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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 34  |  Issue : 3  |  Page : 115-120

Maternal hyperthyroidism during pregnancy and offspring risks of attention-deficit/hyperactivity disorder and autism spectrum disorder: A nationwide study


1 Department of Psychiatry, Veterans General Hospital; Division of Psychiatry, Faculty of Medicine; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
2 Department of Psychiatry, Veterans General Hospital; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
3 Department of Family Medicine, Taipei Veterans General Hospital; Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan

Date of Submission27-May-2020
Date of Decision29-Jul-2020
Date of Acceptance05-Aug-2020
Date of Web Publication28-Sep-2020

Correspondence Address:
Shih- Jen Tsai
No. 201, Section 2, Shih-Pai Road, Taipei 112
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TPSY.TPSY_27_20

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  Abstract 


Objective: Thyroid hormones are crucial in normal brain development. Abnormal thyroid hormones in pregnancy may impair neurodevelopment in the offspring. In this study, we intended to determine whether prenatal hyperthyroidism can increase the offspring risk of autism spectrum disorders (ASD) or attention-deficit/hyperactivity disorder (ADHD). Methods: In our study, we identified 330 study pairs (mothers with hyperthyroidism and their children) and 1,320 matched control pairs (mothers without hyperthyroidism and their children) between 1998 and 2008 from the Taiwan Longitudinal Health Insurance. The offspring risk of major neurodevelopmental disorders, including ADHD and ASD, was analyzed in the follow-up period (from childbirth to the end of 2011). Results: The results of logistic regression analysis using adjustment for demographic data and maternal mental health disorders showed that prenatal hyperthyroidism significantly increased the offspring risk of ADHD (odd ratio = 2.23; 95% confidence interval [CI] = 1.19–4.18, p < 0.05) and nonsignificantly increased the risk of ASD (odds ratio = 6.62; 95% CI = 1.08–40.47) after having adjusted for children's demographical data and for maternal mental disorders. Conclusion: Those results suggest that prenatal hyperthyroidism increased the risk of ADHD and ASD in offspring, regardless of demographic conditions and maternal mental health disorders. We suggest that hyperthyroidism in pregnant women should be carefully managed and that additional studies are necessary to clarify the underlying mechanisms which maternal hyperthyroidism leads to neurodevelopmental risks.

Keywords: neurodevelopment disorders, pregnancy, prenatal hyperthyroidism, thyroid hormones


How to cite this article:
Chen MH, Huang KL, Hsu JW, Bai YM, Chen TJ, Tsai SJ. Maternal hyperthyroidism during pregnancy and offspring risks of attention-deficit/hyperactivity disorder and autism spectrum disorder: A nationwide study. Taiwan J Psychiatry 2020;34:115-20

How to cite this URL:
Chen MH, Huang KL, Hsu JW, Bai YM, Chen TJ, Tsai SJ. Maternal hyperthyroidism during pregnancy and offspring risks of attention-deficit/hyperactivity disorder and autism spectrum disorder: A nationwide study. Taiwan J Psychiatry [serial online] 2020 [cited 2020 Oct 26];34:115-20. Available from: http://www.e-tjp.org/text.asp?2020/34/3/115/296463




  Introduction Top


Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are two of the most common neurodevelopmental disorders. Both increases in prevalence and economic burden justify vigorous research to uncover its pathogenesis. Most plausible neurodevelopmental theories of ASD and ADHD focus predominantly on genetic factors[1]. But studies of monozygotic twins suggest the presence of nonheritable, prenatal, and perinatal risk factors for both disorders [2],[3]. For example, a case–control study using 190 ethnic Han children with and without autism has shown seven prenatal and seven perinatal risk factors associated with autism, such as maternal secondhand smoke exposure and maternal unhappy emotional state[4]. Some studies demonstrated that prenatal environments (e.g., prenatal exposure to acetaminophen, maternal gestational diabetes mellitus, and maternal alcohol use during pregnancy) are implicated in developing ADHD. But those issues remain to have insufficient evidence to support a definite causal relationship [5],[6].[7].

