Relation of Prematurity and Brain Injury to Crying Behavior in Infancy
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ABSTRACT
OBJECTIVES. The objective of this study was to assess crying behavior during infancy in very preterm infants with or without brain injury.
METHODS. A total of 125 very low birth weight infants survived during January 2001 to July 2004 in Turku University Hospital, Finland. They were categorized according to the most pathologic brain finding either in ultrasound or MRI. Baby Day Diary was used to assess crying behavior at term, 6 weeks, and 5 months of corrected age. The behavior of a group of term control infants (n = 49) was assessed at 5 months.
RESULTS. Severe brain injuries in very low birth weight infants did not affect the duration of fussing or crying. In very low birth weight infants, brain injuries did not affect the frequency of fussing or crying bouts or the development of circadian rhythm in crying behavior. At 5 months of corrected age, fussing bouts were more frequent in very low birth weight infants compared with term control infants (6.4 per day vs 4.5 per day), and very low birth weight infants were held more (169 minutes [97] vs 130 minutes [69], respectively).
CONCLUSIONS. This prospective study using a validated cry diary showed that brain injuries that are related to prematurity do not have major effects on crying behavior or development of circadian rhythm. Prematurity does not increase the duration but increases the frequency of fussing and crying at 5 months of corrected age compared with term control infants. It also seems that prematurity and brain pathology may increase caregiving activity in the form of holding.
Key Words: preterm ? VLBW ? MRI ? ultrasound ? fussing ? crying ? behavior ? diary ? follow-up ? brain injury
Abbreviations: IVH—intraventricular hemorrhage ? WM—white matter ? PVL—periventricular leukomalacia ? VLBW—very low birth weight ? TR—repetition time ? TE—echo time
The crying pattern of healthy term infants is characterized by an increase in the amount of crying during the first month of life and clustering of crying in the evening hours.1–4 Healthy preterm infants seem to have the similar crying pattern with maximum amount of crying at 6 weeks of corrected age.5 In healthy term infants, excessive crying during the first 3 months of life has not been shown to correlate to later behavioral or developmental problems.6,7 It has been suggested that an increased amount of crying is attributable to transient individual differences in the ability to regulate behavioral distress state.8,9 However, persistent crying problems that last beyond 3 months of life have been shown to correlate to later sleeping and feeding problems10; to cognitive problems7; and to hyperactivity, other behavioral problems, or academic difficulties at school age.7,11
To our knowledge, spontaneous crying of preterm infants has been examined only in 1 study,5 which excluded all infants with brain injury, such as intraventricular hemorrhage (IVH). Other studies of crying behavior in preterm infants have focused on crying behavior in a test situation. Wolf et al12 showed that preterm infants compared with term infants were more irritable in neurobehavioral assessment situations at different age points between the due date and 6 months. In this study, infants with brain hemorrhages (grades 3–4) were excluded.
Very little is known of the effect of early brain injuries on later fussing and crying behavior of preterm infants. The most common brain injuries include IVH and white matter (WM) injuries, such as periventricular leukomalacia (PVL) and ventriculomegaly. The incidence of these findings correlates inversely to gestational age. The impact of brain injuries on pain reaction was studied by Oberlander et al,13 who assessed the pain reaction to heel stick in very preterm infants with and without brain injuries. In their study, no differences were found in crying response to heel stick or heel squeezing.
To our knowledge, no studies have described the impact of prematurity and related brain injuries on spontaneous fussing and crying behavior. The objective of this study was to assess prospectively crying behavior in very low birth weight (VLBW) infants with or without brain injury.
METHODS
The study population consisted of VLBW infants (birth weight 1500 g and gestational age 37 weeks at birth). Exclusion criteria were (1) infants whose caregiver was not able to follow the instructions in Finnish or in Swedish and (2) long distance to home (ie, the family’s living outside the hospital catchment area was an exclusion criterion for practical reasons). A total of 151 VLBW infants were born between January 2001 and July 2004; 22 of them died before discharge, most of them during the first week of life. Four infants were excluded (1 whose caregiver could not speak Finnish or Swedish and 3 who lived outside the hospital catchment area). A total of 125 remained eligible for the study, and all of the families decided to participate. One (0.8%) infant was lost during follow-up. Brain imaging was performed in all cases, and the parents were asked to complete a detailed diary at term, at 6 weeks, and at 5 months of corrected age.
The study is a part of a larger multidisciplinary project in which one focus is the linguistic development of VLBW infants. Therefore, a control group of healthy term infants (n = 49) from singleton, primiparous pregnancies and from native Finnish or Swedish speaking families were recruited for the prenatal diary at 5 months of age. The birth weight had to be above 2.0 SD, and no admissions to neonatal care were allowed. The control infants were examined at one year of age, and their growth, development, and physical examination (J.M.) were normal. No imaging studies were performed for the control infants.
All infants were born in Turku University Hospital. At an early stage of follow-up, the research physician (J.M.) instructed the caregiver or nurses of the VLBW infants to complete the Baby Day Diary, and the psychologist (R.K.) instructed all of the control families to complete the Baby Day Diary.14
The PIPARI (Development and Functioning in Very Low Birth Weight Infants From Infancy to School Age) Study protocol has been approved by the Ethics Review Committee of the Hospital District of the South-West Finland. All families gave in informed consent.
Serial Cranial Ultrasound Examinations
Cranial ultrasound examinations in the NICU were performed for all study infants at 3 to 5 days of age, at 7 to 10 days of age, at 1 month of age, and monthly thereafter until discharge from the hospital to detect IVH, caudothalamic cysts, cystic PVL, and striatothalamic vasculopathy. The ultrasound examinations were performed using a 7-MHz vector transducer (Sonos 5500 Hewlett-Packard, Andover, MA). The classification of IVH (grades I to IV) was done according to Papile et al.15 Only multiple cysts with typical location were classified as cystic PVL. These examinations were done as a part of the clinical service by the attending neonatologist.
