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Biomedical subjects

S E Waisbren

Publications and source records attributed to S E Waisbren.

At least 19 recordsLinked to original sources

A review of the psychosocial effects of false-positive results on parents and current communication practices in newborn screening.

As more states adopt expanded newborn screening for metabolic disorders, the overall number of false positives increases. False-positive screening results have been associated with increased anxiety and stress in parents of infants who require follow-up testing, even after the infant's good health is confirmed. This article reviews the literature on the negative impact of false-positive newborn screening results on parents, along with a review of current communication practices for follow-up screening. The results of this review suggest that parental stress and anxiety can be reduced with improved education and communication to parents, specifically at the time of follow-up screening. Communication strategies with sample materials are proposed.

Anxiety↗

The knowledge gap in expanded newborn screening: survey results from paediatricians in Massachusetts.

Massachusetts currently offers an optional expanded newborn screening programme that tests for 20 biochemical genetic disorders in addition to the mandated newborn screening tests, including phenylketonuria (PKU) and nine other biochemical genetic disorders. We conducted a mail survey of 550 paediatricians listed in the 2000 Massachusetts Healthcare Directory to determine paediatricians' preparedness in discussing expanded newborn screening and its results with families, and to determine in what specific format physicians in Massachusetts would prefer to receive educational materials and updates. Of surveys mailed, 35% (190/550) were returned within the allotted 3 weeks: 25 paediatricians (14%) were unaware of expanded newborn screening; 78 respondents (42%) indicated feeling less than prepared talking about test results with families; 100 paediatricians (54%) indicated a lack of information about metabolic disorders; 134 (73%) preferred information sent in postal mailings, 62 (34%) preferred grand rounds, 60 (33%) preferred educational seminars, and 58 (32%) preferred websites. Other formats receiving preferences of less than 30% included e-mail (27%), phone calls (8%), video (6%), and distance learning (1%). Paediatricians are ill-prepared for expanded newborn screening for biochemical genetic disorders. To address this problem, paediatricians in Massachusetts indicated a preference for unsolicited periodic mailings including short reviews and brochures.

Attitude of Health Personnel↗

Maternal histidinaemia: pregnancies and offspring outcomes.

Untreated pregnancies and their outcomes were studied in 10 women with histidinaemia and their 26 pregnancies. The mean maternal assigned histidine level was 727+/-186 micromol/L (range 484-1,053). Six women had classic histidinaemia (assigned level >700 micromol/L) and the remaining four had mild (atypical) histidinaemia. The pregnancies were uneventful, with only one spontaneous loss and 25 live births. Birth measurements were normal and no congenital anomalies were observed. Growth and development were normal in all offspring. IQ among the 23 offspring tested was 103+/-12 (range 79-122). Four offspring required special education for brief periods and one for several years, but this frequency, as well as that of 12% for attention deficit hyperactive disorder, was not significantly different from expected in the general population. It would appear that maternal histidinaemia, unlike maternal phenylketonuria, can be added to the list of maternal inborn errors of metabolism that are nonteratogenic.

Adolescent↗

Iodine sufficiency and measurements of thyroid function in maternal hypothyroidism.

