Postnatal changes in cerebral blood flow velocity in term intra-uterine growth-restricted neonates Sriparna Basu1, Shashikant Dewangan1, Sandeep Barman1, Ram Chandra Shukla2, Ashok Kumar1 Departments of 1Pediatrics and 2Radiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India Background: Intra-uterine growth-restricted (IUGR) fetuses are prone to hypoxic changes in the brain and neurodevelopmental sequelae in later life. Chronic hypoxaemia may also lead to polycythaemia in the fetal and neonatal period. Aim: To evaluate venous haematocrit and cerebral blood flow velocity (CBFV) in term IUGR neonates in the immediate postnatal period. Methods: This was a prospective observational study of 54 clinically healthy term IUGR neonates as cases and 50 term, appropriate-for-gestational-age (AGA), healthy neonates as controls. IUGR was defined as birthweight ,10th per centile for gestational age. Neonates with perinatal asphyxia, sepsis and other systemic diseases were excluded. Resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV) and vascular diameter were measured in the internal carotid, vertebral and middle cerebral arteries by transcranial colour Doppler ultrasound between 48 and 72 hours of life, along with the estimation of venous haematocrit. Neonates were observed for development of any complications until discharge and followed up clinically and radiologically for a minimum 6 months. Results: Significantly higher resistance (RI and PI) and lower PSV was recorded in all the cerebral arteries of the IUGR than the AGA group whereas no difference was observed in vascular diameters. Mean haematocrit was significantly higher in the IUGR than in the AGA group [55.7 (4.22) vs 45.1 (2.79) g/dl]. Haematocrit was positively correlated with RI and PI, and negatively correlated with PSV. After discharge, three infants in the IUGR group showed hypertonia and delayed developmental milestones along with hypoxic changes in MRI of the brain. Conclusions: Compared with their AGA counterparts, higher venous haematocrit and lower CBFV were observed in clinically healthy, term IUGR neonates during the early neonatal period. Delayed developmental milestones and hypoxic changes were detected by MRI in three infants. Since the study was limited by its sample size, larger studies are required to document the clinical significance of decreased CBFV and its usefulness as a marker of poor prognosis for future neurodevelopment. Keywords: Cerebral blood flow velocity, Haematocrit, Intra-uterine growth restriction, Newborn, Transcranial colour Doppler ultrasound

Introduction Worldwide each year, it is estimated that 18 million neonates are born with low birthweight (LBW) and that half of them are in south Asia.1 Though not a disease in itself, LBW has a major influence on neonatal and infant survival, as well as under-5 and long-term morbidity.2 LBW infants account for only 14% of births but 60–80% of neonatal deaths,3 and those who survive the critical neonatal period may suffer impaired physical and mental growth.4 In

Correspondence to: S Basu, Department of Paediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi – 221005, India. Fax: z91 542 236 7568; email: [email protected]

ß W. S. Maney & Son Ltd 2014 DOI 10.1179/2046905514Y.0000000124

developing countries, LBW is largely attributed to intra-uterine growth restriction (IUGR) as opposed to prematurity in developed countries.5 In India, LBW is a major health problem, affecting 30% of births and IUGR is considered the main causal factor of LBW delivery secondary to low maternal weight, anaemia and young age.6 Although a number of studies have documented poor neurological outcome in preterm IUGR neonates,7,8 the number of studies on the cerebral insult of IUGR infants who are born at term is limited. Placental dysfunction is an important risk factor for neurodevelopmental delay in IUGR infants. In preterm IUGR infants, abnormal motor and neurological

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delay is common.9,10 Cognitive abnormalities related to specific brain areas increase in frequency as gestation advances, suggesting a different pathophysiology and evolving vulnerability of the fetal brain.9 Speech delay, motor dysfunction and lower scholastic performance have been documented in preterm and term IUGR infants.10 Chronic intrauterine hypoxia in an IUGR fetus leads to several changes in different organ systems, including cerebral blood flow (CBF), and the process of haematopoiesis. A redistribution of blood flow away from the gut with brain, heart and adrenalsparing effects has been documented in IUGR fetuses.11 While most studies have correlated altered pulsatility index and peak systolic velocity in fetal anterior and middle cerebral arteries with immediate perinatal outcome,12,13 there is little literature on CBF in the postnatal period and its association with delayed neurodevelopmental outcome in IUGR infants. Moreover, it is known that chronic hypoxia in utero may lead to haematopoiesis and subsequent alteration in arterial and venous flow in IUGR fetuses,14 but it is not known whether the increased haematocrit is responsible for altered CBF in postnatal life. The study aimed to assess venous haematocrit and cerebral blood flow velocity (CBFV) in clinically healthy, term, IUGR neonates.