The cranial ultrasound examination at term was performed by a pediatric radiologist (H.R.). IVH, PVL, porencephalic cysts, caudothalamic cysts, striatothalamic vasculopathy, and ventriculomegaly were determined. The reference values that Virkola16 introduced for VLBW infants at term were used to define ventriculomegaly. The oblique widths of the frontal horns of the lateral ventricles were measured from the coronal plane at the level of the foramen of Monro. On parasagittal views, the sagittal diameters of the trigone of the posterior horns were measured. Ventriculomegaly was defined as severe when at least 2 of the 4 horns of the lateral ventricles were dilated and as mild when 1 horn only was dilated. The cutoff measurement value for a dilated frontal horn was 2.0 mm (SD: 0.8 mm) for oblique width of the right ventricle and 2.2 mm (SD: 0.99 mm) of the left ventricle. For a posterior horn, the cutoff values were 9.9 mm (SD: 1.39 mm) for the sagittal diameter of trigone of the right ventricle and 10.2 mm (SD: 1.57 mm) of the left ventricle. The ultrasound examinations at term were performed with a 7.5-MHz sector transducer (Aloka SSD 2000, Aloka Co Ltd, Tokyo, Japan) during January 2001 to August 2002 and an 8-MHz vector transducer (General Electric Logic 9) during September 2002 to July 2004. All ultrasound examinations were archived for later reading and measurements.
MRI of the Brain
An MRI of the brain was performed at term on the same day as the ultrasound examination in 124 of 125 infants. One infant had 5 days between the ultrasound and the MRI. The imaging took place during postprandial sleep without sedation or anesthesia. The infants were swaddled to calm them and to reduce movement artifacts in the imaging. The MRI equipment was an open 0.23 Tesla Outlook GP (Philips Medical Inc, Vantaa, Finland), equipped with a multipurpose flexible coil that fit the head of the infant. The open MRI equipment permitted good visual control and easy access to the infant. Axial T2-weighted fast spin echo images with a repetition time (TR) of 9999 ms and an echo time (TE) of 200 ms were obtained. In this sequence, the flip angle was 90 degrees, the slice thickness was 6 mm, the field of view was 220 x 220 mm2, and the matrix was 256 x 256. T1-weighted FE 3-dimensional sequences with a TR of 30 ms, a TE of 10 ms, a flip angle of 45 degrees, a slice thickness of 5 mm, a field of view of 220 x 220 mm2, and the matrix of 256 x 256 were obtained in coronal plane. Coronal T2-weighted fast spin echo 3-dimensional sequences with a TR of 4000 ms, a TE of 350 ms, a flip angle of 90 degrees, a slice thickness of 5 mm, a field of view of 187 x 250 mm2, and a matrix of 192 x 256 were obtained as well. The total imaging time was 25 minutes.
A neuroradiologist (R.P.) analyzed the MRI findings according to a scoring system that was modeled after Maalouf et al.17,18 The width of the extracerebral space was classified according to McArdle et al.19 The scoring system of the MRI of the brain is described in detail in the Appendix. The neuroradiologist was blinded to the clinical information and to the result of the ultrasound examinations of the infant.
Classification of the Study Groups
The infants were categorized into the 3 groups according to the most pathologic brain imaging finding either in the ultrasound examinations or in the MRI: (1) normal group, (2) intermediate group with brain imaging findings of unclear significance, and (3) brain pathology group (Table 1). The normal group consisted of VLBW infants with normal brain anatomy and the width of extracerebral space 4 mm. The intermediate brain pathology group consisted of VLBW infants with IVH grade 1 to 2, dilation of no more than 1 horn of the 4 horns of the lateral ventricles, or caudothalamic cysts in any cranial ultrasound examination. MRI findings in the intermediate brain pathology group included the width of extracerebral space of 5 mm or caudothalamic cysts or IVH grades 1 to 2. The infants with IVH grades 3 to 4, WM cysts or ventriculomegaly with 2 to 4 horns dilated, abnormal T1 or T2 signals in cortex, basal ganglia, thalamus, cerebellum or internal capsule, hypoplasia of corpus callosum, increased width of extracerebral space (6 mm), ventriculitis or other major brain anomaly were included in the brain pathology group. A total of 123 (98%) of the 125 MRIs and all 125 cranial ultrasound examinations were performed successfully.
Brain injuries were evaluated at multiple time points using 2 imaging techniques. Early examinations screen hemorrhages that may resolve with time. Later imaging is used to screen for WM injuries for which MRI is superior to ultrasound. The subgroup division was made according to the current knowledge of the significance of various findings. Findings that are known to be related to later developmental problems formed the brain pathology group, whereas findings with unclear significance formed the intermediate brain pathology group.
Baby Day Diary
The Baby Day Diary is a validated method14 to study infant fussing and crying. Bout length and frequency both are informative in determination of excessive crying.9 The parents of preterm infants completed the Baby Day Diary at term, at 6 weeks, and at 5 months of corrected age for 3 days at each age point. A 24-hour day was divided into 5-minute sections in which the parents recorded the following mutually exclusive infant behaviors: sleeping, awake content, awake fussy, crying, and feeding. Fussing was explained to the parents as negative vocalization that is not crying. Holding the infant, moving with the infant, and taking care of the infant were recorded as the caregiver's behaviors with the infant. The parents of the term infants completed the diary at 5 months of age for 3 days.
The parents were asked to complete the diary during a normal day without acute illnesses or any vaccinations. The diary day was excluded when the infant was febrile (temperature >38°C), when the infant had received a vaccination or had had an invasive procedure the same day, or when the diary was incompletely filled in. When the infant was in the hospital when the diary was due to be filled, a nurse completed the diaries if the mother was not present.
