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Thyroxine Levels During Pregnancy in Healthy Women and Early Child Neurodevelopment

Julvez, Jordia,b,c,d; Alvarez-Pedrerol, Mara,b; Rebagliato, Marisac,e,f; Murcia, Marioc,f; Forns, Joana,b,c; Garcia-Esteban, Raquela,b,c; Lertxundi, Nereag,h; Espada, Mercedesc,i; Tardón, Adoninaj; Riaño Galán, Isolinak; Sunyer, Jordia,b,c,l

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doi: 10.1097/EDE.0b013e318276ccd3
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Brain development depends on an adequate supply of thyroid hormones. These hormones regulate the processes of dendritic and axonal growth, synaptogenesis, neuronal migration, and myelination. The fetus relies on the mother’s thyroid hormones in the early stages of pregnancy, and so it is important that pregnant women have adequate hormone levels.1,2

The human brain develops from a strip of cells along the dorsal ectoderm of the embryo, with the majority of this development taking place during the intrauterine period. If these processes are disturbed, owing either to the lack of essential hormones and nutrients or to the toxic effect of an agent, there is little possibility for later repair, and the functional consequences can be permanent.3

Hypothyroidism during pregnancy has long been known to cause neurologic deficits and mental retardation. Iodine status has improved in Europe during the last 10 years, and severe iodine deficiency disorders, such as cretinism, have been largely eliminated through the iodination of salt.2,4–7 Nevertheless, a few small studies have suggested that in mildly iodine-deficient or iodine-sufficient regions, reduced thyroid function of healthy pregnant women without a diagnosis of thyroid pathology can impair the child’s neurodevelopment.8–14 Some of these studies have recommended the implementation of a systematic screening for hypothyroidism early in pregnancy. With this in mind, a randomized, controlled trial was conducted after screening pregnant women for a high thyrotropin (TSH) level, a low free thyroxine (T4) level, or both. The difference in offspring cognitive function was assessed for 390 women in the treatment group and 404 in the control group, with 3-year-old children in both groups showing similar cognitive scores.15 Current guidelines do not regard universal screening for hypothyroidism as justified by current evidence.16

Still, there is justification for further investigating the effects of antenatal screening and treatment of thyroid deficiency. A human fetus does not start to secrete its own thyroid hormones until about 18–20 weeks of uterine life. Animal studies have demonstrated that a fetus is fully dependent on the mother’s circulating free T4 during early development.15

As part of the Spanish cohort project INMA—INfancia y Medio Ambiente (Environment and Childhood)17—we aimed to ascertain whether thyroid function in healthy pregnant women is associated with a cognitive delay in their young children after accounting for a wide range of cofactors. The associations for mothers diagnosed with thyroid pathology, medically treated and untreated, were also explored.


Study Population

A total of 2644 pregnant women were recruited at their first routine prenatal care visit between 2004 and 2008 in the main public hospital or referral health center in defined regions.17 The mother-child pairs included in the study had thyroid-hormone testing before the 21st week of gestation, had a Bayley test before 23 months of age (n = 2,098) and did not have neurologic pathologies (n = 2,080). In total, 319 mother-child pairs were then excluded owing to preterm birth (<37 weeks of gestational age; n = 80), lack of child cooperation during testing (n = 133), an extreme value of TSH (126 mU/l; n = 1), and a thyroid disorder diagnosed before pregnancy (n = 105); the latter were included in a secondary analysis. The main analyses were based on 1761 mother-child pairs, but 118 observations were further excluded in the multivariate models. The analyses without excluding participants except for the extreme value of TSH, included 2097 mother-child pairs (n = 1,954 in the multivariate models). Participants provided informed consent and the study was approved by the ethics committee of all Spanish institutions involved in the project INMA, and the Institut Municipal d’Investigacio Medica, Barcelona (

