Written ＆ Image credit to Professor Edward Chia-Cheng Lai research team.

A research team in Taiwan has overturned previous understandings of the risk of ADHD in the offspring of mothers with diabetes. Their findings have attracted significant attention both domestically and internationally, showcasing the potential of Taiwan's National Health Insurance data to contribute to global medical research. The team, led by Professor Edward Chia-Cheng Lai, in collaboration with the international academic research organization NeuroGEN (Neurological and mental health Global Epidemiology Network), and under long-term support from the National Science and Technology Council and National Cheng Kung University, published their research findings in the top biomedical journal Nature Medicine Maternal diabetes and risk of attention-deficit/hyperactivity disorder in offspring in a multinational cohort of 3.6 million mother–child pairs.

ADHD is a common neurodevelopmental disorder in children, often diagnosed during school age, which is characterized by inattention and poor organizational skills and often affects the child’s emotional stability and motor control. This disorder impacts multiple aspects of life, including learning, social interaction skills, and self-esteem. The symptoms are usually long-lasting and can persist into adolescence or early adulthood. Some of the factors believed to contribute to this condition include genetics, environmental risks during pregnancy, and other influences after birth. Many previous studies have found that if mothers have diabetes during pregnancy, this may be linked to the emergence of neurodevelopmental disorders in the offspring. If this association between diabetes during pregnancy and the risk of ADHD in offspring were to be confirmed, the focus of further research should be on early intervention and prevention.

However, while these previous studies investigating similar clinical questions have found that gestational diabetes can increase the risk of neurodevelopmental disorders, including ADHD in offspring, these studies were also limited by the nature of their observational designs, and they did not fully take into account the effects of familial genetics or environmental factors, which may have led them to inaccurate conclusions. In other words, there remained the possibility that the observed link between gestational diabetes and ADHD in the offspring was actually related to the mother’s general genetic predisposition towards both diabetes and ADHD in the offspring. The further investigation and verification of these associations has hitherto been difficult, due to the small sample sizes with limited numbers of pregnant women, a minority group, available for study.

Recognizing the clinical significance and challenges of this issue, Professor Lai's research team saw the opportunity to increase the sample sizes through international collaboration, and initiated contact with NeuroGEN. This international network focuses on epidemiological research related to neurodevelopmental and neurodegenerative diseases, collecting appropriate data and designing suitable research methods to explore potential factors affecting neurological diseases, to aid in future prevention or treatment. The current collaborative research includes approximately 3.6 million mother-child pairs across seven countries, including Taiwan, New Zealand, Hong Kong, Finland, Iceland, Norway, and Sweden. By using a so-called sibling control analysis study design, Prof. Lai’s team was able to manage the effects of factors like familial genetics that are difficult to assess and measure. The researchers found that while traditional research indicated a slight increase in ADHD risk among offspring of mothers with diabetes, there was no such increase in risk when genetic and environmental factors were properly accounted for. These results suggest that familial genes and environmental factors might be the true causes of ADHD in the offspring, not gestational diabetes, overturning our previous understanding and providing more accurate evidence for clinical consideration.

Given the ethical considerations, research involving pregnant women and offspring often cannot utilize standard randomized clinical trial methods, leaving hospital and insurance databases, such as Taiwan's National Health Insurance Research Database (NHIRD), as crucial sources of anonymized electronic medical records and health data that can be put to good use for medical research. However, these real-world data are not collected in a truly random manner, and are prone to research biases, necessitating meticulous analytical processes and reasoning to accurately establish proper causal relationships, which is essential to ensure correct clinical judgments and decisions. Over the past several years, Professor Lai has strongly advocated for strengthening "causal inference" in real-world data analysis, publishing several papers in top journals on topics like psychiatric drugs and the risk of falls (BMJ 2021 Sep 9;374: n1925) and cardiovascular events in conjunction with polypharmacy (BMJ 2023 Sep 27;382: e076045). His approach has been to compare traditional and advanced research methods, and the results often overturn previous understandings of drugs and their side effects, thus producing more accurate clinical evidence. Furthermore, through the international cooperation, these efforts significantly contribute to showcasing Taiwan's academic capabilities and enhancing Taiwan’s visibility on the global stage.