MECHANISMS IN ENDOCRINOLOGY: Maternal thyroid dysfunction during pregnancy and behavioural and psychiatric disorders of children: a systematic review

in European Journal of Endocrinology
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  • 1 School of Public Health, University of Queensland, Brisbane, Australia
  • 2 College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
  • 3 Institute for Social Science Research, University of Queensland, Brisbane, Australia

Background

Maternal thyroid dysfunction during pregnancy may lead to persistent neurodevelopmental disorders in the offspring appearing in later life. This study aimed to review the available evidence concerning the relationship between maternal thyroid status during pregnancy and offspring behavioural and psychiatric disorders.

Methods

Systematic electronic database searches were conducted using PubMed, Embase, PsycNET, Scopus, Google Scholar and Cochrane library. Studies including gestational thyroid dysfunction as the exposure and offspring behavioural and psychiatric disorders as the outcome were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed and, after thorough screening by two independent reviewers, 13 articles remained eligible for inclusion in this study.

Results

Indicators of maternal thyroid dysfunction, including low and high thyroid hormone level and autoimmune thyroiditis, during early pregnancy, were found to be associated with several offspring behavioural and psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), autism, pervasive developmental problems, externalising behaviour, in addition to epilepsy and seizure. The majority of associations were found with low maternal thyroid hormone level.

Conclusion

Maternal thyroid function during pregnancy, particularly hypothyroidism, is associated with behavioural and psychiatric disorders in children. Further studies are needed with a capacity to adjust for a fuller range of confounding factors.

Abstract

Background

Maternal thyroid dysfunction during pregnancy may lead to persistent neurodevelopmental disorders in the offspring appearing in later life. This study aimed to review the available evidence concerning the relationship between maternal thyroid status during pregnancy and offspring behavioural and psychiatric disorders.

Methods

Systematic electronic database searches were conducted using PubMed, Embase, PsycNET, Scopus, Google Scholar and Cochrane library. Studies including gestational thyroid dysfunction as the exposure and offspring behavioural and psychiatric disorders as the outcome were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed and, after thorough screening by two independent reviewers, 13 articles remained eligible for inclusion in this study.

Results

Indicators of maternal thyroid dysfunction, including low and high thyroid hormone level and autoimmune thyroiditis, during early pregnancy, were found to be associated with several offspring behavioural and psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), autism, pervasive developmental problems, externalising behaviour, in addition to epilepsy and seizure. The majority of associations were found with low maternal thyroid hormone level.

Conclusion

Maternal thyroid function during pregnancy, particularly hypothyroidism, is associated with behavioural and psychiatric disorders in children. Further studies are needed with a capacity to adjust for a fuller range of confounding factors.

Introduction

A developing foetus is entirely dependent on maternal thyroid hormone in the first trimester of pregnancy, and although foetal production of thyroid hormone begins during the second trimester, the developing foetus remains partially reliant on maternally supplied thyroid hormone for the remainder of the pregnancy (1). Thyroid hormone disorders are contributors to the majority of maternal pregnancy-related complications and adverse pregnancy outcomes (2). Maternal hypothyroidism is strongly associated with preterm birth, low birth weight, reduced head circumference growth in infants and young children, placental abruption, cognitive delay and many other abnormal neurobehavioural problems of exposed offspring (3, 4, 5, 6, 7, 8). On the other hand, maternal hyperthyroidism is also found to be robustly associated with maternal and foetal adverse events, such as pre-eclampsia, miscarriage, stillbirth, preterm birth and intrauterine growth restriction (4).

Evidence suggest that disorders in maternal thyroid hormone during pregnancy may lead to offspring neurodevelopmental disorders, which become apparent later in life. In turn, the aforementioned adverse events during pregnancy can disrupt the function of the developing nervous system resulting in poor offspring neurodevelopment (9). Both animal and human studies have established that important phases of neocortex development can be altered by early maternal thyroid dysfunction and result in persistent negative consequences in offspring (10, 11, 12, 13). One of the mechanism by which thyroid hormones may influence brain development is via the regulation of the expression of brain-derived neurotrophic factor and Reln gen; Reln produces Reeln, essential for the proper migration and the establishment of neocortical layers (14).

A research finding reported that approximately one-fourth of youth experience mental health disorder for the last 1 year and one-third experience a lifetime disorder (15). Although no single factor during intrauterine development leads to psychiatric disorders in children, maternal thyroid hormone plays a major role in foetal brain development and is therefore implicated in the development of a range of offspring behavioural and psychiatric problems (16). This is supported by several research findings suggesting associations between early pregnancy thyroid disorders and cognitive development of offspring (6, 17, 18, 19, 20, 21, 22, 23, 24). There are however fewer studies investigating the potential relationship between maternal thyroid disorders during pregnancy and behavioural and psychiatric disorders in offspring at different ages, and no systematic reviews on the subject. The aims of this review were to summarise and identify the impact of maternal thyroid status during pregnancy on offspring behavioural and mental health outcomes.

Methods

Searching strategy

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed for this systematic review (25). A systematic literature search of PubMed, EMBASE, Cochrane, PsycINFO, Scopus and Google Scholar were conducted using keywords (Fig. 1). We also searched references and citations from resulting studies to identify potential additional papers. The search was limited to studies published in the English language since 1996. The following search terms were used in different combinations and Boolean operators: thyroid*, thyroid, ‘maternal thyroid function’, ‘maternal thyroid dysfunction’, ‘maternal thyroid hormone’, hypothyroidism, hyperthyroidism, hypothyroxinemia, hyperthyroxinemia, pregnan*, gestation*, ‘behavioral development’, ‘behavioural development’, behavio*, neurological, neurodevelopment, mental disorder, mental illness, attention deficit, depression, anxiety, cogniti*, IQ, psychopathology, child, child*, adolescent and offspring. Duplicates were removed. Titles, abstracts and the content of the articles were screened to determine the suitability for inclusion.

Figure 1
Figure 1

Flow diagram showing the number of articles sourced at each stage of the systematic review.

Citation: European Journal of Endocrinology 177, 5; 10.1530/EJE-16-0860

Study selection

Studies were assessed for eligibility according to the inclusion criteria. These criteria included studies with paired study participants of mothers and their offspring, maternal thyroid status determined during all stages of pregnancy, child behavioural and/or psychiatric disorders measured, and both retrospective and prospective cohort studies. Appropriateness of statistical analysis was also assessed, studies with only descriptive analysis being excluded. Animal studies, conference papers and studies that did not fulfil the inclusion criteria were excluded. A total of 13 articles were eligible (Fig. 1).

