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(CEP)
[1–3] [PREPRINTER stage]
Editorial
Infant colic—a baby’s migraine?
Cephalalgia 0(0) 1–3 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102415576224 cep.sagepub.com
Amy A Gelfand
All babies cry. Colicky babies cry more. Infant colic, or excessive crying in an otherwise healthy and well-fed infant, affects approximately 5–19% of babies (1). Infant crying peaks at age 5–6 weeks (corrected for gestational age at birth) and generally decreases by age 3–4 months. Colic is an amplified version of this developmental crying pattern (2,3). While the name ‘‘colic’’ implies a gastrointestinal etiology, direct evidence for this localization is lacking. In the historic 1954 paper by Wessel et al., the syndrome was described as ‘‘Paroxysmal fussing in infancy, sometimes called colic’’(4). ‘‘Paroxysmal fussing’’ may be a more apt descriptive term as all that is clear is that the infants are in distress. While definitions of infant colic vary (5), Wessel’s criteria are commonly used and are the criteria used in the International Classification of Headache Disorders, third edition beta (ICHD-III beta) (appendix): crying for at least three hours a day, at least three days a week, for at least three weeks (or one week for modified Wessel’s criteria) (4,6,7). Despite much research, the cause of infant colic remains poorly understood. Often colic is assumed to be related to feeding—something in the milk, the mother’s diet, the formula or intestinal gas. However, several randomized, placebo-controlled trials have not found gastrointestinal-based treatments to be effective (8–10). Moreover, young infants feed every couple of hours around the clock, yet colicky crying tends to happen more in the evening (2,3). It is important that we ultimately determine the cause of infant colic, as inconsolable and excessive crying causes caregiver frustration and is associated with shaken baby syndrome—a form of child abuse with significant neurologic morbidity and mortality (3,11,12). One percent of parents of 1-month-olds admit to having shaken their baby at least once to try to stop crying, and 2.2% have tried shaking, slapping or smothering. By age 6 months, 5.6% have tried one of these dangerous techniques (11). An association between infant colic and migraine has been reported in several retrospective case-control studies (13–15). In a cross-sectional study, mothers with migraine were more than twice as likely to have an
infant with colic, pointing to the possible genetic relationship between infant colic and migraine (6). A recent meta-analysis found the odds of migraine were increased if there was a history of infant colic (odds ratio (OR) 5.6 (95% confidence interval (CI) 3.3–9.5)) (16). What the field has been missing—until now—has been a prospective cohort study examining the relationship between infant colic and migraine, as previous studies’ findings could have been explained by recall bias. In the paper by Sillanpaa and Saarinen, published in this edition of Cephalalgia, the authors used the Finnish Family Competence Study—a study that sampled the general population in a region in Finland and enrolled parents expecting their first child in 1986. At 3 months of age, colic status was assessed using a combination of input from parents and an experienced nurse who spoke to the parents about the frequency, severity, and duration of their baby’s crying episodes. When they grew to age 18, the adolescents completed a questionnaire regarding migraine status using ICHD criteria. Of the 1267 babies originally sampled, migraine outcome data were available in 787 (62%). The proportion with a history of colic did not differ in those who were lost to follow-up. The main finding was that having a history of infant colic predicted development of migraine without aura (relative risk (RR) 2.7 (95% CI 1.5–4.7)), but not migraine with aura. While Wessel’s criteria for colic were not used, this is only a modest limitation as crying duration is often estimated by parents in colic studies. The finding of an association between infant colic and migraine without aura, but not migraine with aura, is interesting and speaks to likely differences in underlying genetics. Migraine is a highly inherited disorder in that the majority of migraineurs have a
UCSF Headache Center, Department of Neurology, University of California San Francisco, USA; Division of Child Neurology, UCSF, USA Corresponding author: Amy A Gelfand, UCSF Headache Center, 2330 Post St, 6th Floor, San Francisco, CA 94115, USA. Email: [email protected]
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(CEP)
[1–3] [PREPRINTER stage]
