Unraveling the causal pathways of maternal smoking and breastfeeding in the development of neuropsychiatric disorders: A Mendelian randomization perspective

Background: Maternal smoking around birth (MSAB) and early-life breastfeeding (BAB) represent critical factors that may exert enduring effects on neuropsychiatric health. Although previous research has examined these exposures separately, the combined impact of both on disorders such as ADHD, ASD, BD, MDD, ANX, and SCZ remains unclear. This study aims to evaluate the causal relationships between MSAB and BAB and the risk of developing these neuropsychiatric disorders through Mendelian randomization (MR) analysis.

Methods: A two-sample MR analysis was conducted to investigate the potential causal effects of MSAB and BAB on a range of neuropsychiatric disorders. Genetic variants associated with MSAB and BAB were obtained from genome-wide association studies (GWAS), while summary data for neuropsychiatric disorders were gathered from large GWAS consortia. The primary MR analysis was conducted using the inverse-variance weighted (IVW) method, with additional sensitivity analyses performed to confirm the robustness of the findings. A False Discovery Rate (FDR) correction was applied to control for the issue of multiple comparisons and reduce the risk of Type I errors.

Results: The IVW analysis indicated that there were significant associations between MSAB and an increased risk of the following conditions: The IVW analysis indicated significant associations between MSAB and an increased risk of ADHD (odds ratio [OR] = 5.36, 95 % confidence interval [CI] = 2.58-7.63, p-value for false discovery rate [PFDR] = 0.004) and major depressive disorder (MDD) (OR = 1.92, 95 % CI = 1.29-2.88, PFDR = 0. Furthermore, significant associations were observed between MSAB and an increased risk of bipolar disorder (BD) (OR = 6.33, 95 % CI = 1.56-8.73, PFDR = 0.020), anxiety disorders (ANX) (OR = 1.03, 95 % CI = 1.00-1.05, PFDR = 0.039), and attention deficit hyperactivity disorder (ADHD) (OR = 5.36, 95 % CI = 2.58-7.63, PFDR = 0.004). No significant associations were identified between MSAB and Autism Spectrum Disorder (ASD) or Schizophrenia (SCZ). In contrast, the results indicated that BAB was associated with a protective effect against ADHD (OR = 0.17, 95 % CI = 0.04-0.63, PFDR = 0.025), MDD (OR = 0.26, 95 % CI = 0.12-0.58, PFDR = 0.006), and ANX (OR = 0.96, 95 % CI = 0.49-0.99, PFDR = 0.030). No significant effects of BAB were observed for ASD, BD, or SCZ.

Conclusions: This study shows that maternal smoking around the time of birth increases the risk of attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), bipolar disorder (BD), and anxiety disorders (ANX). In contrast, breastfeeding during infancy offers protective benefits against ADHD, MDD, and ANX. These findings underscore the vital importance of maternal health behaviours during the perinatal and infant feeding periods. They also highlight the need for targeted public health interventions aimed at reducing the risk of neuropsychiatric disorders.