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Table of Contents   
ORIGINAL RESEARCH  
Year : 2015  |  Volume : 26  |  Issue : 6  |  Page : 582-587
Analysis of adverse events with use of orthodontic sequential aligners as reported in the manufacturer and user facility device experience database


1 Director and Consultant Oral Pathologist, Marundeeshwara Oral Pathology Services and Analytics, Chennai, Tamil Nadu, India
2 Department of Dentistry, Madurai Medical College and Hospital, Madurai, Tamil Nadu, India

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Date of Submission10-Nov-2015
Date of Decision26-Dec-2015
Date of Acceptance12-Jan-2016
Date of Web Publication18-Feb-2016
 

   Abstract 

Background: Sequential aligners (SAs) introduced about a decade ago, changed the practice of orthodontics as we knew it but the adverse events and reactions (AER) associated with SA is not known. The Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is a reliable database that has AERs reported. The manuscript attempts to review the AER associated with SA using the MAUDE database.
Materials and Methods: The authors downloaded and reviewed the SA-related AER from MAUDE for a period of 5 years. In-depth analysis of the site and nature of intraoral and extraoral AERs were performed. We attempted to calculate the probability of pathologies being directly related to SA use, using Bayes' theorem.
Results: In the study period of 5 years, 175 cases of AER registered with MAUDE database owing to use of SA. Of the 175 cases, 129 (73.71%) instances were mandatory reports filed by the manufacturer. Of all AERs, 32 (18.29%) cases had been diagnosed/suspected to have an allergic reaction, 20 (11.43%) of them with anaphylactic reaction and 4 (2.29%) of them with angioedema. Lesions involving tongue, throat, and lip such as soreness, inflammation, and hives were more commonly reported. In addition, 12 cases (6.86%) reported of nausea, 11 (6.29%) of gastrointestinal issues (stomach upset, diarrhea, and vomiting), 13 (7.43%) of neuromuscular issues (muscle cramps, spasm, and pain), 13 (7.43%) of cough, 10 (5.71%) of persistent headache, 3 (1.71%) of fever, and 12 (6.86%) of cardiac-related issues were identified.
Conclusions: The AERs associated with SA has been described. Though the MAUDE database is not an exact, wholesome and reliable source to identify the potential AER, currently, it is the only available source of AERs associated with SA use. The nature of AERs with the use of SA and its potential pathogenesis and implications has been discussed.

Keywords: 1,6-hexanediol diacrylate, adverse events, allergy, anaphylaxis, malocclusion, MAUDE database, methylene diphenyl diisocyanate, orthodontics, thermoplastic resins, transparent fixed appliances, sequential aligners

How to cite this article:
Thavarajah R, Thennukonda RA. Analysis of adverse events with use of orthodontic sequential aligners as reported in the manufacturer and user facility device experience database. Indian J Dent Res 2015;26:582-7

How to cite this URL:
Thavarajah R, Thennukonda RA. Analysis of adverse events with use of orthodontic sequential aligners as reported in the manufacturer and user facility device experience database. Indian J Dent Res [serial online] 2015 [cited 2018 Oct 19];26:582-7. Available from: http://www.ijdr.in/text.asp?2015/26/6/582/176919
The pursuit of invisible and comfortable fixed orthodontic appliances has led to the development, refinement of technologies such as lingual orthodontics and sequential aligners (SAs). [1] Among such developments, SAs have caught the fancy of the patient as they are described to be "Metal-free," "Invisible," "technology-driven," and "sophisticated" conveniently dispensed and has been aggressively marketed among dental professionals and potential patients alike. [2] The SA is reported to use high-grade thermoplastic resin using a thermoforming process on models of patients. A patient wearing SA is expected to wear a single set of appliance for a period of no <14 days (after which they are replaced), and at least 20-22 h for each day. The malocclusion is slowly relieved by the use of constant, controlled forces using at least 12-40 sets of different aligners, depending on the degree of malocclusion. [1],[3],[4]

The polyurethane thermoplastic (PUT) material used in such aligners is reported to be a proprietary one with each corporation claiming their own formulations and "hypo-allergenic materials." The safety and biological nature of such thermoplastic material have been an issue of contention among professionals. [3],[4],[5],[6],[7] There are occasional reports of allergy to such SA materials. [3] Traditionally, PUT resins with regular use are supposed to release methylene diphenyl diisocyanate (MID) and 1,6-hexanediol diacrylate (HD), both of which are known toxins, with a melting point of about 37-39°C and 5°C, respectively. [8],[9] At this temperature, they are released from PUT. At a concentration of above 0.02 parts per million (ppm, MID are known to predispose the affected the individual to contact dermatitis and host of other allergic reactions. The workplace environmental exposure level norms propose that 8 h time-weighted average for MID to be 0.005 ppm and for HD is 1 mg/m 3 beyond which they may prove toxic to humans. [8],[9],[10],[11],[12],[13],[14],[15] In addition, SA is often continually exposed to salivary proteins, enzymes, buffers, liquids/solid foods, inhaled and exhaled air, microtrauma caused by swallowing, and speech along with the microbiological product interaction, none of which can be mimicked in the laboratory. [1],[5] The resultant shift in the immunobiology of the host tissue is largely unknown.

