Abstract
Iron poisoning was a leading cause of pediatric morbidity and mortality. We sought to assess whether the removal of strict iron packaging requirements in 2003 resulted in an increase in iron-related morbidity and mortality in pediatric exposures. We performed a retrospective cohort study utilizing the National Poison Data System from 2000 to 2017. A total of 4110 exposures met inclusion criteria: 847 from before (2000-2003) and 3263 after removal of unit-dose package regulations (2004-2017). The incidence of any marker of severity (7.2% vs 3.8%; odds ratio = 0.51, 95% confidence interval = 0.37-0.69) and frequency of deferoxamine use were both higher in the early time period (2.6% vs 1.0%; odds ratio = 0.38, 95% confidence interval = 0.22-0.66). There was no difference in the frequency of key serious effects (acidosis, elevated transaminases, hypotension). Despite removal of iron packaging regulations in the United States, there continues to be a decrease in the incidence of severe iron exposures in children.
Introduction
Ingestion of large amounts of iron results in gastrointestinal (GI) toxicity, metabolic acidosis, shock, acute respiratory distress syndrome, hepatotoxicity, and death.1,2 Treatment includes supportive care with volume resuscitation, electrolyte management, decontamination via whole bowel irrigation (WBI), and deferoxamine.3,4 Despite aggressive care, severe outcomes including liver transplant and death may occur.4-6
In the mid-1990s, Berkovitch et al identified an increase in the number and severity of pediatric iron poisonings. 7 Armed with this information and several highly publicized cases from California, the US Food and Drug Administration issued new regulations in 1997 requiring child-resistant unit-dose packaging for iron products containing 30 mg or more of elemental iron.8,9 In 2005, Tenenbein reviewed annual reports from the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System and National Poison Data System (NPDS) and found a reduction in the number of exposures and deaths from iron per year after the passage of the regulation. 10
Unit-dose iron packaging regulations were removed in 2003 following the court ruling of Nutritional Health Alliance versus Food and Drug Administration. 9 It has been previously stated that there was no resultant increase in iron-related morbidity and mortality. 11 Unfortunately, these conclusions are drawn from a limited study without thorough evaluation of the incidence since the change in regulation. We sought to identify if there has been an increase in the incidence of severe iron exposures in pediatric patients in the United States after 2003 using data from NPDS.
Methods
This is a retrospective cohort study of pediatric iron exposures reported to the NPDS from 2000 to 2017. The NPDS is a database owned and maintained by the AAPCC. Specialists in Poison Information, usually pharmacists and nurses with training in toxicology, receive calls from the public, health care professionals, and others. Calls are coded for substance of exposure, dose, patient demographics, location of exposure, clinical effects, duration of effects, therapies provided, location of management, and medical outcome. Specific known medical outcomes are no effect, minor effect (exposure caused minimal symptoms), moderate effect (symptoms were more prolonged, more severe, or more systemic than minor and may necessitate treatment), major effect (symptoms were potentially life-threatening and necessitated therapy), and death.
Inclusion criteria were cases that involved (1) exposure to an iron-containing pharmaceutical product only (single-substance exposure), (2) exposure to a product with ≥30 mg elemental iron per dosage unit, (3) patients age 0 to 12 years, (4) cases followed to a known medical outcome, and (5) patients managed in a health care facility. Cases in which the iron formulation contained <30 mg per dosage unit or the milligram dose of iron per dosage unit was unknown were excluded.
The cohort was divided into 2 groups based on whether the exposure was before (2000-2003) or after (2004-2017) removal of packaging regulations. The primary outcome was incidence of severe disease due to pediatric iron exposures. We defined severe disease by presence of one or more clinical effects (acidosis, hypotension, liver injury) related to the exposure or the administration of life-saving therapies (deferoxamine, intubation/ventilation, and vasopressors). The incidence of these events in the 2 cohorts was compared using χ2 tests with odds ratio (OR) and 95% confidence intervals (CIs). Continuous data were compared using Student’s t test and are presented as mean and standard deviation (SD). A sensitivity analysis was performed by removing of 2004 and 2005 to allow for washout of the previously manufactured stock of restricted iron packaging. All analyses were performed using Prism 8.0.1 for Mac (GraphPad Software, San Diego, CA).
The institutional review board reviewed the study and deemed it not human subject research.
Results
There were 358 463 exposures among children aged 0 to 12 years to an iron-containing product over the 18-year period: 102 197 from 2000 to 2003 and 256 264 cases from 2004 to 2017. Only 4110 exposures met inclusion criteria (Figure 1): 847 from 2000 to 2003 and 3263 from 2004 to 2017. Most cases were excluded because the exposure was considered nontoxic (eg, dosed ingested was less than a potentially toxic quantity) and therefore not followed to a known outcome (67%). The mean age was 2.1 years (SD = 1.6), and 53.4% were male. The age and gender distributions were similar in the 2 time periods (Table 1). Reason for exposure was primarily unintentional-general (91.8%; n = 3775), followed by therapeutic error (5.9%; n = 242). Fewer patients were referred to a health care facility by the poison center in the late group (41.7% vs 52.5%; OR = 0.65, 95% CI = 0.56-0.75).
Exclusion and flow of pediatric exposures to iron containing products.
Demographics and Clinical Outcomes of Included Iron Exposures.
Abbreviation: SD, standard deviation.
