European J Pediatrics 2019 (Dec); 178 (12): 1903-1911 ~ FULL TEXT
Anne Cathrine Joergensen, Raquel Lucas, Lise Hestbaek, Per Kragh Andersen, Anne-Marie Nybo Andersen
Section of Epidemiology, Department of Public Health,
Faculty of Health and Medical Science,
University of Copenhagen,
Oster Farimagsgade 5, Box 2099,
DK-1014, Copenhagen K, Denmark.
Neurobiological mechanisms can be involved in early programming of pain sensitization. We aimed to investigate the association between early-life pain experience and pre-adolescence spinal pain. We conducted a study of 29,861 pre-adolescents (age 11-14) from the Danish National Birth Cohort. As indicators of early-life pain, we used infantile colic and recurrent otitis media, reported by mothers when their children were 6 and 18 months. Self-reported spinal pain (neck, middle back, and/or low back pain) was obtained in the 11-year follow-up, classified according to severity. Associations between early-life pain and spinal pain in pre-adolescents were estimated using multinomial logistic regression models. To account for sample selection, inverse probability weighting was applied. Children experiencing pain in early life were more likely to report severe spinal pain in pre-adolescence. The association appeared stronger with exposure to two pain exposures (relative risk ratio, 1.31; 95% CI, 1.02-1.68) rather than one (relative risk ratio, 1.14; 95% CI, 1.05-1.24). We observed similar results when using headache and abdominal pain as outcome measures, underpinning a potential neurobiological or psychosocial link in programming of pain sensitization.
Conclusion: Experience of early-life pain is seemingly associated with spinal pain in pre-adolescence. The study highlights that early-life painful experiences can influence programming of future pain responses.
How this fits in |
What is Known:
What is New:
Spinal pain in pre-adolescents is common, causes marked discomfort and impairment in everyday life, and may be an important predictor of spinal pain later in life.
Neurobiological mechanisms have been suggested as involved in early programming of pain sensitization.
Pain exposure in early postnatal life in terms of infantile colic and recurrent otitis media is associated with spinal pain in pre-adolescence; thus, experience of such painful conditions in the early postnatal period may seemingly influence programming of future pain sensation.
Keywords: Back pain,; Epidemiology; Pain sensitivity,; Pre-adolescence,; Spinal pain,.
From the Full-Text Article:
Spinal pain (i.e., neck, middle back, and/or low back pain) is a
prevailing problem among school-aged children [13, 26, 31]. The 6-month prevalence of severe spinal pain was recently estimated to 11% of 11-year-olds in Denmark increasing rapidly with age . Spinal pain can cause marked discomfort and impairment in children’s everyday life and have lifelong problems, physically and mentally [13, 17, 27, 47]. In addition,
pediatric-onset of spinal pain is suggested as an important
predictor of spinal pain in later life [20, 51]. However, little is known about the etiology and early-life factors predisposing to spinal pain, which makes effective and targeted prevention of spinal pain in young people difficult .
Mechanisms involved in pain susceptibility are still not well understood. Neurobiological mechanisms are involved in the production and perception of pain including the nociceptive system and the hypothalamic-pituitary-adrenal (HPA) axis (i.e., stress response) [7, 19, 44]. These mechanisms are particularly sensitive for programming and modulations in the perinatal period due to the ongoing maturation of the neurobiological systems and significant brain development [19, 32, 35]. Changes in the functioning of the nociceptive system can be induced by recurrent and persistent pain experience in early life [19, 44]. Such changes can persist well beyond infancy and result in profound and long-lasting effects on pain processing [19, 44] including decreased pain threshold ,
hyperalgesia [18, 50], and allodynia . The HPA axis is a key mechanism underlying the link between early-life development and later-life disease [14, 40]. Childhood adversities and early-life stressors can lead to excessive activation of the HPA stress response. This, in turn, can result in long-term alterations in HPA axis responsiveness [7, 32, 35] and in enhanced susceptibility to the development of chronic pain in later life  for example fibromyalgia  and chronic back pain . Thus, dysfunction of the HPA axis may also impact the nociceptive system .