2 positive family history (17,18). However, except in the case of familial hemiplegic migraine, the genetics of migraine have not been untangled. The clinical phenotype of migraine varies among individuals—some have aura, some have nausea, some have osmophobia, etc. Lumping all migraineurs as if they were all the same in a genome-wide association study is unlikely to yield discoveries. Detailed clinical phenotyping that divides migraineurs into more homogeneous subgroups might facilitate gene discovery, and colic may prove to be one such phenotype. It is still not known whether infant colic is a form of migraine itself, or simply a marker of migraine genetics. It is possible that the babies cry because of headache or because of abdominal pain akin to abdominal migraine. It is also possible that they are more sensitive to stimuli than other babies and express that sensitivity through excessive crying. With rapid brain development, neonates’ visual perceptual ability increases significantly during the first few weeks of life (19). This could explain why colic does not begin until about 2 weeks of life, even though babies are feeding and interacting from birth onward. There may also be a role for circadian biology in colic, as there is in migraine. Age 3 months is when the infant’s endogenous melatonin secretion takes on a circadian rhythm that allows for nighttime sleep consolidation (20–23). Rhythmic melatonin secretion, either in itself or mediated by the ability to sleep through the night, could explain why colic resolves around age 3 months. Particularly in young children, sleep can help terminate a migraine attack (24). Now with these prospective study results in hand, it is important to disseminate knowledge of the association between infant colic and migraine to general pediatricians, as recognition that infant colic can precede development of migraine headache could help avoid diagnostic delay of migraine in children. It is also time to apply what we know about treating childhood migraine to helping babies with colic. We know that during a migraine attack children want to climb in bed and pull the covers over their heads and be in a dark, quiet room. A behavioral intervention wherein caregivers are trained to decrease stimulation when colicky crying starts—turn off the lights, quiet the musical toy—could potentially help babies and in turn help frustrated caregivers remain calm. There is in fact some evidence that such a strategy may be effective (25). Moving forward, observational studies should address whether there are associations between infant colic and other childhood periodic syndromes such as benign paroxysmal torticollis and abdominal migraine. Treatment trials for infant colic should focus on behavioral interventions, or well-studied and safe medications in this age group. Given the totality of the evidence for an association between infant colic and
Cephalalgia 0(0) migraine, it would seem well justified to bring infant colic into the main body of ICHD-III. Conflicts of interest Dr Gelfand receives salary support from the National Institutes of Health/National Center for Advancing Translation Sciences (NIH/NCATS) 8KL2TR000143-09, and research grants from the Migraine Research Foundation and Allergan. She has received honoraria from Journal Watch Neurology, and was paid a consulting fee by FCB, a medical communications agency in New York, NY.
References 1. Lucassen PL, Assendelft WJ, van Eijk JT, et al. Systematic review of the occurrence of infantile colic in the community. Arch Dis Child 2001; 84: 398–403. 2. Brazelton TB. Crying in infancy. Pediatrics 1962; 29: 579–588. 3. Barr RG, Trent RB and Cross J. Age-related incidence curve of hospitalized Shaken Baby Syndrome cases: Convergent evidence for crying as a trigger to shaking. Child Abuse Negl 2006; 30: 7–16. 4. Wessel MA, Cobb JC, Jackson EB, et al. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 1954; 14: 421–435. 5. Reijneveld SA, Brugman E and Hirasing RA. Excessive infant crying: The impact of varying definitions. Pediatrics 2001; 108: 893–897. 6. Gelfand AA, Thomas KC and Goadsby PJ. Before the headache: Infant colic as an early life expression of migraine. Neurology 2012; 79: 1392–1396. 7. van den Berg MP, van der Ende J, Crijnen AA, et al. Paternal depressive symptoms during pregnancy are related to excessive infant crying. Pediatrics 2009; 124: e96–e103. 8. Metcalf TJ, Irons TG, Sher LD, et al. Simethicone in the treatment of infant colic: A randomized, placebo-controlled, multicenter trial. Pediatrics 1994; 94: 29–34. 9. Sung V, Hiscock H, Tang ML, et al. Treating infant colic with the probiotic Lactobacillus reuteri: Double blind, placebo controlled randomised trial. BMJ 2014; 348: g2107. 10. Kukkonen K, Savilahti E, Haahtela T, et al. Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: Randomized, double-blind, placebo-controlled trial. Pediatrics 2008; 122: 8–12. 11. Reijneveld SA, van der Wal MF, Brugman E, et al. Infant crying and abuse. Lancet 2004; 364: 1340–1342. 12. Fujiwara T, Barr RG, Brant R, et al. Infant distress at five weeks of age and caregiver frustration. J Pediatr 2011; 159: 425–30.e1–2. 13. Jan MM and Al-Buhairi AR. Is infantile colic a migrainerelated phenomenon? Clin Pediatr (Phila) 2001; 40: 295–297. 14. Bruni O, Fabrizi P, Ottaviano S, et al. Prevalence of sleep disorders in childhood and adolescence with headache: A case-control study. Cephalalgia 1997; 17: 492–498.
