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doi: 10.1111/ppe.12095
Gestational Age, Small for Gestational Age, and Infantile Colic Ioanna Milidou,a Charlotte Søndergaard,b Morten Søndergaard Jensen,c Jørn Olsen,d Tine Brink Henriksena,c a
Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital b
Department of Pediatrics, Herning Regional Hospital
c
Department of Pediatrics, Aarhus University Hospital
d
Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
Abstract Background: Preterm and growth restricted infants may have developmental delays and deviations from normal organ function related to the gastrointestinal tract and the central nervous system. Since both organ systems are hypothesised to be involved in the pathogenesis of infantile colic, a condition characterised by excessive crying during the first months of life, impaired fetal growth and preterm birth may be risk factors for infantile colic. Methods: A total of 62 761 liveborn singletons from the Danish National Birth Cohort (1996 to 2002) were studied. Infantile colic was defined according to Wessel’s modified criteria based on maternal interview conducted at 6 months post-partum. Results: A total of 2605 (4.2%) infants were born preterm, 54 441 (86.7%) at term, and 5715 (9.1%) post-term. A total of 4964 (7.9%) infants fulfilled Wessel’s modified criteria for infantile colic. The risk for infantile colic increased with decreasing gestational age after adjustment for covariates. The highest odds [odds ratio (95% confidence interval)] was observed for infants born before 32 completed gestational weeks (1.5 [95% CI 1.0, 2.2], reference: 40 gestational weeks). Small for gestational age infants (birthweight below 10th percentile) had an increased odds of infantile colic (1.2 [95% CI 1.1, 1.3]) in all gestational age groups. Conclusions: We observed an increased risk of infantile colic in preterm and small for gestational age infants in a large cohort. Our results suggest that the aetiology of infantile colic may be found in the prenatal, perinatal, and neonatal period. Keywords: infantile colic, excessive crying, preterm birth, gestational age, birthweight, small for gestational age, fetal growth retardation, modified Wessel’s criteria. Excessive crying in infancy, commonly known as infantile colic, is a condition characterised by repeated episodes of crying and fussing during the first months of life that affects almost 10% of all infants. Wessel’s ‘rule of threes’ defines infantile colic by ‘crying more than three hours per day, more than three days per week, more than three weeks, in an otherwise healthy and well-fed infant’.1 It causes a disproportionate degree of parental concern and accounts for many contacts to the health care system. It may even, on rare occasions, lead to parental violence towards the child.2 Despite its frequent occurrence, the nature of the condition remains enigmatic. Lactose intolerance causing gastrointestinal discomfort has been suspected, and some infants seem to improve with changing of infant formula.3 However, deviations Correspondence: Ioanna Milidou, Perinatal Epidemiology Research Unit, Aarhus University Hospital Skejby, Brendstrupgårdsvej 100, DK 8210, Aarhus, Denmark. E-mail: [email protected]
from normal organ function, most notably of the gastrointestinal tract and the central nervous system, have been suggested.4–11 Preterm infants and infants with impaired fetal growth often have developmental delays or deviations from normal organ function related to both organ systems.12–16 Moreover, those infants are more often hospitalised during the neonatal period, undergo more medical procedures, have specific morbidity, show different growth patterns, and are more often treated with medication such as caffeine, antibiotics, and steroids than full-term infants with normal fetal growth. Many of these factors interact with maturation and development and may affect the function of multiple organs. Thus, impaired fetal growth and preterm birth may be risk factors for infantile colic. Normal infant crying increases to an average of 2 h per day at approximately 6 weeks of age and then declines.17–20 Preterm born infants seem to reach their peak of daily crying at approximately 6 weeks after © 2013 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2014, 28, 138–145
Gestational age, small for gesttional age, and infantile colic their due date was expected,21 but little is known about the association between prematurity and infantile colic. A recent report from the Danish Institute for Social Research found that infantile colic, defined as daily episodes of ‘colic’ regardless of duration of the episodes, was 30% more common among infants born before 37 gestational weeks compared with infants with longer gestation.22 We have previously reported an increased risk of infantile colic in preterm babies in a study with limited power.23 The same study assessed different proxy measures of fetal growth restriction in relation to infantile colic and found contradictory results,23 which is not surprising given the imperfection of these measures to identify the truly growth restricted infants. To our knowledge, no other studies have investigated infantile colic among preterm or possibly growth-restricted infants. We used a large cohort with prospectively collected data in order to investigate the main effects of preterm birth and low birthweight for gestational age, and expected that infants who were both preterm and growth restricted would carry the higher risk for infantile colic.