The Food and Drug Administration (FDA) of the USA government oversees all the health-related products and devices. The Manufacturer and User Facility Device Experience (MAUDE) (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/search.cfm) is a database maintained by the FDA that receives both individual voluntary reports from health care providers and consumers, and individual mandatory reports from manufacturers and user facilities. [16] It is mandated by the FDA that once the manufacturers or the distributor network becomes aware of adverse events and reactions (AER), they are to report to FDA within 30 days while user facilities are obligated to file the AER within 10 days in the prescribed narrative format. The reporting by patients or their immediate attendant is voluntary. The MAUDE database contains the submitted anonymous narrative description of the AER, manufacturer's versions and conclusions about reported events.

There is a paucity of data in literature with regards to adverse events rising with the use of SA. The aim of this study is to collate and list the possible AER associated with the use of SA.


   Materials and Methods Top


In this study, all AER, as defined by FDA (any undesirable experience associated with the use of a medical product in a patient) by the usage of SA, as identified by the unique code supplied, (NXC) between October 1, 2010, and September 30, 2015, were collected from the MAUDE database. These data were then categorized as below:

  • Informant: Patient/immediate relative; dentist; other health care professionals (nondentists); others
  • Reported by patient/immediate relative; manufacturer
  • The manufacturer and the type of SA used
  • Preexisting conditions
  • Nature of AER and related details
  • Use of medications, re-insertion, details of use.


These data were then entered in Statistical Package for Social Services (SPSS version 20.0, IBM, IL, USA). Descriptive statistics were performed and presented.

For this study population, the rate of AER were categorized intraoral complications; Facial complication in the facial region; head and neck complication; head, neck, and dental complication; head, neck, and oropharyngeal complications; head, neck, dental, and oropharyngeal complications. The frequency and percentage were calculated. Bayes theorem was used to identify the probability of having an AER for a particular site. [17]



Where P (A 1 |B) the probability of having a specific type of AER related to aligner use; P (A 1 ) is the probability of having an AER; P (B|A 1 ) is the Conditional probability of having a specific site of AER given having AER; P (A 2 ) is the probability of not having AER and P (B|A 2 ) is the conditional probability of having similar type of sign/symptom even in absence of AER (same as chance in the general population).

Using the above formulae, a calculation page was constructed in Microsoft Excel. A value from rate of AER was used along with prior assumption as mentioned -1 in 100 to 100,000 to calculate probabilities of an AER occurrence. The results of such probabilities are presented.


   Results Top


In the study period of 5 years, there were 175 cases of AER registered with MAUDE database. Of the 175 cases, 129 (73.71%) instances were mandatory reports filed by the manufacturer. The informant was a dentist in 65 (37.14%), health professional in 63 (36.00%), patient or immediate attendant in 45 (25.71%), and others in 2 (1.14%). There were 14 brands from 6 manufacturers, with 1 manufacturer having 151 AERs reported. In the last 3 months of 2010, there were 8 cases of AERs, 59 in 2011, 24 in 2012, 28 in 2013, 27 in 2014, and 29 cases in first 9 months of 2015 being reported at MAUDE. Of the 46 cases with known stage of treatment, 32 (69.57%) were in the first phase of treatment and another 11 (23.91%) in initial four phases of treatment.

In the 175 AER instances, medications were required in 55 (31.43%, no detail in 119 cases) instances, 24 (13.71%) patients removed SA and retried them. Of the 175 cases, 59 (33.71%) declared that they discontinued use of SA (109 - no details available) after the occurrence of AER. Among the AERs, 7 (4%) declared that they had known the history of allergy to certain food items and or latex, 1 patient (0.6%) had each of angioedema, diabetics, posttraumatic stress disorder, and another one had a long-standing "incipient lesion." Of all the AERs, 32 (18.29%) cases had been diagnosed/suspected to have an allergic reaction, 20 (11.43%) of them with anaphylactic reaction, and 4 (2.29%) of them with angioedema. They were diagnosed by their physician or at the emergency room consultation.

