Susan E. Waisbren

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 childs 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.

Expanded Newborn Screening for Biochemical Disorders: The Effect of a False-Positive Result

BACKGROUND. Newborn screening programs now identify children with >30 biochemical genetic disorders. False-positive identifications may increase as disorders are added to screening panels. Concerns arise regarding the potential impact on parental stress, family relationships, and perceptions of the childs health. METHODS. Parents of 173 infants with false-positive screening results for a biochemical genetic disorder in the expanded newborn screening panel were compared with parents of 67 children with normal screening results. Parents completed an interview that elicited information about demographic features, child and parental health, and understanding of newborn screening. Parents also completed the parenting stress index. RESULTS. Parents in the false-positive group attained higher total scores on the PSI than did parents in the normal-screened group, scoring higher on the parent-child dysfunction subscale and the difficult child subscale. Only approximately one third of parents in the false-positive group reported knowing the correct reason for repeat screening. Mothers who reported knowing the correct reason for their childs repeat screening test experienced less total stress than did mothers who were misinformed, were not informed, or did not remember. CONCLUSIONS. False-positive screening results may affect parental stress and the parent-child relationship. Improved communication with parents regarding the need for repeat screening tests may reduce the negative impact of false-positive results.

Effects of Untreated Maternal Phenylketonuria and Hyperphenylalaninemia on the Fetus

Abstract We studied the effects of maternal phenylketonuria and hyperphenylalaninemia on 53 offspring from untreated pregnancies in 22 mothers who were identified by routine screening of umbilical-cord blood. The IQ of the offspring was significantly correlated with both maternal IQ (r = 0.83, P 1100 μmol per liter) in the mother has a substantial cognitive effect on her offspring but that the effect of mild hyperphenylalaninemia may have been overst...

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 ≥ 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.

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

SummaryAs 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.

Phenylketonuria Scientific Review Conference: State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

The adult galactosemic phenotype

BackgroundClassic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression.MethodsThirty-three adults (mean age = 32.6 ± 11.7 years; range = 18–59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures.ResultsThe sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55–122). All subjects followed a dairy-free diet and 75–80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression.ConclusionsTaken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

Psychiatric symptoms and disorders in phenylketonuria

Psychological and psychiatric problems are well documented across the lifespan of individuals with early-treated phenylketonuria (PKU). Early-treated children and adolescents tend to display attentional problems, school problems, lower achievement motivation, decreased social competence, decreased autonomy, and low-self-esteem. As they enter adulthood, early-treated individuals may carry forward low self-esteem and lack of autonomy but also tend to develop depressed mood, generalized anxiety, phobias, decreased positive emotions, social maturity deficits, and social isolation. The correlation between level of metabolic control and severity of symptoms suggests a biological basis of psychiatric dysfunction. Additionally, psychosocial factors such as the burden of living with a chronic illness may contribute to psychological and psychiatric outcomes in PKU. The lack of a PKU-specific psychiatric phenotype combined with the observation that not everyone with PKU is affected highlights the complexity of the problem. More research on psychiatric and psychological outcomes in PKU is required. Of particular importance is the routine monitoring of emotional, behavioral, and psychosocial symptoms in individuals with this metabolic disorder. Longitudinal studies are required to evaluate the impact of new and emerging therapies on psychiatric and psychosocial functioning in PKU. Unidentified or untreated emotional and behavioral symptoms may have a significant, lifelong impact on the quality of life and social status of patients.

Stability of blood phenylalanine levels and IQ in children with phenylketonuria.

Variability of metabolic control in phenylketonuria (PKU) potentially affects cognitive outcome in early and continuously treated children with this condition. The possibility that homeostasis is more important than the absolute level of exposure to phenylalanine (phe) has not previously been examined. A meta-analysis of 40 studies showed that in children with phenylketonuria (PKU), mean lifetime blood phe levels were significantly correlated with Full Scale IQ (FSIQ) (r=-0.34). A similar correlation (r=-0.35) was found between FSIQ and mean exposure during 0-12 years of age. Most of the studies in the meta-analysis, however, included children who had discontinued the phe restricted diet. None examined the impact of fluctuations in metabolic control in continuously treated children. This is important because new therapies may increase stability in blood phe levels. The question has arisen whether these therapies are beneficial in children whose blood phe levels are generally within the recommended range of 120-360 micromol/L. In this study, we describe the relationship between FSIQ and two parameters of metabolic control: (1) mean blood phe level of all reported specimens for each subject, and (2) variability of the blood phe level as indicated by the standard deviation of blood phe levels for each subject. Analyses were performed using lifetime phe levels and levels during three periods (0-6 years, 0-10 years, and >10 years of age). The most recent FSIQ for each child was used in the correlation analyses. Data were collected from medical records on all 46 children born between 1999 and 2006 with early and continuously treated PKU followed at the Metabolism Program at Childrens Hospital Boston. The mean age of the children at the time of their most recent FSIQ test was 7.5+3.3 (2.9-15.5) and their mean FSIQ was 104+15 (68-143). The mean lifetime blood phe level in these children was 312+132 micromol/L (125-852). The standard deviation of blood phe levels was 182+72 micromol/L (96-336). The correlation between lifetime blood phe levels and most recent FSIQ was -.17 (p=0.38) and the correlation between standard deviation of blood phe levels and most recent FSIQ was -.36 (p=.058), not reaching significance, but indicating a trend. These results indicate that stability of blood phe levels may be more important to cognitive functioning than overall exposure to phe in early and continuously treated PKU. In treating PKU, attention should be given to variability in blood phe levels as well as maintenance of phe levels within the recommended range.

Review of neuropsychological functioning in treated phenylketonuria: an information processing approach

Phenylketonuria is no longer associated with mental retardation and other devastating neurological effects. Nonetheless, learning disabilities and IQ loss are common, even in early‐treated individuals. Until recently, IQ was used as the sole measure of mental functioning in this population. As specific academic deficits were recognized and as greater variety of tests became available, evaluation of children with phenylketonuria has included neuropsychological testing. A review of the 21 published reports highlights the areas of consensus and the need for additional well designed studies in the future. Problem solving, particularly abstract reasoning and executive functions, appears to be impaired in children with phenylketonuria. Reaction time, or speed of mental processing, appears to be the other important area affected in PKU. An information processing model is presented as paradigm for further research and development of remedial strategies for children with phenylketonuria.