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The Excessively Crying Infant: Etiology and Treatment Samira Akhnikh, MD; Adèle C. Engelberts, MD, PhD; Bregje E. van Sleuwen, PhD; Monique P. L’Hoir, PhD; and Marc A. Benninga, MD, PhD Abstract Samira Akhnikh, MD, is from the Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital/Academic Medical Center. Adèle C. Engelberts, MD, PhD, is from the Department of Pediatrics, Orbis Medical Center. Bregie E. van Sleuwen, PhD, is from the TNO Child Health. Monique P. L’Hoir, PhD, is from the TNO Child Health. Marc A. Benninga, MD, PhD, is from the Department of Pediatric Gastroenterology and Nutrition Emma Children’s Hospital/Academic Medical Center. Address correspondence to: Marc A. Benninga, MD, PhD, Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital/Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; email: m.a.benninga@ amc.nl. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00904481-20140325-07
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Excessive crying, often described as infantile colic, is the cause of 10% to 20% of all early pediatrician visits of infants aged 2 weeks to 3 months. Although usually benign and selflimiting, excessive crying is associated with parental exhaustion and stress. However, an underlying organic cause is found in less than 5% of these infants. In the majority of cases, treatment consists not of “curing the colic,” although usually it is possible to reduce crying, but of helping the parents to get through this challenging period in their baby’s development. The aims of this review are to discuss definition, etiology, and evaluate different treatment regimes in infants who cry excessively.
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nfants’ crying is regarded as a normal part of neurobehavioral development. It follows a typical curve that peaks during the sixth week postpartum at a stable mean duration of 110 to 118 minutes per day, and declines to below 1 hour per day by 12 weeks of age (Figure 1).1-3 In the first weeks of life, crying concentrates specifically in late afternoon.4 Infants who are born preterm experience their peak in crying at 6 weeks corrected age and thus appear to have a delayed peak to their parents.5 Often, the increase in crying coincides with dismissal from the neonatal ward and can cause anxiety and loss of confidence in parents. Due to the specific age-related pattern, it has been thought that there is a correlation with the development of a circadian rhythm.6
Others argue, however, that the rule of three has proved to be impractical to apply, culturally biased, overly-dependent on the amount of crying, and insensitive to features such as the hard-tosoothe nature of crying that underlie its impact on parents.10 Reijneveld et al.7 showed that 10 relatively small differences in the definition of excessive crying lead to the inclusion of dissimilar groups of infants. It
DEFINITION OF EXCESSIVE CRYING Despite its potentially substantial negative health consequences, no consensus has been reached on the definition of excessive crying for young infants.7 It is important to stress that every definition of excessive crying for infants relates only to healthy, well-developing babies. Since the crying bouts occur without obvious cause, their unexplained nature is one of the main reasons for parents’ concerns. The most commonly used definition is Wessel’s “rule of three,” which states that crying in an otherwise healthy baby aged 2 weeks to 4 months that occurs more than 3 hours per day, more than 3 days in any week for at least 3 weeks may be called excessive.8 In 2006, a panel of experts in the field of pediatric gastroenterology defined infant colic as including all of the following in infants from birth to 4 months of age: 1) paroxysms of irritability, fussing, or crying that start and stop without obvious cause; 2) episodes lasting 3 or more hours per day and occurring at least 3 days per week for at least 1 week; and 3) absence of failure to thrive.9
is therefore of major importance that researchers in the field of excessive crying and functional gastrointestinal disease use the same, clearly described definition, preferably including both duration of crying and parental distress. Either an e-diary or a paper diary is useful in objectively measuring both duration of crying and behavior of caregivers.11 This will improve the comparability of studies regarding insights in cause and treatment of these infants. Many infants cry excessively in the first 3 months of life, and this can cause much parental stress and even depression. In a study of 3,259 infants aged 6 months attending a well-baby clinic, nearly 6% of all parents reported taking at least one action to stop their infant’s crying that could be considered dangerous or leading to child abuse (ie, smothering, slapping, or shaking); one in five admitted to more than one of these three interventions.12 There is evidence that suggests that especially high-pitched crying leads to a more harsh response from the caregiver.13 Higher scores on the Edinburgh postnatal depression scale were found in mothers who reported
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Contrasting opinions exist regarding the relationship between gastrointestinal causes and excessive crying.
colic or excessive infant crying, with increased odds of high scores at 6 months even if the crying was resolved.14 ETIOLOGY The etiology of excessive crying remains unclear, although it has been appreciated as a manifestation of normal infant behavior and development. It has been suggested that there is an imbalance of the central nervous system in infants who cry excessively.15 The fact that neurologically impaired children can have abnormal cry characteristics, (eg, the flat, high-pitched cry typical in Cri du Chat syndrome) offers some support for this theory, as does the fact that preterm infants and small-for-date infants are at increased risk for excessive crying.16 Others have proposed a major role for environmental factors, such as psychosocial issues, domestic violence, inadequate parent-infant interaction, or parental anxiety.17,18 A major consideration is, of course, whether the parental anxiety and even depression is caused by the excessive crying or vice versa. Also, it would seem logical that parental problems can influence the perception of their child’s crying. A nested casecontrol study in Turkey showed that infant colic was associated with various perinatal factors (maternal education, smoking habits, hostility scores, and domestic violence), and having colic in infancy negatively affected the sleeping pattern and the height of the infant.19 In a large prospective study, the risk of having an excessively crying infant was significantly increased if mothers or fathers had depressive symptoms during the pregnancy.15 Contrasting opinions exist regarding the relationship between gastrointestinal causes, such as lactose intolerance, cow’s milk allergy, and gastroesophageal reflux disease, and excessive crying. There is no evidence for an association between lactose intolerance and soy feeds and excessive crying.
