Intrauterine Blood Flow and Postnatal Development David Ley, Karel Marsϗl

Fetal experience forms the basis for postnatal life.

This relationship may be obvious in the newborn in- fant, although it is sometimes not apparent until later in development. One fetal condition with known im- plications for later life is intrauterine growth restric- tion (IUGR), which ranges from being an important factor in perinatal mortality to affecting morbidity in adulthood.

The process of growth, usually measurable as change in anatomical size, is intimately related to that of development, the latter referring to a gradual ac- quisition of physiological function. Dobbing defined the brain growth spurt as that transient period of growth when the brain is growing most rapidly and the period of time when the brain is most susceptible to adverse influence [1]. Fetal malnutrition during the brain growth spurt may reduce the number of sy- napses per neuron by 40% [2]. Other authors have demonstrated a lower myelin lipid content in the brain of a small-for-gestational age (SGA) newborn as compared with that of an appropriate-for-gesta- tional age (AGA) newborn [3, 4]. In the human, a large part of the brain growth spurt takes place in the years after birth; therefore, the nutritional as well as the psychosocial environment during the first postna- tal years may add to, but equally compensate for, pre- vious adverse influence during fetal development.

Background

Neurodevelopmental Outcome in IUGR In follow-up studies of fetal growth restriction, IUGR has been defined mainly on the basis of gestational age-related birth weight (birth weight SGA). A study group selected on the basis of such a definition will not only include truly growth-restricted infants of various etiologies, but also genetically small but healthy infants. This is probably the main reason why the numerous follow-up studies of SGA infants pub- lished in the past did not give a clear answer to the question concerning the effect of IUGR on neurode- velopmental outcome. Another major reason for in- consistent results concerning outcome are the con-

founding variables associated with impaired fetal growth, perhaps the two most important variables being prematurity at birth and social class. The lower the socioeconomic status of the parents, the higher the chance of delivering an SGA infant, and, indepen- dent of this, the greater the risk of poor cognitive outcome [5].

In prospective studies, SGA infants rarely devel- oped major neurological impairment such as cerebral palsy and seizures, although Fitzhardinge and Stevens [6] reported an incidence of 7% major neurological sequelae at 4±6 years of age in children born SGA.

On the other hand, retrospective studies of children with cerebral palsy have shown fetal growth restric- tion to be an important etiological factor [7].

Several studies have shown an increased frequency of minor neurological dysfunction at early school age [8, 9] and of attention deficit disorder [10] in chil- dren born SGA. Ounsted et al. [11] found signifi- cantly lower neurobehavioral scores in SGA infants from 2 months up to the age of 1 year. One study, distinguishing SGA infants according to body propor- tions at birth, found children with symmetrical IUGR to have lower developmental scores at 3 years of age than those with asymmetrical IUGR, both groups having lower scores than AGA infants [12]. Berg [13]

found an increased risk of neurological abnormality at 7 years of age in children born SGA only in the presence of hypoxia-related factors, especially in those children with symmetrical body proportions at birth. A part of the cohort previously studied by Fitz- hardinge and Stevens [6] has been examined at a later age. Only minor differences were found between those born SGA and those born AGA after the exclu- sion of subjects with complications related to asphyx- ia at birth [14].

In a recent review, an intriguing hypothesis was offered, supported by substantial evidence concerning the perinatal anatomical and biochemical correlates of minor neurological dysfunction and behavioral problems observed in numerous follow-up studies of children in perinatal risk groups [15]. Studies using single photon emission computed tomography (SPECT) in children with minor neurological abnor- malities have shown evidence of hypoperfusion in the

Intrauterine Blood Flow and Postnatal Development

David Ley, Karel Marsϗl

striatum (globus pallidus and putamen). The striatum samples information from the entire cortex through spiny neurons, enormously rich in glutaminergic sy- napses. Repeated asphyxia in fetal sheep causing hy- potension and acidosis resulted in neuronal loss pri- marily in the striatum [16]. The reason for preferen- tial neuron loss in the striatum may partly be due to its localization in an arterial border zone making it vulnerable in a state of circulatory compromise.

Furthermore, perhaps most importantly, the spiny neurons will be at risk from the high levels of nox- ious glutamine released during hypoxia/ischemia in this area. IUGR is, as previously mentioned, asso- ciated with fetal hypoxia and circulatory changes.

One may speculate that the increased frequency of minor neurological dysfunction observed in children with IUGR may be due to damage induced by isch- emia in the striatal area.

IUGR and Cardiovascular Morbidity

An increasing body of studies have appeared on the relationship between suboptimal fetal growth and morbidity in adulthood. An early study on Swedish male army conscripts suggested that being born SGA may be a predictor of raised blood pressure in early adult life [17]. Epidemiological surveys of men born in Britain during the first three decades of the 19th century have shown an inverse relationship between weight at birth and blood pressure in adult age [18].

Morbidity in cardiovascular disease and incidence of non-insulin-dependent diabetes have further been demonstrated to relate to low birth weight [19, 20].

Barker and coworkers have speculated that changes in fetal blood flow and in activities of substances en- gaged in the regulation of fetal growth such as insulin and insulin-like growth factor I (IGF-I) may perma- nently affect vessel wall structure and have persisting effects on metabolism [21]. An increased vulnerabil- ity to maternal glucocorticoid levels in the growth-re- stricted fetus has also been suggested as a mechanism that may alter vasoregulatory mechanisms during fe- tal life and lead to subsequent hypertension [22].

Results from prospective postnatal studies have not been as convincing as those derived from large popu- lations studied retrospectively. No inverse correlation was found between size at birth and blood pressure at 8 years of age in a cohort of 616 prematurely deliv- ered children. On the contrary, blood pressure de- creased with decreasing birth weight for gestational age [23]. Williams et al. [24] observed a weak inverse association between blood pressure and birth weight for gestational age in children at 7 years of age, but when the same cohort was analyzed at 18 years of age, the relationship had disappeared. In a Dutch study, a U-shaped relationship was shown between

birth weight for gestational age and blood pressure at 4 years of age, implying an increase in blood pressure in children with both low and high birth weight for gestational age [25].

Postnatal Implications

of Abnormal Fetal Blood Flow

Abnormal flow velocity waveform in the umbilical ar- tery has been shown in a large number of studies to be associated with adverse outcome of pregnancy and high perinatal mortality rate [26, 27]. A multicenter European study [28] differentiated the outcome ac- cording to the presence, absence, or reversal of the end-diastolic flow in the umbilical artery. The odds ratio for perinatal mortality was 4.0 with absent end- diastolic flow and 10.6 with reversed end-diastolic flow when compared with high-risk pregnancies with positive end-diastolic flow in the umbilical artery.

The experience from descriptive studies has been used to design randomized controlled trials, which showed that the use of Doppler velocimetry as a method of fetal surveillance in high-risk pregnancies leads to a significant decrease of perinatal mortality [29]. The Doppler method became a method of choice for monitoring fetal health in pregnancies with complications caused by placental dysfunction. The changes of blood velocities recorded from the fetal descending aorta using Doppler ultrasound have been shown to parallel those found in the umbilical artery [30].

Neonatal Outcome

Several studies have been published on the associa- tion between abnormal fetal blood flow and short- term perinatal outcome. Absent or reverse end-dias- tolic flow (AREDF) in the umbilical artery or fetal descending aorta has been associated with an in- creased neonatal mortality and increased morbidity in terms of cerebral intraventricular hemorrhage and necrotizing enterocolitis (NEC) [31±34]. The relation- ship between abnormal fetal aortic velocities and ne- crotizing enterocolitis in the neonate is supported by the study by Kempley et al. [35], who found de- creased velocities in the superior mesenteric artery in SGA infants who had absent end-diastolic velocities in the aorta during fetal life.

