High Tsh Levels in Pregnancy Linked to Low Baby Iq
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Abstract
Context
Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Show remains scarce for the potential adverse effects of loftier FT4 and whether associations differ in countries with different iodine status.
Objective
To assess the clan of maternal thyroid function in early pregnancy with kid neurodevelopment in countries with a different iodine status.
Design, Setting, and Participants
Meta-analysis of individual participant data from 9036 female parent–kid pairs from three prospective population-based nascency cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Written report of Parents and Children, U.k.). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease.
Main Outcomes
Child nonverbal IQ at 5 to 8 years of age, exact IQ at 1.v to 8 years of age, and autistic traits within the clinical range at v to eight years of age.
Results
FT4 <2.fifth percentile was associated with a three.nine-point (95% CI, −5.7 to −2.2) lower nonverbal IQ and a 2.1-point (95% CI, −four.0 to −0.1) lower verbal IQ. A suggestive clan of hypothyroxinemia with a greater take chances of autistic traits was observed. FT4 >97.5th percentile was associated with a ane.ix-fold (95% CI, 1.0 to iii.iv) greater run a risk of autistic traits. No independent associations were institute with TSH.
Conclusions
Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Farther studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay.
Thyroid hormone regulates crucial processes of brain development, including the proliferation, migration, and differentiation of neuronal cells, equally shown in creature studies (1, 2). Considering the fetal thyroid gland is not functionally mature until approximately week 18 of pregnancy (3), the fetus is dependent on placental transfer of maternal thyroid hormone during this flow. Acceptable maternal thyroid hormone concentrations during early pregnancy are therefore essential for optimal fetal brain development.
Previous studies focused mainly on the possible adverse effects of depression maternal hormone availability on fetal encephalon development. In several studies, either overt hypothyroidism or low maternal free T4 (FT4) was associated with a lower child IQ (4–eight), lower gray matter book (4), a greater risk of autistic traits (viii), impaired psychomotor function (10), and schizophrenia (11). Although the clan of high maternal FT4 on kid neurodevelopment has been less well studied, experimental evidence from rodents has indicated that loftier hormone availability might also have adverse effects (12–18). A recent study from The Netherlands has shown that loftier maternal FT4 is associated with lower IQ and grey matter volumes in the kid (4). Even so, it is unclear whether these findings from an iodine-sufficient population in Kingdom of the netherlands (xix) tin can be extrapolated to other countries with a dissimilar iodine status and whether high maternal FT4 is also associated with other adverse neurodevelopmental outcomes other than IQ.
Neither of the 2 randomized controlled trials that studied the outcome of levothyroxine treatment in women with subclinical hypothyroidism or hypothyroxinemia on child IQ showed any benefit of treatment (20, 21). However, these negative results could be ascribable to a relatively tardily beginning of treatment in both trials (13 weeks and xvi to 18 weeks, respectively), a relatively high dose was given that might take led to potential overtreatment (20), or a lack of power to detect the expected 3- to iv-point difference in IQ (21, 22). Therefore, further studies are required to better quantify and replicate the potential effects of both depression and loftier maternal thyroid hormone availability on fetal neurodevelopment. These studies can aid improve the design of future controlled trials.
The aim of the nowadays study was to investigate the clan of maternal thyroid office in early pregnancy across the full range of FT4 and TSH concentrations with the child's IQ and autistic traits in three prospective nascence cohorts.
Materials and Methods
Study blueprint and populations
For the present study, we used individual participant data from 3 prospective population-based nascence cohorts: Infancia y Medio Ambiente [INMA (Environment and Babyhood project), Spain, iii regions] (23), Generation R (The Netherlands) (24), and the Avon Longitudinal Study of Parents and Children (ALSPAC, United kingdom of great britain and northern ireland) (25). In INMA, the eligible study participants were pregnant women with a singleton pregnancy residing in the regions of Valencia, Sabadell, and Gipuzkoa from November 2003 to Jan 2008. In Generation R, the eligible report participants were meaning women living in the Rotterdam area with an expected delivery date from April 2002 to January 2006. In ALSPAC, the eligible written report participants resided in a divers area in the southwest of England, with an expected date of delivery from April 1991 to Dec 1992 [the written report website of ALSPAC contains details of all the information available through a fully searchable data dictionary (26)]. For the present report, eligible women were enrolled in the three cohorts during the get-go half of pregnancy (≤18th calendar week of gestation). Women with multiple pregnancies or fertility treatment and/or using medication affecting the thyroid or having a known thyroid disease were excluded (Fig. i). The local upstanding committees approved the nowadays report at written report enrollment; all participants and/or parents or guardians of the children provided informed consent.
Figure 1.
Flowchart for the selection of the final study population. IVF, in vitro fertilization.
Figure 1.
Flowchart for the selection of the terminal study population. IVF, in vitro fertilization.
Thyroid role
Thyroid function was measured in serum samples stored at −eighty°C (INMA and Generation R) or −20°C (ALSPAC). The samples were obtained at early pregnancy [(mean ± SD) gestational age: INMA, 13.1 ± 1.iii weeks; Generation R, 13.4 ± two.0 weeks; ALSPAC, 11.0 ± three.two weeks] (Table 1). Dissimilar assays were used to measure FT4 and TSH ( Supplemental Table 1). Although thyroid peroxidase antibody (TPOAb) was not measured in INMA, TPOAb measurements were available from Generation R and ALSPAC. The FT4 and TSH concentrations were logarithmically transformed, and cohort-specific SD scores were calculated with a mean of 0 and a SD of 1 based on the data of TPOAb-negative women, as advocated by the guidelines when defining population-based reference ranges (27).
Table one.