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180 160 140
Minutes/Day of Distress
Furthermore, if there are no other symptoms of cow’s milk allergy, there is little evidence that this would explain the infant’s excessive crying. Several well-designed, randomized, controlled trials have clearly shown that there was no difference in efficacy between the use of proton-pump inhibitors (PPIs) and placebo in infants with excessive crying and suspected gastroesophageal reflux (GER).20 Indeed, the U.S. Food and Drug Administration (FDA) advises to only use PPIs for infants with an endoscopically documented acid-induced condition such as erosive esophagitis.21 Furthermore, they stated that the riskbenefit relationship between the administration of PPIs in infants with GER or gastroesophageal reflux (GERD) without a documented acid-induced condition is not favorable because no benefit can be attributed to the PPI.21 In recent years, it has been suggested that aberrancies in the infant intestinal microbiota affect gut motor function and gas production, leading to abdominal pain and excessive crying. For example, studies have shown that the intestinal microbiota in infants with colic differs from that of healthy control infants, with lower counts of lactobacilli and higher numbers of Gram-negative bacteria in stools of infants with excessive crying.22,23 A recent study in infants with colic showed a significantly reduced microbiota diversity at 14 and 28 days of life.24 In addition, proteobacteria were increased in infants with colic, whereas bifidobacteria and lactobacilli were increased in control infants.24 Two European studies including more than 8,000 infants showed that smoking by either one or both parents of more than 15 cigarettes a day was associated with a doubled risk of excessive crying.25,26 Whether this association is causal is unknown. There is no evidence for an effect of smoking through breastfeeding.27 Smoking during pregnancy was not associated with exces-
120 100 80 60 40 20 0 W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12
Recording Week Figure 1. Crying amounts and patterns from three North American studies illustrating absence of secular trend. (Adapted from Barr et al.3)
sive crying in a Dutch study, whereas in contrast, a Danish study found a significant association between smoking in the pregnancy and excessive crying.25,26 It is important to note that a retrospective review of 237 afebrile patients younger than 1 year of age who presented at an emergency department with a chief complaint of crying, irritability, screaming, colic, or fussiness showed that only 5.1% of the children had a serious underlying cause. Urinary tract infections were the most prevalent medical condition, especially in very young infants.28 Therefore, afebrile infants who cry excessively in the first few months of life should undergo urine evaluation. TREATMENT AND SUPPORT OF CHILDREN AND PARENTS In this part of the review, the support of families with an excessively crying infant is described. There is often insufficient evidence to firmly advocate a specific treatment. These families need
support, however, to prevent a large demand on health care, serious psychosocial effects on families, and behavioral problems later on. The following gives a practical approach to support the families based on what evidence there is. Each intake of parents with an excessively crying infant should begin with: • Recognition, support, and reassurance of parents. • Information about the normal crying pattern, co- and self-regulation, and about the prevention of the shaken baby syndrome/abusive head trauma. • Full cooperation between caregiver and parents. This empowers parents, who may lose confidence in their parenting abilities, and ensures compliance with the chosen strategy. • Referral to the family doctor or pediatrician to rule out medical problems should take place early on. (Treatment that follows from a medical diagnosis such as cow’s Healio.com/Pediatrics | e71
CME milk allergy or a urinary tract infection will not be discussed in this review.) • Discourage change of feeds (from breast to formula or from one formula to another). Breastfeeding should not be stopped in order to reduce excessive crying. • The relationship between parents, child, and the health care worker is of great importance and may need some time to develop. If problems are complex, it is preferable to consult other professionals for advice instead of immediately referring parents, thus preventing “shopping behavior.” The proposed care can be given by the health care worker, general practitioner, or pediatrician. INFORMING AND COUNSELING PARENTS If the health care professional is convinced that the issue at hand involves an “excessively crying infant” — which means that a medical explanation in all reasonableness has been excluded — parents should be informed extensively about the normal pattern of infant crying as described previously. This normal period can feel endlessly long and very stressful for the parents, child, and his or her siblings. Excessive crying is often related to fatigue of both the child and his or her parents.1 Explicitly point out that in 95% of cases, no physical or health problems are found. Inform parents about warning signs for ill health, such as poor growth. Furthermore, most children cry more at the end of the day, and there are no illnesses that occur only between the hours of 6 to 8 p.m. It is important to explain how stress affects both parents and the child. A baby who, for any reason, is off balance (eg, due to illness or fatigue) cries more, thus demanding more care, and thereby may bring the parent(s) out of balance, which in turn will affect the baby, etc. Parents and child end up in a vicious circle.1 If parents, after this exe72 | Healio.com/Pediatrics
planation and with ongoing support, fail to restore normal interaction, appropriate professionals should be consulted. Often parents receive many types of advice, sometimes conflicting. It is important to settle upon a plan with the parents and agree to stick to it. This can only work if, through support and compassion, a relationship has been formed based on
A baby who, for any reason, is off balance (eg, due to illness or fatigue) cries more, thus demanding more care. trust. The treatment or support given must be in line with the views of the parents and fit the family system. Each intervention may take some time to achieve results, and parents should be aware of this. Parents can choose one of the approaches classified as “evidence-based,” albeit at quite different levels of evidence. TREATMENTS FOR WHICH THERE IS SOME EVIDENCE Applying Regularity and Uniformity in Daily Care A consistent, recurring pattern of childcare throughout the day is beneficial.29-33 The behavioral components of the intervention include regularity in the sequence of the events surrounding sleep and feeding and uniformity in the place where the child sleeps and plays on his or her own.34 It should be emphasized that this does not mean a fixed time schedule, but instead, rather, a consistent approach. This comprises a recurring pattern of sleeping, feeding right after waking, positive interaction/cuddling and playing with a parent, playing on their own (preferably in a playpen), and being put to bed awake as soon as signs of weariness appear (eg, yawning, whining, rubbing of eyes, overactive behavior). This
approach offers the child predictability and the possibility to improve his or her self-regulating ability. It has proved to be effective in healthy parents, even those with mild psychological problems.35 Specific attention is offered to mothers who breastfeed, as this should be continued. If this approach is not effective, it can be helpful to add swaddling.29 Although not more effective, it does reduce crying more quickly. Health care providers should be clear about indications and contraindications for swaddling.34 Video Home Training (VHT)36 VHT is intended for parents with parenting stress. Its purpose is to solve problems in the socio-emotional development of the child (0-4 years). It has been shown to be effective in improving the interaction and communication between parents and child and in improving the interaction between depressed mothers and their babies.36-39 However, there have been no studies specifically conducted on improving the interaction in families with an excessively crying infant. In theory, if interaction issues play a role and parental sensitivity could be improved upon, one would assume VHT can be beneficial. However, a cautious approach is warranted. Baby Massage A Cochrane review showed that baby massage may have a beneficial effect for infants younger than 6 months of age.40 There was some evidence of benefits on mother-infant interaction, sleeping, and crying. There was no evidence of harm. Because there is no clear-cut definition what baby massage encompasses, results are difficult to interpret. In only one study of low quality, the result of baby massage on excessive crying was analyzed.41 A positive effect on crying at age 3 and 6 months was found. These findings may be sufficient to support the use of baby massage as method of support; however, more studies are needed.