Data extraction

The title and abstracts of articles yielded from the electro­nic search were carefully screened. Two authors (D F and K B) extracted information independently from each study using the data extraction form and discrepancies were resolved by consensus. Information extracted included characteristics of participants, sample size, study design, study country, maternal thyroid status, child outcomes with behavioural and psychiatric disorders measured and outcome ascertainment, presence of statistical associations and potential confounders included in each study.

Study analysis

We undertook a narrative analysis of the included studies. Meta-analysis was not conducted due to heterogeneity of the exposure and outcome variables. Methodological quality of each study was assessed with points attributed for representative sampling, validated exposure and outcome measures, appropriate control of potential confounders and overall quality.

Results

After removing duplicates, 5305 records were identified by the electronic database searches. Based on the title screening, 850 records were eligible for abstract screening, of which 60 articles met the criteria for full article review. Following thorough review of the articles, 13 (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38) remained eligible (Fig. 1). All eligible studies were conducted in European countries with the exception of two studies from the USA. All studies were based on (a) population-based prospective birth cohort studies and (b) national register-based retrospective studies. Sample sizes ranged from 287 to 1 699 693, with the large samples derived from registry studies. One study was based on very few participants (16 cases, 11 controls). Exposure variables included hypothyroidism, subclinical hypothyroidism, mild and severe hypothyroxinaemia, subclinical hyperthyroidism, hyperthyroidism, thyroid-stimulating hormone (TSH), free thyroxine (fT4) and thyroperoxidase antibodies positive (TPO-Abs+) or autoimmune thyroiditis. Study outcomes included ADHD, autism, internalising and externalising behaviours, schizophrenia, oppositional defiant problems, as well as epilepsy and seizure disorders.

As shown in (Table 1), maternal thyroid status was measured during the first trimester and early second trimester in six studies (26, 27, 28, 29, 34, 35, 38); in one study it was measured during late second trimester (32) and in four studies timing was not reported (30, 31, 33, 36). Offspring outcomes were measured between 3 and 8 years of age in most studies (26, 27, 29, 31, 32, 33, 34, 35), except for some studies where outcomes were measured in young adulthood (28, 36) and from age 15 through to 31 years (30).

Table 1

Characteristics of studies with maternal thyroid dysfunction exposure and offspring’s behavioural and psychiatric disorders.

Study year, referenceCountryStudy designParticipantsMaternal thyroid statusChild OutcomeChild outcomes ascertainmentAssociation between maternal thyroid status and child outcome
2015, (26)NetherlandsPopulation-based birth cohortHypothyroxinaemiaADHDConners’ Parent Rating Scale–Revised Short Form (CPRS-R:S) reported by mothersβ = 0.07 (0.03, 0.14), P = 0.04
SCHβ = −0.01 (−0.07, 0.05), P = 0.80
HypothyroxinaemiaOppositional Scale Scoreβ = 0.02 (−0.04, 0.08), P = 0.49
2015, (27)FinlandNested case–control design (Birth cohort)HypothyroxinaemiaSchizophreniaDiagnosis from psychiatric hospital admissions and psychiatric outpatient treatment based on ICD-10 F20 and ICD-10 F25OR = 1.7 (1.13, 2.55), P = 0.010
HypothyroidismOR = 0.86 (0.23, 3.24), P = 0.827SCHOR = 0.80 (0.47, 1.37), P = 0.424
HyperthyroidismOR = 0.87 (0.41, 1.82), P = 0.706Subclinical hyperthyroidismOR = 1.91 (1.14, 3.20), P = 0.014
2015, (28)FinlandNested case–control design (Birth cohort)TPO-Ab+AutismDiagnosis from psychiatric hospital admissions and outpatient visits of childhood autism (ICD-10F84.0)OR = 1.78 (1.16, 2.75), P = 0.009
HypothyroidismOR = 0.67 (0.27, 1.63), P = 0.37SCHOR = 1.17 (0.72, 1.90), P = 0.54
HyperthyroidismOR = 1.06 (0.54, 2.10), P = 0.86Subclinical hyperthyroidismOR = 1.10 (0.67, 1.83), P = 0.71
2014, (29)FinlandPopulation-based birth cohortHypothyroxinaemiaInattention (boys)Teachers evaluated the children’s ADHD symptoms at 8 years using the Rutter B2 scaleOR = 0.75 (0.33, 1.69)
Inattention (girls)OR = 0.66 (0.15, 2.83)
Hyperactivity (boys)OR = 0.69 (0.31, 1.56)
Hyperactivity (girls)OR = 1.07 (0.31, 3.65)
Combined ADHD (boys)OR = 0.61 (0.18, 2.03)
Combined ADHD (girls)NA
High TSHInattention (boys)OR = 0.76 (0.51, 1.12)
Inattention (girls)OR = 1.14 (0.66, 1.97)
Hyperactivity (boys)OR = 1.07 (0.75, 1.52)
Hyperactivity (girls)OR = 1.20 (0.70, 2.03)
Combined ADHD (boys)OR = 0.89 (0.52, 1.50)
Combined ADHD (girls)OR = 1.69 (0.79, 3.56)
2014a, (30)DenmarkCohort (register) studyHypothyroidism (1977–1995 group)AnxiolyticsDrug prescription registers and psychiatric diagnoses based on ICD-8: 295.0–301.9 and ICD-10: F20.0–F48.9HR = 1.23(1.03, 1.48)
AntipsychoticsHR = 1.22(1.03, 1.44)
AntidepressantsHR = 1.07 (0.98, 1.17)
Hypothyroidism (1996–2005 group)
AnxiolyticsHR = 0.96 (0.84, 1.10)
AntipsychoticsHR = 1.04 (0.92, 1.17)
AntidepressantsHR = 1.00 (0.95, 1.06)
2014b, (31)DenmarkCohort (register) studyHypothyroidismADHDDiagnosed at hospital based on F90 (ICD–10)HR = 1.10 (0.98, 1.25)
HyperthyroidismHR = 1.18 (1.03, 1.36)
HypothyroidismAutism spectrum disorder (ASD)Diagnosed at hospital based on F84 (ICD–10)HR = 1.30 (1.11, 1.53)
HyperthyroidismHR = 1.18 (0.96, 1.45)
2013, (33)DenmarkCohort (register) studyHypothyroidismEpilepsyRegisters diagnosed based on ICD-8 and ICD-10HR = 1.22 (1.06, 1.40), P = 0.005
HyperthyroidismHR = 1.20 (1.09, 1.32), P < 0.001
HypothyroidismSeizureHR = 1.20 (1.11, 1.30), P < 0.001
HyperthyroidismHR = 1.08 (1.02, 1.15), P = 0.009
HypothyroidismNeonatal seizureHR = 1.78 (1.30, 2.44), P < 0.001
HyperthyroidismHR = 1.22 (0.92, 1.62), P = 0.161
HypothyroidismFebrile seizureHR = 1.21 (1.10, 1.32), P<0.001
HyperthyroidismHR = 1.03 (0.95, 1.11), P = 0.464
2013, (32)NetherlandsCohort studyMild hypothyroxinaemiaAUTISTIC SYMPTOMSPervasive developmental problems (PDP)Parent-reported using 2 instruments: the PDP subscale of the CBCL for toddlers (CBCL 1.5–5) and the SRSOR = 1.41 (0.78, 2.57), P = 0.26
Severe hypothyroxinaemiaOR = 2.60 (1.30, 5.18), P = 0.01
TPO-Abs+OR = 0.78 (0.28, 2.16), P = 0.63
Mild hypothyroxinaemiaSocial responsiveness scale (SRS)β = 0.02 (−0.01, 0.04), P = 0.33
Severe hypothyroxinaemiaβ = 0.05 (0.01, 0.10), P = 0.01TPO-Abs+β = 0.03 (−0.01, 0.06), P = 0.11
2012, (34)NetherlandsCohort studyTPO-Abs+
Internalising problems
CBCL 1.5–5 reported by parentsOR = 1.21 (0.84, 1.74), P = 0.31
Affective problemsOR = 1.02 (0.63, 1.65), P = 0.95
Anxiety problemsOR = 1.27 (0.81, 2.00), P = 0.29
Externalising problemsOR = 1.64(1.17, 2.29), P = 0.004
ADHD problemsOR = 1.77(1.15, 2.72), P = 0.01
Oppositional deviant problemsOR = 1.39 (0.95, 2.03), P = 0.09
2011, (35)NetherlandsCohort studyHypothyroxinaemiaInternalisingCBCL 1.5–5 reported by parentsβ = −0.19 (−0.75, 0.37), P = 0.51
Externalisingβ = −0.17 (−0.53, 0.87), P = 0.64
TSHInternalisingβ = 0.10 (−0.01, 0.21), P = 0.07
Externalisingβ = 0.22 (0.04, 0.40), P = 0.02
ADHDβ = 0.08(0.01, 0.15), P = 0.05
Oppositional defiantβ = 0.08(0.02, 0.14), P = 0.01
fT4Internalisingβ = 0.01 (−0.13, 0.15), P = 0.91
Externalisingβ = −0.02 (−0.16, 0.20), P = 0.80
Total T4Internalisingβ = 0.09 (−0.04, 0.22), P = 0.19
Externalisingβ = 0.12 (−0.06, 0.30), P = 0.19
2011, (36)USACohort studyTSHADHDCBCL 1.5–5 reported by mothersβ = −0.65(−1.26, −0.04)
fT4β = −0.10 (−2.03, 1.82)
Total T4β = 0.00 (−0.28, 0.27)
2004, (38)ItalyProspective follow-upHypothyroxinaemiaADHD(DSM-IV-TR)χ2, 2.34; P = 0.001
1999, (37)USACohort studyHypothyroidismAttention (Children of women with hypothyroidism)Attention (Children of treated women with hypothyroidism) Attention (Children of untreated women with hypothyroidism)Performance Test by certified psychologistsP = 0.08