Thyroid Hormone Measurement

Specialized nurses from each of the referral health centers collected maternal blood samples at the first visit (median gestational age: 13 weeks; range: 8–20 weeks). The samples were stored within 1 hour of collection at −80°C for several months and delivered to the reference laboratory (Normative Public Health Laboratory of Bilbao, Basque Country). Transport conditions followed standard protocols, using insulated boxes and dry ice to prevent sample degradation during the 8-hour trip to the reference lab. The TSH and free T4 assessment used a solid-phase, time-resolved sandwich fluoroimmunoassay (AutoDELFIA, PerkinElmer Life and Analytical Sciences, Wallac Oy, Turku, Finland) and a lanthanide metal europium (Eu) label. The between-assay coefficients of variation for low, medium, and high hormone concentration were 3.0%, 3.1%, and 2.6% for TSH and 6.1%, 4.1%, and 4.0% for free T4. The intra-assay coefficients of variation were 7.7%, 2.1%, and 1.7% for TSH; 3.7%, 3.0%, and 3.3% for free T4.

Important physiologic changes in serum thyroid hormone levels take place during pregnancy.18 Considering the wide range of gestational age at sampling, hormone concentrations were standardized by gestational age. Linear regression analyses with multivariable fractional polynomials were used to estimate the relation between outcome (free T4 and TSH levels) and gestational age.19 We examined nonlinearity by allowing up to two polynomial terms for gestational age with powers chosen among {−3, −2, −1, –½, 0 (log), ½, 1, 2, 3}. The best-fit fractional polynomial of degrees 1 and 2 were defined as those that maximized the likelihood. The final polynomial powers for gestational age resulted in a model with minimum deviance from the null model (straight line on 1 df).

The fitted model for free T4 (with standard error in parenthesis) is 10.53 (0.03) + 9.46 (0.65) × (gestational age at sampling/10)−0.5 (see Fig. 1). The fitted model for TSH (with standard error in parenthesis) is 1.46 (0.03) + 0.03 (0.02) × (gestational age at sampling) (see Fig. 2).

Observed and estimated (first-degree fractional polynomial model with 95% confidence limits) free T4 levels.
Observed and estimated (linear model with 95% confidence limits) TSH levels.

The standardized residuals resulting from each thyroid hormone parameter regressed on gestational age were used to define gestational-age-adjusted free T4 and TSH.20 Afterward, six dichotomous variables and two ordinal variables were created using the 10th, 5th, and 2.5th percentiles for free T4, and 90th, 95th, and 97.5th percentiles for TSH as cutoff points.

Neurodevelopmental Assessment

Child neurodevelopment was assessed at approximately 14 months of age (median 14 months; range 11–23 months; standard deviation 1.8 months) using the Bayley Scales of Infant Development.21 Eleven psychologists were trained to administer the test. The psychologists were not informed of the mother’s or the child’s exposure information. All testing was done at each region’s primary care center in the presence of the mother and inside a comfortable well-lit room with noise insulation. Psychologists flagged children whose Bayley tests were of poor quality because of basic pathologies (Down syndrome, autism) or lack of cooperation of the child (owing to fatigue, bad mood, illness, etc): these were excluded from the main analyses. The Bayley Scales of Infant Development, first edition, is one of the most psychometrically valid measurements for examining infants’ mental and psychomotor development from 1 to 30 months of age. These tests include the mental scale (163 items), the psychomotor scale (81 items), and the behavior scale (30 items). We used only the mental and psychomotor scales. The mental scale assesses cognitive development such as visual performance function, memory, and first verbal outcomes. The psychomotor scale assesses fine and gross motor development. Raw scores were standardized by age at assessment22 and centered to a mean of 100, with a standard deviation of 15 to compute index scores (mental and psychomotor scores). This was to obtain indexes in accordance with a local normative sample and to avoid the use of U.S. norms provided in the manual. To limit interobserver variability, we applied a strict protocol, including interobserver trainings and three sets of quality controls (interobserver reliability tests) undertaken during the fieldwork. The inter-rater reliability was estimated by intraclass correlation with coefficients of 0.90 for mental scale and 0.96 for psychomotor scale. Furthermore, Cronbach’s alpha coefficient was used to determine the internal consistency of each of the scales. A good coefficient would be a value ≥0.7023: for the mental scale, the alpha coefficient was 0.70 and for the psychomotor scale was 0.73.