Previous studies on the association between early-life pain
and later-life pain sensation have primarily focused on experiences in the neonatal intensive care unit (NICU), typically present among preterm children, as proxy measures for pain exposures in early postnatal life. In NICUs, infants are most often exposed to physiological and environmental stressors in relation to e.g. neonatal illness, neonatal surgery, and noxious stimuli exposures (e.g., medical procedures) [18, 55].
It may be worth investigating pain complaints in relation to
other painful conditions appearing in the early postnatal period. Two common conditions causing pain in infants are infantile colic and acute otitis media [11, 43]. Infantile colic is characterized by repeated episodes of excessive crying or
fussing during the first months of life and affects 10–20 %
of all infants [11, 59]. Acute otitis media is one of the commonest infections in early life with 60–70%of all children experiencing at least one episode. Before the age of 1 year, 10–20% will experience recurrent otitis media (≥ 3 episodes) and, accordingly, experience frequent acute ear pain, fever, and general illness [42, 53].
To investigate the impact of early-life pain experience on
future pain responses, we aimed to study whether complete
unrelated early-life pain experience in terms of infantile colic
and recurrent otitis media was associated with self-reports of
spinal pain in pre-adolescents, taking advantage of prospectively collected data in the large-scale Danish National Birth Cohort (DNBC).
Material and methods
The DNBC is a population-based cohort of mothers and their
children born from 1996 to 2003 with follow-ups during pregnancy
and through childhood and young adulthood . Further details of the DNBC are described elsewhere .
The baseline population in the present study was DNBCchildren
born from singleton pregnancies in the period 1998–2003, and for whom mothers had provided information about infant pain experiences in the 6- and 18-month interviews. Of these, 29,861 children participated in the 11-year follow-up (DNBC-11) and provided full information on explanatory and outcomes measures (Fig. 1).
Approval of the study was obtained from the Danish Data
Protection Agency through the joint notification of the Faculty
of Health and Medical Sciences at the University of Copenhagen and the DNBC Steering Committee. All data were stored and processed at Statistics Denmark and no personally identifiable data were accessible.
Pain exposures in early life
Indicators for early-life pain experience were infantile colic
and recurrent otitis media. Infantile colic was assessed in
the first maternal interview postpartum when the children were around 6 months of age. The mothers were asked to report hours of excessive crying per day and the number of days per week in which crying exceeded more than 3 h. Hence, infantile colic was defined as crying for more than 3 h a day and more than 3 days a week. This definition was adapted from the BRule of three^ originally proposed by Wessel and colleagues  and the Rome IV criteria . Acute otitis media episodes were assessed by maternal reports at the 6- and 18-month interviews. Since otitis media is most prevalent after 6 months of age, we used data from the 18-month interview. Recurrent otitis media was defined as three or more episodes of acute otitis media [33, 42]. Subsequently, we conducted a measure of early-life pain experience categorized as no pain exposure, one pain exposure (infantile colic or recurrent otitis media), and both pain exposures (infantile colic and recurrent otitis media).
The DNBC-11 included a subdivision of The Young Spine
Questionnaire (YSQ), designed as a standardized tool of measuring back and neck pain in children age 9–11 . The YSQ includes questions on pain frequency (often/once in a while/once or twice/never) and intensity (from 1 Bno pain^ to 6 Bvery much pain^ based on the Faces Pain Scale-Revised (FPS-r)) of neck-, middle back-, and low back pain [21, 30].
We combined the pain frequency and intensity for each spinal region into no pain, moderate pain or severe pain . No pain was defined as a report of no pain or a pain of 1 or 2 on FPS-r occurring Bonce in a while^ or Bonce or twice.^ Severe pain was defined as pain of 4 or more on FPS-r and occurring at least Bonce in a while.^ Moderate pain was every combination of frequency and intensity in-between no pain and severe pain. Subsequently, we constructed the main outcome of interest Spinal pain as a composite variable including the three spinal regions categorized according to severity . For further details regarding the data collection, exact classification of the applied pain groups and testing of a variety of additional case definitions of spinal pain, see the previous study by Joergensen et al. .