McDonnell et al. [36] performed a case-control

study of AREDF, matching for gestational age and

pregnancy complications in 61 pairs of infants. They

found that AREDF was associated with a higher de-

gree of growth restriction, thrombocytopenia, and

NEC. A more recent case-control study of umbilical

AREDF, including 36 pairs of infants, matching for

the same variables as in the study by McDonnell et al. [36] but also for degree of deviation in birth weight, found no differences in outcome except a lower prevalence of ventilator requirement for RDS in infants with AREDF [37]. In a prospective study of mothers with pregnancy-induced hypertension, Ero- nen et al. [38] found AREDF in the umbilical artery to be associated with a higher incidence of gastro-in- testinal complications, bronchopulmonary dysplasia, intraventricular hemorrhage, and vascular hypoten- sion in the newborns. Although the infants with AREDF were delivered at an earlier gestational age, AREDF remained as a predictor of poor perinatal outcome after correction for prematurity. The in- creased morbidity of infants who showed AREDF in utero was confirmed by other authors with regard to the occurrence of cerebral hemorrhage, anemia, and hypoglycemia [28], as well as chronic lung disease, retinopathy of prematurity, and impaired intestinal motility [39].

Weiss et al. [40] found an increased frequency of abnormal neurological signs in newborn infants with AREDF as compared with a control group, matched for gestational age, with normal umbilical velocity waveforms in the umbilical artery. They found also in fetuses with preceding AREDF a significant increase in the cord blood levels of brain type isoenzyme of creatine kinase (CK-BB) as a possible indication of intrauterine brain cell damage [41]. Rizzo et al. [42]

described a decreased fetal cerebrovascular resistance as determined by a decreased pulsatility index (PI) in the internal carotid artery to be associated with post- asphyxial encephalopathy, as determined by neurolog- ical signs, in a cohort of high-risk pregnancies. On the other hand, in a study of 117 infants delivered be- tween 25 and 33 gestational weeks in high-risk preg- nancies, no relationship was observed between the ra- tio of PI in the fetal umbilical and cerebral circula- tion, and neither cerebral hemorrhage nor neurologi- cal abnormality in the neonatal period [43]; however, both Ley and Marɗl [44], and Scherjon et al. [45]

found a sustained abnormal cerebral blood flow in growth-restricted neonates and preterm neonates who showed signs of brain sparing in utero. It was specu- lated that this might be due to a different setting of cerebral autoregulation as a consequence of intrauter- ine redistribution of blood flow.

Long-Term Neurodevelopmental Implications

In comparison with the large body of studies pub- lished on short-term perinatal outcome of abnormal fetal blood flow [27], relatively few investigations have attempted to evaluate long-term consequences (Table 12.1).

Weiss et al. [46] found that the combination of AREDF in the umbilical artery, severe RDS, and deliv- ery before 28 gestational weeks was predictive of neu- rological abnormality at 6 months of age. A similar finding of a greater risk of permanent neurological sequelae at the age of 18 months was reported by Val- camonico et al. [47] for growth-restricted fetuses with AREDF in the umbilical artery. Abnormal fetal heart rate patterns were shown to be more predictive of poor cognitive outcome at 2 years of age than abnor- mal waveforms in the umbilical artery in fetuses of high-risk pregnancies delivered before 34 gestational weeks [48]. In a descriptive follow-up study, Wilson et al. [49] found no association between abnormal umbilical velocity waveforms and major neurological abnormality at 5 years of age. Similarly, in a group of 193 infants born to women with severe preeclampsia, there were no differences between those with and without AREDF in utero, when their neurodevelop- mental outcome was evaluated at the age of 2 and 4 years [50]. The only exception was the lower Perfor- mance subscale test at 24 months in the infants with previous AREDF.

The study by Vossbeck et al. [39] demonstrated that infants with AREDF born before 30 gestational weeks and followed up for between 1 and 8 years were more often mentally retarded (44 vs 25%) and had more often severe motor impairment (38 vs 19%) than the matched controls. Another 5-year prospec- tive follow-up of fetuses with AREDF showed 6 of 42 infants to be mentally handicapped [26]. A long-term impairment of intellectual capacity and partial neuro- developmental delay was also observed at school age in 23 infants who have had severely compromised blood flow in utero [51].

In the previously referred study by Scherjon et al.

[43], subsequent assessment of neurological signs at 6 and 12 months of age showed no relationship be- tween the ratio of PI in the fetal umbilical and cere- bral circulation and neurological abnormality. A par- allel study showed that infants at 6 months of age with a raised umbilical artery/middle cerebral artery PI ratio had shorter visual evoked potential latencies as compared to infants with a normal ratio (Fig. 12.1) [52]. This was interpreted as a sign of accelerated neurophysiological maturation, being of benefit to the fetus. At the age of 3 years, the adverse neurodevelop- mental development, as evaluated by Hempel exami- nation [53] in a subgroup of 96 infants from the orig- inal cohort, was related to neonatal cranial ultrasound abnormality, rather than to the signs of brain sparing in utero [54]. The authors interpreted this finding as confirmation of their interpretation of the brain spar- ing as being beneficial. Seventy-three of the children were examined subsequently at the age of 5 years.

The mean IQ score was significantly lower for chil-

Table 12.1. Intrauterine blood flo w and postnatal neur odev elopment. ADHD att ention deficit hyperac tivity disorder , AEDF absent end-diastolic flo w , AG A appro priat e-f or- gestational age ,AREDF absent or rev erse end-diast olic flo w ,BFC blood flo w class, CI confidence int er val, C/P ratio cere bro placental ratio = ratio betw een the middle cer ebral ar te ry and umbilical ar ter y PI, c.s .cesar ean section, EDF end-diastolic flo w ,GA gestational age ,IUGR intraut erine gr owth restric tion, PI pulsatility index, REDF rev erse end- diast olic flo w ,RI resistance index, RR risk ratio ,S/D syst olic-t o-diast olic ratio ,UA umbilical ar te ry ,U/C PI ratio ratio betw een the umbilical ar ter y and middle cere bral ar ter y PI, vag. vaginal delive ry Study Study gr oup Control gr oup Follo w-up study Ref er enc e Number Doppler finding

GA at bir th (w eeks) Number

Doppler finding

GA at bir th (w eeks) Ag e Test Finding in the study gr oup Umbilical ar ter y [46] 37 AREDF 26±40 37 Normal RI 32.4 (3.3) Up to 6 months Neur ology at dischar ge Mor e infants with abnormal neuro logical ev aluation [48] 25

Abnormal S/D

,c .s. < 34 17

Normal S/D

,c .s. < 34 2 years D en ver

Poor cognitiv e pr ogr ess, 40 Pr et erm, va g. < 34 Ba yley

dela yed mot or dev elopment 67 Term, vag . >37 [49] 7

Abnormal PI

32.1 23 Normal 36.6 4±6 years Neur ological exam No significant diff er ences 10 AREDF (3.4) (2.5) D en ver

[47] 20 AREDF ~31 26 Positiv e EDF ~33 1±2 years Uzgiris and Hunt

M ilit erni

Botto s

Gr eat er risk of permanent neuro logical sequelae [50] 31 AEDF < 34 (?) 95 Positiv e EDF < 34 (?) Ev er y 6 months up to 4 years Amiel-Tisson

Griffith

Snijders-O omen

No diff ere nces in the dev elopmental quotients or mot or out comes; at 2 years lo w er per formance subscale test [39] 16 AREDF 27 16 Mat ched contr ols (A GA)

