Published online June 1, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. e1342-e1350 (doi:10.1542/peds.2005-2857)
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ARTICLE

Visual Function at 11 Years of Age in Preterm-Born Children With and Without Fetal Brain Sparing

Joke H. Kok, PhD, MDa, Liesbeth Prick, PhD, MDb, Elly Merckelb, Yolande Everhardb, Gijs J.Q. Verkerkc and Sicco A. Scherjon, PhD, MDd

a Departments of Neonatology
b Ophthalmology
c Rehabilitation, Emma Children's Hospital and Academic Medical Center, Amsterdam, Netherlands
d Department of Obstetrics, Leiden University Medical Center, Leiden, Netherlands


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. We have demonstrated earlier an accelerated maturation of the visual evoked potential in the first year of life in preterm infants with antenatal brain sparing. We have now assessed visual functioning at 11 years of age in the same cohort and compared the groups with and without brain sparing.

DESIGN/METHODS. One hundred sixteen survivors included in a study on the outcome of preterm infants born at <33 weeks' gestation with and without fetal brain sparing and admitted to the NICU were followed extensively. Ninety-eight infants (85%) were again assessed at 11 years of age. Data were available for fetal Doppler measurements indicating brain sparing, neonatal cerebral ultrasound scanning, and developmental outcome in the first 5 years. Mean birth weight was 1303 g; mean gestational age was 29.8 weeks. The infants were divided into 2 groups with and without brain sparing. Visual functioning was estimated by measuring visual acuity, visual fields, eye position, and binocular function and by visual motor tests.

RESULTS. Six percent of the children were found to have a visual acuity of <0.8, 12% had strabismus, and 14% to 46% showed abnormal results on the visual motor tests. No statistical differences were found between the 2 groups. However, children with severe cerebral ultrasound diagnoses in the neonatal period were found to have significantly more abnormalities on visual functioning and lower scores on visual motor tests than children without these morbidities.

CONCLUSIONS. Children with fetal brain sparing do not demonstrate a different development of their visual functioning at late school age. However, an abnormal cerebral ultrasound in the neonatal period is associated with impaired visual function in later life.

Key Words: very low birth weight infant • fetal brain sparing • developmental outcome • visual function • intrauterine growth retardation

Abbreviations: IUGR—intrauterine growth restriction • ICH—intracranial hemorrhage • ROP—retinopathy of prematurity • VMI—visual motor integration • U/C—umbilical/cerebral • MAT—Motor Accuracy Test • MVPT-R—Motor-Free Visual Perception Test, Revised • Movement ABC—Movement Assessment Battery for Children

Preterm birth with or without intrauterine growth restriction (IUGR) is associated with significant mortality and morbidity both in the neonatal period and in later life.1 New approaches, both in obstetric and neonatal treatment of the preterm-born infant introduced after 1985, such as the use of antenatal corticoids and surfactant, as well as new modes of respiratory support and regionalization of care, have improved outcome.2

Because of placental insufficiency, a reduction of umbilical blood flow is seen in pregnancies with IUGR,3 whereas the blood flow to the brain is preserved by a compensatory mechanism. This centralizing of blood flow to the fetal brain is called the "brain-sparing effect."4 This term may be somewhat misleading. It suggests a relative protection of the brain during fetal development and does not necessarily reassure a normal developmental outcome. Especially in case of decompensation, the hemodynamic changes are found to be associated with fetal hypoxia5 and possibly even with adverse neurodevelopmental outcome.

Cranial ultrasound has been shown to be very useful in the prediction of neurodevelopmental outcome.6 Emphasis has moved to define not only intracranial hemorrhage (ICH) and ventricular dilation7 but also white matter injury.8 Neonates with ICH9 but especially neonates with ischemic white matter lesions are prone to visual-acuity deficits.10,11 A much earlier confrontation with visual stimuli during a period of rapid maturation and the possible deleterious effects of illnesses sustained during the perinatal period place the preterm-born infant at significant risk for impairment of the visual system.12 Besides the widely known retinopathy of prematurity (ROP), the incidence of refractive errors, strabismus, amblyopia, and cortical visual impairment is reported to be high (≥40%) in preterm-born infants, especially when (cystic) periventricular leukomalacia was present.13–16 Although severe visual loss is rare in preterm-born infants, little is known of minor impairment of visual function and defects of the visual fields. The quality of the visual input may be important for optimal visual development, as well as for other fields of neurodevelopment,17 most probably by alterations at the level of neuronal connectivity. Failure of the myelination process, related to defects in the visual tract, might contribute to poor developmental outcome. Myelination of the optic nerve and tract is incomplete at term and continues during the first 2 postnatal years.18

