj3 antagonist$).tw. 6 kanner$.tw.
The significance of the between‐group difference was not reported. S11 (MH "Detoxification, Alternative Therapy") #2 [mh "Developmental Disabilities"] Therefore, we rated risk of performance bias and risk of detection bias as unclear. Cochrane Database of Systematic Reviews (CDSR) 2014, Issue 11, part of the Cochrane Library. Science Citation Index ‐ expanded: 1970 to 4 December 2013, searched 5 December 2013 (18 records) It is perplexing that the trialists would use an unconventional and atheoretical regression approach without the critical step of including a cross‐validation sample, and given the relatively small sample size and the apparently large set of variables (the number of tested variables was not revealed). An overview of risk of bias is illustrated in Figure 2 . This review found no high‐quality evidence to suggest that chelation is an effective treatment for improving ASD symptoms.
These factors, when combined, preclude confidence in the findings. #19 (chelation or chelating or chelator*) PGI: Parental Global Impressions. 12 ("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).mp. S20 S9 AND S19 17 complexon$.af. Severity of autism symptoms was assessed using the Pervasive Developmental Disorder Behavior Inventory (PDD‐BI), the Autism Treatment Evaluation Checklist (ATEC), the Severity of Autism Scale (SAS) and the Autism Diagnostic Observation Schedule (ADOS). Changes in autism symptoms (Parental Global Impressions (PGI)) DocType=All document types; Language=All languages; 26 or/12‐25 CINAHL Plus (Cumulative Index to Nursing and Allied Health Literature) (EBSCOhost), 1937 to current.
15 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).mp. #8 TS=(dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb) 21 remove duplicates from 20 For children in the experimental group who completed phase two of the trial, the mean score on the ADOS communication subscale decreased from 7.8 at the beginning of phase two, to 7.1 at the end of phase two. Urine was collected to assess excretion of toxic metals and essential minerals. 14 2,2’‐dipyridyl/ or caseins/ or chitosan/ or citric acid/ or cuprizone/ or dimercaprol/ or dithizone/ or ditiocarb/ or edetic acid/ or egtazic acid/ or fura‐2/ or humic substances/ or nitrilotriacetic acid/ or penicillamine/ or pentetic acid/ or phytochelatins/ or razoxane/ or succimer/ or technetium tc 99m pentetate/ or thenoyltrifluoroacetone/ or trientine/ or unithiol/ #1[mh ^"child development disorders, pervasive"] We attempted to minimise bias by having two review authors independently screen studies for inclusion, extract and manage data and assess risk of bias in included studies. Results from the included study show that multiple rounds of oral DMSA did not have an effect on any of the ASD symptoms measured in children found to be high excreters who had already received three doses of a pharmaceutical chelating agent.
This attempt to persuade readers to disregard differences across heavy metals, however, is undermined by the presented regression analyses, which show inconsistencies in the direction of the effects that metal excretion has on various change indices. 0% to 29% might not be important For children in the experimental group who completed phase two of the trial, the mean (SD) score on the PDD‐BI aggressiveness subscale decreased from 13.4 (9.8) at the beginning of phase two, to 9.8 (6.7) at the end of phase two. 4 autis$.tw. Condition autis% or asperger% or PDD% or ASD% or pervasive AND Intervention edetate or Edetic Acid or Egtazic Acid or "Fura‐2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide No sources of support supplied Latin American Caribbean Health Sciences Literature (LILACS) (search.bvsalud.org/portal/advanced/?lang=en).
DocType=All document types; Language=All languages; #7 TS= ("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown NEAR/1(compound or ether)) or cyclodextrin or cyclophane or cuprizone) #11
1937 to current, searched 6 November 2014. 7 childhood schizophrenia.tw. If evidence emerges that supports a causal link between heavy metals and autism, further trials with methods suitable to ensure safety and to demonstrate that chelation removes heavy metals, improves social communication and reduces restricted repetitive behaviours seen in autism will be needed. Randomised controlled trials.
75% to 100% represents considerable heterogeneity (Higgins 2011) Children in the control group received a placebo lotion that was identical in packaging and contained a similar formulation (with the exception of glutathione). The between‐group difference was reported to be non‐significant. 23 (dimercaprol or dimercapto succinic acid or dimercaptosuccinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).mp. 6 asperger$.tw.
