Severity of prematurity and age impact early postnatal development of GABA and glutamate systems.

Gamma-aminobutyric acid (GABA) and glutamatergic system perturbations following premature birth may explain neurodevelopmental deficits in the absence of structural brain injury. Using GABA-edited spectroscopy (MEscher-GArwood Point Resolved Spectroscopy [MEGA-PRESS] on 3 T MRI), we have described in-vivo brain GABA+ (+macromolecules) and Glx (glutamate + glutamine) concentrations in term-born infants. We report previously unavailable comparative data on in-vivo GABA+ and Glx concentrations in the cerebellum, the right basal ganglia, and the right frontal lobe of preterm-born infants without structural brain injury. Seventy-five preterm-born (gestational age 27.8 ± 2.9 weeks) and 48 term-born (39.6 ± 0.9 weeks) infants yielded reliable MEGA-PRESS spectra acquired at post-menstrual age (PMA) of 40.2 ± 2.3 and 43.0 ± 2 weeks, respectively. GABA+ (median 2.44 institutional units [i.u.]) concentrations were highest in the cerebellum and Glx higher in the cerebellum (5.73 i.u.) and basal ganglia (5.16 i.u.), with lowest concentrations in the frontal lobe. Metabolite concentrations correlated positively with advancing PMA and postnatal age at MRI (Spearman's rho 0.2-0.6). Basal ganglia Glx and NAA, and frontal GABA+ and NAA concentrations were lower in preterm compared with term infants. Moderate preterm infants had lower metabolite concentrations than term and extreme preterm infants. Our findings emphasize the impact of premature extra-uterine stimuli on GABA-glutamate system development and may serve as early biomarkers of neurodevelopmental deficits.

Impaired in vivo feto-placental development is associated with neonatal neurobehavioral outcomes.

BACKGROUND: Fetal growth restriction (FGR) is a risk factor for neurodevelopmental problems, yet remains poorly understood. We sought to examine the relationship between intrauterine development and neonatal neurobehavior in pregnancies diagnosed with antenatal FGR. METHODS: We recruited women with singleton pregnancies diagnosed with FGR and measured placental and fetal brain volumes using MRI. NICU Network Neurobehavioral Scale (NNNS) assessments were performed at term equivalent age. Associations between intrauterine volumes and neurobehavioral outcomes were assessed using generalized estimating equation models. RESULTS: We enrolled 44 women diagnosed with FGR who underwent fetal MRI and 28 infants underwent NNNS assessments. Placental volumes were associated with increased self-regulation and decreased excitability; total brain, brainstem, cortical and subcortical gray matter (SCGM) volumes were positively associated with higher self-regulation; SCGM also was positively associated with higher quality of movement; increasing cerebellar volumes were positively associated with attention, decreased lethargy, non-optimal reflexes and need for special handling; brainstem volumes also were associated with decreased lethargy and non-optimal reflexes; cerebral and cortical white matter volumes were positively associated with hypotonicity. CONCLUSION: Disrupted intrauterine growth in pregnancies complicated by antenatally diagnosed FGR is associated with altered neonatal neurobehavior. Further work to determine long-term neurodevelopmental impacts is warranted. IMPACT: Fetal growth restriction is a risk factor for adverse neurodevelopment, but remains difficult to accurately identify. Intrauterine brain volumes are associated with infant neurobehavior. The antenatal diagnosis of fetal growth restriction is a risk factor for abnormal infant neurobehavior.

Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia.

INTRODUCTION: The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. METHODS: We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. RESULTS: Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO2), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. CONCLUSION: Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO2 and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.

The Impact of Surgical Patent Ductus Arteriosus Closure on Autonomic Function in Premature Infants.

