Relation between Early Over- and Undertreatment and Behavioural Problems in Preadolescent Children with Congenital Hypothyroidism.

OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration. RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.

Individualized treatment to optimize eventual cognitive outcome in congenital hypothyroidism.

BACKGROUND: In congenital hypothyroidism (CH), age-specific reference ranges (asRR) for fT4 and thyrotropine (TSH) are usually used to signal over/under-treatment. We compared the consequences of individual fT4 steady-state concentrations (SSC's) and asRR regarding over-treatment signaling and intelligence quotient at 11 y (IQ11) and the effect of early over-treatment with high L-T4 dosages on IQ11. METHODS: Sixty-one patients (27 severe, 34 mild CH) were psychologically tested at 1.8, 6, and 11 y. Development scores were related to over-treatment in the period 0-24 mo, relative to either individual fT4SSC's or asRR. Three groups were formed, based on severity of over/under-treatment 0-5 mo (severe, mild, and no over/under-treatment). RESULTS: FT4 and TSH asRR missed 41-50% of the over-treatment episodes and consequently 22% of the over-treated patients, classified as such by fT4SSC's. Severe over-treatment 0-5 mo led to lowered IQ11's and to a 5.5-fold higher risk of IQ11 < 85 than other treatment regimes. Under-treatment had no effect on development scores. Initial L-T4 dosages >10 µg/kg resulted in a 3.7-fold higher risk of over-treatment than lower dosages. CONCLUSIONS: Data suggest that asRR, compared to fT4SSC's, signal over-treatment insufficiently. Using fT4SSC's and avoiding over-treatment may optimize cognitive outcome. Lowered IQ11's are usually a late complication of severe early over-treatment.

Maternal early-pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study.

CONTEXT: Hypertensive disorders during pregnancy are associated with a wide range of maternal and fetal complications, and only a few risk factors are known for the development of these disorders during pregnancy. Conflicting and limited data are available on the relationship between thyroid (dys)function and the risk of hypertensive disorders of pregnancy. OBJECTIVE: The objective of the investigation was to study the associations between early-pregnancy thyroid dysfunction, thyroid function within the normal range, and the risk of hypertensive disorders. DESIGN, SETTING, AND PARTICIPANTS: In early pregnancy, serum TSH, free T4 (FT4), and thyroperoxidase antibody (TPOAb) levels were determined in 5153 pregnant women. No interventions were done. The associations of thyroid function with the risk of hypertensive disorders were studied. MAIN OUTCOME MEASURES: Mean blood pressures and hypertensive disorders, including pregnancy-induced hypertension (n = 209) and preeclampsia (n = 136), were measured. RESULTS: Hyperthyroid mothers had a higher risk of hypertensive disorders [odds ratio (OR) 3.40 [95% confidence interval (CI) 1.46-7.91], P = .005], which was mainly due to an increased risk of pregnancy-induced hypertension [OR 4.18 (95% CI 1.57-11.1), P = .004]. Hypothyroidism and hypothyroxinemia were not associated with hypertensive disorders. Within the normal range, the high-normal FT4 levels were associated with an increased risk of hypertensive disorders [OR 1.62 (95% CI 1.06-2.47), P = .03], which was mainly due to an increased risk of preeclampsia [OR 2.06 (95% CI 1.04-4.08), P = .04]. The TPOAb status was not associated with hypertensive disorders. CONCLUSIONS: We show that biochemical hyperthyroidism and also high-normal FT4 levels during early pregnancy are associated with an increased risk of hypertensive disorders. These data demonstrate that these associations are even seen for a mild variation in thyroid function within the normal range.

Soluble Flt1 and placental growth factor are novel determinants of newborn thyroid (dys)function: the generation R study.