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CME Fennel Extract and Herbal Tea The available evidence on alternative medication for excessive crying was discussed in a review.42 One wellconducted study reported benefit from fennel extract compared to placebo, and in another trial, herbal tea containing fennel, licorice, vervain chamomile, and mint significantly improved colic scores. However, there were some methodological concerns. There is some support for the effect of fennel from animal studies. In absence of side effects, these interventions may be supported, although further studies are advised. TREATMENTS NOT RECOMMENDED Chiropractic and spinal manipulation are recommended against because of the lack of evidence for their effectiveness, as well as the potentially serious side effects.43,44 Except in cases of proven cow’s milk allergy, change of feeds should be actively discouraged. In a Dutch study, 19% of women who stopped breastfeeding gave excessive crying of their infant as their reason for doing so;45 however, the amount of excessive crying was similar in breastfed and bottle-fed infants.46 Furthermore, 17% of the change in artificial feeds was due to crying. These data demonstrate that there is a schism between the reality and parental perception of the effect of feeds on excessive crying. Simethicon has not been proven effective in treating excessive crying.47-49Although there is evidence that babies settle more and better when placed prone, this does not comply with safe sleeping advice for the prevention of cot death and should be actively discouraged. NEITHER DISCOURAGED NOR ENCOURAGED Continuous carrying is not part of Western societies’ usual method of baby care but is considered normal behavior in many parts of the world. Picking up a crying baby to console him or her is
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normal parental behavior. When babies cry excessively for a longer period, carrying the child does not seem to reduce the excessive crying.50-52 However, the literature also does not prove that continuous carrying has a negative impact. Although there is evidence from two randomized, controlled trials for a beneficial role of the probiotic Lactobacillus reuteri DSM 17938 for infant colic, it is too soon to recommend its use therapeutically.53,54 It has only been studied in a population of mothers who breastfed at least partially, and both studies were financed by the manufacturer. It is available in some countries as “BioGaia.” Parents and health care workers can also consciously decide not to try to lessen the burden of crying but to instead strengthen the parental coping strategies. Many interventions, such as nurse-family partnerships; neonatal programs, such as Infant Behavioral Assessment and Intervention Program for premature infants; and paramedical care, such as physical therapy, can be used to support parents.55 PREVENTION FOR HIGH-RISK GROUPS As discussed previously, there are groups of parents and infants who are at high risk of crying excessively. (Table 1). Furthermore, the relative risk for excessive crying increases with decreasing gestational age in preterms compared to term infants. Small for gestational age children also have increased risk of excessive crying in all gestational age groups.16 Identifying the groups of parents and infants at increased risk is important because information on crying can be given before it becomes excessive. Furthermore, early support and, if necessary, referral to more specialized care may prevent more serious problems including child abuse, although no studies are available to confirm this.
TABLE 1.
At High Risk for Infantile Excessive Crying and Associated Problems • Pregnant women with anxiety and/or with little support. •P regnant women with many somatic symptoms. •P arents with much stress or little social support. •P arents with anxiety or other psychological problems. •P arents with depression or other psychiatric problems. • Teenage parents. •P arents with addiction. •P arental unemployment; financial problems. •P remature and/or small for gestational age children. • Children with an especially high, penetrating and loud cry.
LONG-TERM PROGNOSIS Most of the children who have cried excessively during their first 4 months have no increased risks of developing psychological, social, or other problems. Some parents, however, may continue to perceive their child as more vulnerable, temperamental, or more rebellious, even when he or she gets older.27,56 Any child who continues crying after 4 months should be followed up because unsolved excessive crying may disturb the parent-child interaction and regulation, which may in turn cause long-lasting psycho-social or somatic problems. Research shows that infants who continue to cry after 4 to 6 months are at higher risk for feeding, sleeping, and behavioral problems, among which are hyperactivity and somatic problems.57,58 CONCLUSION Infants who cry excessively place a large demand on health care. Although there is no consensus on the definition of excessive crying, health care workers should be aware of the parental percepHealio.com/Pediatrics | e73
CME tion that is indicative of more serious problems that can arise. The disruption that a crying infant can bring to families and the long-term sequela are often underestimated. Education regarding the normal pattern of crying in infants should be given early on so that parents can have a realistic view of what to expect. If parents still perceive the crying as excessive and medical conditions have been ruled out, support is essential to prevent long-term problems in parentinfant interaction and the ensuing possibility of child abuse. Of the many strategies to reduce the crying itself, bringing regularity into the system of childcare is the most appropriate first choice. Adding interventions such as swaddling, baby massage, and fennel extract are possibilities, but more studies should be conducted to confirm the benefits of these practices. The most promising area of research is that into the intestinal microbiota. The randomized, controlled trials that have been conducted seem promising, and there is a relevant biological hypothesis that underlies the intervention. Future studies should be conducted with special attention to which probiotic strain is chosen, and results should be corrected for the various risk factors for crying and the type of feeds. REFERENCES 1. Kurth E, Kennedy HP, Spichiger E, et al. Crying babies, tired mothers: what do we know? A systematic review. Midwifery. 2011;27:187-194. 2. Wolke D, Samara M, Alvarez Wolke M. Meta-analysis of fuss/cry durations and colic prevalence across countries. Presented at: 11th International Infant Cry Research Workshop; June 8-10, 2011; the Netherlands. 3. Barr RG, Trent RB, Cross J. Age-related incidence curve of hospitalized Shaken Baby syndrome (SBS) cases: convergent evidence for crying as a trigger to shaking. Child Abuse Negl. 2006;30:7-13. 4. Barr RG. The normal crying curve: what do we really know? Dev Med Child Neurol. 1990;32:356-362. 5. Barr RG, Chen S, Hopkins B, Westra T. Crying patterns in preterm infants. Dev Med Child Neurol. 1996;38:345-355. 6. Shamir R, St James-Roberts I, Di Lorenzo C,
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et al. Infant crying, colic, and gastrointestinal discomfort in early childhood: a review of the evidence and most plausible mechanisms. J Pediatr Gastroenterol Nutr. 2013;57 Suppl 1:S1-45. 7. Reijneveld SA, Brugman E, Hirasing RA. Excessive infant crying: the impact of varying definitions. Pediatrics. 2001;108:893-897. 8. Wessel MA, Cobb JC, Jackson EB, et al. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics. 1954;14:421-435. 9. Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519-1526. 10. Barr RG, Paterson JA, MacMartin LM, et al. Prolonged and unsoothable crying bouts in infants with and without colic. J Dev Behav Pediatr. 2005;26:14-23. 11. Lam J, Barr RG, Catherine N, et al. Electronic and paper diary recording of infant and caregiver behaviors. J Dev Behav Pediatr. 2010;31:685-693. 12. Reijneveld SA, van der Wal M, Brugman E, et al. Infant crying and abuse. Lancet. 2004;364:1340-1342. 13. Out D, Pieper S, Bakermans-Kranenburg MJ, et al. Intended sensitive and harsh caregiving responses to infant crying: the role of cry pitch and perceived urgency in an adult twin sample. Child Abuse Negl. 2010;34:863-873. 14. Vik T, Grote V, Escribano J, et al. Infantile colic, prolonged crying and maternal postnatal depression. Acta Paediatr. 2009;8:1344-1348. 15. 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:e96-103. 16. Milidou I, Søndergaard C, Jensen MS, et al. Gestational age, small for gestational age, and infantile colic. Paediatr Perinat Epidemiol. 2014;28:138-145. 17. Douglas P, Hill P. Managing infants who cry excessively in the first few months of life. BMJ. 2011;15:343. 18. Talge NM, Neal C, Glover V. Early Stress, Translational Research and Prevention Science Network: fetal and neonatal experience on child and adolescent mental health. antenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry. 2007;48:245-261. 19. Yalçin SS, Orün E, Mutlu B, et al. Why are they having infant colic? A nested casecontrol study. Paediatr Perinat Epidemiol. 2010;24:584-596. 20. Van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935. 21. Chen IL, Gao WY, Johnson AP, et al. Proton pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gastroenterol Nutr. 2012;54:8-14. 22. Rhoads JM, Fatheree NY, Norori J, et al.