Potential confounders selected a priori were child’s sex, gestational age, parity, maternal age at childbirth, and parental educational level identified using the methods of causal diagrams . Information on gestational age (term/preterm), parity (nulliparous/parous), and maternal age at childbirth (≤ 25, 26–30, 31–35, > 35 years) was obtained from the Danish Medical Birth Registry . We obtained information on parental education at childbirth from the Danish population’s education register . Educational level was operationalized as the highest of the parent’s ongoing or completed education and categorized into three groups according to the International Standard Classification of Education (ISCED) 2011: low (ISCED 0–2), medium (ISCED 3–4), and high (ISCED 5–8) . All national registries applied were available at Statistics Denmark and linked to DNBC-data through the unique individual personal identification number assigned to all persons with a permanent residence in Denmark .
Statistical analysesweremade using STATAv.15.We reported
descriptive statistics by proportions and analyzed for heterogeneity using the chi-squared test. To examine associations between early-life pain experience and spinal pain at age 11–14, we applied crude and adjusted multinomial logistic regression models to estimate and report relative risk ratios
(RRR) and their corresponding 95% confidence intervals
(CI) . In all analyses, no spinal pain was considered as the reference outcome. Taking dependency between siblings in the sample (n = 2481) into account, we applied a robust standard error estimator . Further, we used Wald tests to
examine potential interactions between child’s sex and earlylife
pain. Tests showed no signs of interactions (pModerate =
0.76/pSevere = 0.97); hence, the main regression analyses were
simply adjusted for all the a priori identified potential
Almost half of the 54,321 eligible singletons at baseline
did not participate in DNBC-11. To evaluate whether
selection forces may have biased our results, we firstly
performed a loss to follow-up analysis. Here we explored
the extent to which the applied study population differentiated
on several important characteristics from those lost to follow-up . For this purpose, we applied the Danish registry data to obtain information on children lost to follow-up in DNBC-11. Secondly, we compared the original analyses with analyses using inverse probability
weighting (IPW) accounting for selection from attrition
Further, we conducted IPW-analyses to account for
the study population being a selected sample of the source
population using a reference population consisting of all
children born in Denmark from 1998 to 2003 (n = 380,243). The probability of participating in the study was estimated for each individual using a given set of variables predicting selection into the cohort and loss to follow-up. We hereto estimated weight for each child (i.e., the inverse of the probability of selection) such that each participant was representing not only him/herself but also children with similar characteristics that did not participate in the study .
Finally, we performed a number of sensitivity analyses
to examine the robustness of the findings including analyses
using alternative definitions of spinal pain as well as
additional somatic symptoms as outcome measures (for
the definition of headache and abdominal pain, see
Supplementary File 5).
Almost 12% of pre-adolescents in the age range from 11 to 14
in the DNBC reported severe spinal pain and almost 30%
reported moderate pain, most frequent among girls (Table 1).
Pre-adolescents with early-life pain experience differed from
their peers without pain experience in early life (Table 2).
They were characterized by lower parental education, lower
maternal age at childbirth, and they were more often born
preterm. In addition, boys were more often exposed to otitis
media in early life. In contrast, children with infantile colic
were more often girls and firstborn.
Association between early-life pain experience and pre-adolescence spinal pain
Results from the multinomial regression model showed that
early-life pain experience increased the risk ratio of reporting
spinal pain at age 11–14 (Table 3). The association was stronger
for severe than for moderate pain. We observed a doseresponse
effect between the numbers of early-life pain exposures and the risk of pre-adolescence spinal pain. Examining the association for infantile colic and otitis media separately, we observed an association with spinal pain for both pain indicators of which infantile colic had a slightly stronger effect on spinal pain in pre-adolescents than otitis media (Table 3). We found no interaction with sex (for sex-stratified analyses, see Supplementary File 1).
For all analyses, we observed similar patterns to those of overall spinal pain analyzing neck,middle back, and low back pain separately (Supplementary Files 2–4). Likewise, using daily
life consequences (refrainment of physical activity, school absenteeism, and care-seeking behavior) attributable to spinal
pain as outcome measures of spinal pain, the results were in
accordance with those of the applied definition of spinal pain.
In term, the risk estimates were stronger (data not shown).
To add to the interpretation of the findings regarding spinal
pain, we performed analyses using headache and abdominal
pain as alternative somatic symptoms as outcome measures.
