Sex Differences in Pediatric Poisonings by Age Group: a Toxicology Investigators’ Consortium (ToxIC) Analysis (2010–2016)

Abstract

Introduction

Poisoning is a continued cause of morbidity and mortality in the pediatric population [1, 2]. Children younger than 20 represented close to 60% of all exposures reported to the National Poison Data System (NPDS) in 2017, and analgesics exposure was the most common cause of mortality due to poisoning in children < 5 years old [3]. The pediatric population is especially vulnerable to adverse drug reactions due to their unique physiological profile, such as their lower muscle mass and subsequently less gluconeogenic precursors, leading to increased risk of hypoglycemia [2, 4]. Even in low acuity cases, pediatric pharmaceutical ingestions lead to hospital admissions and cause significant healthcare cost burden [5, 6]. The rise in unintentional pediatric poisonings has been linked to increased adult prescription use, especially of opioid, medication for addiction treatment, attention deficit hyperactivity disorder (ADHD), cardiovascular, and sedative hypnotic agents [1, 6–9].

Understanding the epidemiology of pediatric poisonings is important to develop more targeted interventions. Underlying causes of increasing reports of adolescent suicide attempts, particularly involving analgesics, psychotropic medications, and ADHD medications, are not well understood, but may be correlated with adolescent risky behavior, increased information sharing, and self- medication practices [10–12].

Current literature shows sex-based differences in risk behaviors and mental health diagnoses among adolescents, which may be due to exploration of gender and societal norms during puberty [13]. Boys are more prone to substance use disorders and self-medication, while girls are more at risk for suicide attempts [12, 13]. Previous research on sex differences in pharmaceutical ingestions has demonstrated sex-based differences in drug metabolism, and that females experience more adverse drug reactions, which may be due to lesser representation in clinical trials and subsequent lack of sex-specific dosing regimens [14, 15]. Examining sex differences, by age group, in a pediatric population may reveal how sex and age interact to modulate risk factors, clinical features, and treatment of poisonings. In this study, we set out to evaluate sex-based characteristics by age group in cases of pediatric poisonings that were evaluated by a medical toxicologist and submitted to the ToxIC (Toxicology Investigator’s Consortium) registry.

Patients and Methods

The ToxIC registry was established by the American College of Medical Toxicology in 2010 to create a central, de-identified database of patients seen by medical toxicologists in both inpatient and outpatient settings [16]. With over 50 participating facilities from the USA, Canada, Israel, and Saudi Arabia, the database captures more than 50,000 cases of toxicological exposures [16]. After consultation, medical toxicologists voluntarily complete forms, including information such as age and sex demographics, setting and reason for encounter (e.g., intentional and nonintentional exposures), toxicological agent, symptoms, and clinical interventions.

Cases of pediatric patients that were ≤ 18 years of age with known toxicological exposures from January 2010 through December 2016 were included in the study sample and analyzed. For consistency, standard categories for age and reason for encounter utilized in the ToxIC case submission system were also used in this study.

ToxIC defines “intentional pharmaceutical” as “intended use of approved medication for any purpose including self-harm, misuse/abuse, therapeutic use, or unknown.” Subcategories of intentional pharmaceutical use are also defined as follows: “attempt at self-harm”; “misuse/abuse”; “therapeutic use”; and “unknown.” “Attempt at self-harm” is further differentiated as either “suicide attempt,” where there is “at least some intent to die,” “no suicidal attempt,” where there “no intent to die, behavior for other reason such as to relieve stress,” or “suicidal intent unknown,” where “intent to die is unknown and cannot be inferred.” “Misuse/abuse” is defined as “no attempt at self-harm.” When selecting “misuse/abuse” as reason for encounter, the toxicologist can then select one or more of the following subcategories: “use of a prescription medication without a valid prescription”; “taking any prescription medication in doses greater than prescribed”; “taking any over the counter medication in doses higher than labeled”; “taking excess doses or using another’s medication for medical reasons (e.g., to treat a pain exacerbation)”; “taking a medication in an attempt to illicit a pleasurable sensation (e.g., to get “high”)”; or “taking the medication in an attempt to avoid withdrawal.” “Intentional non-pharmaceutical” as reason for exposure can also be similarly further defined, with one additional category: “drug concealment,” defined as “conceal drug with intent to avoid law enforcement.” Cases were excluded from the analysis if age or primary reason for encounter were missing, or if the toxicologist indicated that the consult was not related to a toxicological exposure. Demographic data of race, ethnicity, and pregnancy status were queried and reported as relative frequencies based on sex. Frequencies were categorized, and definitions used, based on the ToxIC Registry Data Sheet. Descriptive statistics (frequencies and percentages) were generated to summarize the reason for the encounter, exposure agent, route of administration, vital sign abnormalities, complications, and interventions performed by age group and by sex. When reporting descriptive statistics, any cases with “missing” or “N/A” were not included, but any cases with “unknown/uncertain” were still included. The study was presented to the lead author’s Institutional Review Board; it was reviewed and assigned a determination of Not Human Research, given that the study design involved analysis of an existing database housing de-identified data.