Distribution of Maternal and Child Characteristics
| Variable | INMA (n = 1289) | Generation R (n = 4660) | ALSPAC (n = 3087) |
|---|---|---|---|
| Maternal TSH, median (IQR), mIU/L | i.24 (0.84–1.81) | 1.36 (0.85–2.03) | ane.00 (0.64–i.46) |
| Maternal FT4, median (IQR), pmol/L | x.6 (9.seven–11.half dozen) | 14.8 (xiii.2–16.7) | sixteen.2 (fourteen.8–17.vii) |
| Thyroid disease entities, a n (%) | |||
| Hypothyroxinemia | 32 (two.5) | 111 (ii.4) | 61 (2.0) |
| Subclinical hypothyroidism | 31 (2.4) | 140 (3.0) | 110 (3.half dozen) |
| Subclinical hyperthyroidism | 20 (1.6) | 69 (1.5) | 34 (1.1) |
| TPOAb positivity, n (%) | NA | 254 (five.8) | 392 (12.8) |
| Gestational age at blood sampling, mean ± SD, wk | thirteen.1 ± 1.iii | thirteen.4 ± two.0 | eleven.0 ± 3.2 |
| Maternal educational level, n (%) | |||
| Depression | 281 (21.9) | 353 (eight.0) | 736 (24.7) |
| Medium | 537 (41.eight) | 1904 (42.9) | 1828 (61.three) |
| High | 468 (36.4) | 2179 (49.1) | 416 (14.0) |
| Maternal ethnicity, due north (%) | |||
| Castilian | 1202 (93.iv) | NA | NA |
| Latin-American | 60 (4.7) | NA | NA |
| European/other | 25 (1.nine) | NA | NA |
| Dutch | NA | 2606 (56.seven) | NA |
| Indonesian | NA | 150 (3.3) | NA |
| Cape Verdean | NA | 170 (three.vii) | NA |
| Moroccan | NA | 225 (iv.9) | NA |
| Dutch Antilles | NA | 104 (ii.three) | NA |
| Surinamese | NA | 351 (7.six) | NA |
| Turkish | NA | 356 (7.8) | NA |
| Asian | NA | 51 (1.ane) | NA |
| Other, non-Western | NA | 162 (3.5) | NA |
| Other, Western | NA | 418 (9.1) | NA |
| White | NA | NA | 2924 (98.6) |
| Nonwhite | NA | NA | 42 (i.4) |
| Maternal age, hateful ± SD, y | 31.five ± 4.0 | 30.3 ± 4.8 | 28.0 ± 4.half-dozen |
| Parity, n (%) | |||
| 0 | 731 (56.8) | 2721 (58.4) | 1410 (47.2) |
| 1 | 472 (36.vii) | 1386 (29.7) | 1033 (34.6) |
| ≥2 | 84 (6.5) | 553 (11.9) | 543 (xviii.2) |
| Maternal smoking, n (%) | |||
| Never smoked | 883 (69.4) | 3085 (73.5) | 2391 (79.2) |
| Smoked at the commencement of pregnancy | 174 (thirteen.7) | 396 (9.4) | 142 (four.7) |
| Continued smoking | 216 (17.0) | 719 (17.1) | 486 (16.1) |
| Prepregnancy BMI, median (IQR), kg/one thousandii | 22.v (20.viii–25.1) | 22.six (20.7–25.2) | 22.one (twenty.5–24.2) |
| Child female sex activity, n (%) | 635 (49.iii) | 2313 (49.6) | 1500 (48.6) |
| Child autistic traits within clinical range, n (%) | 16 (1.iv) | 117 (3.1) | 206 (7.5) |
| Variable | INMA (n = 1289) | Generation R (n = 4660) | ALSPAC (north = 3087) |
|---|---|---|---|
| Maternal TSH, median (IQR), mIU/50 | 1.24 (0.84–1.81) | 1.36 (0.85–ii.03) | 1.00 (0.64–1.46) |
| Maternal FT4, median (IQR), pmol/L | 10.6 (9.7–xi.6) | 14.viii (13.2–16.7) | xvi.2 (14.8–17.7) |
| Thyroid disease entities, a due north (%) | |||
| Hypothyroxinemia | 32 (2.5) | 111 (2.4) | 61 (ii.0) |
| Subclinical hypothyroidism | 31 (2.4) | 140 (3.0) | 110 (3.6) |
| Subclinical hyperthyroidism | xx (one.6) | 69 (i.5) | 34 (1.1) |
| TPOAb positivity, n (%) | NA | 254 (v.8) | 392 (12.8) |
| Gestational age at blood sampling, mean ± SD, wk | xiii.i ± 1.iii | 13.4 ± 2.0 | 11.0 ± iii.2 |
| Maternal educational level, northward (%) | |||
| Low | 281 (21.nine) | 353 (eight.0) | 736 (24.seven) |
| Medium | 537 (41.8) | 1904 (42.nine) | 1828 (61.iii) |
| High | 468 (36.4) | 2179 (49.ane) | 416 (xiv.0) |
| Maternal ethnicity, n (%) | |||
| Spanish | 1202 (93.4) | NA | NA |
| Latin-American | sixty (4.7) | NA | NA |
| European/other | 25 (1.9) | NA | NA |
| Dutch | NA | 2606 (56.7) | NA |
| Indonesian | NA | 150 (iii.3) | NA |
| Cape Verdean | NA | 170 (3.7) | NA |
| Moroccan | NA | 225 (4.nine) | NA |
| Dutch Antilles | NA | 104 (2.3) | NA |
| Surinamese | NA | 351 (7.6) | NA |
| Turkish | NA | 356 (7.8) | NA |
| Asian | NA | 51 (one.1) | NA |
| Other, non-Western | NA | 162 (3.5) | NA |
| Other, Western | NA | 418 (9.1) | NA |
| White | NA | NA | 2924 (98.6) |
| Nonwhite | NA | NA | 42 (i.4) |
| Maternal age, mean ± SD, y | 31.5 ± 4.0 | 30.three ± 4.8 | 28.0 ± 4.6 |
| Parity, n (%) | |||
| 0 | 731 (56.8) | 2721 (58.4) | 1410 (47.ii) |
| 1 | 472 (36.7) | 1386 (29.7) | 1033 (34.half dozen) |
| ≥2 | 84 (6.five) | 553 (11.9) | 543 (18.two) |
| Maternal smoking, north (%) | |||
| Never smoked | 883 (69.4) | 3085 (73.five) | 2391 (79.2) |
| Smoked at the beginning of pregnancy | 174 (13.seven) | 396 (nine.iv) | 142 (4.seven) |
| Continued smoking | 216 (17.0) | 719 (17.i) | 486 (16.1) |
| Prepregnancy BMI, median (IQR), kg/m2 | 22.v (20.8–25.1) | 22.6 (20.7–25.2) | 22.1 (20.5–24.two) |
| Child female sex activity, n (%) | 635 (49.3) | 2313 (49.half dozen) | 1500 (48.6) |
| Child autistic traits inside clinical range, n (%) | 16 (one.4) | 117 (3.1) | 206 (7.5) |
Information might not sum to 100 considering of rounding.