P = 0.01

P = 0.80

P = 0.01

P = 0.03

P = 0.04

fT4, free thyroxine; GA, gestational age; ICD, International Classification of Diseases; SCH, subclinical hypothyroidism; TSH, thyroid-stimulating hormone; TPO-Abs+, thyroperoxidase antibodies positive; CBCL, Child behaviour checklist; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition- Text Revision.

Overall, the included studies reported associations between maternal hypothyroxinaemia during early pregnancy and several behavioural and psychiatric disorders. Both high and low levels of maternal thyroid hormones were associated with ADHD, schizophrenia, epilepsy and seizure. Maternal TPO-Abs+ and high TSH concentration were found to be associated with externalising behaviour of children aged 3 whereas none of the studies found an association with internalising behaviour. These associations are described in more detail in the following sub-sections.

Attention deficit hyperactivity disorder

Of 13 studies included in this review, seven studies investigated the association between maternal thyroid dysfunction and offspring ADHD or ADHD symptoms. Andersen et al. (31) found a correlation between maternal hyperthyroidism and offspring ADHD at age 3 using a large register-based cohort, adjusted for covariates. The study sampled 857 014 mother–child pairs, singletons only. The gestational age at which the thyroid function measured was not reported by authors.

Ghassabian et al. (35) also reported an association between maternal autoimmune thyroiditis, at mean gestational age of 13.5 (s.d. = 1.8) weeks, and increased risk of offspring ADHD problems (OR = 1.77 (1.15, 2.72)) at age 3 (n = 3139 mother–child pairs). Another study by Ghassabian et al. (29), among similar age group of children, also found an association between high TSH concentration during pregnancy, at mean gestational age of 13.3 (s.d. = 1.7) weeks, and offspring ADHD (n = 3736 mother–child pairs). In both studies, the authors adjusted for some of the potential confounders.

In a population-based birth cohort study of 3873 mother–child pairs Modesto et al. found that offspring born from hypothyroxinaemic mothers, at mean gestational age of 13.6 (s.d. = 1.9) weeks, were found to be at increased risk of ADHD at age 8 (β = 0.07 (0.03, 0.14)). The study was adjusted for a large number of potential confounders including maternal and child socio-demographic characteristics and maternal mental health during pregnancy (27). Similarly, a study by Haddow et al. (37) found association between maternal hypothyroidism and offspring attention at age 7–9 with Conners’ Continuous Performance Test (CCPT). However, the authors did not adjust for confounders that might play a role in the association. Vermiglio et al. (38) also demonstrated that ADHD prevalence was significantly higher in children aged 8–10 years born from hypothyroxinaemic mothers in iodine-deficient area. However, this study was unadjusted for confounders and a very low number of cases (16 ADHD cases from iodine-deficient area and 11 age-matched controls from iodine-sufficient area).

