Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R Study

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1 ORIGINAL ARTICLE Endocrine Care Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R Study Jens Henrichs, Jacoba J. Bongers-Schokking, Jacqueline J. Schenk, Akhgar Ghassabian, Henk G. Schmidt, Theo J. Visser, Herbert Hooijkaas, Sabine M. P. F. de Muinck Keizer-Schrama, Albert Hofman, Vincent V. W. Jaddoe, Willy Visser, Eric A. P. Steegers, Frank C. Verhulst, Yolanda B. de Rijke, and Henning Tiemeier The Generation R Study (J.H., V.V.W.J.) and Departments of Internal Medicine (T.J.V., Y.B.d.R.), Immunology (H.H.), and Epidemiology (A.H., V.V.W.J., H.T.), Erasmus Medical University Center, 3000 DR Rotterdam, The Netherlands; Institute of Psychology (J.H., J.J.S., H.G.S.), Erasmus University, 3000 DR Rotterdam, The Netherlands; and Departments of Endocrinology (J.J.B.-S.), Child and Youth Psychiatry (A.G., F.C.V., H.T.), Paediatrics (S.M.P.F.d.M.K.-S., V.V.W.J.), Obstetrics and Gynaecology (W.V., E.A.P.S.), and Clinical Chemistry (Y.B.d.R.), Erasmus Medical Center Sophia Children s Hospital, 3000 CB Rotterdam, the Netherlands 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) ; P and OR 1.80; 95% CI ; P 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR 2.03; 95% CI ; P 0.007). Conclusions: Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood. (J Clin Endocrinol Metab 95: , 2010) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2010 by The Endocrine Society doi: /jc Received February 21, Accepted May 12, First Published Online June 9, 2010 Abbreviations: df, Degrees of freedom; FT 4, free T 4 ; GEE, generalized estimating equations; LDS, Language Development Survey; MCDI, MacArthur Communicative Development Inventory; OR, odds ratio; PARCA, Parent Report of Children s Abilities. J Clin Endocrinol Metab, September 2010, 95(9): jcem.endojournals.org 4227

2 4228 Henrichs et al. Maternal Thyroid Function and Child Cognition J Clin Endocrinol Metab, September 2010, 95(9): Thyroid hormones play a major role in neurodevelopment from early pregnancy onward. Animal studies demonstrated that thyroid hormones are involved in neocorticogenesis and the formation of the hippocampus and cytoarchitecture of the somatosensory cortex (1, 2). In humans, low levels of thyroid hormones during pregnancy can lead to mental retardation in the offspring (3). During early gestation, the fetus depends entirely on maternal thyroid hormones that cross the placenta because the fetal thyroid function does not begin before wk of pregnancy (4, 5). Even after the onset of fetal thyroid hormone production, the fetus continues to rely upon maternal thyroid hormones (4). Maternal gestational hypothyroidism is associated with neurodevelopmental deficits in children aged 7 9 yr (6). Less is known, however, about the effect of early pregnancy maternal thyroid hormone levels across the entire range on cognitive functioning. Pregnant women with normal TSH levels often have low free T 4 (FT 4 ) levels, even in areas in which iodine intake is sufficient within the general population. This condition is termed as hypothyroxinemia and was long considered to be without consequences for the fetus. However, recent findings suggest that hypothyroxinemia can negatively affect child health outcomes, including neonatal behavior and infant cognitive functioning (7 10). This restimulated an old debate emphasizing the harmful effects of maternal hypothyroxinemia on child development (11, 12). However, except for the original cohort study (n 1394) of Man and Jones (11), evidence for the adverse effect of hypothyroxinemia stems from rather small study samples (n 350) (7 12). Subsequently, current