Abbreviations: BMI, trunk mass alphabetize; IQR, interquartile range; NA, not available.
a Based on the 2.fifth and 97.5th population-based percentiles.
Table 1.
Distribution of Maternal and Child Characteristics
| Variable | INMA (n = 1289) | Generation R (n = 4660) | ALSPAC (due north = 3087) |
|---|---|---|---|
| Maternal TSH, median (IQR), mIU/50 | i.24 (0.84–i.81) | 1.36 (0.85–2.03) | one.00 (0.64–1.46) |
| Maternal FT4, median (IQR), pmol/L | 10.6 (nine.7–xi.half-dozen) | 14.8 (thirteen.2–sixteen.7) | xvi.2 (14.8–17.vii) |
| Thyroid disease entities, a northward (%) | |||
| Hypothyroxinemia | 32 (2.5) | 111 (two.four) | 61 (2.0) |
| Subclinical hypothyroidism | 31 (2.4) | 140 (3.0) | 110 (3.half dozen) |
| Subclinical hyperthyroidism | 20 (1.6) | 69 (1.5) | 34 (1.1) |
| TPOAb positivity, n (%) | NA | 254 (5.8) | 392 (12.8) |
| Gestational age at claret sampling, mean ± SD, wk | xiii.ane ± 1.iii | 13.4 ± 2.0 | 11.0 ± 3.2 |
| Maternal educational level, northward (%) | |||
| Low | 281 (21.9) | 353 (8.0) | 736 (24.7) |
| Medium | 537 (41.8) | 1904 (42.9) | 1828 (61.iii) |
| Loftier | 468 (36.iv) | 2179 (49.1) | 416 (xiv.0) |
| Maternal ethnicity, n (%) | |||
| Castilian | 1202 (93.4) | NA | NA |
| Latin-American | threescore (4.vii) | NA | NA |
| European/other | 25 (ane.9) | NA | NA |
| Dutch | NA | 2606 (56.7) | NA |
| Indonesian | NA | 150 (three.3) | NA |
| Cape Verdean | NA | 170 (3.7) | NA |
| Moroccan | NA | 225 (4.9) | NA |
| Dutch Antilles | NA | 104 (2.3) | NA |
| Surinamese | NA | 351 (7.6) | NA |
| Turkish | NA | 356 (7.viii) | NA |
| Asian | NA | 51 (one.1) | NA |
| Other, non-Western | NA | 162 (iii.5) | NA |
| Other, Western | NA | 418 (9.1) | NA |
| White | NA | NA | 2924 (98.6) |
| Nonwhite | NA | NA | 42 (1.four) |
| Maternal age, mean ± SD, y | 31.5 ± 4.0 | 30.3 ± iv.viii | 28.0 ± iv.6 |
| Parity, n (%) | |||
| 0 | 731 (56.viii) | 2721 (58.4) | 1410 (47.2) |
| 1 | 472 (36.seven) | 1386 (29.7) | 1033 (34.half-dozen) |
| ≥2 | 84 (6.v) | 553 (11.nine) | 543 (eighteen.2) |
| Maternal smoking, n (%) | |||
| Never smoked | 883 (69.4) | 3085 (73.5) | 2391 (79.ii) |
| Smoked at the beginning of pregnancy | 174 (13.7) | 396 (9.4) | 142 (4.7) |
| Continued smoking | 216 (17.0) | 719 (17.1) | 486 (16.1) |
| Prepregnancy BMI, median (IQR), kg/gtwo | 22.5 (20.viii–25.1) | 22.6 (20.7–25.2) | 22.1 (xx.five–24.two) |
| Child female person sex, n (%) | 635 (49.iii) | 2313 (49.half-dozen) | 1500 (48.6) |
| Child autistic traits within clinical range, northward (%) | 16 (1.4) | 117 (three.1) | 206 (7.5) |
| Variable | INMA (due north = 1289) | Generation R (n = 4660) | ALSPAC (north = 3087) |
|---|---|---|---|
| Maternal TSH, median (IQR), mIU/L | ane.24 (0.84–1.81) | ane.36 (0.85–2.03) | 1.00 (0.64–i.46) |
| Maternal FT4, median (IQR), pmol/L | 10.6 (9.7–xi.half-dozen) | 14.viii (thirteen.2–16.7) | 16.two (14.8–17.7) |
| Thyroid disease entities, a due north (%) | |||
| Hypothyroxinemia | 32 (2.v) | 111 (two.4) | 61 (ii.0) |
| Subclinical hypothyroidism | 31 (2.4) | 140 (iii.0) | 110 (iii.half-dozen) |
| Subclinical hyperthyroidism | 20 (ane.6) | 69 (1.5) | 34 (1.i) |
| TPOAb positivity, n (%) | NA | 254 (5.8) | 392 (12.viii) |
| Gestational age at blood sampling, hateful ± SD, wk | xiii.i ± ane.three | thirteen.iv ± 2.0 | 11.0 ± 3.2 |
| Maternal educational level, north (%) | |||
| Low | 281 (21.9) | 353 (8.0) | 736 (24.7) |
| Medium | 537 (41.8) | 1904 (42.9) | 1828 (61.three) |
| High | 468 (36.four) | 2179 (49.1) | 416 (14.0) |
| Maternal ethnicity, due north (%) | |||
| Castilian | 1202 (93.4) | NA | NA |
| Latin-American | 60 (4.seven) | NA | NA |
| European/other | 25 (one.ix) | NA | NA |
| Dutch | NA | 2606 (56.7) | NA |
| Indonesian | NA | 150 (iii.three) | NA |
| Greatcoat Verdean | NA | 170 (three.7) | NA |
| Moroccan | NA | 225 (four.nine) | NA |
| Dutch Antilles | NA | 104 (ii.iii) | NA |
| Surinamese | NA | 351 (7.6) | NA |
| Turkish | NA | 356 (7.eight) | NA |
| Asian | NA | 51 (1.i) | NA |
| Other, non-Western | NA | 162 (3.5) | NA |
| Other, Western | NA | 418 (nine.1) | NA |
| White | NA | NA | 2924 (98.vi) |
| Nonwhite | NA | NA | 42 (one.4) |
| Maternal age, hateful ± SD, y | 31.v ± 4.0 | xxx.3 ± 4.8 | 28.0 ± 4.6 |
| Parity, north (%) | |||
| 0 | 731 (56.8) | 2721 (58.4) | 1410 (47.2) |
| ane | 472 (36.7) | 1386 (29.vii) | 1033 (34.6) |
| ≥2 | 84 (6.v) | 553 (11.9) | 543 (18.2) |
| Maternal smoking, n (%) | |||
| Never smoked | 883 (69.4) | 3085 (73.5) | 2391 (79.two) |
| Smoked at the kickoff of pregnancy | 174 (13.seven) | 396 (9.iv) | 142 (four.7) |
| Continued smoking | 216 (17.0) | 719 (17.one) | 486 (16.1) |
| Prepregnancy BMI, median (IQR), kg/g2 | 22.5 (xx.eight–25.ane) | 22.6 (20.7–25.2) | 22.ane (xx.5–24.2) |