Searched 10 December 2013 (9 records) S7 childhood schizophren* S2 autis* or asperger* Specific causes of ASD are currently unknown. Condition autis% or asperger% or PDD% or ASD% or pervasive AND Intervention "2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* See the section below for theories about the link between autism and heavy metals. He was an unpaid Board Member of Support and Advocacy for Autism Spectrum Individuals and Families. For children in the control group who completed phase two of the trial, the mean score on the ADOS sociability subscale decreased from 8.1 at the beginning of phase two, to 7.9 at the end of phase two.
Searched 7 November 2014. 18 alternative medicine/ 21 (edetate or Edetic Acid or Egtazic Acid or Fura‐2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).mp. 2 Developmental Disabilities/ 1946 to November Week 3 2013, searched 5 December 2014 (130 records) 22 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).mp. (21516) This phase assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who had received a three‐day course of oral DMSA.
Some may present with behavioural symptoms (e.g. irritability, aggression, anxiety, self injury, hyperactivity); these features do not determine the diagnosis, rather they are co‐occurring symptoms. However, they have also been used for unapproved reasons, including treatment of patients with Alzheimer’s disease, coronary heart disease and ASD (Ernst 2000; Dans 2002; Sinha 2006; Hedge 2009). #13MeSH descriptor: [Chelating Agents] explode all trees 17 ferrozine/ or pentetic acid/ or deferoxamine/ or enterobactin/ Only 65 participants completed phase one, and 49 heavy metal excreting participants were included in phase two. 5 asperger$.tw.
Natalie Silove’s salary is paid by NSW Health Service ‐ The Sydney Children’s Hospital Network #22 (dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb) Embase (Ovid), 1980 to Week 44. Limited to 2013 to 2014 (no records) 20 10 and 19 30 remove duplicates from 29 14 enterochelin/ S4 (pervasive N3 child*) #4 (pervasive near/3 child*) Limited to 2013 to 2014 (no records) It has been suggested that increased levels of toxic metals result in more severe symptoms of ASD, and that excretion of these heavy metals brought about by use of pharmaceutical chelating agents (chemicals that are injected into the blood stream to bind to and remove toxic heavy metals from the body) may lead to improvement of symptoms. #23 (edetate or Edetic Acid or Egtazic Acid or "Fura‐2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide) The experimental group received up to six more rounds of oral DMSA. 16 complexon$.tw. For children in the experimental group who completed phase two of the trial, the mean (SD) score on the PDD‐BI social approach behaviours subscale increased from 63.8 (20.6) at the beginning of phase two, to 70.8 (23.6) at the end of phase two. 11 ("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).af.
However, the numerous side effects of chelation therapy, including hypocalcaemia, renal impairment, musculoskeletal and gastrointestinal symptoms and even death (Morgan 2002; Brown 2006; Kosnett 2010), have led to the withdrawal of at least one planned study. S12 (MH "Chelating Agents+") #21 ("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown next (compound or ether)) or cyclodextrin or cyclophane or cuprizone) 10 or/1‐9 DocType=All document types; Language=All languages; Complete blood count (CBC) However, genetic factors and prenatal and perhaps postnatal environmental factors are believed to contribute to the onset of ASD, although the role of environmental triggers remains uncertain (Hallmayer 2011).  2 Developmental disabilities/ Scientific Electronic Library Online (SciELO) (scielo.br/cgi‐bin/wxis.exe/iah/). Two review authors (SJ and SS) independently extracted the following information from the included study using a data extraction form designed and piloted for this review.
Ovid MEDLINE, 1946 to October Week 5 2014. One hypothesis is that mercury or other heavy metals are present in greater quantities in children with ASD, compared with their peers, as a result of intrauterine exposure to maternal stores or intake, increased intake from immunisations (thimerosal), oral ingestion (fish or medication), inhalation (airborne pollution), increased absorption, altered metabolism or decreased excretion (Bernard 2001; Goldman 2001; Holmes 2003; Levy 2003; Counter 2004; Kern 2007). We first searched databases for this review in December 2013 and repeated the searches, beginning on 6 November 2014, to find new studies published in the intervening period.
6 kanner$.tw. Similar inconsistencies are evident upon examination of Pb9 with PDD‐BI and SAS. 8 Rett$.tw.
Database content last updated 4 December 2014. Further well‐designed studies from multiple locations and using larger numbers of participants are needed to better ascertain the effects of chelation for ASD. Finally, trialists downplayed the variability of heavy metal levels and the severity of ASD, stating, “Since the toxic metal excretions exhibit considerable correlation amongst themselves, one should refrain from reading too much into the relationships between specific metals and severity of autism" (p 6).