obstetric guidelines still do not recommend routine screening of the maternal prenatal thyroid function (13). We studied a large population-based cohort with verbal and nonverbal cognitive measures in early childhood. Our aim was to investigate whether low FT 4 concentrations in pregnant women with normal TSH levels negatively affect offspring cognitive development. To this aim, we defined mild and severe hypothyroxinemia, representing FT 4 concentrations below the 10th and 5th percentile, respectively, in line with previous research (7). We also examined whether continuous measures of maternal TSH and FT 4 levels in early pregnancy predict verbal cognitive functioning at 18 and 30 months and nonverbal cognitive functioning at 30 months. We hypothesized that, in particular, severe maternal hypothyroxinemia is associated with cognitive delay in early childhood. Subjects and Methods Design This study was embedded in the Generation R Study, a population-based cohort from fetal life onward in Rotterdam, The Netherlands, that has been described previously (14). All children were born between April 2002 and January The study has been approved by the Medical Ethics Committee of the Erasmus Medical Center, Rotterdam. Written informed consent was obtained from all adult participants. Population for analysis Data on thyroid function was complete in 4892 pregnant women. Women receiving T 4 treatment were excluded (n 36). This left 4856 eligible subjects. Of these, 1147 mothers did not provide information on any cognitive outcome. We excluded 50 children who were assessed outside the age range of the cognitive measures. This left 3659 children (75.3% of the 4856 eligible subjects) in one or more of our analyses. Analyses of language functioning at 18 months were based on 3411 observations, those of language functioning at 30 months on 2819 observations, and those of nonverbal cognitive functioning at 30 months on 2748 observations. Thyroid parameters We collected maternal blood samples in early pregnancy (mean 13.3 wk; SD 1.7). In 2295 neonates, cord blood was also obtained. Maximally 3 h after sampling, blood was transported to our laboratory for storage at 80 C. TSH and FT 4 concentrations were assayed in batches of over a 6-month period using Vitros ECI Immunodiagnostic, (ORTHO Clinical Diagnostics, Rochester, NY). The normal range for maternal FT 4 (11 25 pmol/liter) was based on the reference range used in our laboratory for nonpregnant women. The normal range for maternal TSH ( mu/liter) during early pregnancy was based on the recommendations of The Endocrine Society Clinical Practice Guideline (2007) (15). In line with previous research, we used two definitions for low maternal FT 4 concentrations in early pregnancy (7). Maternal mild and severe hypothyroxinemia were defined as normal TSH levels and FT 4 concentrations below the 10th percentile (FT pmol/liter) and 5th percentile (FT pmol/liter), respectively. Based on previous research, we used the following cutoffs to define high TSH levels (TSH 1 SD above the gestational age-specific mean) and low FT 4 concentrations (FT 4 1 SD below the gestational age-specific mean) at birth (16). Neonates were categorized as hypothyroid when displaying high TSH and low FT 4 levels at birth. Maternal hypothyroidism (TSH 2.5 mu/liter and FT 4 11 pmol/liter) and hyperthyroidism (TSH 0.03 mu/liter and FT 4 25 pmol/liter) were not studied as determinants due to the small number of at-risk children (n 54 and n 29, respectively). The interassay coefficients of variation for maternal TSH and FT 4 were and %, respectively, and the intraassay coefficients of variation for maternal TSH and FT 4 were and %, respectively.

