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ARTICLE

Relation of Prematurity and Brain Injury to Crying

Behavior in Infancy

Jonna Maunu, MDa, Jarkko Kirjavainen, MDb, Riikka Korja, Psych Licc, Riitta Parkkola, MDd, Hellevi Rikalainen, MDd, Helena Lapinleimu, MDe, Leena Haataja, MDa, Liisa Lehtonen, MDe, and the PIPARI Study Group

aDepartment of Pediatric Neurology, Turku University Hospital, Turku, Finland;bDepartment of Pediatric Neurology, Central Hospital of Central Finland, Jyväskylä, Finland;

cDepartment of Child Psychiatry, Turku University Hospital, Turku, Finland;dDepartment of Radiology, Turku University Hospital, Turku, Finland;eDepartment of

Pediatrics, Turku University Hospital, Turku, Finland

The authors have indicated they have no financial relationships relevant to this article to disclose.

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 accord-ing to the most pathologic brain findaccord-ing 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.

www.pediatrics.org/cgi/doi/10.1542/ peds.2005-1333

doi:10.1542/peds.2005-1333

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

Accepted for publication Jan 6, 2006 Address correspondence to Jonna Maunu, MD, Turku University Central Hospital, Pediatric Research Unit, Va¨ha¨-Ha¨meenkatu 1 A 3, 20500 Turku, Finland. E-mail: jonna. maunu@utu.fi

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T

HE CRYING PATTERNof healthy term infants is char-acterized 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.5In healthy term

infants, excessive crying during the first 3 months of life has not been shown to correlate to later behavioral or

developmental problems.6,7It has been suggested that an

increased amount of crying is attributable to transient individual differences in the ability to regulate

behav-ioral distress state.8,9 However, persistent crying

prob-lems 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

behav-ioral problems, or academic difficulties at school age.7,11

To our knowledge, spontaneous crying of preterm

infants has been examined only in 1 study,5which

ex-cluded all infants with brain injury, such as intraventric-ular 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 neu-robehavioral assessment situations at different age points between the due date and 6 months. In this study, infants with brain hemorrhages (grades 3– 4) were ex-cluded.

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 leukoma-lacia (PVL) and ventriculomegaly. The incidence of these findings correlates inversely to gestational age. The im-pact of brain injuries on pain reaction was studied by

Oberlander et al,13who 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

weightⱕ1500 g and gestational ageⱕ37 weeks at birth).

Exclusion criteria were (1) infants whose caregiver was not able to follow the instructions in Finnish or in Swed-ish 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

preg-nancies 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 aboveⱕ2.0

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 examina-tion (J.M.) were normal. No imaging studies were per-formed 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 per-formed 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 there-after until discharge from the hospital to detect IVH, caudothalamic cysts, cystic PVL, and striatothalamic vas-culopathy. The ultrasound examinations were per-formed 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 per-formed by a pediatric radiologist (H.R.). IVH, PVL, porencephalic cysts, caudothalamic cysts, striatothalamic vasculopathy, and ventriculomegaly were determined.

The reference values that Virkola16introduced for VLBW

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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 trans-ducer (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 Sep-tember 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 swad-dled 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

⫻ 220 mm2, and the matrix was 256256.

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 ⫻220 mm2,

and the matrix of 256⫻256 were obtained in coronal

plane. Coronal T2-weighted fast spin echo 3-dimen-sional 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⫻250 mm2, and a matrix of 192

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.17,18The 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 find-ings 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 spaceⱕ4 mm. The intermediate brain

pa-thology 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 cra-nial ultrasound examination. MRI findings in the inter-mediate 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, thal-amus, cerebellum or internal capsule, hypoplasia of

cor-pus callosum, increased width of extracerebral space (ⱖ6

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

TABLE 1 Findings on the Brain Ultrasound and MRI of VLBW Infants VLBW Infants

Normal Group

Intermediate Brain Pathology Group

Brain Pathology

Group

Ultrasound n⫽34 n⫽48 n⫽41

No IVH 34 (100) 36 (75.0) 20 (48.8)

IVH grades 1–2 0 15 (31.3) 12 (29.3)