On contrary, a study also found that abnormal levels of thyroid hormone were positively associated with child outcomes. Chevrier et al. (32) found an association (β = −0.65 (−1.26, −0.04)) between increasing maternal TSH concentration at mean gestational age of 26.9 (s.d. = 3.4) weeks, and reduced risk of ADHD at the age of 5 years in the offspring (n = 287 mother–child pairs). This study also adjusted for potential confounders such as maternal age, income, delivery complications and a 5-minute Apgar score. A further study (34) found no overall association, but an increased risk of ADHD problems (OR = 1.39 (1.07–1.80)) among only female offspring born from mothers with higher TSH concentrations.

Most of the studies exhibited strong methodologies and were sufficiently powered, with capacity to adjust for potential confounders (n = 3189 to 857 014). Across these studies, ADHD was assessed using different instruments, including the Conners’ Parent Rating Scale–Revised Short Form reported by mothers (27), teachers evaluation using Rutter Scale B2 (34), and Child Behaviour Checklist (CBCL) reported by parents (29, 32, 35), although one study used hospital diagnosis and dispensed prescriptions of medications as indicators of ADHD which is more reliable given that appropriate recording and data extraction are applied (31).

Autism

Three studies investigated the relationship between autism problems and maternal thyroid function with all reporting a statistically significant association. Using a cohort study of 4039 mother–child pairs, Roman et al. (26) found a positive association (OR = 2.6 (1.30, 5.18)) between maternal severe hypothyroxinaemia, at mean gestational age of 13.4 (s.d. = 1.9) weeks, and autism problems in offspring at age 6. The authors have adjusted the model for a wide range of potential confounders, including demographics, socio-economic position, lifestyle factors and mental health status, which were not comprehensively controlled in other studies (Table 2). In support of this, Andersen et al. (31) have also reported the increased risk of autism spectrum disorder of the offspring at age 3 with maternal hypothyroidism during pregnancy (HR = 1.30 (1.11, 1.53)). Importantly, this study failed to adjust for some important confounding variables such as antenatal maternal psychopathology and birth weight. Further, Brown et al. (36) examined the relationship between maternal autoimmune thyroiditis during pregnancy and offspring autism among 960 case–control pairs, and they have confirmed a positive association (OR = 1.78 (1.16, 2.75)). The authors did not adjust the model as no covariate was associated with the outcome in univariate analyses.

Table 2

Confounders and covariates adjusted in the association between maternal thyroid function and offspring’s behavioural and psychiatric disorder.

MaternalOffspring
Study year, referencePaternal ageAgePsychopathologySmokingBMIMarital statusIncomeEducational levelParityGenderGAApgar scoreBirthweightNo. of siblings
2015, (26)
2015, (27)
2015, (28)
2014, (29)
2014a, (30)
2014b, (31)
2013, (33)
2013, (32)
2012, (34)
2011, (35)
2011, (36)
2004, (38)
1999, (37)

Both Brown et al. (36) and Anderson et al. (31) identified cases of autism based on hospital-based clinical diagnosis whereas Roman et al. (26) used validated parent-reported instruments of the CBCL for toddlers (CBCL 1.5–5) and the Social Responsiveness Scale (SRS) (39). In some of these studies, hyperthyroidism was not associated with offspring autism as reported by Brown et al. and Anderson et al. (31, 36). Further studies are warranted to give a conclusive statement on whether hyperfunctioning of thyroid gland is not linked with autism.

Internalising and externalising behaviour

Only two studies tested the relationship between offspring internalising and externalising behaviour and maternal thyroid dysfunction. In a study of 3139 mother–child pairs (35), the odds of offspring externalising behaviour at age 3 were higher among children exposed to maternal prenatal autoimmune thyroiditis (OR = 1.64 (1.17, 2.29)) at mean gestational age of 13.5 (s.d. = 1.8) weeks compared with those who were not. High maternal TSH concentration, at mean gestational age of 13.3 (s.d. = 1.7) weeks (β = 0.22 (0.04, 0.40)), were also associated with increased offspring externalising behaviour at ages 1.5 and 3 years, whereas no associations were found with internalising behaviour (29). In both studies, the CBCL was used to obtain a standardised rating of the child’s problem behaviour by parents. Both studies also adjusted for potential confounders but maternal psychopathology and smoking status were not universally controlled for.

Oppositional defiant problems

Three studies investigated relationships between maternal thyroid hormone ascertained in the first trimester and early second trimester with offspring oppositional defiant disorder measured at ages 3 and 8. Of these three studies, only one found a positive association (β = 0.08 (0.02, 0.14)) (29); the other two found no apparent associations between hypothyroxinaemia and autoimmune thyroiditis and offspring’s oppositional defiant problems at ages 3 and 8, respectively (27, 35).

Offspring oppositional defiant problems were measured using parental reports from the CBCL (1.5–5) in two studies (29, 35) and maternal reports of the CPRS-R:S (27). Parental reports are somehow problematic when assessing child’s behaviour. It has been argued that parents often score their children as less affected in the domains of social deficits and communication and more affected on restricted interests and stereotypies than clinicians. Hence, future research using both clinician observation and parent interview is warranted to increase the reliability and validity of the diagnosis (40).

Schizophrenia

There is scant evidence on the relationship between maternal thyroid dysfunction and mental health problems in offspring. Only one study investigated the association of maternal thyroid dysfunction and schizophrenia in the offspring, finding increased odds of schizophrenia in offspring of mothers who experienced hypothyroxinaemia (OR = 1.7 (1.13, 2.55)) and subclinical hyperthyroidism (OR = 1.91 (1.14, 3.20)) during pregnancy (28). The study comprised of 1010 case–control pairs for fT4 investigation at a mean gestational age of 11 (s.d. = 4) weeks, and 948 case–control pairs for TSH investigation at a mean gestational age of 10.8 (s.d. = 4.1) weeks. Offspring included in the assessment ranged from childhood up to 26 years. The association remained after adjustment for maternal psychiatric history and maternal smoking during pregnancy. Interestingly, preterm birth was found to be a mediator in this relationship reducing the risk by 28% (28), strengthening suggestions that associations may be mediated via adverse obstetric outcomes.