Background Patent ductus arteriosus (PDA) is a common complication of prematurity and a risk factor for poor outcome. Infants undergoing surgical PDA ligation are at highest risk for neurodevelopmental injury. Autonomic dysfunction has been described in premature infants with PDA. Aim To interrogate the autonomic nervous system by analysis of advanced heart rate variability (HRV) metrics before and after surgical closure of the PDA. Study Design Prospective, observational study. Subjects Twenty-seven infants born before 28 weeks' gestation were included in this study. Methods Continuous electrocardiogram data were sampled at a rate of 125 Hz for a total of 6 hours before and 6 hours after 30 hours of surgical closure. HRV was determined by detrended fluctuation analysis to calculate the short and long root mean square (RMSL and RMSS) and α components at two time scales (long and short). Results Gestational age (GA) was positively associated with RMSL, RMSS, and αS and was negatively associated with αL. There was no difference between RMSs, RMSL, αS, or αL before and after surgery; however, median heart rate was lower after surgery (p < 0.01). Conclusion Advancing GA is highly associated with increasing HRV; however, surgical ligation does not affect HRV in the postoperative period.

Cerebrospinal Fluid and Parenchymal Brain Development and Growth in the Healthy Fetus.

OBJECTIVE: The objective of this study was to apply quantitative magnetic resonance imaging to characterize absolute cerebrospinal fluid (CSF) development, as well as its relative development to fetal brain parenchyma in the healthy human fetus. DESIGN: We created three-dimensional high-resolution reconstructions of the developing brain for healthy fetuses between 18 and 40 weeks' gestation, segmented the parenchymal and CSF spaces, and calculated the volumes for the lateral, third, and fourth ventricles; extra-axial CSF space; and the cerebrum, cerebellum, and brainstem. From these data, we constructed normograms of the resulting volumes according to gestational age and described the relative development of CSF to fetal brain parenchyma. RESULTS: Each CSF space demonstrated major increases in volumetric growth during the second half of gestation: third ventricle (23-fold), extra-axial CSF (11-fold), fourth ventricle (8-fold), and lateral ventricle (2-fold). Total CSF volume was related to total brain volume (p < 0.01), as was lateral ventricle to cerebral volume (p < 0.01); however, the fourth ventricle was not related to cerebellar or brainstem volume (p = 0.18-0.19). RELEVANCE: Abnormalities of the CSF spaces are the most common anomalies of neurologic development detected on fetal screening using neurosonography. Normative values of absolute CSF volume, as well as relative growth in comparison to intracranial parenchyma, provide valuable insight into normal fetal neurodevelopment. These data may provide important biomarkers of early deviations from normal growth, better distinguish between benign variants and early disease, and serve as reference standards for postnatal growth and development in the premature infant.

Prenatal evaluation of atelencephaly.

Atelencephaly is a rare lethal congenital brain malformation characterized by underdevelopment of the prosencephalon and is often accompanied by the facial features seen in some cases of holoprosencephaly, such as cyclopia. We report a case of atelencephaly in the fetus with characteristic ultrasound findings. In addition, we report the findings on fetal MRI, which have not been previously described in the literature.

3-D volumetric MRI evaluation of the placenta in fetuses with complex congenital heart disease.

INTRODUCTION: Placental insufficiency remains a common cause of perinatal mortality and neurodevelopmental morbidity. Congenital heart disease (CHD) in the fetus and its relationship to placental function is unknown. This study explores placental health and its relationship to neonatal outcomes by comparing placental volumes in healthy pregnancies and pregnancies complicated by CHD using in vivo three-dimensional MRI studies. METHODS: In a prospective observational study, pregnant women greater than 18 weeks gestation with normal pregnancies or pregnancies complicated by CHD were recruited and underwent fetal MR imaging. The placenta was manually outlined and the volume was calculated in cm(3). Brain volume was also calculated and clinical data were also collected. Relationships, including interactive effects, between placental and fetal growth, including brain growth, were evaluated using longitudinal multiple linear regression analysis. RESULTS: 135 women underwent fetal MRI between 18 and 39 weeks gestation (mean 31.6 ± 4.4). Placental volume increased exponentially with gestational age (p = 0.041). Placental volume was positively associated with birth weight (p < 0.001) and increased more steeply with birth weight in CHD-affected fetuses (p = 0.046). Total brain and cerebral volumes were smaller in the CHD group (p < 0.001), but brainstem volume (p < 0.001) was larger. Placental volumes were not associated with brain volumes. DISCUSSION: Impaired placental growth in CHD is associated with gestational age and birth weight at delivery. Abnormalities in placental development may contribute to the significant morbidity in this high-risk population. Assessment of placental volume by MRI allows for in vivo assessments of placental development.