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birth for all livebirths was retrieved from the Danish Medical Birth Registry.26 It is mandatory for the attending health personnel to complete a structured form for the Birth Registry immediately after birth. The gestational age is calculated based on date of last menstrual period but replaced with ultrasound-based estimates (at least one routine ultrasound examination was made for 93% of all pregnancies in Denmark at the time of the study) in case of discrepancy between the two sources. We corrected birthweight and gestational age mismatches in the registry data with priority on birthweight, because it is considered more accurate. Infants with incompatible birthweight for gestational age according to Alexander’s national reference (n = 53),27 or with gestational ages below 168 or above 315 days (n = 45), were identified. The gestational age recorded in the registry was replaced by the gestational age reported by the mother in the interview (completed gestational weeks) if it was compatible with the birthweight (n = 55); we excluded mother and child if no interview data on gestation was available (n = 43).
Methods Study population We used data from the Danish National Birth Cohort (DNBC), a nationwide population-based cohort of pregnant women and their offspring from 1996 through 2002 recruited early in pregnancy by their general practitioner.24 About 60% of the invited women accepted to participate, resulting in a total of 101 042 pregnancies, approximately 30% of all Danish pregnant women during the study period.25 Data on maternal lifestyle (smoking, alcohol, caffeine intake, and dietary habits), health status including medication, weight and height, working, living, and socioeconomic conditions was collected by two computer-assisted telephone interviews around gestational weeks 17 and 32. When the child was 6 months old, the mother was interviewed on the last part of the pregnancy and on the infant’s behaviour, development and nutrition, as well as frequency and duration of crying episodes.
Explanatory variables Information on gestational age, anthropometric measures at birth, and Apgar score at 1 and 5 min after © 2013 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2014, 28, 138–145
Outcome ascertainment Infantile colic was assessed by maternal interview at 6 months post-partum based on the modified Wessel’s criteria: crying or fussing for more than 3 h a day for more than 3 days a week.28 The first period with crying and fussing had to start before the age of 3 months for infants born at term. In order to compensate for the later onset of the crying among preterm infants,21 a correction was made allowing for the first episode to start at the age of 3 months plus the interval between the actual and the expected date of birth (i.e. the advancement of birth). This correction was not entirely possible for infants born before 28 complete weeks of gestation because the interview was conducted around 6 months post-partum; for those infants (n = 49), the allowed period for manifestation of infantile colic was restricted to a maximum of 6 months post-partum, and an indicator variable was created to identify them in the statistical analysis. For each reported colicky period, the mothers were asked to report hours of crying and fussing per day, number of days per week in which crying and fussing exceeded three hours, and age of the infant. The questionnaire is available at the DNBC homepage.29
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I. Milidou et al.