IVH grades 3–4 0 0 10 (24.4)

PVL cysts 0 0 2 (4.9)

Caudothalamic cysts 0 14 (29.2) 8 (19.5)

Striatothalamic vasculopathy 0 0 1 (2.4)

Ventriculomegalya

1 dilated horn 0 20 (41.7) 4 (9.8)

2 to 4 dilated horns 0 0 34 (83.0)

MRI n⫽33 n⫽48 n⫽40

Normal 33 (100) 21 (44.0) 8 (20.0)

Caudothalamic cysts 0 15 (31.3) 6 (15.0)

WM injuryb 0 0 13 (32.5)

Capsula interna injury 0 0 15 (37.5)

Thalamus injury 0 0 0

Cortical injury 0 0 2 (5.0)

Corpus callosum hypoplasia 0 0 3 (7.5)

Cerebellum hypoplasia 0 0 2 (5.0)

Ventriculitis 0 0 9 (22.5)

Width of extracerebral space

⬍5 mm 33 (100) 42 (87.5) 35 (85.4)

5 mm 0 6 (12.5) 2 (4.9)

⬎5 mm 0 0 3 (7.3)

One infant may have several findings. The classification into study groups was done according to the worst finding in any examination. The number (%) of patients for each finding is pre-sented according to the study groups. Brain ultrasound examination was performed success-fully on all study patients, and MRI was performed successsuccess-fully on 121 of 123 patients. aCriteria for dilation was derived from Virkola.16

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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 pa-thology group, whereas findings with unclear signifi-cance 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

cry-ing.9The 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 behav-iors: sleeping, awake content, awake fussy, crying, and feeding. Fussing was explained to the parents as negative vocalization that is not crying. Holding the infant, mov-ing with the infant, and takmov-ing 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 vaccina-tions. The diary day was excluded when the infant was

febrile (temperature ⬎38°C), when the infant had

re-ceived 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– 6:00AM, 6:00AM–12:00PM,

12:00PM– 6:00PM, and 6:00PM–12:00AM).

Data Analysis

The data are given as means (SD) [minimum, maxi-mum] 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 vari-ance or Kruskal-Wallis Test for continuous variables, followed by multiple comparisons using Tukey’s

hon-estly significant difference method or Mann-WhitneyU

test with Bonferroni correction. Parental characteristics of term control infants were compared with VLBW

in-fants’ 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

ofP⬍.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 clas-sified according to ultrasound examinations: 1 of them into the normal group and the other into the brain pathology group because of ventriculomegaly. In addi-tion, 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 re-turned 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 pa-thology 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 nor-mal group. In the nornor-mal 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 gesta-tional age, in the percentage of cesarean sections, in maternal age, or in the level of parental education be-tween the groups of VLBW infants. The fathers of the term control infants had more years of education com-pared 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

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TABLE 2 Infant and Parent Characteristics in the Study Groups VLBW Infants Comparison of Groups of VLBW Infants, P Term Control Infants ( n ⫽ 49) Comparison of VLBW Infants With Control Infants, P VLBW Normal Group ( n ⫽ 34) VLBW Intermediate Brain Pathology Group ( n ⫽ 48) VLBW Brain

Pathology (n

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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 inter-mediate brain pathology group compared with the

nor-mal 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 cry-ing decreased with increascry-ing 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 dif-ferences at any age points. The number of bouts in-creased from term to 6 weeks of age and then dein-creased 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,

respec-tively) in VLBW infants compared with term control infants (Table 4). When the bout frequency was pared among all 4 study groups, the number of

com-bined fussing and crying bouts did differ (P ⫽ .033,

analysis of variance). In pair-wise comparisons, the only significant difference was found between the brain

pa-thology 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 ac-cording 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 du-ration of fussing and crying or in the dudu-ration 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)

per-sisted even when the hospitalized VLBW infants were excluded. Although the infants in the brain pathology

TABLE 3 Duration of Fussing, Crying, Holding, and Missing Data at Term, at 6 Weeks, and at 5 Months of Corrected Age According the Parental Diaries

VLBW Infants Term Control Infants (n⫽49)

Comparison of Groups,P

Normal Group (n⫽34)

