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Abstract

Context

Infant colic is a common and distressing disorder of early infancy. Its etiology is unknown, making treatment challenging. Several articles have suggested a link to migraine.

Objective

The objective of this article was to perform a systematic review and, if appropriate, a meta-analysis of the studies on the relationship between infant colic and migraine.

Data sources

Studies were identified by searching PubMed and ScienceDirect and by hand-searching references and conference proceedings.

Study selection

For the primary analysis, studies specifically designed to measure the association between colic and migraine were included. For the secondary analysis, studies that collected data on colic and migraine but were designed for another primary research question were also included.

Data extraction

Data were abstracted from the original studies, through communication with study authors, or both. Two authors independently abstracted data.

Main outcomes and measures

The main outcome measure was the association between infant colic and migraine using both a fixed-effects model and a more conservative random-effects model.

Results

Three studies were included in the primary analysis; the odds ratio for the association between migraine and infant colic was 6.5 (4.6–8.9, p < 0.001) for the fixed-effects model and 5.6 (3.3–9.5, p = 0.004) for the random-effects model. In a sensitivity analysis wherein the study with the largest effect size was removed, the odds ratio was 3.6 (95% CI 1.7–7.6, p = 0.001) for both the fixed-effects model and random-effects model.

Conclusions

In this meta-analysis, infant colic was associated with increased odds of migraine. If infant colic is a migrainous disorder, this would have important implications for treatment. The main limitation of this meta-analysis was the relatively small number of studies included.

Keywords

Infant colic migraine pediatric

Introduction

Infant colic, excessive crying in an otherwise healthy infant, affects 5%–19% of babies (1,2). Normal infant crying increases in the first weeks of life, peaks around 5 to 6 weeks of age, and tapers off by 3 months of age (3,4). Infant colic is an amplified version of this developmental crying pattern, often with bouts of prolonged inconsolable crying in the evenings (2 –5). While definitions of what constitutes an excessive amount of infant crying vary (6), crying for at least three hours per day for at least three days per week in the preceding week (6 –10), or in the preceding three weeks, are two commonly employed definitions in research (10,11). Colicky crying is highly distressing to caregivers and is associated both with caregiver frustration (12) and Shaken Baby Syndrome (4,13,14).

While infant colic is often assumed to be due to abdominal discomfort, no direct evidence for an abdominal localization exists and treatments that assume a primary gastrointestinal etiology have been largely unsuccessful (15 –17). Despite much research, our understanding of the etiology of infant colic has not evolved significantly since Wessel’s original description in 1954 (10). Several studies have reported an association between migraine headache and infant colic (11,18,19). If infant colic is an early-life manifestation of migrainous tendencies, this would have significant implications for treatment.

Migraine is a largely inherited (20 –22) disorder of the brain (23) characterized by paroxysmal attacks of headache associated with sensitivity symptoms such as photophobia and phonophobia (24). This meta-analysis seeks to assess whether there is an association between infant colic and migraine, and if so to estimate the effect size of that association.

Methodology

The objective of this study was to perform a systematic review of the studies on the relationship between infant colic and migraine, and a quantitative meta-analysis if sufficient study data existed, in order to provide the best estimate of the association between infant colic and migraine. To identify articles, AAG searched PubMed (most recently on March 19, 2014) for the terms “migraine and colic” and “’infant colic’ and headache.” The search was restricted to articles that were in English and between 1975 and 2013. All abstracts were reviewed by the search author for eligibility. Journal articles were also searched for in the electronic database Science Direct (most recently on March 19, 2014) using the terms “migraine and colic” for the time period 1993–2013. Given the high number of returns in this database, the search author reviewed all titles and excluded those that were clearly not relevant to the research question and then reviewed the abstracts of the remaining articles.

For the systematic review, any type of article, i.e. original research, case report, editorial, that discussed the relationship between infant colic and migraine was fully reviewed and included.

Inclusion criteria for the meta-analysis primary analysis were set a priori: To be included, a study had to have the primary research question of examining the association between migraine and infant colic. Design of the study could be cross-sectional, case-control, or cohort.