Statistical analysis Statistical analyses were performed using stata 11 software (Statacorp, Texas). We modelled infantile colic as a binary outcome using logistic regression, with gestational age and birthweight as explanatory variables. We estimated odds ratios (OR) with 95% confidence intervals [CI] for infantile colic. We initially investigated the risk of infantile colic according to gestational age (complete gestational weeks 24–31; 32–36; 37–38; 39; 40; 41; 42–43), using infants born in gestational week 40 as reference. We explored our data by estimating the risk of infantile colic in 500 g birthweight intervals, using birthweights between 3500 g and 4000 g as reference. We then investigated the risk of infantile colic when taking both gestational age and birthweight into account simultaneously. For that purpose, we identified infants born with a birthweight below the 10th percentile of birthweight of all infants in the DNBC born in the same gestational week; we pooled gestational weeks 24 to 27, and 43 to 44 due to few observations in the very preterm and post-term weeks. Infants weighing below the 10th percentile were characterised as small for gestational age (SGA), and their risk (odds) for developing infantile colic was compared with larger infants. In order to explore whether this association was modified by gestational age, we compared the risk of infantile colic in SGA infants to non-SGA infants for each of the aforementioned gestation groups, and repeated the analysis allowing for interaction between gestational age and SGA status. A similar comparison was made among preterm infants (born before 37 complete gestational weeks), full-term infants (born between 37 and 41 complete gestational weeks), and post-term infants (born after 41 complete weeks). We decided a priori to adjust all analyses for the following covariates known to affect birthweight and length of gestation: maternal age (continuous), first parity (binary), maternal height (continuous and squared continuous), maternal pre-pregnancy weight (continuous), and child’s sex.30,31 Smoking during pregnancy is associated with infantile colic, low birthweight, and preterm birth, and was therefore included in the model, after evaluating possible effect measure modification using stratified analyses. The family’s socioeconomic status, defined as the couple’s combined educational level and occupational status (in four groups) was included in the model, as it has pre-
viously been shown to modify health outcomes among preterm infants,32 and because maternal reports on infant crying could be influenced by social conditions.
Results A total of 62 761 mothers gave birth to a liveborn singleton (first birth in the cohort) with complete data on gestational age, birthweight, and crying symptoms; 2605 (4.2%) infants were born preterm, 54 441 (86.7%) at term, and 5715 (9.1%) post-term. According to the definition, 10% of infants within each gestational age were classified as SGA. Maternal and infant baseline characteristics are presented in Table 1. Primiparous women and smokers more often gave birth to SGA or preterm infants, and the same tendency, although less pronounced, was observed among women of lower socioeconomic status and women who were concerned about pregnancy and birth. A total of 4964 (7.9%) infants fulfilled Wessel’s modified criteria for infantile colic. The reported crying period occurred before the age of 8 weeks for virtually all participants. The distribution of the time of the crying followed the usual crying patterns for both full-term and post-term infants, while preterm infants showed a more flat distribution without the characteristic peak at 6 weeks, and a shift towards later onset of the crying period (data not shown). Table 2 shows that the risk of infantile colic increased by decreasing gestational age. The higher risk was observed among infants born before 32 weeks of gestation while being born after 41 complete weeks of gestation was associated with slightly reduced occurrence of infantile colic. Associations were similar in strata defined by maternal smoking after adjustment for the selected covariates (data not shown). In a univariate analysis, lower birthweight was also associated with higher risk of infantile colic (results not shown). Being born SGA was associated with higher odds of infantile colic for all infants (OR = 1.2 [1.1, 1.3]). Infants born SGA had a higher odds of infantile colic at all but one gestational age stratum and the association was statistically significant at 37–38 and at 40 complete gestational weeks (Table 3). The exception was observed for infants born before 32 complete gestational weeks, but this estimate was based on only two infants with colic. The interaction term between gestational age and SGA was non-significant, and the model including it showed no significantly better fit. © 2013 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2014, 28, 138–145
Gestational age, small for gesttional age, and infantile colic
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Table 1. Maternal and child characteristics (n = 62 761) according to gestational age at birth and weight for gestational age, the Danish National Birth Cohort, 1997–2002 Infant
Mother and child characteristics
Born at term, not SGA (n = 54 149)
Primiparae, % Social class, % High-grade professionals and managers Middle-grade professionals Skilled workers, students Unskilled workers, unemployed, social security Mother’s age, %
