(2024) 24:508
Pavlova et al. BMC Pediatrics
https://doi.org/10.1186/s12887-024-04951-4

BMC Pediatrics

RESEARCH

Open Access

Early childhood risk factors for later onsetof pediatric chronic pain: a multi‑methodlongitudinal study
Maria Pavlova1, Melanie Noel2,3,4, Serena L. Orr3,4,5,6,8, Andrew Walker7,9, Sheri Madigan2, Sheila W. McDonald5,
Suzanne C. Tough5 and Kathryn A. Birnie2,3,4,5,9*Abstract
Background Pediatric chronic pain (i.e., pain lasting ≥ 3 months) is prevalent, disabling, and costly. It spikes in adolescence, interrupts psychosocial development and functioning, and often co-occurs with mental health problems.
Chronic pain often begins spontaneously without prior injuries and/or other disorders. Prospective longitudinalcohort studies following children from early childhood, prior to chronic pain onset, are needed to examine contributing factors, such as early pain experiences and mental health. Using data from a longitudinal community pregnancy
cohort (All Our Families; AOF), the present study examined the associations between early developmental risk factors,
including early childhood pain experiences and mental health symptoms, and the onset of pediatric chronic painat ages 8 and 11 years.
Methods Available longitudinal AOF data from child age 4 months, as well as 1, 2, 3, 5, 8, and 11 years, were used.
Mothers reported their child’s pain experiences (e.g., hospitalizations, vaccinations, gut problems) at each timepointfrom 4 months to 8 years, child chronic pain at age 8, and child mental health symptoms at ages 5 and 8 years. Children reported their chronic pain frequency and interference at age 11. Adaptive least absolute shrinkage and selection operator (LASSO) regressions were used to select predictor variables. Complete case analyses were complemented by multiple imputation using chained equation (MICE) models.
Results Gut problems, emergency room visits, frequent pain complaints, and headaches at age 5 or earlier, as well
as female sex, were associated with increased risk of maternal reported child chronic pain at age 8. Maternal reported
chronic pain at age 8 was associated with higher levels of child-reported pain frequency and pain interferences at age
11. Boys self-reported lower levels of pain interference at age 11.
Conclusions Some, but not all, painful experiences (e.g., gut problems, ER visits, pain complaints) in early life contribute to pediatric chronic pain onset and should be considered for screening and early intervention.
Keywords Cohort study, Pediatric chronic pain, Internalizing symptoms, Early life pain experiences*Correspondence:
Kathryn A. Birnie
kathryn.birnie@ucalgary.ca
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
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Pavlova et al. BMC Pediatrics(2024) 24:508

Pediatric chronic pain (i.e., pain lasting ≥ 3 months) isa prevalent condition that affects 1 in 5 youth [1] andimposes high societal costs estimated at $19 billion USD
annually [2]. Pediatric chronic pain tends to spike in adolescence [1], and can interrupt cognitive, psychological,
social, and physical development and functioning [3].
Chronic pain often co-occurs with, and is exacerbated by,internalizing mental health symptoms (e.g., anxiety anddepressive symptoms), which tend to persist into adulthood [4–6].
Youth and families with lived experience of chronic
pain, as well as policymakers and healthcare professionals, have identified prevention and early treatment ofchronic pain as a top priority [7]. As chronic pain often
spontaneously begins without any prior injuries [1], prospective longitudinal cohort studies that follow children
from early childhood, prior to chronic pain onset, areessential to identify, and differentiate between, contributing risk factors and co-occurring issues. Yet, such cohort
studies are exceedingly rare [8].
Pediatric chronic pain often initially presents in primary care settings. Pain complaints are one of the mostcommon problems seen in primary care accounting for
up to 15% of pediatric primary care appointments [9]. In
the average 3.3 years it takes for youth to access tertiarycare for pediatric chronic pain [10], their pain symptoms
continue to be primarily managed by family physicians
and pediatricians. Therefore, recognizing, screening for,and addressing early risk factors that are associated withthe onset of chronic pain are important for primary careproviders.
Retrospective reports of adults with chronic pain andcross-sectional data suggest that premature birth, aswell as painful procedures and injuries earlier in life,
may result in physiological changes to the nervous system (e.g., abnormal synaptic connectivity, decreased pain
threshold, hyperinnervation) [11, 12] and, thus, contribute to chronic pain onset. Internalizing and externalizing (e.g., aggression, impulsivity) symptoms commonly
co-occur with pediatric chronic pain at rates higher thantheir peers without pain [5, 13]. Emerging evidence fromprospective studies with clinical samples suggests thatchronic pain in adolescence predicts the onset of depression, suicidality, and anxiety symptoms, as well as opioid
use and risk for socioeconomic disparities [14–17]. However, more population-based prospective cohort studies
that employ multiple informants (e.g., youth, parents) areneeded to determine what early risk factors may confer
risk to children’s chronic pain onset and maintenance.
To-date, only a few population-based prospective studies have examined whether or which early life painful
experiences and mental health symptoms may contribute to the development of pediatric chronic pain [18, 19].

Page 2 of 12

Using multi-informant (mothers, children) data froman existing Canadian longitudinal pregnancy cohort,
we aimed to address this gap. Specifically, we examined
the associations between maternal reported early childdevelopmental risk factors (i.e., early pain experiences
and mental health symptoms) and the later onset ofpediatric chronic pain at age 8 and 11 years, as reported
by mothers and children, respectively. Given the associations between mental health symptoms and pediatricchronic pain [13], as well as potential contributions ofearly painful experiences to chronic pain onset [11, 12],
we hypothesized that higher levels of internalizing andexternalizing mental health symptoms, as well as higher
rates of early painful experiences (e.g., repeated injuries,
hospitalizations) would be associated with higher risks ofchronic pain at age 8 and 11.