Other outcomes

A national register study by Andersen et al. (30) identified an association between maternal hypothyroidism and medical prescription of anxiolytics and antipsychotics in adolescents and young adults ranging from age 15 to 31, in which the authors indicate higher risk of offspring anxiety and psychosis might be due to maternal hypothyroidism during pregnancy (n = 542 100). In a second study using the same study population but larger sample size (n = 1 699 693) (33), maternal hypothyroidism was also statistically associated with epilepsy, seizure, neonatal seizure and febrile seizure in the offspring ascertained from hospital records. Offspring febrile seizure and epilepsy were diagnosed at median age of 1.4 and 5.3 years respectively by ICD-8 and ICD-10. In addition to hypothyroidism, maternal hyperthyroidism was found to increase the risk of offspring epilepsy and seizure but not the risk to neonatal and febrile seizure. In both studies, the large sample size allowed for increased statistical power of the study. However, lifestyle factors such as smoking and alcohol use during pregnancy were not adjusted for, making it difficult to verify the independent effect of thyroid disease on child outcomes. Also, maternal thyroid diseases were hospital-based diagnosis that accounts for symptomatic cases only. As to asymptomatic cases, these would have been identified in prospective studies given the opportunity to screen for full thyroid parameter test.

Discussion

Evidence from a range of scientific disciplines suggests that perinatal and obstetric factors are determinants of offspring mental health in later life stages (1, 13, 41, 42, 43, 44, 45, 46, 47). In this review, which focused on behavioural and psychiatric disorders of offspring born from mothers with thyroid dysfunction during pregnancy, we found that maternal thyroid dysfunction was associated with offspring mental health problems not only in early childhood but also in late adolescence and adulthood. Further, both maternal hypothyroidism and hyperthyroidism were strongly linked with behavioural and psychiatric problems among offspring. These epidemiological findings are supported by numerous studies which have shown that both low and high maternal thyroxine levels impact foetal brain size and structure (12, 13).

ADHD is among the most common neurobehavioural disorders in children and can persist into adulthood (48), and was the most investigated outcome in our eligible studies. The combined evidence of these studies indicates that maternal thyroid dysfunction may be directly implicated in the development of ADHD. The majority found positive associations between early gestational thyroid malfunction and ADHD problems in offspring (27, 29, 31, 35, 37). All studies (27, 29, 35, 37) but the study by Andersen et al. (31) were prospective population-based cohort studies and also had sufficient sample size to achieve adequate power, with capacity to adjust for potential confounders showing strong methodologies. However, the study by Andersen et al. (31) is the only study that ascertained offspring ADHD based on F90 (ICD-10) clinical diagnosis. Of the remaining studies, Pakkila et al. (34) found only a weak association among girls born from mothers with increased concentrations of TSH in the first trimester. In this study, ADHD was diagnosed based on a teacher-evaluated questionnaire, whereas the majority of the other studies used clinically measured outcomes or parent-reported CBCL, perhaps accounting for the difference in findings. Finally, a counterintuitive relationship was found by Chevrier et al. (32), which showed an increased concentration of maternal TSH reduced the risk of offspring ADHD at age 5. However, in this study gestational thyroid hormone was analysed during late second trimester unlike the other studies, most of which were conducted during the first and early second trimester as recommended (49, 50). This discrepancy might indicate either a chance finding or alternatively that early and not late pregnancy is a sensitive period in which thyroid hormone level is a determinant of childhood ADHD problems. Variation in the ages at which the behavioural and psychiatric disorders were assessed in children may account for some variations in the findings. Our review did not show age-patterned differences. However, it is important to bear in mind that thyroid hormone insufficiency in early life may alter neuronal plasticity including permanent modifications of synaptic plasticity in adult life through epigenetic modifications of genes involved (51). The obvious heterogeneity among the relatively small number of studies, particularly concerning heterogeneity of the exposure, precluded a meta-analysis capable of producing an estimate of the hypothesised association. However, the evidence currently available indicated an increased risk of ADHD in offspring of mothers with abnormal thyroid levels during early pregnancy, and we encourage further research in this area.

Studies included also suggested that children born of mothers with low levels of thyroxine during pregnancy were at an increased risk of autism (26, 31). Similarly, an increased risk of autism was found in offspring of mothers who had autoimmune thyroiditis during pregnancy (36); however, it was not clear whether the effect took place after birth due to the already transferred placental antibodies or during intrauterine growth. Diagnosis of autism was made by using ICD-10 clinical diagnosis in both studies by Brown et al. (36) and Anderson et al. (31) while Roman et al. (26) used validated parent-reported instruments (CBCL 1.5–5 and SRS) (39). The additional strength of the study by Brown et al. (36) is the use of matched controls and the ability to examine a wide range of offspring up to age 20. A study by Roman et al. also suggested that low maternal T4 plus inactivation of brain deiodinases lowered tissue levels of triiodothyronine (T3) resulting in abnormal neuronal migration. This neuropathological anomaly was suggested to be mediated via reelin dysregulation that is known to occur in the brains of subjects with autism (52). Berbel et al. (53) have reported that some of the T3-regulated genes at the transcriptional level are involved in corticogenesis. Many of these genes have been found to be altered in ASD, ADHD, schizophrenia and anxiety cases. Therefore, thyroid hormone imbalance at critical periods might cause permanent neurodevelopmental changes leading to these neurologic disorders. Hyperthyroidism on the other hand showed no relationship with child autism problems and more studies are needed to investigate if there indeed is no relationship.

Maternal autoimmune thyroiditis (35) and high maternal TSH concentrations (29) were found to increase the odds of offspring externalising behaviour and oppositional defiant disorders but not internalising behaviour. Such findings are in line with expectations, as being a determinant element in foetal brain development thyroid hormone deficiency may be more likely implicated in neurobehavioural disorders. Studies have found that thinner brain cortex is strongly related with externalising behaviours in children, suggesting prenatal thyroid hormone deficiency, known to negatively impact foetal brain development, may increase the risk of externalising behaviours via this mechanism (54, 55). The consistent finding in these studies may increase once inference that maternal thyroid dysfunction during pregnancy has impact on offspring externalising behaviour but not on internalising behaviour. However, both of these limited studies were from the same cohort study, used the same instrument to ascertain the cases (CBCL 1.5–5) and included similar offspring age groups. Hence, further researches are needed before we conclude on the specificity of prenatal thyroid regulation to externalising and not internalising behaviour problems among offspring.

The relationship between maternal thyroid dysfunction and schizophrenia was only investigated by one study, Gyllenberg et al. (28), which found almost double risk of schizophrenia in offspring born of mothers with hypothyroxinaemia and subclinical hyperthyroidism during pregnancy. This could be explained by the fact that reductions in circulating thyroid hormone concentrations mediate impaired neurological development. The authors also confirmed that the relationship between maternal hypothyroxinaemia and schizophrenia was mediated by preterm birth indicating that adverse birth outcomes could play a major role in the relationship. Though Gyllenberg et al. examined prospectively matched case–controls and included adults of up to age 26, further studies are needed.