These results were in line with those of spinal pain; however,
results of abdominal pain were less robust (Supplementary
We further tested the impact of having had at least one
episode of otitis media before 6 months (i.e., same period as
infantile colic). This showed similar results to those of 18
months; however, the affected proportion of children were markedly lower (n = 1425) and the results were not statistically
significant (data not shown).
Selection of study participants
Children lost to follow-up constituted 45%(Fig. 1). They were
more often boys, preterm born, born to parous mothers, and
from families with lower educational and income status, and
their mothers were younger at childbirth (Supplementary File
6). In IPW analyses accounting for selection from attrition,
effect estimates were essentially unaffected (Supplementary
Finally, we performed sub-analyses in a reference population
consisting of all children born in Denmark in the corresponding
period, in which we applied IPW to account for selection both into the cohort and attrition. These estimates were also essentially unaffected by IPW (Supplementary File 8).
In this study, we examined the impact of early-life pain experience on spinal pain in pre-adolescence. Children experiencing pain in early life were more likely to report spinal pain. The association appeared stronger with exposure to two pain exposures rather than one, and infantile colic was seemingly more strongly associated with spinal pain in pre-adolescents than otitis media.
Our results are concordant with our hypotheses. Pain experience
results from a complex interplay of biological and psychosocial
influences, and it is possible that the observed associations
are attributable to specific characteristics of the children
or the familial environment such as children’s attention to
pain, parental modeling of pain, or social learning [29, 49, 57] rather than or concurrently with a neurobiological impact of the pain experience itself. Nevertheless, there are biological
reasons to suspect that pain experience in early postnatal life affects both the nociceptive system and the HPA axis with
both short- and long-term consequences on the pain sensation
[7, 19, 44]. Thus, the findings of this study can be due to the amount of pain experience itself (i.e., affecting the nociceptive system) or the distress related to the pain experience (i.e., affecting the HPA axis), or both, making it difficult to disentangle and interpret the effects of physical versus psychological stress .
We observed slightly stronger associations for infantile
colic than for otitis media. This may be explained by the
first months of life being more sensitive to alterations in
the neurobiological mechanisms or it may be related to
the nature of infantile colic and otitis media. Applying
the measure of otitis media at 6 months did not reveal
timing as a main issue. However, since infantile colic
exposes the child to longer cumulative pain duration compared
with one episode of otitis media, we cannot exclude
that timing constituted a main issue. Also, the subjective
pain experiences caused by infantile colic and otitis media
in terms of topography and intensity are likely to differ.
Moreover, longitudinal studies have indicated that infantile
colic is associated with inefficient sensory processing
 and exhibited emotional and behavioral problems [6,
8]; hence, it is likely that otitis media does not have the same potential as infantile colic to sensitize children in terms of pain and distress.
Our analyses revealed no sex differences, which is in contrast
to the existing literature regarding programming of the
HPA axis [5, 9, 35, 58] and the nociceptive system [2, 46]. This may be explained by the complex interplay between
biological and psychosocial influencing pain experience [2, 46, 56].
In addition to the main analyses of spinal pain, we found
relevant correlations between early-life pain experience and
additional somatic symptoms in terms of headache and abdominal
pain. Thus, the early-life relation to spinal pain in
pre-adolescents is seemingly not an exclusive correlation.
However, it has become increasingly acknowledged that vulnerability to spinal pain develops and becomes apparent already in childhood and subsequently tracks into adult life [13, 20, 28, 51]. Therefore, further analyses are necessary to investigate whether the mechanisms involved in the development of spinal pain in pre-adolescents diverge from those of other somatic symptoms.
As mentioned, parental modeling of pain can be an
important mechanism influencing children’s pain perception
and behavior. Parents are central in developing selfesteem,
self-confidence, and effective coping mechanisms in their children. Parental modeling of pain behaviors is shown to affect children’s own pain outcomes . It is also theorized that within the family, a specific cognitive style exists for coping with pain that is associated with a child’s response to pain experience . In addition, parental
pain behavior has been associated with children’s
report of spinal pain [10, 48]. Both infantile colic and recurrent otitis media induce a disproportional degree of parental concern and distress [11, 39, 43]. It could be
speculated whether experience of having children with
pain in early life makes parents exaggerate their children’s
pain, starting a trajectory where they amplify the pain, which in turn increases the children’s attention to pain.
