Cerebrovascular disorders in children with the factor V Leiden mutation.

Since 1995, at least 128 children with a cerebrovascular disorder, cerebral palsy, or both and the factor V Leiden mutation have been reported. The majority of these strokes were in the first year of life, many of them in the perinatal period. Two thirds had an additional exogenous risk factor for thrombosis, and 42% had another recognized endogenous prothrombotic risk factor in combination with the mutation. We review the association of the factor V Leiden mutation and a cerebrovascular disorder in children younger than 16 years of age and describe the clinical features of 8 children with cerebral palsy and the Leiden mutation. This mutation should be considered in the evaluation of children with a stroke or its sequelae, including infants with perinatal stroke.

Congenital abnormalities among children with cerebral palsy: More evidence for prenatal antecedents.

OBJECTIVES: To investigate the association between cerebral palsy (CP) and congenital abnormalities among children with very low, low, and normal birth weight. STUDY DESIGN: A population-based, case-control study among the cohort of 155,636 live births delivered between 1983 and 1985 in 4 California counties. Children with moderate or severe congenital CP (n = 192) diagnosed by age 3 were identified from 2 California State service agencies, and 551 control children were randomly sampled from birth certificate files. Information on congenital abnormalities diagnosed by the age of 1 year was obtained from the California Birth Defects Monitoring Program registry. Odds ratios (OR) and 95% CIs were calculated to estimate risk for CP associated with congenital abnormalities. RESULTS: Among singletons, congenital abnormalities were present in 33 (19.2%) children with CP and 21 (4.3%) control children (OR = 5.2, 95% CI 2.8-9.7). For each birth weight group, the percent of children with congenital abnormalities among children with CP exceeded that among control children. Structural abnormalities of the central nervous system were more common among children with CP (OR = 16.2, 95% CI 5.8-49.3) than control children. In contrast, the percent of children with non-central nervous system abnormalities only was similar between case patients and control subjects. CONCLUSION: These findings provide further evidence that factors operating in the prenatal period contribute significantly to the etiology of CP.

The epidemiology of mental retardation of unknown cause.

OBJECTIVE: To describe selected infant and maternal characteristics for children with mild and severe mental retardation (MR) of unknown cause. STUDY DESIGN: Children with MR of unknown cause born in California between 1987 and 1994 were identified through service agency records and compared with the total population of California live births for selected characteristics recorded on the birth certificate. RESULTS: For both children with mild and severe MR, risk was increased among males, low birth weight children, and children born to women of black race, older age at delivery, and lower level of education. Increased risk for mild MR was found for multiple births, second or later-born children, and children whose mothers were born outside of California. Increased risk for severe MR was observed among children born to Hispanic mothers; children born to Asian mothers also had increased risk for severe MR but decreased risk for mild MR. CONCLUSIONS: These results provide clues for understanding the underlying causes of MR and suggest that both biological and social factors are important.

Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation.

There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5). Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.

Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia.

OBJECTIVE: Our aim was to examine magnesium sulfate tocolysis and cerebral palsy in infants born prematurely to women without preeclampsia. STUDY DESIGN: We conducted a retrospective case-control study of infants with birth weights <1500 g and of infants with birth weights from 1500 to 1999 g who were born at <33 weeks' gestation. The study infants were born in level 2 or level 3 hospitals from 1988 through 1994 to women without preeclampsia, were delivered >3 hours after admission, and had survived to age 2 years. RESULTS: Among 170 children with cerebral palsy and 288 control subjects, similar proportions of case mothers (58%) and control mothers (62%) had received magnesium sulfate tocolysis. In women with some tocolytic treatment, these proportions were 78% and 76%, respectively. The duration of treatment with magnesium was comparable for case and control women, as were the intervals from beginning and termination of treatment to delivery. Adjustment for gestational age, birth weight, and other variables did not alter this result. CONCLUSION: Magnesium exposure was not associated with a lower risk of cerebral palsy in infants born prematurely to women without preeclampsia. The difference between this finding and that in our previous study showing an apparent neuroprotective effect of magnesium is not explained by the more restrictive selection criteria used here and may be related to a number of changes in medical practice between the 2 periods.

Causes of cerebral palsy.

Risk factors for cerebral palsy in term or near-term children include intrauterine exposure to infection or inflammation and disorders of coagulation. Interruption of the oxygen supply during birth contributes approximately 6% of spastic cerebral palsy. Low Apgar score, need for resuscitation, and seizures are nonspecific indicators of neonatal illness that do not identify cause. Although not entirely consistent, current evidence suggests that in utero infection may predispose very preterm and more mature infants to cerebral palsy and that antenatal exposure to steroids may be somewhat protective. Recognition of a broader set of causal possibilities encourages hope for new strategies for the prevention of cerebral palsy.