Altered fecal microflora and increased fecal calprotectin in infants with colic. J Pediatr. 2009;155:823-828. 23. Savino F, Cordisco L, Tarasco V, et al. Molecular identification of coliform bacteria from colicky breastfed infants. Acta Paediatr. 2009;98:1582-1588. 24. De Weerth C, Fuentes S, Puylaert P, de Vos WM. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013;131:e550-558. 25. Reijneveld SA, Lanting CI, Crone MR, Van Wouwe JP. Exposure to tobacco smoke and infant crying. Acta Paediatr. 2005;94:217-221. 26. Søndergaard C, Henriksen TB, Obel C, Wisborg K. Smoking during pregnancy and infantile colic. Pediatrics.2001;108:342-346. 27. Canivet CA, Ostergren PO, Jakobsson IL, et al. Infantile colic, maternal smoking and infant feeding at 5 weeks of age. Scand J Public Health. 2008;36:284-291. 28. Freedman SB, Al-Harthy N, Thull-Freedman J. The crying infant: diagnostic testing and frequency of serious underlying disease. Pediatrics. 2009;123:841-848. 29. Sleuwen van BE, L’Hoir MP, Engelberts AC, et al. Comparison of behavior modification with and without swaddling as interventions for excessive crying. J Pediatr. 2006;149:512-517. 30. Keefe MR, Froese-Fretz A, Kotzer AM. Newborn predictors of infant irritability. J Obstet Gynecol Neonatal Nurs. 1998;27:513-520. 31. Keefe MR, Barbosa GA, Froese-Fretz A, et al. An intervention program for families with irritable infants. MCN Am J Matern Child Nurs. 2005;30:230-236. 32. Keefe MR, Kajrlsen KA, Lobo ML, et al. Reducing parenting stress in families with irritable infants. Nurs Res. 2006;55:198-205. 33. Wolke D, Gray P, Meyer R. Excessive infant crying: a controlled study of mothers helping mothers. Pediatrics. 1994;94:322-332. 34. Blom MA, van Sleuwen BE, de Vries H, et al. Health care interventions for excessive crying in infants: regularity with and without swaddling. J Child Health Care. 2009;13:161-176. 35. Sleuwen van BE. Infants that cry excessively: the effect of regularity and swaddling. Thesis. Utrecht: Universiteit Utrecht; 2008. 36. Eliëns M. Protocol video-hometraining excessive crying infants. Associative Intensive Homecare. [In Dutch]. Eindhoven: De Combinatie; 2003. 37. Juffer F, Bakermans-Kranenburg MJ, IJzendoorn van MH. Promoting Positive Parenting: An Attachment-Based Intervention. New York, NY: Lawrence Erlbaum Associates; 2007. 38. Velderman MK. The Leiden VIPP and VIPPR Study: Evaluation of a Short-Term Preventive Attachment-Based Intervention. Proefschrift Rijksuniversiteit Leiden. Leiden: Mosterd & Van Onderen; 2005. 39. Doesum van K. An early preventive intervention for depressed mothers and their infants,
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CME its efficacy and predictors of maternal sensitivity. Thesis. Radboud University Nijmegen; 2007. 40. Underdown A, Barlow J, Chung V, StewartBrown S. Massage intervention for promoting mental and physical health in infants aged under six months. Cochrane Database Syst Rev. 2006;4:CD005038. 41. Shuan XL, Romg QG, Yan YM, et al. Study of touch intervention of infant sleep disorder. J Nursing Continual Educ. 2004;19:973-976. 42. Perry R, Hunt K, Ernst E. Nutritional supplements and other complementary medicines for infantile colic: A systematic review. Pediatrics. 2011;127:720-733. 43. Olafsdottir E, Forshei S, Fluge G, Markestad T. Randomised controlled trial of infantile colic treated with chiropractic spinal manipulation. Arch Dis Child. 2001;84:138-141. 44. Holla M, Ijland MM, van der Vliet AM, et al. Death of an infant following ‘craniosacral’ manipulation of the neck and spine. Ned Tijdschr Geneeskd. 2009;153:828-831. 45. Bulk-Bunschoten AMW. Feeding practices in the Netherlands in the first four months of life.
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Thesis. Amstelveen; 2003. 46. 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. 47. Danielsson B, Hwang CP. Treatment of infantile colic with surface active substance (simethicone). Acta Paediatr Scand. 1985;74:446-450. 48. Metcalf TJ, Irons TG, Sher LD, Young PC. Simethicone in the treatment of infant colic: A randomized, placebo-controlled, multicenter trial. Pediatrics. 1994;94:29-34. 49. Sethi KS, Sethi JK. Simethicone in the management of infant colic. Practitioner. 1988;232:508. 50. Barr RG, Konner M, Bakeman R, Adamson L. Crying in !kung san infants: a test of the cultural specificity hypothesis. Dev Med Child Neurol. 1991;33:601-610. 51. Lucassen P. Colic in infants. Clin Evid (Online). 2010:0309. 52. St. James-Roberts I, Alvarez M, Csipke E, et al. Infant crying and sleeping in london, copenhagen and when parents adopt
a “proximal” form of care. Pediatrics. 2006;117:e1146-1155. 53. Savino F, Tarasco V. New treatments for infant colic. Curr Opin Pediatr. 2010;22:791-797. 54. Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;162:257-262. 55. Koldewijn K, Wolf MJ, van Wassenaer A, et al. The Infant Behavioral Assessment and Intervention Program for very low birth weight infants at 6 months corrected age. J Pediatr. 2009;154:33-38. 56. Rautava P, Lehtonen L, Helenius H, Sillanpää M. Infantile colic: child and family three years later. Pediatrics. 1995;96:43-47. 57. Wolke D, Rizzo P, Woods S. Persistant infant crying and hyperactivity problems in middle childhood. Pediatrics. 2002;109:1054-1060. 58. Rao MR, Brenner RA, Schisterman EF, et al. Longterm cognitive development in children with prolonged crying. Arch Dis Child. 2004;89:989-992.
