Acta Padiatr Suppl422: 83-4. 1997

Long-term effects of intrauterine growth retardation I Kjellmer, M Liedholm, B Sultan, M Wennergren, C Wallin Gotborg and M Thordstein Depa flment of Paediatrics, Depa flment of Obstetrics and Gynaecology and Department of Physiology, University of Goteborg, Sweden

KjelImer I, Liedholm M, Sultan B, Wennergren M, Wallin Gotborg C, Thordstein M. Long-term effects of intrauterine growth retardation. Acta Paediatr 1997; Suppl422: 83-4. Stockholm. ISSN 0803-5326 Intrauterine growth retardation (IUGR) was studied both after experimental induction in rats and spon- taneously occurring in man. The growth-retarded rat pups were compared to appropriately grown litter mates with developmental and behavioural tests at 50 and 90 days of age. Female rats exhibited no differences between growth-retarded and control rats but growth-retarded male rats had poor performance at 50 but not at 90 days compared to male controls. In the patient study 25 growth-retarded babies were compared with 21 appropriately grown controls. The growth-retarded babies had delayed latency periods of the visual evoked potentials at term and 6 weeks later, and at follow-up (18 months) demonstrated significantly more developmental and behavioural problems than the control group. Development, evoked potentiah, fetus, intrauterine growth retardation, neonate

I Kjellrner, Department of Paediatrics, East Hospital, 416 85 Goteborg, Sweden

Intrauterine growth retardation (IUGR) has been associated both with “heavy” neurodevelopmental impairment, such as mental retardation, cerebral palsy and epilepsia, and with less conspicuous problems, such as learning and behavioural dfficulties (1, 2). Some investigators have questioned the importance of growth retardation as a causative factor in relation to perinatal vascular-anoxic lesions (3) and even suggested that with modern perinatal care the association between growth retardation and cerebral malfunction may be lost (4).

The association between IUGR and impairments of neural and developmental functions is far from a simple cause-and-effect relationship. First, IUGR may be one symptom among several others of an early genetic, chromosomal or infectious aberration affecting both the CNS and the growth of the fetus. Second, IUGR may cause the unfortunate combination of an increased risk for intra- partum asphyxia and an exaggerated vulnerability of the brain towards oxygen deficiency or a preponderance for neonatal hypoglycaemia with negative effects on the CNS.

It was therefore considered of interest to study, both experimentally and clinically, groups of individuals born with IUGR but without perinatal asphyxia or other complications and to compare their immediate behaviour and neurophysiology and their long-term behaviour and development with appropriate control individuals. Pre- liminary accounts of these studies have been presented previously (5,6).

Intrauterine growth retardation was induced in rat pups by ligating one uterine artery. Growth-retarded and appropriately grown rat pups from the same litter could be compared. A battery of developmental and behavioural tests were applied when the rats were prepubertal (50 days) and when they were young adults (90 days). One group of

animals was subjected to daily handling and extra testing (with other test methods) before 50 days (“enriched environment”).

Female rats demonstrated no differences between growth-retarded and control rats. Male rats exhibited sig- nificant differences between growth-retarded and control rats inasmuch as the growth-retarded rats at 50 days had greater difficulties in radial maze testing and an aberrant exploratory behaviour. These differences had largely vanished at 90 days of age. Male growth-retarded rats that were raised in the enriched environment did not differ from their controls at 50 days.

It may be speculated that we used inappropriate tests for the females and that another battery of tests would have disclosed some differences between the growth-retarded and the control females. On the other hand, previous observations (7) support the possibility that females are less vulnerable than males with regard to adverse effects of growth retardation.

The clinical study relied on the antenatal diagnosis of fetuses that were small for gestational age (SGA) or appro- priate for gestational age (AGA). The SGA group consisted of 25 babies and the control group consisted of 21. No perinatal history of asphyxia occurred. The socioeconomic situations for the families of both groups were similar and represented families with better economy and higher education than Swedish average.