CONTEXT: Adequate thyroid hormone availability during fetal and early life is crucial for normal child growth and development. Fetal growth heavily depends on angiogenesis. Placental growth factor (PlGF) is a proangiogenic factor sharing high homology with vascular endothelial growth factor, whereas soluble FMS-like tyrosine kinase-1 (sFlt1) is a potent antagonist of vascular endothelial growth factor and PlGF signaling. Because the thyroid is a highly vascularized organ, we hypothesized that fetal angiogenic factors influence in utero thyrogenesis and impair newborn thyroid function. Therefore, we investigated the association between sFlt1 and PlGF on newborn thyroid function. DESIGN, SETTING, AND PARTICIPANTS: sFlt1, PlGF, TSH, and free T4 (FT4) were determined in cord serum of 3525 newborns from a large prospective cohort study. Analyses were adjusted for relevant maternal and child covariates. RESULTS: sFlt1 levels were positively associated with TSH (ß 0.07 ± 0.02 mU/L; P < .001) and inversely with FT4 (ß -0.58 ± 0.11; P < .001). PlGF showed a positive association with FT4 (ß 0.19 ± 0.02; P < .001). Elevated levels of sFlt1 were associated with a 2.8-fold increased risk of hypothyroxinemia (P = .04). Decreased levels of PlGF were associated with a 6.7-fold increased risk of hypothyroxinemia (P < .001). Within the normal range, a dose-dependent effect of sFlt1 on thyroid dysfunction was observed: high-normal sFlt1 levels were associated with a 17.7-fold increased risk of hypothyroxinemia (P < .001) and a 2.7-fold increased risk of hyperthyrotropinemia (P = .01). CONCLUSION: Fetal angiogenic factors sFlt1 and PlGF are associated with newborn thyroid function. Possible effects are most likely mediated through effects on in utero thyrogenesis. Abnormal as well as normal-range fetal sFlt1 and PlGF levels influence the risk of impaired newborn thyroid function, which has been associated with adverse neurodevelopmental effects. These data provide important novel insights into the physiology of thyrogenesis and into the etiology of newborn thyroid (dys)function.

Maternal thyroid hormones during pregnancy, childhood adiposity and cardiovascular risk factors: the Generation R Study.

OBJECTIVE: Variation in maternal thyroid function during early pregnancy may permanently affect childhood growth and cardiovascular development. We examined the associations of early pregnancy maternal TSH and free T4 (FT4) levels with childhood growth, body composition and cardiovascular characteristics. METHODS: We performed a population-based prospective cohort study among 5646 mothers and their children. Maternal thyroid parameters were assessed in early pregnancy (median: 13·2 weeks; 95% range: 9·7-17·6 weeks). Childhood growth was repeatedly measured from birth to 6 years. At the age of 6 years, childhood body mass index (BMI), total body and abdominal fat distribution, blood pressure and left ventricular mass were measured. RESULTS: Maternal thyroid parameters were not consistently associated with childhood length and weight growth characteristics. Lower maternal TSH levels were associated with lower childhood BMI, total fat mass, abdominal subcutaneous fat mass area and diastolic blood pressure (P-values <0·05), but not with preperitoneal abdominal fat mass area, systolic blood pressure or left ventricular mass. Higher maternal FT4 levels were associated with lower childhood BMI, abdominal subcutaneous and preperitoneal fat mass area (P for trends <0·05), but not with other cardiovascular characteristics. Clinically maternal hypothyroid or hyperthyroid statuses were not associated with childhood growth, body fat or cardiovascular outcomes. CONCLUSIONS: Maternal thyroid function during early pregnancy may influence childhood body composition and cardiovascular development. Further studies are needed to replicate these findings and to examine the influence of maternal thyroid hormone levels during pregnancy on long-term growth and cardiovascular development in the offspring.

Women with high early pregnancy urinary iodine levels have an increased risk of hyperthyroid newborns: the population-based Generation R Study.