In the analysis, both the duration and the frequency of infants' behaviors (fussing, crying, awake content, sleeping, and feeding) and caregiver behaviors (moving, holding, and caretaking) were calculated as mean per day. The 24-hour day was subdivided further into 6-hour periods (12:00 AM–6:00 AM, 6:00 AM–12:00 PM, 12:00 PM–6:00 PM, and 6:00 PM–12:00 AM).
Data Analysis
The data are given as means (SD) [minimum, maximum] or percentages. The figure in parentheses is the numerical value of 1 SD. The differences between the VLBW groups were tested using 1-way analysis of variance or Kruskal-Wallis Test for continuous variables, followed by multiple comparisons using Tukey's honestly significant difference method or Mann-Whitney U test with Bonferroni correction. Parental characteristics of term control infants were compared with VLBW infants' parental characteristics using t tests for normally distributed continuous variables. Pearson's 2 test or Fisher's exact test was used for categorical variables.
SPSS for Windows (version 12.0; SPSS, Chicago, IL) statistical package was used for analysis. The cutoff point of P < .05 was considered as statistically significant.
RESULTS
According to brain imaging, 35 of 125 VLBW infants were classified into the normal group, 48 infants into the intermediate brain pathology group, and 42 infants into the brain pathology group. The 2 infants whose MRI was not successful because of movement artifacts were classified according to ultrasound examinations: 1 of them into the normal group and the other into the brain pathology group because of ventriculomegaly. In addition, there were 49 term infants in the control group.
The Baby Day Diaries were completed and returned at term by 117 (94%) of 125 families of the VLBW infants, at 6 weeks of corrected age by 121 (97%) families, and at 5 months of corrected age by 117 (94%) families. All 49 families of the control infants completed and returned the diaries. There were 2 infants with no diaries: 1 infant in the normal group and the other infant in the brain pathology group. A total of 123 infants with at least 1 complete diary remained in the study. The final group sizes in the analyses were 34 VLBW infants in the normal group, 48 VLBW infants in the intermediate brain pathology group, and 41 infants in the brain pathology group.
Eleven (9%) of the diaries were completed in the hospital at term, 1 at 6 weeks of age, and 1 at 5 months of age. A total of 16 (1.5%) of the 1065 completed and returned diary days were excluded from the analysis because of a febrile illness (n = 12) or a vaccination day (n = 4). In addition, 7 (0.7%) diary days were omitted because the caregiver failed to complete any 1 of the 3 diary days. The days analyzed were described by the parents as "normal days for the infant." The corrected age at the beginning of the first diary day was 0.6 days (SD: 4.1) at term, 46 days (SD: 6.1) at 6 weeks, and 154 days (SD: 8.5) at 5 months. For the control infants, the diaries were completed within 1 week of the age of 5 months.
The VLBW infants in the brain pathology group were more immature, had lower birth weight, and had more neonatal morbidity compared with the VLBW infants in the intermediate brain pathology group and in the normal group. In the normal group, 75% of infants were female, whereas approximate 40% were female in the intermediate brain pathology group and in the brain pathology group. There were no significant differences in the proportion of infants who were small for gestational age, in the percentage of cesarean sections, in maternal age, or in the level of parental education between the groups of VLBW infants. The fathers of the term control infants had more years of education compared with the parents of VLBW infants (Table 2). The preterm infants who met the selection criteria of the control infants (singletons, first borns, and Finnish- or Swedish-speaking families) had similar background data as the term control infants (age of the mother: 28.8 vs 28.5; maternal education >12 years: 73.3% vs 72.2%; paternal education >12 years: 43.3% vs 41.7%; nuclear family: 93.3% vs 94.4%, in preterm and control group, respectively).
Daily Fussing and Crying Measures
In VLBW infants at term, the duration of combined fussing and crying was significantly higher in the intermediate brain pathology group compared with the normal group (P = .017). There were no other differences in total daily duration of fussing and crying between the groups (Table 3). The daily duration of fussing and crying decreased with increasing age in all study groups.
When fussing was explored alone, the duration was significantly higher (P = .020) in the intermediate brain pathology group compared with the normal group at term. When crying was explored alone, there were no differences in the daily duration of crying among the VLBW groups (Table 3).
When the frequency of fussing and crying bouts was compared among the VLBW groups, there were no differences at any age points. The number of bouts increased from term to 6 weeks of age and then decreased to the 5 months of age in a similar way in all of the VLBW groups. There were no differences when fussing and crying were explored separately.
When all VLBW infants were compared with the term control infants, there was no difference in the combined duration of fussing and crying or, separately, crying or fussing alone at 5 months of age. However, the number of combined fussing and crying bouts and fussing bouts, separately, was higher (P = .009 and P = .006, respectively) in VLBW infants compared with term control infants (Table 4). When the bout frequency was compared among all 4 study groups, the number of combined fussing and crying bouts did differ (P = .033, analysis of variance). In pair-wise comparisons, the only significant difference was found between the brain pathology group and control infants (P = .003; Table 4). Because the term control infants were singletons and first borns, we made additional analyses using singleton and first-born status as covariants. In these additional analyses, the results remained unchanged between VLBW infants and term control infants at 5 months of corrected age.
The duration of fussing and crying was explored according to the quartiles of a day (Fig 1). The emerging circadian rhythm was seen over the time period in all groups of VLBW infants. No consistent differences were found among the groups.
At term, VLBW infants who were still in the hospital (n = 11) cried significantly more (79 minutes vs 39 minutes; P = .003) than the infants at home (n = 106). However, there was no difference in the combined duration of fussing and crying or in the duration of fussing (data not shown).
Daily Holding
At term, the VLBW infants in the brain pathology group were held significantly more (P = .009) compared with the other VLBW groups. The difference (P = .012) persisted even when the hospitalized VLBW infants were excluded. Although the infants in the brain pathology group were held most at each time point, the difference was statistically significant at 5 months but not at 6 weeks of corrected age. No other differences were found in parental behavior (moving with the infant or taking care of the infant) among the VLBW infants. When all VLBW infants were compared with the control group, the VLBW infants were held significantly more than term infants. In contrast, the VLBW infants were moved (in a stroller or in a car) less (P < .001) compared with the term control infants at 5 months of age (Table 3).