Methods
Study design and participants

The All Our Families (AOF) cohort is a well-characterized ongoing longitudinal pregnancy cohort that began in
May 2008 with 3,387 pregnant women in a large Western
Canadian urban centre. Community-based sampling wasused to recruit pregnant women at primary care clinics
and through routine blood screening at the sole providerof laboratory services in the region; the study information was also available via posters to allow for passive
recruitment. Recruitment and cohort baseline characteristics have been previously reported [20, 21]. Data werecollected using online surveys at multiple time points
between 2008 and 2022. Mothers completed questionnaires twice during pregnancy and 7 times since theirchild’s birth (i.e., 4 months, 1, 2, 3, 5, 8, and 11 years).
Children completed self-report questionnaires at the ageof 11 years. Eligible participants for this study included
mothers who were recruited into the AOF cohort andwere not lost to follow-up/discontinued their participation, as well as their children who provided assent toparticipate in the study. The institutional research ethics board approved the study (REB13-0868). Participants
provided consent/assent using an online survey form.
Procedures and measures

Available data from 4 months, 1, 2, 3, 5, 8, and 11 years
timepoints were used. The data were collected between
May 2008 and January 2022. Participants were contacted
to complete each timepoint’s surveys based on theirchild’s birthdate.
Outcomes

Chronic pain at age 8 Children were categorized ashaving chronic pain at age 8 if their mothers reported

Pavlova et al. BMC Pediatrics(2024) 24:508

their child having pain for ≥ 3 months at any point since
Grade 1, and/or often or always complaining of pain,
having headaches, and/or stomach problems. Using a
conservative approach, a mother was required to haveprovided a negative (“No”) response to all four items
to confirm the absence chronic pain. An affirmative
response to any of the four items indicated the presenceof chronic pain. Mothers who did not respond to all four
items of the composite variable were excluded from analysis. Data on the absence or presence of chronic pain atage 8 years were available for 1,583 participants (out of
2,074 mothers who completed at least a portion of thestudy’s questionnaires at that timepoint) and included inPage 3 of 12

the analyses (Fig. 1). Mothers also reported on the location and frequency of the child’s pain.
Chronic pain at age 11 We used youth reports of pain
frequency and pain interference to determine the presence of chronic pain. Youth self-reported the frequencyof pain using an item from the Pain Questionnaire [22].
Youth were prompted to report pain frequency regardless of maternal reports of children’s pain at age 8. In linewith previous research [23], frequency of pain at age 11
was dichotomized into those with moderate to high frequency (weekly, almost every day, every day) and low
to none (none, once per month, 2–3 times per month).

Fig. 1 aStarting at Q4, sample size decreased due to research flow constraints (e.g., ethics approval). Only participants eligible to participate
based on their child’s age received Q4, Q5, and Q6 surveys. Starting at Q7, all participants who were active in the study received surveys. b Youthparticipants needed their mother’s consent to be eligible to complete the survey

Pavlova et al. BMC Pediatrics(2024) 24:508

A total of 1,019 youth reported pain frequency at age
11 (out of 1,034 youth who completed at least a part ofthe study questionnaires). All youth who reported pain
frequency of at least once per month (n = 818) were
prompted to report their pain interference using four of
the Patient-Reported Outcomes Measurement Information System (PROMIS)-25 Pediatric Profile items [24].
The PROMIS-25 instrument assesses children’s physicaland socio-emotional functioning; only items assessing
pain interference were used. The four items assess how
much pain interfered with daily activities (e.g., sleeping, walking, running, paying attention). The raw scores
were converted into t-scores. Based on a populationbased pediatric sample, t-scores between 50 and 58
indicate moderate levels of pain interference, whereast-scores ≥ 59 suggest severe pain interference levels[25].
The PROMIS instruments have demonstrated excellent psychometric qualities and have been previously
used in research on pediatric chronic pain [24]. A totalof 813 youth reported pain interference at age 11 years(Fig. 1). Additionally, youth reported their pain location,
pain intensity (0, no pain-10, worst pain possible numerical rating scale), and whether their pain was present for
3 months or longer. Past population-based studies (e.g.,[26, 27]) used a similar approach of assessing the presence of chronic pain, that is a combination of questions
regarding pain chronicity, intensity, location, and frequency. To our knowledge, this is the first populationbased study to also assess pain interference.
Predictors

Early life painful experiences At each timepoint,
mothers reported on a variety of potentially painfulchildhood experiences (e.g., neonatal intensive care stay,
surgeries, hospitalizations, vaccinations, medical procedures, gut problems). A list of 86 potentially painful
experiences was compiled and reviewed by pediatric pain
researchers (KAB, MN, SLO, MP) (see Table S1, Supplementary Materials). Through expert opinion supported
by existing research, the research team reduced the list to
70 variables representing experiences that are likely painful as supported by previous research [27–34]. The variables were subsequently grouped according to the type of
painful experience (see Table S1, Supplementary Materials). To further reduce the number of potential predictors, each variable group was coded as a single variable(e.g., a reported hospitalization at any point between
4 months and 8 years resulted in a “1 = yes” hospitalization variable). To reflect a repeated nature of multiple
vaccinations, a total number of vaccine injections wasrecorded and used in the analyses.

