The hypothesis has been put forward that humans and wildlife species adverse suffered adverse health effects after exposure to endocrine-disrupting chemicals. Reported adverse effects include declines in populations, increases in cancers, and reduced reproductive function. The U.S. Environmental Protection Agency sponsored a workshop in April 1995 to bring together interested parties in an effort to identify research gaps related to this hypothesis and to establish priorities for future research activities. Approximately 90 invited participants were organized into work groups developed around the principal reported health effects-carcinogenesis, reproductive toxicity, neurotoxicity, and immunotoxicity-as well as along the risk assessment paradigm-hazard identification, dose-response assessment, exposure assessment, and risk characterization. Attention focused on both ecological and human health effects. In general, group felt that the hypothesis warranted a concerted research effort to evaluate its validity and that research should focus primarily on effects on development of reproductive capability, on improved exposure assessment, and on the effects of mixtures. This report summarizes the discussions of the work groups and details the recommendations for additional research.

Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop.

BACKGROUND
Maternal thyroid function during early pregnancy is an important determinant of early fetal brain development because the fetal thyroid is unable to produce any T4 before 12–14 weeks' gestation. Overt maternal hypothyroidism as seen in severe iodine-deficient areas is associated with severely impaired neurological development of the offspring. At present, it is not known whether low free T4 (fT4) levels during pregnancy in healthy women from iodine sufficient areas may affect fetal neurodevelopment.

METHODS
Neurodevelopment was assessed at 10 months of age in a cohort of 220 healthy children, born after uncomplicated pregnancies and deliveries, using the Bayley Scales of Infant Development. Maternal TSH, fT4 and TPO antibody status were assessed at 12 and 32 weeks' gestation. Maternal gestational fT4 concentration was defined as an independent parameter for child development.

RESULTS
Children of women with fT4 levels below the 5th (<9.8 pmol/l, n = 11) and 10th (<10.4 pmol/l, n = 22) percentiles at 12 weeks' gestation had significantly lower scores on the Bayley Psychomotor Developmental Index (PDI) scale at 10 months of age, compared to children of mothers with higher fT4 values (t test, mean difference: 14.1, 95% confidence interval (CI): 5.9–22 and 7.4, 95% CI: 1.1–13.9, respectively). At 32 weeks' gestation, no significant differences were found. In the group of women with the lowest 10th percentile fT4 concentrations at 12 weeks' gestation, a positive correlation was found between the mothers' fT4 concentration and children's PDI scores (linear regression, R: 0.46, P = 0.03). After correction for confounding variables, a fT4 concentration below the 10th percentile at 12 weeks' gestation was a significant risk factor for impaired psychomotor development (RR): 5.8, 95% CI: 1.3–12.6).

CONCLUSIONS
Low maternal plasma fT4 concentrations during early pregnancy may be an important risk factor for impaired infant development.

Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy

Preterm infants (babies born before 37 weeks) are at risk of development problems, including problems with cognitive and motor development. Cognitive development refers to thinking and learning ability, and motor development refers to the way children move, such as sitting, crawling and walking. Early developmental interventions aim to reduce cognitive and motor problems; however, the benefits of these programmes are not clear. A review of 22 trials supports early developmental intervention programmes post discharge from hospital for preterm infants to improve cognitive development in the short to medium term (up to pre-school age). There is evidence that early developmental interventions improve motor outcome during infancy; however, the effect is small. There is little evidence of an effect on long-term cognitive and motor outcomes (up to school age). The early developmental intervention programmes in this review had to commence within the first 12 months of life, focus on the parent-infant relationship and/or infant development and, although they could commence while the baby was still in hospital, they had to have a component that was delivered post-discharge from hospital. The early developmental intervention programmes included in this review are different in content, frequency of intervention and focus of intervention. The variability in the intervention programmes limits the conclusions that can be made about the effectiveness of early developmental interventions.

https://espace.library.uq.edu.au/view/UQ:292593/UQ292593_OA.pdf

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants

The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia - defined as thyroxine (T4) concentrations that are low for the stage of pregnancy - is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine-placental 'barrier' to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the 'free' T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and 'free' T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild-moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible.

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Role of thyroid hormone during early brain development.