3 J Clin Endocrinol Metab, September 2010, 95(9): jcem.endojournals.org 4229 Verbal and nonverbal cognitive development Verbal and nonverbal cognitive development were assessed using three mailed parent-report measures at 18 and 30 months. Dutch, English, Turkish, and Arabic versions were available. Expressive vocabulary at 18 months was assessed with the age-appropriate short form of the MacArthur Communicative Development Inventory (MCDI) (17). This instrument contains a list of 112 words based on the original MCDI consisting of 680 words (18). Mothers were asked to identify each word they have heard their child say. Expressive vocabulary sum scores were converted into age- and gender-specific percentile scores as described in the MCDI manual (17). In line with a previous study, expressive language delay at 18 months was defined as vocabulary scores below the 15th percentile (19). Internal consistency of MCDI expressive vocabulary was At 30 months, mothers completed the Language Development Survey (LDS), a 310-word vocabulary checklist (20, 21). Mothers identified each word that their child used spontaneously and indicated whether the child had begun combining words into phrases. LDS vocabulary sum scores were converted into ageand gender-specific percentile scores as described in the LDS manual (20). Expressive language delay at 30 months was operationalized as LDS vocabulary scores below the 15th percentile or no word combinations. Internal consistency of the LDS vocabulary score was Nonverbal cognitive development at 30 months was assessed using the parent-administered and parent-report part of the Parent Report of Children s Abilities (PARCA) (22). PARCA scores were calculated by summing the 22 parent-administered items (assessing matching-to-sample, block building, and imitation) and the 26 parent-report questions (assessing quantitative skills, spatial abilities, symbolic play, planning and organizing, adaptive behaviors, and memory). Nonverbal cognitive delay was defined as nonverbal cognitive scores below the 15th age- and gender-specific percentile. Mailed parent-report measures are time-saving, cost efficient, and necessary tools to assess large population-based samples. All three measures, i.e. MCDI, LDS, and PARCA, are age appropriate and highly reliable measures with high concurrent and predictive validity (17, 18, 20 25). In a population-based sample, Rescorla and Alley (23) showed that the LDS is able to reliably and validly identify language delay in toddlers. Furthermore, within a population-based sample, PARCA and MCDI scores predicted language problems later in childhood (24). In large population-based studies, detailed cognitive examinations by researchers are not feasible because young children are often too shy to respond to strangers according to their abilities; typically, more global tests such as the Bailey Scales are used. As a proxy for a validation of the parent-report measures in our study, we related the parent-report measures to such a standardized developmental score. In a subgroup of 697 children, trained research assistants performed age-adapted neurodevelopmental assessments at 14 months with an adapted version of Touwen s examination of neurodevelopment (26). General nonoptimal neurodevelopment was significantly correlated with word production scores at 18 and 30 months (r 0.15; P 0.001, and r 0.20; P 0.001, respectively) as well as with nonverbal cognitive scores at 30 months (r 0.11; P 0.010), indicating that low cognitive scores as reported by parents are correlated with observed neuromotor problems. Covariates Information about maternal age, education, prenatal smoking, prenatal distress, and child ethnicity was obtained by questionnaires during pregnancy. The highest completed education represents the maternal educational level. Child ethnicity was based on the country of birth of the parents and grandparents. Maternal prenatal smoking was classified as no smoking, smoking until pregnancy was known, and continued smoking during pregnancy. At 20 wk pregnancy, we measured maternal prenatal distress using the Brief Symptom Inventory (27). Infant gender, birth weight, Apgar scores 1 min after birth, and mode of delivery were derived from medical records. Gestational age was established by fetal ultrasound examinations. Statistical analysis Continuous measures of TSH and FT 4 were expressed in SD scores to make effect estimates comparable. We included mild and severe maternal hypothyroxinemia as categorical determinants in our analyses. We examined associations of maternal thyroid function with language delay and nonverbal cognitive delay in early childhood using logistic