measurement of peripheral venous haematocrit. All neonates were observed until discharge for the development of any complications. They had monthly clinical follow-up for a minimum of 6 months. During follow-up, the developmental milestones normal for that age and the tone were assessed. At the earliest suspicion of any abnormality, the infants were sent for detailed developmental screening and early stimulation physiotherapy. If the parents were able to afford it, magnetic resonance imaging (MRI, 1.5 Tesla) or computerised tomographic scan (CT) of the brain was undertaken at the age of 3 months to detect any radiological abnormality.

Assessment of cerebral blood flow velocity (CBFV) Cranial ultrasonography was undertaken initially to exclude any intracranial pathology or malformations. All the Doppler examinations were undertaken by a single observer to avoid any inter-observer variation. Resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV) and vascular diameter were measured in the internal carotid arteries (ICA) vertebral arteries (VA) and middle cerebral artery (MCA) of both sides using a Toshibo Nemio 30 ultrasound and colour Doppler machine with a highfrequency linear array (8 MHz for ICA and VA) and curvilinear array (3.75 MHz for MCA) transducer. All measurements were undertaken in a thermoneutral environment without any pressure provocation. Infants were swaddled and, if necessary, oral dextrose was used as a pacifier. RI and PI were calculated according to the formulae of the ultrasound blood flow imaging technique.17 The value of each parameter was assessed three times and the mean value was recorded. In the absence of any statistically significant variation between the RI, PI, diameter and PSV values of both sides of the same artery, a mean value was calculated for each parameter.

Methods Study population The prospective observational study was conducted in the Neonatal Intensive Care Unit (NICU), Sir Sunderlal Hospital, Institute of Medical Sciences, Banaras Hindu University over a period of 2 years. The study group was 54 term, clinically healthy IUGR neonates. IUGR was defined as birthweight below the 10th percentile for gestational age.15 Fifty healthy, term, appropriate-for-gestational age (AGA) neonates served as controls. Neonates with a maternal history of eclampsia/magnesium therapy/ use of tocolysis or corticosteroids and intrauterine infections, delivery room resuscitation, systemic or metabolic disorders and congenital malformations were excluded. Informed consent was obtained from the parents of all the study subjects. Demographic details and antenatal investigations including fetal Doppler velocimetry were recorded for all infants. The cord was clamped within 1 minute of birth, as per the unit protocol. Birthweight was recorded within 1 hour of birth on an electronic weighing scale (Seca weighing machine) with an accuracy of 5 g. Gestational age was assessed from the first day of the last menstrual period and confirmed by the modified Ballard Score.16 CBFV was assessed by transcranial colour Doppler (TCD) ultrasound 48–72 hours after delivery along with

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Statistical analysis The statistical programme SPSS version 16.0 (SPSS Inc, Chicago, IL) was used for data entry and analysis. The independent samples t-test, Mann– Whitney U-test and x2 test were used to compare parametric and non-parametric variables between the two groups. The Pearson correlation coefficient was calculated to detect the correlation between haematocrit values and CBFV parameters. P,0.05 was considered statistically significant. Ethical approval was obtained from the institute’s ethics committee.