Summary OBJECTIVE To evaluate the impact of maternal hypothyroxinaemia during early gestation (fT4 below the lowest tenth percentile and TSH within the reference range: 0·15‐2·0 mIU/l) on infant development, together with any subsequent changes in fT4 during gestation. DESIGN A prospective 3-year follow-up study of pregnant women and their children up to the age of 2 years. MEASUREMENTS Child development was assessed by means of the Bayley Scales of Infant Development in children of women with hypothyroxinaemia (fT4 below the tenth percentile at 12 weeks’ gestation) at 12 weeks’ gestation (cases), and in children of women with fT4 between the 50th and 90th percentiles at 12 weeks’ gestation, matched for parity and gravidity (controls). Maternal thyroid function (fT4 and TSH) was assessed at 12, 24 and 32 weeks’ gestation. The mental and motor function of 63 cases and 62 controls was compared at the age of 1 year, and of 57 cases and 58 controls at the age of 2 years. RESULTS Children of women with hypothyroxinaemia at 12 weeks’ gestation had delayed mental and motor function compared to controls: 10 index points on the mental scale (95% CI: 4·5‐15 points, P = 0·003) and eight on the motor scale at the age of 1 year (95% CI: 2·3‐12·8 points, P = 0·02), as well as eight index points on the mental (95% CI: 4‐12 points, P = 0·02), and 10 on the motor scale (95%CI: 6‐16 points, P = 0·005) at the age of 2 years. Children of hypothyroxinaemic women in whom the fT4 concentration was increased at 24 and 32 weeks’ gestation had similar scores to controls, while in the controls, the developmental scores were not influenced by further declines in maternal fT4 at 24 and 32 weeks’ gestation. CONCLUSIONS Maternal hypothyroxinaemia during early gestation is an independent determinant of a delay in infant neurodevelopment. However, when fT4 concentrations increase during pregnancy in women who are hypothyroxinaemic during early gestation, infant development appears not to be adversely affected. In the past decade, interest has been rekindled in the relationship between maternal plasma thyroid hormone concentration during pregnancy and subsequent infant neurodevelopment (Pop et al ., 1995, 1999a; Haddow et al ., 1999; Lazarus, 1999; Smit et al ., 2000). It is well known that both maternal thyroid dysfunction during pregnancy (especially hypothyroidism) and severe iodine deficiency adversely affect the outcome of neurodevelopment in children (Delange, 1994; Glinoer, 1997; Mestman, 1999). Even in areas in which there is sufficient iodine intake in the general population, pregnant women often have fT4 plasma levels in the lower ranges, without elevated TSH. This is defined as hypothyroxinaemia, and is generally regarded as a normal condition. However, there is growing concern that hypothyroxinaemia during early gestation could be harmful to the offspring (Pop et al ., 1999b; Utiger, 1999; Morreale de Escobar et al ., 2000). In fact, little is known about maternal fT4 levels during normal pregnancy, or their relationship to the development of the child. This paper describes the results of a longitudinal prospective study that investigates whether maternal thyroid hormone levels, assessed in women without (sub)clinical thyroid function at three different trimesters during pregnancy, are adversely related to child development at 1 and 2 years of age.

Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study

Background Premature infants who have transient hypothyroxinemia in the first weeks of life may have developmental delay and neurologic dysfunction. Whether thyroxine treatment during this period results in improved developmental outcomes is not known. Methods We carried out a randomized, placebo-controlled, double-blind trial of thyroxine supplementation in 200 infants born at less than 30 weeks' gestation. Thyroxine (8 μg per kilogram of birth weight) or placebo was administered daily, starting 12 to 24 hours after birth, for six weeks. Plasma free thyroxine concentrations were measured weekly for the first eight weeks after birth. Scores on the Bayley Mental and Psychomotor Development Indexes and neurologic function were assessed at 6, 12, and 24 months of age (corrected for prematurity). Results Mortality and morbidity up to the time of discharge from the hospital were similar in the study groups. At 24 months of age, 157 infants were evaluated. Overall, neither mental nor psychomotor scores differed...

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Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation

Objective. After intrauterine growth restriction we found at the age of 6 months an acceleration of neurophysiologic maturation. However, at later ages impaired cognitive outcome has been reported. Therefore, we investigated in children with and without fetal hemodynamic adaptation to intrauterine growth restriction whether the accelerated neurophysiologic maturation in infancy might be associated with impaired cognitive outcome at preschool age. Design. At 5 years of age cognitive function was assessed using the Revision of the Amsterdam Children9s Intelligence Test in 73 preterm infants (26–33 weeks) who were prospectively followed from the antenatal period up to the age of 5 years. Maternal educational level was used as a background variable to estimate the confounding effects of socioeconomic status on cognitive function. Fetal Doppler studies were performed and the umbilical artery pulsatility index (PI) divided by the middle cerebral artery PI ratio (U/C ratio) was calculated. A U/C ratio >0.725 was considered as an indication of fetal cerebral hemodynamic adaptation to a compromised placental perfusion, ie, fetal brain-sparing. Visual-evoked potentials (VEPs) were recorded at 6 months and 1 year of age. In addition, data on neurologic status at 3 years were available. Results. Mean IQ score was significantly lower for children born with a raised U/C ratio (87 ± 16) compared with children with a normal U/C ratio (96 ± 17). VEP latencies decreased significantly in infants with a normal U/C ratio, whereas no decrease was found in infants with a raised U/C ratio. Variables contributing significantly to the variance of cognitive function were: U/C group, VEP latency maturation, level of maternal education, and neurodevelopmental outcome at 3 years. The linear regression model explained 33% of the variance in cognitive function. Conclusions. Both being born with a raised U/C ratio and an acceleration of VEP latencies are negatively associated with cognitive outcome at 5 years of age. Fetal brain-sparing, although a seemingly beneficial adaptive mechanism for intact neurologic survival, is, however, later associated with a poorer cognitive outcome.