regression. Because language functioning was assessed repeatedly, we used generalized estimating equations (GEE) to estimate the possible effects on language delay across ages more precisely and to reduce the error derived from multiple testing at different ages. Additionally, to test a dose-response relation in the lower tail of the FT 4 distribution, P-for-trend was calculated based on the following categories in pregnant women with normal TSH: 1) FT 4 levels above the 10th percentile, 2) FT 4 levels within the 5 10th percentile, and 3) FT 4 below the 5th percentile in relation to the risk of verbal and nonverbal cognitive delay. Note that mild hypothyroxinemia combines the last two categories. Regression models were adjusted for maternal age, education, prenatal distress and prenatal smoking, birth weight, gestational age at blood sampling, and child ethnicity. The choice of confounders was determined a priori and based on earlier literature (6 8). Covariates were included in the analyses if the effect estimates of maternal thyroid function changed meaningfully ( 5%). Apgar score, mode of delivery, and gestational age at birth did not pass this threshold. Finally, to test whether our results were influenced by child ethnicity (and the language spoken at home), we reran our analyses among Dutch children only (n 2404). Nonresponse analysis When comparing children with information on maternal thyroid function and cognitive functioning with eligible children not included because of missing data, included children had a higher birth weight [mean 3437 g (SD 563) vs. mean 3340 g (SD 571), t 5.23, P 0.001] and were more likely to be Dutch (65.7 vs. 38.7%, ; degrees of freedom (df) 2; P 0.001] than children of nonresponding mothers. Participating mothers were more likely to be more highly educated (percent with higher education is 31.7 vs. 12.7%, ; df 2; P 0.001). Results Table 1 presents the baseline characteristics of the study participants. Almost 66% of the children were Dutch, and

4 4230 Henrichs et al. Maternal Thyroid Function and Child Cognition J Clin Endocrinol Metab, September 2010, 95(9): TABLE 1. Subject characteristics (n 3659) Mean (SD) a Maternal characteristics Age (yr) 30.9 (4.5) Education (%) Primary education 15.8 Secondary education 52.5 Higher education 31.7 Smoking during pregnancy (%) No smoking during pregnancy 75.8 Smoking until pregnancy was known 9.3 Continued smoking during pregnancy 14.9 Maternal prenatal distress score median (95% range) b 0.13 ( ) TSH (per mu/liter) 1.61 (1.4) FT 4 (per pmol/liter) 15.3 (3.7) Hypothyroidism (yes, %) 1.5 Hyperthyroidism (yes, %) 0.8 Mild hypothyroxinemia (yes, %) c 8.5 Severe hypothyroxinemia (yes, %) c 4.3 Infant characteristics Gender (boys, %) 49.5 Birth weight (g) 3437 (563) Gestational age (wk) 39.9 (1.7) Apgar score 1 min after birth 8.63 (1.1) FT 4 levels at birth (pmol/liter) d 20.9 (3.41) TSH at birth (mu/liter) d 12.1 (8.4) High TSH (yes, %) d 13.9 Low FT 4 at birth (yes, %) d 10.8 Child hypothyroidism (yes, %) 1.3 Ethnicity (%) Dutch 65.7 Cape Verdean 1.8 Moroccan 3.5 Dutch Antilles 2.0 Surinamese 5.3 Turkish 5.8 Other Western 10.0 Other non-western 5.8 Mode of delivery (%) Spontaneous vaginal 70.9 Instrumental vaginal 16.0 Cesarean section 13.1 Age at 18 months assessment, months median (95% range) 18.1 ( ) Age at 30 months assessment, months median (95% range) 30.6 ( ) Expressive vocabulary at 18 months (score) 19.2 (19.1) Expressive vocabulary at 30 months (score) (61.0) Nonverbal cognitive functioning at 30 months (score) 47.1 (5.5) a Unless otherwise indicated. b Based on the Global Severity Index of the Brief Symptom Inventory (27). c Percentages of mild and severe hypothyroxinemia are lower than expected, i.e. less than 5% or less than 10%, due to different amounts of missing data on maternal FT 4 or TSH. d Neonatal thyroid parameters at birth were complete in 2295 neonates. 16% of the mothers had a primary education. On average, children were born at term [mean 39.9 wk (SD 1.7)]. Based on the criteria described above, 1.5% of the mothers had hypothyroidism, 0.8% had hyperthyroidism, 8.5% had mild hypothyroxinemia, and 4.3% had severe hypothyroxinemia. In a subgroup of 1815 children, we tested whether thyroidal status differed among neonates of mothers with and without hypothyroxinemia. Neonates of mothers with severe hypothyroxinemia were not more likely to be hypothyroid (percent hypothyroidism, 1.3 vs. 1.2%; ; df 2; P 0.964) or to have higher TSH levels [mean 12.9 pmol/liter (SD 12.6) vs pmol/liter (SD 8.1); t 1.00; P 0.317], but they were more likely to have lower FT 4 levels [mean 19.9 mu/liter (SD 3.5) vs mu/liter (SD 3.39); t 1.82; P 0.017] than neonates of mothers with normal prenatal thyroid function. A similar pattern of results was observed when comparing the

