Long QT syndrome in children: the value of the rate corrected QT interval in children who present with fainting.

OBJECTIVE: A strategy was evaluated for identifying a proportion of children with long QT syndrome (LQTS) using the rate corrected QT interval (QTc) to systematically evaluate children who faint. METHODS: QTc measurements and rates of fainting for the present analysis are available from families with KVLQT1, HERG, or SCN5A genotypes. QTc distributions in affected and unaffected children were documented and detection and false positive rates were modelled. RESULTS: The mean QTc (SD) in 117 affected children was 0.484 seconds (0.031), and 0.420 seconds (0.021) among 133 unaffected children. At a cut off of 0.49 seconds, QTc measurement will identify 42.5% of affected and 0.1% of unaffected persons with a history of fainting who are alive at the time of testing. Assumptions include a prevalence of 1:5000 for LQTS, 2% mortality with the first arrhythmia, and a rate of fainting of 50% in affected children and 7% in unaffected children. Given these variables, a QTc cut off of 0.49 seconds detects 42 of 200 affected, along with 70 unaffected children out of a population of 1 million. If QTc > or = 0.49 seconds is found in either parent of children with a QTc of 0.44 through 0.48 seconds, another 21 affected and 25 unaffected children will be identified. CONCLUSION: Systematically performing QTc measurements as part of the evaluation of children who faint might optimally identify about one third of patients with LQTS with few false positives and thereby offer an opportunity to prevent some sudden deaths.

Long QT syndrome in children: the value of rate corrected QT interval and DNA analysis as screening tests in the general population.

OBJECTIVE: To evaluate two hypothetical screening strategies for identifying children with long QT syndrome (LQTS), a cause of sudden death in childhood. METHODS: Families with KVLQT1, HERG, or SCN5A genotypes provided electrocardiographic (ECG) data for this analysis. This is the first time such genotype-phenotype information has been available. Using the LQTS genotype, the distributions of QTc in affected and unaffected children were established and screening performance for various QTc cut off points were modelled. The detection rate for DNA mutation analysis was determined from published experience. RESULTS: The mean QTc (SD) was 0.484 seconds (0.031) in 117 affected children and 0.420 seconds (0.021) in 133 unaffected children. A QTc cut off of 0.50 seconds in a population of 1 million children would identify 61 of the 200 affected children, and 100 unaffected children. Estimates of testing costs for a screening programme in the newborn period would be $327 869/case detected and $2 222 000/death avoided. Although not presently available for routine use, DNA analysis could, theoretically, identify 100 of the 200 children with LQTS within the same population, along with an estimated 100 unaffected children. CONCLUSION: The only available screening test for LQTS is ECG measurement. If DNA technology becomes available for screening, unit costs must be very low to be competitive. There are multiple problems with screening for LQTS: only a minority of children will be detected, cost/death avoided is high, and pilot studies would need to be in place for 5-10 years to document efficacy.

Maternal thyroid deficiency and pregnancy complications: implications for population screening.

OBJECTIVE: To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. METHODS: TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. RESULTS: Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9-9.5). Other pregnancy complications did not occur more frequently. CONCLUSION: From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

Adaptive mechanisms of developing brain. The neuroradiologic assessment of the preterm infant.

Since the 1980s, cranial sonography has been routinely performed in premature infants. This has produced a wealth of information about the more dramatic central nervous system lesions of IVH, PVL, and late VM. This information has included timing and evolution of these lesions and their eventual correlation with outcome. For two reasons the advent of MR imaging scanning has produced an interest in using this modality to evaluate these same infants. First, MR imaging gives an obviously superior image, and its ability to detect lesions is far superior to that of ultrasound. Second, the ability of cranial sonography to detect all of the children with CP or low IQ is limited. In our studies of outcome in very low-birth weight infants grade 3 to 4 IVH, PVL, or VM are able to detect only about 50% of the infants who developed CP by 3 years. This condition should be highly correlated with structural brain disease; an imaging modality that was more sensitive to central nervous system lesions should offer an advantage in predicting outcome. In the only prospective assessment of the ability of these two modalities to predict outcome at 3 years, van de Bor and colleagues found MR imaging did not do better than cranial sonography. This was largely because both modalities detected the most severe lesions, and most children with milder lesions on MR imaging had normal outcome. Studies of late (age 1 to teenage years) MR imaging scans in preterm infants show that a high percentage have white matter lesions but these lesions correlate poorly with outcome. If our concern when counseling parents is to alert them when a serious adverse outcome is likely in their child, then cranial sonography is to be favored precisely because it is less able to detect subtle lesions, which the developing brain has the capacity to overcome. On the other hand, if our aim is to detect all lesions, even though these lesions do not predict serious adverse outcomes, then MR imaging is to be favored. Research aimed at discovering etiologies and mechanisms of brain injury in these high-risk infants should use the more sensitive modality MR imaging. Finally, the interesting observation that preterm infants fare as well as they do despite MR imaging-identified lesions might stimulate research studying the adaptive mechanisms of developing brain.