Intermediate Brain Pathology Group

(n⫽48)

Brain Pathology (n⫽41)

Fussing⫹crying/d at term 114 (76)关0, 402兴a 166 (103)17, 453兴a 140 (88)10, 443.048

Fussing⫹crying/d at 6 wk 104 (63)关0, 250兴 130 (68)关17, 298兴 123 (84)关5, 423兴 .287

Fussing⫹crying/d at 5 mo 71 (48)关15, 190兴 86 (53)关2, 278兴 87 (49)关0, 188兴 69 (41)关0, 177兴 .181

Crying/d at term 33 (40)关0, 193兴 48 (43)关0, 187兴 46 (43)关0, 177兴 .223

Crying/d at 6 wk 30 (26)关0, 97兴 35 (33)关0, 183兴 35 (31)关0, 138兴 .781

Crying/d at 5 mo 13 (11)关0, 42兴 14 (15)关0, 68兴 18 (19)关0, 95兴 14 (15)关0, 75兴 .534

Fussing/d at term 82 (50)关0, 208兴a 117 (76)8, 285兴a 93 (55)0, 267.038

Fussing/d at 6 wk 74 (48)关0, 180兴 95 (54)关12, 237兴 88 (67)关3, 378兴 .254

Fussing/d at 5 mo 58 (41)关10, 165兴 73 (42)关0, 210兴 69 (40)关0, 157兴 56 (33)关0, 167兴 .120

Holding/d at term 232 (110)关20, 432兴b 262 (115)38, 517314 (114)117, 552兴b .009

Holding/d at 6 wk 263 (139)关43, 612兴 263 (142)关0, 577兴 319 (142)关45, 672兴 .128

Holding/d at 5 mo 188 (112)关10, 433兴b 137 (87)0, 367194 (85)17, 337兴c 130 (69)0, 435兴b,c .001

Diaries kept in hospital: term/6 wk/5 mo 4/0/0 3/0/1 4/1/0 -/-/0

Missing data at term 6.1 (10.9)关0, 55兴 13.2 (29.5)关0, 157兴 9.4 (24.6)关0, 140兴 .420

Missing data at 6 wk 7.3 (20.3)关0, 85兴 5.6 (11.5)关0, 50兴 8.3 (22.4)关0, 135兴 .778

Missing data at 5 mo 4.2 (11.1)关0, 58兴 7.5 (15.5)关0, 73兴 7.5 (13.9)关0, 63兴 3.4 (14.6)关0, 100兴 .520

Data are mean per day (SD),关min, max兴if not otherwise indicated. Statistical analysis between the groups was done by ANOVA. aP.05.

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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 pa-rental 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 fre-quency 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

FIGURE 1

Total duration of fussing and crying (in minutes) according to the quartiles of a day. Data were derived from the parental diaries at term (A), at 6 weeks of corrected age (B), and at 5 months of corrected age (C). Mean values are presented.aStatistically significant study group differences (P.05, analysis of variance).

TABLE 4 Number of Started Fussing and Crying Bouts at Term, at 6 Weeks, and at 5 Months of Age According the Parental Diaries in the Study Groups

VLBW Infants Term Control Infants (n⫽49)

Comparison of Groups (ANOVA)P

Normal Group (n⫽34)

Intermediate Brain Pathology Group

(n⫽48)

Brain Pathology Group (n⫽41)