OBJECTIVES: To test the hypothesis that thyroglobulin (Tg) and free T4 (FT4) concentrations more than 2SD from the control mean are not increased in pregnancy in an iodine replete area in the absence of elevated TSH concentrations. The second hypothesis to be tested was that if such abnormalities in FT4 and Tg in the absence of elevated TSH concentrations were to exist they would not be associated with lowered IQs in the progeny. DESIGN: Cross-sectional study in New England comparing TSH, Tg, antibodies to Tg and FT4 in volunteer nonpregnant women 20-40 years old with those in hypothyroid mothers and matched euthyroid control mothers. The results are contrasted with those from similar studies reported from iodine deficient areas. SUBJECTS: Sera obtained at 17 weeks gestation and stored at -20 degrees C for 8 years were retrieved and analysed from 62 mothers with subclinical hypothyroidism and 124 matched euthyroid mothers. The diagnosis of hypothyroidism was made by finding a TSH concentration > 97.7 percentiile for 25 000 consecutive pregnant women. Sera were also analysed from 53 healthy nonpregnant volunteer women aged 20-40 years. MEASUREMENTS: TSH, Tg and Tg antibodies were measured in the sera of the nonpregnant volunteers, and Tg and Tg antibodies in the sera of the pregnant women who had previously been analysed for TSH and FT4. The incidence of FT4 concentrations below the 2.3 percentile of nonpregnant laboratory controls was compared for the euthyroid and hypothyroid mothers and the laboratory normal controls. RESULTS: Thirty-one per cent of the 62 hypothyroid mothers had FT4 concentrations below the 2.3 percentile compared with only one (0.8%) of the euthyroid mothers. Mean Tg concentrations did not differ between the nonpregnant controls and the euthyroid pregnant women, 14 +/- 10 vs. 16 +/- 10 micro g/l. Tg concentration in the hypothyroid mothers was 44 +/- 61, significantly greater than for either of the euthyroid control groups, P < 0.005. Positive antibodies to Tg were found in 9% and 10% of the control groups and 57% of the hypothyroid mothers, P < 0.0005. When TSH is included as an independent variable in multiple linear and logistic regressions, FT4 and Tg no longer correlate significantly with IQs. CONCLUSIONS: The incidences of FT4 concentrations more than 2SD below the control mean and of Tg > 2SD above the control mean are significantly increased in hypothyroid mothers in iodlne-sufficient New England. However, in the absence of elevated TSH concentrations, the incidences of such abnormalities in FT4 and TG are negligible. Indeed, concentrations for FT4, Tg and Tg antibodies for nonpregnant and pregnant controls in our iodine-replete area do not differ significantly from each other or from previously reported normative concentrations with the methods used. Thus, pregnancy in New England neither increases Tg nor lowers FT4 concentrations.

Adult↗

Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency.

Early diagnosis and improved treatment are leading to the potential for increased reproductive capability in homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency, but information about reproductive outcome and risk of thromboembolism in pregnancy is limited. To provide further information, clinical and biochemical information was obtained on women with maternal homocystinuria, on their pregnancies and on the offspring. This information included blood sulphur amino acids and total homocysteine, CbetaS gene mutations and developmental and cognitive scores in the offspring. The study involved 15 pregnancies in 11 women, of whom 5 were pyridoxine-nonresponsive and 6 were pyridoxine-responsive. Complications of pregnancy included pre-eclampsia at term in two pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and two pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced live-born infants with normal or above-normal birth measurements. One offspring has multiple congenital anomalies that include colobomas of the iris and choroid, neural tube defect and undescended testes. He is also mentally retarded and autistic. A second offspring has Beckwith-Wiedemann syndrome. The remaining 10 offspring were normal at birth and have remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities and maternal thromboembolic events in this series suggest that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, a cautious approach would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation.

Adolescent↗

Newborn screening compared to clinical identification of biochemical genetic disorders.

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their child's needs.

Adolescent↗

Relation of severity of maternal hypothyroidism to cognitive development of offspring.

BACKGROUND: An association between maternal subclinical hypothyroidism and low intelligence quotient (IQ) in the offspring has recently been shown. OBJECTIVE: To provide evidence for the causality of the association by testing the hypothesis that severity of maternal hypothyroidism correlates inversely with IQ of the offspring. METHODS: IQ scores were compared among 8 year old offspring of 124 control mothers whose thyroid stimulating hormone (TSH) concentrations were < 98th percentile of a cohort of 25,000 mothers at 17 weeks gestation, of 28 untreated hypothyroid women whose TSH was between the 98th and 99.85th percentiles, and of 20 untreated women whose TSH concentration was > or = 99.85th percentile. RESULTS: Mean (SD) IQs for each group of children (in ascending order of maternal TSH concentration) were 107 (13), 102 (15), and 97 (14). The difference between the extremes was significant (p = 0.003). The percentage of children with IQs > 1 SD below the control mean was 15, 21, and 50 respectively (p = 0.003). The odds ratio of having an IQ > 1 SD below the control mean, after controlling for socioeconomic status, was 4.7 (p = 0.006) for the third group compared with the controls. CONCLUSIONS: The inverse correlation between severity of maternal hypothyroidism and IQ of the offspring supports a causal relation and makes the need to screen for and treat pregnant women for hypothyroidism even more compelling.

Case-Control Studies↗

High cognitive outcome in an adolescent with mut- methylmalonic acidemia.