27 13±91 months Lietz

Kaufman

Ba yley

Incr eased risk for mental retar dation and sev ere mot or impairment [46] 23 AREDF 28±40 23 Mat ched contr ols 28±40 6 years (3±8.5 years) Kaufman

Man-Dra wing test

Zurich Neur omot or te st

Long-t erm impairment of int ellectu al de- velopment and par tial neuro dev elopmen- tal dela y [60]

27 9 AEDF REDF 27±37 27±32

40 Positiv e EDF 26±38 5±12 years BAS-II

QNST-II

SDQ

Educational achiev e-

ment Visu

al functio n, hear- ing

AEDF ± not associat ed with adv erse neu- rodeve lopmental out come; REDF ± associat ed with a wide range of pr oblems

Table 12.1 (continued) Study Study gr oup Control gr oup Follo w-up study Ref er enc e Number Doppler finding

GA at bir th (w eeks) Number

Doppler finding

GA at bir th (w eeks) Ag e Test Finding in the study gr oup Fetal middle cer ebral ar ter y [52] 34 Raised U/C PI ratio

26±33 (med

31+5) 56 Normal U/ C PI ratio

26±33 (med

29+5) 6 and 12 months Visu al ev oked pot en- tials Accelerat ed neuro ph ysiological maturation (beneficial adaptiv e pr ocess) [54] 34 Raised U/C PI ratio

26±33 31+4

62 Normal U/ C PI ratio

26±33 29+6

3 years Hempel te st

No association with Hempel out come [55] 28 Raised U/C PI ratio

26±33 30+6

45 Normal U/ C PI ratio

26±33 29+4

5 years RAKIT

Fetal brain sparing associat ed with a poor er cognitiv e out come [57]

16 15 AREDF Abnormal C/P

ratio

28±36 27±39

31 Mat ched AG A

27±39 27±39

4.5 years D en ver

Kaufman

Snijders-O omen

Impair ed cognitiv e dev elopment Fetal aor tic isthmus [58] 5 UA PI >95th per- centile;

³ 29 39 UA PI >95th per- centile;

³ 29 2±4 years Amiel-Tisson

Griffith

RR of 2.05 (95% CI 1.49±2.83) for neuro de- velopmental deficit retro grade net isthmic flo w

ant egrade net isthmic flo w Fetal descending aor ta [63] 42

Abnormal BFC

(36 AREDF)

29±41 105

Normal BFC

(nor- mal aor tic PI)

32±42 7 years Touw en

Abnormal BFC was significant pr edic tor of minor neur ological dysfunction [64] 41

Abnormal BFC

(35 AREDF)

29±41 105

Normal BFC

(nor- mal aor tic PI)

32±42 6.5 years WPPSI

Abnormal BFC was significant pr edic tor of impair ed int ellec tual out come [71] 28

IUGR (19

AREDF) 35±41 23

AGA Normal BFC

36±42 18 years W AIS

W ender Utah

Incr eased rat e of ADHD and emotional disturbance ,decr eased cognitiv e capacity [72] 19

IUGR (19

AREDF) 35±41 23

AGA Normal BFC

36±42 18 years Quantitativ e analysis of ocular fundus phot ograph y

Decreased neur or etinal rim ar ea of the op- tic ner ve disc [73] 26

IUGR (17

AREDF) 34±41 20

AGA Normal BFC

36±42 18 years Rar ebit micr odot perimetr y Decreased central field vision (lo w er Rare- bit hit rat e)

Den ver Developmental Scr eening Test;

Ba yley scales of infant dev elopment;

Uzgiris and Hunt 's crit eria of postural functio n;

M ilit erni' s crit eria of sensorial functio n;

Bot- tos 'crit eria of cognitiv e function;

Mot or dev elopmental assessment according to Amiel-Tisson;

Griffith 's mental dev elopmental scales;

Snijders-Oomen non-v erbal int elli- gence scale for Young Childr en;

standar diz ed neur ological examination according to Lietz;

Kaufman Assessment Batt er y for Childr en;

Man Dra wing Test accor ding to Ziler ;

Zurich Neur omot or Test according to Lar go and Caflisch;

British Ability Scales;

Quick Neur ological Scr eening Test;

Str ength and Difficulties Questionnair e;

Hempel exam- ination of neur ological dev elopment;

Revision of the Amst er dam Childr en 's Int elligence Test;

Touw en 's examination of the child with minor neur ological dysfunction;

W echsler Pr eschool and Primar y Scale of Int elligence;

W echsler Adult Int elligence Scale;

W ender Utah Rating Scale .

dren born with signs of brain sparing, i.e., with a raised umbilical artery/middle cerebral artery PI ra- tio, than for those with normal intrauterine blood flow [55]. This led the authors to revise their previous interpretation of the fetal brain sparing as being a beneficial adaptive mechanism.

Chan et al. [56] used the ratio of resistance indices in the umbilical and cerebral circulation of high-risk fetuses and did not find any association with major neurological handicap at 2 years of age. Cerebropla- cental PI ratio was used by Kutschera et al. [57] to characterize the intrauterine blood flow. At the age of 3±6 years, they did not find any difference in the cog- nitive, neurological, and somatic development be- tween the group with abnormal cerebroplacental ratio and the group with AREDF in the umbilical artery;

however, both groups showed impaired cognitive de- velopment as compared with controls [57].

Fouron et al. [58] followed up a group of 44 fe- tuses with abnormal umbilical artery Doppler velo-

cimetry and related their neurodevelopmental condi- tion at 2 to 4 years of age to the flow patterns in the fetal aortic isthmus. All 5 fetuses with retrograde net isthmic flow had non-optimal neurodevelopment.

This finding seems to support the previous conclu- sion by the authors that the Doppler examination of the aortic isthmus flow pattern in utero might identi- fy fetuses with impending cerebral hypoxia [59].

In a recent paper by Schreuder et al. [60], the neu- rodevelopmental outcome at 5±12 years of age was related to the presence (n=40), absence (n=27), or reversal (n=9) of the end-diastolic flow velocity in the umbilical artery. The absence of diastolic flow was not associated with adverse outcome; however, the reversal of end-diastolic flow was associated with a wide range of problems at school age, decreased mental ability, and impaired neuromotor function.

Fig. 12.1. a Recording of visual evoked potentials at cor- rected age of 6 months (top) and 12 months (bottom) of infant born very preterm with normal intrauterine blood flow. The P

latency has shortened between 6 and 12 months from 150 to 120 ms. (From [52]). b Recording of vi-

sual evoked potentials at corrected age of 6 months (top)

and 12 months (bottom) of infant born very preterm, who

showed signs of brain sparing in utero. The P

latency did

not change between 6 and 12 months, being 133 and 129

ms, respectively. (From [52])

The Malmæ±Lund Study

We have performed a longitudinal follow-up study (up to 18 years of age) of subjects previously exam- ined during antenatal life with measurements of in- trauterine blood flow and fetal growth. The study has focused on evaluating possible effects of IUGR with abnormal fetal blood flow on subsequent neurological and cardiovascular development including neural and vascular morphology and function.

Background Material

In two longitudinal prospective studies, serial fetal blood flow velocity examinations and measurements of fetal growth using ultrasound and Doppler velocim- etry were performed in 178 pregnancies during a 3- year period, 1982±1985, at the Department of Obste- trics and Gynecology in Malmæ [61, 62]. The blood flow velocity waveform in the fetal aorta was trans- formed into a semi-quantitative variable, blood flow class (BFC), four BFCs being defined to describe the appearance of the waveform, with emphasis on its dia- stolic part. These classes were as follows: BFC 0 (nor- mal), positive flow throughout the heart cycle and a normal pulsatility index; BFC I, positive flow through- out the cycle and a pulsatility index 5 mean +2SD of normal; BFC II, non-detectable end-diastolic velocity;

and BFC III, absence of positive flow throughout the major part of the diastole and/or reverse flow in dia- stole. Fetal aortic BFC was defined according to the re- sult of the last measurement performed before delivery.