Although we have demonstrated that redistribution of the circulation to the brain is associated with IUGR,19 there was no independent association with neurologic outcome at 3 years of age.20 This was also confirmed in other studies, in which neurologic outcome at 5 years could not be predicted by antenatal Doppler studies.21,22

We found unexpectedly an accelerated maturation of visual evoked potentials in the first year of life in infants who showed fetal brain sparing as a result of hemodynamic adaptation to placental insufficiency, independent of gestational age at delivery.23 Also, we found an abnormal visual motor integration (VMI) on the RAKIT (Revision of the Amsterdam Children's Intelligence Test)24 at 5 years of age. Because of the essential role of visual function in motor development and cognitive development, this study was designed to investigate whether preterm-born infants with brain sparing in the fetal period are at higher risk to develop visual function disturbances at school age than preterm infants without fetal brain sparing. We also analyzed the influence of other perinatal risk factors on visual outcome.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The study group has been described in more detail in previously published studies.20,22,23 The initial cohort of 128 preterm-born infants was formed from infants who were admitted to the NICU of the Academic Medical Center, University of Amsterdam, in 1989 and who were included in a perinatal study on the effects of fetal brain sparing on infant outcome. From March 1989 until December 1989, all mothers with a threatening preterm delivery (>25 and <34 weeks), both singleton and multiple births, were included in the study. A total of 116 infants survived the first year of life and were extensively followed until 5 years of age. Almost all children were assessed at 6, 12, and 24 months and 3 and 5 years of age to evaluate outcome of different developmental domains.20,22,23 For this study, children were invited to visit the outpatient clinic at the age of 11 years. Approval was obtained by the medical ethical review board of our hospital. Informed consent was obtained from all parents.

Clinical Protocol and Previous Follow-up Data
Prenatal Doppler Measurements
The technique of Doppler investigation was described previously.19 Briefly, measurements from the umbilical artery and the middle cerebral artery were performed within 1 week before delivery. Doppler measurements were not available for attending obstetricians and were not used for timing of delivery. Pulsatility index of the umbilical artery and the middle cerebral artery were recorded, and the ratio between them (the umbilical/cerebral [U/C] ratio) was calculated. We considered a U/C ratio >0.72 as fetal brain sparing.25 The last Doppler measurement before delivery was used for statistical analysis. Fetuses with chromosomal disorders or major congenital abnormalities were excluded from the study.

Data on Delivery
Birth weight and birth weight ratio, calculated according to the Dutch growth curves,26 and gestational age at delivery, use of antenatal steroids, multiple pregnancy, and Apgar score at 5 minutes were obtained from the original study database.

Neonatal Data
Data on respiratory distress syndrome, surfactant use, oxygen dependence at 28 days after birth, septicemia, and cranial ultrasound diagnosis were obtained from the original study database. For this study, data on ROP were extracted from the medical charts, and when this information was lacking, local pediatricians were contacted for data on screening of ROP in the medical charts of their hospitals.

Cranial ultrasound was performed, as described previously,27 on 6 predefined occasions during the first week of life and were repeated 1 week and 1 month after birth. The most severe ultrasound abnormality, as assessed 4 weeks after birth, was used for classification. For the classification of ICHs, the classification of Volpe was used28; for the classification of ischemic echodensities, a modified classification system according to Pidcock et al29 was used. We made a composite outcome of intracranial ultrasound findings as described by Scherjon et al.27 Briefly, the criteria were as follows: normal, no ICH or a subependymal hemorrhage, echodensities less bright than the choroids plexus; suspect, intraventricular hemorrhage (<50% of lumen filled), any echodensities brighter than the choroid plexus, lasting <3 days; and abnormal, intraventricular hemorrhage (>50% of lumen filled) and any intraparenchymal hemorrhage, any echodensities brighter than the choroids plexus and lasting for >3 days. For each child, a socioeconomic score was available.