5 J Clin Endocrinol Metab, September 2010, 95(9): jcem.endojournals.org 4231 TABLE 2. Maternal thyroid function in early pregnancy and expressive language delay at 18 and 30 months Maternal thyroid function measure One time point Across ages Expressive language delay at age 18 months a Expressive language delay at age 30 months b Expressive language delay at 18 and 30 months n OR (95% CI), P n OR (95% CI), P n OR (95% CI), P TSH, per SD ( ), ( ), ( ), FT 4, per SD ( ), ( ), ( ), Mild hypothyroxinemia c 2736 e 1.33 ( ), e 1.47 ( ), e 1.44 ( ), Severe hypothyroxinemia d 2736 e 1.77 ( ), e 1.78 ( ), e 1.80 (1, ), Models were adjusted for maternal age, maternal educational level, maternal smoking during pregnancy, maternal prenatal distress, gestational age at blood sampling, birth weight, and child ethnicity. The sample size of the respective analysis is represented by n. a Expressive language delay at 18 months was defined as an expressive vocabulary score below the 15th age- and gender-specific percentile. b Expressive language delay at 30 months was defined as an expressive vocabulary score below the 15 th age- and gender-specific percentile or no word combinations. c Mild maternal hypothyroxinemia was defined as normal TSH levels and FT 4 concentrations below the 10th percentile. d Severe maternal hypothyroxinemia was defined as normal TSH levels and FT 4 concentrations below the 5th percentile. e Mothers with abnormal TSH levels during early pregnancy were excluded. thyroid status of neonates of mothers with or without mild hypothyroxinemia (data not shown). Table 2 presents adjusted associations of maternal thyroid function in early pregnancy with expressive language delay at 18 months, 30 months, and across ages. Maternal TSH and FT 4 levels were not related to the different measures of language functioning with one exception: higher FT 4 predicted a lower risk of expressive language delay at 30 months. Consistent with this pattern, mild hypothyroxinemia was associated, albeit nonsignificantly, to language delay at 18 and 30 months [odds ratio (OR) 1.33; 95% confidence interval (CI) ; P and OR 1.47; 95% CI ; P 0.051, respectively]. However, in an analysis across ages, mild hypothyroxinemia was significantly related to expressive language delay (OR 1.44; 95% CI ; P using GEE). Severe hypothyroxinemia predicted a higher likelihood of expressive language delay at both time points, i.e. 18 and 30 months (Table 2) and across ages (OR 1.80; 95% CI ; P 0.002). TABLE 3. Table 3 shows associations between maternal thyroid function in early pregnancy and nonverbal cognitive delay assessed only at 30 months after adjustment for confounders. Again, severe hypothyroxinemia predicted a higher risk of nonverbal cognitive delay at 30 months (OR 2.03; 95% CI ; P 0.007). We found dose-response relations in the lower range of the FT 4 distribution with verbal and nonverbal cognitive delay in early childhood. There was a dose-response relation of maternal FT 4 categories with expressive language delay (OR per category 1.30; 95% CI ; P for trend using GEE; other data not shown). Substantively identical results emerged if we reran the different regression analyses including only indigenous Dutch children (data not shown). In a subset of children with cord blood data, we additionally adjusted the association between maternal thyroid function and cognitive development for neonatal thyroid status. The effect estimates remained essentially unchanged. For example, severe hypothyroxinemia predicted a higher risk of nonverbal cognitive delay at 30 Maternal thyroid function in early pregnancy and nonverbal cognitive delay at age 30 months Maternal thyroid function measure n Nonverbal cognitive delay, a OR (95% CI), P TSH, per SD ( ), FT 4, per SD ( ), Mild hypothyroxinemia b 2086 d 1.37 ( ), Severe hypothyroxinemia c 2086 d 2.03 ( ), Models were adjusted for maternal age, maternal educational level, maternal smoking during pregnancy, maternal prenatal distress, gestational age at blood sampling, birth weight, and child ethnicity. The sample size of the respective analysis is represented by n. a Nonverbal cognitive delay was defined as a score below the 15th age- and gender-specific percentile. b Mild maternal hypothyroxinemia was defined as normal TSH levels and FT 4 concentrations below the 10th percentile. c Severe maternal hypothyroxinemia was defined as normal TSH levels and FT 4 concentrations below the 5th percentile. d Mothers with abnormal TSH levels during early pregnancy were excluded.