OBJECTIVE: Iodine deficiency during pregnancy results in thyroid dysfunction and has been associated with adverse obstetric and foetal effects, leading to worldwide salt iodization programmes. As nowadays 69% of the world's population lives in iodine-sufficient regions, we investigated the effects of variation in iodine status on maternal and foetal thyroid (dys)function in an iodine-sufficient population. DESIGN, PARTICIPANTS AND MEASUREMENTS: Urinary iodine, serum TSH, free T4 (FT4) and TPO-antibody levels were determined in early pregnancy (13·3 (1·9) week; mean (SD)) in 1098 women from the population-based Generation R Study. Newborn cord serum TSH and FT4 levels were determined at birth. RESULTS: The median urinary iodine level was 222·5 µg/l, indicating an iodine-sufficient population. 30·8% and 11·5% had urinary iodine levels <150 and >500 µg/l, respectively. When comparing mothers with urinary iodine levels <150 vs ≥150 µg/l, and >500 vs ≤500 µg/l, there were no differences in the risk of maternal increased or decreased TSH, hypothyroxinaemia or hyperthyroidism. Mothers with urinary iodine levels >500 µg/l had a higher risk of a newborn with decreased cord TSH levels (5·6 ± 1·4 (mean ± SE) vs 2·1 ± 0·5%, P = 0·04), as well as a higher risk of a hyperthyroid newborn (3·1 ± 0·9 vs 0·6 ± 0·3%, P = 0·02). These mothers had newborns with higher cord FT4 levels (21·7 ± 0·3 vs 21·0 ± 0·1 pm, P = 0·04). Maternal urinary iodine levels <150 µg/l were not associated with newborn thyroid dysfunction. CONCLUSIONS: In an iodine-sufficient population, higher maternal urinary iodine levels are associated with an increased risk of a hyperthyroid newborn.

Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study.

CONTEXT: Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study. DESIGN: Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels. RESULTS: Of all women, 5.0% had a premature delivery (<37 weeks), 4.4% had a spontaneous premature delivery, and 1.4% had a very premature delivery (<34 weeks). High TSH levels and subclinical hypothyroidism were associated with premature delivery but not with spontaneous premature delivery. Maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery, a 3.4-fold increased risk of spontaneous premature delivery, and a 3.6-fold increased risk of very premature delivery (all P < .01). TPOAb positivity was associated with a 1.7-fold increased risk of premature delivery (P = .01), a 2.1-fold increased risk of spontaneous premature delivery (P = .02), and a 2.5-fold increased risk of very premature delivery (P = .04). These effects remained similar after correction for TSH and FT4 levels. CONCLUSIONS: Hypothyroxinemia and TPOAb positivity are associated with an increased risk of premature delivery. The increased risk in TPOAb-positive women seems to be independent of thyroid function.

Association of gestational maternal hypothyroxinemia and increased autism risk.

OBJECTIVE: Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6-18) and autistic symptoms in children. METHODS: The mother-and-child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation=1.9, range=5.9-17.9), maternal thyroid function tests (serum thyrotropin [TSH], free thyroxine [fT4], and thyroid peroxidase [TPO] antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4<5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score>98th percentile and SRS score in the top 5% of the sample (n=81, 2.0%). RESULTS: Severe maternal hypothyroxinemia (n=136) was associated with an almost 4-fold increase in the odds of having a probable autistic child (adjusted odds ratio=3.89, 95% confidence interval [CI]=1.83-8.20, p<0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B=0.23, 95% CI=0.03-0.37); SRS results were similar. No risk was found for children of TPO-antibody-positive mothers (n=308). INTERPRETATION: We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions.

Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment?

