Ex-Vivo MRI of the Normal Human Placenta: Structural-Functional Interplay and the Association With Birth Weight.

BACKGROUND: Advanced magnetic resonance imaging (MRI) methods are increasingly being used to assess the human placenta. Yet, the structure-function interplay in normal placentas and their associations with pregnancy risks are not fully understood. PURPOSE: To characterize the normal human placental structure (volume and umbilical cord centricity index (CI)) and function (perfusion) ex-vivo using MRI, to assess their association with birth weight (BW), and identify imaging-markers for placentas at risk for dysfunction. STUDY TYPE: Prospective. POPULATION: Twenty normal term ex-vivo placentas. FIELD STRENGTH/SEQUENCE: 3 T/ T1 and T2 weighted (T1 W, T2 W) turbo spin-echo, three-dimensional susceptibility-weighted image, and time-resolved angiography with interleaved stochastic trajectories (TWIST), during passage of a contrast agent using MRI compatible perfusion system that mimics placental flow. ASSESSMENT: Placental volume and CI were manually extracted from the T1 W images by a fetal-placental MRI scientist (D.L., 7 years of experience). Perfusion maps including bolus arrival-time and full-width at half maximum were calculated from the TWIST data. Mean values, entropy, and asymmetries were calculated from each perfusion map, relating to both the whole placenta and volumes of interest (VOIs) within the umbilical cord and its daughter blood vessels. STATISTICAL TESTS: Pearson correlations with correction for multiple comparisons using false discovery rate were performed between structural and functional parameters, and with BW, with P < 0.05 considered significant. RESULTS: All placentas were successfully perfused and scanned. Significant correlations were found between whole placenta and VOIs perfusion parameters (mean R = 0.76 ± 0.06, range = 0.67-0.89), which were also significantly correlated with CI (mean R = 0.72 ± 0.05, range = 0.65-0.79). BW was correlated with placental volume (R = 0.62), but not with CI (P = 0.40). BW was also correlated with local perfusion asymmetry (R = -0.71). DATA CONCLUSION: Results demonstrate a gradient of placental function, associated with CI and suggest several ex-vivo imaging-markers that might indicate an increased risk for placental dysfunction. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

INTRODUCTION: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI. METHODS: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T1 weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location; number of bifurcations, generations and vessels diameters. RESULTS: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings. DISCUSSION: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

INTRODUCTION: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI. METHODS: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T1 weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location, number of bifurcations, generations and vessels diameters. RESULTS: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings. DISCUSSION: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.

Automatic Measurement of Fetal Brain Development from Magnetic Resonance Imaging: New Reference Data.

BACKGROUND: Accurate fetal brain volume estimation is of paramount importance in evaluating fetal development. The aim of this study was to develop an automatic method for fetal brain segmentation from magnetic resonance imaging (MRI) data, and to create for the first time a normal volumetric growth chart based on a large cohort. SUBJECTS AND METHODS: A semi-automatic segmentation method based on Seeded Region Growing algorithm was developed and applied to MRI data of 199 typically developed fetuses between 18 and 37 weeks' gestation. The accuracy of the algorithm was tested against a sub-cohort of ground truth manual segmentations. A quadratic regression analysis was used to create normal growth charts. The sensitivity of the method to identify developmental disorders was demonstrated on 9 fetuses with intrauterine growth restriction (IUGR). RESULTS: The developed method showed high correlation with manual segmentation (r2 = 0.9183, p < 0.001) as well as mean volume and volume overlap differences of 4.77 and 18.13%, respectively. New reference data on 199 normal fetuses were created, and all 9 IUGR fetuses were at or below the third percentile of the normal growth chart. DISCUSSION: The proposed method is fast, accurate, reproducible, user independent, applicable with retrospective data, and is suggested for use in routine clinical practice.

Facial Expression in Response to Smell and Taste Stimuli in Small and Appropriate for Gestational Age Newborns.

Small for gestational age newborns can later suffer from eating difficulties and slow growth. Nutritional preferences can be influenced by changes in sensory perception of smell and taste. To determine whether these could be detected at birth, the authors examined the different recognition pattern of smell and taste in small for gestational age newborns compared to appropriate for gestational age controls, as expressed by gusto-facial and naso-facial reflexes. The authors performed video analysis of facial expressions of 10 small for gestational age and 12 control newborns exposed to various tastes and smells. No difference in the facial recognition patterns for taste or smell was demonstrated between small for gestational age and controls, except for perception of distilled water. Newborns show recognizable patterns of facial expression in response to taste and smell stimuli. Perception of taste and smell in small for gestational age newborns is not different from controls, as measured by the method of facial recognition.