Assessments at 11 Years of Age on Visual Functioning
Visual Acuity, Visual Field, and Orthoptic Assessment
Ophthalmologic and orthoptic examinations were performed by experienced pediatric orthoptists (Drs Merckel and Everhard). The examination included the following:

  1. Ophthalmologic history regarding visual acuity, refractive errors, and strabismus was obtained.
  2. The corrected monocular and binocular visual acuity was determined. Acuity was expressed in Snellen acuity values assessed with Landolt-C-optotypes15 or with the Amsterdam Picture Chart. A visual acuity of ≥0.8 is considered normal.
  3. Eye position and binocular function were assessed with the cover test and the alternating cover test at 30 cm and 2.5 m to categorize manifest or latent squint and esodeviation or exodeviation.
  4. Stereoscopic vision was tested using the TNO random-dot stereo test.30
  5. Visual fields were tested with the Humphrey 91 screening test.31 When the children were not able to cooperate in Humphrey perimetry, the visual fields were assessed according to simple confrontation techniques as described by Donders.32 The final results were categorized in present or absent defects for each eye.

VMI Assessments
The visual motor assessment was performed by 2 experienced occupational therapists (Drs Verkerk and I. Hemmen). The assessment included the following tasks:

  1. The Beery-Buktenica developmental test of VMI,33 in which increasingly complex geometric figures have to be copied with pencil on paper. The overall performance is converted into a standard score, based on chronological age, with a mean of 100 and an SD of 15. Results of >1 SD were considered as performing below or above age level.
  2. The Motor Accuracy Test (MAT)34 was used to test the ability to trace directly over a printed black line using a red fine liner pencil with the preferred hand within 1 minute. The distance and the total length of the drawn line that is off the printed black line are measured and converted into scores, the accuracy, and the adjusted score with their additional SDs. The scores differ in that the adjusted score also includes the speed of the tracing. SD >0.9 is considered as performing below or above the age level. The results were extrapolated according to age, because norm data are available only until 10 years (mean age was 11.6 years).
  3. The Motor-Free Visual Perception Test, Revised (MVPT-R)35 measures visual perceptual abilities, spatial relationships, visual discrimination, visual closure, visual memory, and figure-ground perception. A figure is presented and a matching item of 4 alternatives should be selected by pointing. The performance of the child is converted into a standard score that is based on the chronological age with a mean of 100 and an SD of 15. SD > 1 is considered as performing below or above the age level. For the first 3 tests, the child is sitting at a table; the tasks are presented at a distance of ~30 cm.
  4. To get an impression of the ability to handle moving objects while standing, a subtest from the Movement Assessment Battery for Children (Movement ABC)36 was included. The ball skills offered were 2 tasks: to catch a ball and to throw a ball at a goal; the child had 10 opportunities for each task. The number of catches and hits was scored and compared with the test table of the Movement ABC, which is expressed in percentiles. A result of <5th percentile is considered to be below normal.

Statistical Analyses
Statistical analysis was performed with SPSS 11.5 for windows (SPSS, Chicago, IL). The primary outcome variables visual acuity, strabismus, visual field defects, VMI, visual perception test (MVPT-R), MAT, and ball tasks were first analyzed in the total cohort (n = 98). In addition, outcome was analyzed in the 2 subgroups defined according to a normal (n = 58) or a raised (n = 31) U/C ratio. As test of significance, the {chi}2 or linear by linear association was used as appropriate for dichotomous variables, whereas the t test or analysis of variance was used for continuous measurement.

All data were first analyzed using univariate analysis. After having detected the most significant variables (a significance level of P < .15 was used), logistic regression analysis was used to determine which variable influences the final outcome. Logistic regression was used to estimate the independent association of obstetric and neonatal variables with outcome parameters at the age of 11 years. As outcome variables, both visual motor function outcome parameters (normal or abnormal MAT, VMI, or MVPT-R results), and results from the ophthalmologic examination (normal or abnormal vision; strabismus or visual fields) were analyzed. The following explaining variables were included in the full model: U/C ratio, birth weight, use of antenatal corticoids, gestational age, gender, Apgar score at 5 minutes, asphyxia, sepsis, respiratory distress syndrome, intracranial abnormalities, bronchopulmonary dysplasia at the age of 28 weeks, and socioeconomic status. The inclusion in the model was partly based on differences between outcome groups as found by univariate testing, but possibly important variables (as known from the literature) were studied as well.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Ninety-eight children of the original cohort of 116 neonates were assessed at ~11 years of age, representing 85% of the survivors of the original cohort. Seven children could not be traced, and 9 parents refused to participate. Two children could not attend the follow-up session because they were living abroad. The 18 children who did not participate in the follow-up study showed similar perinatal characteristics as the assessed group (data not shown).