Other Covariates

Information on education, socioeconomic background, demographic factors, marital status, maternal health and obstetric history, parity, medication use, alcohol and smoking habits, and dietary intake was obtained through questionnaires administered during pregnancy (first and third trimester) and when the child was 1 year old. Information on brand name, dose and timing of consumption of specific potassium iodide supplements and vitamin/mineral preparations containing iodine was obtained by a structured questionnaire. We defined iodine supplement consumers as women who were taking iodine supplements during the first 6 months of pregnancy (categorized as <150 or ≥150 μg/day). Usual dietary iodine intake during pregnancy was assessed with a 100-item, semiquantitative food frequency questionnaire administered to pregnant women at 10–13 weeks and at 28–32 weeks: their association with urinary iodine concentration and thyroid function have previously been reported for our study sample.24,25 Women also reported their consumption of iodized salt during pregnancy. Levels of maternal plasma of 25-hydroxyvitamin D3 were determined by high-performance liquid chromatography using a BioRAD kit according to Clinical and Laboratory Standard Institute protocols. The specific season (spring, summer, fall, and winter) during sample extraction was recorded. Urine cotinine concentrations (ng/ml) during pregnancy were analyzed by competitive immunoassay cotinine micro-plate enzyme immunoassay (Ora Sure Technologies, Inc.). Anthropometric measures of the children were obtained at birth and at 1 year of age by specially trained pediatricians and from clinical records.

Statistical Analysis

The associations between free T4 and TSH (as dichotomous and ordinal variables) and the Bayley mental and psychomotor scales were evaluated using multivariate linear regression analysis. The regression models included child's sex, region, and psychologist as mandatory covariates. We then introduced maternal education and maternal social class covariates to improve the precision of the model, as these are important predictors of child neurodevelopment. These two variables were not collinear in the model.

Other covariates were evaluated as potential confounders if they had been reported to be associated with neurodevelopment or thyroid function in the literature, or if they showed a relation with thyroid parameters in our data. Examined covariates included birth weight and height; gestational age; type of delivery; exclusive breastfeeding; paternal social class; paternal education; parental countries of birth; parental ages at birth; maternal prepregnancy weight and height; parity at child’s birth; maternal smoking during the first trimester of pregnancy; maternal cotinine concentration (in trimester-3 spot urine samples); circulating vitamin D during pregnancy and year-season of sampling; alcohol consumption during pregnancy; mothers working when child is 1–1.5 years; child day-care attendance; and main child-care provider. Covariates were retained only if they modified the coefficient of the thyroid parameter in the basic model by >5%. Maternal iodine indicators were excluded from the final models as they were not considered potential confounders and their inclusion in preliminary analyses did not modify the thyroid parameter coefficients (data not shown).

The final multivariate model included sex, region, psychologist, maternal education, parental social class, gestational age and weight at birth, circulating vitamin D during pregnancy and year-season of sampling, urine cotinine levels during pregnancy, maternal parity, and father’s age at birth. TSH is a major determinant of total T4 and was included in the free T4 model as a covariate; the two variables did not show evidence for collinearity in the model. We repeated the final models including all the participants without any restriction (n = 2,097), additionally adjusting for test quality and child neurologic pathology. Finally, the association between previously diagnosed thyroid disorder and children’s Bayley scores was studied repeating the same multivariate models. All analyses were conducted with the STATA 10 statistical software package.


Table 1 shows the demographic characteristics of children and parents in the main analysis. Half of the children were girls, 33% had attended nursery school and 58% had no siblings at birth. Three percent of these term-born children had low birth weight (<2,500 g).

Characteristics of the Study Population (n = 1,761)a

Table 2 presents the thyroid hormone and TSH concentrations of pregnant women in the main analysis. None of the women included in the main analysis reported any diagnosed thyroid disorder, although about 2.5% of the women exceeded the TSH level of 4 mU/l.