Feasibility of noninvasive fetal electrocardiographic monitoring in a clinical setting.

Cardiac rhythm is an essential component of fetal cardiac evaluation. The Monica AN24 is a fetal heart rate monitor that may provide a quick, inexpensive modality for obtaining a noninvasive fetal electrocardiogram (fECG) in a clinical setting. The fECG device has the ability to acquire fECG signals and allow calculation of fetal cardiac time intervals between 16- and 42-week gestational age (GA). We aimed to demonstrate the feasibility of fECG acquisition in a busy fetal cardiology clinic using the Monica fetal heart rate monitor. This is a prospective observational pilot study of fECG acquired from fetuses referred for fetal echocardiography. Recordings were performed for 5-15 min. Maternal signals were attenuated and fECG averaged. fECG and fetal cardiac time intervals (PR, QRS, RR, and QT) were evaluated by two cardiologists independently and inter-observer reliability was assessed using intraclass coefficient (ICC). Sixty fECGs were collected from 50 mothers (mean GA 28.1 ± 6.1). Adequate signal-averaged waveforms were obtained in 20 studies with 259 cardiac cycles. Waveforms could not be obtained between 26 and 30 weeks. Fetal cardiac time intervals were measured and were reproducible for PR (ICC = 0.89; CI 0.77-0.94), QRS (ICC = 0.79; CI 0.51-0.91), and RR (ICC = 0.77; CI 0.53-0.88). QT ICC was poor due to suboptimal T-wave tracings. Acquisition of fECG and measurement of fetal cardiac time intervals is feasible in a clinical setting between 19- and 42-week GA, though tracings are difficult to obtain, especially between 26 and 30 weeks. There was high reliability in fetal cardiac time intervals measurements, except for QT. The device may be useful for assessing atrioventricular/intraventricular conduction in fetuses from 20 to 26 and >30 weeks. Techniques to improve signal acquisition, namely T-wave amplification, are ongoing.

Specialized delivery room planning for fetuses with critical congenital heart disease.

Improvements in fetal echocardiography have increased recognition of fetuses with congenital heart disease (CHD) that require specialized delivery room (DR) care. In this study, care protocols for these low-volume and high-risk deliveries were created. Elements included (1) diagnosis-specific DR care plans and algorithms, (2) a multidisciplinary team with expertise, (3) simulation, (4) checklists, and (5) debriefing. The purpose of this study was to assess the accuracy of fetal echocardiography to predict the need for specialized DR care and determine the effectiveness of the care protocols for the treatment of patients with critical CHD. Fetal and postnatal medical records and echocardiograms of fetuses with CHD assigned to an advanced level of care were reviewed. Safety and outcome variables were analyzed to determine care plan and algorithm efficacy. Thirty-four fetuses were identified: 12 delivered at Children's National Medical Center and 22 at the adult hospital. Diagnoses included hypoplastic left heart syndrome, aortic stenosis, d-transposition of the great arteries, tetralogy of Fallot with absent pulmonary valve, complex pulmonary atresia, arrhythmias, ectopia cordis, and conjoined twins. Delivery at Children's National Medical Center was associated with a shorter time to specialty care or intervention. Measures of physiologic stability and survival were similar. Need for specialized care was predicted in 84% of deliveries. For hypoplastic left heart syndrome, intervention was predicted in 10 of 11 deliveries and for d-transposition of the great arteries in 10 of 12 deliveries. Care algorithms addressed most DR events. Of the unanticipated events, none were unrecoverable. DR survival was 100%, and survival to discharge was 83%. In conclusion, fetal echocardiography predicted the need for specialized DR care in fetuses with critical CHD. Algorithm-driven protocols enable planning such that maternal and infant risk is minimized and outcomes are good.