Blood pressure values in 8-12 year old children with a history of intrauterine growth retardation.

BACKGROUND: Epidemiological studies have found that intrauterine growth retardation (IUGR) is closely related to hypertension and is associated with a reduced number of nephrons that may be a predisposing factor for the development of hypertension. OBJECTIVES: To determine whether blood pressure levels of children with a history of IUGR are higher than those of children without IUGR. METHODS: Diastolic, systolic and mean arterial blood pressure levels were measured in 64 children aged 8-12 years old with a history of IUGR (mean birth weight 1780 +/- 422 g) and compared with 64 age and gender-matched controls who had a normal birth weight (mean 3134 +/- 594 g). RESULTS: Contrary to previous reports, systolic blood pressure values were significantly lower in the IUGR group compared to the controls (91.6 +/- 11.3 vs. 96.6 +/- 13.9, P = 0.027). There was no difference in diastolic blood pressure values. In the IUGR group, systolic blood pressure correlated significantly with current weight (P < 0.01) and body mass index (P < 0.05), and diastolic blood pressure with weight gain between age 2 and 4 years (P < 0.05). None of the blood pressure values correlated with birth weight. CONCLUSIONS: Children born with IUGR have lower systolic blood pressure levels than matched controls at age 8-12 years. These data indicate that postnatal weight gain in this group has a greater impact on systolic blood pressure than birth weight.

Intrauterine growth-restricted neonates born at term or preterm: how different?

Late onset intrauterine growth restriction is a common form of growth restriction, mainly caused by placenta-vascular insufficiency. Whether the intrauterine or extrauterine environment offers a better long-term outcome for the growth-restricted fetus remains unclear. We compared the risk factors and long-term outcomes of late onset growth-restricted neonates delivered between 31-36 weeks of gestation vs those delivered at term. This prospective cohort study included 114 preterm and 193 term born growth-restricted neonates. They underwent a neurobehavioral examination (neonatal period), a neurodevelopmental assessment and the Bayley Scales of Infant Development (age 2 years), and neuromotor assessment and the Wechsler Preschool and Primary Scale of Intelligence (age 6 years). Growth-restricted neonates born prematurely exhibited a significantly higher incidence of maternal hypertension, a maternal history of abortions and stillbirths, increased intrapartum and postnatal complication rates, and abnormal neonatal neurobehavioral scores than expected. Both preterm and term born growth-restricted groups, however, exhibited comparable long-term neurodevelopmental and cognitive outcomes at ages 2 and 6 years. Although prematurely born neonates undergo an earlier growth restriction process and exhibit a higher perinatal risk factor profile, their long-term outcomes are comparable to those of growth-restricted neonates born at term.

The effects of vascular intrauterine growth retardation on cortical astrocytes.

OBJECTIVE: We sought to determine the pathogenesis of neurodevelopmental impairments in survivors of intrauterine growth retardation (IUGR). METHODS: We used an experimental rabbit vascular IUGR model. We ligated 25% of uteroplacental vessels (partial ischemia) of one-half of the fetuses on day 25 at the end of the third trimester. We then determined hemispheral DNA and protein levels, and used glial fibrillary acidic protein (GFAP) staining to count the labeled astrocytes at the superficial cortical layers. RESULTS: Ischemic fetuses were significantly smaller than control fetuses and presented a disproportionately small body and a relatively larger head compared with the normal body/head ratio, confirming the study model as that of asymmetric IUGR. Hemispheral DNA was unchanged in IUGR fetuses, but they had decreased brain weight, hemispheral protein content, and a reduced number of mature (GFAP-positive) cortical astrocytes compared with control fetuses. CONCLUSION: Vascular IUGR, as demonstrated in our asymmetric IUGR model, adversely affected brain growth, cell size, and cortical astrocytes maturation. In view of the neurotrophic and neuroprotective functions of astrocytes, a reduced number of mature astrocytes during this critical period of development may be implicated in the pathogenesis of the neurodevelopmental impairments observed in IUGR.

Cerebral palsy--long-term medical, functional, educational, and psychosocial outcomes.

Cerebral palsy, typically diagnosed in childhood, clearly continues into adulthood. This study describes the long-term medical, functional, educational, and psychosocial outcomes of people with cerebral palsy. Of the 203 people with cerebral palsy diagnosed and treated at the Child Development Center in Tel Aviv between 1975 and 1994, 163 (80%; age range 8-30 years, mean age 18.9 years, and median age 19 years) participated in a cross-sectional telephone survey. Half the respondents have chronic health problems: 78% report they experience gross motor disability, of whom 22% are wheelchair users; 30% to 50% need help in various activities of daily living; 35% have mental retardation; 79% completed 12 years or more of schooling; 78% live with their parents; 25% have served in the army; 23% have a driver's license; and 23% work in competitive employment. The large majority is involved in varied leisure activities and report a high level of life satisfaction.