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The Excessively Crying Infant: Etiology and Treatment Samira Akhnikh, MD; Adèle C. Engelberts, MD, PhD; Bregje E. van Sleuwen, PhD; Monique P. L’Hoir, PhD; and Marc A. Benninga, MD, PhD Abstract Samira Akhnikh, MD, is from the Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital/Academic Medical Center. Adèle C. Engelberts, MD, PhD, is from the Department of Pediatrics, Orbis Medical Center. Bregie E. van Sleuwen, PhD, is from the TNO Child Health. Monique P. L’Hoir, PhD, is from the TNO Child Health. Marc A. Benninga, MD, PhD, is from the Department of Pediatric Gastroenterology and Nutrition Emma Children’s Hospital/Academic Medical Center. Address correspondence to: Marc A. Benninga, MD, PhD, Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital/Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; email: m.a.benninga@ amc.nl. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00904481-20140325-07
© Shutterstock
Excessive crying, often described as infantile colic, is the cause of 10% to 20% of all early pediatrician visits of infants aged 2 weeks to 3 months. Although usually benign and selflimiting, excessive crying is associated with parental exhaustion and stress. However, an underlying organic cause is found in less than 5% of these infants. In the majority of cases, treatment consists not of “curing the colic,” although usually it is possible to reduce crying, but of helping the parents to get through this challenging period in their baby’s development. The aims of this review are to discuss definition, etiology, and evaluate different treatment regimes in infants who cry excessively.
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nfants’ crying is regarded as a normal part of neurobehavioral development. It follows a typical curve that peaks during the sixth week postpartum at a stable mean duration of 110 to 118 minutes per day, and declines to below 1 hour per day by 12 weeks of age (Figure 1).1-3 In the first weeks of life, crying concentrates specifically in late afternoon.4 Infants who are born preterm experience their peak in crying at 6 weeks corrected age and thus appear to have a delayed peak to their parents.5 Often, the increase in crying coincides with dismissal from the neonatal ward and can cause anxiety and loss of confidence in parents. Due to the specific age-related pattern, it has been thought that there is a correlation with the development of a circadian rhythm.6
Others argue, however, that the rule of three has proved to be impractical to apply, culturally biased, overly-dependent on the amount of crying, and insensitive to features such as the hard-tosoothe nature of crying that underlie its impact on parents.10 Reijneveld et al.7 showed that 10 relatively small differences in the definition of excessive crying lead to the inclusion of dissimilar groups of infants. It
DEFINITION OF EXCESSIVE CRYING Despite its potentially substantial negative health consequences, no consensus has been reached on the definition of excessive crying for young infants.7 It is important to stress that every definition of excessive crying for infants relates only to healthy, well-developing babies. Since the crying bouts occur without obvious cause, their unexplained nature is one of the main reasons for parents’ concerns. The most commonly used definition is Wessel’s “rule of three,” which states that crying in an otherwise healthy baby aged 2 weeks to 4 months that occurs more than 3 hours per day, more than 3 days in any week for at least 3 weeks may be called excessive.8 In 2006, a panel of experts in the field of pediatric gastroenterology defined infant colic as including all of the following in infants from birth to 4 months of age: 1) paroxysms of irritability, fussing, or crying that start and stop without obvious cause; 2) episodes lasting 3 or more hours per day and occurring at least 3 days per week for at least 1 week; and 3) absence of failure to thrive.9
is therefore of major importance that researchers in the field of excessive crying and functional gastrointestinal disease use the same, clearly described definition, preferably including both duration of crying and parental distress. Either an e-diary or a paper diary is useful in objectively measuring both duration of crying and behavior of caregivers.11 This will improve the comparability of studies regarding insights in cause and treatment of these infants. Many infants cry excessively in the first 3 months of life, and this can cause much parental stress and even depression. In a study of 3,259 infants aged 6 months attending a well-baby clinic, nearly 6% of all parents reported taking at least one action to stop their infant’s crying that could be considered dangerous or leading to child abuse (ie, smothering, slapping, or shaking); one in five admitted to more than one of these three interventions.12 There is evidence that suggests that especially high-pitched crying leads to a more harsh response from the caregiver.13 Higher scores on the Edinburgh postnatal depression scale were found in mothers who reported
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Contrasting opinions exist regarding the relationship between gastrointestinal causes and excessive crying.
colic or excessive infant crying, with increased odds of high scores at 6 months even if the crying was resolved.14 ETIOLOGY The etiology of excessive crying remains unclear, although it has been appreciated as a manifestation of normal infant behavior and development. It has been suggested that there is an imbalance of the central nervous system in infants who cry excessively.15 The fact that neurologically impaired children can have abnormal cry characteristics, (eg, the flat, high-pitched cry typical in Cri du Chat syndrome) offers some support for this theory, as does the fact that preterm infants and small-for-date infants are at increased risk for excessive crying.16 Others have proposed a major role for environmental factors, such as psychosocial issues, domestic violence, inadequate parent-infant interaction, or parental anxiety.17,18 A major consideration is, of course, whether the parental anxiety and even depression is caused by the excessive crying or vice versa. Also, it would seem logical that parental problems can influence the perception of their child’s crying. A nested casecontrol study in Turkey showed that infant colic was associated with various perinatal factors (maternal education, smoking habits, hostility scores, and domestic violence), and having colic in infancy negatively affected the sleeping pattern and the height of the infant.19 In a large prospective study, the risk of having an excessively crying infant was significantly increased if mothers or fathers had depressive symptoms during the pregnancy.15 Contrasting opinions exist regarding the relationship between gastrointestinal causes, such as lactose intolerance, cow’s milk allergy, and gastroesophageal reflux disease, and excessive crying. There is no evidence for an association between lactose intolerance and soy feeds and excessive crying.