When studies were identified that collected data on migraine status and infant colic but were designed around a different primary research question, we analyzed these studies in a secondary analysis. If it was not possible with these latter type of studies to determine how many in the migraine and no-migraine groups had colic, respectively, the study authors were contacted to ask for clarification, and the study was included in the secondary analysis if clarification as to group assignment was provided. Case reports were excluded from the meta-analysis.

For those studies that fulfilled meta-analysis inclusion criteria, as well as all articles from the systematic review, the references sections were hand-searched by the search author for additional articles. In addition, to check for unpublished data the search author electronically searched the abstracts from the most recent conference proceedings from two professional societies, the American Headache Society (AHS) and the International Headache Society (IHS; AHS years 2010, 2011, and 2012; IHS years 2007, 2009, 2011, and 2013) using the terms “colic,” “infant,” “crying,” “baby,” “babies,” “pediatric” and “childhood.”

For articles that met inclusion criteria for the meta-analysis, the following data were abstracted in an unblinded fashion independently by two authors (AAG and IEA): study first author and year, number with migraine who had colic, number with migraine who did not have colic, number without migraine who had colic, and number without migraine who did not have colic.

Analysis

Statistical analyses were performed in STATA version 12.0 (College Station, TX) and Comprehensive Meta-Analysis v2.2. In our analysis, infant colic was the risk factor being examined and migraine was the outcome variable. Both fixed-effects (FEM) and random-effects models (REM) were fit to the studies. The Mantel-Haenszel FEM (25) computes the effect estimate as a weighted average of the individual study estimates, each weighted by the inverse of the study variance.

The REM (26) assumes that each study has its own mean µ_i and variance σ_i² (i.e. that it follows its own treatment effect distribution), but that the µ_i is drawn from a superpopulation of treatment effects with its own mean µ and variance τ² that describes the between-study heterogeneity. As in the FEM, µ is estimated by a weighted average of the study effects but the weights, 1/(τ²+ σ_i²), are the inverses of the sums of the within-study variances σ_i² and the between-study variance τ². When τ²= 0 so that the treatment effects µ_i are all the same, this reduces to the FEM.

Cochran’s Q and the I² test were performed to examine heterogeneity in the meta-analyses.

A preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist and flow diagram were completed (27).

A sensitivity analysis was performed removing each study in the primary and secondary analyses and then calculating the FEM and REM to identify whether any study’s removal changed the overall conclusions.

Results

Thirty-six articles were identified in the PubMed searches. Three studies met inclusion criteria for the primary analysis (11,18,19) and an additional two met inclusion criteria for the secondary analysis (28,29).

Of the three articles included in the primary analysis, two were case-control studies and one was cross-sectional. The case-control studies examined the frequency of infant colic history in children with migraine compared to children without migraine, while the cross-sectional study used maternal migraine status as a marker for migraine genetics in the infants and examined the frequency of infant colic in mothers with migraine compared to mothers without migraine (18). In the Jan and Al-Buhairi case-control study, children were diagnosed with migraine by a pediatric neurologist using IHS criteria for migraine. The children’s mean age at the time of the study was 10 years in the migraine group and 9.5 years in the non-migraine control group. Parental recall of whether the child had had infant colic was measured using a structured questionnaire wherein colic was defined as “repeated crying for at least 3 hours per day, 3 days a week for a minimum of 3 weeks during the first 3 months of life” (11). In the Romanello et al. case-control study, children were diagnosed with migraine using IHS criteria. The children’s mean age at the time of the study was 10.1 years in the migraine group and 9.0 years in the control group. Parental recall of whether the child had had infant colic was measured using a structured questionnaire wherein colic was defined “according to the criteria by Wessel” (19). It was not stated whether this meant crying for at least three hours per day more than three days per week in the preceding week (the definition for “fussy” in the Wessel paper), or in the preceding three weeks (the definition for “seriously fussy” in the Wessel paper (10)). In addition, the children’s health care booklets were reviewed by the researchers to see whether infant colic had been recorded in the child’s health record during infancy; there was perfect concordance as to colic status between parental recall and the health booklet in the 99.1% of children whose booklets were available for review (19). In the Gelfand et al. cross-sectional study (18), mothers were determined to have migraine if they reported either a physician diagnosis of migraine, as a clinical diagnosis of migraine has been shown to agree with IHS criteria 98% of the time (30), or if they screened positive on IDMigraine, a well-validated instrument with a high-positive predictive value (0.93) for migraine (31). Infant colic status was measured at the time the mothers brought their infants for their well-baby two-month check-ups; the mean age of the colicky infants was 8.0 weeks and of the non-colicky infants 8.3 weeks. Colic was defined according to the mother’s response on a structured questionnaire to the question “Has your baby cried for at least 3 hours a day, at least 3 days a week, for at least a week?” (18).