Methylmalonic acidemia is an inborn error of metabolism known to be a cause of ketoacidosis and mental retardation. The less severe mut(-) form of the disorder, however, has been described with only mild to moderate cognitive deficits or, rarely, with normal neurodevelopment in asymptomatic cases. Nevertheless, there has been no detailed documentation of long-term neuropsychological function in the mut(-) form and relatively few IQ scores. We performed longitudinal developmental and neuropsychological assessments on a girl with symptomatic mut(-) methylmalonic acidemia whose biochemical abnormalities were in the moderately severe range and who had had recurrent episodes of ketoacidosis. At almost 12 years of age, her full scale IQ on the Wechsler Intelligence Scale, third edition, was 129 with very superior and superior scores on nonverbal and verbal skills, respectively. On the National Achievement Test she scored above the 99th percentile in the Basic Battery and is considered to be a gifted student. This outcome suggests that the spectrum of cognitive attainment in mut(-) methylmalonic acidemia is wide and that even a moderate degree of biochemical severity with ketoacidotic episodes may not result in cognitive deficit. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:192-195, 2000.

Adolescent↗

Outcome at age 4 years in offspring of women with maternal phenylketonuria: the Maternal PKU Collaborative Study.

CONTEXT: Untreated maternal phenylketonuria (PKU) increases risk for developmental problems in offspring. The extent to which this risk is reduced by maternal dietary therapy at various stages of pregnancy is not known. OBJECTIVE: To determine whether dietary treatment during pregnancy of women with PKU affects developmental outcomes of offspring. DESIGN: The Maternal PKU Collaborative Study, an ongoing, longitudinal prospective study begun in 1984. SETTING: A total of 78 metabolic clinics and obstetrical offices in the United States, Canada, and Germany. PARTICIPANTS: A total of 253 children of women with PKU (n = 149), with untreated mild hyperphenylalaninemia (n = 33), or without known metabolic problems (comparison group; n = 71) were followed up to age 4 years. INTERVENTION: Women with PKU were offered a low-phenylalanine diet prior to or during pregnancy with the aim of maintaining metabolic control (plasma phenylalanine < or =10 mg/dL [< or =605 micromol/L]). Women with mild hyperphenylalaninemia, who had plasma phenylalanine levels of no more than 10 mg/dL (605 micromol/L) on a normal diet, were not treated. MAIN OUTCOME MEASURES: Children's scores on cognitive and behavioral assessments (McCarthy Scales of Children's Abilities, Test of Language Development, Achenbach Child Behavior Checklist, Vineland Adaptive Behavior Scales, and Home Observation for Measurement of the Environment), compared by maternal metabolic status at 0 to 10 weeks', 10 to 20 weeks', and after 20 weeks' gestation. RESULTS: Scores on the McCarthy General Cognitive Index decreased as weeks to metabolic control increased (r = -0.58; P<.001). Offspring of women who had metabolic control prior to pregnancy had a mean (SD) score of 99 (13). Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks' gestation had a General Cognitive Index score 2 SDs below the norm. Overall, 30% of children born to mothers with PKU had social and behavioral problems. CONCLUSIONS: Our data suggest that delayed development in offspring of women with PKU is associated with lack of maternal metabolic control prior to or early in pregnancy. Treatment at any time during pregnancy may reduce the severity of delay.

Child Behavior↗

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.

Adult↗

Maternal gamma-cystathionase deficiency: absence of both teratogenic effects and pregnancy complications.

gamma-Cystathionase deficiency (cystathioninemia-cystathioninuria) is a disorder of the transsulfuration pathway characterized by the accumulation of cystathionine in blood and urine. There are probably no clinical consequences. However, maternal gamma-cystathionase deficiency has not been reported. We studied 2 pregnancies and the offspring of these pregnancies in a woman with the pyridoxine-nonresponsive form of the disorder. The outcomes were favorable, suggesting that maternal gamma-cystathionase deficiency may not be deleterious to the pregnant woman or the fetus.

Adult↗

Personality profiles of mothers of children with mitochondrial disorders.