Perinatal characteristics of the children are given in Table 1. In 9 children, no antenatal Doppler measurements were performed. Mean U/C ratio in the group with brain sparing (n = 31) amounted to 1.71 ± 1.19 vs 0.43 ± 0.15 in the group without brain sparing (n = 58; P < .001). Fetuses with an abnormal U/C ratio were more often growth restricted as defined classically by growth curve characteristics. In 1989, in our hospital, antenatal corticosteroids were given for pregnancies with normal fetal growth only. Therefore, infants with a normal U/C ratio more often received antenatal corticoids. We did not find a statistically significant difference in the use of surfactant between the 2 groups: 6.9% in the normal U/C ratio group compared with 3.3% in the abnormal U/C ratio group (P = .47). However, at the time of the study period, surfactant was used only as a rescue treatment, in case of need of artificial ventilation with a fraction of inspired oxygen ≥60%. The incidence of intracranial ultrasound abnormalities, both severe ICHs and persisting echodensities as a sign of cerebral ischemia, was not significantly different between the 2 groups. The incidence of an intraventricular hemorrhage (grade 2 and higher) was for the normal and abnormal U/C group 15.5% and 9.7% (P = .44), respectively. The incidence of intraparenchymal echodensities that persisted for >3 days was not significantly different between the normal and the abnormal U/C ratio group: 17.2% and 6.5%, respectively (P = .156).


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  		TABLE 1 Perinatal Characteristics of the Children as Assessed at 11 Years of Age

 
Because of early transfer to level 2 units, data on ROP screening were scarce. Therefore, we contacted the local pediatricians who cared for these infants after discharge from the NICU to provide data on ROP screening for this study. For 18 patients, no data on ROP were recorded; for 32 patients, neonatal charts had already been destroyed; in the other 48 patients, ROP screening had been documented. From the available data (50%), no infants received a diagnosis of ROP grade 2 or more. No infants had any treatment for ROP.

At the follow-up visit at 11 years of age, anthropometric data were obtained in all children (Table 2). Only a slight difference in head circumference was found between the abnormal and normal U/C ratio group in favor of the children with a normal U/C ratio. This difference was not statistically different.


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  		TABLE 2 Anthropometric Data of the Follow-up Cohort at 11 Years

 
All children underwent orthoptic and ophthalmologic examination for assessment of visual acuity, visual fields, eye position, and binocular vision. The results are depicted in Table 3.


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  		TABLE 3 Outcome of Orthoptic and Ophthalmologic Examination at 11 Years of Age

 
Five children in the normal U/C ratio group had a major impairment of visual acuity in 1 eye (<0.3). One child had a visual acuity of <0.3 in both eyes and was classified as having severe visual impairment. None of the children in the abnormal U/C group had a visual impairment.

Visual fields were tested with the Humphrey method in 90 children. Four children showed abnormalities of the visual fields. In these children, visual field defects were located in the nasal as well as the lower quadrants. In 8 cases (4 of the normal U/C ratio group, 2 of the abnormal U/C ratio group, and 2 of the group without antenatal Doppler measurement), the children were not able to perform the Humphrey perimetry, mainly because of severe motor and cognitive disabilities. In these children, the Donders confrontative method was used. In 3, visual field defects that were not located in specific quadrants were found.

Significantly more children with an abnormal U/C ratio had occlusion therapy during infancy because of amblyopia with or without strabismus. Of all children who had occlusion therapy during infancy, 70% had problems with binocularity. Of the 12 children with strabismus, 6 had esotropia and 6 had exotropia.