In 74 cases the pregnancy resulted in a birth weight 52SD below the mean of the normal population, i.e., they fulfilled the criterion of being SGA at birth.

In 3 cases the fetus died in utero.

Fetal Aortic Blood Flow and Postnatal Neurodevelopment

Neurological and Cognitive Development at 7 Years of Age

At the age of 6.5 years, 148 children (84% of the background population) underwent an intellectual evaluation and at 7 years of age, 149 (85%) children underwent a neurological examination with special emphasis on minor neurological dysfunction (MND) [63, 64]. The neurological assessment consisted of an age-specific and standardized examination which comprised 64 test items grouped into six subsystems or clusters as described by Touwen [65]. The subsys- tems were: posture; sensorimotor apparatus; coordi- nation and balance; fine manipulative ability; dyski- nesia; and miscellaneous dysfunctions. According to the number of deviant subsystems, the result of the

neurological examination was classified as normal, MND-1 (one to two deviant subsystems) or MND-2 (more than two deviant subsystems). The intellectual development was evaluated by a psychologist using a standardized intelligence test (Wechsler Preschool and Primary scale of Intelligence, WPPSI) [66].

The frequency of the more severe form of MND, MND-2, was significantly higher in the BFC III group (8 of 21) than in the group with BFC 0 (normal) (14 of 105; Fig. 12.2) [63]. The frequency of MND-1 was higher in the BFC II group (8 of 21) than in the group with BFC 0 (35 of 91). The group of children with BFC III deviated more frequently in three neurological sub- systems as compared with the BFC 0 group; coordina- tion and balance, dyskinesia, and fine motor ability.

The group with abnormal fetal BFC had a lower mean verbal IQ as compared with the group with normal fetal BFC [64]. The groups did not differ sig- nificantly in performance IQ, although a tendency to- wards lower mean performance IQ was observed in the group with abnormal fetal BFC. Global IQ was significantly lower in the group with abnormal fetal BFC. The largest discrepancies between groups were found in the subtests information, comprehension, and arithmetic. These subtests have been shown to be good predictors of reading and school achievement [67, 68]. Furthermore, children with a learning dis- ability have been shown to obtain low scores within these specific subtests [69].

To enable an assessment of the aggregate effect of probable risk variables on neurodevelopmental out- come we performed multivariate analysis [64]. This

Fig. 12.2. Neurological score at 6 years of age in relation

to fetal aortic blood flow class, gestational age at birth and

birth weight for gestational age. Higher score indicates in-

creasing deviation from optimality. AGA appropriate-for-ge-

stational age, SGA small-for-gestational age (From [92])

analysis included independent ante- and postnatal variables and an evaluation of the effect of socio-eco- nomic variables and interval complications occurring during postnatal life. In multivariate analysis, MND-1 was best predicted by the combination of increasing birth-weight deviation and male sex, whereas the best combination of variables contributing significantly to MND-2 was abnormal BFC and male sex. Global IQ£85 was best predicted by abnormal BFC, fetal ge- stational age at measurement, and social group. Fetal gestational age at measurement was present as an additional risk factor, due to interaction with BFC.

When the last BFC measurement was normal and performed after 37 gestational weeks of pregnancy, only one child of 40 had a global IQ<85. The dicho- tomous variable SGA/AGA showed no association with any of the intellectual outcome variables. The as- sociation of fetal growth restriction to both short- term and long-term outcome will generally be more powerfully expressed when using a continuous vari- able, such as birth-weight deviation, as compared with birth-weight categories.

A reduction in mean fetal aortic blood flow veloc- ity has been correlated to hypoxia in the IUGR fetus, blood±gas values being obtained by cordocentesis [70]. The association found between an abnormal fe- tal aortic waveform and unfavorable neurodevelop- mental outcome, which remained after adjustment for other confounding variables, may be attributed to fe- tal hypoxia. The fetal aortic velocity waveform re- flects conditions both in the peripheral fetal circula- tion and in the placental circulation. The hemody- namic mechanism responsible for the abnormal wave- form may therefore be both reduced peripheral blood supply due to hypoxia or increased impedance of the placental circulation, or both.

Cognitive Outcome at 18 Years of Age

We continued the prospective follow-up study on a subgroup of the previously described cohort. A total of 51 subjects were examined at a median age of 18.2 years [71]. Twenty-eight of the subjects, 18 women and 10 men, were SGA at birth with a median devia- tion of weight at birth of ±31% (range ±42 to ±22%) from the gestational age-related mean, at a median gestational age of 38.7 completed weeks (35±41 weeks). Nine subjects had BFC III, 10 subjects had BFC II, 2 subjects had BFC I, and 7 subjects had a normal BFC. The remaining 23 subjects, 13 women and 10 men, had a normal estimated fetal weight, normal aortic BFC, and an AGA weight at birth with median weight deviation ±2% (±10 to 22%) at a median gestational age of 39.7 weeks (36±42 weeks).

At 18 years of age, a psychologist evaluated the cognitive capacity using the Wechsler Adult Intelli-

gence Scale (WAIS) that, similarly to the WIPPSI test performed at 6 years of age, consists of several sub- tests resulting in a performance IQ and a verbal IQ.

The SGA subjects had a lower performance IQ as compared with those with birth-weight AGA, but did not differ significantly in verbal IQ. Fetal aortic blood flow class was not related to global IQ; however, the subjects with BFC II and III had a lower processing speed index (PSI) as compared with those with BFC 0 and I. The PSI measures fine motor ability, visual and working memory, and psychomotor speed. We found a high correlation between cognitive test results at 6 years and those at 18 years of age. Interestingly, the correlation between test results at the respective ages was higher for the SGA group. The results suggest that cognitive level at 6 years of age as determined by a standardized IQ test is more predictive of cognitive level at 18 years of age in subjects with IUGR than in those with normal fetal growth and birth weight. A retrospective assessment of attention deficit hyperac- tivity disorder (ADHD), the Wender Utah Rating scale, showed that the rate of ADHD was increased in the group with birth-weight SGA. These subjects had low IQ scores at both 6 and 18 years of age and also reported more psychiatric symptoms at 18 years.

Although the majority of subjects with IUGR had IQ score within the normal range at 18 years of age, we found an increased rate of individuals with multiple impairments, i.e., ADHD, decreased cognitive capaci- ty, and emotional disturbance.

Retinal Neural Morphology and Function At 18 years of age, all subjects had an eye examina- tion, including fundus photography after cycloplegia.

Quantitative analysis of fundus photographs, utilizing a computer-assisted digital mapping system, evaluated two outcome measures: (a) the neuroretinal rim area (obtained by subtraction of the cup area from the op- tic disc area) as a measure of the optic nerve central nervous tissue; and (b) the number of branching points of retinal arterioles and venules as a measure of vascularization. The mean of the measurements from the two eyes in one subject represented the val- ue of each ocular fundus variable. Visual function was assessed by using Rarebit perimetry which is a recently developed method for measuring central field vision [72].

We found that a more pronounced negative birth-

weight deviation was associated with a decrease in

neuroretinal rim area (p=0.0001) [73]. The subjects

with fetal aortic BFC III had a reduced neuroretinal

rim area, median 1.59 mm

(range 1.33±1.86 mm

) as

compared with those with fetal aortic BFC II

(1.85 mm

; range 1.37±2.13 mm

) and to those with

normal fetal aortic BFC (2.22 mm

; range 1.70±

2.71 mm

; p<0.05 and p<0.0001, respectively; Figs.