Results

From a total of 51,440 cases, 12,699 cases were analyzed (flow diagram, Fig. 1). There were 7517 females (59.2% of all cases) and 5182 males (40.8% of all cases). Those under 2 years old represented 12.5% of the study group (n = 1584): 17.2% were 2–6 years old (n = 2178), 8.6% were 7–12 years old (n = 1097), and 61.7% were 13–18 years old (n = 7840). Among 1584 cases under 2 years, there were 747 females (47.2% of cases < 2 years) and 837 males (52.8% of cases < 2 years). Among 2178 cases aged 2–6 years, there were 954 females (43.8% of cases 2–6 years) and 1224 males (56.2% of cases 2–6 years). Among 1097 cases aged 7–12 years, there were 555 females (50.6% of cases 7–12 years) and 542 males (49.4% of cases 7–12 years). Among 7840 cases aged 13–18 years, there were 5261 females (67.1% of cases 13–18 years) and 2579 males (32.9% of cases 13–18 years). For all ages taken together, the most common primary reason for a pediatric toxicology consult was for reported intentional pharmaceutical exposure (6736/12,699 or 53.0% of all cases), with females representing (4900/6736) 72.7% of those cases. The second most common primary reason for consult was intentional non-pharmaceutical (2165/12,699 or 17% of all cases) with males representing (1213/2165) 56.0% of those cases. Further demographics for all cases and by age group are described in Tables 1, ​,2,2, ​,3,3, ​,4,4, and ​and55.

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Fig. 1

Flow diagram for pediatric poisonings reported to the Toxicology Investigators’ Consortium 2010–2016. Unknown data—indicated by medical toxicologist as “unknown”; Missing data—data not reported by the medical toxicologist

When analyzing all pediatric cases by sex, cases involving intentional pharmaceutical use as reason for the consult represented 65.2% of all female cases (4900/7517) and 35.4% of all male cases (1836/5182). Intentional use of non-pharmaceuticals (defined by the consortium as the “use of a substance other than an approved medications for any purpose”) was found in 12.7% of all female cases (952/7517) and in 23.4% of all males cases (1213/5182). Unintentional use of pharmaceuticals and non-pharmaceuticals combined was found in 23.9% of all male cases (1237/5182) and 13.0% of all female cases (974/7517). Envenomations (snake, spider, scorpion, other) were reported in 7.7% of all male cases (399/5182) and 4.3% of all female cases (322/7157).

Detailed toxicological exposure data by age group and by sex are reported in Tables 6, ​,7,7, ​,8,8, ​,9,9, ​,10,10, ​,11,11, ​,12,12, ​,13,13, ​,14,14, and ​and1515.

When analyzing all pediatric cases by age group, among 1584 cases for patients with age less than 2 years (747 females and 837 males), the most common reported reason for consult was intentional non-pharmaceutical exposure (487/1584 or 30.7% of cases) with females representing (247/487) 50.7% of these cases. The most common agent involved among all reported exposures in this age group was cardiovascular medications (188/1522 or 12.4% of cases), with females representing (101/188) 53.7% of those cases.

Among 2178 cases for patients with age 2–6 years (954 females and 1224 males), the most common reported reason for consult was intentional non-pharmaceutical exposure (718/2178 or 33% of cases) with males representing (396/718) 55.2% of these cases. The most common agent involved among all reported exposures in this age group was cardiovascular medications (288/2091 or 13.8% of cases) with males representing (172/288) 59.7% of those cases.