Database : article #14 [mh "Iron Chelating Agents"] CDSR 2014, Issue 11, searched 6 november 2014. 19 or/11‐18 3 (PDD or PDDs or ASD or ASDs).tw. 4 (pervasive adj3 child$).tw.
The trial that we found was conducted in two phases. #26 #11 and #25 Low risk: if a study has a protocol and all prespecified outcomes were reported in the prespecified manner, or if a study has no protocol but all expected outcomes have been reported. ADOS: Autism Diagnostic Observation Schedule. #6 TS =(metal near/3 antagonist*) The quality of the evidence is poor, with only one study, which had methodological shortcomings, included in this review. #1 TS=(autis* or asperger* or ASD or ASDs or PDD or PDDs or Pdd‐NOS or ("pervasiv* development* disorder*" ) or kanner* or Rett*) Blinding was not done (performance bias) #3(pervasive next development* next disorder*):ti,ab Database of Abstracts of Reviews of Effects (DARE) 2014, Issue 4, part of the Cochrane Library. metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com/mrct/search.html). 2014 (Issue 11), searched 6 November 2014. #18complexon*:ti,ab Given that both the experimental group and the control group received an initial round of oral DMSA in phase one, carry‐over effects may have occurred. The included study compared one round of oral DMSA versus multiple rounds of oral DMSA. #19(chelation or chelating or chelator*):ti,ab 2013 (Issue 11), searched 5 December 2013 (2 records) #6 autis* Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed.
15 Iron Chelating Agents/ #4 TS=(chelation or chelating or chelator*) In the included study, 77 children completed the required blood collection at the beginning of the trial. Currently no clinical trial evidence suggests that pharmaceutical chelation is an effective intervention for ASD. Phase 1 ‐ 1 round of oral DMSA: 10 mg/kg dose, 3 ×/d, for 3 days #23(edetate or Edetic Acid or Egtazic Acid or "Fura‐2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide):ti,ab Incomplete outcome data.
3 (PDD or PDDs or PDD‐NOS or ASD or ASDs).tw. The severity of ASD varies considerably from person to person, and great variability in symptoms and manifestations has been reported. Individuals with ASD have difficulty showing social‐emotional reciprocity (e.g. participating in reciprocal conversations, maintaining eye gaze), communicating verbally and non‐verbally, forming and maintaining relationships and understanding the social behaviour of others (Shattuck 2007; APA 2013). This review included only one study, which compared children who received one round of oral dimercaptosuccinic acid (DMSA) versus children who received multiple rounds of oral DMSA, and found no significant differences with regard to autism spectrum disorder (ASD) symptoms. Limited to 2013 to 2014 (no records) S13 complexon* Prenatal mercury poisoning may result in neurological impairment, global developmental delay and intellectual disability, and postnatal exposure can result in memory loss, irritability, fatigue, intention tremor, skin discolouration and other organ involvement, including kidney dysfunction (e.g. nephrotic syndrome, tubular dysfunction, or both) (Bakir 1973; Amin‐Zaki 1974; Grandjean 1997; Goldman 2001; Counter 2004).
An alternative hypothesis is that mercury or other heavy metals can cause ASD through altered cellular functioning, which does not require increased body stores or circulating mercury or other heavy metals. The between‐group difference was reported to be non‐significant. All randomised controlled trials of pharmaceutical chelating agents compared with placebo in individuals with ASD.
DocType=All document types; Language=All languages; One of these studies also reported elevated levels of heavy metals (lead, thallium and tungsten) in urine (Adams 2013). His work is not related to chelation, and he receives no personal funds. Natalie Silove: contributed to the write‐up of the protocol and the review and reviewed the included study.
Searched 7 November 2014. High risk: if no blinding of outcome assessment was reported and the outcome measurement was likely influenced by lack of blinding, or if blinding of outcome assessment was reported but it is likely that blinding could have been broken and the outcome measurement influenced by lack of blinding. S18 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin) DocType=All document types; Language=All languages; Searched 7 November 2014. For children in the control group who completed phase two of the trial, the mean score on the ADOS communication subscale decreased from 6.7 at the beginning of phase two, to 5.9 at the end of phase two. ATEC: Autism Treatment Evaluation Checklist.
One trial, which had methodological issues and a relatively small sample size, is insufficient to provide robust evidence on chelation for ASD. Natalie receives no personal funds. WorldCat (limited to theses and dissertations) (www.worldcat.org/)). S8 Rett* We rated risk of attrition bias as low, given that the reason for missing data was deemed unlikely to be related to the true outcome.