Results Initially, 68 term IUGR neonates were recruited for the study. Subsequently, 14 of them were excluded

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when they developed different systemic and metabolic complications, so the study group was 54 term IUGR neonates. A total of 50 gestational agematched neonates of normal birthweight (.2500 g) served as controls. Both groups were comparable with respect to mean (SD) gestational age [39 (1.9) weeks in cases and 39.2 (1.4) weeks in controls], male:female ratio (1.16:1 in cases and 1.08:1 in controls) and other antenatal variables (Table 1). Mean (SD) birthweights in IUGR and AGA groups were 1993 (203) and 2914 (282) g, respectively (P,0.001). Antenatal Doppler velocimetry was undertaken for 38 fetuses in the IUGR group. Seven of them demonstrated absent or reversed flow in the umbilical artery, indicating chronic intra-uterine hypoxia. None had any alteration of blood flow in the MCA. None of the neonates in the AGA group had abnormal antenatal ultrasonography or Doppler velocimetry. Venous haematocrit and different parameters of CBFV (RI, PI, PSV and vascular diameter) for the three major cerebral arteries (ICA, VA and MCA) are summarised in Table 2. CBFV data in the tables are the average of those in the left and right side. Significantly higher haematocrit was recorded in the IUGR group than in the AGA neonates [55.7 (4.22) vs 45.1 (2.79) g/dl, P,0.001], although none of the IUGR infants showed any complications related to polycythaemia in the postnatal period and none required partial exchange transfusion. RI and PI were found to be significantly higher in the IUGR infants than in their AGA counterparts, whereas PSV was significantly lower in all three cerebral arteries. No difference was observed between vascular diameters. At the age of 6 months, cranial MRI was undertaken in 48 infants and cranial CT scan in 16. Neuroimaging was normal in 51 infants. MRI was abnormal in three infants, two of whom showed increased signal intensity in the periventricular white matter in association with a deficit in myelination

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(periventricular leucomalacia), and the third had periventricular leucomalacia and encephalomalacia with ongoing gliosis in the cortex and subcortical white matter in the perirolandic and perisylvian region. All of them had hypertonia and delayed developmental milestones. None had abnormal blood flow in the umbilical artery during antenatal Doppler velocimetry. Mean (SD) haematocrit was higher [62.0 (1.0) vs 55.33 (4.05) g/dl] and CBFV lower with high resistance (data not shown) in the IUGR neonates with hypoxic changes in the brain compared with those with uncomplicated survival. Table 3 shows significant correlation between haematocrit and different parameters of CBFV by the Pearson correlation test. Haematocrit was positively correlated with RI and PI and negatively correlated with PSV.

Discussion The study identified increased resistance and decreased PSV in asymptomatic, term IUGR neonates compared with their AGA counterparts in the presence of similar vascular diameters. IUGR neonates also had higher venous haematocrit. Three infants in the IUGR group had features of abnormal neurodevelopment along with leucomacia and encephalomalacia on MRI. No prenatal or perinatal insult such as perinatal asphyxia or chorio-amnionitis/neonatal sepsis was documented in any of them, and the postnatal period was uneventful. The most common cause of IUGR is placental insufficiency resulting in chronic hypoxia which can be demonstrated by abnormal results in Doppler velocimetry of the umbilical artery. Neurodevelopmental dysfunction in the three IUGR infants with MRI brain abnormality might have been associated with impaired blood supply to the brain. Suboptimal scores for social interactive, attention capacity, state organisation and motor skills in growth-restricted neonates have been attributed to abnormal results of prenatal MCA Doppler studies.18 Chronic hypoxia in IUGR fetuses leads to an increase in placental vascular resistance

Table 1 Comparison of maternal and neonatal demographic parameters between the IUGR and AGA groups Parameter

IUGR Group n554 (%)

AGA Group n550 (%)

P-value

Birthweight, g, mean (SD) [IQR] Gestational age, wks, mean (SD) [IQR] Male:female ratio Maternal age, yrs, mean (SD) Antenatal care taken, n Gravida, median Mode of delivery, n SVD Caesarean section Presentation, n Vertex Breech

1993 (203) [1820–2140] 39 (1.9) [38–40] 1.16:1 26.5 (3.8) 23 2

2914 (282) [2693–3108] 39.2 (1.4) [38–40] 1.08:1 25.8 (3.5) 34 2

,0.001* 0.67* 0.86{ 0.63* ,0.01{ 0.44*

37 17

36 14

0.70{

54 2

47 3

0.56{

IUGR, intrauterine growth-restricted; AGA, appropriate for gestational age; IQR, interquartile range; SVD, spontaneous vaginal delivery; * independent samples t-test; { x2 test.