Impact of congenital heart disease on fetal brain development and injury.

PURPOSE OF REVIEW: Advances in cardiac surgical techniques and intensive care have led to improved survival in babies with congenital heart disease (CHD). Although it is true that the majority of children with CHD today survive, many have impaired neurodevelopmental outcome. Although continuing to improve short-term morbidity and mortality are important goals, recent research has focused on defining the impact of CHD on brain development and brain injury in utero. RECENT FINDINGS: The impact of CHD on the developing brain of the fetus and infant will be discussed. Neurologic abnormalities detectable prior to surgery will be described and postnatal progression of abnormalities will be highlighted. Potential causes of these findings will be discussed, including altered cerebral blood flow in utero, and brain development and risk for in-utero and postnatal brain injury. Finally, neurologic and developmental outcome after surgical repair of CHD will be reviewed. SUMMARY: Neurodevelopmental evaluation preoperatively and postoperatively in CHD patients should be standard practice, not only to identify those with impairments who would benefit from intervention services but also to identify risk factors and strategies to optimize outcome. Fetal management and intervention strategies for specific defects may ultimately play a role in improving in-utero hemodynamics and increasing cerebral oxygen delivery to enhance brain development.

Magnetic resonance volumetric assessments of brains in fetuses with ventriculomegaly correlated to outcomes.

OBJECTIVES: The purpose of this study was to correlate 2-dimensional magnetic resonance (MR) measurements of lateral ventricular width and 3-dimensional measurements of lateral ventricular and supratentorial parenchymal volumes to postnatal outcomes in fetuses with ventriculomegaly. METHODS: A total of 307 fetuses (mean gestational age, 26.0 weeks; range, 15.7-39.4 weeks) had MR volumetry after referral for ventriculomegaly. Fetuses were grouped into those with (n = 114) and without (n = 193) other central nervous system (CNS) anomalies. Pregnancy and postnatal neurodevelopmental outcomes up to 3 years of age were obtained. A subgroup analysis was performed excluding fetuses with other CNS anomalies. Logistic regression analysis was performed to assess which measurement was most predictive of outcomes. RESULTS: There were 50 terminations, 2 stillbirths, and 255 live births. Seventy-five cases were lost to follow-up. Among 180 live-born neonates with follow-up, 140 had abnormal and 40 had normal outcomes. Atrial diameter (P < .0001), frontal horn diameter (P < .0001), and ventricular volume (P = .04) were predictive of live birth, with 92% specificity at 60% sensitivity. Among fetuses without other CNS anomalies, 180 of 193 pregnancies (93%) resulted in live deliveries, with atrial diameter (P < .0001), frontal horn diameter (P = .003), and ventricular volume (P = .008) associated with live birth and atrial diameter having the highest specificity (>99% at 60% sensitivity). Parenchymal volume was not associated with normal or abnormal outcomes (either live birth versus death or normal versus abnormal neurodevelopmental outcome). Among live-born neonates, no age-adjusted threshold for any of the measurements reliably distinguished between normal and abnormal neurodevelopmental outcomes. CONCLUSIONS: Ventricular volume and diameter, but not parenchymal volume, correlate with live birth in fetuses with ventriculomegaly. However, once live born, neither 2- nor 3-dimensional measurements can distinguish a fetus that will have a normal outcome.

The syndrome of perisylvian polymicrogyria with congenital arthrogryposis.