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180 160 140
Minutes/Day of Distress
Furthermore, if there are no other symptoms of cow’s milk allergy, there is little evidence that this would explain the infant’s excessive crying. Several well-designed, randomized, controlled trials have clearly shown that there was no difference in efficacy between the use of proton-pump inhibitors (PPIs) and placebo in infants with excessive crying and suspected gastroesophageal reflux (GER).20 Indeed, the U.S. Food and Drug Administration (FDA) advises to only use PPIs for infants with an endoscopically documented acid-induced condition such as erosive esophagitis.21 Furthermore, they stated that the riskbenefit relationship between the administration of PPIs in infants with GER or gastroesophageal reflux (GERD) without a documented acid-induced condition is not favorable because no benefit can be attributed to the PPI.21 In recent years, it has been suggested that aberrancies in the infant intestinal microbiota affect gut motor function and gas production, leading to abdominal pain and excessive crying. For example, studies have shown that the intestinal microbiota in infants with colic differs from that of healthy control infants, with lower counts of lactobacilli and higher numbers of Gram-negative bacteria in stools of infants with excessive crying.22,23 A recent study in infants with colic showed a significantly reduced microbiota diversity at 14 and 28 days of life.24 In addition, proteobacteria were increased in infants with colic, whereas bifidobacteria and lactobacilli were increased in control infants.24 Two European studies including more than 8,000 infants showed that smoking by either one or both parents of more than 15 cigarettes a day was associated with a doubled risk of excessive crying.25,26 Whether this association is causal is unknown. There is no evidence for an effect of smoking through breastfeeding.27 Smoking during pregnancy was not associated with exces-
120 100 80 60 40 20 0 W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12
Recording Week Figure 1. Crying amounts and patterns from three North American studies illustrating absence of secular trend. (Adapted from Barr et al.3)
sive crying in a Dutch study, whereas in contrast, a Danish study found a significant association between smoking in the pregnancy and excessive crying.25,26 It is important to note that a retrospective review of 237 afebrile patients younger than 1 year of age who presented at an emergency department with a chief complaint of crying, irritability, screaming, colic, or fussiness showed that only 5.1% of the children had a serious underlying cause. Urinary tract infections were the most prevalent medical condition, especially in very young infants.28 Therefore, afebrile infants who cry excessively in the first few months of life should undergo urine evaluation. TREATMENT AND SUPPORT OF CHILDREN AND PARENTS In this part of the review, the support of families with an excessively crying infant is described. There is often insufficient evidence to firmly advocate a specific treatment. These families need
support, however, to prevent a large demand on health care, serious psychosocial effects on families, and behavioral problems later on. The following gives a practical approach to support the families based on what evidence there is. Each intake of parents with an excessively crying infant should begin with: • Recognition, support, and reassurance of parents. • Information about the normal crying pattern, co- and self-regulation, and about the prevention of the shaken baby syndrome/abusive head trauma. • Full cooperation between caregiver and parents. This empowers parents, who may lose confidence in their parenting abilities, and ensures compliance with the chosen strategy. • Referral to the family doctor or pediatrician to rule out medical problems should take place early on. (Treatment that follows from a medical diagnosis such as cow’s Healio.com/Pediatrics | e71
CME milk allergy or a urinary tract infection will not be discussed in this review.) • Discourage change of feeds (from breast to formula or from one formula to another). Breastfeeding should not be stopped in order to reduce excessive crying. • The relationship between parents, child, and the health care worker is of great importance and may need some time to develop. If problems are complex, it is preferable to consult other professionals for advice instead of immediately referring parents, thus preventing “shopping behavior.” The proposed care can be given by the health care worker, general practitioner, or pediatrician. INFORMING AND COUNSELING PARENTS If the health care professional is convinced that the issue at hand involves an “excessively crying infant” — which means that a medical explanation in all reasonableness has been excluded — parents should be informed extensively about the normal pattern of infant crying as described previously. This normal period can feel endlessly long and very stressful for the parents, child, and his or her siblings. Excessive crying is often related to fatigue of both the child and his or her parents.1 Explicitly point out that in 95% of cases, no physical or health problems are found. Inform parents about warning signs for ill health, such as poor growth. Furthermore, most children cry more at the end of the day, and there are no illnesses that occur only between the hours of 6 to 8 p.m. It is important to explain how stress affects both parents and the child. A baby who, for any reason, is off balance (eg, due to illness or fatigue) cries more, thus demanding more care, and thereby may bring the parent(s) out of balance, which in turn will affect the baby, etc. Parents and child end up in a vicious circle.1 If parents, after this exe72 | Healio.com/Pediatrics
planation and with ongoing support, fail to restore normal interaction, appropriate professionals should be consulted. Often parents receive many types of advice, sometimes conflicting. It is important to settle upon a plan with the parents and agree to stick to it. This can only work if, through support and compassion, a relationship has been formed based on
A baby who, for any reason, is off balance (eg, due to illness or fatigue) cries more, thus demanding more care. trust. The treatment or support given must be in line with the views of the parents and fit the family system. Each intervention may take some time to achieve results, and parents should be aware of this. Parents can choose one of the approaches classified as “evidence-based,” albeit at quite different levels of evidence. TREATMENTS FOR WHICH THERE IS SOME EVIDENCE Applying Regularity and Uniformity in Daily Care A consistent, recurring pattern of childcare throughout the day is beneficial.29-33 The behavioral components of the intervention include regularity in the sequence of the events surrounding sleep and feeding and uniformity in the place where the child sleeps and plays on his or her own.34 It should be emphasized that this does not mean a fixed time schedule, but instead, rather, a consistent approach. This comprises a recurring pattern of sleeping, feeding right after waking, positive interaction/cuddling and playing with a parent, playing on their own (preferably in a playpen), and being put to bed awake as soon as signs of weariness appear (eg, yawning, whining, rubbing of eyes, overactive behavior). This
approach offers the child predictability and the possibility to improve his or her self-regulating ability. It has proved to be effective in healthy parents, even those with mild psychological problems.35 Specific attention is offered to mothers who breastfeed, as this should be continued. If this approach is not effective, it can be helpful to add swaddling.29 Although not more effective, it does reduce crying more quickly. Health care providers should be clear about indications and contraindications for swaddling.34 Video Home Training (VHT)36 VHT is intended for parents with parenting stress. Its purpose is to solve problems in the socio-emotional development of the child (0-4 years). It has been shown to be effective in improving the interaction and communication between parents and child and in improving the interaction between depressed mothers and their babies.36-39 However, there have been no studies specifically conducted on improving the interaction in families with an excessively crying infant. In theory, if interaction issues play a role and parental sensitivity could be improved upon, one would assume VHT can be beneficial. However, a cautious approach is warranted. Baby Massage A Cochrane review showed that baby massage may have a beneficial effect for infants younger than 6 months of age.40 There was some evidence of benefits on mother-infant interaction, sleeping, and crying. There was no evidence of harm. Because there is no clear-cut definition what baby massage encompasses, results are difficult to interpret. In only one study of low quality, the result of baby massage on excessive crying was analyzed.41 A positive effect on crying at age 3 and 6 months was found. These findings may be sufficient to support the use of baby massage as method of support; however, more studies are needed.