Reliability of placental histology using archived specimens.

Archived placental materials provide a resource for retrospective studies of perinatal outcomes. Using archived specimens, we evaluated inter-rater reliability in the assessment of placental histological features possibly associated with neonatal illness and long-term neurological outcome. Five expert placental pathologists independently reviewed archived placental specimens on 30 subjects born during 1983-85 in six different hospitals. Moderate to substantial agreement among the raters was observed for a variety of indicators of inflammation, presence of macrophages with pigment and indicators of villous maturity, increased syncytial knots and maternal vasculopathy. Existing pathology reports for these specimens from routine histology examinations conducted at the time of delivery were in substantial agreement with expert review for the presence of any subchorionitis/chorionitis/chorioamnionitis. In conclusion, considerable inter-rater agreement was observed for several relatively common and potentially important placental findings. Archived placental materials and pathology reports may be useful in retrospective studies.

Selection of neonates for neuroprotective therapies: one set of criteria applied to a population.

OBJECTIVES: To estimate the proportion of children with cerebral palsy (CP) who had signs of birth asphyxia" in the early hours of life, and to examine the nature of the illnesses in those infants. DESIGN: Population-based case-control study. SETTING: All births in 4 northern California counties, 1983 through 1985. SUBJECTS: Eighty-four full-term singleton children surviving to age 3 years with spastic CP and 366 full-term control children. MAIN OUTCOME MEASURE: Moderate or severe spastic CP. RESULTS: Of 84 full-term children with spastic CP, 18 had 5-minute Apgar scores of less than 6, 20 required intubation for ventilation in the delivery room, and 5 had an initial blood pH of 7.00 or less. Three (3.6%) of the 84 children had all 3 signs evaluated, a prevalence of 0.019 per 1000 survivors. All 3 had neonatal seizures. When we relaxed the pH cutoff to 7.10 or less, there were 19 children with CP who met at least 2 criteria. Eight of these 19 infants were born in level I facilities. In these children there was evidence of maternal or infant infection (n = 7), abnormal coagulation factor, thrombosis, or thrombocytopenia (n = 8); or other complication predating birth (n = 9). CONCLUSIONS: Neuroprotective therapy offered to neonates with these early characteristics, even if perfectly effective, would be unlikely to prevent most CP. Most of these depressed infants with CP had nonasphyxial conditions that may have contributed to adverse neurological outcome.

Interferons and cerebral palsy.

OBJECTIVE: To explore the association of neonatal interferons (IFNs) with spastic cerebral palsy (CP) and with other measured substances. STUDY DESIGN: Assays of archived neonatal blood of 31 predominantly term children with CP and 65 children in a control group were obtained by recycling immunoaffinity chromatography with laser-enhanced fluorescence and chemiluminescence detection. RESULTS: Fourteen of 31 children with spastic CP had concentrations of IFNs-alpha, beta, and gamma exceeding any control. Levels of interleukins-1, 6, 8, tumor necrosis factor-alpha, chemokines, colony stimulating factors, transforming growth factor-beta, complement components and regulators, certain neuropeptides, and thyroid hormones also differed from control levels in these 14 children. The 17 children with CP whose IFN concentrations were within the control range had levels of inflammatory cytokines higher than but near to control values; 13 of these 17 had values for coagulation factors that exceeded control values. Seven of 9 children with spastic diplegia had high IFNs, and 8 of 10 hemiplegic children had normal IFNs. CONCLUSION: Neonatal IFNs exceeding control concentrations were associated with other biochemical and clinical indicators of inflammation and with spastic diplegia. In these children with CP, IFNs within the control range were associated with concentrations of other inflammatory markers that were near to control values and with spastic hemiplegia.

Neonatal cytokines and coagulation factors in children with cerebral palsy.

