This study was embedded within the Generation R, a population-based birth cohort in the Netherlands where children were followed up from birth until young adulthood. Of the 4997 eligible mother-child pairs with data on maternal thyroid levels (excluding twins), 3873 pairs of children and caregivers (77.5%) were included in the main analyses. Maternal hypothyroxinemia, characterized by low levels of free thyroxine coexisting with reference thyrotropin levels, and children’s symptoms of attention-deficit hyperactivity disorder (ADHD) were the main outcome measures. Maternal thyroid hormone levels (thyrotropin, free thyroxine, thyroid peroxidase antibodies) were measured at a mean (SD) of 13.6 (1.9) weeks of gestation. Children’s ADHD symptoms were assessed at 8 years of age using the Conners’ Parent Rating Scale–Revised Short Form; higher scores indicate more ADHD symptoms (possible range, 0-36). Maternal hypothyroxinemia (n=127) in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age after adjustments for child and maternal factors (increase in ADHD scores, 7% [95% CI, 0.3%, 15%]). The results remained essentially unchanged when women with elevated levels of thyroid peroxidase antibodies were excluded. The authors concluded that children exposed to maternal hypothyroxinemia in early pregnancy had more ADHD symptoms, independent of confounders. This finding suggests that intrauterine exposure to insufficient thyroid hormone levels influences neurodevelopment in offspring.

Relevance: Fetal origin of disease(s) in later childhood and even adulthood has captured the attention and imagination of researchers all over the world. Many of these conditions are related to ‘nature and nurture’ encountered by the developing fetus in the internal and external maternal environment. An important example of this complex interaction is that fetal brain growth and development in early gestation are significantly influenced by maternal thyroxine levels, as fetal production of thyroid hormones does not begin until halfway through gestation. Thus maternal hypothyroidism in early pregnancy adversely impacts fetal neurodevelopment. More recently, it has been demonstrated that even in the absence of clinical or biochemical hypothyroidism, just the presence of low free thyroid hormone (FT4) without a concomitant increase in thyroid stimulating hormone (TSH/thyrotropin) – a condition referred to as hypothyroxinemia – can also result in adverse neurodevelopmental outcomes in infancy and childhood. This can manifest as developmental delay in all sectors, decreased psychomotor skill, lower intelligence quotient (IQ), and behavioral problems. This study [1] explores the association between maternal hypothy-roxinemia in the first trimester of pregnancy and behavioral disorders in mid-childhood, especially ADHD.

Critical appraisal: This study provides an opportunity to critically appraise a well-designed and conducted cohort study using one of several tools available for the purpose. Table I presents the findings using the Critical Appraisal Skills Programme checklist [2]. In addition, there are several other items recommended to be presented in cohort study reports as per the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) statement [3,4], but several of these are not related to the design or conduct of such studies; hence are not elaborated here.

TABLE I Critical Appraisal of the Study 

Extendibility: Although the epidemiological setting of this study (in terms of population characteristics, health-care system, childhood outcomes etc) are very different from our setting, the biological plausibility of maternal hypothyroxinemia resulting in adverse impact on fetal neurodevelopment with neuro-cognitive and behavioral impacts in later life, makes it difficult to ignore the findings. However, replication of a similar study in India could yield different results for the reasons explained.

Conclusions: This well-designed cohort study suggests that maternal hypothyroxinemia (even without clinical manifestations) in the first trimester of pregnancy could increase the risk of development and/or manifestation of ADHD-like behavioral disorders in mid-childhood.

1. Modesto T, Tiemeier H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC, et al. Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/hyperactivity disorder symptoms in children. JAMA Pediatr. 2015 Jul 6. [Epub ahead of print]

2. Critical Appraisal Skills Programme. 12 questions to help you make sense of cohort study. Available from: http://media.wix.com/ugd/dded87_e37a4ab637fe46a0869f9f 977dacf134.pdf. Accessed August 14, 2015.

3. STROBE statement. STrengthening the Reporting of OBservational studies in Epidemiology. Available form: http://www.strobe-statement.org/ Accessed August 14, 2015.