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doi: 10.1111/ppe.12095
Gestational Age, Small for Gestational Age, and Infantile Colic Ioanna Milidou,a Charlotte Søndergaard,b Morten Søndergaard Jensen,c Jørn Olsen,d Tine Brink Henriksena,c a
Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital b
Department of Pediatrics, Herning Regional Hospital
c
Department of Pediatrics, Aarhus University Hospital
d
Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
Abstract Background: Preterm and growth restricted infants may have developmental delays and deviations from normal organ function related to the gastrointestinal tract and the central nervous system. Since both organ systems are hypothesised to be involved in the pathogenesis of infantile colic, a condition characterised by excessive crying during the first months of life, impaired fetal growth and preterm birth may be risk factors for infantile colic. Methods: A total of 62 761 liveborn singletons from the Danish National Birth Cohort (1996 to 2002) were studied. Infantile colic was defined according to Wessel’s modified criteria based on maternal interview conducted at 6 months post-partum. Results: A total of 2605 (4.2%) infants were born preterm, 54 441 (86.7%) at term, and 5715 (9.1%) post-term. A total of 4964 (7.9%) infants fulfilled Wessel’s modified criteria for infantile colic. The risk for infantile colic increased with decreasing gestational age after adjustment for covariates. The highest odds [odds ratio (95% confidence interval)] was observed for infants born before 32 completed gestational weeks (1.5 [95% CI 1.0, 2.2], reference: 40 gestational weeks). Small for gestational age infants (birthweight below 10th percentile) had an increased odds of infantile colic (1.2 [95% CI 1.1, 1.3]) in all gestational age groups. Conclusions: We observed an increased risk of infantile colic in preterm and small for gestational age infants in a large cohort. Our results suggest that the aetiology of infantile colic may be found in the prenatal, perinatal, and neonatal period. Keywords: infantile colic, excessive crying, preterm birth, gestational age, birthweight, small for gestational age, fetal growth retardation, modified Wessel’s criteria. Excessive crying in infancy, commonly known as infantile colic, is a condition characterised by repeated episodes of crying and fussing during the first months of life that affects almost 10% of all infants. Wessel’s ‘rule of threes’ defines infantile colic by ‘crying more than three hours per day, more than three days per week, more than three weeks, in an otherwise healthy and well-fed infant’.1 It causes a disproportionate degree of parental concern and accounts for many contacts to the health care system. It may even, on rare occasions, lead to parental violence towards the child.2 Despite its frequent occurrence, the nature of the condition remains enigmatic. Lactose intolerance causing gastrointestinal discomfort has been suspected, and some infants seem to improve with changing of infant formula.3 However, deviations Correspondence: Ioanna Milidou, Perinatal Epidemiology Research Unit, Aarhus University Hospital Skejby, Brendstrupgårdsvej 100, DK 8210, Aarhus, Denmark. E-mail: [email protected]
from normal organ function, most notably of the gastrointestinal tract and the central nervous system, have been suggested.4–11 Preterm infants and infants with impaired fetal growth often have developmental delays or deviations from normal organ function related to both organ systems.12–16 Moreover, those infants are more often hospitalised during the neonatal period, undergo more medical procedures, have specific morbidity, show different growth patterns, and are more often treated with medication such as caffeine, antibiotics, and steroids than full-term infants with normal fetal growth. Many of these factors interact with maturation and development and may affect the function of multiple organs. Thus, impaired fetal growth and preterm birth may be risk factors for infantile colic. Normal infant crying increases to an average of 2 h per day at approximately 6 weeks of age and then declines.17–20 Preterm born infants seem to reach their peak of daily crying at approximately 6 weeks after © 2013 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2014, 28, 138–145
Gestational age, small for gesttional age, and infantile colic their due date was expected,21 but little is known about the association between prematurity and infantile colic. A recent report from the Danish Institute for Social Research found that infantile colic, defined as daily episodes of ‘colic’ regardless of duration of the episodes, was 30% more common among infants born before 37 gestational weeks compared with infants with longer gestation.22 We have previously reported an increased risk of infantile colic in preterm babies in a study with limited power.23 The same study assessed different proxy measures of fetal growth restriction in relation to infantile colic and found contradictory results,23 which is not surprising given the imperfection of these measures to identify the truly growth restricted infants. To our knowledge, no other studies have investigated infantile colic among preterm or possibly growth-restricted infants. We used a large cohort with prospectively collected data in order to investigate the main effects of preterm birth and low birthweight for gestational age, and expected that infants who were both preterm and growth restricted would carry the higher risk for infantile colic.