We explored the association of inflammatory mediators and markers of autoimmune and coagulation disorders with cerebral palsy (CP), examining 53 analytes in dried neonatal blood of 31 children with spastic CP, most born at term, and 65 control children. Ultramicroanalysis was performed by recycling immunoaffinity chromatography coupled with laser-enhanced fluorescence and chemiluminescence detection. Reactive antibodies to lupus anticoagulant, anticardiolipin, antithrombin III, and the translational product of the factor V Leiden mutation were isolated by recycling immunoaffinity chromatography and measured by capillary electrophoresis with chemiluminescence-enhanced immunoassay. Higher concentrations of interleukins (ILs) 1, 8, 9, tumor necrosis factor-alpha, and RANTES were observed in these children with CP than in any control child. There were also substantial elevations of IL-6, 11, 13, and other chemokines and colony-stimulating factors in children with CP. Antiphospholipid antibody was present in a titer of 1:100 or greater in 4 children with CP and no control child. Using cuts empirically chosen by recursive partitioning, we found higher concentrations of antibody to antithrombin III, to a translational product of factor V Leiden mutation, and to proteins C and S in children with CP than in controls. We conclude that inflammation and these coagulation abnormalities, which have interacting pathways, are important in the etiology of CP.

Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight.

OBJECTIVE: Our purpose was to examine the association of cerebral palsy with conditions that can interrupt oxygen supply to the fetus as a primary pathogenetic event. STUDY DESIGN: A population-based case-control study was performed in four California counties, 1983 through 1985, comparing birth records of 46 children with disabling spastic cerebral palsy without recognized prenatal brain lesions and 378 randomly selected control children weighing > or = 2500 g at birth and surviving to age 3 years. RESULTS: Eight of 46 children with otherwise unexplained spastic cerebral palsy, all eight with quadriplegic cerebral palsy, and 15 of 378 controls had births complicated by tight nuchal cord (odds ratio for quadriplegia 18, 95% confidence interval 6.2 to 48). Other potentially asphyxiating conditions were uncommon and none was associated with spastic diplegia or hemiplegia. Level of care, oxytocin for augmentation of labor, and surgical delivery did not alter the association of potentially asphyxiating conditions with spastic quadriplegia. Intrapartum indicators of fetal stress, including meconium in amniotic fluid and fetal monitoring abnormalities, were common and did not distinguish children with quadriplegia who had potentially asphyxiating conditions from controls with such conditions. CONCLUSION: Potentially asphyxiating conditions, chiefly tight nuchal cord, were associated with an appreciable proportion of unexplained spastic quadriplegia but not with diplegia or hemiplegia. Intrapartum abnormalities were common both in children with cerebral palsy and controls and did not distinguish between them.

Magnesium sulfate tocolysis and risk of neonatal death.

OBJECTIVE: Our purpose was to evaluate the association between in utero exposure to magnesium sulfate and neonatal death. STUDY DESIGN: Case-control comparison was performed of singleton infants who died at 0 to 28 days and control infants who survived to age 3 years and did not have disabling cerebral palsy. All subjects were born between 1983 and 1985 to mothers resident in one of four northern California counties. RESULTS: Magnesium sulfate tocolysis was associated with a decreased risk of neonatal mortality (odds ratio 0.25, 95% confidence interval 0.6 to 1.1). Adjustment for birth weight and gestational age increased the inverse association (odds ratio 0.09, 95% confidence interval 0.01 to 0.93). The association between neonatal mortality and magnesium sulfate was not altered by maternal infection, gender, maternal race or ethnicity, maternal age, level of care, breech presentation, surgical delivery, corticosteroids, abruptio placentae, placenta previa, or bleeding on admission. CONCLUSIONS: Magnesium sulfate tocolysis was not associated with increased neonatal mortality in premature infants. Thus any association of magnesium with reduced long-term neurologic morbidity is unlikely to be the result of selective mortality of vulnerable infants.

Assessment of gestational age using birth certificate data compared with medical record data.

We assessed the extent to which use of medical record data might improve gestational age estimates compared with reliance on the birth certificate alone. Using population-based data from four northern Californian counties, we constructed an algorithm to select the best gestational age estimate from antenatal assessments recorded in medical records. A total of 172 singletons with moderate or severe congenital cerebral palsy from the California Cerebral Palsy Project were compared with 472 randomly selected controls with regard to discrepancies between the algorithm-derived estimated gestational age (bestgest) and an estimate based solely on the last menstrual period as recorded on birth certificates. Agreement between bestgest and birth certificate estimated gestational age was exact or within one week for at least 60% of both cases and controls in each of the three birthweight strata. In general, the greater the birthweight of the babies, the better the agreement. The mean number of weeks of overestimation by the birth certificate was 0.7 weeks for cases and 1.1 weeks for controls in the lowest birthweight group (< 1500 g). When compared with bestgest, clinical examination of the infant also tended to overestimate gestational age. In the < 1500 g birthweight group, cases were twice as likely as controls to have a bestgest of 'low certainty,' but antenatal estimates of 'high certainty' were obtained for at least a third of very low birthweight babies born during the mid-1980s. More widespread use of early ultrasound in more recent birth cohorts may result in a greater proportion of accurate antenatal estimates. When a distinction between immaturity and intrauterine growth retardation is important to the understanding of the aetiology of the outcome under investigation, the use of antenatal estimates from medical records may substantially improve the certainty of the data.