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(CEP)
[1–3] [PREPRINTER stage]
3
Gelfand 15. Romanello S, Spiri D, Marcuzzi E, et al. Association between childhood migraine and history of infantile colic. JAMA 2013; 309: 1607–1612. 16. Gelfand AA, Goadsby PJ and Allen IE. The relationship between migraine and infant colic: A systematic review and meta-analysis. Cephalalgia 2015; 35: 63–72. 17. Russell MB, Hilden J, Sorensen SA, et al. Familial occurrence of migraine without aura and migraine with aura. Neurology 1993; 43: 1369–1373. 18. Russell MB, Fenger K and Olesen J. The family history of migraine. Direct versus indirect information. Cephalalgia 1996; 16: 156–160. 19. Møller HU. Milestones and normative data. In: Taylor D, Hoyt C (eds) Pediatric ophthalmology and strabismus, 3rd edn. Edinburgh: Elsevier, 2005, p.40. 20. Kennaway DJ, Goble FC and Stamp GE. Factors influencing the development of melatonin
21.
22.
23. 24.
25.
rhythmicity in humans. J Clin Endocrinol Metab 1996; 81: 1525–1532. Henderson JM, France KG, Owens JL, et al. Sleeping through the night: The consolidation of self-regulated sleep across the first year of life. Pediatrics 2010; 126: e1081–e1087. Henderson JM, France KG and Blampied NM. The consolidation of infants’ nocturnal sleep across the first year of life. Sleep Med Rev 2011; 15: 211–220. Epstein LG and Zee PC. Infantile colic and migraine. JAMA 2013; 309(15): 1636–1637. Aaltonen K, Ha¨ma¨la¨inen ML and Hoppu K. Migraine attacks and sleep in children. Cephalalgia 2000; 20: 580–584. McKenzie S. Troublesome crying in infants: Effect of advice to reduce stimulation. Arch Dis Child 1991; 66: 1416–1420.
(CEP)
[1–3] [PREPRINTER stage]
Editorial
Infant colic—a baby’s migraine?
Cephalalgia 0(0) 1–3 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102415576224 cep.sagepub.com
Amy A Gelfand
All babies cry. Colicky babies cry more. Infant colic, or excessive crying in an otherwise healthy and well-fed infant, affects approximately 5–19% of babies (1). Infant crying peaks at age 5–6 weeks (corrected for gestational age at birth) and generally decreases by age 3–4 months. Colic is an amplified version of this developmental crying pattern (2,3). While the name ‘‘colic’’ implies a gastrointestinal etiology, direct evidence for this localization is lacking. In the historic 1954 paper by Wessel et al., the syndrome was described as ‘‘Paroxysmal fussing in infancy, sometimes called colic’’(4). ‘‘Paroxysmal fussing’’ may be a more apt descriptive term as all that is clear is that the infants are in distress. While definitions of infant colic vary (5), Wessel’s criteria are commonly used and are the criteria used in the International Classification of Headache Disorders, third edition beta (ICHD-III beta) (appendix): crying for at least three hours a day, at least three days a week, for at least three weeks (or one week for modified Wessel’s criteria) (4,6,7). Despite much research, the cause of infant colic remains poorly understood. Often colic is assumed to be related to feeding—something in the milk, the mother’s diet, the formula or intestinal gas. However, several randomized, placebo-controlled trials have not found gastrointestinal-based treatments to be effective (8–10). Moreover, young infants feed every couple of hours around the clock, yet colicky crying tends to happen more in the evening (2,3). It is important that we ultimately determine the cause of infant colic, as inconsolable and excessive crying causes caregiver frustration and is associated with shaken baby syndrome—a form of child abuse with significant neurologic morbidity and mortality (3,11,12). One percent of parents of 1-month-olds admit to having shaken their baby at least once to try to stop crying, and 2.2% have tried shaking, slapping or smothering. By age 6 months, 5.6% have tried one of these dangerous techniques (11). An association between infant colic and migraine has been reported in several retrospective case-control studies (13–15). In a cross-sectional study, mothers with migraine were more than twice as likely to have an
infant with colic, pointing to the possible genetic relationship between infant colic and migraine (6). A recent meta-analysis found the odds of migraine were increased if there was a history of infant colic (odds ratio (OR) 5.6 (95% confidence interval (CI) 3.3–9.5)) (16). What the field has been missing—until now—has been a prospective cohort study examining the relationship between infant colic and migraine, as previous studies’ findings could have been explained by recall bias. In the paper by Sillanpaa and Saarinen, published in this edition of Cephalalgia, the authors used the Finnish Family Competence Study—a study that sampled the general population in a region in Finland and enrolled parents expecting their first child in 1986. At 3 months of age, colic status was assessed