Growth patterns in children with intrauterine growth retardation and their correlation to neurocognitive development.

The relationship between somatic growth and neurocognitive outcome was studied in a cohort of 136 children with intrauterine growth retardation. The children were followed up from birth to 9 to 10 years of age by annual measurements of growth parameters, neurodevelopmental evaluations, and IQ. The rate of catch-up for height between 1 and 2 years of age was significantly higher than the catch-up for weight (P < .001). The cognitive outcome at 9 to 10 years correlated with head circumference at all ages. The neurodevelopmental outcome at 9 to 10 years correlated with weight at all ages. Correlation with head circumference was more significant with IQ, while with weight it was stronger with the neurodevelopmental score. Height at 1 year was a significant predictor for IQ and neurodevelopmental outcome at 9 to 10 years. These findings are of distinct importance for prediction of subsequent neurodevelopmental outcome in children with intrauterine growth retardation.

The neurocognitive outcome of mild isolated fetal ventriculomegaly verified by prenatal magnetic resonance imaging.

OBJECTIVE: Neurocognitive outcome of preschool children, prenatal diagnosis of isolated mild ventriculomegaly compared with 2 control groups. STUDY DESIGN: Case-controlled study at the University Hospital of Tel Aviv between October 1999 and December 2002. Study groups consisted of 12 children with bilateral isolated mild ventriculomegaly, and 16 children with unilateral isolated mild ventriculomegaly, mean age 4.4 years, prenatally diagnosed by both ultrasound and fetal magnetic resonanace imaging. Control groups consisted of 16 children with normal prenatal magnetic resonance imaging and 16 regular kindergarten children. A neurodevelopmental examination and the Kaufman Assessment Battery for Children were performed. RESULTS: The neurodevelopmental and Kaufman scores were within normal range in the study groups. No significant differences between the study and control groups for most measures; however, Kaufman achievement score was significantly lower for the bilateral isolated mild ventriculomegaly group (P < .05) compared with the kindergarten children. CONCLUSION: Preschool children with isolated mild ventriculomegaly performed within normal range compared with the controls. Nevertheless, a significant percentage of the children demonstrated developmental difficulties, lower achievement scores, justifying early school years follow-up.

Upper limb movements and outcome in intrauterine-growth-retarded infants at 2 years.

This study aims to examine the usefulness of spontaneous upper limb movements (ULM) as an early marker for predicting neurodevelopmental outcome in infants with intrauterine-growth retardation (IUGR). The assessment of general movements (GMs) during the first 20 weeks is an accepted method for early detection of brain dysfunction. During this period, spontaneous upper limb movements were examined in 32 infants with IUGR and 32 appropriate-for-gestational-age-matched controls. ULM (arms, forearms and hands) were scored as optimal or suboptimal by sequential videotape recordings in the writhing (term-2 weeks: score 0-5); early fidgety (9-11 weeks: score 0-6); and late fidgety (14-16 weeks: score 0-6) periods, and correlated with neurodevelopmental score at 2 years of age. The mean ULM score was lower in the IUGR infants than the controls (p<0.05) and in the IUGR group was lower in the infants with abnormal outcome (p<0.05). Significant correlations were found between ULM and 2-year neurodevelopmental scores in the IUGR group. The ULM during late-fidgety period was most predictive for 2-year neurodevelopmental score. No difference was found in the mean ULM score between the pre-term and term IUGR infants. We conclude that ULM score can serve as an early predictor for neurodevelopmental outcome at 2 years of age in infants with IUGR.

Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study.

One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age.

A Long-term, epidemiological survey of outcome and adjustment of children with developmental disabilities.

The medical, educational, and psychosocial outcomes of 3224 subjects (age range, 7-33 years; mean age, 20.06 years; SD, 5.74) diagnosed and treated in the Institute for Child Development in Tel Aviv between the years 1975 and 1994 were assessed by a telephone interview. Results indicate that only 9% of the subjects are seriously disabled, and 8% are mentally retarded. Over the years, subjects were referred to the Child Development Center at an increasingly younger age, probably reflecting greater professional and parental awareness of the importance of early intervention. The nature of interventions changed, so that physiotherapy, occupational therapy, and psychological guidance were more often provided. While more children were referred to special education at kindergarten, the percentage of those graduating from regular schools has increased. Most completed 12 years of schooling and successfully acquired full or partial matriculation certificates. As adults, most function independently; fulfill civic obligations, such as their army service; are fully employed; and express satisfaction with their life. These results suggest that children with developmental disabilities who receive early intervention are likely to be functionally independent and to be satisfied with their lives, although they continue to need medical services and require some government support. Further studies are essential to examine the correlation of specific risk factors and early interventions with outcome.