The ScienceDirect search yielded 483 articles, including one article and one abstract that would have met inclusion criteria for the secondary analysis had it been possible to match colic status to migraine status in individuals (32,33.) Authors from three studies (29,32,33) were contacted to request clarification for matching migraine status to colic status in individuals and this was possible in one (29).

The search of conference proceedings did not identify any unpublished data, only the abstract version of one of the studies identified in the PubMed search for the primary analysis (18). The searches also revealed several references relevant to the systematic review but not meeting criteria for inclusion in the meta-analysis: a case report (34), two studies (one an abstract, one an article) on “hyperactive” infants that did not specifically measure colic (35,36), a review article on pediatric migraine and childhood periodic syndromes that included a discussion of infant colic (37), two editorials on the relationship between colic and migraine (38,39) and a summary of one of the studies (40), as well as an abstract that discussed how using a history of periodic syndromes, including infant colic, might be a way to help diagnose migraine in patients who do not meet International Classification of Headache Disorders (ICHD) criteria for migraine (41).

In summary, five studies contributed to the quantitative analysis (11,18,19,28,29) and an additional 10 publications contributed to the qualitative synthesis (32 –41) for a total of 15 in the qualitative synthesis. The PRISMA flow diagram (Figure 1) depicts the results of the search process pictorially.

Figure 1.

PRISMA flow diagram for colic and migraine meta-analysis (27). For more information, visit www.prisma-statement.org.

For the primary analysis, there were a total of 265 subjects with migraine and 626 without migraine. The study populations were drawn from France, Italy, Saudi Arabia, and the United States (US). Of those with migraine, 174 (66%) also had colic. Of those without migraine, 145 (23%) had colic. For the secondary analysis, the additional study populations were drawn from Italy and Spain. There were 701 individuals with migraine and 2174 without migraine. Of those with migraine, 240 also had colic (34%). Of those without migraine, 394 (18%) had colic.

The odds ratios (ORs) estimating the measure of association between infant colic and migraine for the individual studies are shown in Table 1.

Table 1.

Odds ratios for the measure of association between infant colic and migraine in the individual studies.

	Publication year and study design	Geographic location of the study sample	Total n in study	Migraineurs with colic n (%)	Migraineurs without colic n (%)	Non-migraineurs with colic n (%)	Non-migraineurs without colic n (%)	Odds ratio for the association between colic and migraine (95% CI)
Study first author	Publication year and study design	Geographic location of the study sample	Total n in study	Migraineurs with colic n (%)	Migraineurs without colic n (%)	Non-migraineurs with colic n (%)	Non-migraineurs without colic n (%)
Studies included in the primary analysis
Jan (11)	2001, Case-control	Saudi Arabia	58	15 (26%)	14 (24%)	6 (10%)	23 (40%)	4.1 (1.3–13.1)
Gelfand^a (18)	2012, Cross-sectional	USA	154	8 (5%)	20 (13%)	14 (9%)	112 (73%)	3.2 (1.2–8.6)
Romanello (19)	2013, Case-control	France, Italy	679	151 (22%)	57 (8%)	125 (18%)	346 (51%)	7.3 (5.1–10.6)
Studies added in the secondary analysis
Bruni (28)	1997, Case-control study of sleep disorders in children with headache	Italy	1057	63 (6%)	101 (10%)	240 (23%)	653 (62%)	1.7 (1.2–2.4)
Marugán-Miguelsanz (29)	2013, Case-control study on the natural history of irritable bowel syndrome	Spain	36	3 (8%)	4 (11%)	9 (25%)	20 (56%)	1.6 (0.3–8.6)

CI: confidence interval; USA: United States. ^aMaternal migraine status was used as a marker of infant migraine genetics in this cross-sectional study. Not all percentages add to 100 because of rounding error.

