The association of prenatal exposure to thyroid hormone and antithyroid drugs with adverse offspring outcomes

Abstract

Hypothyroidism and hyperthyroidism are two conditions that occur when the thyroid gland produces too little or too much thyroid hormone. These thyroid dysfunctions are common among women of childbearing age but are often overlooked as they may not cause any symptoms. However, if left untreated or poorly controlled, they can lead to a range of complications in both mothers and babies, including maternal anemia, postpartum hemorrhage, preterm delivery, low birth weight, intellectual disability, developmental delays, and even miscarriage. The first-line medications used to treat hypothyroidism and hyperthyroidism in pregnant women are levothyroxine (L-T4) and antithyroid drugs (ATD), respectively. Unfortunately, there is limited knowledge regarding the impact of these treatments on the long-term growth and development of the offspring if they were exposed prenatally. This thesis aims to address the knowledge gaps in three parts. The first part was a systematic review and meta-analysis, which provided insight into the potential risks that maternal thyroid dysfunction in pregnant women may pose to their children. The findings from the first part emphasized the increased risk of various adverse outcomes in the offspring, particularly neuropsychiatric disorders, and this informed the rationale for the second part. The second part consisted of two cohort studies that utilized a population-wide database managed by the Hong Kong Hospital Authority, which provides healthcare services for over 7.5 million people in Hong Kong. These studies investigated the impact of prenatal exposure to L-T4 and ATD on the growth and neuropsychological development of offspring, including preterm birth, small for gestational age (SGA), attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and seizure/epilepsy. The results indicated that children prenatally exposed to L-T4 had higher risks of preterm birth and seizure/epilepsy. In comparison, children born to mothers who received ATD during pregnancy had higher risks of preterm birth, SGA, ADHD, and seizure/epilepsy. However, it is essential to note that these elevated risks may be due to underlying maternal thyroid diseases rather than treatment exposure. The findings in the second part helped healthcare providers better understand the safety of thyroid-related treatments during pregnancy. Given the observed association between maternal thyroid disorders and an increased risk of offspring seizure/epilepsy, the third part of the thesis was a Mendelian Randomization (MR) study to examine the causal relationship between thyroid-related traits and the risk of epilepsy. The findings from the MR study suggested insufficient evidence for a causal relationship, indicating the need for further research on the role of thyroid hormones in epilepsy onset, as well as the associations of thyroid dysfunction with other neuropsychiatric disorders. Overall, this thesis contributes to the safety profile of L-T4 and ATD in the real-world setting and highlights the importance of considering maternal thyroid disorders as potential risk factors for adverse birth and neuropsychiatric outcomes in offspring. It also underscores the need for additional research to comprehend the causal relationships between thyroid diseases and neuropsychiatric disorders and to identify the safest and most effective treatments for pregnant women with thyroid disorders, considering both mothers and their children.