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CME Fennel Extract and Herbal Tea The available evidence on alternative medication for excessive crying was discussed in a review.42 One wellconducted study reported benefit from fennel extract compared to placebo, and in another trial, herbal tea containing fennel, licorice, vervain chamomile, and mint significantly improved colic scores. However, there were some methodological concerns. There is some support for the effect of fennel from animal studies. In absence of side effects, these interventions may be supported, although further studies are advised. TREATMENTS NOT RECOMMENDED Chiropractic and spinal manipulation are recommended against because of the lack of evidence for their effectiveness, as well as the potentially serious side effects.43,44 Except in cases of proven cow’s milk allergy, change of feeds should be actively discouraged. In a Dutch study, 19% of women who stopped breastfeeding gave excessive crying of their infant as their reason for doing so;45 however, the amount of excessive crying was similar in breastfed and bottle-fed infants.46 Furthermore, 17% of the change in artificial feeds was due to crying. These data demonstrate that there is a schism between the reality and parental perception of the effect of feeds on excessive crying. Simethicon has not been proven effective in treating excessive crying.47-49Although there is evidence that babies settle more and better when placed prone, this does not comply with safe sleeping advice for the prevention of cot death and should be actively discouraged. NEITHER DISCOURAGED NOR ENCOURAGED Continuous carrying is not part of Western societies’ usual method of baby care but is considered normal behavior in many parts of the world. Picking up a crying baby to console him or her is
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normal parental behavior. When babies cry excessively for a longer period, carrying the child does not seem to reduce the excessive crying.50-52 However, the literature also does not prove that continuous carrying has a negative impact. Although there is evidence from two randomized, controlled trials for a beneficial role of the probiotic Lactobacillus reuteri DSM 17938 for infant colic, it is too soon to recommend its use therapeutically.53,54 It has only been studied in a population of mothers who breastfed at least partially, and both studies were financed by the manufacturer. It is available in some countries as “BioGaia.” Parents and health care workers can also consciously decide not to try to lessen the burden of crying but to instead strengthen the parental coping strategies. Many interventions, such as nurse-family partnerships; neonatal programs, such as Infant Behavioral Assessment and Intervention Program for premature infants; and paramedical care, such as physical therapy, can be used to support parents.55 PREVENTION FOR HIGH-RISK GROUPS As discussed previously, there are groups of parents and infants who are at high risk of crying excessively. (Table 1). Furthermore, the relative risk for excessive crying increases with decreasing gestational age in preterms compared to term infants. Small for gestational age children also have increased risk of excessive crying in all gestational age groups.16 Identifying the groups of parents and infants at increased risk is important because information on crying can be given before it becomes excessive. Furthermore, early support and, if necessary, referral to more specialized care may prevent more serious problems including child abuse, although no studies are available to confirm this.
TABLE 1.
At High Risk for Infantile Excessive Crying and Associated Problems • Pregnant women with anxiety and/or with little support. •P regnant women with many somatic symptoms. •P arents with much stress or little social support. •P arents with anxiety or other psychological problems. •P arents with depression or other psychiatric problems. • Teenage parents. •P arents with addiction. •P arental unemployment; financial problems. •P remature and/or small for gestational age children. • Children with an especially high, penetrating and loud cry.
LONG-TERM PROGNOSIS Most of the children who have cried excessively during their first 4 months have no increased risks of developing psychological, social, or other problems. Some parents, however, may continue to perceive their child as more vulnerable, temperamental, or more rebellious, even when he or she gets older.27,56 Any child who continues crying after 4 months should be followed up because unsolved excessive crying may disturb the parent-child interaction and regulation, which may in turn cause long-lasting psycho-social or somatic problems. Research shows that infants who continue to cry after 4 to 6 months are at higher risk for feeding, sleeping, and behavioral problems, among which are hyperactivity and somatic problems.57,58 CONCLUSION Infants who cry excessively place a large demand on health care. Although there is no consensus on the definition of excessive crying, health care workers should be aware of the parental percepHealio.com/Pediatrics | e73
CME tion that is indicative of more serious problems that can arise. The disruption that a crying infant can bring to families and the long-term sequela are often underestimated. Education regarding the normal pattern of crying in infants should be given early on so that parents can have a realistic view of what to expect. If parents still perceive the crying as excessive and medical conditions have been ruled out, support is essential to prevent long-term problems in parentinfant interaction and the ensuing possibility of child abuse. Of the many strategies to reduce the crying itself, bringing regularity into the system of childcare is the most appropriate first choice. Adding interventions such as swaddling, baby massage, and fennel extract are possibilities, but more studies should be conducted to confirm the benefits of these practices. The most promising area of research is that into the intestinal microbiota. The randomized, controlled trials that have been conducted seem promising, and there is a relevant biological hypothesis that underlies the intervention. Future studies should be conducted with special attention to which probiotic strain is chosen, and results should be corrected for the various risk factors for crying and the type of feeds. REFERENCES 1. Kurth E, Kennedy HP, Spichiger E, et al. Crying babies, tired mothers: what do we know? A systematic review. Midwifery. 2011;27:187-194. 2. Wolke D, Samara M, Alvarez Wolke M. Meta-analysis of fuss/cry durations and colic prevalence across countries. Presented at: 11th International Infant Cry Research Workshop; June 8-10, 2011; the Netherlands. 3. Barr RG, Trent RB, Cross J. Age-related incidence curve of hospitalized Shaken Baby syndrome (SBS) cases: convergent evidence for crying as a trigger to shaking. Child Abuse Negl. 2006;30:7-13. 4. Barr RG. The normal crying curve: what do we really know? Dev Med Child Neurol. 1990;32:356-362. 5. Barr RG, Chen S, Hopkins B, Westra T. Crying patterns in preterm infants. Dev Med Child Neurol. 1996;38:345-355. 6. Shamir R, St James-Roberts I, Di Lorenzo C,
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et al. Infant crying, colic, and gastrointestinal discomfort in early childhood: a review of the evidence and most plausible mechanisms. J Pediatr Gastroenterol Nutr. 2013;57 Suppl 1:S1-45. 7. Reijneveld SA, Brugman E, Hirasing RA. Excessive infant crying: the impact of varying definitions. Pediatrics. 2001;108:893-897. 8. Wessel MA, Cobb JC, Jackson EB, et al. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics. 1954;14:421-435. 9. Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology. 2006;130:1519-1526. 10. Barr RG, Paterson JA, MacMartin LM, et al. Prolonged and unsoothable crying bouts in infants with and without colic. J Dev Behav Pediatr. 2005;26:14-23. 11. Lam J, Barr RG, Catherine N, et al. Electronic and paper diary recording of infant and caregiver behaviors. J Dev Behav Pediatr. 2010;31:685-693. 12. Reijneveld SA, van der Wal M, Brugman E, et al. Infant crying and abuse. Lancet. 2004;364:1340-1342. 13. Out D, Pieper S, Bakermans-Kranenburg MJ, et al. Intended sensitive and harsh caregiving responses to infant crying: the role of cry pitch and perceived urgency in an adult twin sample. Child Abuse Negl. 2010;34:863-873. 14. Vik T, Grote V, Escribano J, et al. Infantile colic, prolonged crying and maternal postnatal depression. Acta Paediatr. 2009;8:1344-1348. 15. 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:e96-103. 16. Milidou I, Søndergaard C, Jensen MS, et al. Gestational age, small for gestational age, and infantile colic. Paediatr Perinat Epidemiol. 2014;28:138-145. 17. Douglas P, Hill P. Managing infants who cry excessively in the first few months of life. BMJ. 2011;15:343. 18. Talge NM, Neal C, Glover V. Early Stress, Translational Research and Prevention Science Network: fetal and neonatal experience on child and adolescent mental health. antenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry. 2007;48:245-261. 19. Yalçin SS, Orün E, Mutlu B, et al. Why are they having infant colic? A nested casecontrol study. Paediatr Perinat Epidemiol. 2010;24:584-596. 20. Van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935. 21. Chen IL, Gao WY, Johnson AP, et al. Proton pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gastroenterol Nutr. 2012;54:8-14. 22. Rhoads JM, Fatheree NY, Norori J, et al.