Searched 20 November 2014 Ovid MEDLINE In‐Process and Other Non‐indexed Citations, 5 November 2014. Phase 2 ‐ up to 6 more rounds of oral DMSA: Each round consisted of 10 mg/kg dose, 3 ×/d, for 3 days, followed by 11 days of no DMSA. 1 exp pervasive developmental disorders/ 15 (chelation or chelating or chelator$).af. Seached 9 December 2013 ( 5 records) A total of 82 children, aged three to eight years, enrolled in the included study, of whom 77 completed the required initial blood collection (to assess baseline liver and kidney function, red blood cell (RBC) glutathione, and complete blood count (CBC)). University of Melbourne, Australia.
Unclear risk: if lack of information prohibits judgement of low or high risk of bias, or if the study did not address this outcome. Individuals of any age diagnosed with ASD using established diagnostic criteria (e.g. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV)) or standardised diagnostic instruments (e.g. the Childhood Autism Rating Scale (CARS), the Autism Diagnostic Observation Scale (ADOS), the Autism Diagnostic Interview ‐ Revised (ADI‐R)) were eligible for inclusion in this review. (www.controlled‐trials.com/mrct/search.html) 22 ("2,2’‐Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).mp. Limited to em=201349‐201444 (35 records) High risk: if participants and trial investigators had foreknowledge of intervention assignment.
Limited to up=20131125‐20141103 (23 records) Given the deleterious effects of chelation, misinterpretation and misuse of the study of Adams et al to justify the use of chelation for ASD is unethical and potentially places children unnecessarily in harm’s way. Searched 20 November 2014 24 10 and 23 For children in the control group who completed phase two of the trial, the mean score on the ADOS stereotyped behaviours and restricted interests subscale was 3.5 at the beginning of phase two and 3.5 at the end of phase two. Changes in the following non‐core behaviours, using any measure (e.g. #12 #11 AND #3 Study flow diagram.
4 autis$.tw. Google Scholar (scholar.google.com/). (www.worldcat.org) Searched 7 November 2014 (no new records) As such, the included trial was able to answer only the following question. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. #17 (Fursultiamin* or TTFD or "thiamine tetrahydrofurfuryl disulfide") Review question DocType=All document types; Language=All languages; Background 20 (dimercaprol or dimercaptosuccinic acid or dimercapto succinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).mp. During phase two, four children dropped out after experiencing adverse events, including sleep problems (n = 1; experimental group), worsening of behaviours and skills (n = 1; experimental group), increased self stimulatory behaviour (n = 1; control group) and regression of behaviour (n = 1; control group).
DocType=All document types; Language=All languages; #8 kanner* Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Advanced search: autism OR aspergers OR ASD OR pervasive | chelation OR chelating OR chelator OR DMSA #3 #2 OR #1 DARE 2014, Issue 4, searched 6 November 2014. For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD‐BI social approach behaviours subscale increased from 68.2 (25.4) at the beginning of phase two, to 72.6 (20.2) at the end of phase two.
To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms. Searched 9 December 2013 (no records)
Chelation for autism spectrum disorder (ASD)
<
p>It has been suggested that the severity of autism spectrum disorder (ASD) symptoms is positively correlated with the level of circulating or stored toxic metals, and that excretion of these heavy metals, brought about by the use of pharmaceutical chelating agents, results in improved symptoms. DocType=All document types; Language=All languages; For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD‐BI aggressiveness subscale decreased from 11.4 (8.1) at the beginning of phase two, to 8.4 (7.2) at the end of phase two. #9 TS= (edetate or Edetic Acid or Egtazic Acid or "Fura‐2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide) 20 (chelation or chelating or chelator$).tw. Of these, 65 children completed phase one, 49 high heavy metal excreters continued to phase two and 41 completed phase two. 18 16 and 17 Searched 9 December 2013 (2 records) In the event of uncertainties and differences of opinion, resolution was reached through discussions with the third and fourth review authors (NS and KW).
S16 (dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb) 11 or/1‐10 #11 #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 During the second phase, a subset of participants ‐ high heavy metal excreters ‐ from phase one were randomly assigned to receive three days of oral DMSA (experimental group) or placebo (control group) followed by 11 days off, with this cycle repeated up to six times. Few studies have examined the effectiveness of chelation for ASD, and no true randomised placebo‐controlled trials were identified for this review. (search.bvsalud.org/portal/advanced/?lang=en) The included study also appears to have biases related to the validity of the statistical conclusions. Type of ASD (e.g. autistic disorder vs Asperger’s disorder) This phase tested whether topical glutathione was absorbed and whether topical glutathione was effective for increasing the effectiveness of oral DMSA. 