In the primary analysis, the pooled OR (95% confidence interval (CI)) was 6.5 (4.6–8.9, p < 0.001) for the FEM (Figure 2(a)) and 5.6 (3.3–9.5, p = 0.004) for the REM (Figure 2(b)). Neither test for heterogeneity was statistically significant, indicating homogeneous studies; for both models the I² values were 32.8% and p values were 0.23.

Figure 2.

(a) Forest plot for primary analysis fixed-effects model. (b) Forest plot for primary analysis random-effects model.

In the secondary analysis, the cumulative OR (95% CI) was 3.4 (2.7–4.3, p < 0.001) in the FEM and 3.2 (1.4–7.5, p = 0.007) in the REM. Both tests for heterogeneity in these models were significant (p value < 0.001), indicating that the REM was appropriate.

In the sensitivity analysis no individual study changed the overall outcome of the meta-analysis. The Romanello study (19) had the largest effect size estimate of all the individual studies and had provided 73.6% of the weight in the primary analysis FEM and 61.5% in the primary analysis REM (27.8% of the weight in the secondary analysis FEM and 25.1% of the weight in the secondary REM). With the Romanello study removed, the cumulative OR in the sensitivity primary analysis FEM was OR 3.6 (1.7–7.6, p = 0.001), and the same in the sensitivity primary analysis REM (OR 3.6 (1.7–7.6, p = 0.001)).

The cumulative OR in the sensitivity secondary analysis FEM, with the Romanello study removed, was OR 1.9 (1.4–2.6), p < 0.001) and in the REM was OR 2.0 (95% CI 1.4–2.9), p = 0.001).

Discussion

In this meta-analysis, infant colic was associated with increased odds of migraine (OR 5.6, 95% CI 3.3–9.5) in the primary analysis REM. Each of the three studies in the primary analysis (11,18,19) independently demonstrated an association between infant colic and migraine, with the effect size estimate in the individual studies ranging from OR 3.2 (95% CI 1.2–8.6) (18) to 7.3 (95% CI 5.1–10.6) (19). Tests for heterogeneity demonstrated the studies in the primary analysis had good combinability. The FEM demonstrated a slightly larger effect size estimate (OR 6.5, 95% CI 4.6–8.9); however, this model assumes the samples in the studies represent the whole range of effect sizes and as the studies in the secondary analysis demonstrated smaller effect sizes than what was seen in the primary analysis studies, the REM is preferable as it does not assume that the studies are homogeneous with the same distribution. The REM results in a more conservative estimate than the FEM. The secondary analysis included studies that had not specifically been designed to measure an association between infant colic and migraine (28,29), hence the methods used to assess colic and migraine status may not have been as well developed. Not surprisingly given the different primary research questions of these studies, there was heterogeneity in this analysis. Nonetheless, there was still a statistically significant association between infant colic and migraine, OR 3.2 (95% CI 1.4–7.5, REM).

Despite much research over the nearly 60 years since Wessel’s initial 1954 description of infant colic (10), we have not made significant progress in understanding its etiology or finding effective therapy. It is important we ultimately determine the etiology of infant colic and find effective treatment strategies, as inconsolable crying is associated with caregiver frustration (12) and Shaken Baby Syndrome (4,13,14). Of parents of 1-month-old babies, 1% admit to having shaken their baby at least once in an effort to stop the baby’s crying, and 2.2% have either shaken, slapped, or smothered the baby at least once to try to stop their crying (42). For parents of 6-month-old babies, the percentage of parents who have tried one of these dangerous techniques rises to 5.6% (42). Therapies that reduce infant crying could ease caregivers’ frustration and protect infants from harm.