The incidence of severe iron poisoning as defined by presence of at least one of the a priori defined effects or treatments decreased from 7.2 per 100 cases during 2000 to 2003 to 4.0 per 100 cases during 2004 to 2017 (OR = 0.56, 95% CI = 0.42-0.77). Use of deferoxamine was 2.6% in the early group and 1.0% in the late group (OR = 0.38, 95% CI = 0.22-0.66). There was a decrease in decontamination strategies, including WBI and gastric lavage in the late group. There was increased utilization of intravenous fluids in the late group. The result of the sensitivity analysis was consistent with the main analysis (any marker of severity OR = 0.47, 95% CI = 0.34-0.65; deferoxamine administration OR = 0.36, 95% CI = 0.20-0.63). There was no mention of ventilator or vasopressor use in the early group, limiting comparisons. The frequency of severe clinical effects did not differ between the groups (Table 2). There was one death in 2004 to 2017 and none in 2000 to 2003.
Primary Outcome Including Individual Key Interventions and Key Clinical Effects.
Abbreviations: CI, confidence interval; IV, intravenous; WBI, whole bowel irrigation; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
Interventions performed.
Discussion
Despite the removal of unit-dose iron packaging regulations in the United States, we did not identify an increase in severe iron exposures in pediatric patients. We identified a decrease in the frequency of severe pediatric iron ingestions.
We believe deferoxamine administration is an appropriate marker of disease severity because it is the treatment of choice for severe iron toxicity.1,11,12 Deferoxamine is indicated for iron intoxication with markedly elevated serum iron concentrations (≥500 µg/dL) and/or when significant clinical effects of iron poisoning are present, including metabolic acidosis, hypotension, and liver injury. Features of serious iron poisoning can be present within a few hours (hypotension, acidosis) or may be delayed up to 3 days (liver injury) after the overdose. 13 Although the overall use of deferoxamine was low across both time periods, the decrease in frequency of deferoxamine use suggests less serious poisonings in 2004 to 2017 compared with 2000 to 2003.
Additionally, the decreased frequency of decontamination procedures (WBI and lavage) in the late group could be due to ingestion of smaller quantities of iron or because treating health professionals deemed GI decontamination unnecessary. Alternatively, trends away from routine GI decontamination may have contributed to the decline in use of these procedures.
It has already been proposed that the rate of severe iron exposures was decreasing prior to the initiation of the iron packaging regulations and continued education and awareness might have further contributed to the decrease. 14 It is possible that our results reflect continued education and awareness among the population with at-risk children. Another explanation is that manufacturers continued to use child-resistant packaging even after the regulation was reversed, although some products are available in standard non-child-resistant containers.
We identified a decrease in the proportion of patients referred by poison centers to a health care facility in the late group. This reduction was from approximately 53% to 41% (P < .001). It is possible this was driven by a reduction in the number of large or serious ingestions. Alternatively, the AAPCC and American Academy of Clinical Toxicology published guidelines for referral to health care facilities for iron ingestions in 2005. 15 This consensus guideline may have reduced the number of referrals and decreased the use of aggressive GI decontamination.
The decrease in the number of iron-related deaths previously reported by other authors has some important limitations.10,11 These results were based off of the NPDS annual reports, which as of 2006, include only single-substance exposures in Table 2. 16 The previous study and conclusions were limited to analysis of only iron and iron salts rather than including multivitamins that can have large quantities of elemental iron. To address these limitations, we used individual cases, limited the analysis to single-substance exposures, and included multivitamins that contain large quantities of elemental iron.
Our study is limited in that it is a retrospective cohort design. The number of cases that met inclusion is relatively small, especially in the 2000 to 2003 group. Furthermore, not all cases of iron exposure are reported to poison centers and any analysis of the epidemiology should be assumed to be underreporting. Additionally, it is possible that some clinical effects and treatments are underreported, but likely that the more serious effects and life-saving interventions are captured. We included only patients managed in a health care facility since we wanted to evaluate the potentially more serious cases. As such, we excluded almost 80 000 cases managed on site (at home). Serum iron concentrations are often reported to poison centers, but not uploaded to the NPDS, so it is unknown what proportion of the exposures were verified by laboratory findings. Another large number of excluded cases are those in which the iron dosage per unit was unknown. There are also a large number of cases not followed because they were judged either nontoxic or only minimal effects possible. However, these cases by definition would not be expected to involve high enough doses to produce toxicity.
Conclusion
Removal of iron packaging regulations in the United States did not result in an increase in iron-related morbidity and mortality in pediatric patients. In fact, there continues to be a decrease in the incidence of severe iron exposures in children.
Footnotes
Authors’ Note
The American Association of Poison Control Centers (AAPCC) maintains the national database of information logged by the country’s poison control centers. Case records in this database are from self-reported calls: they reflect only information provided when the public or health care professionals report an actual or potential exposure to a substance (eg, an ingestion, an inhalation, or a topical exposure, etc), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs, and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
The study was presented at the 39th Congress of the European Association of Poisons Centres and Clinical Toxicologists, May 24, 2019, Naples, Italy.
Author Contributions
All authors contributed to the conception and design of the study, JBL contributed to acquisition, analysis, and interpretation. EQH and WKS contributed to interpretation. JBL drafted the manuscript. All authors critically revised the manuscript, gave final approval for the manuscript, and agree to be accountable for all aspects of work ensuring integrity and accuracy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