BACKGROUND: Optimal treatment of children with congenital hypothyroidism (CHT) is still debated. Our objective was to evaluate whether early undertreatment (UT) and overtreatment (OT) influence cognitive development at age 11 years. METHODS: Sixty-one patients (27 severe CHT, 34 mild CHT) were psychologically tested at ages 1.8 (Mental Development Index), 6 [intelligence quotient (IQ) 6], and 11 years (IQ11). Scores for cognitive development were related to initial levels of TSH normalization (fast, moderate, or slow) and to total durations of the UT and OT episodes within the first 2 years of life (no, short, or long UT/OT). UT and OT were defined as a free T4 (fT4) concentration below or above the individual fT4 steady-state concentration range (±2 SD). RESULTS: Patients with fast and moderate TSH normalization had higher Mental Development Index scores than patients with slow TSH normalization; 14.2 and 7.7 points higher, respectively (P = .001). TSH normalization had no significant effect on IQ11. Patients with long and short overtreatment had IQ11s that were -17.8 and -13.4 points lower, respectively, than the IQ11s of patients with no overtreatment (P = .014). UT without OT was associated with normal development scores, but UT with OT was associated with -14.7 points lower IQ11s than UT without OT (P = .005). CONCLUSIONS: Our study suggests that CHT overtreatment during the first 2 years leads to lowered cognitive outcomes at 11 years, whereas undertreatment, if not complicated by overtreatment, results in a normal cognitive development. Fast TSH normalization at initial treatment leads to above-normal development scores at a young age but does not affect IQ at age 11 years.

Ethnic differences in maternal thyroid parameters during pregnancy: the Generation R study.

CONTEXT: Abnormal maternal thyroid function during pregnancy is associated with various complications. International guidelines advocate the use of population-based trimester-specific reference ranges for thyroid function tests. When unavailable, an upper TSH limit of 2.5 for the first trimester and 3.0 mU/L for the second and third trimesters is recommended. Although interindividual differences in thyroid function tests can partially be explained by ethnicity, data on the influence of ethnicity on TSH and free T4 reference ranges during pregnancy are sparse. DESIGN: Serum TSH, free T4, T4, and TPO-antibody levels were determined during early pregnancy in 3944 women from the Generation R study, Rotterdam, The Netherlands. RESULTS: The study population consisted of 2765 Dutch, 308 Moroccan, 421 Turkish, and 450 Surinamese women. Mean TSH levels were higher in Dutch and Turkish women than in Moroccan or Surinamese women (1.50-1.48 vs 1.29-1.33 mU/L; P < .01). Although no differences in free T4 were seen, T4 was lowest in Dutch women (142 vs 150-156 nmol/L; P < .01). Turkish women had the highest frequency of TPO-antibody positivity (9.3% vs 5.0-5.8%; P < .05) and of elevated TSH levels in the second trimester (11.0% vs 3.8-7.3%; P < .01). A comparison of disease prevalence between a population-based vs an ethnicity-specific reference range changed the diagnosis for 18% of women who were initially found to have abnormal thyroid function test results. CONCLUSIONS: We show ethnic differences in serum TSH, T4, and TPO-antibody positivity and found significant diagnostic discrepancies depending on whether population or ethnicity-specific reference ranges were used to diagnose thyroid disease.

Experience in treating congenital hypothyroidism: implications regarding free thyroxine and thyrotropin steady-state concentrations during optimal levothyroxine treatment.

BACKGROUND: A major problem in the treatment of patients with congenital hypothyroidism (CHT) is that the optimal individual target values of thyrotropin (TSH) and free thyroxine (fT(4)) are unknown. We investigated whether patients with CHT have during treatment considered optimal stable fT(4) and TSH steady-state concentrations (SSCs) that can be used as target values, and whether TSH or fT(4) is more useful in guiding decisions regarding therapy. METHODS: From 60 early-treated patients with CHT, TSH and fT(4) follow-up samples within the age interval 1.5-132 months (postinitial period) and within TSH interval 0.5-10 mU/L were selected. TSH and fT(4) SSCs were estimated by taking the individual mean values of a series of determinations, under the most euthyroid conditions possible (n=1257), for the whole age and TSH intervals, as well as for the age intervals 1.5-24, 25-72, and 73-132 months, as well as, for fT(4), for the two split TSH intervals 0.5-4.49 and 4.5-10 mU/L. For all SSCs, the within-subject coefficient of variation (CV(w)) was determined. Further, fT(4) SSCs were assessed for the first 6 weeks after therapy initiation. RESULTS: For both TSH and fT(4), individual SSCs differed significantly (p<0.001). The 95% confidence interval for TSH SSCs was 1.1-5.7 mU/L and for fT(4) SSCs 16.6-28.7 pmol/L. Mean CV(w) values for TSH and fT(4) SSCs were 60.9% and 13.1%, respectively. Individual fT(4) and TSH SSCs were reproducible when assessed for the three age intervals, both slightly decreasing with age (p≤0.033), and fT(4) SSCs were reproducible for the two split TSH intervals, with a slight fT(4) difference (p<0.001). fT(4) SSCs were largely independent of the administered LT(4) dosage (range 2.4-6.1 µg/kg). fT(4) SSCs of the initial period were comparable to those of postinitial period with a mean±SD difference of 1.0±3.5 pmol/L, p=0.07. CONCLUSIONS: Our study suggests that in CHT during therapy considered optimal, stable TSH and fT(4) SSCs can be found slightly decreasing with age and largely independent of the administered LT(4) dosage (range 2.4-6.1 µg/kg). In clinical follow-up, fT(4) SSCs may be more valuable as individual target values than TSH SSCs.