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birth for all livebirths was retrieved from the Danish Medical Birth Registry.26 It is mandatory for the attending health personnel to complete a structured form for the Birth Registry immediately after birth. The gestational age is calculated based on date of last menstrual period but replaced with ultrasound-based estimates (at least one routine ultrasound examination was made for 93% of all pregnancies in Denmark at the time of the study) in case of discrepancy between the two sources. We corrected birthweight and gestational age mismatches in the registry data with priority on birthweight, because it is considered more accurate. Infants with incompatible birthweight for gestational age according to Alexander’s national reference (n = 53),27 or with gestational ages below 168 or above 315 days (n = 45), were identified. The gestational age recorded in the registry was replaced by the gestational age reported by the mother in the interview (completed gestational weeks) if it was compatible with the birthweight (n = 55); we excluded mother and child if no interview data on gestation was available (n = 43).
Methods Study population We used data from the Danish National Birth Cohort (DNBC), a nationwide population-based cohort of pregnant women and their offspring from 1996 through 2002 recruited early in pregnancy by their general practitioner.24 About 60% of the invited women accepted to participate, resulting in a total of 101 042 pregnancies, approximately 30% of all Danish pregnant women during the study period.25 Data on maternal lifestyle (smoking, alcohol, caffeine intake, and dietary habits), health status including medication, weight and height, working, living, and socioeconomic conditions was collected by two computer-assisted telephone interviews around gestational weeks 17 and 32. When the child was 6 months old, the mother was interviewed on the last part of the pregnancy and on the infant’s behaviour, development and nutrition, as well as frequency and duration of crying episodes.
Explanatory variables Information on gestational age, anthropometric measures at birth, and Apgar score at 1 and 5 min after © 2013 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2014, 28, 138–145
Outcome ascertainment Infantile colic was assessed by maternal interview at 6 months post-partum based on the modified Wessel’s criteria: crying or fussing for more than 3 h a day for more than 3 days a week.28 The first period with crying and fussing had to start before the age of 3 months for infants born at term. In order to compensate for the later onset of the crying among preterm infants,21 a correction was made allowing for the first episode to start at the age of 3 months plus the interval between the actual and the expected date of birth (i.e. the advancement of birth). This correction was not entirely possible for infants born before 28 complete weeks of gestation because the interview was conducted around 6 months post-partum; for those infants (n = 49), the allowed period for manifestation of infantile colic was restricted to a maximum of 6 months post-partum, and an indicator variable was created to identify them in the statistical analysis. For each reported colicky period, the mothers were asked to report hours of crying and fussing per day, number of days per week in which crying and fussing exceeded three hours, and age of the infant. The questionnaire is available at the DNBC homepage.29