12.3, 12.4). These findings indicate that IUGR is asso- ciated with a reduced axonal area in the optic nerve at young adult age. Degree of deviation in weight at birth and extent of fetal blood flow velocity abnorm- ality were both associated with an increased reduc- tion of the axonal area of the optic nerve. The ob- served reduction in axonal area may reflect either re- duced axonal growth with a reduction of axonal vol- ume or a decrease in the number of axons, i.e., in the number of neurons.

It can be speculated as to whether the observed re- duction in axonal area is restricted to the optic nerve tract or represents a more global affection of neuro- nal growth within the brain. We found a strong asso- ciation between MND at 6 years of age and a reduced axonal area suggesting that other regions of the cen- tral nervous system might be affected. The subjects with severe MND at 6 years of age had among other deviations consistent abnormalities in test items measuring coordination and balance suggestive of changes in the cerebellum or basal ganglia [63]. Ex- perimental studies on induced fetal growth restriction during late pregnancy in guinea pigs and fetal sheep have shown a reduction in volume of cerebellar layers and in the number of Purkinje neurons in the cere- bellum [74, 75]. Neuroradiological studies on humans following IUGR with volumetric quantification of the cerebellar region have, to our knowledge, not yet been performed.

Fetal hypoxia as well as fetal malnutrition may be considered as plausible causes for the observed re- duction in axonal area of the optic nerve. Fetal mal- nutrition during IUGR may be an important factor in disturbing cellular growth and differentiation in the central nervous system. Trophic factors, such as IGF- I, are essential for cellular growth and differentiation as well as for tissue repair after a damaging insult.

Undernutrition in humans and in experimental ani- Fig. 12.3. Relationship between neuroretinal rim area of

the optic nerve examined at 18 years of age and fetal aor- tic blood flow class (BFC). BFC III corresponds to absent or reverse flow in diastole. (From Ley et al. [72])

Fig. 12.4. a Ocular fundus photography showing a re- duced neuroretinal rim area of the optic nerve in a 18- year-old male subject with an SGA birth weight and reverse diastolic flow in fetal descending aorta (BFC III).

b Neuroretinal rim area of the optic nerve in an 18-year-

old male subject with normal fetal growth and normal fetal

aortic blood flow. (From Ley et al. [73])

mals decreases IGF-I expression in many tissues and in the circulation [76, 77]. Circulatory levels of IGF-I have been shown to be decreased in SGA fetuses and in fetuses with abnormal blood flow velocity [78, 79].

In our study at 18 years of age, the central field vi- sion, as represented by the Rarebit mean hit rate [72], ranged from 93 to 100% in subjects with birth- weight AGA and from 48 to 100% in those with birth-weight SGA with the median hit rate being sig- nificantly lower in the SGA group as compared with that in the AGA group (p=0.03). Eight of the SGA subjects and none of the controls had a hit rate below the normal range (p=0.006). The deviant hit rates detected by the Rarebit microdot perimetry in some SGA subjects may reflect defects in the matrix of de- tectors, i.e., the neural channels, and may be caused by disturbed axonal growth or development. This finding of abnormal function lends support to the previously mentioned morphological finding of re- duced neuroretinal rim area in subjects with IUGR.

Fetal Aortic Blood Flow and Postnatal Cardiovascular Function

Aortic Vessel Wall Characteristics and Blood Pressure at 9 Years of Age

We used an electronic phase-locked echo-tracking system DIAMOVE (Teltec, Lund, Sweden) for non-in- vasive monitoring of pulsatile diameter changes in the descending aorta [81, 82] of a subgroup of 68 children from the original Malmæ cohort. Neither ab- normal fetal aortic blood flow nor birth-weight devia- tion were reflected in any significant changes in elas- tic modulus or stiffness of the abdominal aorta at 9 years of age [80]. Within the examined group, the subjects with the highest body weight at the time of examination had the highest levels of systolic blood pressure. These results support the hypothesis that the link between fetal growth failure and high blood pressure in adult life may mainly be expressed among those with obesity.

Children born SGA had significantly lower vessel diameters than those born AGA and these differences remained significant after adjustment for body sur- face area. These findings resemble in part those of Stale et al. [83] who found lower values of end-dia- stolic diameters in SGA fetuses than in AGA fetuses of the same gestational age using an identical tech- nique for aortic measurements; however, when the fe- tal aortic diameters were adjusted for estimated fetal weight, the relationship was reversed. The larger weight-related diastolic diameter taken together with the finding of a lower relative pulse amplitude in the SGA fetuses suggested an increase in diastolic blood pressure, possibly as a response to the increased pe-

ripheral resistance, namely that of the placental circu- lation, found in pregnancies complicated by IUGR.

The present findings obtained at 9 years of age [80]

showed no evidence of an increase in diastolic blood pressure related to restricted fetal growth. On the contrary, IUGR was associated with lower diastolic blood pressure. As the influence of the increased re- sistance to fetal blood flow caused by the abnormal placenta in fetal growth restriction will cease to exist after birth, it would seem plausible that the postu- lated compensatory increase in blood pressure during the fetal period would no longer be present in child- hood.

Pulse pressure was significantly higher within the group of children born SGA than in those born AGA [80]. An increase in pulse pressure has previously been described in SGA infants at 6 weeks of age [84]

and has been associated with signs of low arterial compliance and hypertensive disease in adults [85, 86]; however, we were unable to detect any corre- sponding changes in aortic compliance in association with either abnormal fetal aortic blood flow or SGA birth weight. A previous study of human aortic com- pliance and its normal variation with age found a profound increase in compliance between 4 and 11 years of age [87]. Aortic compliance thereafter exhib- ited a gradual decrease with values beyond 16 years being similar to those of healthy adults. This may im- ply that changes in aortic vessel compliance due to fetal causes may be detectable at a later age when aortic compliance decreases due to the normal ageing process. The increase in pulse pressure observed in the SGA group [80] might suggest, in the absence of changes in elastic modulus and stiffness of the abdominal aorta, the possibility of corresponding changes in more peripheral segments of the arterial tree.

Size and Function of Large Arteries at 18 Years of Age

At 18 years of age [88], vascular mechanical proper- ties of the common carotid artery (CCA), abdominal aorta (AO), and popliteal artery (PA) were assessed by echo-tracking sonography in 21 adolescents with IUGR and abnormal fetal aortic blood flow, and in 23 adolescents with normal fetal growth and normal fetal aortic blood flow, all belonging to the Malmæ- Lund follow-up cohort [71±73, 89]. Endothelium-de- pendent and endothelium-independent vasodilatation of the brachial artery was measured by high-resolu- tion ultrasound.

The IUGR group had significantly smaller mean

vessel diameters compared with controls in the AO

and PA in proportion to the body size, with a similar

trend in the CCA. Stiffness in all three vascular re-

gions was comparable between the two groups. Men from the IUGR group had a lower compliance coeffi- cient in the AO (corrected for body surface area) than men from the control group. The time course of vaso- dilatation in the IUGR group appeared to be different from the control group with higher values of flow- mediated vasodilatation at 2 min after cuff deflation in the IUGR group. Smaller aortic dimensions and the lower aortic compliance coefficient seen in male adolescents with previous IUGR may influence the fu- ture cardiovascular health of these individuals. Sus- tained flow-mediated vasodilatation may indicate an increased synthesis of nitric oxide in response to forearm occlusion.

Retinal Vascular Morphology at 18 Years of Age [89]

In the cohort of young adults, followed by us, we found that increasing negative birth-weight deviation was associated with a decrease in the number of ret- inal vascular branching points (p=0.02; Fig. 12.5).