Visual motor testing could be performed in all children (Table 4). Twenty-six percent of all assessed children showed a VMI test below age level, but no significant difference was found between the U/C ratio groups. The disk-subset score as assessed at 5 years of age showed a fairly good correlation with the visual motor test at 11 years of age (r = 0.33; P < .01).


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  		TABLE 4 Outcome of Visual Motor Tests at 11 Years of Age

 
Also, very low scores were found on the MAT. Nearly half of the cohort performed below –0.9 SD, and the normal U/C ratio as well as the abnormal U/C ratio group showed similar results. Only 7 children scored higher than normal. Approximately 15% of the children had a low score on the MVPT-R. No statistically significant differences could be demonstrated between the U/C ratio groups.

A substantial percentage of the children (20%–30%) had problems with motor skills such as catching and throwing a ball as compared with the reference values. No differences were found between the U/C ratio groups.

Concerning visual motor function, logistic regression analysis revealed no clear independent association between certain explaining variables around birth and the studied outcome variables. MAT was associated with gestational age (P < .01), whereas VMI was associated with socioeconomic status (P < .03). MVPT-R was associated with asphyxia (P < .01) and intracranial abnormalities (P < .01).

Strabismus was associated with intracranial abnormalities (P < .01) as well as with asphyxia (P < .04). Strabismus is the only variable at 11 years that had an independent negative association with a high U/C ratio (P < .03). The other 2 ophthalmologic outcome parameters (visual acuity and visual fields) had no independent association with any of the explaining variables.

Table 5 shows the relation between the cerebral ultrasound findings in the neonatal period and visual outcome. The number of infants with an abnormal U/C ratio is significantly less in the group of abnormal cerebral ultrasound findings. Children with abnormalities on the neonatal ultrasound show significantly more impaired visual outcome in any of the tested domains.


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  		TABLE 5 Visual Function in Relation to Intracranial Ultrasound Findings in the Neonatal Period of the Cohort at 11 Years of Age

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Visual Function in the U/C Ratio Groups
In this study, we evaluated visual function at 11 years of age in a cohort of preterm infants with and without fetal brain sparing. Although we demonstrated differences in visual function at 1 and 5 years of age in this cohort in previous studies,22,23 we could not demonstrate any significant difference in visual functioning between the 2 groups at the age of 11 using extensive visual function testing.

The only difference was a higher percentage of children with a history of occlusion therapy in the group with fetal brain sparing compared with children without fetal brain sparing. It could be argued that the finding of the maturational differences of the visual evoked potentials in the first year of life and the opposite finding in VMI tests results at 5 years in our study group was a finding by chance and not a real pathologic phenomenon. However, a similar cohort of children with and without fetal brain sparing were followed in Sweden.37 These investigators found an abnormal retinal vascular morphology in young adult life in the group with growth restriction, which they attributed to changes in fetal programming of infants with IUGR as described by Barker et al.38 This finding also indicates an association between an abnormal development in visual function and IUGR.

Visual Function in the Whole Cohort
The findings in the whole group are intriguing as compared with a normal population. This cohort showed a relatively high incidence of problems on visual functioning. We found a high percentage of children with strabismus (12%), whereas 6% of the children had severe visual impairment in 1 or both eyes, although no infant received a diagnosis of severe ROP. Binocular vision was absent in 12% of the children. Cooke et al39 conducted a similar study at the age of 7 years in children who were born at <32 weeks' gestational age compared with matched term control infants and found similar percentages of poor visual acuity, strabismus, and stereoscopic vision in the preterm children.

Holmstrom et al40 reported an incidence of visual acuity abnormalities of ~45%. We found a much lower incidence (17%) of visual acuity of <0.8 in 1 or both eyes. The cohort of Holmstrom et al consisted of a large group of infants with an extremely low gestational age: 60% of the infants were born at <29 weeks' gestation; as a consequence, a high incidence (40%) of ROP was diagnosed. Unfortunately, we were not able to gather sufficient information on ROP screening in the neonatal period. It seemed that, irrespective of national guidelines for ROP screening, no careful documentation had been recorded. Also, one third of the medical charts had been destroyed after a period of 10 years. Therefore, we were not able to evaluate relationships of ROP screening results with final visual acuity.