Maternal thyroid hormone parameters during early pregnancy and birth weight: the Generation R Study.

CONTEXT: Maternal hyperthyroidism during pregnancy is associated with an increased risk of low birth weight, predisposing to neonatal morbidity and mortality. However, the effects of variation in maternal serum thyroid parameters within the normal range on birth weight are largely unknown. OBJECTIVE: The aim was to study the effects of early pregnancy maternal serum thyroid parameters within the normal range on birth weight, as well as the relation between umbilical cord thyroid parameters and birth weight. DESIGN, SETTING, AND PARTICIPANTS: In early pregnancy, serum TSH, FT4 (free T(4)), and thyroid peroxidase antibody levels were determined in 4464 pregnant women. Cord serum TSH and FT4 levels were determined in 2724 newborns. Small size for gestational age at birth (SGA) was defined as a gestational age-adjusted birth weight below the 2.5th percentile. The associations between normal-range maternal and cord thyroid parameters, birth weight, and SGA were studied using regression analyses. RESULTS: In mothers with normal-range FT4 and TSH levels, higher maternal FT4 levels were associated with lower birth weight [ß = -15.4 (3.6) g/pmol · liter, mean (SE); P = 1.6 × 10(-5)], as well as with an increased risk of SGA newborns [odds ratio (95% confidence interval) = 1.09 (1.01-1.17); P = 0.03]. Birth weight was positively associated with both cord TSH [ß = 4.1 (1.4) g/mU · liter; P = 0.007] and FT4 levels [ß = 23.0 (3.2) g/pmol · liter; P = 9.2 × 10(-13)]. CONCLUSIONS: We show that maternal high-normal FT4 levels in early pregnancy are associated with lower birth weight and an increased risk of SGA newborns. Additionally, birth weight is positively associated with cord TSH and FT4 levels. These data demonstrate that even mild variation in thyroid function within the normal range can have important fetal consequences.

Low urinary iodine excretion during early pregnancy is associated with alterations in executive functioning in children.

The rare but deleterious effects of severe iodine deficiency during pregnancy on cognitive functioning of children are well known. Reports on possible associations between mild-to-moderate maternal iodine deficiency and child development, however, are scarce. In a population-based cohort we examined the association between maternal urinary iodine during early pregnancy and executive functioning in children at 4 y of age. In addition, we investigated the modification of this association by maternal diet and thyroid function. During pregnancy, we measured urinary iodine and thyroid hormone concentrations in 1156 women. In 692 of their children impairment of executive functioning was assessed by the Behavior Rating Inventory of Executive Function. Five hundred mothers of Dutch national origin completed an FFQ. Analyses were performed by using regression models. The children of mothers with low urinary iodine showed higher scores on the problem scales of inhibition [ß = 0.05 (95% CI: 0.01, 0.10), P = 0.03] and working memory [ß = 0.07 (95% CI: 0.02, 0.12), P = 0.003]. Although maternal dietary intake and thyroid hormone concentration did not significantly modify these associations, the associations between urinary iodine and problems of inhibition were attenuated after adjustment for maternal psychological symptoms. In addition, the consumption of bread [ß = 0.61 (95% CI: 0.27, 0.95), P < 0.001] and eggs (ß = 1.87 (95% CI: 0.13, 3.62), P = 0.04] was associated with higher urinary iodine. Thus, low maternal urinary iodine during pregnancy is associated with impaired executive functioning in children. Because these symptoms were subclinical and occurred at an early age, future studies are needed to show whether these children are more vulnerable to develop later clinical disorders.