| Kid female sexual activity, n (%) | 635 (49.iii) | 2313 (49.half-dozen) | 1500 (48.6) |
| Child autistic traits within clinical range, n (%) | xvi (ane.4) | 117 (3.1) | 206 (seven.v) |
Data might non sum to 100 because of rounding.
Abbreviations: BMI, body mass index; IQR, interquartile range; NA, not available.
a Based on the 2.5th and 97.5th population-based percentiles.
Hypothyroxinemia [normal (ii.5th-97.5th percentile) TSH; depression (<ii.fifth percentile) FT4], subclinical hypothyroidism [high (>97.5th percentile) TSH, normal FT4], and subclinical hyperthyroidism (depression TSH, normal FT4) were defined according to the two.5th and 97.5th population-based percentiles of the whole study population in INMA, because TPOAb measurements were not available. Thyroid disease entities were defined using the same population-based percentiles in Generation R and ALSPAC. Yet, in these cohorts, the population-based percentiles were based on the results from TPOAb-negative women. The reference group consisted of euthyroid women (TSH and FT4 between the two.5th and 97.5th percentiles). Additionally, to amend the statistical power, nosotros identified the thyroid disease entities using the fifth and 95th population-based percentiles. The untransformed 2.5th and 97.5th population-based percentiles based on TPOAb-negative women when possible were 0.14 and 3.86, 0.05 and 4.13, and 0.07 and two.58 mIU/Fifty for TSH and 8.4 and xiv.0, ten.4 and 22.1, and 12.6 and 22.5 pmol/L for FT4 in INMA, Generation R, and ALSPAC, respectively.
Nonverbal and verbal IQ
In INMA, nonverbal and verbal IQ were assessed past a psychologist at a median age of 4.6 years using the McCarthy Scales of Children's Abilities (28). In Generation R, nonverbal IQ was assessed by trained staff at a median age of 6.0 years using a subset of the Snijders Oomen Nonverbal Intelligence Test (2.v-7-Revised) (29), and verbal IQ was estimated past the parent-reported short course of the McArthur Communicative Development Inventory (30) obtained at a median age of 1.5 years. In ALSPAC, nonverbal and exact IQ were assessed by trained staff at a median age of eight.6 years using the Wechsler Intelligence Calibration For Children, tertiary UK edition (31). To homogenize the unlike scores, raw cohort-specific scores were standardized to a mean of 100 and a SD of fifteen (new score = 100 + 15 × SD).
Autistic traits inside the clinical range
Autistic traits are symptoms that represent subclinical deficits in social behavior, advice, and or restricted, repetitive patterns of behavior common to autism spectrum disorder (ASD) only that do not run into the clinical ASD diagnosis (32). Autistic traits within the clinical range were defined equally the presence of an autistic traits score greater than the specific cutoff for each cess tool, which had been previously validated in other studies to discover children at risk of ASD. In INMA, autistic traits were assessed with the Childhood Autism Spectrum Exam by a psychologist at a median age of 4.6 years, with a cutoff of ≥15 points to define autistic traits within the clinical range (33). In Generation R, autistic traits were assessed using the Pervasive Developmental Bug subscale of the Kid Behavior Checklist for Toddlers (CBCL one½-five) by the parents at a median historic period of 5.nine years, with a cutoff of ≥98th percentile to define autistic traits inside the clinical range (34). In ALSPAC, autistic traits were assessed with the Social Communication Disorder Checklist past the parents at a median age of vii.half dozen years of age, with a cutoff of nine or more points to define autistic traits within the clinical range (35).
Potential confounding variables
A direct acyclic graph (36) facilitated decision making regarding which covariates should be adapted for in the assay. Information on maternal variables [age, educational level (low, medium, high), ethnicity (cohort-specific categories), parity (zero, one, two or more than), prepregnancy body mass index, and smoking during pregnancy (never smoked, smoked in the beginning or until pregnancy confirmed, continued smoking)] was collected during pregnancy using questionnaires. Gestational age at blood sampling was defined using ultrasonography or the terminal menstrual period. Child sex and historic period at IQ or autistic trait ascertainment were obtained during the study visits.
Statistical analyses
We used linear regression models to report the association of maternal FT4, TSH, and thyroid disease entities with child nonverbal or verbal IQ. We used logistic regression models to study the association of maternal FT4, TSH, and thyroid disease entities with child autistic traits within the clinical range.