In this cohort, strabismus was found in 12%. This is an ~3 times higher incidence than in a normal population. The incidence of strabismus is found to be 5% in normal preschool children in the Netherlands, and the incidence of amblyopia is 3% and of refractive errors is 5%.41 In other cohorts of preterm infants13,39,40,42 the incidence of strabismus varied between 13% and 22%.

We found a much higher incidence of strabismus (36%) in children with severe abnormal cerebral ultrasound findings; this was also found by others.9,16 The higher incidence of strabismus in preterm-born neonates seems to be related to cerebral lesions, because the incidence of strabismus in neonates without cerebral ultrasound defects (6%) is comparable to that in the normal population (5%).

We tested the visual fields with Humphrey perimetry and found abnormalities in ~5% of the children, mainly in the nasal fields. Using a Damato campimeter, O'Connor et al42 detected in just 1 child of 293 abnormal visual fields. Larsson et al43 assessed the visual fields by other methods. In their study, only preterm infants who were cryotreated for ROP showed constriction of the peripheral fields, whereas all preterm infants showed reduced neural capacity of the central fields.

Because a validated test on writing capacities is not available for this age group, we preferred to include a test on motor accuracy in the test battery. Remarkably, nearly 50% of the children scored below age level. It is possible that these subnormal scores have been biased by our need to extrapolate our findings for age. In addition, 26% of the children scored below age level on the VMI, and >20% of the children showed problems with the ball tasks of the Movement ABC. However, the results of MVPT-R were in agreement with the normal population. It is interesting that a strong association with orthoptic and ophthalmologic examinations could not be detected. Similar results were also found in the study of Cooke et al.39

Head Circumference
Although the abnormal U/C ratio group had a smaller head circumference compared with the normal U/C ratio group, the difference was not statistically significant (P < .07). In contrast to the recent findings by Cooke et al,39 we did not find any relationship between visual outcome test and head circumference (data not shown). Even after subdivision into normal and abnormal U/C ratio, no relation could be shown.

In this respect, it is important to mention that Tolsa et al44 demonstrated a significant reduction of intracranial volume and cerebral gray matter volume with a 3-dimensional MRI technique in infants with IUGR. In that cohort, however, infants were of a similar gestational age, whereas in our cohort, the abnormal U/C group had a higher gestational age compared with the normal group. This could have diminished the chance to detect a possible effect in our cohort.

Abnormal Neonatal Cerebral Ultrasound Findings and Visual Function
Abnormal visual functioning at 11 years was strongly associated with an abnormal cerebral ultrasound result in the neonatal period. The children who developed cerebral hemorrhages and/or periventricular leukomalacia in the neonatal period showed bad visual outcomes on various domains, visual acuity, visual fields, strabismus, and visual motor function tests. Even the outcome of the MVPT-R, which is developed to test visual perception while avoiding motor function disorders, is much worse in the children with cerebral damage.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
On the basis of these follow-up data up to the age of 5, we suggest that the brain-sparing effect is a benign adaptive mechanism that occurs in the fetus with IUGR.19,20 This extended follow-up study has confirmed the adaptive mechanism of brain sparing on visual function. In children with antenatal brain sparing, we found an accelerated maturation of visual evoked potentials during the first year of life, whereas visual motor function was impaired at 5 years of age. However, we could not demonstrate any difference in visual functioning at 11 years of age in these children.


   ACKNOWLEDGMENTS
 
The study was supported by a grant from the Dutch Brain Foundation.

We thank Aleid van Wassenaer, Judy Briët, Inge Hemmen, Rinske Bos, and Tonnie Kelderman for advice, performing tests, and administrative help.


   FOOTNOTES
 
Accepted Dec 12, 2006.

Address correspondence to Joke H. Kok, PhD, MD, Emma Children's Hospital AMC, Department of Neonatology H3 229, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: j.h.Kok{at}amc.uva.nl

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


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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S. J. Roza, E. A. P. Steegers, B. O. Verburg, V. W. V. Jaddoe, H. A. Moll, A. Hofman, F. C. Verhulst, and H. Tiemeier
What Is Spared by Fetal Brain-Sparing? Fetal Circulatory Redistribution and Behavioral Problems in the General Population
Am. J. Epidemiol., November 15, 2008; 168(10): 1145 - 1152.
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