Crying⫹fussing bouts/d at term 8.8 (5.1) 10.3 (6.4) 10.3 (6.6) .472

Crying⫹fussing bouts/d at 6 wk 10.0 (6.1) 10.3 (6.8) 11.2 (8.1) .768

Crying⫹fussing bouts/d at 5 mo 7.7 (5.5) 7.4 (5.0) 8.9 (5.9)a 5.7 (3.5)a .033

Crying bouts/d at term 2.4 (2.2) 3.3 (2.3) 3.5 (2.9) .155

Crying bouts/d at 6 wk 2.9 (2.0) 2.8 (2.4) 3.2 (2.9) .724

Crying bouts/d at 5 mo 1.5 (1.4) 1.4 (1.3) 1.7 (1.5) 1.2 (1.4) .476

Fussing bouts/d at term 6.4 (3.5) 7.0 (4.9) 6.9 (4.4) .809

Fussing bouts/d at 6 wk 7.2 (4.9) 7.5 (5.4) 7.9 (5.8) .828

Fussing bouts/d at 5 mo 6.2 (5.0)b 6.0 (4.1)b 7.1 (4.8)c 4.5 (2.7)b,c .027

Data are mean (SD). Statistical analysis between the groups was done by ANOVA. When frequency of combined fussing and crying bouts was compared pair-wise between all VLBW infants and control infants, the difference was statistically significant atP⫽.009 and fussing bouts separately atP⫽.006.

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infants were shown to be more irritable than term

in-fants in test situations.12To explain the discrepancy, we

analyzed the amount of holding, which may be used as an intervention to prevent distress behavior. Some

stud-ies have suggested that holding20 and rapid maternal

responsiveness4reduce 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 hold-ing reduces the amount of cryhold-ing, there is a possibility that increased holding may mask the tendency of pre-term infants to cry more compared with pre-term infants. The more frequent fussing bouts that are found in pre-term infants may indicate an increased reactivity to in-ternal or exin-ternal stimuli in preterm infants compared with term infants. If holding helps an infant to regulate his or her behavioral states, then the bout length re-mains short and the total duration of crying does not increase. The potential difference in reactivity may orig-inate from differences in the brain function as a result of immaturity. However, this is not supported as our find-ing was that structural brain injuries do not have a consistent effect on reactivity (bout frequency). The al-ternative explanation may be that more frequent paren-tal 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 night-time compared with daynight-time 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.21,22These data are consistent with

an earlier report showing clustering of crying in the evening hours in healthy preterm infants at 6 weeks of

age.5Sleeping 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

behav-ior.14The 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, in-cluding more fussing at term in infants with intermedi-ate 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 STUDY

Name Birth date Date of imaging Radiologist

A. Cortex

1. Normal

2. Grade 1 (1 area affected)

3. Grade 2 (2 areas affected; describe which)

4. Grade 3 (3 areas affected; describe which)

B. Basal ganglia and thalami

1. Normal

2. Grade 1 (Focal lesions but posterior part of internal capsule not affected)

3. Grade 2 (focal lesions in lentiform nuclei or thalami and abnormal signal in posterior part of internal cap-sule)

4. Grade 3 (large changes in basal ganglia or thalami and abnormal posterior part of internal capsule)

C. Posterior limb of internal capsule

1. Normal (high signal intensity in at least one third of the area on T1-weighted image and low signal inten-sity in at least one third of the area on T2-weighted image)

2. Grade 1 (asymmetrical posterior limbs of internal capsules on T2-weighted images)

3. Grade 2 (low signal intensity on T1-weighted images and high signal intensity on T2-weighted images)

D. White matter

1. Normal

2. Grade 1 (small hemorrhages and/or abnormal high T1 and T2 signal intensities in WM but white and gray matter can be visually separated)

3. Grade 2 (large hemorrhages or abnormal high T1 and T2 signal intensities extending to gray matter)

E. Germinal matrix

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2. Grade 1 (high-intensity signals as a result of small, local hemorrhages on 1 or both sides)

3. Caudothalamic cysts: side and size (mm)

F. Width of lateral ventricles

1. Normal

2. Dilation of frontal horns

3. Dilation of occipital horns

4. Dilation of all of the horns of the lateral ventricles

G. Ventriculitis

1. No

2. Yes

H. Corpus callosum

1. Normal

2. Hypoplastic

I. Posterior fossa structures

1. Normal

2. Hemorrhage: define the location

3. Anomaly: define

J. Myelination pattern corresponds to 㛭㛭㛭 gestational

weeks

K. Ventricular/brain ratio

L. The width of extracerebral space (mm) Other findings

ACKNOWLEDGMENTS

This study was supported by grants from The Lea and Arvo Ylppo¨ 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 Matoma¨ki, BSc (sta-tistics 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, Pa¨ivi Rautava, MD, Milla Reiman, medical student, Hellevi Rikalainen, MD, Taija Saanisto, MSc (statistician), Katriina Saarinen, physio-therapist, Elina Savonlahti, MD, Matti Sillanpa¨a¨, MD, Suvi Stolt, Phil Lic, Pa¨ivi Tuomikoski-Koiranen, RN, and

Tuula A¨ a¨rimaa, MD.