Missing Data
The total duration of missing data (minute of "do not remember" in the diary) did not differ among the VLBW groups. There were no differences in total duration of missing data (minutes) among all VLBW infants and term control infants. When all hospitalized (n = 11) VLBW infants were compared with VLBW infants at home at term, the missing data were significantly higher in the hospitalized group than in the nonhospitalized group (45 [55; 0, 157] vs 6.3 [14; 0, 78]; P < .001). There were no differences in missing data at 6 weeks or at 5 months of corrected age between the hospitalized and nonhospitalized groups (Table 3).
DISCUSSION
This study describes the total duration of fussing and crying, frequencies of fussing and crying bouts, and parental holding among VLBW infants with or without early brain damage. The main finding was that severe structural brain injuries in preterm infants did not affect the amount (either duration or frequency) of fussing and crying; neither did severe brain injuries affect the development of circadian rhythm. Prematurity itself did not increase the total duration of fussing or crying when compared with term control infants. However, the frequency of fussing bouts but not crying bouts was higher in preterm infants.
To our knowledge, this is the first study to assess systematically spontaneous fussing and crying behavior in very preterm infants with brain injuries. Our finding is in contrast to an earlier result whereby the preterm infants were shown to be more irritable than term infants in test situations.12 To explain the discrepancy, we analyzed the amount of holding, which may be used as an intervention to prevent distress behavior. Some studies have suggested that holding20 and rapid maternal responsiveness4 reduce the amount of crying. Our study showed that the amount of holding was not higher in infants with brain injury compared with those without brain injury except at term. Therefore, it is not likely that holding was masking a persistent difference in crying behavior related to brain injury.
Preterm infants were held more than term infants. Although it has not been shown consistently that holding reduces the amount of crying, there is a possibility that increased holding may mask the tendency of preterm infants to cry more compared with term infants. The more frequent fussing bouts that are found in preterm infants may indicate an increased reactivity to internal or external stimuli in preterm infants compared with term infants. If holding helps an infant to regulate his or her behavioral states, then the bout length remains short and the total duration of crying does not increase. The potential difference in reactivity may originate from differences in the brain function as a result of immaturity. However, this is not supported as our finding was that structural brain injuries do not have a consistent effect on reactivity (bout frequency). The alternative explanation may be that more frequent parental intervening with, for example, holding results in far more fragmented fussing behavior in preterm infants.
The development of the circadian rhythm was seen so that crying was evenly distributed around the day at term, but the amount of crying was lower during nighttime compared with daytime at 6 weeks and 5 months of age in all VLBW groups. These trajectories reflect the development of circadian rhythm at the same corrected age as in term infants.21,22 These data are consistent with an earlier report showing clustering of crying in the evening hours in healthy preterm infants at 6 weeks of age.5 Sleeping time concentrated in the night hours as age increased (data not shown).
The diary that was used in this study has been shown to be reliable in estimating spontaneous crying behavior.14 The diary data were collected from 3 time points over a 5-month period, making it possible to explore developmental trends. At each time point, a recording for 3 subsequent days was used to minimize day-to-day variability in the behavior. The completion and return rate of the diaries was high. The proportion of missing data was small, ranging from 0.2% to 0.9% of the total minutes of a day.
CONCLUSIONS
It is a comforting message for the parents of preterm infants that the infants will not have major differences in their crying behavior or development of circadian rhythm even if they have abnormal findings in brain imaging. However, minor differences were found, including more fussing at term in infants with intermediate brain pathology and more frequent fussing in very preterm infants compared with term infants at 5 months of corrected age. It also seems that prematurity and brain pathology increase caregiving activity in the form of holding.
APPENDIX: SCORING OF THE BRAIN MRI AT TERM IN THE PIPARI
Name
ACKNOWLEDGMENTS
This study was supported by grants from The Lea and Arvo Ylpp? Foundation and The South-Western Finnish Foundation of Neonatal Research.
The PIPARI Study Group includes Satu Ekblad, RN, Eeva Ekholm, MD, Leena Haataja, MD, Pentti Kero, MD, Jarkko Kirjavainen, MD, Riikka Korja, Psych Lic, Harry Kujari, MD, Helena Lapinleimu MD, Liisa Lehtonen, MD, Hanna Manninen, MD, Jaakko Matom?ki, BSc (statistics student), Jonna Maunu, MD, Petriina Munck, MA, Pekka Niemi, PhD, Pertti Palo, MD, Riitta Parkkola, MD, Jorma Piha, MD, Annika Pihlgren, MA, Liisi Rautava, medical student, P?ivi Rautava, MD, Milla Reiman, medical student, Hellevi Rikalainen, MD, Taija Saanisto, MSc (statistician), Katriina Saarinen, physiotherapist, Elina Savonlahti, MD, Matti Sillanp??, MD, Suvi Stolt, Phil Lic, P?ivi Tuomikoski-Koiranen, RN, and Tuula ??rimaa, MD.
FOOTNOTES
Accepted Jan 6, 2006.
Address correspondence to Jonna Maunu, MD, Turku University Central Hospital, Pediatric Research Unit, V?h?-H?meenkatu 1 A 3, 20500 Turku, Finland. E-mail: jonna.maunu@utu.fi
The authors have indicated they have no financial relationships relevant to this article to disclose.
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a Department of Pediatric Neurology, Turku University Hospital, Turku, Finland
b Department of Pediatric Neurology, Central Hospital of Central Finland, Jyv?skyl?, Finland
c Department of Child Psychiatry, Turku University Hospital, Turku, Finland
d Department of Radiology, Turku University Hospital, Turku, Finland
e Department of Pediatrics, Turku University Hospital, Turku, Finland(Jonna Maunu, MDa, Jarkko )
OBJECTIVES. The objective of this study was to assess crying behavior during infancy in very preterm infants with or without brain injury.