A study by Andersen et al. revealed an association between hypothyroidism during pregnancy and anxiety, affective disorders, psychosis, epilepsy, seizure, neonatal seizure and febrile seizure among offspring (30, 33). These disorders may have resulted due to structural and functional abnormalities associated with altered prenatal maternal thyroid exposure (8). Animal studies have demonstrated that progeny exposed to altered prenatal thyroid showed aberrations in cell migration coupled with subtle changes in the cytoarchitectonic structure, increasing the risk of impaired brain function (10, 56). This is in agreement with the above study findings where lower concentrations of maternal thyroxine hormone were highly related with these neurological disorders in offspring. Further prospective cohort studies are still needed to identify the stages of pregnancy most predictive of offspring neurological disorders.

To the best of our knowledge, this is the first systematic review to examine the association between maternal gestational thyroid dysfunction and offspring’s behavioural and psychiatric outcomes. Thyroid function assessment is challenging due to the dramatic variation occurring across the pregnancy, and the variance in assessment of thyroid functioning along with variations in outcomes made meta-analysis impossible.

Although most of the articles reviewed are of a good quality, none of the articles considered offspring’s thyroid status at the time of behavioural and psychiatric outcomes measured. Offspring thyroid status may be an important confounder variable and also suggested that maternal thyroid hormone level is related with offspring’s thyroid function (57). Studies accounting for both maternal and offspring thyroid functions are needed to confirm the independent effect of maternal thyroid hormone during pregnancy. In addition, maternal alcohol use, smoking and substance use during pregnancy were not universally included across the studies, which may have confounded the associations of interest. These factors have been found to increase the risk of thyroid hormone imbalance during pregnancy, consequently affecting the pregnancy outcome (58, 59, 60, 61). Evidence also suggests that exposure to maternal tobacco, cannabis and alcohol use during pregnancy may lead to detrimental neurologic effects on the offspring (62). Moreover, the majority of the studies did not adjust for pregnancy-related complications and birth outcomes such as hypertensive disorders of pregnancy, birth weight and gestational age at birth, nor explore the potential of these factors to play an intermediary role. In addition, there is no information, except for a handful of well-controlled studies, on the possible influence of maternal comorbidities, in the association between maternal thyroid dysfunction and offspring neurobehavioural disorders. Only two studies (26, 27) had the capacity to include a wide variety of confounders in their analysis as shown in Table 2. Lastly, maternal and offspring’s iodine and zinc intake should be accounted for in any future research, as brain function may be impaired due to transient or long-term deficiencies of these elements and of course iodine is a precursor for thyroid hormone synthesis (60). Likewise, selenium is also important for thyroid health. It is essential in the metabolism of thyroid hormone which removes the thyroid-harming substances (63). Thus selenium deficiency alone or in combination with iodine deficiency in pregnant women may lead to impairments in the developing foetal nervous system. Hence, in addition to iodine supplementation, the need for selenium supplementation during pregnancy should be explored more.

In conclusion, evidence presented in our review indicated that disorders in maternal thyroid hormone during pregnancy are risk factors for offspring ADHD and autism, and externalising behaviour problems and other related behavioural and psychiatric problems in childhood. Further studies are needed with the capacity to investigate the association with consideration of a fuller range of confounding factors.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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    Flow diagram showing the number of articles sourced at each stage of the systematic review.

  • 1

    Escobar GMD, Obregón MAJ, Rey FED. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Practice and Research Clinical Endocrinology and Metabolism 2004 18 225248. (doi:10.1016/j.beem.2004.03.012)

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  • 2

    Männistö T, Mendola P, Grewal J, Xie Y, Chen Z & Laughon SK. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. Journal of Clinical Endocrinology and Metabolism 2013 98 27252733. (doi:10.1210/jc.2012-4233)

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  • 3

    van Mil NH, Steegers-Theunissen RP, Bongers-Schokking JJ, El Marroun H, Ghassabian A, Hofman A, Jaddoe VW, Visser TJ, Verhulst FC & de Rijke YB Maternal hypothyroxinemia during pregnancy and growth of the fetal and infant head. Reproductive Sciences 2012 19 13151322. (doi:10.1177/1933719112450338)

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  • 4

    Stagnaro-Green A & Pearce E. Thyroid disorders in pregnancy. Nature Reviews Endocrinology 2012 8 650658. (doi:10.1038/nrendo.2012.171)

  • 5

    Pakkila F, Mannisto T, Hartikainen AL, Ruokonen A, Surcel HM, Bloigu A, Vaarasmaki M, Jarvelin MR, Moilanen I & Suvanto E. Maternal and child's thyroid function and child’s intellect and scholastic performance. Thyroid 2015 25 13631374. (doi:10.1089/thy.2015.0197)

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  • 6

    Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, De Muinck Keizer-Schrama SMPF, Hofman A & Jaddoe VVW Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. Journal of Clinical Endocrinology and Metabolism 2010 95 42274234. (doi:10.1210/jc.2010-0415)

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  • 7

    Ganaie MA, Charoo BA, Sofi RA, Ahmed A & Bhat JI. Maternal overt hypothyroidism and neurobehavioral outcome of neonates: a cohort study from an iodine-deficient area of Northern India. Indian Pediatrics 2015 52 864866. (doi:10.1007/s13312-015-0733-8)

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  • 8

    Chan S & Kilby MD. Thyroid hormone and central nervous system development. Journal of Endocrinology 2000 165 18. (doi:10.1677/joe.0.1650001)

  • 9

    Soleimani F, Zaheri F & Abdi F. Long-term neurodevelopmental outcomes after preterm birth. Iranian Red Crescent Medical Journal 2014 16 e17965. (doi:10.5812/ircmj.16711)

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  • 10

    Ausó E, Lavado-Autric R, Cuevas E, Del Rey Escobar F, Morreale De Escobar G & Berbel P. A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 2004 145 40374047. (doi:10.1210/en.2004-0274)

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  • 11

    Stenzel D & Huttner WB. Role of maternal thyroid hormones in the developing neocortex and during human evolution. Frontiers in Neuroanatomy 2013 7 19. (doi:10.3389/fnana.2013.00019)

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  • 12

    Stagnaro-Green A & Rovet J. Pregnancy: maternal thyroid function in pregnancy – a tale of two tails. Nature Reviews Endocrinology 2016 12 1011. (doi:10.1038/nrendo.2015.212)

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  • 13

    Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, Steegers EA, Visser TJ, White T & Tiemeier H Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinology 2016 4 3543. (doi:10.1016/S2213-8587(15)00327-7)

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  • 14

    Sui L, Ren W-W & Li B-M. Administration of thyroid hormone increases reelin and brain-derived neurotrophic factor expression in rat hippocampus in vivo. Brain Research 2010 1313 924. (doi:10.1016/j.brainres.2009.12.010)

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  • 15

    Merikangas KR, Nakamura EF & Kessler RC. Epidemiology of mental disorders in children and adolescents. Dialogues in Clinical Neuroscience 2009 11 720.