We studied these associations using a one-pace and a two-pace arroyo. In the one-step approach, nosotros assessed nonlinearity betwixt FT4 and TSH and each consequence using restricted cubic splines with three to five knots. An ANOVA examination was used to report an overall P value for the null hypothesis that the hateful IQ or probability of autistic traits within the clinical range was similar beyond the whole distribution of TSH or FT4. In the two-step arroyo, we combined cohort-specific effect estimates of the association betwixt FT4, TSH, and thyroid affliction entities and each issue using random furnishings meta-analyses. For this analysis, FT4 and TSH concentrations were categorized as <2.5th, <5th, >95th, or >97.5th percentiles using women with values within the interquartile range (within the 25th and 75th percentile range) as the reference group. Compared with the one-step approach, the 2-stride arroyo allows for differences in participant characteristics between cohorts, and heterogeneity between cohorts can be calculated (37). Heterogeneity was assessed using the Cochrane Q test and the I 2 statistic (38). All models were adjusted for maternal age, educational level, ethnicity, parity, prepregnancy BMI, smoking, gestational age at blood sampling, and child sexual practice. Because one-step arroyo models could not be adjusted for age at IQ or autistic trait ascertainment, cohort, and ethnicity at the aforementioned time owing to collinearity, we adjusted them only for ethnicity. The 2-step arroyo models could be adjusted for these variables because the effect estimates were calculated separately by accomplice.
As a sensitivity analysis, we adjusted the analyses of autistic traits for nonverbal IQ, a linguistic communication- and civilization-costless measure out of cognitive ability. Additionally, when we observed associations betwixt maternal TSH and child IQ or autistic traits, we repeated the analysis stratifying past low-, mid-, and high-normal FT4. Finally, all analyses were repeated in the TPOAb-negative women only.
We applied inverse probability weighting to correct for potential differential loss to follow-up (39). We performed multiple imputation using chained equations to business relationship for missing values for the potential confounding variables (forty). A total of 25 data sets were generated and analyzed using standard procedures for multiple imputation. Statistical analyses were performed in STATA, version 14.0 (StataCorp, Higher Station, TX) and R statistical software, version three.iii.2, package rms and lme4 (R Foundation, Vienna, Austria).
Results
After exclusions, the final study population included 9036 mother–child pairs (Fig. 1), the characteristics of which are shown in Table 1. The hateful maternal age varied across the cohorts: 31.5 years in INMA, 30.3 years in Generation R, and 28.0 years in ALSPAC. The percentage of mothers who continued smoking during pregnancy was similar amongst the cohorts (~16% to 17%). Autistic traits within the clinical range occurred in 1.iv% of the children in INMA, three.1% in Generation R, and 7.v% in ALSPAC. The two nearly prevalent thyroid affliction entities were hypothyroxinemia (2.0% to 2.5% across the cohorts) and subclinical hypothyroidism (two.4% to three.6% beyond the cohorts). Compared with the final written report population, the women non included in the analysis had a lower level of education, were less often native or white, and were younger in all three cohorts ( Supplemental Tabular array 2).
Nonverbal IQ
We observed a statistically pregnant nonlinear association betwixt maternal FT4 and mean nonverbal IQ (Fig. ii). FT4 ≤2.5th percentile was associated with a 3.9-point (95% CI, −five.7 to −2.iii; P < 0.001) lower nonverbal IQ. Similar results were observed when using the fifth percentile cutoff. A high FT4 was not associated with the nonverbal IQ. TSH ≥97.5th and ≥95th percentile was associated with a statistically nonsignificant slightly greater nonverbal IQ (1.5 points; 95% CI, −0.iii to 3.3; P = 0.100; and i.2 points, 95% CI, −0.1 to 2.5; P = 0.063, respectively; Supplemental Fig. 1). However, the sensitivity assay showed that this association was driven by women with a FT4 concentration in the mid- or high-normal range ( Supplemental Tabular array 3). No heterogeneity was observed among the cohorts. The results remained like later excluding TPOAb-positive women.
Figure ii.
Association of maternal FT4 during early pregnancy with child nonverbal IQ. Association shown as (a) a continuous association depicted as the hateful child nonverbal IQ (black line) with 95% CI (gray area) and by cohort-specific maternal FT4 concentrations in the (b) <two.fifth percentile, (c) >97.5th percentile, (d) <5th percentile, and (due east) >95th percentile compared with interquartile range (between 25th and 75th percentiles), depicted as consequence estimate (dot) with the 95% CI per cohort and overall as estimated by random effects meta-analysis (diamond). The I 2 for each model was every bit follows: for FT4 <2.5th percentile, I 2 = 0.0%; for FT4 >97.5th percentile, I 2 = 48.5%; for FT4 <fifth percentile, I ii = 0.0%: for FT4 >95th percentile, I 2 = 37.8%.
Figure two.
Association of maternal FT4 during early on pregnancy with child nonverbal IQ. Association shown as (a) a continuous association depicted as the mean kid nonverbal IQ (black line) with 95% CI (greyness area) and by accomplice-specific maternal FT4 concentrations in the (b) <2.5th percentile, (c) >97.5th percentile, (d) <5th percentile, and (e) >95th percentile compared with interquartile range (between 25th and 75th percentiles), depicted as result estimate (dot) with the 95% CI per cohort and overall equally estimated by random effects meta-analysis (diamond). The I 2 for each model was as follows: for FT4 <2.5th percentile, I ii = 0.0%; for FT4 >97.5th percentile, I 2 = 48.5%; for FT4 <5th percentile, I 2 = 0.0%: for FT4 >95th percentile, I 2 = 37.8%.
Verbal IQ
A statistically nonsignificant linear clan was plant between maternal FT4 and mean verbal IQ (Fig. iii). FT4 ≤2.5th percentile was associated with a two.one-betoken (95% CI, −4.0 to −0.1; P = 0.039) lower verbal IQ. In contrast, the clan of FT4 at the fifth percentile or less was associated with a statistically nonsignificant slightly lower exact IQ (−1.4 points; 95% CI, −2.9 to 0.2; P = 0.078). A high FT4 was not associated with exact IQ. A depression TSH was also not associated with exact IQ ( Supplemental Fig. 2). TSH ≥97.fifth percentile was associated with a greater verbal IQ (1.ix points; 95% CI, 0.1 to iii.7; P = 0.039). However, no association was found for TSH ≥95th percentile. The sensitivity analysis showed that the positive association of a loftier TSH ≥97.fifth percentile with verbal IQ was driven past women with a FT4 concentration in the mid- or high-normal range ( Supplemental Table 4). No heterogeneity was observed amid the cohorts. The results remained like after excluding TPOAb-positive women.