METHODS. A total of 125 very low birth weight infants survived during January 2001 to July 2004 in Turku University Hospital, Finland. They were categorized according to the most pathologic brain finding either in ultrasound or MRI. Baby Day Diary was used to assess crying behavior at term, 6 weeks, and 5 months of corrected age. The behavior of a group of term control infants (n = 49) was assessed at 5 months.
RESULTS. Severe brain injuries in very low birth weight infants did not affect the duration of fussing or crying. In very low birth weight infants, brain injuries did not affect the frequency of fussing or crying bouts or the development of circadian rhythm in crying behavior. At 5 months of corrected age, fussing bouts were more frequent in very low birth weight infants compared with term control infants (6.4 per day vs 4.5 per day), and very low birth weight infants were held more (169 minutes [97] vs 130 minutes [69], respectively).
CONCLUSIONS. This prospective study using a validated cry diary showed that brain injuries that are related to prematurity do not have major effects on crying behavior or development of circadian rhythm. Prematurity does not increase the duration but increases the frequency of fussing and crying at 5 months of corrected age compared with term control infants. It also seems that prematurity and brain pathology may increase caregiving activity in the form of holding.
Key Words: preterm ? VLBW ? MRI ? ultrasound ? fussing ? crying ? behavior ? diary ? follow-up ? brain injury
Abbreviations: IVH—intraventricular hemorrhage ? WM—white matter ? PVL—periventricular leukomalacia ? VLBW—very low birth weight ? TR—repetition time ? TE—echo time
The crying pattern of healthy term infants is characterized by an increase in the amount of crying during the first month of life and clustering of crying in the evening hours.1–4 Healthy preterm infants seem to have the similar crying pattern with maximum amount of crying at 6 weeks of corrected age.5 In healthy term infants, excessive crying during the first 3 months of life has not been shown to correlate to later behavioral or developmental problems.6,7 It has been suggested that an increased amount of crying is attributable to transient individual differences in the ability to regulate behavioral distress state.8,9 However, persistent crying problems that last beyond 3 months of life have been shown to correlate to later sleeping and feeding problems10; to cognitive problems7; and to hyperactivity, other behavioral problems, or academic difficulties at school age.7,11
To our knowledge, spontaneous crying of preterm infants has been examined only in 1 study,5 which excluded all infants with brain injury, such as intraventricular hemorrhage (IVH). Other studies of crying behavior in preterm infants have focused on crying behavior in a test situation. Wolf et al12 showed that preterm infants compared with term infants were more irritable in neurobehavioral assessment situations at different age points between the due date and 6 months. In this study, infants with brain hemorrhages (grades 3–4) were excluded.
Very little is known of the effect of early brain injuries on later fussing and crying behavior of preterm infants. The most common brain injuries include IVH and white matter (WM) injuries, such as periventricular leukomalacia (PVL) and ventriculomegaly. The incidence of these findings correlates inversely to gestational age. The impact of brain injuries on pain reaction was studied by Oberlander et al,13 who assessed the pain reaction to heel stick in very preterm infants with and without brain injuries. In their study, no differences were found in crying response to heel stick or heel squeezing.
To our knowledge, no studies have described the impact of prematurity and related brain injuries on spontaneous fussing and crying behavior. The objective of this study was to assess prospectively crying behavior in very low birth weight (VLBW) infants with or without brain injury.
METHODS
The study population consisted of VLBW infants (birth weight 1500 g and gestational age 37 weeks at birth). Exclusion criteria were (1) infants whose caregiver was not able to follow the instructions in Finnish or in Swedish and (2) long distance to home (ie, the family’s living outside the hospital catchment area was an exclusion criterion for practical reasons). A total of 151 VLBW infants were born between January 2001 and July 2004; 22 of them died before discharge, most of them during the first week of life. Four infants were excluded (1 whose caregiver could not speak Finnish or Swedish and 3 who lived outside the hospital catchment area). A total of 125 remained eligible for the study, and all of the families decided to participate. One (0.8%) infant was lost during follow-up. Brain imaging was performed in all cases, and the parents were asked to complete a detailed diary at term, at 6 weeks, and at 5 months of corrected age.
The study is a part of a larger multidisciplinary project in which one focus is the linguistic development of VLBW infants. Therefore, a control group of healthy term infants (n = 49) from singleton, primiparous pregnancies and from native Finnish or Swedish speaking families were recruited for the prenatal diary at 5 months of age. The birth weight had to be above 2.0 SD, and no admissions to neonatal care were allowed. The control infants were examined at one year of age, and their growth, development, and physical examination (J.M.) were normal. No imaging studies were performed for the control infants.
All infants were born in Turku University Hospital. At an early stage of follow-up, the research physician (J.M.) instructed the caregiver or nurses of the VLBW infants to complete the Baby Day Diary, and the psychologist (R.K.) instructed all of the control families to complete the Baby Day Diary.14
The PIPARI (Development and Functioning in Very Low Birth Weight Infants From Infancy to School Age) Study protocol has been approved by the Ethics Review Committee of the Hospital District of the South-West Finland. All families gave in informed consent.
Serial Cranial Ultrasound Examinations
Cranial ultrasound examinations in the NICU were performed for all study infants at 3 to 5 days of age, at 7 to 10 days of age, at 1 month of age, and monthly thereafter until discharge from the hospital to detect IVH, caudothalamic cysts, cystic PVL, and striatothalamic vasculopathy. The ultrasound examinations were performed using a 7-MHz vector transducer (Sonos 5500 Hewlett-Packard, Andover, MA). The classification of IVH (grades I to IV) was done according to Papile et al.15 Only multiple cysts with typical location were classified as cystic PVL. These examinations were done as a part of the clinical service by the attending neonatologist.