6 4232 Henrichs et al. Maternal Thyroid Function and Child Cognition J Clin Endocrinol Metab, September 2010, 95(9): months (OR 2.19; 95% CI ; P 0.016; other data not shown) after additional adjustment for neonatal FT 4. Discussion This study showed that maternal hypothyroxinemia predicted a higher risk of verbal and nonverbal cognitive delay in early childhood. Thus, our main hypothesis that hypothyroxinemia is associated with poor cognitive functioning in early childhood was supported by the data of this large and diverse population-based sample. In this study, maternal early pregnancy TSH levels across the entire range did not predict cognitive outcomes. Previous research showed that very high maternal TSH levels ( 98th percentile) during pregnancy accompanied by low T 4 levels, i.e. maternal clinical hypothyroidism, result in neurodevelopmental deficits (6). Most likely, high maternal TSH levels during pregnancy do not lead to offspring neurodevelopmental deficits if not accompanied by low T 4 levels. Our findings support the argument of Morreale de Escobar et al. (28) that not elevated maternal prenatal TSH levels but maternal hypothyroxinemia, i.e. low FT 4 level, is the principal factor leading to poor neurodevelopment of children. However, high maternal TSH levels should not be disregarded as an indicator of poor maternal thyroid function during pregnancy, because negative effects of maternal gestational hypothyroidism on neuropsychological outcome have been reported (6). Mild hypothyroxinemia was less strongly related to expressive language delay and not related to nonverbal cognitive functioning, whereas severe hypothyroxinemia was negatively associated with all cognitive outcomes in early childhood. These findings suggest that a certain threshold in pregnant women with normal TSH levels must be reached before low concentrations of FT 4 affect children s neurodevelopmental outcomes. In our study, this threshold manifests itself around pmol/liter. A previous Dutch study of child developmental outcomes reported a somewhat lower threshold for maternal FT 4 concentrations, i.e pmol/liter (7). However, these differences may be due to differences in FT 4 measurement methods. In a subset of our sample, we addressed whether the effects of maternal hypothyroxinemia on children s cognitive development were explained by neonatal thyroid function at birth. Although neonates of mothers with hypothyroxinemia had lower FT 4 levels, this did not explain why maternal hypothyroxinemia was associated with cognitive delay in early childhood. The effects of maternal hypothyroxinemia on offspring cognitive development are not mediated by the neonatal thyroid status. The structure of cognitive abilities in early childhood is far from clear, but the distinction between language and nonlanguage emerges early (29). We observed that severe maternal hypothyroxinemia predicted a higher risk of both verbal and nonverbal cognitive delay. This suggests that maternal hypothyroxinemia below a certain threshold has a consistent effect and impacts on general cognitive development in early childhood. A number of mechanisms may explain the relation between maternal hypothyroxinemia and adverse cognitive development in the offspring. First, low levels of FT 4 available to early-pregnancy embryonic tissues may account for this relation (28). Animal studies suggest that maternal hypothyroxinemia is causally related to adverse cognitive outcome. In the offspring of hypothyroxinemic rats, the fetal brain histogenesis was negatively affected, and the cytoarchitecture of the hippocampus and somatosensory cortex was permanently altered (1). Moreover, the offspring of rats treated with a goitrogen for 3 d before the start of neocorticogenesis had similar alterations in the hippocampus and cytoarchitecture of the somatosensory cortex (2). Morreale de Escobar et al. (30) extrapolated these results to humans and argued that the first trimester of pregnancy constitutes a critical period in which subtle FT 4 insufficiency may affect brain development. Second, low FT 4 levels can indicate suboptimal placental function during early pregnancy (31). Cognitive delays might, therefore, not only be a direct consequence of low FT 4 levels but also reflect early placental insufficiency (31). Indeed, placental insufficiency and poorer cognitive functioning have been associated (32). Third, our results may also partly be explained by genetic effects. Genetic factors largely determine cognitive abilities (33). Thyroid function also has a genetic basis (34). Therefore, it is possible that a common genetic factor underlies maternal prenatal thyroid function and offspring cognitive development. Maternal hypothyroxinemia during pregnancy can have different causes. Deficiency of iodine, an essential component of thyroid hormones, determines thyroid hormone plasma levels. Clinical studies of iodine supplementation provide good evidence for the importance of this micronutrient. Delayed iodine supplementation of hypothyroxinemic mothers during pregnancy increases the risk of neurodevelopmental delay in children (9). Moreover, thyroid peroxidase antibodies and autoimmunity can cause hypothyroxinemia; pregnant women with positive antibodies are more prone to develop hypothyroxinemia (35). The strengths of this population-based study are the large sample size, information on early pregnancy maternal thyroid function across the entire range, and information on numerous potential confounders.