Thyroid hormones play an important rôle in many fundamental processes underlying brain development and maturation[8]. The developing fetus/embryo depends on the maternal supply of thyroid hormones. Their synthesis through the fetal thyroid gland commences at mid-gestation, and the establishment of adverse consequences of severe maternal thyroid hormone deficiency on the neurodevelopment of offspring is well-understood[8]. A study by Fetene et al. examined the rôle of maternal thyroid function during pregnancy on offspring ADHD in 2,912 mother–child pairs[9]. The investigators found that levels of thyroid-stimulating hormone (TSH), free thyroxine, and thyroid peroxidase antibodies are not associated with ADHD in children aged 7.5 and 15 years. Similarly, meta-analyses of eligible studies revealed that maternal subclinical hypothyroidism and hypothyroxinemia are not associated with ADHD and that their effect on the risk of ASD in offspring is unclear[10]. But study examined ASD and TSH levels measured in mid-pregnancy maternal serum, have demonstrated inverse associations between ASD and log-transformed TSH levels in maternal serum samples[11]. A retrospective cohort study using records from 397,201 children demonstrated that children of hypothyroid women had higher ASD rates than children of women without the diagnosis (adjusted hazard ratios [HR] = 1.31; 95% confidence interval (CI) = 1.13–1.53)[12]. Furthermore, compared with white children, prenatal hypothyroidism was associated with an increased risk of ASD in children of women of other/mixed race–ethnicity, suggesting that maternal hypothyroidism is associated with offspring ASD in a manner dependent on race[12].

Exposure to excessive amounts of circulating thyroid hormones is a pathological syndrome called hyperthyroidism. Toxic multinodular goiter and solitary hyperfunctioning nodules are the major causes of this syndrome, with Graves' disease being the most common factor[13]. About 1–2 cases of gestational hyperthyroidism occur per 1,000 pregnancies[14]. The extent to which maternal hyperthyroidism during pregnancy affects offspring neurodevelopment outcomes is unclear. Relative to the above association of maternal hypothyroidism and offspring ADHD/ASD risks, the relationship between maternal hyperthyroidism and offspring ADHD and ASD risks has much less studied. As mentioned, the Avon Longitudinal Study of Parents and Children failed to support the association of maternal hyperthyroidism with offspring ADHD and ASD risks[9]. But Andersen et al. demonstrated that maternal overt hyperthyroidism (HR = 2.2, 95% CI = 1.1–4.4]) is associated with ASD in the child[15]. Assessing the association between neonatal TSH and subsequent neurodevelopmental disorders, Villanger et al. found a U-shaped pattern with elevated likelihoods of ADHD diagnosis at lower and higher TSH levels, indicating that ADHD risk is elevated among newborns with hyperthyroid status[16]. Increasing evidence has suggested a significant relationship between maternal and neonatal hyperthyroidism [17,] [18]. The logic of maternal hyperthyroidism increasing offspring ADHD and ASD risks needs further investigation.

In this study, we intended to retrospectively evaluate the effects of women with hyperthyroidism during pregnancy on the offspring risk of ADHD and ASD. We hypothesized that maternal hyperthyroidism would be related to increased risks of offspring ADHD and ASD.


  Methods Top


Data source

We used the Taiwan National Health Insurance Research Database (NHIRD), namely the Longitudinal Health Insurance Database 2010, in the current study. NHIRD is audited and released by the National Health Research Institute for scientific and study purposes. Claims data of subjects included in the NHIRD are anonymous to maintain individual privacy. Using a unique personal identification number assigned to each resident in Taiwan, all of the information was linked together. Following Chen et al.'s and Cheng et al.'s methods [19],[20], the recorded family kinships in the NHIRD were used for genealogy reconstruction. Only blood relatives or spouses were qualified to be dependents of the insured patients. With unique personal identifiers, we identified the following family relationship groups: parents, offspring, siblings, and twins. The sibling relationship was confirmed if subjects had the same father or mother. Siblings were identified as twins if they shared a birth date. Comprehensive information on insured subjects is included in the database, including demographic data, dates of clinical visits, and disease diagnoses. The used diagnostic codes were based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan [19].[20],[21],[22]. The institutional review board at Taipei Veterans General Hospital approved this study (IRB protocol number = 2018-07-016AC, and the date of approval = May 27, 2018) without the stipulation of obtaining any informed consent.

Inclusion criteria of mothers with hyperthyroidism before childbirth and their offspring

We enrolled two mother–child cohorts, namely prenatal hyperthyroid mother–child (case) cohort and nonprenatal hyperthyroid mother–child (control) cohort, in this study between 1998 and 2008 for the investigation of the association between prenatal hyperthyroidism and offspring risk of major neurodevelopmental disorders, including ADHD and ASD, in the follow-up period (from childbirth to end of 2011). Hyperthyroidism was diagnosed by board-certified internal medicine physicians, family medicine physicians, and endocrinologists at least twice based on ICD-9-CM code of 242 before the childbirth. A control cohort (1: 4) was randomly identified based on ages (± 1 year) (mothers and children), sexes (mothers and children), residence, income, and familial relationship after the exclusions of case cohort and mothers who had any thyroid disease (ICD-9-CM codes: 240–246) at any time. For example, a 40-year-old mother with hyperthyroidism before childbirth having an eight-year-old son would be matched with four 40-year-old mothers without any thyroid disease having an eight-year-old son.