4. STROBE Statement—Checklist of items that should be included in reports of cohort studies. Available from: http://www.strobe-statement.org/fileadmin/Strobe/uploads/checklists/STROBE_checklist_v4_cohort.pdf. Accessed August 14, 2015.

5. No authors listed. The Bradford Hill Criteria. Available from: http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality%20criteria.pdf. Accessed August 14, 2015.

Critical appraisal: The Generation R study is a commendable study that has generated a lot of data that may apply to several health conditions. In the present study, the authors suggest that maternal hypothyroxinemeia may result in ADHD. From a developmental pediatrician’s viewpoint, the most important concern is the case definition of ADHD used besides the limitations given. The Conners’ Parent Rating Scales–Revised short version is a screening tool that is not used in isolation. Individual items are rated and raw scores converted to standardized T scores [1]. Children with T scores above certain levels are considered ‘at risk’ of ADHD and require detailed evaluation. In this study, only raw scores of all children were used. Thus even children who were ‘not at risk’ got included. Having higher scores is not paramount to having ADHD if cut-off levels are not applied. Since persistence of symptoms in multiple settings and functional impairment were not assessed, normal variants and behavior problems got inadvertently included. Given the limitations of epidemiological studies, ‘probable’ criteria could have been defined and relative/attributable risks for children with and without ‘probable’ ADHD determined in exposed and not-exposed children.

Discussion: Maternal hypothyroxinemeia has also been associated with cognitive impairment and autistic features [2,3]. All three entities can exist in isolation or together (if symptoms are not accountable by cognitive level). Even though differentiation is not feasible by parental reports, it is not really required if we consider aberrant development and behaviour collectively. This gets explained by the neurobiological role of maternal thyroxine during embryogenesis and substantiated by the neuro-radiological abnormalities seen in some deficient models.

Clinical application: Proving causality becomes meaningless without available intervention. Although the role of prophylactic iodine in pregnancy is established, there are still conflicting results regarding efficacy of L-thyroxine supplementation in preventing adverse neuro-cognitive outcomes [4]. Extensive research is required before prophylaxis becomes a reality.

1. Conners CK. Conners Parent Rating Scales–Revised short version (CPRS-R:S). New York 1997, Multi-Health systems Inc.

2. Ghassabian A, El Marroun H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC, et al. Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. J Clin Endocrinol Metab. 2014; 99:2383-90.

3. Roman GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VWV, HofmanA, de Rijke YB, et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013;74:733-42.

4. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinemia during early pregnancy and subsequent child development: A 3-year follow up study. Clin Endocrinol. 2003;59:282-8.

Critical appraisal: The strength of this population-based prospective study is the large sample size and that they followed-up the cohort over long-term. Several neurocognitive symptoms in children born to hypothyroxinemic mothers have been studied in the past, but there have been only very few studying ADHD and maternal hypothyroxinemia. This study also has several additional noteworthy methodological refinements. The most common age group of presentation of ADHD is between 6-8 yrs which the authors have precisely studied. The investigators also made effort to separately analyze the data by excluding TPO positive mothers and mothers who took thyroid medication which could have confounded the results; however the association still remained positive.

The association between maternal thyroid function and children’s ADHD and oppositional scores were examined using linear regression. The statistical analysis could have been more refined by using a multiple logistic regression model.

Conclusions: Viewed in conjunction with the previously reported data, this study provides further support to the possible role of prenatal exposure to thyroid hormone insufficiency in causing adverse cognitive outcomes in offspring.

1. Glinoer D, Delange F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid. 2000;10:871-87.

2. Elahi S, Nagra SA. Low maternal iodine intake and early pregnancy hypothyroxinemia: Possible repercussions for children. Indian J Endocrinol Metab. 2014;18:526-30.

3. Henrichs J, Ghassabian A, Peeters RP, Tiemeier H. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol. 2013;79:152-62.

4. Furnica RM, Lazarus JH, Gruson D, Daumerie C. Update on a new controversy in endocrinology: isolated maternal hypothyroxinemia. J Endocrinol Invest. 2015; 38:117-23.

5. Negro R, Soldin OP, Obregon M-J, Stagnaro-Green A. Hypothyroxinemia and pregnancy. Endocr Pract. 2011;17:422-9.

6. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics. 2006;117:161-7.