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Table 2 Comparison of haematocrit and blood flow velocity in different cerebral arteries between IUGR and AGA groups [mean (SD)] Parameter

IUGR n554

AGA n550

Mann–Whitney U-test P-value

Haematocrit, g/dl [IQR] ICA RI VA RI MCA RI ICA PI VA PI MCA PI ICA PSV, cm/s VA PSV, cm/s MCA PSV, cm/s ICA D, mm VA D, mm MCA D, mm

55.7 0.77 0.82 0.89 1.15 1.21 1.27 38.41 36.92 35.38 2.8 2.7 2.54

45.1 0.45 0.50 0.54 0.78 0.82 0.87 50.6 49.38 48.06 2.82 2.71 2.57

,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 NS NS NS

(4.22) [53–58] (0.14) (0.11) (0.12) (0.13) (0.15) (0.12) (7.03) (4.38) (5.42) (0.15) (0.14) (0.16)

(2.79) [42–47] (0.12) (0.17) (0.18) (0.09) (0.11) (0.1) (5.3) (3.29) (5.42) (0.13) (0.12) (0.15)

IUGR, intrauterine growth-restricted; AGA, appropriate for gestational age; IQR, interquartile Range; ICA, internal carotid artery; VA, vertebral artery; MCA, middle cerebral artery; RI, resistance index; PI, pulsatility index; PSV, peak systolic velocity; D, diameter; NS, not significant.

with redistribution of blood flow, leading to cerebral vasodilation, also known as the brain-sparing effect.19 This process is identified clinically by decreased MCAPI and increased MCA-PSV.20 Mari et al. demonstrated that high MCA-PI and low MCA-PSV were associated with fetal demise whereas lowering of MCA-PI and increased MCA-PSV was associated with a better perinatal outcome.13 Recent studies have suggested that the magnitude of increase in cerebral perfusion is not similar in the entire cerebral circulation.21 Regionalisation of brain redistribution of blood flow, in relation to the intensity and duration of the hypoxic insult, has been reported in animal experiments.21,22 The existence of regional brain redistribution in human fetuses with severe growth restriction and its progression during fetal deterioration has been investigated.23 The authors found that brain blood perfusion in fetal growth restriction has an internal regional redistribution pattern which changes substantially with progression of hypoxic fetal deterioration. After an initial and early increase in perfusion in the frontal area, progression of fetal deterioration was rapidly associated with a pronounced decrease in frontal perfusion, together with an increase towards the basal ganglia. The authors suggested that the protective effect of increased blood perfusion may

initially be more intense in areas controlling higher functions, but that from the early stages of fetal hypoxic deterioration they may progressively shift to brain regions controlling basic survival and motor function. Our study documented reduced blood flow in all three major cerebral vessels; regional blood flow was not assessed. All of these studies dealt with cerebral blood flow in the fetus. However, correlation of prenatal haemodynamic findings with long-term outcome has not been established. Current observations assume that the onset of a brain-sparing effect in fetuses, as indicated by reduced PI in the MCA Doppler, represents a protective haemodynamic response in the entire fetal brain. It might be that a decrease in MCA-PI and an increase in PSV aids the immediate survival of growth-restricted fetuses with redistribution of blood flow. After birth, in the absence of hypoxic stimulus, there is constriction of cerebral vessels which determines their long-term prognosis. In the present study, three infants developed hypertonia, delayed developmental milestones and abnormal MRI. Increased resistance and decreased PSV in cerebral arteries were documented in all of them. There was significant correlation between raised haematocrit and decreased CBFV in the IUGR

Table 3 Pearson correlation test between haematocrit and different parameters of cerebral blood flow velocity Parameters