Memory functions of children born with asymmetric intrauterine growth restriction.

OBJECTIVE: Learning difficulties are frequently diagnosed in children born with intrauterine growth restriction (IUGR). Models of various animal species with IUGR were studied and demonstrated specific susceptibility and alterations of the hippocampal formation and its related neural structures. The main purpose was to study memory functions of children born with asymmetric IUGR in a large-scale cohort using a long-term prospective paradigm. METHODS: One hundred and ten infants diagnosed with IUGR were followed-up from birth to 9 years of age. Their performance was compared with a group of 63 children with comparable gestational age and multiple socioeconomic factors. Memory functions (short-term, super- and long-term spans) for different stimuli types (verbal and visual) were evaluated using Visual Auditory Digit Span tasks (VADS), Rey Auditory Verbal Learning Test (Rey-AVLT), and Rey Osterrieth Complex Figure Test (ROCF). RESULTS: Children with IUGR had short-term memory difficulties that hindered both serial verbal processing system and simultaneous processing of high-load visuo-spatial stimuli. The difficulties were not related to prematurity, neonatal complications or growth catch-up, but were augmented by lower maternal education. Recognition skills and benefits from reiteration, typically affected by hippocampal dysfunction, were preserved in both groups. CONCLUSIONS: Memory profile of children born with IUGR is characterized primarily by a short-term memory deficit that does not necessarily comply with a typical hippocampal deficit, but rather may reflect an executive short-term memory deficit characteristic of anterior hippocampal-prefrontal network. Implications for cognitive intervention are discussed.

Neuropsychological outcome of children with intrauterine growth restriction: a 9-year prospective study.

OBJECTIVE: The aim was to evaluate the effect of late-onset intrauterine growth restriction on the neuropsychological profile and on academic achievements at 9 years of age using a large-scale prospective paradigm. STUDY DESIGN: We followed up 123 infants diagnosed with late-onset intrauterine growth restriction yearly for 9 years. They were matched with 63 children for gestation age and multiple socioeconomic factors and evaluated by an extensive neuropsychological battery to assess intelligence quotient, academic achievements, learning and memory, visuomotor skills, visuospatial integration, attention, language, executive functions, and creativity. RESULTS: Children with intrauterine growth restriction had lower intelligence quotient and more frequent neuropsychological difficulties. Difficulties in executive functioning, inflexibility-creativity, and language, indicative of frontal lobe dysfunction, were typically affected by intrauterine growth restriction and were rarely identified in the control group. Learning difficulties accompanied by lower academic achievements were more prevalent in the intrauterine growth restriction group, particularly when anthropometric catch-up was incomplete. CONCLUSIONS: The longitudinal findings reaffirm that functional coherence depends on preestablished structural growth and reorganization of the central nervous system. The neuropsychological profile at 9 years of age indicates that late-onset intrauterine growth restriction compromises frontal network functioning.

NAP enhances neurodevelopment of newborn apolipoprotein E-deficient mice subjected to hypoxia.

Perinatal hypoxic injury is associated with significant neonatal morbidity and long-term neurodevelopmental complications. NAP, a peptide derived from ADNP (activity-dependent neuroprotective protein), has previously shown neuroprotective abilities in various adult animal models. To evaluate its neuroprotective role in neonatal hypoxic-ischemic injury, we evaluated the neurodevelopmental outcome in apolipoprotein E (ApoE)-deficient (knockout) mice (a breed prone to brain damage during hypoxic insult) exposed to postnatal global hypoxic damage with and without treatment with NAP. ApoE-deficient (n = 80) and control (C57B6) mice pups (n = 81) were exposed to postnatal global hypoxia (35 min of 8% O(2) within 24 h of birth) or room air with or without subsequent subcutaneous NAP treatment during postnatal days 1 to 14. Pups were then evaluated for neonatal motor reflex attainment, spatial learning ability in the Morris water maze, and locomotor open-field activity. The C57B6 and ApoE-deficient anoxic groups showed significantly slower achievement of neonatal reflexes, diminished locomotor activity, and diminished spatial learning ability compared with their control groups. This was more pronounced in the anoxic ApoE-deficient pups. NAP treatment had a pronounced effect on neurodevelopmental outcome in both breeds, particularly in the ApoE-deficient mice. ApoE-deficient and control mouse pups exposed to postnatal hypoxia and treated with NAP showed improvement in neurodevelopmental outcome compared with nontreated mice pups. ApoE-deficient mice show a greater susceptibility to hypoxic damage and better response to NAP treatment.