Page 4 of 12

Children’s mental health At the 5- and 8-year timepoints, mothers also reported children’s mental healthsymptoms (i.e., depression and anxiety symptoms, behavioural problems) using parent rating scales of the Behavioural Assessment System for Children—Second Edition(BASC-2) [35]. The BASC-2 was normed using generaland clinical samples and demonstrated high levels of reliability and validity [35]. The BASC-2 t-scores normed insamples of both boys and girls were used for analyses.
T-scores ≥ 60 were considered elevated and indicative ofclinically significant levels of depressive/anxiety symptoms and behavioural problems.
Sociodemographic variables Mothers reported theirage, education, race/ethnicity, and household income, as
well as their child’s gestational age at birth and sex.
Statistical analyses

Continuous demographic and early life pain experiencevariables were tested for normality using the Shapiro–
Wilk test and presented as median (interquartile range).
Binary variables were presented as count (percentage).
The BASC-2 subscale t-scores were dichotomized using
clinically significant elevations (i.e., t-scores ≥ 60) as a
cut-off point [35]. Based on clinical importance and literature review, up to 24 variables were considered for multivariable regression models of chronic pain at age 8 andpain frequency and pain interference at age 11 (discussed
above and presented in Supplementary Materials). Variables were omitted from model inclusion consideration if
they presented with > 40% missingness [36] or near-zero
variance [37]. Hospitalizations and ear tube insertion
variables were omitted due to missingness; painful dental procedures and neonatal intensive care variables wereomitted due to near-zero variance. Continuous predictors(i.e., number of vaccinations, maternal age, gestationalage) were mean centered prior to model development.
We used adaptive least absolute shrinkage and selection operation (LASSO) regression for final variableselection. Adaptive LASSO’s oracle property assigns
specific weights to each coefficient based on the correlation structure of the data, thus allowing for theidentification of the correct nonzero coefficient variables [43]. Weights were derived using initial binomial(chronic pain age 8, pain frequency age 11) and gaussian(pain interference age 11) ridge regressions with tenfold
cross-validation. The weights represented the absolutereciprocal values of the ridge regression coefficients andwere subsequently transferred to LASSO regression andincorporated penalty terms. All included variables were
subjected to penalization. LASSO regressions (binomial
or gaussian) were completed for each outcome using

Pavlova et al. BMC Pediatrics(2024) 24:508

tenfold cross-validation. We selected the tuning parameter (lambda) that minimized the cross-validation prediction error. Non-zero coefficients found via LASSO weretransferred to unrestricted multivariable logistic (chronic
pain age 8, pain frequency age 11) or multivariable linear regression (pain interference age 11) models for final
presentation of adjusted associations between predictors
and pain outcomes at ages 8 and 11. Adjusted associations were presented as either odds ratio (OR) with 95%
confidence interval (CI) and p values for binary outcomes, or coefficient with 95% CI and p values for paininterference. In line with Althouse’s [38] and Rothman’s[39] recommendations for analysing large datasets withmultiple variables, p values were not adjusted.
Imputed data models of each outcome (i.e., chronic
pain at age 8, pain frequency at age 11, pain interferenceat age 11) were generated for the analyses. Little’s test was
initially run to determine if data was missing completely
at random (p < 0.05). We imputed up to 58 models of thedata set (number of imputations were set to the percentage of incomplete cases) with 20 iterations using multiple
imputed chained equations (MICE) with predictive mean
matching and logistic regression. Specific to each outcome, variables with > 40% missingness were not considered for imputation [36]. Following imputation, pooled
multivariable logistic and linear regression models wereconstructed using the same variables as our complete
case adaptive LASSO models. We chose to present our
imputed associations for our primary analyses as the useof multiple imputation, versus listwise deletion, has beenargued to produce less biased results [40]. Presented
OR and coefficients, 95% CI, and p values represent thepooled estimates from individual models completed oneach of the imputed datasets. Analyses were conductedusing SPSS 25.0 and R Studio version 2022.2.3.492 withR statistical software version 4.2.1 using packages glmnet (version 4.1–7) [41] and mice (version 3.15.0) [42] for
adaptive LASSO and MICE, respectively.

Results
Sample characteristics are presented in Table 1.
Chronic pain at age 8 years

Data on chronic pain was available for 1,583 children, and
18% (n = 288) of children were reported by their mothers
to have chronic pain at the age of 8 years. Among thoseexperiencing pain at 8 years, most children had stomach(47%) and leg (22%) pain, with most (72%) experiencing
pain multiple times per week.
Imputed case analysis demonstrated that children
with gut problems (adjusted [a]OR = 3.19 [2.36 to 4.31],
p < 0.001) at the age of 5 years or younger were more
likely to develop chronic pain by the age of 8 years

Page 5 of 12(Table 2). Children who were reported to have headaches sometimes (aOR = 1.65 [1.14 to 2.41], p = 0.009)
or often/always (aOR = 5.42 [1.93 to 15.20], p = 0.001)
and complain of pain often/always (aOR = 2.59 [1.15
to 5.83], p = 0.022) at age of 5 years were more likely todevelop chronic pain by the age of 8 years, as compared
to children who were reported to never have headaches
or never complain of pain. Children who visited an emergency room at least once before the age of 8 years weremore likely to develop chronic pain at the age of 8 years(aOR = 1.99 [1.31 to 3.02], p = 0.001), as compared to children who never visited an emergency room. Boys wereless likely to develop chronic pain at the age of 8 years,
as compared to girls (adjusted OR = 0.75 [0.56 to 0.99],
p = 0.043). Complete case analysis demonstrated similar
associations (Table 2).
Chronic pain, pain frequency, and pain interference at age
11