Altered fecal microflora and increased fecal calprotectin in infants with colic. J Pediatr. 2009;155:823-828. 23. Savino F, Cordisco L, Tarasco V, et al. Molecular identification of coliform bacteria from colicky breastfed infants. Acta Paediatr. 2009;98:1582-1588. 24. De Weerth C, Fuentes S, Puylaert P, de Vos WM. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics. 2013;131:e550-558. 25. Reijneveld SA, Lanting CI, Crone MR, Van Wouwe JP. Exposure to tobacco smoke and infant crying. Acta Paediatr. 2005;94:217-221. 26. Søndergaard C, Henriksen TB, Obel C, Wisborg K. Smoking during pregnancy and infantile colic. Pediatrics.2001;108:342-346. 27. Canivet CA, Ostergren PO, Jakobsson IL, et al. Infantile colic, maternal smoking and infant feeding at 5 weeks of age. Scand J Public Health. 2008;36:284-291. 28. Freedman SB, Al-Harthy N, Thull-Freedman J. The crying infant: diagnostic testing and frequency of serious underlying disease. Pediatrics. 2009;123:841-848. 29. Sleuwen van BE, L’Hoir MP, Engelberts AC, et al. Comparison of behavior modification with and without swaddling as interventions for excessive crying. J Pediatr. 2006;149:512-517. 30. Keefe MR, Froese-Fretz A, Kotzer AM. Newborn predictors of infant irritability. J Obstet Gynecol Neonatal Nurs. 1998;27:513-520. 31. Keefe MR, Barbosa GA, Froese-Fretz A, et al. An intervention program for families with irritable infants. MCN Am J Matern Child Nurs. 2005;30:230-236. 32. Keefe MR, Kajrlsen KA, Lobo ML, et al. Reducing parenting stress in families with irritable infants. Nurs Res. 2006;55:198-205. 33. Wolke D, Gray P, Meyer R. Excessive infant crying: a controlled study of mothers helping mothers. Pediatrics. 1994;94:322-332. 34. Blom MA, van Sleuwen BE, de Vries H, et al. Health care interventions for excessive crying in infants: regularity with and without swaddling. J Child Health Care. 2009;13:161-176. 35. Sleuwen van BE. Infants that cry excessively: the effect of regularity and swaddling. Thesis. Utrecht: Universiteit Utrecht; 2008. 36. Eliëns M. Protocol video-hometraining excessive crying infants. Associative Intensive Homecare. [In Dutch]. Eindhoven: De Combinatie; 2003. 37. Juffer F, Bakermans-Kranenburg MJ, IJzendoorn van MH. Promoting Positive Parenting: An Attachment-Based Intervention. New York, NY: Lawrence Erlbaum Associates; 2007. 38. Velderman MK. The Leiden VIPP and VIPPR Study: Evaluation of a Short-Term Preventive Attachment-Based Intervention. Proefschrift Rijksuniversiteit Leiden. Leiden: Mosterd & Van Onderen; 2005. 39. Doesum van K. An early preventive intervention for depressed mothers and their infants,
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CME its efficacy and predictors of maternal sensitivity. Thesis. Radboud University Nijmegen; 2007. 40. Underdown A, Barlow J, Chung V, StewartBrown S. Massage intervention for promoting mental and physical health in infants aged under six months. Cochrane Database Syst Rev. 2006;4:CD005038. 41. Shuan XL, Romg QG, Yan YM, et al. Study of touch intervention of infant sleep disorder. J Nursing Continual Educ. 2004;19:973-976. 42. Perry R, Hunt K, Ernst E. Nutritional supplements and other complementary medicines for infantile colic: A systematic review. Pediatrics. 2011;127:720-733. 43. Olafsdottir E, Forshei S, Fluge G, Markestad T. Randomised controlled trial of infantile colic treated with chiropractic spinal manipulation. Arch Dis Child. 2001;84:138-141. 44. Holla M, Ijland MM, van der Vliet AM, et al. Death of an infant following ‘craniosacral’ manipulation of the neck and spine. Ned Tijdschr Geneeskd. 2009;153:828-831. 45. Bulk-Bunschoten AMW. Feeding practices in the Netherlands in the first four months of life.
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Thesis. Amstelveen; 2003. 46. 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. 47. Danielsson B, Hwang CP. Treatment of infantile colic with surface active substance (simethicone). Acta Paediatr Scand. 1985;74:446-450. 48. Metcalf TJ, Irons TG, Sher LD, Young PC. Simethicone in the treatment of infant colic: A randomized, placebo-controlled, multicenter trial. Pediatrics. 1994;94:29-34. 49. Sethi KS, Sethi JK. Simethicone in the management of infant colic. Practitioner. 1988;232:508. 50. Barr RG, Konner M, Bakeman R, Adamson L. Crying in !kung san infants: a test of the cultural specificity hypothesis. Dev Med Child Neurol. 1991;33:601-610. 51. Lucassen P. Colic in infants. Clin Evid (Online). 2010:0309. 52. St. James-Roberts I, Alvarez M, Csipke E, et al. Infant crying and sleeping in london, copenhagen and when parents adopt
a “proximal” form of care. Pediatrics. 2006;117:e1146-1155. 53. Savino F, Tarasco V. New treatments for infant colic. Curr Opin Pediatr. 2010;22:791-797. 54. Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;162:257-262. 55. Koldewijn K, Wolf MJ, van Wassenaer A, et al. The Infant Behavioral Assessment and Intervention Program for very low birth weight infants at 6 months corrected age. J Pediatr. 2009;154:33-38. 56. Rautava P, Lehtonen L, Helenius H, Sillanpää M. Infantile colic: child and family three years later. Pediatrics. 1995;96:43-47. 57. Wolke D, Rizzo P, Woods S. Persistant infant crying and hyperactivity problems in middle childhood. Pediatrics. 2002;109:1054-1060. 58. Rao MR, Brenner RA, Schisterman EF, et al. Longterm cognitive development in children with prolonged crying. Arch Dis Child. 2004;89:989-992.
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