Disease classification and assessment of covariates

Maternal mental disorders included schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM codes: 296, except for 296.2, 296.3, 296.9, and 296.82), and major depressive disorder (ICD-9-CM codes: 296.2 and 296.3). Offspring neurodevelopmental disorders included ASD (ICD-9-CM code: 299) and ADHD (ICD-9-CM code: 314). These disorders were diagnosed at least twice by board-certified psychiatrists on the basis of their clinical judgment and diagnostic interviews. Demographic data, including age, sex, place of residence, and income status, in 2010 were displayed in the table and were adjusted in our study. The place of residence was classified into five categories according to the level of urbanization[23].

Statistical analysis

Chi-square statistics and F-tests were used to compare categorical and continuous variables, respectively, between prenatal hyperthyroid mother–child (case) and nonprenatal hyperthyroid mother–child (control) cohorts. Two logistic regression models were done to investigate the prenatal hyperthyroidism with the offspring risk of neurodevelopmental disorders. Model 1 was adjusted for the demographic data, including ages of parents and children, sexes of parents and children, level of urbanization, and income. Model 2 was additionally adjusted for mental disorders of mothers, including schizophrenia, bipolar disorder, and major depressive disorder. We did not adjust for maternal ADHD (n = 1) and ASD (n = 0) in the regression model because of rare cases in our sample.

All data were computed and statistical analyses were done using the Statistical Package for the Social Science software version 17 (SPSS Inc., Chicago, Illinois, USA) and Statistical Analysis System software version 9.1 (SAS Institute, Cary, North Carolina, USA). The differences between groups were considered significant if two-tailed p-values were smaller than 0.05.


  Results Top


As shown in [Table 1], 330 mother–child case pairs and 1,320 matched control pairs were included in our study. Children of mothers having prenatal hyperthyroidism were more significant to develop ADHD (4.8% vs. 2.5%, p < 0.05) but not in developing ASD (0.9% vs. 0.2%, nonsignificant difference) than those of mothers without any thyroid disease.
Table 1: Demographic data and prevalence of mental disorders among the offspring of mothers with or without hyperthyroidism

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As shown in [Table 2], the results of logistic regression with adjustment of age, sex, level of urbanization, and income showed that children of mothers having prenatal hyperthyroidism significantly increased in developing ADHD (odds ratio [OR] = 2.15, 95% CI = 1.15–4.02, p < 0.05) and ASD (OR = 6.49, 95% CI = 1.06–39.72, p < 0.05) compared with those of mothers having no any thyroid disease. Logistic regression showed the consistent results that prenatal hyperthyroidism was significantly associated with the offspring ADHD (OR = 2.23, 95% CI = 1.19–4.18, p < 0.05) and ASD (OR = 6.62, 95% CI = 1.08–40.47, p < 0.05) risks after additionally adjusting for maternal mental disorders [Table 2].
Table 2: Logistic regression models of maternal hyperthyroidism and mental disorders of their children

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  Discussion Top


Based on a thorough study, this is the first large nationwide population-based cohort study to investigate the risk of ASD and ADHD in the offspring of pregnant women with hyperthyroidism. The main finding of our study [Table 2] is that, adjustments for demographic data and maternal mental health disorders, hyperthyroidism in pregnant mothers significantly increased the risk of both ADHD (OR = 2.23; 95% CI = 1.19–4.18, p < 0.05) and ASD (OR = 6.62; 95% CI = 1.08–40.47, p < 0.05) in offspring. The findings mean that maternal thyroid hormones are required for the neurodevelopment of progeny. A previous study has been found to be associated between maternal hypothyroidism and ASD/ADHD in children[12],[24],[25] but not others [9],[10]. But the case numbers of ASD were few in the current study, which may confound the robustness of our findings in the association between maternal hyperthyroidism and offspring ASD.