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

BACKGROUND: When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS: In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS: The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS: Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (i.e., from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.

Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage.

OBJECTIVES: To determine if cerebral palsy (CP) rates were lower in the active treatment group compared with the control group, as improved survival rates of very low-birth-weight infants are postulated to be the cause of the increased incidence of CP in preterm infants, to evaluate relationships between multiple prenatal, perinatal, and postnatal variables and CP to understand better its antecedents in very low-birth-weight infants in the era of surfactant replacement therapy, and to determine the usefulness of a cranial ultrasonographic (US) scan in predicting CP. DESIGN: Inception cohort follow-up study as part of a randomized controlled trial of low-dose indomethacin sodium for the prevention of intraventricular hemorrhage. SETTING: Neonatal intensive care units at 3 medical centers. PATIENTS: Infants with birth weights between 600 and 1250 g were eligible, and 505 infants were enrolled in the original study. Of these infants, 440 (87%) survived; neurologic examinations were completed on 381 infants (86%) at 36 months corrected age. MAIN OUTCOME MEASURES: Statistical analyses were performed to identify the antecedents of CP, including the results of frequent cranial US scans obtained throughout the newborn period. RESULTS: Cerebral palsy was found in 36 (9.5%) of 381 infants at 36 months corrected age (range, 33-39 months corrected age). Univariate analysis identified chorioamnionitis, treatment with surfactant, bronchopulmonary dysplasia, and abnormal cranial US findings as antecedents of CP. Periventricular leukomalacia and ventriculomegaly were associated with the highest detection rates for CP (37% and 30%, respectively) with acceptable false-positive rates. Multivariate analysis identified bronchopulmonary dysplasia and an abnormal cranial US scan showing grade 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, or ventriculomegaly as independent predictors of CP. Odds ratios for the detection of CP using cranial US findings tabulated by hospital day were in the range of 7 to 26 beginning on day 2. CONCLUSION: The results suggest that cranial US findings are useful predictors of CP during a patient's stay in the hospital.

Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial.

OBJECTIVES: Low-dose indomethacin has been shown to prevent intraventricular hemorrhage (IVH) in very low birth weight neonates, and long-term neurodevelopmental follow-up data are needed to validate this intervention. We hypothesized that the early administration of low-dose indomethacin would not be associated with adverse cognitive outcome at 36 months' corrected age (CA). METHODS: We enrolled 431 neonates of 600 to 1250 g birth weight with no IVH at 6 to 12 hours in a randomized, prospective trial to determine whether low-dose indomethacin would prevent IVH. A priori, neurodevelopmental follow-up examinations, including the Stanford-Binet Intelligence Scale and Peabody Picture Vocabulary Test-Revised, and standard neurologic examinations were planned at 36 months' CA. RESULTS: Three hundred eighty-four of the 431 infants survived (192 [92%] of 209 infants receiving indomethacin versus 192 [86%] of 222 infants receiving saline), and 343 (89%) children were examined at 36 months' CA. Thirteen (8%) of the 166 infants who received indomethacin and 14 (8%) of 167 infants receiving the placebo were found to have cerebral palsy. There were no differences in the incidence of deafness or blindness between the two groups. For the 248 English-monolingual children for whom IQ data follow, the mean gestational age was significantly younger for the infants who received indomethacin than for those who received the placebo. None of the 115 infants who received indomethacin was found to have ventriculomegaly on cranial ultrasound at term, compared with 5 of 110 infants who received the placebo. The mean +/- SD Stanford-Binet IQ score for the 126 English-monolingual children who had received indomethacin was 89.6 +/- 18.92, compared with 85.0 +/- 20.79 for the 122 English-monolingual children who had received the placebo. Although maternal education was strongly correlated with Stanford-Binet IQ at 36 months' CA, there was no difference in educational levels between mothers of the infants receiving indomethacin and the placebo. CONCLUSIONS: Indomethacin administered at 6 to 12 hours as prophylaxis against IVH in very low birth weight infants does not result in adverse cognitive or motor outcomes at 36 months' CA.