BACKGROUND: Bilateral perisylvian polymicrogyria (BPP) is a well-recognized malformation of cortical development commonly associated with epilepsy, cognitive impairment, and oromotor apraxia. Reports have suggested the association of BPP with arthrogryposis multiplex congenita. We sought to investigate the clinical, electrophysiological, and neuroradiological features of this combined syndrome to determine if there are unique features that distinguish BPP with arthrogryposis from BPP alone. METHODS: Cases of BPP with congenital arthrogryposis were identified from a large research database of individuals with polymicrogyria. Clinical features (including oromotor function, seizures, and joint contractures), MR brain imaging, and results of neuromuscular testing were reviewed. RESULTS: Ten cases of BPP with congenital arthrogryposis were identified. Most cases had some degree of oromotor apraxia. Only a few had seizures, but a majority of cases were still young children. Electrophysiological studies provided evidence for lower motor neuron or peripheral nervous system involvement. On brain imaging, bilateral polymicrogyria (PMG) centered along the Sylvian fissures was seen, with variable extension frontally or parietally; no other cortical malformations were present. We did not identify obvious neuroimaging features that distinguish this syndrome from that of BPP without arthrogryposis. CONCLUSIONS: The clinical and neuroimaging features of the syndrome of BPP with congenital arthrogryposis appear similar to those seen in cases of isolated BPP without joint contractures, but electrophysiological studies often demonstrate coexistent lower motor neuron or peripheral nervous system pathology. These findings suggest that BPP with arthrogryposis may have a genetic etiology with effects at two levels of the neuraxis.

Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors?

OBJECTIVE: Although cerebellar hemorrhagic injury is increasingly diagnosed in infants who survive premature birth, its long-term neurodevelopmental impact is poorly defined. We sought to delineate the potential role of cerebellar hemorrhagic injury in the long-term disabilities of survivors of prematurity. DESIGN: We compared neurodevelopmental outcome in 3 groups of premature infants (N = 86; 35 isolated cerebellar hemorrhagic injury, 35 age-matched controls, 16 cerebellar hemorrhagic injury plus supratentorial parenchymal injury). Subjects underwent formal neurologic examinations and a battery of standardized developmental, functional, and behavioral evaluations (mean age: 32.1 +/- 11.1 months). Autism-screening questionnaires were completed. RESULTS: Neurologic abnormalities were present in 66% of the isolated cerebellar hemorrhagic injury cases compared with 5% of the infants in the control group. Infants with isolated cerebellar hemorrhagic injury versus controls had significantly lower mean scores on all tested measures, including severe motor disabilities (48% vs 0%), expressive language (42% vs 0%), delayed receptive language (37% vs 0%), and cognitive deficits (40% vs 0%). Isolated cerebellar hemorrhagic injury was significantly associated with severe functional limitations in day-to-day activities. Significant differences were noted between cases of cerebellar hemorrhagic injury versus controls on autism screeners (37% vs 0%) and internalizing behavioral problems (34% vs 9%). Global developmental, functional, and social-behavioral deficits were more common and profound in preterm infants with injury to the vermis. Preterm infants with cerebellar hemorrhagic injury and supratentorial parenchymal injury were not at overall greater risk for neurodevelopmental disabilities, although neuromotor impairment was more severe. CONCLUSIONS: Cerebellar hemorrhagic injury in preterm infants is associated with a high prevalence of long-term pervasive neurodevelopment disabilities and may play an important and underrecognized role in the cognitive, learning, and behavioral dysfunction known to affect survivors.

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study.

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.

Hemodilution elevates cerebral blood flow and oxygen metabolism during cardiopulmonary bypass in piglets.