Cochrane Central Register of Controlled Trials (CENTRAL) 2014, Issue 11, part of the Cochrane Library. Moreover, because minerals and metal ions are essential elements that serve important functions in multiple biological processes, excessive removal can lead to deleterious results, for example, a child with ASD recently experienced fatal myocardial necrosis resulting from hypocalcaemia after receiving chelation therapy (Brown 2006).
The ATEC was administered at the beginning of phase one and at the end of phase two. Low risk: if other sources of bias (e.g. contamination, recruitment bias) do not appear to exist. It is interesting that trialists found differential directions of heavy metal excretion and change in ASD indices, yet they attempted to convince the reader not to read too much into these differences. Children in the control group received up to six rounds of placebo (methyl cellulose), which was similar to DMSA in appearance and was packaged in identical bottles.
Severity of autism symptoms (Pervasive Developmental Disorder Behavior Inventory (PDD‐BI); Autism Treatment Evaluation Checklist (ATEC); Severity of Autism Scale (SAS); Autism Diagnostic Observation Schedule (ADOS)) Adverse effects commonly reported with the use of pharmaceutical chelating agents are listed in Table 1 . High risk: if a non‐random component was used in the sequence generation process. S9 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 
Social Sciences Citation Index: 1970 to 4 December 2013, searched 5 December 2013 (18 records) HTA 2013, Issue 4, searched 5 December 2013 (no records) Chelation therapy is administered for approved uses in a highly controlled environment, which is different from the process followed by practitioners administering chelation for unapproved uses, such as for ASD. Historically, Asperger’s disorder, autistic disorder, atypical autism and pervasive developmental disorder not otherwise specified (PDD NOS) were considered separate, diagnosable conditions that fall within the autism spectrum. The PDD‐BI, SAS and ADOS were administered at the beginning of phase two and at the end of phase two.
Stephen James: wrote the protocol and the review, screened records, reviewed the included study, assessed risk of bias and managed production of the review. Search on : autism OR autistic OR asperger OR ASD OR pervasive [All indexes] and chelation OR chelating OR DMSA [All indexes] 3 pervasive development$ disorder$.tw. The purpose of this review was to assess the evidence for the effects of pharmaceutical chelating agents for symptoms of ASD. Pharmaceutical chelating substances (referred to as chelation therapy throughout this review) are approved for treating patients with heavy metal poisoning. It is also uncertain whether parents knew that all children would receive at least one round of oral DMSA during the first phase, and that only high excreters would continue on to the second phase.
Outcome data were incomplete (attrition bias) #12[mh "Chelation Therapy"] Forty‐nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. S1 (MH "Child Development Disorders, Pervasive+") 19 complexon$.tw. For children in the experimental group who completed phase two of the trial, the mean score on the ADOS stereotyped behaviours and restricted interests subscale decreased from 3.9 at the beginning of phase two, to 3.5 at the end of phase two. 16 (metal adj3 antagonist$).af.
Based on our judgement that missing data and dropouts in the included study were unlikely related to the outcomes (and missing data appeared balanced across intervention groups, with similar reasons for missing data across groups), we did not contact the trial investigators for further information. 12 Chelation Therapy/ Each round consisted of three days on placebo, followed by 11 days off. ABC, CARS), as assessed separately. 2 (pervasive adj3 child$).tw. Although we attempted to minimise publication bias by using a comprehensive search strategy and by searching multiple sources, we may have failed to identify relevant trials.
Between 6% and 11% of families of children with ASD in various English‐speaking countries, including the United States, Canada and Australia, have sought out and tried chelation therapy; most of these families perceived that chelation therapy improved symptoms (Green 2006; Goin‐Kochel 2009; Christon 2010). For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD‐BI social pragmatic problems subscale decreased from 13.9 (7.5) at the beginning of phase two, to 9.9 (7.5) at the end of phase two. High risk: if missing data were reported and no appropriate methods were used to impute missing data, or if the reason for missing data is likely to be related to the true outcome.
Participants, caregivers and investigators in the included study were reported to be blinded to the treatment condition; however, it is unclear whether all lab technicians and ADOS evaluators were blinded. Study characteristics Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms. Natalie Silove works at the Children’s Hospital Westmead, which is enrolling up to eight participants in a phase two drug trial in adolescents with fragile X syndrome.