Among 1097 cases for patients with age 7–12 years (555 females and 542 males), the most common reason for consult was intentional pharmaceutical (390/1097 or 35.6% of cases), with females representing (266/390) 68.2% of these cases. The most common pharmaceutical agent involved among all reported exposures in this age group was analgesics (97/1058 or 9.2% of cases) with females representing (85/97) 87.6% of those cases.

Among 7840 cases for patients age 13–18 years (5261 females and 2579 males), the most common reason for consult was intentional pharmaceutical (6204/7840 or 79.1% of cases), with females representing (4570/6204) 73.7% of these cases. The most common pharmaceutical agent involved among all reported exposures in this age group was analgesics (2248/7630 or 29.5% of cases) with females representing (1842/2248) 81.9% of those cases.

Among 38 reported cases that died during their hospital stay, 7 were < 2 years of age (3 females, 4 males), 3 were age 2–6 years (1 female, 2 males), and 28 were age 13–18 (16 females, 12 males). In the age < 2 years decedents, reasons for encounter were 4 unintentional pharmaceutical, 1 intentional pharmaceutical, 1 intentional non-pharmaceutical, and 1 for interpretation of toxicology laboratory data. Among decedents aged 2–6 years, reasons for encounter included 1 for withdrawal, 1 for environmental evaluation, and 1 for “more than one reason.” Among deaths in the age group 13–18, 19 were seen for intentional pharmaceutical, 4 for intentional non-pharmaceutical, 2 for interpretation of toxicology laboratory data, 2 for environmental evaluation, and 1 for organ system dysfunction.

Discussion

Pediatric cases queried from the ToxIC registry from 2010 to 2016 showed that more than half of the encounters were patients aged 13–18 and intentional pharmaceutical was the most common reported exposure. These findings suggest that this age group may be at increased risk of self-harm attempts through toxicological ingestions. Existing studies have also shown a rapid increase in intentional poisonings among adolescents in recent years, with drug overdoses and poisonings identified as the sixth highest cause of death in pediatrics in 2016 [17, 18]. Our results once again point to an urgent need for public health initiatives that identify and reduce adolescent poisonings, with a particular focus on self-harm attempts.

Given the common availability of pharmaceutical agents in home environments, as well as that an estimated 19.8% of children and adolescents are prescribed at least one medication, [19] prevention interventions, such as safer medication storage, safer pharmaceutical packaging, prescribing precautions, and prevention education may be important to reducing morbidity [20]. Among patients aged 7–12 years, intentional pharmaceutical exposures were most common, further suggesting that efforts may be needed to ensure medications are stored more safely in the household. Analgesics were the most common pharmaceutical agent among reported exposures in both the 7–12- and 13–18-year age groups, consistent with studies that have shown that over the counter products like analgesics are more likely to be stored improperly, thus potentially increasing access [1]. Existing literature suggests that analgesics are the most likely agent used in suicidal intent [18, 21]. Interestingly, analgesics are also the most common self- medication agent used by adolescents, due to perceived safety and widespread availability [12]. Together, these findings suggest that caregivers and adolescents may benefit from medication education specifically directed to analgesics, their storage, and their appropriate use.

In both under 2-year and the 2–6-year age groups, cardiovascular medications were most commonly implicated in reported exposures. Prior studies of children presenting to emergency departments with poisoning by medications have implicated cardiovascular medications as a common reported exposure [1, 7]. Prior ToxIC registry analyses of pediatric exposures have also implicated cardiovascular medications as a common reported etiology of toxicity [22]. While NPDS studies most commonly report analgesics as the most common agent involved in pediatric poisonings [3], cases reported to ToxIC registry are potentially higher acuity cases seen by a toxicologist, and thus, medications with potential to cause more severe toxicity may be more commonly reported in ToxIC-based research.

Our results describe characteristics in toxicological consultations by sex. Our study case numbers by sex among patients with unintentional pharmaceutical and non-pharmaceutical exposures aged 2–6 years appear to align with the most recent NPDS data, which reported increased risk of pediatric exploratory ingestions among males [23], and prior studies that show that toddler males were more prone to accidental ingestions [24]. While the reasons are unclear, males may express more exploratory behavior that puts them at risk for encountering improperly stored pharmaceuticals. Our study finding that envenomations were reported in 7.7% of all male cases and 4.3% of all female cases is consistent with studies that show males are more at risk for snakebites than females [25].