The nature of AERs varied considerably in terms of site and presentation as detailed in [Table 1] and [Table 2]. In 23 (13.14%) cases, the distant sites such as limbs and generalized involvement as rashes or hives were involved. These symptoms were grouped as intraoral AERs 68 (38.86%), 77 (44%) AERs in facial region, 96 (54.86%) in head and neck AERs, 108 (61.71%) in head, neck, and dental AERs, 132 (75.43%) as head, neck, and oropharyngeal AERs, and 139 (79.43%) as head, neck, dental, and oropharyngeal AERs. There were exclusive 20 (11.43%) dental complaints - 4 (2.3%) occlusion issues, 3 (1.7%) dental decay, 5 (2.9%) periodontal issues leading to loss of teeth and 8 (4.6%) complaints of either unfavorable attrition, loss of veneers, and chipping of teeth.
Table 1: Some of the common sites involved in the adverse reactions in the study population


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Table 2: Comparison of adverse reaction sites as reported by manufacturer and patient sources


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Twelve cases (6.86%) reported of nausea, 11 (6.29%) of gastrointestinal issues (stomach upset, diarrhea, and vomiting), 13 (7.43%) of neuromuscular issues (muscle cramps, spasm, and pain), 13 (7.43%) of cough, 10 (5.71%) of persistent headache, 3 (1.71%) of fever, and 12 (6.86%) of cardiac issues ranging from chest pain, fast heartbeat, sinus arrhythmia to a case of suspected congestive heart failure. Two cases of candidiasis and one case of herpes infection were reported. Interestingly, one case of associated trigeminal neuralgia, ovarian cancer, gastrointestinal tumor, malignant melanoma, and liver damage was reported. Also, two cases of oral squamous cell carcinoma (OSCC) were reported. On comparing the incidence of AERs, there was no statistical significant difference in the pattern of AERs as reported by manufacturers or patients [Table 2].

In most of the situations, the manufacturer's narrative claims that the condition and symptoms most probably are not related to use of SA. As MAUDE database does not allow root cause analysis, we attempted to calculate the probability of pathologies being directly related to SA use, using Bayes' theorem. It was assumed that the prevalence of abnormalities in the general population (spontaneously and unrelated to SA) was assumed to be 1 in 100,000 [Table 3]. The probability of having an AER was assumed to be 1 in 100, 1 in 1000, and 1 in 10,000 [Table 3]. The probability of various intraoral sites AERs as directly related to SA use is depicted in [Table 3] for each of the assumed "priori."
Table 3: Bayesian projection to associate adverse reaction to aligner use than those claimed to be unrelated in nature


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   Discussion Top


Experiments designed to mimic SA intraorally, barring microbial interactions and microtrauma revealed that with use, SA trays exhibited surface and molecular changes, particularly reduction in isocyanate bond numbers. [1] However, the extract of the artificial saliva incubated with SA revealed no traces of deductible organic residues. [1],[5] This could be due to the fact that the devices lacked sufficient sensitivity to detect minute levels of organic residues. Moreover, the background or environmental presence of toxins such as MID and HD, fumes from resins used in flooring, paints and various PUT resin products used in day to day life is not considered. In real life scenario, the amount of toxins from SA leeching out may be acting synchronously and cumulatively with background toxins to cause allergic or anaphylactic reactions or trigger nonspecific reactions. The elevated immunoglobulin E levels in few narrative reports in MAUDE database is a testimony to this. In addition, in cell cultures, oral epithelial cells reacted to SA to have certain deleterious changes. Continuous exposure of the most commonly involved SA material, led to changes in gingival cell viability, membrane permeability, and adhesion of epithelial cells in an artificial environment, mimicking oral cavity. Such changes are reported to lead to reduced epithelial integrity. This may lead to microleakage and hapten formation, probably resulting in an isocynate allergy. [5]

The allergic and anaphylactic reactions due to SA materials are sparse in dental/allergic literature. One of the basic dictum of medical practice is "do no harm," and thus all practicing medical professionals are required to have adequate knowledge of all the potential threats to patients safety. [18] In the current scenario, to the best of our knowledge, MAUDE is the only relatively reliable source of such knowledge base of AER mediated by dental devices and products. In a report in Journal of American Dental Association in the early 2015, [18] the rate of adverse events as concerned to dentistry was being listed, a 1 st time, to the best of our knowledge. This report was more of a safety warning that dental devices and materials are not free from risky events. But such reports help to collect and share knowledge of unknown, unheard, and unreported risks. The limitations of reports originating from MAUDE databases are that the content is not validated and has the chance of multiple reporting, degree of severity nor is casual/definitive association not being provided. [18] However, the narrative reports have definitive details that have been taken for this analysis. The AERs have been due to technique or biological issues such as those considered here in. Unless a root cause analysis is presented, the definitive conclusion could not be arrived. However, in the present condition, AERs reported in MAUDE database are much clearer yet as any study on archival reports carries a degree of limitation. Also, MAUDE for dentistry is relatively underutilized resource and does not cover contributions from all of the dentists in the US or other parts of the globe. However, the data presented provides a robust estimate of the AERs rather than as in real time scenario. [18] MAUDE also carries a note that it should not be used to evaluate rates of AERs or to compare AER rates across devices. [18]