At the age of 11 years, 1,019 children reported theirpain frequency. Eighty percent of children (n = 818)
self-reported experiencing pain and aches at least oncea month, with 31% of children reporting having weekly
or daily pain. Thirty-nine percent of children reported
having chronic pain (i.e., pain lasting ≥ 3 months). Of
these, children reported having muscle and joint pain(24%), headaches (22%), leg pain (21%), and abdominal
pain (18%). Children, who endorsed having pain at least
once per month, reported an average pain intensity levelof 4.05/10 (SD = 1.65) and an average pain interference
score of 48.94/74.00 (t-score; SD = 8.36), which is indicative of normal pain interference (i.e., when a child experiences pain, it does not stop them from participating indaily activities for a long period of time) Ten percent ofyouth (n = 81) reported severe levels of pain interference(i.e., t-scores ≥ 59), and 34% of youth endorsed moderatelevels of pain interference (i.e., t-scores between 50 and58).
Out of the 818 youth who reported having pain at least
once per month, 689 youth had mothers who reported
their child’s pain at age 8. Of the 689 youth with data
available at both ages 8 and 11, 129 were reported chronic
pain at age 8 and self-report having pain at least once permonth at age 11. 560 youth reported having pain at age
11 at least once per month, while their mothers did notreport them having chronic pain at age 8.
Chronic pain at the age of 8 years was associated with
1.91 increased odds of experiencing frequent pain at theage of 11 (aOR = 1.91 [1.30 to 2.81], p = 0.001; Table 3).
Chronic pain at the age of 8 years was also associatedwith 2.58-point increase in the level of pain interference at age 11 (2.58 [0.95 to 4.20], p = 0.002) (Table 4).
Boys, as compared to girls, reported lower levels of painPavlova et al. BMC Pediatrics(2024) 24:508

Page 6 of 12

Table 1 Variables considered for chronic pain, pain frequency and pain interference model inclusion at ages 8 and 11
Chronic pain at age 8(N = 1583)a

Pain frequency at age 11(N = 1019)a

Pain interferenceat age 11 (N = ­818)

Maternal age at child’s birth (years, median (IQR [range])

31 (28–34 [18-45])

31 (28–34 [18-43])

31 (28–33 [18-43])

Maternal race/ethnicity (non-Caucasian, n/N, %)290/1576 (18.4)

201/1014 (19.8)

155/814 (19.0)

Family income (< $60,000, n/N, %)212/1522 (13.9)

133/978 (13.6)

106/785 (13.5)

Maternal education (high school or less, n/N, %)113/1574 (7.2)

59/1015 (5.8)

47/815 (5.8)

Child gestational age at birth (weeks, median (IQR [range])

39 (38–40 [24-43])

39 (38–40 [29-43])

39 (38–40 [29-43])

Child sex at birth (male, n/N, %)801/1583 (50.6)

537/1019 (52.7)

426/818 (52.1)

Number of vaccinations (median (IQR), [range])

6 (5–6 [0–7])

6 (5–6 [0–7])

6 (5–6 [0–7])

Hospitalization (n/N, %)253/905 (28.0)

188/569 (33.0)

152/451 (33.7)

Surgery (n/N, %)195/1406 (13.9)

152/826 (18.4)

119/666 (17.9)

Ear infections (n/N, %)587/1030 (57.0)

369/681 (54.2)

296/541 (54.7)

Ear tube insertion (n/N, %)27/920 (2.9)

17/643 (2.6)

15/506 (3.0)

Painful dental procedures (n/N, %)36/1366 (2.6)

29/911 (3.2)

21/730 (2.9)

Emergency room visits (n/N, %)771/1101 (70.0)

493/723 (68.2)

398/577 (69.0)

Gut problems (n/N, %)490/1428 (34.3)

293/844 (34.7)

249/681 (36.6)

NICU stay (n/N, %)63/1477 (4.3)

40/964 (4.1)

34/772 (4.4)

Serious injury (n/N, %)175/1396 (12.5)

124/948 (13.1)

102/762 (13.4)

Anxiety (n/N t-score ≥ 60, yes)

338/1400 (24.1)

134/984 (13.6)

107/789 (13.6)

Depression (n/N t-score ≥ 60, yes)

277/1399 (19.8)

135/983 (13.7)

116/788 (14.7)

Externalizing problems (n/N t-score ≥ 60, yes)

145/1400 (10.4)

107/984 (10.9)

81/789 (10.3)

Behavioral symptoms index (n/N t-score ≥ 60, yes)

181/1399 (12.9)

aDemographicsb

Early life pain ­experiences

BASC-2 ­scoresc

Child has headaches
Never1160/1400 (82.9)

804/949 (84.7)

636/763 (83.4)

Sometimes

221/1400 (15.8)

136/949 (14.3)

119/763 (15.6)

Often/always

19/1400 (1.3)

9/949 (0.9)

8/763 (1.0)

Never1157/1400 (82.6)

795/949 (83.8)

640/763 (83.9)

Sometimes

217/1400 (15.5)

142/949 (15.0)

115/763 (15.1)

Often/always

26/1400 (1.9)

12/949 (1.3)

8/763 (1.0)

Never772/1399 (55.2)

555/948 (58.5)

425/762 (55.8)

Sometimes

591/1399 (42.2)

376/948 (39.7)

323/762 (42.4)

Often/always

36/1399 (2.6)

17/948 (1.8)

14/762 (1.8)

Never890/1400 (63.6)

628/948 (66.2)