Figure three.
Clan of maternal FT4 during early pregnancy with child exact IQ. Association shown as (a) a continuous association depicted equally the mean child verbal IQ (blackness line) with 95% CI (gray area) and by accomplice-specific maternal FT4 concentrations in the (b) <2.fifth percentile, (c) >97.fifth percentile, (d) <5th percentile, and (east) >95th percentile compared with interquartile range (between 25th and 75th percentiles), depicted equally issue approximate (dot) with the 95% CI per cohort and overall as estimated by random furnishings meta-assay (diamond). The I ii for each model was equally follows: for FT4 <2.5th percentile, I ii = 0.0%; for FT4 >97.5th percentile, I two = 0.0%; for FT4 <5th percentile, I two = 0.0%: for FT4 >95th percentile, I 2 = 0.0%.
Effigy 3.
Association of maternal FT4 during early on pregnancy with child verbal IQ. Association shown as (a) a continuous clan depicted every bit the mean child verbal IQ (black line) with 95% CI (gray area) and by accomplice-specific maternal FT4 concentrations in the (b) <2.5th percentile, (c) >97.5th percentile, (d) <fifth percentile, and (east) >95th percentile compared with interquartile range (between 25th and 75th percentiles), depicted as effect estimate (dot) with the 95% CI per cohort and overall equally estimated by random effects meta-analysis (diamond). The I two for each model was equally follows: for FT4 <2.5th percentile, I two = 0.0%; for FT4 >97.5th percentile, I 2 = 0.0%; for FT4 <5th percentile, I 2 = 0.0%: for FT4 >95th percentile, I ii = 0.0%.
Autistic traits
No continuous clan was constitute for maternal FT4 with kid autistic traits (Fig. four). FT4 ≤2.5th percentile was non associated with autistic traits, but FT4 ≤5th percentile was associated with a statistically nonsignificant slightly greater risk of autistic traits [odds ratio (OR), ane.5; 95% CI, 1.0 to 2.three; P = 0.080). FT4 ≥97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to three.4; P = 0.043) greater hazard of autistic traits. A similar association was found afterwards adjusting for nonverbal IQ (data non shown). FT4 ≥95th percentile was non associated with autistic traits. TSH was not associated with autistic traits ( Supplemental Fig. 3). No heterogeneity was observed amidst the cohorts. The results remained like subsequently excluding TPOAb-positive women.
Figure 4.
Clan of maternal FT4 during early pregnancy with kid autistic traits inside the clinical range. Association shown as (a) a continuous clan depicted as the hateful risk of child autistic traits within the clinical range (black line) with 95% confidence interval (grey area) and past cohort-specific maternal FT4 concentrations in the (b) <2.fifth percentile, (c) >97.fifth percentile, (d) <fifth percentile, and (east) >95th percentile compared with interquartile range (betwixt 25th and 75th percentiles) depicted as issue estimate (dot) with 95% CI per cohort and overall equally estimated past random effects meta-analysis (diamond). The I 2 for each model was as follows: for FT4 <2.5th percentile, I 2 = seven.iv%; for FT4 >97.5th percentile, I 2 = 0.0%; for FT4 <5th percentile, I 2 = 0.0%; for FT4 >95th percentile, I 2 = 0.0%.
Figure iv.
Clan of maternal FT4 during early pregnancy with child autistic traits within the clinical range. Association shown as (a) a continuous association depicted every bit the mean risk of kid autistic traits inside the clinical range (black line) with 95% confidence interval (gray area) and by accomplice-specific maternal FT4 concentrations in the (b) <2.5th percentile, (c) >97.5th percentile, (d) <5th percentile, and (east) >95th percentile compared with interquartile range (betwixt 25th and 75th percentiles) depicted equally effect estimate (dot) with 95% CI per cohort and overall every bit estimated by random effects meta-analysis (diamond). The I 2 for each model was as follows: for FT4 <2.5th percentile, I ii = seven.4%; for FT4 >97.5th percentile, I ii = 0.0%; for FT4 <5th percentile, I two = 0.0%; for FT4 >95th percentile, I 2 = 0.0%.
Clinical illness entities
Highly like results were obtained when FT4 and TSH were combined into clinical disease entities. Hypothyroxinemia, based on the 2.5th and 97.5th population-based percentiles, was associated with a 3.8-signal (95% CI, −five.seven to −2.0; P < 0.001) lower nonverbal IQ and a ii.eight-indicate (95% CI, −iv.eight to −0.vii; P = 0.007) lower verbal IQ ( Supplemental Fig. 4) merely was non associated with autistic traits. For hypothyroxinemia, based on the fifth and 95th population-based percentiles, similar results were establish with nonverbal and verbal IQ, with a 1.8-fold (95% CI, 1.ane to 2.8; P = 0.011) greater hazard was found with autistic traits ( Supplemental Fig. 4), which remained afterwards adjusting for nonverbal IQ (data not shown).
Subclinical hypothyroidism, based on the 2.5th and 97.5th population-based percentiles, was associated with a 1.9-signal (95% CI, 0.1 to 3.6; P = 0.037) greater nonverbal IQ but not with exact IQ or autistic traits ( Supplemental Fig. 5). When defining subclinical hypothyroidism using the fifth and 95th population-based percentiles, the association with nonverbal IQ became statistically non-significant (ane.3 points; 95% CI, −0.2 to ii.9; P = 0.096). Subclinical hyperthyroidism was non associated with nonverbal IQ, verbal IQ, or autistic traits ( Supplemental Fig. six).