140
I. Milidou et al.
Statistical analysis Statistical analyses were performed using stata 11 software (Statacorp, Texas). We modelled infantile colic as a binary outcome using logistic regression, with gestational age and birthweight as explanatory variables. We estimated odds ratios (OR) with 95% confidence intervals [CI] for infantile colic. We initially investigated the risk of infantile colic according to gestational age (complete gestational weeks 24–31; 32–36; 37–38; 39; 40; 41; 42–43), using infants born in gestational week 40 as reference. We explored our data by estimating the risk of infantile colic in 500 g birthweight intervals, using birthweights between 3500 g and 4000 g as reference. We then investigated the risk of infantile colic when taking both gestational age and birthweight into account simultaneously. For that purpose, we identified infants born with a birthweight below the 10th percentile of birthweight of all infants in the DNBC born in the same gestational week; we pooled gestational weeks 24 to 27, and 43 to 44 due to few observations in the very preterm and post-term weeks. Infants weighing below the 10th percentile were characterised as small for gestational age (SGA), and their risk (odds) for developing infantile colic was compared with larger infants. In order to explore whether this association was modified by gestational age, we compared the risk of infantile colic in SGA infants to non-SGA infants for each of the aforementioned gestation groups, and repeated the analysis allowing for interaction between gestational age and SGA status. A similar comparison was made among preterm infants (born before 37 complete gestational weeks), full-term infants (born between 37 and 41 complete gestational weeks), and post-term infants (born after 41 complete weeks). We decided a priori to adjust all analyses for the following covariates known to affect birthweight and length of gestation: maternal age (continuous), first parity (binary), maternal height (continuous and squared continuous), maternal pre-pregnancy weight (continuous), and child’s sex.30,31 Smoking during pregnancy is associated with infantile colic, low birthweight, and preterm birth, and was therefore included in the model, after evaluating possible effect measure modification using stratified analyses. The family’s socioeconomic status, defined as the couple’s combined educational level and occupational status (in four groups) was included in the model, as it has pre-
viously been shown to modify health outcomes among preterm infants,32 and because maternal reports on infant crying could be influenced by social conditions.
Results A total of 62 761 mothers gave birth to a liveborn singleton (first birth in the cohort) with complete data on gestational age, birthweight, and crying symptoms; 2605 (4.2%) infants were born preterm, 54 441 (86.7%) at term, and 5715 (9.1%) post-term. According to the definition, 10% of infants within each gestational age were classified as SGA. Maternal and infant baseline characteristics are presented in Table 1. Primiparous women and smokers more often gave birth to SGA or preterm infants, and the same tendency, although less pronounced, was observed among women of lower socioeconomic status and women who were concerned about pregnancy and birth. A total of 4964 (7.9%) infants fulfilled Wessel’s modified criteria for infantile colic. The reported crying period occurred before the age of 8 weeks for virtually all participants. The distribution of the time of the crying followed the usual crying patterns for both full-term and post-term infants, while preterm infants showed a more flat distribution without the characteristic peak at 6 weeks, and a shift towards later onset of the crying period (data not shown). Table 2 shows that the risk of infantile colic increased by decreasing gestational age. The higher risk was observed among infants born before 32 weeks of gestation while being born after 41 complete weeks of gestation was associated with slightly reduced occurrence of infantile colic. Associations were similar in strata defined by maternal smoking after adjustment for the selected covariates (data not shown). In a univariate analysis, lower birthweight was also associated with higher risk of infantile colic (results not shown). Being born SGA was associated with higher odds of infantile colic for all infants (OR = 1.2 [1.1, 1.3]). Infants born SGA had a higher odds of infantile colic at all but one gestational age stratum and the association was statistically significant at 37–38 and at 40 complete gestational weeks (Table 3). The exception was observed for infants born before 32 complete gestational weeks, but this estimate was based on only two infants with colic. The interaction term between gestational age and SGA was non-significant, and the model including it showed no significantly better fit. © 2013 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2014, 28, 138–145
Gestational age, small for gesttional age, and infantile colic
141
Table 1. Maternal and child characteristics (n = 62 761) according to gestational age at birth and weight for gestational age, the Danish National Birth Cohort, 1997–2002 Infant
Mother and child characteristics
Born at term, not SGA (n = 54 149)
Primiparae, % Social class, % High-grade professionals and managers Middle-grade professionals Skilled workers, students Unskilled workers, unemployed, social security Mother’s age, %