Accordingly, it is possible that pain catastrophizing and
sensitization arise as a function of social learning and
parental modeling of pain [6, 48, 49].
Strengths and limitations
By using data from the DNBC, we were able to perform a
large-scale study of early-life programming of pain in children
including maternal and self-reported variables that are not
available in national registries. The prospective study design
ensured temporality between early-life pain and spinal pain in
pre-adolescents. Another strength of this study was the inclusion of both infantile colic and otitis media as pain indicators. Although they are pathologically very different conditions, occurring at different points during infancy and with different duration periods, the results were robust for both conditions. This validates both as being indicators for pain experience with similar mechanistic relations to pain sensitization.
Both exposures were based on maternal reports,which may have introduced misclassification. We believe this is mainly a
concern for infantile colic. Acute otitis media can be considered more distinct and objective, whereas infantile colic is more likely to be biased due to parental pain modeling and
distress. Additionally, it is difficult to disentangle whether
infantile colic acts as an indicator of preexisting sensitive pain processing rather than a pain exposure itself; thus, a proxy related to children born with a certain susceptibility to pain.
We were able to adjust for several potential confounders;
however, when assessing the potential effect of early-life pain
on subsequent pain sensation, comprehensive inclusion of appropriate psychological and social factors is challenging . For example, preexisting parental concern and parental pain modeling may represent an important role in the findings. The possibility of parental concern being an intermediate step arising from having a child exposed to painful conditions may also exist. Both of which, we were not able to take into account with the data at hand.We did, however, perform a number of sensitivity analyses to reinforce the existence of neurobiological mechanisms as involved in early programming of pain e.g. by applying headache and abdominal pain as alternative somatic outcome measures. Since the association was apparent for all somatic outcomes, it points to the existence of a neurobiological link. In contrast, if the association had been apparent for only one somatic symptom, the etiology of the specific conditions would probably have been more diseasespecific or due to external factors.
Lastly, the risk of selection having biased our results cannot
be disregarded due to DNBC-participants being a selected
sample of the source population and to the large proportion
of children lost to follow-up . However, the weighted
results did not reveal any essential changes to the estimates; therefore, we do not believe selection bias was a major problem
for the findings in this study [24, 36, 38].
Children with pain experience in early life are seeminglymore
likely to report spinal pain in pre-adolescence. This study
highlights that painful early-life experiences can influence
programming of future pain responses; however, whether the
influence is related to the nociceptive system, the stress response or psychosocial factors remain to be explored.
The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation.
Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation, and other minor grants. The DNBC biobank has been supported by the NovoNordisk Foundation and the Lundbeck Foundation. Follow-up of mothers and children have been supported by the Danish Medical Research Council (SSVF 0646, 271-08-0839/06-066023, O602-01042B, 0602-02738B), the Lundbeck Foundation (195/04, R100-A9193), the Innovation Fund Denmark 0603-00294B (09-067124), the Nordea Foundation (02-2013-2014),
Aarhus Ideas (AU R9-A959-13-S804), University of Copenhagen
Strategic Grant (IFSV 2012), and the Danish Council for Independent Research (DFF-4183-00594 and DFF-4183-00152).
Joergensen, MSc, conceptualized and designed the study, contributed to methods development, carried out data management
and analyses and interpretation of results, and drafted the
Prof. Nybo Andersen conceptualized and designed the study, contributed to methods development and to the interpretation of results and critical revision of the manuscript.
Dr. Hestbaek contributed to the conceptualization and design of the study, to methods development, to interpretation of results and to critical revision of the manuscript.
Dr. Lucas contributed to the conceptualization and design of the
study, to methods development, to the interpretation of results and to critical revision of the manuscript.
Prof. Kragh Andersen supervised in statistical methods and analyses and contributed to the interpretation of results and critical revision of the manuscript.
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of this article.
The study was supported by the Danish Council for Independent Research (DFF-7016-00344).
Conflict of interest
The authors declare that they have no conflicts of interest.
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A note on robust variance estimation for cluster-correlated data.
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