Discussion
To the best of our knowledge, the present study is the first individual participant data meta-analysis. We take demonstrated that low maternal FT4 in early pregnancy is associated with lower nonverbal and verbal child IQs. We also plant a suggestive association between maternal hypothyroxinemia and loftier FT4 with a greater take chances of autistic traits inside the clinical range. In contrast to FT4, maternal TSH was not independently associated with nonverbal IQ, verbal IQ, or autistic traits within the clinical range.
The clan betwixt depression maternal FT4 and child IQ, specifically nonverbal IQ, was highly similar among the three cohorts, convincingly replicating the results of previous observational studies (four–9). A contempo randomized controlled trial studied the effects of levothyroxine handling for women with subclinical hypothyroidism or hypothyroxinemia on child full IQ (21). Although levothyroxine treatment of hypothyroxinemia or subclinical hypothyroidism started in mid-pregnancy (weeks 16 to 18), a statistically nonsignificant 1.3 points greater median child IQ was institute after levothyroxine handling compared with placebo. The associations of hypothyroxinemia with a 3.8- and ii.8-signal lower nonverbal and verbal IQ, respectively, found in our study compared with euthyroid women might seem pocket-size on an individual level. Yet, on a population level, this might have effects on educational achievements and capita per income, among others (41).
The consequent association of low maternal FT4 with agin child neurocognitive outcomes, specifically lower nonverbal IQ in three contained cohorts, is particularly relevant given that all three cohorts used a different immunoassay to measure FT4. The value of an FT4 measurement during pregnancy has been under debate, because the absolute values of FT4 might have been under- or overestimated when measured using immunoassays in pregnancy, especially in the third trimester (42–44). Yet, these results suggest that FT4 is a reliable clinical marker of the fetal thyroid state in early pregnancy, a catamenia when maternal FT4 is the sole source of thyroid hormones for the fetus and influences the developmental processes, including proliferation, migration, and differentiation of neuronal cells in various parts of the brain (45). No conclusions about the use of FT4 assays during the later stages of pregnancy, when the fetal thyroid is fully functional, should be drawn from these data.
In our study, the result estimates for nonverbal IQ were larger than for those for verbal IQ. Nonverbal IQ is a language- and culture-free measure of cognitive ability that is less dependent on the learning stimulus received by the kid during the commencement years of life. Therefore, it might be a better neurodevelopmental outcome for detecting the furnishings of maternal exposures in early pregnancy, such as thyroid hormone levels.
Our results did not show an association between loftier maternal FT4 and nonverbal or exact IQ across the 3 cohorts, although we confirmed the previously reported association with the Generation R data (iv). The discrepancies in the clan of high FT4 and nonverbal IQ among the cohorts might have resulted from population differences such as maternal iodine status, which differed considerably among the cohorts. Significant women in Generation R had an adequate iodine status according to the World Wellness Organization [median urinary iodine concentration, 229.half-dozen μg/L (19)]. In contrast, mild to moderate iodine insufficiency was present in the INMA and ALSPAC cohorts [median, 94 to 168 μg/L depending on the region and 91.1 μg/L, respectively (46, 47)]. Although mild-to-moderate iodine deficiency has been associated with adverse neurodevelopmental outcomes, such as lower verbal IQ, worse language skills, reduced educational outcomes, impaired executive part, more beliefs bug, and worse fine motor skills, this was not found in iodine-deficient women in an iodine sufficient population (19, 48–l). Information technology is unclear how much of the clan of iodine deficiency with child neurocognitive outcomes tin can be attributed to impaired thyroid part in the mother or to impaired thyroid function in the fetus. Farther studies should elucidate the mediating part of maternal and fetal thyroid function in the association betwixt maternal iodine and child neurodevelopment.
To date, only ii studies take explored the clan between maternal thyroid function and ASD diagnosis or autistic traits. The Danish written report was based on registry linkage data and showed that maternal diagnosed or treated hypothyroidism was associated with a greater chance of diagnosed ASD (hazard ratio, 1.30; 95% CI, 1.eleven to 1.53) (51). The Dutch study from the Generation R cohort establish that severe hypothyroxinemia, divers as maternal FT4 fifth percentile or less with normal TSH, was associated with a greater adventure of autistic traits (9). In the present meta-analysis of data from Generation R, nosotros as well found an association between hypothyroxinemia using the FT4 fifth percentile or less cutoff and a greater risk of autistic traits. However, when using the FT4 ≤2.fifth percentile cutoff, no greater risk of autistic traits was found, suggesting the possibility of a adventure finding. Also, high FT4 was associated with a greater risk of autistic traits, although just when the more stringent cutoff was used (i.e., FT4 ≥97.5th percentile). Because the crucial part of thyroid hormones in key processes in the pathophysiology of ASD, including neuronal cell migration, synaptogenesis, synapse maintenance, neuronal activity, and fetal growth (52, 53), it is biologically plausible that nonoptimal levels of maternal FT4 during early pregnancy are related to a greater risk of ASD. However, the inconsistent results across cohorts or cutoffs express us from cartoon business firm conclusions regarding this potential association. Further studies focusing on autistic traits or ASD diagnosis are therefore needed to replicate and better empathize the full extent of these results.
TSH is frequently used equally a mark of thyroid status during pregnancy. Subclinical hypothyroidism has been associated with a greater take a chance of miscarriage and preterm delivery, and the beneficial furnishings of levothyroxine treatment for hypothyroid women have been shown in some trials, especially in TPOAb-positive women (54–57). Therefore, the current international guidelines recommend screening for TSH offset, either directly in combination with determining TPOAb condition (27) or determining TPOAb status and FT4 but when TSH is elevated (58). The results from the present study telephone call into question the use of TSH as the only first-line parameter to screen maternal thyroid status in early on pregnancy. First, elevated human chorionic gonadotropin concentrations stimulate the thyroid straight to produce thyroid hormone, which induces a decrease in TSH in early pregnancy (59). Therefore, TSH might not be the best marker for maternal thyroid status in this catamenia. Second, in our study, maternal TSH was not independently associated with nonverbal IQ, exact IQ, or autistic traits, in contrast to FT4. Notwithstanding, owing to the absenteeism of available randomized trials demonstrating the benefit of levothyroxine handling for maternal hypothyroxinemia, screening for FT4 cannot exist advocated.