494/762 (64.8)

Sometimes

496/1400 (35.4)

311/948 (32.8)

261/762 (34.3)

Often/always

14/1400 (1.0)

9/948 (0.9)

7/762 (0.9)

148/856 (17.3)

129/689 (18.7)

Child has ear infections

Child complains of painChild has sore throats

Chronic pain at age 8 (n/N, %)n number of provided affirmative response, N total number who responded, IQR interquartile range, NICU neonatal intensive care unit, BASC Behavior Assessment
System for ChildrenaNumber of children who provided a response to the outcome of interestb

Cumulative number of vaccinations; the rest of the painful experiences are coded as happening ever in life either up to the age of 5 (for age 8 model) or up to theage of 8 (for age 11 model)c

BASC-2 scores reported at age 5 used for age 8 model. BASC-2 scores reported at age 8 used for age 11 models

Pavlova et al. BMC Pediatrics(2024) 24:508

Page 7 of 12

Table 2 Factors associated with chronic pain at age 8
Variablesa

Complete Case (N = 761)b

Imputed Case (N = 1583)

Odds ratio (95% CI)

p value

Odds ratio (95% CI)

p value.001

Visited emergency room (yes)1.73 (1.09 to 2.75).021

1.99 (1.31 to 3.02)

Child has a gut problem (yes)3.08 (2.02 to 4.69)< .001

3.19 (2.36 to 4.31)< .001

BASC-2 depression (t-score ≥ 60, yes)

1.53 (0.90 to 2.59).117

1.44 (0.99 to 2.10).058

BASC-2 behavioral symptoms (t-score ≥ 60, yes)

1.27 (0.69 to 2.33).438

1.31 (0.83 to 2.06).244

BASC-2 child has headaches
Neverreference

Sometimes

1.97 (1.16 to 3.35).012

1.65 (1.14 to 2.41)

reference.009

Often/Always

5.93 (1.60 to 22.0).008

5.42 (1.93 to 15.2).001

BASC-2 child has ear infections
Neverreference

Sometimes

0.63 (0.36 to 1.10).101

0.73 (0.48 to 1.10)

reference.129

Often/Always

0.17 (0.03 to 1.09).062

0.64 (0.21 to 1.95).435

BASC-2 child complains of pain
Neverreference

Sometimes

1.06 (0.68 to 1.66).807

1.22 (0.89 to 1.68)

reference.219

Often/Always

5.54 (1.70 to 18.0).004

2.59 (1.15 to 5.83).022

Child sex at birth (male)

0.65 (0.42 to 0.99).045

0.75 (0.56 to 0.99).043

Gestational age (weeks) mean centered (39.1 weeks)0.90 (0.81 to 0.99).032

0.94 (0.88 to 1.01).092

N number, CI confidence interval, BASC Behavior Assessment System for Childrena

Early life pain experiences of hospitalization and ear tube insertion not considered for adaptive least absolute shrinkage and selection operator (LASSO) regression
inclusion on account of high missingness (> 40%). Painful dental procedure and neonatal intensive care were excluded from inclusion given near-zero varianceb

Adaptive least absolute shrinkage and selection operator (LASSO) regression requires complete cases (no missing data in any variable considered for inclusion)

Table 3 Factors associated with pain frequency at age 11
Variablea

Complete Case (N = 449)b
Odds ratio (95% CI)

Imputed Case (N = 1019)
p value

Odds ratio (95% CI)

P valueChild has a gut problem (yes)1.57 (1.01 to 2.46).047

1.08 (0.79 to 1.49).630

BASC-2 depression (at-risk t-score ≥ 60, yes)

2.05 (1.16 to 3.64).014

1.31 (0.88 to 1.94).185

BASC-2 child complains of pain
Neverreference

Sometimes

1.60 (1.03 to 2.47).035

1.30 (0.97 to 1.74)

reference.078

Often/Always

2.59 (0.63 to 10.7).188

1.31 (0.47 to 3.62).608

Chronic pain at age 8 (yes)1.44 (0.82 to 2.54).207

1.91 (1.30 to 2.81).001

Maternal education (high school or less, yes)

1.92 (0.78 to 4.72).154

1.12 (0.64 to 1.97).695

N number, CI confidence interval, BASC Behavior Assessment System for Childrena

Early life pain experiences of hospitalization and ear tube insertion not considered for adaptive least absolute shrinkage and selection operator (LASSO) regression
inclusion on account of high missingness (> 40%). Painful dental procedure and neonatal intensive care were excluded from inclusion given near-zero varianceb

Adaptive LASSO regression requires complete cases (no missing data in any variable considered for inclusion)interference (-1.87 [-3.02 to -0.72], p = 0.001). No otherpredictors included in the imputed case analyses demonstrated significant associations with pain frequency or
pain interference at age 11 (Tables 3 and 4).
Complete case analyses revealed a different set of significant associations. Specifically, the complete caseanalyses showed that children with a gut problem at age

8 or earlier in life (aOR = 1.57 [1.01 to 2.46], p = 0.047),
children who complained of pain sometimes (aOR = 1.60
[1.03 to 2.47], p = 0.035; as compared to children who
did not complain of pain), and children with clinicallyelevated depressive symptoms (aOR = 2.05 [1.16 to 3.64],
p = 0.014) reported frequent pain at age 11 (Table 3).
Children who complained of pain sometimes at the age

Pavlova et al. BMC Pediatrics(2024) 24:508

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Table 4 Factors associated with pain interference at age 11
Variablea

Complete Case (N = 348)b
Coefficient (95% CI)