BACKGROUND: Hemodilution continues to be widely used during cardiopulmonary bypass (CPB) for both adults and children. Previous studies with nonbypass models have suggested that an increase in cerebral blood flow (CBF) compensates for the reduced oxygen-carrying capacity; however, this increased CBF is achieved by an increase in cardiac output. We hypothesized that even with the fixed-flow perfusion of CPB, CBF would be increased during hemodilution. METHODS: Two experiments were conducted and analyzed separately. In each experiment, 10 piglets were randomized to two different groups, one with a total blood prime yielding a high hematocrit (25% or 30%), and the other with a crystalloid prime resulting in a low hematocrit (10% or 15%). Animals were cooled with pH-stat strategy at full flow (100 or 150 mL.kg(-1).min(-1)) to a nasopharyngeal temperature of 15 degrees C, a period of low flow (50 mL.kg(-1).min(-1)) preceding deep hypothermic circulatory arrest (45 or 60 minutes), and a period of rewarming at full flow. Cerebral blood flow was measured at the beginning of CPB, at the end of cooling, at the end of low flow, 5 minutes after the start of rewarming, and at the end of rewarming by injection of radioactive microspheres. RESULTS: Mean arterial pressure was significantly greater with higher hematocrit at each time point (p< 0.05). Cerebral blood flow and the cerebral metabolic rate of oxygen decreased during cooling and further during low flow bypass but were significantly greater with lower hematocrit during mild hypothermia and at the end of rewarming (p< 0.05). CONCLUSIONS: Hemodilution is associated with decreased perfusion pressure, increased CBF and increased the cerebral metabolic rate of oxygen during hypothermic CPB.

Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial.

OBJECTIVES: Our goal was to determine which of the two major methods of vital organ support used in infant cardiac surgery, total circulatory arrest and low-flow cardiopulmonary bypass, results in better neurodevelopmental outcomes at school age. METHODS: In a single-center trial, infants with dextrotransposition of the great arteries underwent the arterial switch operation after random assignment to either total circulatory arrest or low-flow cardiopulmonary bypass. Developmental, neurologic, and speech outcomes were assessed at 8 years of age in 155 of 160 eligible children (97%). RESULTS: Treatment groups did not differ in terms of most outcomes, including neurologic status, Full-Scale or Performance IQ score, academic achievement, memory, problem solving, and visual-motor integration. Children assigned to total circulatory arrest performed worse on tests of motor function including manual dexterity with the nondominant hand (P =.003), apraxia of speech (P =.01), visual-motor tracking (P =.01), and phonologic awareness (P =.003). Assignment to low-flow cardiopulmonary bypass was associated with a more impulsive response style on a continuous performance test of vigilance (P <.01) and worse behavior as rated by teachers (P =.05). Although mean scores on most outcomes were within normal limits, neurodevelopmental status in the cohort as a whole was below expectation in many respects, including academic achievement, fine motor function, visual-spatial skills, working memory, hypothesis generating and testing, sustained attention, and higher-order language skills. CONCLUSIONS: Use of total circulatory arrest to support vital organs during heart surgery in infancy is generally associated with greater functional deficits than is use of low-flow cardiopulmonary bypass, although both strategies are associated with increased risk of neurodevelopmental vulnerabilities.

The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial.

OBJECTIVES: Despite the technical advantages of total circulatory arrest for vital organ support during infant heart surgery, many centers have moved away from its use because of the demonstrated effects of circulatory arrest of long duration on neurodevelopmental outcomes. Our goal was to determine the functional form of the association between duration of circulatory arrest and risk of neurodevelopmental dysfunction. METHODS: From 1988 to 1992, in a single-center trial, infants with d-transposition of the great arteries underwent the arterial switch operation after random assignment to circulatory arrest or low-flow bypass. The alpha-stat method was used, and hematocrit on bypass was maintained at 20%. Developmental, neurologic, and speech outcomes were assessed at 8 years of age in 155 of 160 eligible children (97%). Outcomes selected for analysis were Full-Scale, Verbal, and Performance IQ, Reading and Mathematics Composite, time to complete the Grooved Pegboard (dominant hand), and the Mayo Test for Apraxia. RESULTS: Nonparametric regression and piecewise linear models indicated that neurodevelopmental outcomes were generally not adversely affected unless the duration of circulatory arrest exceeded a threshold of 41 minutes (95% 1-sided lower confidence limit of 32 minutes). CONCLUSIONS: We found that the effect of duration of total circulatory arrest on later neurodevelopmental outcomes is nonlinear, with little influence at shorter durations and with steadily worsening outcomes after longer durations of circulatory arrest. Because the effects of duration of circulatory arrest may vary according to diagnosis, age at surgery, and other bypass and perioperative variables, this study cannot ascertain a universally "safe" duration of total circulatory arrest.