The results of the present study indicate that the use of SA is associated with a spectrum of allergic/anaphylaxis manifestation. It ranges from a simple sore throat to a full body hives or swelling and or rashes. [Table 4] shows the percentage of such manifestation and reflects that certain sites being involved more commonly than others. As there is no large-scale study to refute or support this claim, it could be assumed that such numbers are robust in nature. Previous such MAUDE database studies in gynecology, cardiac devices have been accepted widely. [19],[20],[21],[22],[23] The present values, though not accurate and whole sum representation of the AERs associated with SA but give a fair projection and also to inform potential patients for fair, decision-making process.
Table 4: Spectrum of adverse reaction in different sites in the study population


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Bayesian statistics follows the probabilistic approach, in which the probability for an event is considered. Unlike the standard, traditional frequentist's approach, [17] this approach helps to determine the probability of an event, like an AER or its site. In this study, we utilized a realistic possibility (among general population) like 1 in 100 to 1 in 100,000 for conditions like sore/reddening/inflamed throat which is much closer to the real-time scenario. If we were to assume that the chance of AER occurrence of 1 in 100/1 in 1000/1 in 10,000 of all SA users, which by itself, is a fair assumption or a "priori." Still, the probability of occurrence of an AER or site, being associated with SA use as given in [Table 3] seems to be in good faith. The probabilities indicate that AER is most commonly associated with SA use rather than other causes, as claimed by the manufacturer.

The high probability for sites such as throat, lips, tongue, and dyspnea to occur is extremely high when assuming that the conditional chance of having an AER with SA use is 1 in 10,000 while those occurring in the general population is 1 in 100,000. Hence, it is prudent that the dispensing dentist needs to ensure every possible precaution before starting on SA. For example, in a single case, where dental surgeon noted an "incipient lesion" in palate which was ignored that after substantial use of SA was diagnosed as OSCC. OSCC in another instance was diagnosed in a nonsmoking, nonalcohol consuming patient with no familial history. Such instances were SA-based orthodontic treatment could have played a role in OSCC causation. There are such orthodontic-OSCC association reports in the literature. [24] In another case, there was a persistent perioral rash, which on consultation with a dermatologist, was diagnosed as a "malign" melanoma, to which interestingly "antibiotics" were prescribed. In yet another cases of gastrointestinal tumor and ovarian cancer, the patient complained that they probably got their tumors owing to use of SA over a period of time. On the contrary, in one instance, the patient had mild allergic symptoms with the use of SA. With each new set of aligners, the patient developed reddening of mucosa. When the SA was regularly washed with soap and water rigorously, the symptoms of redness vanished. This phenomenon could be possibly that toxins being diluted or washed away from SA. [5]

The material used by each SA companies varies. At least 14 brands from 6 companies have found to be associated with SA in MAUDE database during the study period. As the material safety data sheet is not available, the composition of the materials remains obscure. As the process of procuring, composition and manufacturing of SA varies between companies, the exact composition and safety of material remain not clear.

The presence of PUT, MDI, and HD are largely from literature. [3],[4],[5],[25],[26],[27],[28],[29] Similarly, the presence of similar background toxins needs to be considered while suggesting patients for SA to prevent potential AERs. Also, to avoid instance of AERs, patient's predisposal to common allergens should become a part of detailed pretrial history taking to avoid such instances. Nearly, 4% of the study population had a preexisting history of allergy/angioedema which was probably overlooked by the attending dentists. At least, a third of patient required medication such as steroids to control the AERs. This underlines the seriousness of the AERs arising by the use of SA. Interestingly, only a very limited number of malfunction and compatibility issues were noted for such a high precision job.

The high probability of AERs being associated with dyspnea, lesions of throat, lips, and tongue indicates that there is a strong, direct, common immunological mechanism behind the occurrence of AER. This fact warrants a further detailed analysis and wider research. Further clinical research and case reports should be accompanied by a detailed patient allergic and immunologic workup so that AERs can be prevented thereby making SA safe for patients.


   Conclusion Top


The adverse events associated with the use of SAs, to the best of our knowledge, have been listed for the 1 st time. As with any dental material, they are not free from risk of allergic reaction. As MAUDE database has its own limitations, the numbers arrived in this study have to be interpreted with caution. Dentists and patients have to take an informed decision on pertaining issues. The pathways by which the organic residues causing oral -and extra-oral lesions needs to be studied in-depth. Until then, the robust numbers projected here may be useful to the health care professionals for educating the potential users for informed decision-making process.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Correspondence Address:
Dr. Rooban Thavarajah
Director and Consultant Oral Pathologist, Marundeeshwara Oral Pathology Services and Analytics, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.176919

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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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