Imputed Case (N = 818)
p value

Coefficient (95% CI)

p value

Visited emergency room (yes)-1.12 (-2.91 to 0.67).219-0.01 (-1.39 to 1.36).987

Serious injury (yes)-1.65 (-4.09 to 0.78).183-0.98 (-2.72 to 0.76).268

BASC-2 anxiety (at-risk t-score ≥ 60, yes)

0.89 (-1.87 to 3.66).525

1.29 (-0.57 to 3.16).173

BASC-2 depression (at-risk t-score ≥ 60, yes)

1.40 (-1.17 to 3.98).284

1.06 (-0.73 to 2.85).246

BASC-2 child complains of pain
Neverreference

Sometimes

1.85 (0.11 to 3.58).037

0.89 (-0.30 to 2.09)

reference.141

Often/Always

2.15 (-4.00 to 8.30).493-0.56 (-5.16 to 4.04).811

Chronic pain at age 8 (yes)2.26 (-0.16 to 4.67).068

2.58 (0.95 to 4.20).002

Child sex at birth (male)-0.87 (-2.62 to 0.88).328-1.87 (-3.02 to -0.72).001

Gestational age (weeks) mean centered (39.1 weeks)-0.78 (-1.28 to -0.28).002-0.26 (-0.60 to 0.07).119

N number, CI confidence interval, BASC Behavior Assessment System for Childrena

Early life pain experiences of hospitalization and ear tube insertion not considered for adaptive least absolute shrinkage and selection operator (LASSO) regression
inclusion on account of high missingness (> 40%). Painful dental procedure and neonatal intensive care were excluded from inclusion given near-zero varianceb

Adaptive LASSO regression requires complete cases (no missing data in any variable considered for inclusion)of 5 or 8 years, as compared to children who did not complain of pain, also reported higher levels of pain interference, (1.85 [0.11 to 3.58], p = 0.037) (Table 4). Higher
gestational age was associated with 0.78-point decreasein the level of pain interference at age 11 (-0.78 [-1.28 to-0.28], p = 0.002).

Discussion
At age 8, approximately 18% of children in our population-based sample experienced chronic pain (pain lastingfor 3 months or longer), as reported by mothers. At age
11, 39% of children self-reported chronic pain. This study
extends previous research and aligns with patient-identified research priorities [7] by examining associations
between early life (from birth to age 8) painful experiences, as well as children’s mental health symptoms, andchronic pain in late childhood and emerging adolescence.
Results of the imputed case analyses are discussed below.
We found that recurrent gut problems, headaches, pain
complaints, emergency room visits, as well as being born
female, were all uniquely associated with increased risksof child chronic pain at the age of 8 years. Children’s
mental health (i.e., anxiety and depressive symptoms,
behavioural problems) and other types of painful experiences (e.g., ear infections) were not associated withchronic pain at age 8. Moreover, chronic pain at the ageof 8 years was associated with frequent self-reported pain
and higher levels of pain interference at the age of 11.
Boys reported lower levels of pain interference than girls.
Other predictors (i.e. gut problems, serious injuries, anxiety and depressive symptoms, pain complaints, child sex,

and gestational age) were not associated with pain interference or frequency at age 11.
Gut problems (e.g., functional abdominal pain, constipation) are often painful [34] and are common in children
with prevalence increasing from early childhood (4–7%
at age 2–3) up to 11% at age of 6 [43]. Recurrent abdominal pain at age of 3 has been associated with pediatricheadaches and musculoskeletal pain, as well as higher
levels of emotional problems (i.e., anxiety, depressive, andsomatic symptoms), later in childhood (i.e., at the age of
3.5 and 6) [43]. Genetic factors, neonatal painful experiences, and psychological factors (e.g., stress, exposure
to abuse) are thought to contribute to gut pain in childhood [44]; these are similar factors that are hypothesized
to contribute to the onset of pediatric chronic pain [8].
Thus, gut problems and later-onset chronic pain may
share similar etiological factors, with gut problems manifesting earlier in life. At the age of 8 years, gut problems
may transform into recurrent abdominal pain or serve asa precursor of other types of pain (e.g., headaches, musculoskeletal pain). Central nervous system sensitization
is present in children with recurrent abdominal pain andmay contribute to the onset of recurrent headaches andmusculoskeletal pain [45].
Injuries, which are usually associated with pain, are thesecond most common reason for pediatric emergency
room visits [46]. Despite chronic pain often arising in
the absence of injuries [1], a painful injury much earlier
in life may serve as the starting point for some types ofchronic pain (e.g., post-traumatic brain injury [TBI]
headaches). Indeed, over a half of children who suffereda TBI reported persistent pain in multiple body locations,Pavlova et al. BMC Pediatrics(2024) 24:508