7 J Clin Endocrinol Metab, September 2010, 95(9): jcem.endojournals.org 4233 Potential limitations of this study must also be discussed. First, data on verbal and nonverbal cognitive development were based on maternal report. Theoretically, the use of parent-based measures of cognitive development can introduce a reporter bias, but it is hard to conceive how this misclassification could be related to subclinical variations of maternal prenatal thyroid measures, in particular, because mothers were blinded to the determinants of this study. Thus, maternal ratings may be less objective, but most certainly do not introduce bias; i.e. these ratings do not systematically affect the relationships of interest. Moreover, all three parent-based measures of cognitive development, MCDI, LDS, and PARCA, have been shown to be reliable and valid (17, 18, 20 22) and to predict language and language-related problems later in life (24, 25). A review of 23 studies relating parent-report measures with standard tester-administered assessments supports the validity of parental measures (36). Parents have the chance to assess their children s performance in a natural environment, whereas standard cognitive testing requires children to perform at their best in the presence of a stranger. This suggests a possible limit to the validity of standardized tester-based assessment (37). Furthermore, shyness in children is related to underperforming on cognitive tests if assessed by an examiner (38). Before age 2 yr, it is difficult to measure children s cognitive development. Longer follow-up is suggested to study cognitive development of children with hypothyroxinemic mothers. Second, we did not measure urinary iodine as a measure of iodine intake or assess dietary intake of foods likely to be high in iodine, e.g. fish consumption and iodine-containing vitamin intake. However, in previous research, iodinecontaining vitamin intake during pregnancy did not predict cognitive functioning in childhood (39). Third, we cannot rule out the possibility of selective nonresponse and loss to follow-up. Our data were more complete in more highly educated, older mothers with Dutch ethnicity. It is possible that we observed associations between maternal thyroid dysfunction and cognitive outcomes among less severely disturbed individuals. This can lead to underestimation of the associations but is less likely to result in spurious associations. Finally, thyroid sampling in pregnant women was performed during early pregnancy. We suggest that maternal thyroid status throughout the fetal development should also be considered in future studies. In conclusion, this study showed that maternal hypothyroxinemia in early pregnancy is a determinant of verbal and nonverbal cognitive functioning in early childhood. The findings of this large population-based study suggest that even in pregnant women with normal TSH levels, low FT 4 concentrations affect fetal brain development and put children at risk for subsequent neurodevelopmental deficits. It is tempting to recommend thyroid function screening including FT 4 measures of women in early pregnancy. Yet, first clinical trials addressing the potentially beneficial effects of iodine treatment or T 4 supplementation in early pregnancy are needed, before the implementation of FT 4 screening programs can be justified. Acknowledgments Address all correspondence and requests for reprints to: Henning Tiemeier, M.D., Ph.D., Department of Child and Adolescent Psychiatry, Erasmus Medical Center Sophia Children s Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. h.tiemeier@erasmusmc.nl. This work was supported by independent research grants from the Erasmus Medical Center, Rotterdam, The Netherlands Organization for Health Research (ZonMw, Grant No ), the Dutch Brain Foundation, the Jan Dekker/ Ludgardina Bouwman Foundation, Fa. Merck Serono, the Janivo Foundation, and the European Community s 7th Framework Programme (FP7/ ) under grant agreement no (NUTRIMENTHE Project The Effect of Diet on the Mental Performance of Children ). Disclosure Summary: The authors have nothing to disclose. References 1. Lavado-Autric R, Ausó E, García-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G 2003 Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111: Ausó E, Lavado-Autric R, Cuevas E, Del Rey FE, Morreale De Escobar G, Berbel P 2004 A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. 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