REFERENCES

1. Brazelton TB. Crying in Infancy.Pediatrics.1962;29:579 –588 2. Barr RG. The normal crying curve: what do we really know?

Dev Med Child Neurol.1990;32:356 –362

3. St James-Roberts I, Halil T. Infant crying patterns in the first

year: normal community and clinical findings.J Child Psychol

Psychiatry.1991;32:951–968

4. Baildam EM, Hillier VF, Ward BS, Bannister RP, Bamford FN, Moore WM. Duration and pattern of crying in the first year of life.Dev Med Child Neurol.1995;37:345–353

5. Barr RG, Chen S, Hopkins B, Westra T. Crying patterns in preterm infants.Dev Med Child Neurol.1996;38:345–355 6. Lehtonen L, Gormally S, Barr RG. “Clinical pies” for etiology

and outcome in infants presenting with early increased crying. In: Barr RG, Hopkins J, Green JA, eds. Crying as a Sign, a

Symptom, and a Signal. London, United Kingdom: Mac Keith

Press; 2000:169 –178

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Child.2004;89:989 –992

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Pe-diatr.1998;133:224 –231

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13. Oberlander TF, Grunau RE, Fitzgerald C, Whitfield MF. Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks’ postconceptional

age?Pediatrics.2002;110:570 –576

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1988;63:380 –387

15. Papile L-A, Burstein J, Burstein R, Koffler H. Incidence a evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1500 gm.J Pedi-atr.1978;92:529 –534

16. Virkola K.The Lateral Ventricle in Early Infancy[doctoral thesis]. Helsinki, Finland: University of Helsinki; 1988

17. Maalouf EF, Duggan PJ, Ruthenford MA, et al. Magnetic res-onance imaging of the brain in a cohort of extremely preterm infants.J Pediatr.1999;135:351–357

18. Maalouf EF, Duggan PJ, Counsell SJ, et al. Comparisons of findings on cranial ultrasound and magnetic resonance imag-ing in preterm infants.Pediatrics.2001;107:719 –727

19. McArdle CB, Richardson CJ, Nicholas DA, Mirfakhraee M, Hayden CK, Amparo EG. Developmental features of the neo-natal brain: MR imaging. Part II. Ventricular size and extrace-rebral space.Radiology.1987;162:230 –234

20. Hunziker UA, Barr RG. Increased carrying reduces infant crying: a randomized, controlled trial. Pediatrics. 1986;77: 641– 648

21. Kirjavainen J. Excessive Crying and Sleep in Infancy [doctoral thesis]. Turku, Finland: Turku University; 2004

22. Harrison Y. The relationship between daytime exposure to light and night-time sleep in 6 –12-week old infants.J Sleep Res.

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DOI: 10.1542/peds.2005-1333

2006;118;e57

Pediatrics

Helena Lapinleimu, Leena Haataja and Liisa Lehtonen

Jonna Maunu, Jarkko Kirjavainen, Riikka Korja, Riitta Parkkola, Hellevi Rikalainen,

Relation of Prematurity and Brain Injury to Crying Behavior in Infancy

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DOI: 10.1542/peds.2005-1333

2006;118;e57

Pediatrics

Helena Lapinleimu, Leena Haataja and Liisa Lehtonen

Jonna Maunu, Jarkko Kirjavainen, Riikka Korja, Riitta Parkkola, Hellevi Rikalainen,

Relation of Prematurity and Brain Injury to Crying Behavior in Infancy

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Figure

TABLE 1Findings on the Brain Ultrasound and MRI of VLBW Infants
TABLE 3Duration of Fussing, Crying, Holding, and Missing Data at Term, at 6 Weeks, and at 5 Months of Corrected Age According the ParentalDiaries
TABLE 4Number of Started Fussing and Crying Bouts at Term, at 6 Weeks, and at 5 Months of Age According the Parental Diaries in the StudyGroups

References

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