ICA RI

VA RI

MCA RI

ICA PI

VA PI

MCA PI

ICA PSV

VA PSV

MCA PSV

HCT ICA RI VA RI MCA RI ICA PI VA PI MCA PI ICA PSV VA PSV

0.754* 1

0.752* 0.998* 1

0.759* 0.991* 0.993* 1

0.770* 0.985* 0.983* 0.979* 1

0.782* 0.984* 0.983* 0.978* 0.998* 1

0.783* 0.983* 0.982* 0.979* 0.996* 0.998* 1

20.711* 20.865* 20.868* 20.862* 20.850* 20.859* 20.864* 1

20.716* 20.862* 20.863* 20.859* 20.850* 20.860* 20.865* 0.998* 1

2.0731* 20.865* 20.868* 20.866* 20.859* 20.870* 20.875* 0.992* 0.996*

HCT, haematocrit; ICA, internal carotid artery; VA, vertebral artery; MCA, middle cerebral artery; RI, resistance index; PI, pulsatility index; PSV, peak systolic velocity; D, diameter; * P,0.001.

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infants, but it is difficult to determine whether the increased resistance was directly caused by higher haematocrit and increased blood viscosity. Some authors have demonstrated altered haematological indices in the umbilical cord of growth-restricted fetuses, e.g. elevated nucleated red blood cell count and haemoglobin and haematocrit concentration, according to the severity of the condition.24,25 Chronic hypoxia may lead to an increased haemoglobin mass in order to maintain tissue oxygenation. Increased neonatal nucleated red blood cell counts are thought to be related to intrauterine hypoxaemia causing circulatory impairment in fetuses.24 A major limitation of the study was that we were unable to measure cerebral oxygenation by nearinfrared spectroscopy which is a better method of assessing cerebral haemodynamics. Secondly, we could not perform the histopathological examination of the placenta which could have been a diagnostic parameter for demonstration of placental insufficiency in IUGR neonates. The main strength of the study was that it was simple to undertake without much sophistication. TCD ultrasound is an easy, safe and non-painful bedside measurement of CBFV. Though it required some expertise initially, it was not difficult to visualise the major cerebral arteries. Secondly, all possible confounding variables which might have affected cerebral blood flow were excluded. All sick infants, including those who required delivery room resuscitation and those with risk factors of chorio-amnionitis, were excluded as these are known causes of alteration of CBFV. Normothermia was maintained during the examination and a single radiologist performed all the tests to exclude inter-observer variation. Thirdly, we did not introduce any detailed screening test for detection of developmental delay. Only developmental milestones and muscle tone were assessed. Higher haematocrit, increased resistance and decreased PSV in the major cerebral arteries of apparently healthy, term IUGR neonates compared with their AGA counterparts was demonstrated. Three infants developed delayed developmental milestones and hypoxic changes on MRI. The study, however, was limited by its sample size; larger studies should be undertaken to assess the clinical significance of decreased CBFV and its use as a marker of poor prognosis for future neurodevelopment.

References 1 Director General, World Health Organization. Bridging the Gaps, The World Health Report. Geneva: WHO, 1995. 2 Villar J, Belizan JM. The timing factor in the pathophysiology of the IUGR syndrome. Obstet Gynecol Surg. 1982;37:499–506. 3 United Nations Children’s Fund. The State of the World’s Children. New York: UNICEF, 2005. 4 Bang A, Reddy MH, Deshmukh MD. Child mortality in Maharashtra. Econ Polit Wkly. 2002;37:4947–65.