Thyroxine (Free T4) and Thyrotropin (TSH) Concentrations During Pregnancy at a Mean Gestational Age of 13 Weeks (n = 1,761)

Children of women with low free T4 levels showed poorer mental scores than offspring of women above the cutoff points in the adjusted linear regression models (Table 3). An inverse trend was observed when 10th, 5th, and 2.5th percentile groups were pooled into a single ordinal variable, and with all observations above the 10th percentile as the reference group. TSH was not associated with any of the scores. Similar results were observed without excluding any of the participants. There was little evidence for associations with psychomotor scores.

Adjusted Association Between Thyroid Function During Pregnancy and Bayley Scale Scores at 14 Months of Age (n = 1,643)

Children whose mothers reported a diagnosis of thyroid pathology before recruitment and did not follow a thyroid hormone replacement treatment during their first trimester of pregnancy scored lower in the mental scale than children included in the previous analysis (children whose mothers did not report any diagnosed thyroid pathology). The magnitude of the association was similar to that observed with low free T4 levels in Table 3. However, the coefficient decreased by half in children whose mothers were treated for a thyroid disorder (Table 4).

Table 4:
Thyroid Disorder and Bayley Scale Scores (Adjusted Regressions)


Low maternal levels of free T4 during the first half of pregnancy were associated with a cognitive delay in their young children. The magnitude of the impairment increased consistently from the 10th and lower percentiles of the free T4 level range. This association was observed in an apparently healthy population with a mild iodine deficiency.26 Children of mothers reporting prepregnancy thyroid disorder demonstrated a similar cognitive delay. Associations were much weaker for thyroid-treated women. Associations were weak or absent for TSH levels, and the Bayley psychomotor scale seemed to be less sensitive to thyroid function.

These results show some similarities as well as inconsistencies with several earlier studies.10,11,13,14 A previous INMA study that focused on the effects of iodine supplementation on neurodevelopment in subjects from Valencia (n = 643) observed a psychomotor delay in children whose mothers had hyperthyrotropinemia (>4 μU/ml). However, the association was no longer observed when women with a history of thyroid disorder were excluded. Null results were reported in relation to mental development.27 Research led by Pop13 was the first to investigate the relation between thyroid hormone status of 220 apparently healthy pregnant women and infant neurodevelopment in iodine-sufficient areas. Low free T4 during early gestation was associated with higher risk of impaired psychomotor development at 10 months of age, but no delays in mental development were observed. The two former studies confirmed a neurodevelopment delay, as do present findings. However, they identified psychomotor development as the most vulnerable endpoint at early life stages.

Other studies have found impairments in cognitive functions. A study of 65 cases (healthy pregnant women with free T4 levels below the 10th percentile at 12 weeks of gestation) matched with 57 controls demonstrated child cognitive and psychomotor delays at both the age of 1 and 2 years.14 Kooistra et al11 and Henrichs et al10 observed that first-trimester maternal free T4, but not maternal TSH, was an important predictor of some cognitive scores. A study by Haddow9 demonstrated that children of women with subclinical hypothyroidism (high TSH concentrations) performed less well on neuropsychological tests. In contrast to the present results, no association was observed between maternal thyroid function (total T4 and TSH) and child cognitive test scores at the age of 6 months and 3 years in a recent study including 500 healthy pregnant women living in an iodine-sufficient area.28

Both in our research work and in several of the preceding studies, free T4 seems to be the indicator of thyroid dysfunction in healthy pregnant women that is most predictive of a child’s neurodevelopmental outcome. Morreale et al29 also stated that maternal hypothyroxinemia increases the risk for poor neurodevelopment of the fetus more than either clinical or subclinical hypothyroidism (high TSH levels). As a consequence of these reports, the implementation of a universal systematic screening for thyroid dysfunction to avoid potentially preventable alterations in the offspring is being discussed.10,29 Newborn screening for congenital hypothyroidism has become routine in nearly all developed countries. As a result, normal development can generally be achieved through prompt treatment with T4 in newborns.30 Maternal thyroid dysfunction is likely to be more common than congenital hypothyroidism,30,31 and during the first trimester, the fetus is totally dependent on maternal thyroid hormones.2 Currently, screening in pregnant women is recommended only for women at high risk for thyroid dysfunction.16 Nevertheless, Vaidya et al32 observed in a prospective study of 1560 pregnant women that by screening women considered as “high risk” on the basis of a personal or family history of thyroid disease, or a history of other autoimmune disease, 30% of women with overt or subclinical hypothyroidism could have been missed. A recent study also showed that universal screening at the first prenatal visit could detect twice as many thyroid disorders in early pregnancy as more targeted high-risk case findings.33 The latest controlled trial did not find differences between treated and untreated groups, although the levothyroxine therapy was initiated too late in gestation to have a major influence on brain development.15