Neither age at examination, gender, nor the degree of abnormal fetal blood flow were associated with the number of retinal vessel-branching points. It is un- clear whether the finding of reduced vessel-branching points in IUGR subjects is restricted to the retina or whether it reflects a more general affection of vascu- lar growth within the body. A previous study in IUGR rats induced by protein restriction has shown reduced vasculature in the cerebral cortex [90]. Our findings of a reduced size of large arteries in subjects with IUGR detected at 9 and 19 years of age, and that of a reduced number of branches in the retinal vascu- lature, support a general affection of angiogenesis.

Others have shown signs of impaired endothelial function in small and large arteries in school children born SGA [91]. We found that aortic compliance ap- peared unaffected at 9 years of age [80], whereas men at 19 years of age had signs of decreased compliance [88]. These findings of functional and morphological deficits may contribute to a better understanding of the link between restricted fetal growth and cardio- vascular disease.

Conclusion

In conclusion, several studies have shown abnormal fetal hemodynamics in the growth-restricted fetus, especially umbilical AREDF, to be associated with a clear increase in perinatal mortality and neonatal morbidity. The long-term follow-up studies per- formed until now did not show clear evidence of ma- jor neurological handicap being associated with ab- normal fetal hemodynamics. This is not surprising as

the much larger body of prospective follow-up studies on IUGR, in terms of birth-weight SGA, seldom showed an increase in major neurological impairment associated with fetal growth impairment. Minor neu- rological dysfunction, behavioral abnormality, and learning problems at school age, all frequently re- ported as overrepresented in perinatal risk groups, would probably be more adequate as outcome vari- Fig. 12.5. a Ocular fundus photography demonstrating a reduced number of retinal vessel-branching points in an 18-year-old female with an SGA birth weight and abnormal fetal aortic blood flow (BFC III). b Ocular fundus photogra- phy with a normal number of retinal vessel-branching points in an 18-year old female with normal fetal growth and normal fetal aortic blood flow. (From Hellstræm et al.

[89])

ables when assessing the effects of fetal hemody- namics on postnatal neurodevelopment.

Hemodynamic evaluation of the fetus has in- creased our understanding of the physiological mech- anisms involved in fetal growth restriction and is of proven clinical value in the management of high-risk pregnancies. Knowledge of changes in umbilical and fetal blood flow has also been of great value in the definition of true IUGR in subjects with deviation in weight during fetal life or at birth; thus, follow-up studies in subjects with abnormal fetal blood flow with varying degrees of deviation in weight have sup- plied valuable information on effects of IUGR on dif- ferent aspects of postnatal development. Abnormal fe- tal blood flow reflects changes in the feto-placental unit associated with a reduced fetal supply of oxygen and nutrients. Other authors, in addition to us, have shown that such fetal deprivation may lead to long- standing disturbances in morphology and subsequent function of the nervous and cardiovascular system.

This information, coupled with insights derived from experimental and clinical studies allowing for interac- tion with genetic differences, will increase under- standing of mechanisms leading to postnatal morbid- ity due to restricted fetal growth. Furthermore, this knowledge will make it possible to design clinical trials evaluating management protocols aiming not only to prevent perinatal mortality, but also to im- prove the postnatal development and health later in life of individuals with abnormal intrauterine blood flow.

References

1. Dobbing J (1981) The later development of the brain and its vulnerability. In: Davis JA, Dobbing J (eds) Scientific foundation of pediatrics, 2nd edn. William Heinemann Medical Books Ltd., London, pp 744±759 2. Dobbing J (1979) Nutrition and brain development. In:

Thalhammer O, Baumgarten K, Pollak A (eds) Perinatal medicine. Sixth European Congress. Thieme, Stuttgart 3. Chase HP, Welch NN, Dabiere CS, Vasan NS, Butterfield

LJ (1972) Alterations in human brain biochemistry fol- lowing intrauterine growth retardation. Pediatrics 50:

403±411

4. Sarma MKJ, Rao KS (1974) Biochemical compositions of different regions in brains of small-for-date infants.

J Neurochem 22:671±677

5. Breart G (1988) Available evidence relating intrauterine growth retardation to neuromotor dysfunction and mental handicap. In Kubli F, Patel N, Scmidt W (eds) Perinatal events and brain damage in surviving infants.

Springer, Berlin Heidelberg New York, pp 92±98 6. Fitzhardinge PM, Stevens EM (1972) The small for date

infant. II. Neurological and intellectual sequelae. Pedia- trics 50:50±57

7. Hagberg G, Hagberg B, Olow I (1976) The changing panorama of cerebral palsy in Sweden 1954±1970. III.

The importance of fetal deprivation of supply. Acta Paediatr Scand 65:403±408

8. Hadders-Algra M, Huisjes HJ, Touwen BCL (1988) Pre- term or small-for-gestational age infants. Neurological and behavioural development at the age of 6 years. Eur J Pediatr 147:460±467

9. Walther FJ, Raemakers LHJ (1990) Developmental as- pects of subacute fetal distress: behaviour problems and neurological dysfunction. Early Hum Dev 6:1±10 10. Hawdon JM, Hey E, Kolvin I, Fundudis T (1990) Born

too small. Is outcome still affected? Dev Med Child Neurol 32:943±953

11. Ounsted M, Moar VA, Scott WA (1988) Neurological development of small-for-gestational age babies during the first year of life. Early Hum Dev 16:163±172 12. Villar J, Smerigilo V, Martorell R, Brown CH, Klein RE

(1984) Heterogenous growth and mental development of intrauterine growth retarded infants during the first 3 years of life. 74:783±791

13. Berg AT (1989) Indices of fetal growth retardation, perinatal hypoxia-related factors and childhood neuro- logical morbidity. Early Hum Dev 19:271±283

14. Westwood M, Kramer MS, Muntz D, Locett JM, Watters GV (1983) Growth and development of full-term non- asphyxiated small for gestational age newborns: follow up through adolescence. Pediatrics 71:367±382 15. Lou HC (1996) Etiology and pathogenesis of Attention-

Deficit Hyperactivity Disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic en- cephalopathy. Acta Paediatr 85:1266±1271

16. Mallard EC, Williams CE, Johnston BM, Gunning MI, Davis S, Gluckman PD (1995) Repeated asphyxia causes loss of striatal projection neurons in the fetal sheep brain. Neuroscience 65:827±836

17. Gennser G, Rymark P, Isberg PE (1988) Low birth weight and risk of high blood pressure in adulthood.

Br Med J 296:1498±1500

18. Barker DJP, Bull AR, Osmond O, Simmons SJ (1990) Fetal and placental size and risk of hypertension in adult life. Br Med J 301:259±262

19. Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ (1989) Growth in utero, blood pressure in child- hood and adult life, and mortality from cardiovascular disease. Br Med J 298:564±567

20. Hales CN, Barker DJP, Clark PMS (1991) Fetal and in- fant growth and impaired glucose tolerance at age 64.

Br Med J 303:259±262

21. Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS (1993) Type 2 (non-insulin dependent) dia- betes mellitus, hypertension and hyperlipidaemia (syn- drome X): relation to reduced fetal growth. Diabetolo- gia 36:62±67

22. Edwards C, Benediktsson R, Lindsay R, Seckl J (1993) Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension?

Lancet 341:355±357

23. Morley R, Lister G, Leeson-Payne C, Lucas A (1994) Size at birth and later blood pressure. Arch Dis Child 70:536±537

24. Williams S, St George IM, Silva PA (1992) Intrauterine

growth retardation and blood pressure at age seven

and eighteen. J Clin Epidemiol 45:1257±1263

25. Launer LJ, Hofman A, Grobbee DE (1993) Relation be- tween birth weight and blood pressure: longitudinal study of infants and children. Br Med J 307:1451±1454 26. Montenegro N, Santos F, Tavares E, Matias A, Barros