Maternal hypothyroxinemia during pregnancy and growth of the fetal and infant head.

Severe maternal thyroid dysfunction during pregnancy affects fetal brain growth and corticogenesis. This study focused on the effect of maternal hypothyroxinemia during early pregnancy on growth of the fetal and infant head. In a population-based birth cohort, we assessed thyroid status in early pregnancy (median 13.4, 90% range 10.8-17.2), in 4894 women, and measured the prenatal and postnatal head size of their children at 5 time points. Hypothyroxinemia was defined as normal thyroid-stimulating hormone levels and free thyroxine-4 concentrations below the 10th percentile. Statistical analysis was performed using linear generalized estimating equation. Maternal hypothyroxinemia was associated with larger fetal and infant head size (overall estimate ß: 1.38, 95% confidence interval 0.56; 2.19, P = .001). In conclusion, in the general population, even small variations in maternal thyroid function during pregnancy may affect the developing head of the young child.

Maternal early pregnancy and newborn thyroid hormone parameters: the Generation R study.

CONTEXT: Abnormal maternal thyroid parameters are associated with adverse pregnancy outcomes, with consequences for both mother and child. Although various studies have studied maternal thyroid parameters during the first half of pregnancy, little is known about their relations with thyroid parameters of the child. OBJECTIVE: The objective was to study maternal thyroid parameters during the first half of pregnancy as well as their relations with cord thyroid parameters. DESIGN, SETTING, AND PARTICIPANTS: Serum TSH, free T(4) (FT4), T(4), and thyroid peroxidase antibody (TPOAb) levels were determined once between gestational wk 9 and 18 in 5393 pregnant women from the population-based Generation R study. Cord serum TSH and FT4 levels were determined in 3036 newborns. RESULTS: Between gestational wk 9 and 18, the maternal TSH reference range (2.5th to 97.5th percentile) was 0.03-4.04 mU/liter. Gestational age was positively correlated with maternal TSH (r = 0.06, P = 6.3 × 10(-5)) and total T(4) (r = 0.21, P = 1.4 × 10(-44)) and negatively with FT4 (r = -0.27, P=7.3 × 10(-76)) and TPOAb-positivity (r=-0.04, P = 0.01). TPOAb positivity was associated with more subclinical (20.1 vs. 2.4%, P = 1.5 × 10(-39)) and overt hypothyroidism (3.3 vs. 0.1%, P = 1.4 × 10(-10)). Maternal and cord TSH were positively associated (ß = 0.47 ± 0.15, P = 1.3 × 10(-5)) as well as maternal and cord FT4 (ß = 0.11 ± 0.02, P = 4.5 × 10(-6)). CONCLUSIONS: We confirm correlations of maternal thyroid parameters with gestational age during the first half of pregnancy and show a substantially increased risk of (subclinical) hypothyroidism in TPOAb-positive mothers. A substantial part of the mothers had a TSH level above 2.5 mU/liter, underlining the importance of using population-specific reference ranges. Maternal and cord thyroid parameters were positively correlated, the exact biological basis of which remains to be determined.

Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the Generation R Study.