Childhood periodic syndromes, or “Episodic syndromes that may be associated with migraine,” in the parlance of the new ICHD-III (beta version) classification system (24), are thought to be early-life manifestations of those genes that later in life are expressed as migraine headache. For example, benign paroxysmal torticollis has been linked to the familial hemiplegic migraine gene CACNA1A (43). Infant colic is now included in the ICHD-III (beta) (24) appendix among the episodic syndromes that may be associated with migraine. If infant colic is indeed a childhood periodic syndrome, it would be by far the most common one as benign paroxysmal torticollis, benign paroxysmal vertigo, cyclic vomiting syndrome and abdominal migraine occur more rarely in children. Therefore infant colic would be the most important periodic syndrome for pediatric clinicians to know about in terms of identifying children at risk for migraine and helping to diagnose pediatric migraine.

If infant colic is a migrainous phenomenon, it could provide a neurodevelopmental explanation for many of colic’s characteristics. For example, why does colicky crying develop at several weeks of life? Migraineurs experience increased sensitivity to stimuli (24,44,45) and infants’ perceptual abilities are rapidly increasing during the first weeks of life. It is possible that infants with colic have migraine genes that make them more sensitive to stimuli and they express that through increased crying. Similarly, increased sensitivity to stimuli could explain why colicky crying tends to happen in the evenings, as that is when infants are at the end of a long day of stimulation, or as with migraine there may be an influence of circadian biology. Alternatively it is possible that the association between infant colic and migraine is due to a shared genetic predisposition to both disorders, rather than infant colic being an early-life expression of migraine genetics per se.

If infant colic is a migrainous phenomenon, it could also help explain why colic resolves around age 3 months. Age 3 months is approximately when the infant brain develops rhythmic excretion of endogenous melatonin (46) and nighttime sleep consolidation (47,48). The ability of sleep to help terminate migraine attacks (49), particularly in young children (50), is well recognized. Poor sleep can also trigger childhood migraine attacks (51). Developing rhythmic endogenous melatonin excretion and a predictable sleep pattern could help extinguish an age-sensitive manifestation of migraine like colic (38). Melatonin has been shown in a randomized placebo-controlled trial to be effective in the prevention of episodic migraine in adults (52). An open-label study suggests it may be effective in migraine prevention in children (53).

Limitations of this meta-analysis are that the number of studies included was relatively small, none of the included studies were prospective, and migraine status and colic status were obtained in different ways and times in the infants’/children’s lives. Prospective longitudinal cohort studies with prospective crying diaries are needed to identify infants with and without colic, and then to follow them into childhood to determine whether those with colic are indeed more likely to develop migraine headaches in childhood, as well as whether they are more likely to develop the other so-called “childhood periodic syndromes.” The pooled effect size estimates obtained in this study can be used to plan the size required in future prospective cohort studies on the relationship between infant colic and migraine.

Such longitudinal studies would take at least a decade to complete, making them logistically challenging to perform. There has been one published prospective cohort study of children who were “hyperactive” as infants. Excessive crying was one of the features that could lead to a child being classified as “hyperactive,” hence perhaps some of these infants had colic, though excessive crying was not a required feature to be classified as “hyperactive” and defined colic criteria were not used. At follow-up a mean of 10.8 years later, 52.9% of the hyperactive infants had migraine as children vs. 11% of those who were not hyperactive as infants (p < 0.001) (35).

As with all observational studies, there is the potential for bias or confounding to have contributed substantially to the observed measure of association between infant colic and migraine in this meta-analysis. However, given that the measured effect size was relatively large, with an OR between 1.9 and 6.5, depending on the model, and the 95% CIs were relatively narrow, with the lowest lower boundary of 1.4 in the secondary analysis REM, it is less likely that bias and confounding could completely negate the association. Removing the study with the largest estimate of association only attenuated the REM effect size estimate (OR 3.6, (1.7–7.6) in the sensitivity analysis vs. OR 5.6 (3.3–9.5) in the primary analysis). It is also reassuring that the study populations for the included studies were drawn from multiple regions of the world, suggesting the association persists despite ethnic and culturally variability. In addition the studies were performed in different clinical contexts. For example, the Romanello et al. study, which had the largest observed OR, was performed in the highest clinical acuity setting—the emergency department—while the other studies were performed in the neurology clinic or well-child general pediatric outpatient clinic. Some of the observed variation in effect size estimates among the individual studies may be explained by the different clinical contexts in which they were performed.

