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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Pediatrics, St. Johanns Spital, and the Department of Psychology, Faculty of Science, Salzburg University, Salzburg, Austria.
Address reprint requests to: Heinrich Weinerroither, MD, Department of Obstetrics and Gynecology, St. Johanns Spital, Muellner Hauptstrasse 48, Salzburg, A-5020, Austria, E-mail: h.wienerroither{at}lkasbg.gv.at
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Abstract |
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Methods: Absence or reversal of diastolic blood flow in the umbilical artery was found in 38 consecutive growth-restricted fetuses as determined by biometry and Doppler ultrasound between 1988 and 1992. The 23 infants surviving the prenatal and perinatal period who could be tested were compared at school age with a group of children born at the same gestational age after normal intrauterine growth. They were tested for intellectual, neurologic, and social development by a test battery including the Kaufmann Assessment Battery for Children, Man-Drawing Test, Child Behavior Checklist, Zürich Neuromotor Test, and neuropediatric testing.
Results: Intellectual development was significantly better in the control group compared with the study group. In addition, Zürich Neuromotor testing and neuropediatric testing showed significantly better development of control children compared with the study group in 20% of the items tested. There was no detectable difference in social development as measured by the Child Behavior Checklist.
Conclusion: Severely reduced blood flow to the fetus associated with growth restriction was followed by long-term impairment of intellectual development and partial neurodevelopmental delay.
Intrapartum hypoxia and acidosis are considered important factors influencing development of the newborn child. As early as 1843, Little1 described the association between birth asphyxia and poor neurologic development. Recent studies have raised the question of other reasons for neurologic handicaps, suggesting that brain damage, such as cerebral palsy and psychomotor restriction, might be caused by genetic defects, malformations of the central nervous system (CNS), metabolic disorders, or severe prolonged antenatal asphyxia.2–6 The latter, however, cannot be satisfactorily correlated by standardized clinical tests, such as fetal heart rate (FHR) tracing and fetal scalp and umbilical cord blood gas analysis, to the degree and duration of asphyxia and to the extent of damage of fetal tissue. In addition, prospective studies did not show the Apgar score to be a predictor of psychomotor performance in preschool children.3,7 The typical result of restricted blood supply is a small for gestational age (SGA) fetus as determined by ultrasound biometry. Biometric measurements alone cannot differentiate between growth restriction from limited blood supply and other reasons such as genetic determinants. Doppler ultrasound shows altered blood flow patterns caused by hemodynamic placental insufficiency that can result in placental malnutrition. Chronic placental disease leads to impaired fetal growth, and the factors limiting tissue growth in general are also important for the complex and energy-consuming development of the brain. This hypothesis is confirmed by corresponding studies on protein deprivation and brain development.8,9
Ley et al10 studied the capacity of Doppler ultrasound to determine whether chronic impairment of blood supply predicted long-term neurologic deficits in 149 children tested at age 7 years. They found the blood flow pattern to be the best predictor of minor neurologic deficits.10,11 The intellectual development of the same study group was evaluated, and a significant difference was found compared with the control group (mean IQ 96 compared with 103).12
The hemodynamic aspect of placental function can be assessed by Doppler investigation of the umbilical artery. However, there is ongoing controversy about the ideal treatment, particularly in timing of delivery of fetuses with severely abnormal blood flow patterns such as absent or reversed end-diastolic flow in the preterm period. After severe fetal growth restriction (FGR), delayed infant development was found in more than half and significant impairment of central nervous system functions in 20% of the children.13 Consequently, many clinicians consider immediate delivery to be indicated in cases of FGR and the presence of absent or reversed end-diastolic flow in the umbilical artery, depending on gestational age and the availability of neonatal intensive care.14 The decision for preterm delivery, which is the only therapeutic option at present, is more difficult early in pregnancy when termination of malnutrition must be weighed against the risks of prematurity. Improvements are expected to be based on optimized obstetric management protocols and on improved care of the neonate.
The present study focused on the effect of placental insufficiency, defined by FGR and absent or reversed end-diastolic flow in the umbilical artery, on long-term development in the first years of life. Chronic intrauterine malnutrition might have a negative effect on complex functions such as social development or intelligence in the absence of early, detectable, severe deficits. Such disorders, which are difficult to diagnose in the neonate, were investigated. The childrens’ ages corresponded with the age suggested by the scientific test batteries, which enabled assessment of neurologic and psychometric disorders that are not detectable immediately after birth.
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Materials and Methods |
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Thirty-eight children met the criteria. Each child of the study group was matched with the next appropriate for gestational age (AGA) infant of the same gestational week born at our institution. Of these 38 pairs, three parents refused to participate in the study, leaving 35 pairs in the study population, for a participation rate of 92%. Eleven (31%) infants died within the first few months of life, a significantly higher mortality rate than in the control group in which two died (6%, P < .01). One child in the study group was severely handicapped, and valid testing was not possible. The remaining 23 pairs of children were tested at a median age of 5.98 years (range 3.1–8.5 years) in the study group and 6.03 years (range 4.0–8.33 years) in the control group.