The cranial ultrasound examination at term was performed by a pediatric radiologist (H.R.). IVH, PVL, porencephalic cysts, caudothalamic cysts, striatothalamic vasculopathy, and ventriculomegaly were determined. The reference values that Virkola16 introduced for VLBW infants at term were used to define ventriculomegaly. The oblique widths of the frontal horns of the lateral ventricles were measured from the coronal plane at the level of the foramen of Monro. On parasagittal views, the sagittal diameters of the trigone of the posterior horns were measured. Ventriculomegaly was defined as severe when at least 2 of the 4 horns of the lateral ventricles were dilated and as mild when 1 horn only was dilated. The cutoff measurement value for a dilated frontal horn was 2.0 mm (SD: 0.8 mm) for oblique width of the right ventricle and 2.2 mm (SD: 0.99 mm) of the left ventricle. For a posterior horn, the cutoff values were 9.9 mm (SD: 1.39 mm) for the sagittal diameter of trigone of the right ventricle and 10.2 mm (SD: 1.57 mm) of the left ventricle. The ultrasound examinations at term were performed with a 7.5-MHz sector transducer (Aloka SSD 2000, Aloka Co Ltd, Tokyo, Japan) during January 2001 to August 2002 and an 8-MHz vector transducer (General Electric Logic 9) during September 2002 to July 2004. All ultrasound examinations were archived for later reading and measurements.
MRI of the Brain
An MRI of the brain was performed at term on the same day as the ultrasound examination in 124 of 125 infants. One infant had 5 days between the ultrasound and the MRI. The imaging took place during postprandial sleep without sedation or anesthesia. The infants were swaddled to calm them and to reduce movement artifacts in the imaging. The MRI equipment was an open 0.23 Tesla Outlook GP (Philips Medical Inc, Vantaa, Finland), equipped with a multipurpose flexible coil that fit the head of the infant. The open MRI equipment permitted good visual control and easy access to the infant. Axial T2-weighted fast spin echo images with a repetition time (TR) of 9999 ms and an echo time (TE) of 200 ms were obtained. In this sequence, the flip angle was 90 degrees, the slice thickness was 6 mm, the field of view was 220 x 220 mm2, and the matrix was 256 x 256. T1-weighted FE 3-dimensional sequences with a TR of 30 ms, a TE of 10 ms, a flip angle of 45 degrees, a slice thickness of 5 mm, a field of view of 220 x 220 mm2, and the matrix of 256 x 256 were obtained in coronal plane. Coronal T2-weighted fast spin echo 3-dimensional sequences with a TR of 4000 ms, a TE of 350 ms, a flip angle of 90 degrees, a slice thickness of 5 mm, a field of view of 187 x 250 mm2, and a matrix of 192 x 256 were obtained as well. The total imaging time was 25 minutes.
A neuroradiologist (R.P.) analyzed the MRI findings according to a scoring system that was modeled after Maalouf et al.17,18 The width of the extracerebral space was classified according to McArdle et al.19 The scoring system of the MRI of the brain is described in detail in the Appendix. The neuroradiologist was blinded to the clinical information and to the result of the ultrasound examinations of the infant.
Classification of the Study Groups
The infants were categorized into the 3 groups according to the most pathologic brain imaging finding either in the ultrasound examinations or in the MRI: (1) normal group, (2) intermediate group with brain imaging findings of unclear significance, and (3) brain pathology group (Table 1). The normal group consisted of VLBW infants with normal brain anatomy and the width of extracerebral space 4 mm. The intermediate brain pathology group consisted of VLBW infants with IVH grade 1 to 2, dilation of no more than 1 horn of the 4 horns of the lateral ventricles, or caudothalamic cysts in any cranial ultrasound examination. MRI findings in the intermediate brain pathology group included the width of extracerebral space of 5 mm or caudothalamic cysts or IVH grades 1 to 2. The infants with IVH grades 3 to 4, WM cysts or ventriculomegaly with 2 to 4 horns dilated, abnormal T1 or T2 signals in cortex, basal ganglia, thalamus, cerebellum or internal capsule, hypoplasia of corpus callosum, increased width of extracerebral space (6 mm), ventriculitis or other major brain anomaly were included in the brain pathology group. A total of 123 (98%) of the 125 MRIs and all 125 cranial ultrasound examinations were performed successfully.
Brain injuries were evaluated at multiple time points using 2 imaging techniques. Early examinations screen hemorrhages that may resolve with time. Later imaging is used to screen for WM injuries for which MRI is superior to ultrasound. The subgroup division was made according to the current knowledge of the significance of various findings. Findings that are known to be related to later developmental problems formed the brain pathology group, whereas findings with unclear significance formed the intermediate brain pathology group.
Baby Day Diary
The Baby Day Diary is a validated method14 to study infant fussing and crying. Bout length and frequency both are informative in determination of excessive crying.9 The parents of preterm infants completed the Baby Day Diary at term, at 6 weeks, and at 5 months of corrected age for 3 days at each age point. A 24-hour day was divided into 5-minute sections in which the parents recorded the following mutually exclusive infant behaviors: sleeping, awake content, awake fussy, crying, and feeding. Fussing was explained to the parents as negative vocalization that is not crying. Holding the infant, moving with the infant, and taking care of the infant were recorded as the caregiver's behaviors with the infant. The parents of the term infants completed the diary at 5 months of age for 3 days.
The parents were asked to complete the diary during a normal day without acute illnesses or any vaccinations. The diary day was excluded when the infant was febrile (temperature >38°C), when the infant had received a vaccination or had had an invasive procedure the same day, or when the diary was incompletely filled in. When the infant was in the hospital when the diary was due to be filled, a nurse completed the diaries if the mother was not present.