BACKGROUND: Maternal thyroid status and autoimmunity during pregnancy have been associated with impaired development of the offspring in animal and human studies. Our objective was to examine whether elevated titers of maternal thyroid peroxidase antibodies (TPOAbs) in early pregnancy increased the risk of cognitive impairment and problem behavior in preschool children. Second, we aimed at exploring to what extent any effect on child behavior was mediated by maternal thyroid parameters during pregnancy. METHODS: In the Generation R Study, a population-based cohort of 3139 children and their mothers, we measured maternal thyroid parameters (thyrotropin [TSH], free Thyroxine, and TPOAbs) at 13.5±1.8 weeks of gestation. Children's verbal and nonverbal cognitive functioning was measured at 2.5 years using the Language Development Survey and the Parent Report of Children Abilities. At 3 years, children's behavior was assessed using the Child Behavior Checklist. RESULTS: Elevated titers of TPOAbs during pregnancy did not predict the verbal and nonverbal cognitive functioning of the children. However, elevated titers of TPOAbs in mothers were associated with externalizing problems in children (odds ratio [OR]=1.64, 95% confidence interval [CI]: 1.17-2.29, p=0.004). In particular, children of TPOAb-positive mothers were at a higher risk of attention deficit/hyperactivity problems (OR=1.77, 95% CI: 1.15-2.72, p=0.01). To explore whether the effect of maternal TPOAbs on child problem behavior was mediated by maternal thyroid parameters, we added maternal TSH to the model. After correcting for TSH, the effect of TPOAbs on externalizing problems was attenuated slightly but remained significant (OR=1.56, 95% CI: 1.14, 2.14, p=0.005). CONCLUSIONS: Our findings imply that the elevated titers of TPOAbs during pregnancy impact children's risk of problem behavior, in particular, attention deficit/hyperactivity. The observed effect is only partially explained by maternal TSH levels. These findings may point to a specific mechanism of Attention Deficit/Hyperactivity Disorder in children. Nevertheless, we can only speculate about public health implication of the study, as there is no specific treatment for TPOAb-positive pregnant women with normal thyroid function. Further investigation is needed to explore whether TPOAb-positive pregnant women and their children can benefit from close monitoring and early detection of developmental delay in populations at risk.

Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study.

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and child's behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 1½ and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 1½ and 3 y (B = 0.22 per SD of TSH; 95% CI: 0.04, 0.40; B = 0.10 per SD for internalizing scores; 95% CI: -0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life.

Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study.

CONTEXT: Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and children's cognitive development are sparse. OBJECTIVE: Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T(4)(FT(4)) levels across the entire range with cognitive functioning in early childhood. DESIGN AND SETTING: We conducted a population-based cohort in The Netherlands. PARTICIPANTS: Participants included 3659 children and their mothers. MAIN MEASURES: In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT(4) concentrations below the 10th and 5th percentile, respectively. Children's expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Children's Abilities measuring verbal and nonverbal cognitive functioning. RESULTS: Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT(4) predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). CONCLUSIONS: Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood.

Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism.

OBJECTIVES: To evaluate the influence of initial and postinitial treatment factors on cognitive, psychomotor, and psychological outcome in schoolchildren with congenital hypothyroidism (CH). STUDY DESIGN: We studied 45 patients (19 with severe CH and 26 with mild CH) and 37 control children by correlating initial and postinitial treatment factors (free thyroxine and thyroid-stimulating hormone [TSH] concentrations, and the percentage of overtreatment and undertreatment periods) with the results of neuropsychological tests and behavior (as reported on the Teacher Report Form [TRF]). RESULTS: The global IQ of the children with CH was comparable to that of the controls; visuomotor and verbal scores were lower, and total TRF scores were higher. Ethnic group, previous development, and overtreatment predicted IQ and verbal scores, with higher scores seen for the overtreated patients than for the control children and those patients who had not been overtreated. As initial treatment was less satisfactory, total TRF scores were higher. CONCLUSIONS: Our study suggests that initial and postinitial suboptimal treatment of CH leads to abnormalities in IQ and specific fields. Overtreatment may advance cognitive development in 5-1/2- to 7-year-olds. Suboptimal initial treatment may lead to behavioral problems. We recommend that TSH concentrations be maintained within the normal range in patients with CH.