If infant colic is an early-life manifestation of migraine, this would have several management implications. First, expectant parents with a history of migraine could be counseled about the increased risk of having an infant with colic (18). Such foreknowledge might help with coping with the challenges of caring for an inconsolably crying infant. Second, knowledge of the association would alert pediatricians to be on the look-out for migraine in their patients who had colic as infants, which might decrease delay in migraine diagnosis and allow these children to receive appropriate migraine treatment more quickly. Lastly, understanding colic to be a migrainous phenomenon could lead to identification of effective treatment strategies. Behavioral interventions, such as decreasing certain types of stimulation, may be helpful and could be performed safely (17,54). Pharmacologic treatment trials using agents that are effective for migraine in young children and safe in young infants, acetaminophen for example (55), could be pursued. A case report suggests there might be a therapeutic role for cyproheptadine (34). While there are animal data suggesting melatonin may be useful in the treatment of neonates with hypoxic-ischemic brain injury and therefore might safely be used to treat young infants with colic (56), there may be neurodevelopmental reasons why the infant brain does not develop an endogenous rhythm of melatonin excretion until about 3 months of life (46), such as ensuring frequent nighttime feedings to allow adequate weight gain, or preventing excessively deep or prolonged sleep while the cardio-respiratory system is still acclimating to avoid Sudden Infant Death Syndrome. Hence whether a trial of melatonin for the treatment of severe infant colic would be appropriate would require rigorous consideration by experts in the field.

In summary, this meta-analysis provides a pooled effect size estimate of the measure of association between infant colic and migraine headache. A prospective study wherein infants with and without colic are followed longitudinally and observed for the development of migraine headache as children would help further elucidate the magnitude of this relationship by eliminating recall bias. Future studies should collect data on family history of migraine and colic in first-degree relatives in order to determine to what extent an infant with colic’s risk of developing migraine is mediated through genetics. There is great potential to advance our understanding of the pathophysiology and treatment of both of these common and distressing conditions.

Clinical implications

Observational data demonstrate an association between infant colic and migraine.

If infant colic is an early-life manifestation of migraine (i.e. a childhood periodic syndrome), this would have significant treatment implications for this common and distressing disorder of early infancy.

Footnotes

Contributors’ statement

Dr Gelfand conceptualized and designed the study, carried out the initial analyses, drafted the initial manuscript, and approved the final manuscript as submitted. Dr Goadsby assisted in conceptualizing and designing the study, revised the manuscript for important intellectual content, and approved the final manuscript as submitted. Dr Allen assisted in conceptualizing and designing the study, assisted Dr Gelfand with the analyses, revised the manuscript for important intellectual content, and approved the final manuscript as submitted.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of interest

AAG receives grant support from National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) (K12NS001692) and the UCSF Center for Translational Science Institute. She has received honoraria from Journal Watch Neurology and personal compensation for legal consulting. PJG is on the boards of Allergan, Colucid, MAP pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Autonomic Technologies Inc, Boston Scientific, Eli Lilly, Medtronic, Linde gases, Electrocore, Arteaus, AlderBio and BristolMyerSquibb. He has consulted for Pfizer, Nevrocorp, Zogenix, Impax, Zosano, and Dr Reddy, and has been compensated for expert legal testimony. He has received grant support from MAP, MSD, Allergan, and Amgen. He has received honoraria for speaking from Pfizer and Allergan, and payment for editorial work from Journal Watch Neurology and for developing educational materials for the American Headache Society. IEA is on the boards of ResultCare and the Global Healthy Living Institute. She has consulted for Hologic, Amgen, Genentech, Ariad, and Bracco and has been compensated for expert testimony. All authors have no relationships with companies that might have an interest in the submitted work in the last three years; their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and all authors have no non-financial interests that may be relevant to the submitted work.

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The relationship between migraine and infant colic: A systematic review and meta-analysis

Abstract

Context

Objective

Data sources

Study selection

Data extraction

Main outcomes and measures

Results

Conclusions

Keywords

Introduction

Methodology

Analysis

Results

Discussion

Clinical implications

Footnotes

Contributors’ statement

Funding

Conflicts of interest

References