One forcefulness of the present written report was that we investigated the association of maternal thyroid office with kid neurodevelopmental outcomes in a prospective mode using a big data set with detailed information on nonverbal IQ, verbal IQ, and autistic traits, assessed using validated tools. Furthermore, by combining information from 3 different countries, nosotros were able to perform an external replication of previous studies and assess potential differences related to iodine condition, after adjusting for many potential confounding variables. We also used advanced statistical methods, including multiple imputation combined with inverse probability weighting, to reduce possible choice bias.
1 limitation of the nowadays written report was that the child neurodevelopmental outcomes were assessed with different tools at different ages. This might be, for instance, reflected in the different prevalence of children with autistic traits within the clinical range beyond cohorts. The varying occurrence might have resulted from the different ages at the cess and/or the dissimilar types of evaluator but almost likely resulted from the unlike gear up of questions for assessing autistic traits. For example, the Babyhood Asperger Syndrome Exam (Bandage) (33) contains 31 items and is therefore a more extensive questionnaire compared with the CBCL ane½-5, with 13 items (34), and the Social and Communication Disorders Checklist (SCDC), with 12 items (35). The Cast and CBCL one½-v cover questions on all three domains of ASD. In contract to the Bandage and CBCL 1½-5, the SCDC was designed to appraise deficits in social and communications skills but does not assess the ASD domain of restricted and repetitive behaviors and interests. To business relationship for the differences equally best as possible, we standardized all event scores and adapted all analyses for child age at the IQ or autistic traits ascertainment. Nosotros observed trivial heterogeneity among the cohorts. Another limitation was the depression prevalence children with autistic traits within the clinical range, which caused, especially in INMA, bug with statistical power. Furthermore, nosotros only had a single thyroid office measurement available from early pregnancy. Hence, the results should not be generalized to thyroid role in late pregnancy, and the potential effects of individual variations in maternal thyroid hormone availability could non be studied.
In decision, the results from the nowadays written report have confirmed that a depression FT4 is consistently associated with a lower kid IQ. We likewise found a suggestive association of maternal hypothyroxinemia and high FT4 with a greater risk of autistic traits inside the clinical range. FT4 seemed a reliably mark of the fetal thyroid state in early pregnancy, regardless of the blazon of immunoassay used. Further studies should replicate the findings of autistic traits and investigate the potential modifying part of maternal iodine status.
Abbreviations:
-
ALSPAC
Avon Longitudinal Study of Parents and Children
-
ASD
-
Bandage
Babyhood Asperger Syndrome Examination
-
CBCL
Child Behavior Checklist for Toddlers
-
FT4
-
INMA
Infancia y Medio Ambiente (Environment and Childhood project)
-
SCDC
Social and Communication Disorders Checklist
-
TPOAb
thyroid peroxidase antibody
Abbreviations:
Acknowledgments
ALSPAC, United kingdom: Nosotros thank all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, reckoner and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. We also thank the participants of all cohorts for their generous collaboration; Professor Scott Nelson, University of Glasgow, Britain, for the ALSPAC thyroid measurements, which were funded by the Main Scientist Role, Scotland (ETM 97/0357/130024782); 1 M. Castilla of the Public Health Laboratory of Bilbao, Spain, for the thyroid measurements in INMA; and Professor Dr. Yolanda de Rijke, Section of Clinical Chemistry, Erasmus Medical Centre, Academy Medical Center, The netherlands, for the blueprint and measurements of the thyroid hormones in Generation R.
Fiscal Support : EUthyroid Projection: European union's Horizon 2020 research and innovation program (grant 634453). INMA, Kingdom of spain: This study was funded by grants from the Eu (grants FP7-ENV-2011 cod 282957 and Health.2010.2.4.5-i) and Espana: Instituto de Salud Carlos III (grants Red INMA G03/176, CB06/02/0041, FIS-FEDER: PI041436, PI05/1079, PI06/0867, PI081151, FIS- and PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288, Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051, MS13/00054), Generalitat Valenciana: FISABIO (grants UGP xv-230, UGP-fifteen-244, and UGP-15-249), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La Marató de TV3 (grants 090430), Department of Health of the Basque Government (grants 2005111093 and 2009111069), and the Provincial Government of Gipuzkoa (grants DFG06/004 and DFG08/001). Generation R, Kingdom of the netherlands: The Generation R Report was conducted past the Erasmus Medical Center in close collaboration with the Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam expanse, Rotterdam, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam. The Generation R Written report was supported by the Erasmus Medical Center, Rotterdam, the Erasmus University, Rotterdam, The netherlands Organization for Wellness Research and Evolution, The Netherlands Organization for Scientific Research, and the Ministry of Health, Welfare, and Sport. A grant from the Sophia Children'south Infirmary Inquiry Funds supported the neurodevelopmental work on the thyroid. R.P. Peeters is supported by a clinical fellowship from The Netherlands Organization for Health Research and Evolution (project no. 90700412). ALSPAC, United Kingdom: The UK Medical Research Council and Wellcome (grant 102215/two/thirteen/2) and the University of Bristol currently provide core back up for ALSPAC. The publication is the work of the authors and M. Guxens serves equally guarantor for the contents. Data collection was funded from a wide range of sources, every bit detailed in the ALSPAC website (bachelor at: www.bristol.ac.united kingdom of great britain and northern ireland/alspac/about/).
Author Contributions: D.L. performed the data analyses, interpreted the data, and was involved in writing the report. T.I.M.K. and A.D.-B. contributed to the data analyses, interpretation of the information, and writing of the written report. S.C.B., H.T., M.R., M.P.R., One thousand.M., M.East., M.D., J.M.I., and J.S. helped with the interpretation of the data and contributed to the writing of the study. R.P.P. and M.G. supervised the analyses, contributed to the writing of the report, and directed the project.
Disclosure Summary: The authors take nothing to disclose.
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Author notes
These authors contributed equally to this study.
Copyright © 2018 Endocrine Gild
Source: https://academic.oup.com/jcem/article/103/8/2967/4994588
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