In the analysis, both the duration and the frequency of infants' behaviors (fussing, crying, awake content, sleeping, and feeding) and caregiver behaviors (moving, holding, and caretaking) were calculated as mean per day. The 24-hour day was subdivided further into 6-hour periods (12:00 AM–6:00 AM, 6:00 AM–12:00 PM, 12:00 PM–6:00 PM, and 6:00 PM–12:00 AM).
Data Analysis
The data are given as means (SD) [minimum, maximum] or percentages. The figure in parentheses is the numerical value of 1 SD. The differences between the VLBW groups were tested using 1-way analysis of variance or Kruskal-Wallis Test for continuous variables, followed by multiple comparisons using Tukey's honestly significant difference method or Mann-Whitney U test with Bonferroni correction. Parental characteristics of term control infants were compared with VLBW infants' parental characteristics using t tests for normally distributed continuous variables. Pearson's 2 test or Fisher's exact test was used for categorical variables.
SPSS for Windows (version 12.0; SPSS, Chicago, IL) statistical package was used for analysis. The cutoff point of P < .05 was considered as statistically significant.
RESULTS
According to brain imaging, 35 of 125 VLBW infants were classified into the normal group, 48 infants into the intermediate brain pathology group, and 42 infants into the brain pathology group. The 2 infants whose MRI was not successful because of movement artifacts were classified according to ultrasound examinations: 1 of them into the normal group and the other into the brain pathology group because of ventriculomegaly. In addition, there were 49 term infants in the control group.
The Baby Day Diaries were completed and returned at term by 117 (94%) of 125 families of the VLBW infants, at 6 weeks of corrected age by 121 (97%) families, and at 5 months of corrected age by 117 (94%) families. All 49 families of the control infants completed and returned the diaries. There were 2 infants with no diaries: 1 infant in the normal group and the other infant in the brain pathology group. A total of 123 infants with at least 1 complete diary remained in the study. The final group sizes in the analyses were 34 VLBW infants in the normal group, 48 VLBW infants in the intermediate brain pathology group, and 41 infants in the brain pathology group.
Eleven (9%) of the diaries were completed in the hospital at term, 1 at 6 weeks of age, and 1 at 5 months of age. A total of 16 (1.5%) of the 1065 completed and returned diary days were excluded from the analysis because of a febrile illness (n = 12) or a vaccination day (n = 4). In addition, 7 (0.7%) diary days were omitted because the caregiver failed to complete any 1 of the 3 diary days. The days analyzed were described by the parents as "normal days for the infant." The corrected age at the beginning of the first diary day was 0.6 days (SD: 4.1) at term, 46 days (SD: 6.1) at 6 weeks, and 154 days (SD: 8.5) at 5 months. For the control infants, the diaries were completed within 1 week of the age of 5 months.
The VLBW infants in the brain pathology group were more immature, had lower birth weight, and had more neonatal morbidity compared with the VLBW infants in the intermediate brain pathology group and in the normal group. In the normal group, 75% of infants were female, whereas approximate 40% were female in the intermediate brain pathology group and in the brain pathology group. There were no significant differences in the proportion of infants who were small for gestational age, in the percentage of cesarean sections, in maternal age, or in the level of parental education between the groups of VLBW infants. The fathers of the term control infants had more years of education compared with the parents of VLBW infants (Table 2). The preterm infants who met the selection criteria of the control infants (singletons, first borns, and Finnish- or Swedish-speaking families) had similar background data as the term control infants (age of the mother: 28.8 vs 28.5; maternal education >12 years: 73.3% vs 72.2%; paternal education >12 years: 43.3% vs 41.7%; nuclear family: 93.3% vs 94.4%, in preterm and control group, respectively).
Daily Fussing and Crying Measures
In VLBW infants at term, the duration of combined fussing and crying was significantly higher in the intermediate brain pathology group compared with the normal group (P = .017). There were no other differences in total daily duration of fussing and crying between the groups (Table 3). The daily duration of fussing and crying decreased with increasing age in all study groups.
When fussing was explored alone, the duration was significantly higher (P = .020) in the intermediate brain pathology group compared with the normal group at term. When crying was explored alone, there were no differences in the daily duration of crying among the VLBW groups (Table 3).
When the frequency of fussing and crying bouts was compared among the VLBW groups, there were no differences at any age points. The number of bouts increased from term to 6 weeks of age and then decreased to the 5 months of age in a similar way in all of the VLBW groups. There were no differences when fussing and crying were explored separately.
When all VLBW infants were compared with the term control infants, there was no difference in the combined duration of fussing and crying or, separately, crying or fussing alone at 5 months of age. However, the number of combined fussing and crying bouts and fussing bouts, separately, was higher (P = .009 and P = .006, respectively) in VLBW infants compared with term control infants (Table 4). When the bout frequency was compared among all 4 study groups, the number of combined fussing and crying bouts did differ (P = .033, analysis of variance). In pair-wise comparisons, the only significant difference was found between the brain pathology group and control infants (P = .003; Table 4). Because the term control infants were singletons and first borns, we made additional analyses using singleton and first-born status as covariants. In these additional analyses, the results remained unchanged between VLBW infants and term control infants at 5 months of corrected age.
The duration of fussing and crying was explored according to the quartiles of a day (Fig 1). The emerging circadian rhythm was seen over the time period in all groups of VLBW infants. No consistent differences were found among the groups.
At term, VLBW infants who were still in the hospital (n = 11) cried significantly more (79 minutes vs 39 minutes; P = .003) than the infants at home (n = 106). However, there was no difference in the combined duration of fussing and crying or in the duration of fussing (data not shown).
Daily Holding
At term, the VLBW infants in the brain pathology group were held significantly more (P = .009) compared with the other VLBW groups. The difference (P = .012) persisted even when the hospitalized VLBW infants were excluded. Although the infants in the brain pathology group were held most at each time point, the difference was statistically significant at 5 months but not at 6 weeks of corrected age. No other differences were found in parental behavior (moving with the infant or taking care of the infant) among the VLBW infants. When all VLBW infants were compared with the control group, the VLBW infants were held significantly more than term infants. In contrast, the VLBW infants were moved (in a stroller or in a car) less (P < .001) compared with the term control infants at 5 months of age (Table 3).