Maternal infection and cerebral palsy in infants of normal birth weight.

CONTEXT: Exposure to maternal or placental infection is related to risk of preterm birth and, in premature infants, of brain lesions predictive of cerebral palsy (CP). Few studies have investigated whether maternal infection is associated with risk of CP in children of normal birth weight. OBJECTIVE: To investigate maternal infection during the admission for delivery as a possible risk factor for CP in infants born weighing 2500 g or more. DESIGN: Population-based case-control study. SETTING: All hospitals in 4 northern California counties, 1983 through 1985. PARTICIPANTS: A total of 46 children with disabling spastic CP who had no recognized prenatal brain lesions and 378 randomly selected control children weighing 2500 g or more at birth and surviving to age 3 years. MAIN OUTCOME MEASURES: Disabling spastic CP and signs of neonatal morbidity. RESULTS: Maternal fever exceeding 38 degrees C in labor was associated with increased risk of unexplained CP (odds ratio [OR], 9.3; 95% confidence interval [CI], 2.7-31.0), as was a clinical diagnosis of chorioamnionitis. One or more indicators of maternal infection were present in 2.9% of control children, 22% of children with CP (OR, 9.3; 95% CI, 3.7-23.0), and 37% of those with the spastic quadriplegic subtype of CP (OR, 19.0; 95% CI, 6.5-56.0). Newborns exposed to maternal infection, both cases and controls, had 5-minute Apgar scores below 6 more often than those unexposed. Among children with CP, those born to infected women were more often hypotensive, needed intubation, had neonatal seizures, and received a clinical diagnosis of hypoxic-ischemic encephalopathy. CONCLUSION: Intrauterine exposure to maternal infection was associated with a marked increase in risk of CP in infants of normal birth weight. Maternal infection was also linked with low Apgar scores, other evidence of hypotension [corrected] and need for resuscitation, and neonatal seizures-signs commonly attributed to birth asphyxia.

What factors influence whether placentas are submitted for pathologic examination?

OBJECTIVE: Our purpose was to investigate factors associated with submission of placentas for pathologic examination. STUDY DESIGN: In a population-based study of the etiology of cerebral palsy, data were abstracted for 627 singleton survivors to age 3 years. Children included as cases had moderate-to-severe cerebral palsy; controls were randomly selected infants born in the same counties and years. RESULTS: Placentas were submitted for pathologic examination for 150 children (24%) of those included in this study. Placentas were more often submitted for children born weighing <1500 gm than for other birth weight groups (p < 0.0001). Placentas from cesarean section deliveries were submitted more often than those from vaginal deliveries (p < 0.0001), elective repeat as often as indicated or emergency cesarean sections. Maternal and neonatal disorders suggested by the College of American Pathologists as indications for placental examination were present in 161 (43%) of controls born weighing > or = 2500 gm. These indications were not associated with pathologic submissions. CONCLUSIONS: Within birth weight groups the main determinant of placental submission for laboratory examination was surgical delivery, whether indicated or elective. Maternal and infant conditions had little influence on the likelihood of submission.

Prenatal and perinatal factors and cerebral palsy in very low birth weight infants.

OBJECTIVE: To identify prenatal and perinatal characteristics associated with cerebral palsy (CP) in infants born weighing < 1500 gm (very low birth weight, VLBW). DESIGN: All 42 VLBW singleton infants with CP born in the period from 1983 to 1985 in a defined population were compared with 75 randomly selected VLBW control infants. RESULTS: Birth in a level I facility was associated with increased risk of CP (odds ratio (OR) 6.3, 95% confidence interval (CI) 1.8, 19), as was birth within 3 hours of the mother's first admission for delivery (OR 3.2, CI 1.4, 7.4). Delivery occurred within 3 hours of admission to a level I facilty in 24% of VLBW children with CP and no control children (OR (0.5 added to each cell of 2 x 2 table) 49, CI 3.1, 204). Chorionitis was associated with increased risk in children born more than 5 hours after admission (OR 4.3, CI 1.1, 13). Chorionitis followed by neonatal seizures occurred in 14% of VLBW children with CP (in 25% with spastic diplegia) and in no control child (OR (0.5 added to each cell of 2 x 2 table) 26, CI 1.6, 116). Preeclampsia was associated with decreased risk (OR 0.08, CI 0.02, 0.67), as was use of magnesium sulfate (OR 0.14, CI 0.05, 0.51) administered for preeclampsia or preterm labor. Other risk factors for CP included gravidity greater than one (OR 3.9, CI 1.2, 11), short interbirth interval (OR 4.1, CI 1.3, 12), and vaginal bleeding on the day of admission (OR 2.9, CI 1.2, 7.4). CONCLUSIONS: In this population-based study, almost one fourth of the CP in VLBW children occurred in infants delivered in level I facilities soon after their mothers' admissions. Another 14% was in children who had neonatal seizures after birth to women with chorionitis. No control subject experienced either of these sequences.