A 3.5-point decrease in a young child’s cognitive score may be clinically irrelevant for an individual but important for the population. If the whole population is exposed to a risk of low free T4 levels, the Gauss distribution for scores would likely shift to the left. As a consequence, the likelihood of finding borderline children will be increased, and the chances of observing children with a very high cognitive score will be reduced.34 If these effects are permanent, they could pose a considerable social and economic burden.35

Our study population can be considered iodine sufficient or mildly iodine deficient. It is known that thyroid autoimmunity is the main common cause of thyroid dysfunction in iodine-sufficient areas9,36; on the other hand, maternal thyroid autoimmunity has also been related to lower neurodevelopmental outcomes.12,37 Unfortunately, positive autoantibodies to thyroid peroxidase and other parameters of thyroid function were not available in the present population.

A weakness of the present study is the wide range of gestational ages for thyroid function assessment (from 8 to 20 weeks of pregnancy) even though 90% of the sample was collected during weeks 12–15. To account for this, hormone levels were standardized by gestational age at sampling before creating the dichotomous variables. Furthermore, women diagnosed with thyroid pathology but without treatment at inclusion showed a low number of events, and little information about the thyroid pathology was available. For the treated women, no information about the treatment duration, type, and dose was available.

Our results come from a population-based birth cohort that is representative of 40% of Spain’s general population and includes data on a range of confounding variables.38 But increasing the number of cofactors is not enough; there is a need to improve the quality of the data set, which is difficult in a large epidemiologic study.39 This study combines several thyroid-related biomarkers, such as maternal circulating vitamin D and urine cotinine levels, in conjunction with other important health and sociodemographic cofactors.39–41 Moreover, the application of a strict protocol for the neurodevelopmental assessment helped to improve the psychometric characteristics of the outcomes. Finally, the INMA project ( provides the opportunity to evaluate the long-term associations of maternal thyroid function in future neuropsychological evaluations (at present, these children are being assessed at the age of 4–5 years).


We found that low free T4 levels of healthy pregnant women were inversely associated with early child neurodevelopment, similar to the developmental delays among children of women reporting untreated prepregnancy thyroid disorder. These results support further investigation of the possible benefits of a systematic screening of thyroid dysfunction before conception, or at least within the first weeks of pregnancy, including free T4 measurements and in regions considered iodine sufficient. Furthermore, intervention studies are needed that start treatments around the time of conception to assess whether treating hypothyroxinemic and subclinical hypothyroid pregnant women would improve offspring neurodevelopment. Further research is also required to determine the reference ranges of TSH and thyroid hormones in each stage of pregnancy associated with adverse outcomes for both the mother and the child.


We particularly thank all the participants of the INMA PROJECT for their generous collaboration. We thank Silvia Fochs, Anna Sànchez, Maribel López, Muriel Ferrer, and Nuria Pey for their support in the fieldwork of Sabadell; Ana Sabater, Belén Plaza, Lucía Fernández, Sara Martínez, and Vanesa Gallent for their support in the field work of Valencia; Cristina Arias, Isolina Riaño, José Ignacio Suárez Tomás, and Cristina Rodriguez Delhi for their support in the fieldwork of Asturias; Haizea Begiristain, María Jesús Arroyo, Lourdes Arteche, and Mercedes Maiztegi from the Hospital of Zumarraga. A full roster of the INMA PROJECT Investigators can be found at http:// Chelsea Eastman helped to improve the English editing of the text.


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