The Kaufman Assessment Battery for Children was used to evaluate intellectual performance of preschool and school children.16 It distinguishes between problem solving and knowledge of facts. The former set of skills is interpreted as intelligence, the latter is defined as achievement. Problem-solving abilities are measured on two mental processing scales, sequential and simultaneous. The third, a global intelligence scale, is the mental processing composite, a combination of the sequential and simultaneous scales. Finally, the achievement scale provides an estimate of previous learning by using subsets that measured acquired knowledge and application of skills. Man-drawing age and man-drawing quotient were calculated from the Man-Drawing Test.17 Based on 52 details, the assessment used tests graphomotor abilities. The Zürich Neuromotor Test assesses neuromotor maturation between ages 5 and 12 years, including quality and quantity of several fine and gross motor functions.18 Neuropediatric examination included assessment of basic sensory functions, cranial nerves, tendon reflexes, and passive joint mobility. Results were calculated as a neurologic optimality score.19 Visual acuity was assessed by modified stycar test,20 and hearing was tested by audiogram (audiometer ST 10; Bosch, Stuttgart, Germany).
Differences between the study and the control groups were, in most cases, tested by procedures for matched pairs, such as paired t test, Wilcoxon signed-rank test, sign test, and McNemar test. Unpaired t test and Mann-Whitney U test were used when several missing values made pairing impractical, comparing two subgroups of the study group. Before the t test was used, normal distribution was tested by the Kolmogorov-Smirnov test.
In addition, results of the Kaufman Assessment Battery for Children were analyzed by Hotelling multivariate t test as a sum of pair differences. After checking the requirement data of the Man-Drawing Test and the Child Behavior Checklist, they were tested by the Pearson 
2 test. P < .05 was considered statistically significant and P < .001 highly significant.
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and 2). The intelligence level of this group was below average, whereas the control group had results that corresponded to published average levels representing 50% of the normal population. There were no statistically significant differences between the two groups on the Man-Drawing Test and the Child Behavior Checklist. The study group had significantly lower results in 20% of details (especially fine motor items) on the Zürich Neuromotor Test. The rest of the test’s subsets showed the same tendency. Similarly, neuropediatric testing showed significant deficits in 22% of subsets in the study group (Table 2).
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When the study group was subdivided according to intrauterine Doppler ultrasound flow pattern, children who had reversed end-diastolic flow tended to have poorer results both for perinatal data and Kaufman-Assessment Battery for Children testing compared with those who had absent end-diastolic flow (Table 3). The difference was significant for the 5-minute Apgar score (P < .01) and umbilical artery pH (P < .01).
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Discussion |
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Doppler sonography has been shown to be essential in managing high-risk pregnancies by reducing perinatal mortality and morbidity.21 However, there is lack of long-term data on the effects of chronically impaired blood supply to the fetus on complex neurologic functions such as intelligence, motor performance, and social behavior. Such abilities represent complex cerebral networks and are the best indicators of minor but permanent sequelae of deficient cerebral development. In the absence of localized deficits, no major defects, but rather coordinate deficits as occur after known impaired maturation of the corpus callosum, would be expected.8
In the present investigation the study group was characterized as being at high risk by conventional perinatal data, such as Apgar scores and blood gases. However, predictions of further development of the child cannot be deduced from those data. Many neonates develop normally after similar perinatal events. The duration of malnutrition in utero seems to be an essential prognostic factor, which was confirmed when absent and reversed end-diastolic flow groups were compared. Perinatal data, including perinatal mortality rate, were uniformly poorer in fetuses with reversed end-diastolic flow.21 The progressive deterioration from absent to reversed end-diastolic flow resulted in lower umbilical pH values as a marker. However, there were no significant differences in the Kaufman-Assessment Battery for Children between those groups, but there was a tendency toward more impairment in the fetuses with reversed end-diastolic flow. That finding supports the hypothesis that the duration of malnutrition is an essential factor in the persistent negative effect on brain development. Furthermore, the unfavorable results in all subsets of the Kaufman-Assessment Battery in children who had reversed end-diastolic flow suggests prompt prevention of malnutrition. In the course of chronic deterioration of fetal nutrition supply, pathologic flow patterns are usually seen before abnormal FHR tracings, which are currently regarded as an indication for immediate delivery.22 Those severely abnormal flow patterns could prompt earlier intervention, depending on cofactors such as gestational age, glucocorticoid administration, or the availability of neonatal intensive care. The extent to which additional information, such as venous flow, will improve the predictive value for long-term morbidity remains to be determined.
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Footnotes |
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Received May 23, 2000. Received in revised form August 24, 2000. Accepted September 13, 2000.
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2. Low JA, Muir DW, Pater EA, Karchmar EJ. Newborn complications after intrapartam asphyxia with metabolic acidosis of the term fetus. Am J Obstet Gynecol 1995;172:805–10.[Medline]
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16. Kaufman AS, O’Neal MR, Avant AH, Long SW. Introduction to the Kaufman assessment battery for children (K-ABC) for pediatric neuroclinicians. J Child Neurol 1987;2:3–16.
17. Ziler H. Der Mann-Zeichen-Test. Münster, Germany: Aschendorfsche Verlagsbuchhandlung, 1970.
18. Largo RH, Caflisch JA. Neuromotor development from kindergarten age to adolescence. In: Kalverboer AF, Gramsberger A, eds. Handbook on brain and behaviour in human development. Amsterdam: Cluver Academic Publisher, 2000.
19. Keunzle C, Bänzinger O, Martin E, Thun-Hohenstein L, Steinlin M, Good M, et al. Prognostic value of early magnetic resonance imaging in term infants with severe perinatal asphyxia. J Neuropediatr 1994;25:191–200.
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22. Gnirs J. Wertigkeit der dopplersonographie im vergleich zu anderen überwachungsverfahren. In: Steiner H, Schneider KT. Dopplersonographie in geburtshilfe und gynäkologie. München, Germany: Springer, 2000:143–56.
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