The neonates were investigated using flash visual-evoked responses at 40 and 46 weeks’ postconception. The latency periods of the primary visual-evoked responses were delayed significantly in the SGA babies at 40 weeks. The latency periods shortened in both groups between 40 and 46 weeks, but the difference prevailed.

In the SGA group three children at the age of 18 months had definite symptoms of neurodevelopmental handicaps

8 Scandinavian University Press 1997. ISSN 0803-5326

84 I Qellmer et a/. ACTA PEDIATR SUPPL 422 (1997)

(one with obvious mental retardation and two with signs of cerebral palsy). The Griffith test demonstrated that the SGA group had significantly more developmental and behavioural problems than the AGA group. The test pro- tocols also suggest a remarkably uneven developmental profile in several SGA children.

Thus, when care is taken to exclude obvious negative influences from perinatal asphyxia and other acute compli- cations, both experimentally induced IUGR in rats and spontaneously occurring clinical SGA in human newborn infants appear to be associated with a higher rate of aberra- tions of neurodevelopment and behaviour than in appro- priately grown individuals.

Hrbek et al. in 1982 (8) appear to have contributed the first report on the association between clinical SGA and abnormal evoked EEG potentials. Their demonstration of a high incidence of abnormal visual- and somatosensory- evoked responses in growth-retarded neonates has been followed by similar observations in visual-evoked respon- ses by us, previously (5,6) and presently, and by the recent findings by Pierrat et al. (9) that somatosensory-evoked potentials show significantly prolonged latency periods in SGA infants compared to controls and shorter latency periods in breastfed than in formula-fed infants. On the other hand, other investigators failed to demonstrate any difference between the visual-evoked potentials of preterm SGA compared to preterm AGA babies (10); and, studying brainstem auditory-evoked potentials, Pettigrew et al. (1 1) showed a shorter conduction time for SGA than AGA infants.

Therefore, neurophysiological investigations of human growth-retarded babies suggest that certain areas of the brain (cortex) may develop more slowly and more irregu- larly than in appropriately grown infants, while other areas (brainstem) appear to have an accelerated development in growth-retarded individuals.

The present results suggest that growth retardation acquired during the fetal stage not only may be indicative

of underlying disease or malformation in the fetus but that growth retardation contributes to neurodevelopmental impairment, first recognized in neurophysiological record- ings and later in clinical and neuropsychological investiga- tions. This suggests that long-term effects of IUGR might be susceptible to prevention.

Acknow1edgmenr.-This study was supported by the Swedish Medical Research Council (2591) and the Free Masonry Orphanage Foundation, Giiteborg.

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Hawdon JM, Hey E, Kolvin I, Fundidis T. Born too small-is out- come $till affected? Dev Med Child New1 1990; 32: 943-53 Kjelimer I, Thordstein M, Wennergren M. Cerebral function in the growth-retarded fetus and neonate. Biol Neonate 1992; 6 2 265-70 Kjel1me.r I, Thordstein M, Sultan B, Wennergren M. Neurophysio- logical studies in intrauterine growth retardation. In: Lou HC, editor. Brain lesions in the newborn, hypoxic and haemodynamk pathogen- esis, Benzon Symposium 37. Copenhagen: Munksgaard, 1994 287- 301 Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. Br Med J 1988; 297: 1304-8 Hrbek A, Iversen K, Olsson T. Evaluation of cerebral function in newborn infants with fetal growth retardation. In: Coujon J, Mau- guiere F, Revol M, editors, Clinical application of evoked potentials in neurology. New York Raven Press, 1982 89-95 Pierrat V, &en P, Truffert P, Duquennoy C, de Vries LS. Somato- sensory evoked potentials in preterm infants with intrauterine growth retardation. Early Hum Dev 19%,44: 17-25 Petersen S, Pryds 0, Trojaborg W. Visual evoked potentials in term light-for-gestation-age infants and indants of diabetic mothers. Early Hum Dev 1990; 23: 85-91 Pettigrew AG, Edwards DA, Henderson-Smart DJ. The influence of intrauterine growth retardation on brainstem development of preterm infants. Dev Med Child N e w 1 1985; 27: 467-72

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