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5 Agnihotri B, Antonisamy B, Priya G, Fall CH, Raghupathy P. Trends in human birth weight across two successive generations. Indian J Pediatr. 2008;75:111–17. 6 Kumar SG, Kumar HNS, Jayaram S, Kotian MS. Determinants of low birth weight: a case control study in a district hospital in Karnataka. Indian J Pediatr. 2010;77:87–9. 7 Figueras F, Cruz-Martinez R, Sanz-Cortes M, Arranz A, Illa M, Botet F, et al. Neurobehavioral outcomes in preterm, growth-restricted infants with and without prenatal advanced signs of brain-sparing. Ultrasound Obstet Gynecol. 2011;38: 288–94. 8 Morsing E, Asard M, Ley D, Stjernqvist K, Marsa´l K. Cognitive function after intrauterine growth restriction and very preterm birth. Pediatrics. 2011;127:e874–82. 9 Baschat AA. Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction. Ultrasound Obstet Gynecol. 2011; 37:501–14. 10 Leppanen M, Ekholm E, Palo P, Maunu J, Munck P, Parkkola R, et al. Abnormal antenatal Doppler velocimetry and cognitive outcome in very-low birth weight infants at 2 years of age. Ultrasound Obstet Gynecol. 2010;36:178–85. 11 Signorelli M, Taddei F, Frusca T. Reversal of compensatory flow in severe intrauterine growth restriction: middle cerebral artery and intracardiac volume flow modifications. Minerva Ginecol. 2008;60:287–93. 12 Piazze J, Padula F, Cerekja A, Cosmi EV, Anceschi MM. Prognostic value of umbilical-middle cerebral artery pulsatility index ratio in fetuses with growth restriction. Int J Gynaecol Obstet. 2005;91:233–7. 13 Mari G, Hanif F, Kruger M, Cosmi E, Santolaya-forgas J, Treadwell MC. Middle cerebral artery peak systolic velocity: a new Doppler parameter in the assessment of growth-restricted fetuses. Ultrasound Obstet Gynecol. 2007;29:310–16. 14 Baschat AA, Gembruch U, Reiss I, Gortner L, Harman CR, Weiner CP. Neonatal nucleated red blood cell counts in growth-restricted fetuses: relationship to arterial and venous Doppler studies. Am J Obstet Gynecol. 1999;181:190–5. 15 Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol. 1996;87:163–8. 16 Ballard JL, Khoury JC, Wedling K, Wang L, Eilers-Walsman BL, Lipp R. New Ballard score expanded to include premature infants. J Pediatr. 1991;119:417–23. 17 Zwibel WJ, Pellerito JS. Basic concepts of Doppler frequency spectrum analysis and ultrasound blood flow imaging. In: Zwibel WJ, Pellerito JS, eds. Introduction to Vascular Ultrasonography, 5th edn. Philadelphia: Elsevier Saunders, 2005; pp 61–89. 18 Cruz-Martinez R, Figueras F, Oros D, Padilla N, Meler E, Hernandez-Andrade E, et al. Cerebral blood perfusion and neurobehavioral performance in full-term small-for gestationalage fetuses. Am J Obstet Gynecol. 2009;201:474.e1–7. 19 Marsal K. Intrauterine growth restriction. Curr Opin Obstet Gynecol. 2002;14:127–35. 20 Ozcan T, Sbracia M, d’Ancona RL, Copel JA, Mari G. Arterial and venous Doppler velocimetry in the severely growth restricted fetus and associations with adverse perinatal outcome. Ultrasound Obstet Gynecol. 1998;12:39–44. 21 Hilario E, Rey-Santano MC, Goni-de-Cerio F, Alvarez FJ, Gastiasoro E, Mielgo VE, et al. Cerebral blood flow and morphological changes after hypoxic-ischaemic injury in preterm lambs. Acta Paediatr. 2005;94:903–11. 22 Figueroa-Diesel H, Hernandez-Andrade E, Acosta-Rojas R, Cabero L, Gratacos E. Doppler changes in the main fetal brain arteries at different stages of hemodynamic adaptation in severe intrauterine growth restriction. Ultrasound Obstet Gynecol. 2007;30:297–302. 23 Hernandez-Andrade E, Figueroa-Diesel H, Jansson T, RangelNava H, Gratacos E. Changes in regional fetal cerebral blood flow perfusion in relation to hemodynamic deterioration in severely growth-restricted fetuses. Ultrasound Obstet Gynecol. 2008;32:71–6. 24 Axt-Fliedner R, Ertan K, Hendrik HJ, Schmidt W. Neonatal nucleated red blood cell counts: relationship to abnormal fetoplacental circulation detected by Doppler studies. J Ultrasound Med. 2001;20:183–90. 25 Martinelli S, Francisco RP, Bittar RE, Zugaib M. Hematological indices at birth in relation to arterial and venous Doppler in small-for-gestational-age fetuses. Acta Obstet Gynecol Scand. 2009;88:888–93.

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Postnatal changes in cerebral blood flow velocity in term intra-uterine growth-restricted neonates.

Intra-uterine growth-restricted (IUGR) fetuses are prone to hypoxic changes in the brain and neurodevelopmental sequelae in later life. Chronic hypoxa...
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