H, Leite LP (1998) Outcome of 88 pregnancies with ab- sent or reversed end-diastolic blood flow (ARED flow) in the umbilical arteries. Eur J Obstet Gynecol Reprod Biol 79:43±46

27. El Bishy G, Sturgiss SN (2003) Absent-end-diastolic flow velocity in the umbilical artery. Fetal Maternal Med Rev 143:251±271

28. Karsdorp VHM, van Vugt JMG, van Geijn HP, Kostense PJ, Arduini D, Montenegro N, Todros T (1994) Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery. Lancet 344:1664±1668 29. Westergaard HB, Langhoff-Roos J et al. (2001) A criti-

cal appraisal of the use of umbilical artery Doppler ul- trasound in high risk pregnancies: use of meta-anal- yses in evidence-based obstetrics. Ultrasound Obstet Gynecol 17:466±476

30. Gudmundsson S, Marɗl K (1991) Blood velocity wave- forms in the fetal aorta and umbilical artery as predic- tors of fetal outcome: a comparison. Am J Perinatol 8:1±6

31. Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T, Pearce JMF (1987) Doppler studies in the growth re- tarded fetus and prediction of neonatal necrotising en- terocolitis, haemorrhage and neonatal morbidity. Br Med J 294:13±15

32. Brar HS, Platt LD (1988) Reverse end-diastolic flow ve- locity and umbilical artery velocimetry in high-risk pregnancies; an ominous finding with adverse preg- nancy outcome. Am J Obstet Gynecol 159:559±561 33. Malcolm G, Ellwood D, Devonald K, Beilby R, Hender-

son-Smart D (1991) Absent or reversed end diastolic flow velocity in the umbilical artery and necrotising enterocolitis. Arch Dis Child 66:805±807

34. Wilson DC, Harper A, McClure G (1991) Absent or re- versed end diastolic flow velocity in the umbilical ar- tery and necrotising enterocolitis. Arch Dis Child 66:1467

35. Kempley ST, Gamsu HR, Vyas S, Nicolaides K (1991) Effects of intrauterine growth retardation on postnatal visceral and cerebral blood flow velocity. Arch Dis Child 66:1151±1158

36. McDonnell M, Serra-Serra V, Gaffney G, Redman CW, Hope PL (1994) Neonatal outcome after pregnancy complicated by abnormal velocity waveforms in the umbilical artery. Arch Dis Child 70:F84±F89

37. Adiotomre P, Johnstone FD, Laing IA (1997) Effect of absent end diastolic flow velocity in the fetal umbilical artery on subsequent outcome. Arch Dis Child 76:35±

38. Eronen M, Kari A, Pesonen E, Kaaja R, Wallgren EI, 38 Hallman M (1993) Value of absent or retrograde end- diastolic flow in fetal aorta and umbilical artery as a predictor of perinatal outcome in pregnancy-induced hypertension. Acta Paediatr 82:919±924

39. Vossbeck S, Kraus de Camargo O, Grab D, Bode H, Pohlandt F (2001) Neonatal and neurodevelopmental outcome in infants born before 30 weeks of gestation with absent or reversed end-diastolic flow velocities in the umbilical artery. Eur J Pediatr 160:128±134

40. Weiss E, Ulrich S, Berle P (1992) Condition at birth of infants with previously absent or reverse umbilical ar- tery end-diastolic flow velocities. Arch Gynecol Obstet 252:37±43

41. Weiss E, Ulrich S, Berle P, Picard-Maureau A (1994) CK-BB as indicator of prenatal brain-cell injury in fe- tuses with absent or reverse end-diastolic flow veloci- ties of the umbilical arteries. J Perinat Med 22:219±226 42. Rizzo G, Arduini D, Luciano R, Rizzo C, Tortorolo G,

Romanini C, Mancuso S (1989) Prenatal cerebral Dop- pler ultrasonography and neonatal neurologic outcome.

J Ultrasound Med 8:237±240

43. Scherjon SA, Smolders-DeHaas H, Kok JH, Zondervan HA (1993) The ªbrain-sparingº effect: antenatal cere- bral Doppler findings in relation to neurologic outcome in very preterm infants. Am J Obstet Gynecol 169:169±

44. Ley D, Marɗl K (1992) Doppler velocimetry in cerebral 175 vessels of small for gestational age infants. Early Hum Dev 31:171±180

45. Scherjon SA, Smolders-DeHaas H, Oosting H, Kok JH, Zondervan HA (1994) Neonatal cerebral circulation in relation to neurosonography and neurological outcome:

a pulsed Doppler study. Neuropediatrics 25:208±213 46. Weiss E, Ulrich S, Berle P (1992) Blood flow velocity

waveforms of the middle cerebral artery and abnormal neurological evaluations in live-born fetuses with ab- sent or reverse end-diastolic flow velocities of the um- bilical arteries. Eur J Obstet Gynecol Reprod Biol 45:

93±100

47. Valcamonico A, Danti L, Frusca T, Soregaroli M, Zucca S, Abrami F, Tiberti A (1994) Absent end-diastolic ve- locity in umbilical artery: risk of neonatal morbidity and brain damage. Am J Obstet Gynecol 170:796±801 48. Todd AL, Trudinger BJ, Cole MJ, Cooney GH (1992)

Antenatal tests of fetal wellfare and development at age 2 years. Am J Obstet Gynecol 167:66±71

49. Wilson DC, Harper A, McClure G, Halliday H, Reid M (1992) Long term predictive value of Doppler studies in high risk fetuses. Br J Obstet Gynecol 99:575±578 50. Kirsten GF, Van Zyl JI, Van Zijl F, Maritz JS, Odendaal

HJ (2000) Infants of women with severe early pre- eclampsia: the effect of absent end-diastolic umbilical artery doppler flow velocities on neurodevelopmental outcome. Acta Paediatr 89:566±570

51. Wienerroither H, Steiner H, Tomaselli J, Lobendanz M, Thun-Hohenstein L (2001) Intrauterine blood flow and long-term intellectual, neurologic and social develop- ment. Obstet Gynecol 97:449±453

52. Scherjon S, Oosting H, Ongerboer de Visser BW, de Wilde T, Zondervan HA, Kok JH (1996) Fetal brain sparing is associated with accelerated shortening of vi- sual evoked potential latencies during early infancy.

Am J Obstet Gynecol 175:1569±1575

53. Hempel MS (1993) Neurological development during toddling age in normal children and children at risk of developmental disorders. Early Hum Dev 34:47±57 54. Scherjon SA, Oosting H, Smolders-DeHaas H, Zonder-

van HA, Kok JH (1998) Neurodevelopmental outcome at three years of age after fetal ªbrain-sparingº. Early Hum Dev 52:67±79

55. Scherjon S, Briet J, Oosting H, Kok J (2000) The dis-

crepancy between maturation of visual-evoked poten-

tials and cognitive outcome at five years in very pre- term infants with and without hemodynamic signs of fetal brain-sparing. Pediatrics 105:385±391

56. Chan FY, Pun TC, Lam P, Lam C, Lee CP, Lam YH (1996) Fetal cerebral Doppler studies as a predictor of perinatal outcome and subsequent neurological handi- cap. Obstet Gynecol 87:981±988

57. Kutschera J, Tomaselli J, Urlesberger B, Maurer U, Hausler M, Gradnitzer E, Burmucic K, Mçller W (2002) Absent or reversed end-diastolic blood flow in the um- bilical artery and abnormal Doppler cerebroplacental ratio: cognitive, neurological and somatic development at 3 to 6 years. Early Hum Dev 69:47±56