Uncertain value of electronic fetal monitoring in predicting cerebral palsy.

BACKGROUND: Electronic monitoring of the fetal heart rate is commonly performed, in part to detect hypoxia during delivery that may result in brain injury. It is not know whether specific abnormalities on electronic fetal monitoring are related to the risk of cerebral palsy. METHODS: Among 155,636 children born from 1983 through 1985 in four California counties, we identified singleton infants with birth weights of at least 2500 g who survived to three years of age and had moderate or severe cerebral palsy. The children with cerebral palsy were compared with randomly selected control children with respect to characteristics noted in the birth records. RESULTS: Seventy-eight of 95 children with cerebral palsy and 300 of 378 controls underwent intrapartum fetal monitoring. Characteristics found to be associated with an increased risk of cerebral palsy were multiple late decelerations in the heart rate, commonly defined as slowing of the heart rate well after the onset of uterine contractions (odds ratio, 3.9; 95 percent confidence interval, 1.7 to 9.3), and decreased beat-to-beat variability of the heart rate (odds ratio, 2.7; 95 percent confidence interval, 1.1 to 5.8); there was no association between the highest or lowest fetal heart rate recorded for each child and the risk of cerebral palsy. Even after adjustment for other risk factors, the association of abnormalities on fetal monitoring with an increased risk of cerebral palsy persisted (adjusted odds ratio, 2.7; 95 percent confidence interval, 1.4 to 5.4). The 21 children with cerebral palsy who had multiple late decelerations or decreased variability in heart rate on fetal monitoring represented only 0.19 percent of singleton infants with birth weights of 2500 g or more who had these fetal-monitoring findings, for a false positive rate of 99.8 percent. CONCLUSIONS: Specific abnormal findings on electronic monitoring of the fetal heart rate were associated with an increased risk of cerebral palsy. However, the false positive rate was extremely high. Since cesarean section is often performed when such abnormalities are noted and is associated with risk to the mother, our findings arouse concern that, if these indications were widely used, many cesarean sections would be performed without benefit and with the potential for harm.

Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?

OBJECTIVES: To investigate whether in utero exposure to magnesium sulfate (MgSO4) was associated with a lower prevalence of cerebral palsy (CP) in infants born weighing < 1500 g. DESIGN: Singleton infants weighing < 1500 g at birth (very low birthweight, VLBW) and surviving to 3 years with moderate or severe congenital CP were identified among 155,636 children born 1983 through 1985 in four California counties. VLBW children with CP were compared with randomly selected VLBW control survivors with respect to whether their mothers received MgSO4 to prevent convulsions in preeclampsia or as a tocolytic agent, and other information abstracted from labor and delivery records. RESULTS: During the admission for delivery, 7.1% of the 42 VLBW infants with later CP and 36% of the 75 VLBW controls were exposed to MgSO4 (odds ratio (OR) .14, 95% confidence interval (CI) .05, .51). The overall association of MgSO4 with reduced risk of CP was also observed in the subgroup of infants born to women who were not preeclamptic (OR .25, CI .08, .97). Infants with CP were less often exposed antenatally to MgSO4 whether or not there was cotreatment with non-MgSO4 tocolytics (other tocolytics administered, OR for MgSO4 exposure .23, CI .06, 1.2; other tocolytics not administered, OR for MgSO4 .08, CI .02, .68), or antenatal corticosteroids (steroids given, OR for MgSO4 exposure .24, CI .06, 1.3; steroids not given, OR for MgSO4, .08, CI .02, .72). Apparent benefit of magnesium was observed in the presence or absence of a variety of characteristics of pregnancies, births, and infants. CONCLUSION: In this observational study, in utero exposure to MgSO4 was more frequent in controls than in children with CP, suggesting a protective effect of MgSO4 against CP in these VLBW infants.