using a combination of input from parents and an experienced nurse who spoke to the parents about the frequency, severity, and duration of their baby’s crying episodes. When they grew to age 18, the adolescents completed a questionnaire regarding migraine status using ICHD criteria. Of the 1267 babies originally sampled, migraine outcome data were available in 787 (62%). The proportion with a history of colic did not differ in those who were lost to follow-up. The main finding was that having a history of infant colic predicted development of migraine without aura (relative risk (RR) 2.7 (95% CI 1.5–4.7)), but not migraine with aura. While Wessel’s criteria for colic were not used, this is only a modest limitation as crying duration is often estimated by parents in colic studies. The finding of an association between infant colic and migraine without aura, but not migraine with aura, is interesting and speaks to likely differences in underlying genetics. Migraine is a highly inherited disorder in that the majority of migraineurs have a
UCSF Headache Center, Department of Neurology, University of California San Francisco, USA; Division of Child Neurology, UCSF, USA Corresponding author: Amy A Gelfand, UCSF Headache Center, 2330 Post St, 6th Floor, San Francisco, CA 94115, USA. Email: [email protected]
XML Template (2015) [27.2.2015–10:22am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/150028/APPFile/SG-CEPJ150028.3d
(CEP)
[1–3] [PREPRINTER stage]
2 positive family history (17,18). However, except in the case of familial hemiplegic migraine, the genetics of migraine have not been untangled. The clinical phenotype of migraine varies among individuals—some have aura, some have nausea, some have osmophobia, etc. Lumping all migraineurs as if they were all the same in a genome-wide association study is unlikely to yield discoveries. Detailed clinical phenotyping that divides migraineurs into more homogeneous subgroups might facilitate gene discovery, and colic may prove to be one such phenotype. It is still not known whether infant colic is a form of migraine itself, or simply a marker of migraine genetics. It is possible that the babies cry because of headache or because of abdominal pain akin to abdominal migraine. It is also possible that they are more sensitive to stimuli than other babies and express that sensitivity through excessive crying. With rapid brain development, neonates’ visual perceptual ability increases significantly during the first few weeks of life (19). This could explain why colic does not begin until about 2 weeks of life, even though babies are feeding and interacting from birth onward. There may also be a role for circadian biology in colic, as there is in migraine. Age 3 months is when the infant’s endogenous melatonin secretion takes on a circadian rhythm that allows for nighttime sleep consolidation (20–23). Rhythmic melatonin secretion, either in itself or mediated by the ability to sleep through the night, could explain why colic resolves around age 3 months. Particularly in young children, sleep can help terminate a migraine attack (24). Now with these prospective study results in hand, it is important to disseminate knowledge of the association between infant colic and migraine to general pediatricians, as recognition that infant colic can precede development of migraine headache could help avoid diagnostic delay of migraine in children. It is also time to apply what we know about treating childhood migraine to helping babies with colic. We know that during a migraine attack children want to climb in bed and pull the covers over their heads and be in a dark, quiet room. A behavioral intervention wherein caregivers are trained to decrease stimulation when colicky crying starts—turn off the lights, quiet the musical toy—could potentially help babies and in turn help frustrated caregivers remain calm. There is in fact some evidence that such a strategy may be effective (25). Moving forward, observational studies should address whether there are associations between infant colic and other childhood periodic syndromes such as benign paroxysmal torticollis and abdominal migraine. Treatment trials for infant colic should focus on behavioral interventions, or well-studied and safe medications in this age group. Given the totality of the evidence for an association between infant colic and
Cephalalgia 0(0) migraine, it would seem well justified to bring infant colic into the main body of ICHD-III. Conflicts of interest Dr Gelfand receives salary support from the National Institutes of Health/National Center for Advancing Translation Sciences (NIH/NCATS) 8KL2TR000143-09, and research grants from the Migraine Research Foundation and Allergan. She has received honoraria from Journal Watch Neurology, and was paid a consulting fee by FCB, a medical communications agency in New York, NY.