  • 16

    Andersen SL, Olsen J & Laurberg P. Foetal programming by maternal thyroid disease. Clinical Endocrinology 2015 83 751758. (doi:10.1111/cen.12744)

  • 17

    Ghassabian A, El Marroun H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC, Tiemeier H & White T. Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. Journal of Clinical Endocrinology and Metabolism 2014 99 23832390. (doi:10.1210/jc.2013-4281)

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  • 18

    Henrichs J, Ghassabian A, Peeters RP & Tiemeier H. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clinical Endocrinology 2013 79 152162. (doi:10.1111/cen.12227)

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  • 19

    Suarez-Rodriguez M, Azcona-San Julian C, Alzina de Aguilar V. Hypothyroxinemia during pregnancy: the effect on neurodevelopment in the child. International Journal of Developmental Neuroscience 2012 30 435438. (doi:10.1016/j.ijdevneu.2012.07.004)

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  • 20

    Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V & George LM Antenatal thyroid screening and childhood cognitive function. New England Journal of Medicine 2012 366 493501. (doi:10.1056/NEJMoa1106104)

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  • 21

    Downing S, Halpern L, Carswell J & Brown RS. Severe maternal hypothyroidism corrected prior to the third trimester is associated with normal cognitive outcome in the offspring. Thyroid 2012 22 625630. (doi:10.1089/thy.2011.0257)

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  • 22

    Behrooz HG, Tohidi M, Mehrabi Y, Behrooz EG, Tehranidoost M & Azizi F. Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid 2011 21 11431147. (doi:10.1089/thy.2011.0053)

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  • 23

    Klein RZ & Mitchell ML. Maternal hypothyroidism and cognitive development of the offspring. Current Opinion in Pediatrics 2002 14 443446. (doi:10.1097/00008480-200208000-00016)

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  • 24

    Liu H, Momotani N, Noh JY, Ishikawa N, Takebe K & Ito K. Maternal hypothyroidism during early pregnancy and intellectual development of the progeny. Archives of Internal Medicine 1994 154 785787. (doi:10.1001/archinte.1994.00420070109012)

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  • 25

    Moher D, Liberati A, Tetzlaff J & Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine 2009 151 264269. (doi:10.7326/0003-4819-151-4-200908180-00135)

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  • 26

    Roman GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VW, Hofman A, de Rijke YB, Verhulst FC & Tiemeier H. Association of gestational maternal hypothyroxinemia and increased autism risk. Annals of Neurology 2013 74 733742. (doi:10.1002/ana.23976)

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  • 27

    Modesto T, Tiemeier H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC & Ghassabian A. Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/hyperactivity disorder symptoms in children. JAMA Pediatrics 2015 169 838845. (doi:10.1001/jamapediatrics.2015.0498)

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  • 28

    Gyllenberg D, Sourander A, Surcel HM, Hinkka-Yli-Salomaki S, McKeague IW & Brown AS. Hypothyroxinemia during gestation and offspring schizophrenia in a national birth cohort. Biological Psychiatry 2015 79 962970. (doi:10.1016/j.biopsych.2015.06.014)

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  • 29

    Ghassabian A, Bongers-Schokking JJ, Henrichs J, Jaddoe VW, Visser TJ, Visser W, de Muinck Keizer-Schrama SM, Hooijkaas H, Steegers EA & Hofman A Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study. Pediatric Research 2011 69 454459. (doi:10.1203/PDR.0b013e3182125b0c)

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  • 30

    Andersen SL, Olsen J, Wu CS & Laurberg P. Psychiatric disease in late adolescence and young adulthood. Foetal programming by maternal hypothyroidism? Clinical Endocrinology 2014 81 126133. (doi:10.1111/cen.12415)

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  • 31

    Andersen SL, Laurberg P, Wu CS & Olsen J. Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study. BJOG 2014 121 13651374. (doi:10.1111/1471-0528.12681)

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  • 32

    Chevrier J, Harley KG, Kogut K, Holland N, Johnson C & Eskenazi B. Maternal thyroid function during the second half of pregnancy and child neurodevelopment at 6, 12, 24, and 60 months of age. Journal of Thyroid Research 2011 2011 426427. (doi:10.4061/2011/426427)

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  • 33

    Andersen SL, Laurberg P, Wu CS & Olsen J. Maternal thyroid dysfunction and risk of seizure in the child: a Danish nationwide cohort study. Journal of Pregnancy 2013 2013 636705. (doi:10.1155/2013/636705)

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  • 34

    Päkkilä F, Männistö T, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, Bloigu A, Vääräsmäki M, Järvelin MR & Moilanen I The impact of gestational thyroid hormone concentrations on ADHD symptoms of the child. Journal of Clinical Endocrinology and Metabolism 2014 99 E1E8. (doi:10.1210/jc.2013-2943)

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  • 35

    Ghassabian A, Bongers-Schokking JJ, De Rijke YB, Van Mil N, Jaddoe VWV, De Muinck Keizer-Schrama SMPF, Hooijkaas H, Hofman A, Visser W & Roman GC Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the generation R study. Thyroid 2012 22 178186. (doi:10.1089/thy.2011.0318)

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  • 36

    Brown AS, Surcel HM, Hinkka-Yli-Salomäki S, Cheslack-Postava K, Bao Y & Sourander A. Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2015 57 8692. (doi:10.1016/j.pnpbp.2014.10.010)

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  • 37

    Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ & Waisbren SE Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine 1999 341 549555. (doi:10.1056/NEJM199908193410801)

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  • 38

    Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G, Scaffidi G, Castagna MG, Mattina F, Violi MA & Crisa A Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. Journal of Clinical Endocrinology and Metabolism 2004 89 60546060. (doi:10.1210/jc.2004-0571)

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  • 39

    Muratori F, Narzisi A, Tancredi R, Cosenza A, Calugi S, Saviozzi I, Santocchi E & Calderoni S. The CBCL 1.5–5 and the identification of preschoolers with autism in Italy. Epidemiology and Psychiatric Sciences 2011 20 329338. (doi:10.1017/S204579601100045X)

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  • 40

    Lemler M. Discrepancy between parent report and clinician observation of symptoms in children with autism spectrum disorders. In Discussions, 2012 8, Number 2. Retrieved from http://www.inquiriesjournal.com/a?id=803.