in addition to headaches, 3 years after the initial TBI [47].
Further, injuries may be associated with acute stress andpost-traumatic stress symptoms (PTSS) [48]. PTSS often
co-occur with and maintain pediatric chronic pain [6,49]. Some studies demonstrated bidirectional relationship between persistent post-injury pain and PTSS [50].
Other studies, however, showed that baseline PTSS predicted pain levels 3 and 6 months after the initial injury[51]. Thus, it is possible that if most of the emergency
room visits in the present study were related to injuries,
children could have experienced traumatic stress, which,in turn, may have created psychological vulnerability forthe onset of chronic pain. Alternatively, emergency room
visits could have been related to recurrent pain concerns(e.g., headaches, stomach aches). However, the present
study did not ask mothers to report the reason for the
emergency department visits. Therefore, it would bepremature to associate emergency room visits with later
onset of chronic pain.
Pain predicted pain, such that headaches and frequent
pain complaints at the age of 5 years were associatedwith reports of chronic pain at the age of 8 years. In turn,reports of chronic pain at the age of 8 predicted frequent
pain and higher levels of pain interference at the age of
11 years. If pain is unaddressed and unmanaged, pain
intensity and duration may contribute to chronic pain
later in childhood and adolescent years [52]. For example,
in a population-based prospective study, abdominal pain
and pain in other locations (e.g., musculoskeletal pain,
headache) at the age of 12 years predicted the recurrent
abdominal pain at the age of 14 years [53]. In anotherepidemiological study, recurrent headaches and/or
abdominal pain persisting throughout childhood andadolescence (i.e., at ages 7, 11, and 15) predicted physicalsymptoms (e.g., headache, back pain, abdominal pain) in
adulthood (i.e., at the ages of 33 and 36 years) [54, 55].
The results of the study are in line with the identified
sex differences in pediatric chronic pain with more girls,
versus boys, reporting chronic pain [56]. Sex differences
become more pronounced during puberty [1], and cooccurring anxiety has been associated with higher levels of pain in girls [56]. The differences are likely due todissimilar pain mechanisms in males and females andthe influence of sex hormones on pain signalling mechanisms [57].
The imputed case analyses did not reveal any significant associations between internalizing mental
health symptoms at the age of 5 years and chronic pain
later in childhood and in early adolescence. Anxiety, depression, somatic, and post-traumatic symptoms often co-occur with pediatric chronic pain likely
due to shared neurobiological (e.g., inflammation,
genetic influences) and psychological (e.g., avoidance,

Page 9 of 12

catastrophizing) vulnerabilities [5]. Externalizing mental health symptoms (e.g., aggression, impulsivity) arecomorbid with chronic pain in children and intensify the
impact internalizing mental health symptoms on chronic
pain [13]. However, the temporality of the symptoms’
onset is debated [58], which is likely due to paucity of rigorous longitudinal studies. The lack of significant associations between internalizing and externalizing symptoms
and the later development of chronic pain in the present
sample is intriguing and requires future investigations,particularly given that chronic pain predicted the onset
and severity of suicidality in youth [14]. The lack of association may also be the result of dichotomizing mental
health variables into the categories of below and above
clinically elevated symptoms, which reduced the variables’ variance.
Our study identified some of the early life factors thatare associated with the development of chronic pain inchildhood and adolescence (i.e., sex, gut problems, ER
visits, persistent pain complaints). These factors may
serve as potential targets for early screening and preventive interventions, that can be implemented within primary care systems, where early pain symptoms are firstseen and continuously managed. Salamon and Cullinan
highlighted the need for early screening of children to
identify those at risk of developing chronic pain, tracking
pain-related visits, and integrating secondary prevention
interventions (e.g., brief targeted cognitive-behaviouralstrategies delivered individually or in a group format)
within primary care settings [59].
Of note, our study demonstrated that many commonchildhood painful experiences (e.g., vaccines, ear infections) were not associated with development of chronic
pain later in life. One possible explanation could stemfrom continuing progress made in pediatric pain assessment and management locally where the cohort wasrecruited [60]. Several variables (i.e., admission to neonatal intensive care unit, hospitalizations, painful dental procedures) were excluded from the analyses due tomissingness or near-zero variance. Some of these variables (e.g., neonatal intensive care) have been associatedwith altered sensory processing [61] and have a potential to contribute to later onset of chronic pain. Further,social determinants of health variables included in themodels (e.g., ethnicity, income) also were not associatedwith the onset of chronic pain later in childhood/adolescence. This is in contrast to existing findings demonstrating associations between socioeconomic variables(e.g., lower socioeconomic status, lower levels of maternal education, and racialized identity of children) andincreased prevalence of chronic pain and higher levelsof pain-related disability [62, 63]. Future examination ofthese variables in population-based samples is warranted.

Pavlova et al. BMC Pediatrics(2024) 24:508

Given our choice to use the adaptive LASSO method
requiring complete case data for all considered variables, our available sample size represents those thatprovided responses to our outcomes of interest (i.e., pain
outcomes). The degree of missingness in predictor variables (i.e., painful experiences, mental health symptoms)
reduced the number of complete cases available for adaptive LASSO by 52% to 57%. To compensate for this, weused multiple imputation by chained equations (MICE)
to impute missing data within model datasets. We chose
to focus our interpretations on presented imputed effectsizes, as opposed to complete case analyses. Caution
in this approach is advised, however. The use of MICE
imputation assumes that data is missing at random.
However, to confirm that data is missing at random, as
opposed to missing not at random, requires access to thevery data that is missing within the dataset. Indeed, it ispossible that failure to reply to our questionnaires may be
due to systematic reasons (e.g., participants with worse
outcomes were less likely to respond). If such a mechanism is associated with our cohort, one must be cautious
in their interpretation of imputed effect sizes. However,it has been argued that even under a missing not at random assumption, multiple imputation reports less biased
results to complete case analysis [40].
The study had limitations that should be addressed infuture research. First, although chronic pain was assessedby self-report at age 11, only maternal report based onfour items was obtained at the age of 8. Of the four items,
only one of those items directly asked about the presenceof chronic pain; the other items focused on the presence of frequent pain complaints. Compared to existingcohort studies (e.g., 54, 55), pain assessment used in the
AOF cohort was more detailed (particularly at the ageof 11) and in line with the International Association for
the Study of Pain and the International Classification of
Diseases definitions of chronic pain [64]. However, given
the high prevalence [1] and associated cost of pediatricchronic pain [2], future cohort studies should incorporate a more nuanced self- and parent-report assessmentof pain symptoms starting with earlier ages. Additionally, only maternal reports of children’s internalizing andexternalizing symptoms were collected up to age 8. Given
the discrepancies between parental and self-reports ofmental health symptoms [65], it is possible children’s
early-life internalizing and externalizing symptoms were
underreported. Future cohort studies should include
children’s self-report of their mental health and pain
symptoms at earlier points (e.g., late childhood). Second,
the present study reports on youth’s chronic pain at age 8
and 11, whereas chronic pain tends to peak later in adolescence [1]. It is possible that there are additional risk
factors contributing to the development of chronic pain