Missing Data
The total duration of missing data (minute of "do not remember" in the diary) did not differ among the VLBW groups. There were no differences in total duration of missing data (minutes) among all VLBW infants and term control infants. When all hospitalized (n = 11) VLBW infants were compared with VLBW infants at home at term, the missing data were significantly higher in the hospitalized group than in the nonhospitalized group (45 [55; 0, 157] vs 6.3 [14; 0, 78]; P < .001). There were no differences in missing data at 6 weeks or at 5 months of corrected age between the hospitalized and nonhospitalized groups (Table 3).
DISCUSSION
This study describes the total duration of fussing and crying, frequencies of fussing and crying bouts, and parental holding among VLBW infants with or without early brain damage. The main finding was that severe structural brain injuries in preterm infants did not affect the amount (either duration or frequency) of fussing and crying; neither did severe brain injuries affect the development of circadian rhythm. Prematurity itself did not increase the total duration of fussing or crying when compared with term control infants. However, the frequency of fussing bouts but not crying bouts was higher in preterm infants.
To our knowledge, this is the first study to assess systematically spontaneous fussing and crying behavior in very preterm infants with brain injuries. Our finding is in contrast to an earlier result whereby the preterm infants were shown to be more irritable than term infants in test situations.12 To explain the discrepancy, we analyzed the amount of holding, which may be used as an intervention to prevent distress behavior. Some studies have suggested that holding20 and rapid maternal responsiveness4 reduce the amount of crying. Our study showed that the amount of holding was not higher in infants with brain injury compared with those without brain injury except at term. Therefore, it is not likely that holding was masking a persistent difference in crying behavior related to brain injury.
Preterm infants were held more than term infants. Although it has not been shown consistently that holding reduces the amount of crying, there is a possibility that increased holding may mask the tendency of preterm infants to cry more compared with term infants. The more frequent fussing bouts that are found in preterm infants may indicate an increased reactivity to internal or external stimuli in preterm infants compared with term infants. If holding helps an infant to regulate his or her behavioral states, then the bout length remains short and the total duration of crying does not increase. The potential difference in reactivity may originate from differences in the brain function as a result of immaturity. However, this is not supported as our finding was that structural brain injuries do not have a consistent effect on reactivity (bout frequency). The alternative explanation may be that more frequent parental intervening with, for example, holding results in far more fragmented fussing behavior in preterm infants.
The development of the circadian rhythm was seen so that crying was evenly distributed around the day at term, but the amount of crying was lower during nighttime compared with daytime at 6 weeks and 5 months of age in all VLBW groups. These trajectories reflect the development of circadian rhythm at the same corrected age as in term infants.21,22 These data are consistent with an earlier report showing clustering of crying in the evening hours in healthy preterm infants at 6 weeks of age.5 Sleeping time concentrated in the night hours as age increased (data not shown).
The diary that was used in this study has been shown to be reliable in estimating spontaneous crying behavior.14 The diary data were collected from 3 time points over a 5-month period, making it possible to explore developmental trends. At each time point, a recording for 3 subsequent days was used to minimize day-to-day variability in the behavior. The completion and return rate of the diaries was high. The proportion of missing data was small, ranging from 0.2% to 0.9% of the total minutes of a day.
CONCLUSIONS
It is a comforting message for the parents of preterm infants that the infants will not have major differences in their crying behavior or development of circadian rhythm even if they have abnormal findings in brain imaging. However, minor differences were found, including more fussing at term in infants with intermediate brain pathology and more frequent fussing in very preterm infants compared with term infants at 5 months of corrected age. It also seems that prematurity and brain pathology increase caregiving activity in the form of holding.
APPENDIX: SCORING OF THE BRAIN MRI AT TERM IN THE PIPARI
Name
ACKNOWLEDGMENTS
This study was supported by grants from The Lea and Arvo Ylpp? Foundation and The South-Western Finnish Foundation of Neonatal Research.
The PIPARI Study Group includes Satu Ekblad, RN, Eeva Ekholm, MD, Leena Haataja, MD, Pentti Kero, MD, Jarkko Kirjavainen, MD, Riikka Korja, Psych Lic, Harry Kujari, MD, Helena Lapinleimu MD, Liisa Lehtonen, MD, Hanna Manninen, MD, Jaakko Matom?ki, BSc (statistics student), Jonna Maunu, MD, Petriina Munck, MA, Pekka Niemi, PhD, Pertti Palo, MD, Riitta Parkkola, MD, Jorma Piha, MD, Annika Pihlgren, MA, Liisi Rautava, medical student, P?ivi Rautava, MD, Milla Reiman, medical student, Hellevi Rikalainen, MD, Taija Saanisto, MSc (statistician), Katriina Saarinen, physiotherapist, Elina Savonlahti, MD, Matti Sillanp??, MD, Suvi Stolt, Phil Lic, P?ivi Tuomikoski-Koiranen, RN, and Tuula ??rimaa, MD.
FOOTNOTES
Accepted Jan 6, 2006.
Address correspondence to Jonna Maunu, MD, Turku University Central Hospital, Pediatric Research Unit, V?h?-H?meenkatu 1 A 3, 20500 Turku, Finland. E-mail: jonna.maunu@utu.fi
The authors have indicated they have no financial relationships relevant to this article to disclose.
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a Department of Pediatric Neurology, Turku University Hospital, Turku, Finland
b Department of Pediatric Neurology, Central Hospital of Central Finland, Jyv?skyl?, Finland
c Department of Child Psychiatry, Turku University Hospital, Turku, Finland
d Department of Radiology, Turku University Hospital, Turku, Finland
e Department of Pediatrics, Turku University Hospital, Turku, Finland(Jonna Maunu, MDa, Jarkko )