The pregnant spontaneously hypertensive rat as a model of asymmetric intrauterine growth retardation and neurodevelopmental delay.

INTRODUCTION: Hypertension in pregnancy and vascular placental insufficiency are considered common pathogenic factors in human intrauterine growth retardation (IUGR). IUGR neonates experience higher mortality, and the surviving infants have a higher incidence of neurological and intellectual impairment. METHODS: To mimic this condition, we used pregnant spontaneously hypertensive rats (SHR) and performed biometric measurements on Embryonic Day 20, postnatal developmental reflexes, and locomotor activity evaluations. RESULTS: SHR fetuses had significant decreased body weight compared to the Wistar-Kyoto control fetuses (1.51+/-0.02 g vs. 2.05+/-0.01 g, respectively; p<0.0001), and were relatively microcephalic (2.86+/-0.04 cm vs. 3.3+/-0.03 cm, respectively; p<0.0001). Their cephalization index (head circumference/body weight) was increased (1.88+/-0.03 vs. 1.62+/-0.02, respectively; p<0.0001), indicating a "brain-sparing" process. The disproportional ratio indicated that the IUGR type in this model is asymmetric. The SHR pups exhibited a significant (p<0.04) neurodevelopmental delay in the acquisition of neonatal reflexes (righting, negative geotaxis, placing), but they spontaneously caught up with the control pups after approximately 10 days. On Day 30, the SHR pups exhibited significantly increased walking speed and distance and spent less time in quadrant than the controls (p<0.002). CONCLUSION: We speculate that the model of pregnant SHR closely simulate human IUGR caused by hypertension in pregnancy and should enable investigation of mechanisms of hypertension-mediated placenta-vascular injury as well as provide a system for preclinical evaluations of future preventive neuroprotective treatments.

Endocrine profile of children with intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) is a major cause of short stature in childhood. Most but not all children experience catch-up growth by 2 years of age. METHODS: We investigated the endocrine profile (thyroid function, prolactin, cortisol, C-peptide and insulin-like growth factor-I [IGF-IJ levels) of 57 children with IUGR, aged 2-10 years, and compared it with 30 controls whose birth weight was appropriate-for-gestational-age. RESULTS: The hormonal profile for both groups was similar for thyroid hormones, prolactin, C-peptide and IGF-I. Cortisol levels were significantly lower in the IUGR group compared to controls (p <0,05). When the IUGR group was divided into 'catch-up' growth and 'non-catch-up' subgroups, the latter had significantly lower IGF-I levels (p <0.001). CONCLUSIONS: Lower cortisol levels in children born with IUGR may reflect impaired function of the hypothalamic-pituitary-adrenal axis associated with this condition. The significantly lower IGF-I levels of the 'non-catch-up' subgroup may be involved in their failure to grow.

Role of thrombophilic risk factors in children with non-stroke cerebral palsy.

BACKGROUND: Thrombophilic risk factors play an important role in the pathogenesis of perinatal stroke and resultant cerebral palsy (CP). The association between thrombophilia and CP caused by etiologies other than stroke is undetermined. METHODS: We assessed three genetic thrombophilic markers (mutation of Factor V Leiden [FV G1691A], 677T polymorphism of thermolabile methylenetetrahydrofolate reductase [MTHFR] and G20210A mutation of the prothrombin gene) in 49 pediatric patients with non-stroke CP and compared the findings with 118 apparently healthy controls. CP in the study group was due to periventricular leukomalacia (n=27), intraventricular hemorrhage (n=9), hypoxic ischemic encephalopathy (n=4), prematurity with no apparent complication (n=8) and intrauterine growth retardation (n=1). Twenty-five children had spastic diplegia, 20 had spastic quadriplegia and 4 had spastic hemiplegia. CP was graded as being severe in 26 children (53%). RESULTS: No significant difference in the prevalence of thrombophilic risk factors was found between the study and control groups. Twelve study children (24.5%) had at least one of the three thrombophilic mutations compared with 27 controls (23%). There was no significant difference in the prevalence of each thrombophilic risk factor in the various etiologic groups and in the subgroups of mild/severe CP and the control group. CONCLUSION: These findings support the notion that thrombophilia neither contributes to the occurrence nor affects the clinical outcome and severity of non-stroke CP.