Mothers of children with mitochondrial disorders, inherited neurodegenerative diseases, are faced with a frightening diagnosis and numerous demands associated with caring for these children. The psychological profile of mothers whose children carry a mitochondrial disorder is unknown. Forty-two mothers of children with mitochondrial disorders were interviewed and administered the Minnesota Multiphasic Personality Inventory--Second Edition (MMPI-2). Fifty-six per cent of the mothers had scores in the pathological range on three or more scales, most notably on Hypochondriasis, Hysteria and Paranoia scales. The MMPI-2 profile is associated with situational anxiety and stress or may be associated with carrier status characteristics. Whatever the cause, future studies need to determine whether supportive services can reduce the level of anxiety and stress in mothers of children with these disorders.

Adolescent↗

The Resource Mothers Program for Maternal Phenylketonuria.

OBJECTIVES: The purpose of this study was to measure the effectiveness of resource mothers in reducing adverse consequences of maternal phenylketonuria. METHODS: Nineteen pregnancies in the resource mothers group were compared with 64 pregnancies in phenylketonuric women without resource mothers. Weeks to metabolic control and offspring outcome were measured. RESULTS: Mean number of weeks to metabolic control was 8.5 (SE = 2.2) in the resource mothers group, as compared with 16.1 (SE = 1.7) in the comparison group. Infants of women in the resource mothers group had larger birth head circumferences and higher developmental quotients. CONCLUSIONS: The resource mothers program described here improves metabolic control in pregnant women with phenylketonuria.

Adolescent↗

Neonatal neurological assessment of offspring in maternal phenylketonuria.

This study assesses the impact of prenatal and postnatal factors in maternal phenylketonuria (PKU). The Dubowitz Neurological Assessment of the Preterm and Full-term Newborn Infant was administered within the first 8 days of life to 56 offspring of women with PKU and 45 controls. Follow-up testing of the maternal PKU offspring at age 1 year consisted of the Bayley Scales of Infant Development and the Receptive-Expressive Emergent Language Scale (REEL). In addition, the Home Observation for Measurement of the Environment (HOME Scale) was given. Birth weight was lower (z = 2.0, p = 0.045), birth length was lower (z = 2.1, p = 0.03) and birth head circumference was smaller (z = 3.5, p = 0.0005) in the maternal PKU offspring than in the control infants. Examiners rated 29% of the maternal PKU offspring and 9% of the control infants abnormal (Fisher's exact test, p = 0.01). At 1 year of age, 19% of the maternal PKU offspring attained a Bayley Developmental Quotient (DQ) and a score on the Bayley Motor Scale below 85; 19% had receptive language delay; and 26% had expressive language delay. The gestational age at which the mother attained metabolic control was an important factor associated with birth measurements, the Dubowitz Rating and subsequent developmental scores. The Dubowitz Neurological Assessment score did not predict developmental outcome (chi-square = 1.3, p = 0.53), while the HOME score correlated with the DQ (r = 0.36, p = 0.02). In logistic regression analyses, the home environment was a greater determinant of risk for a low DQ than whether or not the mother attained metabolic control prior to pregnancy (OR = 0.85, p = 0.02). These results suggest that treatment strategies addressing both prenatal and postnatal factors will most effectively reduce risks in maternal PKU.

Developmental Disabilities↗

Hydroxyprolinemia: comparison of a patient and her unaffected twin sister.

Hydroxyproline is a major constituent of collagen. It accumulates as the free imino acid in a rarely reported inborn error of metabolism known as hydroxyprolinemia. This metabolic disorder was initially described in association with mental retardation, but subsequent identification in clinically normal individuals has led to the supposition that it is benign. The possibility that hydroxyprolinemia might have an adverse effect on cognitive development without producing mental retardation has not been determined nor has its incidence been reported. We prospectively studied a girl with untreated hydroxyprolinemia identified by routine neonatal urine screening, the only infant found among 1 million screened, and compared her with her unaffected dizygotic twin sister. Plasma and urine hydroxyproline were increased approximately 10-fold and 100-fold, respectively, in the affected twin. Both girls have had normal growth, with the affected twin taller than her sister. On neuropsychologic testing, the affected twin was within normal limits, performing slightly better than her sister on verbal and achievement tests but less well on visual perceptual testing. It appears that hydroxyprolinemia has caused no physical or general cognitive deficits. The possibility of an effect on visual perceptual functioning, although unlikely, cannot be eliminated.

Amino Acid Metabolism, Inborn Errors↗