References 1. Lucassen PL, Assendelft WJ, van Eijk JT, et al. Systematic review of the occurrence of infantile colic in the community. Arch Dis Child 2001; 84: 398–403. 2. Brazelton TB. Crying in infancy. Pediatrics 1962; 29: 579–588. 3. Barr RG, Trent RB and Cross J. Age-related incidence curve of hospitalized Shaken Baby Syndrome cases: Convergent evidence for crying as a trigger to shaking. Child Abuse Negl 2006; 30: 7–16. 4. Wessel MA, Cobb JC, Jackson EB, et al. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 1954; 14: 421–435. 5. Reijneveld SA, Brugman E and Hirasing RA. Excessive infant crying: The impact of varying definitions. Pediatrics 2001; 108: 893–897. 6. Gelfand AA, Thomas KC and Goadsby PJ. Before the headache: Infant colic as an early life expression of migraine. Neurology 2012; 79: 1392–1396. 7. van den Berg MP, van der Ende J, Crijnen AA, et al. Paternal depressive symptoms during pregnancy are related to excessive infant crying. Pediatrics 2009; 124: e96–e103. 8. Metcalf TJ, Irons TG, Sher LD, et al. Simethicone in the treatment of infant colic: A randomized, placebo-controlled, multicenter trial. Pediatrics 1994; 94: 29–34. 9. Sung V, Hiscock H, Tang ML, et al. Treating infant colic with the probiotic Lactobacillus reuteri: Double blind, placebo controlled randomised trial. BMJ 2014; 348: g2107. 10. Kukkonen K, Savilahti E, Haahtela T, et al. Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: Randomized, double-blind, placebo-controlled trial. Pediatrics 2008; 122: 8–12. 11. Reijneveld SA, van der Wal MF, Brugman E, et al. Infant crying and abuse. Lancet 2004; 364: 1340–1342. 12. Fujiwara T, Barr RG, Brant R, et al. Infant distress at five weeks of age and caregiver frustration. J Pediatr 2011; 159: 425–30.e1–2. 13. Jan MM and Al-Buhairi AR. Is infantile colic a migrainerelated phenomenon? Clin Pediatr (Phila) 2001; 40: 295–297. 14. Bruni O, Fabrizi P, Ottaviano S, et al. Prevalence of sleep disorders in childhood and adolescence with headache: A case-control study. Cephalalgia 1997; 17: 492–498.
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(CEP)
[1–3] [PREPRINTER stage]
3
Gelfand 15. Romanello S, Spiri D, Marcuzzi E, et al. Association between childhood migraine and history of infantile colic. JAMA 2013; 309: 1607–1612. 16. Gelfand AA, Goadsby PJ and Allen IE. The relationship between migraine and infant colic: A systematic review and meta-analysis. Cephalalgia 2015; 35: 63–72. 17. Russell MB, Hilden J, Sorensen SA, et al. Familial occurrence of migraine without aura and migraine with aura. Neurology 1993; 43: 1369–1373. 18. Russell MB, Fenger K and Olesen J. The family history of migraine. Direct versus indirect information. Cephalalgia 1996; 16: 156–160. 19. Møller HU. Milestones and normative data. In: Taylor D, Hoyt C (eds) Pediatric ophthalmology and strabismus, 3rd edn. Edinburgh: Elsevier, 2005, p.40. 20. Kennaway DJ, Goble FC and Stamp GE. Factors influencing the development of melatonin
21.
22.
23. 24.
25.
rhythmicity in humans. J Clin Endocrinol Metab 1996; 81: 1525–1532. Henderson JM, France KG, Owens JL, et al. Sleeping through the night: The consolidation of self-regulated sleep across the first year of life. Pediatrics 2010; 126: e1081–e1087. Henderson JM, France KG and Blampied NM. The consolidation of infants’ nocturnal sleep across the first year of life. Sleep Med Rev 2011; 15: 211–220. Epstein LG and Zee PC. Infantile colic and migraine. JAMA 2013; 309(15): 1636–1637. Aaltonen K, Ha¨ma¨la¨inen ML and Hoppu K. Migraine attacks and sleep in children. Cephalalgia 2000; 20: 580–584. McKenzie S. Troublesome crying in infants: Effect of advice to reduce stimulation. Arch Dis Child 1991; 66: 1416–1420.