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  • 41

    Bateson P, Barker D, Clutton-Brock T, Debal D. Developmental plasticity and human health. Nature 2004 430 419421. (doi:10.1038/nature02725)

  • 42

    Trumpff C, Vanderfaeillie J, Vercruysse N, De Schepper J, Tafforeau J, Van Oyen H, Vandevijvere S. Protocol of the PSYCHOTSH study: association between neonatal thyroid stimulating hormone concentration and intellectual, psychomotor and psychosocial development at 4–5 year of age: a retrospective cohort study. Archives of Public Health 2014 72 27. (doi:10.1186/2049-3258-72-27)

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  • 43

    Gilbert ME & Lasley SM. Developmental thyroid hormone insufficiency and brain development: a role for brain-derived neurotrophic factor (BDNF)? Neuroscience 2013 239 253270. (doi:10.1016/j.neuroscience.2012.11.022)

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  • 44

    Chan S, Kachilele S, McCabe CJ, Tannahill LA, Boelaert K, Gittoes NJ, Visser TJ, Franklyn JA & Kilby MD. Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex. Developmental Brain Research 2002 138 109116. (doi:10.1016/S0165-3806(02)00459-5)

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  • 45

    Zhu H, Mao HQ, Chen LQ & Jiang YJ. Effect of maternal autoimmune thyroid disease on intellectual development of infants. Journal of Zhejiang University Medical Sciences 2006 35 292296.

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  • 46

    Rovet JF, Skocic J & Willoughby K. Hippocampal morphometry in offspring of hypothyroid and hyperthyroid women and children with congenital hypothyroidism. Thyroid 2009 19 S27S28. (doi:10.1089/thy.2008.0106)

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  • 47

    Man EB, Brown JF & Serunian SA. Maternal hypothyroxinemia: psychoneurological deficits of progeny. Annals of Clinical and Laboratory Science 1991 21 227239.

  • 48

    Getahun D, Jacobsen SJ, Fassett MJ, Chen W, Demissie K & Rhoads GG. Recent trends in childhood attention-deficit/hyperactivity disorder. JAMA Pediatrics 2013 167 282288. (doi:10.1001/2013.jamapediatrics.401)

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  • 49

    Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R & Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. European Thyroid Journal 2014 3 7694. (doi:10.1159/000362597)

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  • 50

    The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum, Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN & Soldin OP Guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011 21 10811125. (doi:10.1089/thy.2011.0087)

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  • 51

    Georgieff MK, Brunette KE & Tran PV. Early life nutrition and neural plasticity. Development and Psychopathology 2015 27 411423. (doi:10.1017/S0954579415000061)

  • 52

    Roman GC. Autism: transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents. Journal of the Neurological Sciences 2007 262 1526. (doi:10.1016/j.jns.2007.06.023)

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  • 53

    Berbel P, Navarro D & Román GC. An evo-devo approach to thyroid hormones in cerebral and cerebellar cortical development: etiological implications for autism. Frontiers in Endocrinology 2014 5 146. (doi:10.3389/fendo.2014.00146)

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  • 54

    Ameis SH, Ducharme S, Albaugh MD, Hudziak JJ, Botteron KN, Lepage C, Zhao L, Khundrakpam B, Collins DL & Lerch JP Cortical thickness, cortico-amygdalar networks, and externalizing behaviors in healthy children. Biological Psychiatry 2014 75 6572. (doi:10.1016/j.biopsych.2013.06.008)

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  • 55

    Fahim C, He Y, Yoon U, Chen J, Evans A & Perusse D. Neuroanatomy of childhood disruptive behavior disorders. Aggress Behaviour 2011 37 326337. (doi:10.1002/ab.20396)

  • 56

    Gilbert ME, Rovet J, Chen Z & Koibuchi N. Developmental thyroid hormone disruption: prevalence, environmental contaminants and neurodevelopmental consequences. Neurotoxicology 2012 33 842852. (doi:10.1016/j.neuro.2011.11.005)

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  • 57

    Lian XL, Bai Y, Xun YH, Dai WX & Guo ZS. Effects of maternal hyperthyroidism and antithyroid drug therapy on thyroid function of newborn infants. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2005 27 756760.

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  • 58

    Andersen SL, Olsen J, Wu CS & Laurberg P. Smoking reduces the risk of hypothyroidism and increases the risk of hyperthyroidism: evidence from 450 842 mothers giving birth in Denmark. Clinical Endocrinology 2014 80 307314. (doi:10.1111/cen.12279)

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  • 59

    Balhara YPS & Deb KS. Impact of alcohol use on thyroid function. Indian Journal of Endocrinology and Metabolism 2013 17 580587. (doi:10.4103/2230-8210.113724)

  • 60

    Coyle P, Tran N, Fung JNT, Summers BL & Rofe AM. Maternal dietary zinc supplementation prevents aberrant behaviour in an object recognition task in mice offspring exposed to LPS in early pregnancy. Behavioural Brain Research 2009 197 210218. (doi:10.1016/j.bbr.2008.08.022)

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  • 61

    Shields B, Hill A, Bilous M, Knight B, Hattersley AT, Bilous RW & Vaidya B. Cigarette smoking during pregnancy is associated with alterations in maternal and fetal thyroid function. Journal of Clinical Endocrinology and Metabolism 2009 94 570574. (doi:10.1210/jc.2008-0380)

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  • 62

    Zammit S, Thomas K, Thompson A, Horwood J, Menezes P, Gunnell D, Hollis C, Wolke D, Lewis G & Harrison G. Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring. British Journal of Psychiatry 2009 195 294300. (doi:10.1192/bjp.bp.108.062471)

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  • 63

    Pieczynska J & Grajeta H. The role of selenium in human conception and pregnancy. Journal of Trace Elements in Medicine and Biology 2015 29 3138. (doi:10.1016/j.jtemb.2014.07.003)

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