There are four possible explanations for the increased risk of ADHD and ASD in the offspring of mothers with hyperthyroidism during pregnancy. First, thyroid hormones are crucial regulators of early development and play an important rôle in the maintenance of a normal pregnancy and in the development of the fetus, particularly the fetal brain[8]. In addition to cell migration, thyroid hormones regulate the differentiation of neurons, oligodendrocytes, astrocytes, and microglia[8]. Researchers showed that a direct toxic effect on the fetus is caused by an excess of thyroid hormones during pregnancy, where the risk of miscarriage is tripled, with an average birth weight reduction in surviving infants[26]. Expression of astrocytic and neuronal cytoskeletal proteins is compromised by increased thyroid hormones in studies of an animal maternal hyperthyroidism model, indicating that neuronal differentiation is accelerated[27]. Crucial influences on neurodevelopment may be exerted by the aberrant timing of brain development which leads to irreversible yet subtle changes in the synaptic wiring[27]. Untreated or inadequately treated hyperthyroidism is also associated with pregnancy complications and may even program the fetus to long-term neurodevelopment disorders such as ASD and ADHD [8],[29]. Second, hyperthyroidism in women who are of childbearing age is mainly of autoimmune origin and caused by Graves' disease [14],[30]. The physiological changes in the maternal immune system during a pregnancy may influence the brain development in the fetus. It is likely that the autoimmune processes that produce common forms of hyperthyroidism may exert additional effects on fetal neurodevelopment over and beyond those of maternal thyroid dysfunction[31]. Third, maternal thyrotoxicosis during pregnancy is associated with a higher prevalence of low birth weight infants when compared to those with controlled thyroid status [32],[33]. In the 2011–2012 National Survey of Children's Health (n = 95,677), very low birth weight children have 3.2 times higher odds of ASD and 1.7 times higher odds of ADHD[34]. Thus, maternal hyperthyroidism may indirectly increase neurodevelopment disorders through low birth weight in the child. Finally, we cannot exclude that medications used to treat maternal hyperthyroidism may have an adverse effect on neurodevelopment, which warrant further investigation.

Hyperthyroidism is rare in pregnant women and often underdiagnosed[35]. In addition of our study findings, an animal study in the adulthood of the offspring of maternal hyperthyroidism suggests that this delicate prenatal endocrine modification could alter the neuronal structure of specific brain areas and influence the cognition and emotionality of offspring in adulthood[36]. Thus, the management of maternal hyperthyroidism can improve the offspring risk of ASD and ADHD. Actually, a clinical study has shown improved neonatal and obstetric outcomes for hyperthyroidism during pregnancy, when managed in a specialized antenatal endocrine clinic[29].

Study limitations

The readers are warned not to overinterpret the results in this study because six limitations to our findings should be considered.

  • The NHIRD does not provide detailed information on patients, such as tobacco use, alcohol consumption, body mass index data, and family history of psychiatric illness. They are potential risk factors for neurodevelopment disorders in the children [37],[38].
  • The exact levels of thyroid hormones were not available in the NHIRD. Thus, we could not control for those potentially confounding factors.
  • The diagnoses in NHI claims are primarily for administrative billing and do not receive verification for scientific purposes although the data on mothers with hyperthyroidism and the diagnoses of ASD and ADHD in the offspring were highly reliable.
  • Hyperthyroidism is frequently underdiagnosed in pregnancy[39] and may have also been in our study because only subjects seeking a medical evaluation can be identified.
  • We included only 330 prenatal hyperthyroid mother–child pairs and 1,320 nonprenatal hyperthyroid mother–child matched pairs in the current study. They may confound the subanalysis for which specific trimester exposed to maternal hyperthyroidism was related to offspring ADHD and ASD. Further studies are necessary to elucidate it.
  • The age of diagnosis for offspring ADHD and ASD did not differ between case and control cohorts in the current study. A Danish nationwide study reported that children born to mothers with thyroid dysfunction are diagnosed with ASD at a median of 5.3 years of age and initiated medical treatment for ADHD at a median of 8.4 years of age[36]. Whether maternal hyperthyroidism is related to an earlier age of diagnosis for offspring ADHD and ASD, a possible index of greater disease severity needs further investigation.


Summary

In summary, our nationwide population-based retrospective cohort study provides evidence for an increased risk of ASD and ADHD in the offspring of pregnant women with hyperthyroidism. The management of maternal hyperthyroidism may ameliorate the risk of these common neurodevelopmental disorders.


  Acknowledgment Top


The authors thank Emily Ting for English editing.


  Financial Support and Sponsorship Top


This work was supported by grant MOST 107-2634-F-075-002 from the Taiwan Ministry of Science and Technology and grant V109C-196 from the Taipei Veterans General Hospital.


  Conflicts of Interest Top


The authors declare that they have no conflict of interest in writing this report.



 
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