Our study findings that female cases represented 59.2% of all cases, 67.1% of all cases in the age 13–18 years category, and 73.7% of intentional pharmaceutical exposures among cases aged 13–18 years align with previous studies that found that adolescent females were more likely than adolescent males to attempt suicide through self-poisonings [11, 26]. Sex has been acknowledged as a moderator of adolescent suicidal behavior, with females more likely to overdose, while males are more likely to use firearms [27]. While the reasons are unclear, it may be due to exploration of social norms and gender roles during adolescence. Females are more likely to be body-conscious and consider the state of their body after suicide completion, while males are more familiar with using firearms [27].

Previous literature has shown that substance dependence is twice as common in adult and adolescent males as females [28]. Our study findings that males represented 60.4% of intentional non-pharmaceutical exposures and 57.5% of ethanol abuse cases among those aged 13–18 years are consistent with this literature. This may be due to gender norms that influence adolescent males to use substances in social bonding and to treat pain autonomously through self-medication [13]. In both males and females, substance dependence is associated with depression, trauma, and suicide risk [28]. Our results point to the need for further research focused on sex-specific initiatives that target adolescents in substance use prevention.

The most common clinical complication in the pediatric patients included in the ToxIC registry was tachycardia (63.1% were female), and bradycardia (56.4% male). Further research outside of a limited dataset, such as the ToxIC registry, would be needed to determine if there are statistically significant sex-specific differences in cardiotoxicity following pediatric poisonings that may mirror known sex differences in adult cardiotoxicity related to medications, such as antipsychotics and antidepressants [29].

There are several limitations to this study. Given voluntary reporting, cases seen by a toxicologist at institutions participating in the ToxIC registry may go unreported; thus, this data may not represent all bedside toxicology consults performed at ToxIC sites. Further, some toxicological cases presenting to any participating institution may not be evaluated at the bedside by a medical toxicologist, and thus may not be included in the registry. There may have been less severe exposures, or even fatalities at reporting institutions that may have been treated without consultation by a toxicologist. The number of sites participating in the ToxIC registry varies by year, thus making year-to-year comparisons unfeasible within this dataset. Case descriptors selected by the medical toxicologist submitting case information may not be interpreted similarly by all participating toxicologists, thus resulting in confounding of data. For example, when indicating “intentional” as reason for a pediatric exploratory exposure, the registry does not clearly define if the substance was defined as such due to self-administration, or due to administration with specific intent. The nature of voluntary reporting of all case variables, including race, ethnicity, reason for exposure, and presenting signs and symptoms, may result in under-reporting or inaccurate reporting of such findings. We excluded cases where age or reason for the encounter was missing, thus potentially introducing bias into the analysis. Sensitivity analysis around the possibilities for missing data was not performed; thus, it is not possible to estimate potential bias. Further, the ToxIC registry does not capture all toxicology consults seen across the USA, as not all institutions with a toxicology service participate in the ToxIC registry. Thus, this registry is not the appropriate data source to determine the nature or urgency of poisoning prevention strategies. The authors acknowledge that more comprehensive morbidity and mortality data, along with economic analyses, would be needed to define necessary public health interventions related to pediatric poisoning. Data collection was limited to female and male sex. Following the completion of this study, ToxIC has begun to collect data on transgender patients. Thus, a limitation of this study is that transgender data was not collected during the study time period. Confirmatory testing is not typically reported within the ToxIC registry; thus, identification of the agents involved in reported exposures is often provided based on the best judgement of the bedside toxicologist. Lastly, some cases were missing data for specific variables, and therefore, the sample size for those variables was reduced.

Conclusions

We report characteristics of pediatric poisonings reported to the ToxIC registry by age and sex categories. Raw data appeared consistent with the limited existing literature around age- and sex-based risk factors for poisoning presentations. Our findings may provide the groundwork for hypothesis generation around sex- and age-based outcomes, education, and prevention efforts for poisonings among children.

Acknowledgments

Compliance with Ethical Standards

Footnotes

References