The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing.

It is not known how immaturity and disease influence postnatal thyroid function in infants <30 wk of gestational age. We performed serial measurements of plasma thyroxine (T4), free T4 (FT4), triiodothyronine (T3), reverse T3 (rT3), TSH, and T4-binding globulin (TBG) in 100 infants of <30 wk of gestation, during the first 8 postnatal weeks, to investigate the influences of disease and gestational age on the time course of thyroid hormones. One hundred infants were divided twice into two groups: 1) in a group of 25-28 and of 28-30 wk of gestation; and 2) in a sick and a healthy group, with similar gestational ages. The time course of T4, FT4, T3, TSH, and TBG, but not rT3 differed significantly (p < 0.005) between the gestational age groups. T4 and FT4 decreased to levels below the cord blood value with a deeper FT4 nadir on d 7 in the youngest group. Disease decreased T4, FT4, T3, TSH, and TBG concentrations especially during the 1st wk after birth (p < 0.005). However, the FT4 nadir on d 7 was similar in sick and healthy infants. After 3 wk, T4, FT4, T3, and TBG were higher in the sick group compared with the healthy group. rT3 levels were not increased in sick infants. We conclude that the extent of the FT4 decrease after birth in infants of <30 wk gestation is mainly influenced by gestational age and probably reflects a transient depletion of thyroidal hormone reserves. rT3 cannot be used as a marker of nonthyroidal illness in very preterm infants.

Thyroid function in very preterm infants: influences of gestational age and disease

Animal studies have shown that dioxins influence plasma thyroid hormone concentrations. To investigate the effect of chlorinated dioxins and furans on thyroid hormone concentrations in humans, we studied 38 healthy breast-fed infants. The study population was divided into two groups according to the dioxin concentrations in milk fat of their mothers. Blood samples were taken at birth and at the ages of 1 and 11 weeks. At birth a tendency to higher total thyroxine (tT4) concentrations was found in the high exposure group. At the ages of 1 and 11 weeks the increase of mean tT4 concentrations and tT4/thyroxine-binding globulin ratios in the high exposure group reached significance as compared to the low exposure group. At birth and 1 week after birth, mean thyrotropin (TSH) concentrations were similar in both groups, but at the age of 11 weeks the mean TSH concentrations were significantly higher in the high exposure group. We postulate that the observed plasma tT4 elevation in infants exposed to dioxins before and after birth is the result of an effect on the thyroid hormone regulatory system.

Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations.

A prospective observational study was performed in pregnant women with known thyroid disease. We studied the effect of maternal thyroid function in the first half of pregnancy on the neurologic development of the infant in the first 2 y of life. Clinical and thyroid function data were collected from 20 pregnant women with known thyroid disease and their newborn children. Infants were divided into three groups according to their maternal thyroid function within the first half of pregnancy: Group A (n = 7): maternal subclinical hypothyroidism, Group B (n = 6): maternal euthyroidism, and Group C (n = 7): maternal hyperthyroidism or subclinical hyperthyroidism. Neurophysiologic, i.e. motor nerve conduction velocity and somatosensory evoked potentials and neurologic and developmental (Bayley scales) assessments were done. One infant, born to a mother with Graves' disease, developed transient hyperthyroidism. At the age of 6 and 12 mo, the mean mental developmental index (MDI) score was 16 points lower for infants in Group A than for those in Group B (p = 0.03 and 0.02, respectively). At the age of 24 mo, the mean MDI score was 6 points lower, which was not statistically significant. Neurophysiologic and neurologic assessments and the mean Psychomotor Developmental scores did not differ among the three groups. In conclusion, maternal subclinical hypothyroidism in the first half of pregnancy was associated with a lower mean MDI score in their infants during the first year of life.

J. H. Kok

Papers

Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation

The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing.

Thyroid function in very preterm infants: influences of gestational age and disease

Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations.

Neurologic development of the newborn and young child in relation to maternal thyroid function.