58. Fouron JC, Gosselin J, Amiel-Tison C, Infante-Rivard C, Fouron C, Skoll A, Veilleux A (2001) Correlation be- tween prenatal velocity waveforms in the aortic isth- mus and neurodevelopmental outcome between the ages of 2 and 4 years. Am J Obstet Gynecol 184:630±

59. Sonesson SE, Fouron JC (1997) Doppler velocimetry of 636 the aortic isthmus in human fetuses with abnormal ve- locity profiles in the umbilical artery. Ultrasound Ob- stet Gynecol 10:107±111

60. Schreuder AM, McDonnell M, Gaffney G, Johnson A, Hope PL (2002) Outcome at school age following an- tenatal detection of absent or reversed end diastolic flow velocity in the umbilical artery. Arch Dis Child Fetal Neonatal Ed 86:F108±F114

61. Laurin J, Lingman G, Marsal K, Persson P-H (1987) Fe- tal blood flow in pregnancies complicated by intrauter- ine growth retardation. Obstet Gynecol 69:895±902 62. Lingman G, Marɗl K (1986) Fetal central blood circu-

lation in the third trimester of normal pregnancy:

longitudinal study. II. Aortic blood velocity waveform.

Early Hum Dev 13:151±159

63. Ley D, Laurin J, Bjerre I, Marɗl K (1996) Abnormal fe- tal aortic velocity waveform and minor neurological dysfunction at 7 years of age. Ultrasound Obstet Gyne- col 8:160±165

64. Ley D, Tideman E, Laurin J, Bjerre I, Marɗl K (1996) Abnormal fetal aortic velocity waveform and intellec- tual function at 7 years of age. Ultrasound Obstet Gy- necol 8:160±165

65. Touwen BCL (1979) Examination of the child with minor neurological dysfunction. Clinics in develop- mental medicine, no. 71, 2nd edn. SIMP/Heinemann Medical Books, London

66. Psychological corporation (1974) The Wechsler Pre- school and primary scale of intelligence. Manual. Har- court Brace Jovanovich, Publishers I, London

67. Segerstræm RR (1976) A study in the prediction of school readiness and school failure. Academic thesis.

University of Northern Colorado

68. Searls EF (1972) WISC and WPPSI IQs and subtest patterns related to first grade reading achievement.

Thesis, University of Miami

69. Raviv A, Rahmani L, Ber H (1986) Cognitive character- istics of learning disabled and immature children as determined by the Wechsler Preschool and Primary Scale of Intelligence test. J Clin Child Psychol 15:241±

70. Soothill PW, Nicolaides KH, Bilardo CM, Campbell S 247 (1986) Relation of fetal hypoxia in growth retardation

to mean blood velocity in the fetal aorta. Lancet 2:1118±1119

71. Ley D, Tideman E, Brodszki J, Liuba C, Marsal K, Hell- strom A (2002) Decrease in cognitive ability and neu- roretinal rim area in 18 year olds with intrauterine growth restriction and abnormal fetal blood flow.

Czech Gynecology 67:222

72. Martin L, Ley D, Marɗl K, Hellstræm A (2004) Visual function in young adults following intrauterine growth restriction. J Pediatr Ophthalmol Strabismus 48:212±

73. Ley D, Marɗl K, Dahlgren J, Hellstræm A (2004) Ab- 218 normal retinal optic nerve morphology in young adults following intrauterine growth restriction. Pediatr Res 56:139±143

74. Mallard EC, Rees S, Stringer M, Cock ML, Harding R (1998) Effects of chronic placental insufficiency on brain development in fetal sheep. Pediatr Res 43:262±

75. Mallard C, Loeliger M, Copolov D, Rees S (2000) Re- 770 duced number of neurons in the hippocampus and the cerebellum in the postnatal guinea-pig following in- trauterine growth restriction. Neuroscience 100:327±

76. Thissen J-P, Ketelslegers J-M, Underwood LE (1994) 333 Nutritional regulation of the insulin-like growth fac- tors. Endocrinol Rev 15:80±101

77. Lowe WL Jr, Adamo M, Werner H, Roberts CT Jr, Le- Roith D (1989) Regulation by fasting of rat insulin-like growth factor 1 and its receptor: effects on gene ex- pression and binding. J Clin Invest 84:619±626 78. Larsen T, Main K, Andersson AM, Juul A, Greisen G,

Skakkebaek NE (1996) Growth hormone, insulin-like growth factor I and its binding proteins 1 and 3 in last trimester intrauterine growth retardation with in- creased pulsatility index in the umbilical artery. Clin Endocrinol 45:315±319

79. Spencer JA, Chang TC, Jones J, Robson SC, Preece MA (1995) Third trimester fetal growth and umbilical ve- nous blood concentrations of IGF-1, IGFBP-1 and growth hormone at term. Arch Dis Child Fetal Neona- tal Ed 73:87±90

80. Ley D, Stale H, Marɗl K (1997) Aortic vessel wall char- acteristics and blood pressure in children with intrau- terine growth retardation and abnormal foetal aortic blood flow. Acta Paediatr 86:299±305

81. Benthin M, Dahl P, Ruzicka R, Lindstræm K (1991) Cal- culation of pulse-wave velocity using cross correlation:

effects of reflexes in the arterial tree. Ultrasound Med Biol 17:471±478

82. Marɗl K, Stale H (1995) Ultrasound investigations of fetal circulation: In: Brans YW, Hay WW (eds) Physio- logic monitoring and instrument diagnosis in perinatal and neonatal medicine. University Press, Cambridge, pp 329±348

83. Stale H, Marɗl K, Gennser G, Benthin M, Dahl P, Lind- stræm K (1991) Aortic diameter pulse waves and blood flow velocity in the small for gestational age fetus. Ul- trasound Med Biol 17:471±478

84. Gardiner HM, O'Brien C, Greenwald SE, Bull C, Hunter

AS, Robson SC (1995) Postnatal adaptation: vascular

compliance and reactivity in growth retarded and

normal infants. In: Proc 22nd Annual Meeting of the

Society for the Study of Fetal Physiology, Malmæ, Swe- 85. Safar ME, St. Laurent S, Safavian AL, Pannier BM, Lon- den don GM (1987) Pulse pressure in sustained essential hypertension: a haemodynamic study. J Hypertens 5:213±218

86. Pannier B, Brunel P, el-Aroussy W, Lacolley P, Safar ME (1989) Pulse pressure and echocardiographic find- ings in essential hypertension. J Hypertens 7:127±132 87. Newman DL, Lallemand RC (1978) The effect of age on

the distensibility of the abdominal aorta of man. Surg Gynecol Obstet 147:211±214

88. Brodszki J, Lånne T, Marɗl K, Ley D (2005) Intrauter- ine growth restriction and vascular mechanical proper- ties and endothelial function in adolescence. Circula- tion, in press

89. Hellstræm A, Dahlgren J, Marɗl K, Ley D (2004) Ab- normal retinal vascular morphology in young adults following intrauterine growth restriction. Pediatrics 113:e77±e80

90. Bennis-TalebN, Remacle C, Hoet J, Reusens B (1999) A low-protein isocaloric diet during gestation affects brain development and alters permanently cerebral cor- tex blood vessels in rat offspring. J Nutr 129:1613±1619 91. Martin H, Hu J, Gennser G, Norman M (2000) Im- paired endothelial function and increased carotid stiff- ness in 9-year-old children with low birthweight. Circu- lation 102:2739±2744

92. Marɗl K, Ley D (1992) Intrauterine blood flow and

postnatal neurological development in growth-retarded

fetases. Biol Neonate 62:258±264