Page 10 of 12

later in adolescence. Future cohort investigations should
include pain reports later in adolescence. Of note, 39%of youth reported having pain present for 3 months or
longer, which is line with other epidemiological reports[1, 23]. Further, compared to existing population-based
studies, the present investigation used an expanded pain
assessment that included a pain interference measure.
Ten percent of youth reported severe levels of pain interference, which is in line with previous studies [66]. Third,
the study focused on some of the individual predictors ofchronic pain (e.g., sex, internalizing symptoms). Other
individual predictors that may be contributing to chronic
pain onset were not assessed in the present study. For
example, early life adverse events (e.g., childhood maltreatment) have been linked to poor physical outcomes,
including frequent pain [67, 68]. Future cohort studies should consider how adverse childhood events may
contribute to the onset of pediatric chronic pain [69].
Beyond individual predictors, biopsychosocial models
of pediatric chronic pain [8] highlight family and social
factors (e.g., parent chronic pain and mental health) that
contribute to the onset and maintenance of chronic pain
[70–72]. Future studies should examine the contributionsof parental factors in early childhood to the developmentof pediatric chronic pain. Additionally, the study focusedon factors that predict chronic pain later in childhood/adolescence. Protective factors that could buffer against
the onset of chronic pain (e.g., parenting style, social support) should be examined in future studies. Finally, compared to provincial and national statistics, women whochose to participate in the AOF study were older andreported higher income [20]. Further, mothers that continued their study participation tended to be White andreported higher education and income levels, as compared to those who discontinued their participation [20].
Therefore, it is possible that the identified associations
may not generalize to more diverse samples.

Conclusions
Pediatric chronic pain remains prevalent, costly, anddebilitating for a considerable portion of youth. Prevention remains one of the key research objectives on
the pediatric pain research and clinical agenda. Using a
multi-informant prospective cohort data, our study identified potential factors (i.e., female sex, gut problems,persistent pain complaints, ER visits) that may increase
the risk of chronic pain development in late childhoodand early adolescence.
Abbreviations
AOF	All Our Families
BASC-2	Behavior Assessment System for Children, 2nd Edition
CI	Confidence Interval
LASSO	Least Absolute Shrinkage and Selection Operator
MICE	Multiple Imputation using Chained Equation

Pavlova et al. BMC Pediatrics(2024) 24:508

NICU	Neonatal Intensive Care Unit
OR	Odds Ratio
PROMIS	Patient-Reported Outcomes Measurement Information System
TBI	Traumatic Brain Injury

Supplementary Information

Page 11 of 12

2.
3.
4.

The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12887-​024-​04951-4.
Supplementary Material 1.
Acknowledgements
We thank the All Our Families study team for their feedback on the
manuscript.
Authors’ contributions
KAB, MN, SLO, MP developed the idea, interpreted the results, and drafted themanuscript. SCT and SWM conceived, implemented, and managed the AOF
study, assisted in interpretation and provided critical input to the manuscript.
AW analysed the data, assisted in results interpretation, and provided critical
input to the manuscript. SM provided critical input to the manuscript. All
authors reviewed the manuscript.
Funding
This study was funded by an Owerko Catalyst Grant from the University ofCalgary.
Availability of data and materials
The All Our Families data are stored at Secondary Analysis for Generating
Evidence (SAGE), a secure data repository managed by the Alberta Centre
for Child, Family and Community Research (https://policywise.com/sage/).
Inquiries regarding data access procedures and requests for these data can bedirected to data@policywise.com.

Declarations

5.
6.
7.

8.
9.

10.
11.
12.
13.

Ethics approval and consent to participate
The Conjoint Health Research Ethics Board – University of Calgary approved
the study (REB13-0868). Informed consent was obtained from participants,
who also provided informed consent on behalf of their children; children
provided their assent.

14.

Consent for publication
Not applicable.

16.

Competing interests
The authors declare no competing interests.

17.

Author details
1
Department of Psychology, University of Guelph, Guelph, Canada. 2 Department of Psychology, University of Calgary, Calgary, Canada. 3 Alberta Children’s
Hospital Research Institute, Calgary, Canada. 4 Hotchkiss Brain Institute, Owerko
Centre, Calgary, Canada. 5 Community Health Sciences, University of Calgary,
Calgary, Canada. 6 Clinical Neurosciences, University of Calgary, Calgary,
Canada. 7 Alberta Health Services, Calgary, Canada. 8 Department of Pediatrics, University of Calgary, Calgary, Canada. 9 Department of Anesthesiology,
Perioperative and Pain Medicine, Department of Community Health Sciences,
University of Calgary, 2500 University Drive, Calgary, AB T2N 1N4, Canada.

18.

Received: 26 March 2024 Accepted: 16 July 2024

15.

19.
20.
21.
22.

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