Acute hemichorea in a 14-year-old boy.

The differential diagnosis of chorea or hemichorea in an adolescent boy is discussed. Sydenham's chorea, still the most common cause of chorea in childhood, is only one of many important diseases in the differential diagnosis in this clinical situation.

Perinatal cerebrovascular disease in the neonate. Parenchymal ischemic lesions in term and preterm infants.

Acute cerebrovascular injury in term and preterm infants is a cause of significant morbidity. Treatment efforts in the past have focused on attempts to prevent such injury by interceding during labor in term infants and improving neonatal care in preterm infants. Epidemiologic studies suggest that these strategies have had little impact. A new strategy--drug treatment of acute ischemic brain injury--is on the horizon. The recognition and prognostication in ischemic neonatal brain injury takes on a new importance in this light.

The cavum septi pellucidi in term and preterm newborn infants.

We reviewed cranial sonographic studies done on 108 normal newborn infants to determine the prevalence and variability in size of the cavum septi pellucidi (CSP). Infants were classified according to gestational age by 2-week intervals. At 24 weeks, only four normal scans were identified. Between 26 and 34 weeks, ten consecutive normal scans were used since all infants had a CSP. At 36, 38, and 40 weeks, all normal scans were counted in order to obtain a prevalence estimate. A CSP was seen in all normal infants below 36 weeks of gestational age. At 36, 38, and 40 weeks, only 69%, 54%, and 36%, respectively, had CSPs. There was no significant change in the width, depth, or area of the CSP with age, birth weight, or biparietal diameter. A CSP greater than 0.95 cm in width or greater than 0.81 cm in depth is outside the normal range and may represent anomalous development of the midline structures of the brain.

Posthemorrhagic hydrocephalus. Use of an intravenous-type catheter for cerebrospinal fluid drainage.

STUDY OBJECTIVE: To report a 9-year experience with the treatment of posthemorrhagic hydrocephalus (PHH) with the use of an easily inserted external ventricular drain. DESIGN: A case series with a retrospective review of hospital records and cranial ultrasound results, from 1981 through 1989, in all infants with PHH. INTERVENTION: A previously defined method of identification and bedside management of PHH was applied. If infants reached 2 kg of body weight and PHH recurred, a ventriculoperitoneal shunt was inserted. RESULTS: A total of 70 procedures were performed in 24 patients, and all were associated with a decrease in head circumference and ventricular size on ultrasound scan. One infection occurred, and only 12 infants required a ventriculoperitoneal shunt. CONCLUSIONS: This technique compared favorably with other methods of intervention to avoid early placement of a ventriculoperitoneal shunt in preterm infants and offered the advantage of consistently decreasing ventricular size. A multicenter-controlled trial will be needed to compare the safety and efficacy of therapies for PHH.

Does cesarean section protect against intraventricular hemorrhage in preterm infants?

A declining incidence of periventricular-intraventricular hemorrhage (PV-IVH) in preterm infants less than 35 weeks' gestational age during the years 1980 through 1987 led us to investigate the role of the route of delivery. Routine cephalic ultrasound was used to detect PV-IVH in 490 vaginal and 411 cesarean section deliveries. A lower incidence of all PV-IVH and severe PV-IVH was noted in cesarean section deliveries for each 2-year period, with a decline in all PV-IVH in vaginal and cesarean section deliveries from 39% and 31%, respectively, in 1980-1981 to 23% and 11% in 1986-1987. Striking differences were noted for infants less than 1500 g, less than 1000 g, or less than 27 weeks' gestation. For example, in infants less than 1000 g, the incidence of all PV-IVH was 52% in vaginal (n = 101) and 25% in cesarean section deliveries (n = 88), and of severe PV-IVH was 26% and 11%, respectively. These differences did not seem to be influenced by presence or absence of labor, breech presentation, or low Apgar scores. Route of delivery should be considered as an important variable in pharmacologic intervention studies.