This was one of the first studies finding that young maternal age at childbirth in the U.S. population may increase the risk of ADHD and LD in offspring and that advanced maternal age at childbirth seems likely to increase the risk of LD in offspring. In addition, we also found that these associations differ by gender. Furthermore, the relationship between maternal age at childbirth and the risk of LD in offspring presents a U-shaped curve.
Previous epidemiological studies have shown an increased risk of ADHD in the offspring of mothers with young maternal age at childbirth in the Swedish population ; similarly, the risk of ADHD in offspring is also increased for mothers with young maternal age at childbirth in the Danish population . The results of the above two studies are similar to ours and may be explained because the development of ADHD is related to neurotransmission pathways. Therefore, we speculated that the education levels of the subjects with advanced maternal age at childbirth were higher, and these individuals may have greater health knowledge during pregnancy. Therefore, compared to the 25–29-year-old group, participants with advanced maternal age may pay more attention to nutritional supplements and additives during pregnancy, such as folic acid, which are beneficial for neural development, thus reducing the risk of ADHD in their offspring. Other potential reasons are that there are complex ethnic backgrounds in the U.S.; the genetic backgrounds of different races are quite different, and genetic factors are considered to be related to the development of ADHD [36, 37]. In contrast to the results of the present study, a study of the Danish population revealed that advanced maternal age at childbirth (over 35 years old) is a protective factor against ADHD in offspring. While our results showed that the risk of ADHD in offspring of individuals older than 39 is likely to be increased, the difference was not significant, which may be related to the small sample size of our study. Another reason for the difference in study results is that the Danish study did not group and analyze the data of people over 40 years old.
At present, few studies have been conducted on maternal age at childbirth and LD risk in offspring, which may be related to the diagnosis of LD without International Classification of Disease (ICD) standards. Although LD evaluation is subjective, its evaluation is easy to perform and can reflect certain neural functions [38, 39]. At present, the etiology of LD is still unclear. Some scholars have suggested that genetic factors may play a role, and the symptoms of LD are also broader. Adolescents who exhibit abnormalities in reading, writing, listening, speaking, and performing math in will be suggested to have LD. However, the cause of LD in offspring is complex and may not be related to a neural pathway. In this study, we observed a U-shaped curve of maternal age at childbirth and offspring LD risk. It is suggested that the individuals with younger and more advanced maternal ages at childbirth will have a greater risk of having offspring with LD. At present, most of the existing studies suggest that young maternal age at childbirth increases the risk of health effects on offspring. However, controversy exists for subjects with advanced maternal age at childbirth. Appropriate older age of mother is beneficial for the offspring with regard to financial status and education . The social economic position and resources of older mothers are greater than those of younger mothers, and over time, the offspring of older mothers experience the effects of improvements in public health conditions and educational expansion. Although negative effects occur during the perinatal period, there is no difference between these offspring and offspring of mothers with a younger age at childbirth during adulthood . However, it should be noted that the oocytes of older mothers are aging, and accumulated DNA damage  and the imbalance in mitochondrial homeostasis  in aging oocytes have a negative impact on the development of fertilized eggs . DNA damage and mitochondrial function are closely related to nerve development [44, 45]. These characteristics of aging oocytes may explain the decreased learning ability of offspring. However, some researchers suggest that some patients are classified as having LD because of their parents' misunderstanding of the education process and the parents have higher expectations for their offspring . The intelligence or neurodevelopment of offspring may not be abnormal, but the specific molecular mechanism of the relationship between age and LD still requires further research.
Our results indicate that maternal age at childbirth is related to the risk of offspring LD. Due to the recall bias in retrospective cohorts, animal studies may clarify the cause and effect relationship. Some existing mechanistic studies have confirmed that the spatial learning capacity of mice at 32–35 weeks is lower than that of mice at 9–12 weeks, which may be related to the decrease in the expression of vitamin D receptor (VDR) in the early embryogenesis process . In addition, compared with 3-month-old mice, 15–18-month-old mice showed anxiety-like behavior, and the gene expression pattern of the hippocampus also changed . We also speculated that late production age may be related to the egg quality . These possible mechanisms may explain the link between maternal age at childbirth and ADHD and LD risks in offspring. However, there are few studies on the mechanism of the relationship between young maternal age at childbirth and ADHD and LD risk, possibly because few animal models exist. We speculated that the link between young maternal age at childbirth and ADHD and LD risk may arise because the family income and education levels of young mothers are lower than those of older mothers . Additionally, Fall et al found that young maternal age at childbirth may be associated with poor birth outcomes and nutrition for offspring in low- and middle-income countries .
Our results also showed a sex difference in the association of young maternal age at childbirth and the risk of ADHD + LD among male and female offspring. The reason for this phenomenon is that the ADHD incidence rate of boys is higher than that girls [15, 30]. Additionally, sex differences in gonadal steroid hormone levels during perinatal development result in gender differences in neurodevelopment. Furthermore, compared to early-adolescent and middle-aged mice, male offspring have less developed sexual organs , which suggests that androgen may also be low in early-adolescent mice, and changes in hormones in adolescence are related to brain volume and neurodevelopment . Therefore, we speculate that hormonal disorders in the male offspring of young age mothers may cause an neurodevelopmental abnormality that leads to the increased risk of both ADHD and LD in boys rather than girls.
As an advantage, this study is the first to report the association between maternal age at childbirth and offspring ADHD and LD risks in the U.S. population. We found that young or advanced maternal age at childbirth may lead to ADHD and LD risks in offspring. Through the results of subgroup analysis, we identified the susceptible population, which may provide a basis for research on the underlying mechanism or prevention. Applying the RCS model is helpful to determine the association between maternal age at childbirth and the ADHD and LD risks of offspring.
Although the present study results have some scientific significance, there are still several limitations of our study as a whole. First, genetic factors have a great influence on ADHD and LD risks. Even if we consider race as a covariate for adjustment and further analysis, we still cannot exclude the bias of genetic factors. Second, some maternal lifestyles during pregnancy also affect offspring ADHD and LD, although we adjusted for the variable of smoking during pregnancy. In fact, there are additional factors, such as gestational hypertension and gestational diabetes, but we cannot adjust for them because no such data are contained in the NHANES database. Third, in this study, some covariates were missing. To avoid reducing the sample size, we imputed data for the missing variables, but strictly speaking, this approach may have biased the actual results. Fourth, the outcome variables in this study based on self-reported data, leading to potential subjective bias. It is thus necessary for future research to use objective indicators.
In conclusion, the present study results indicated a U-shaped association between maternal age at childbirth and the ADHD and LD risk of offspring in a nationally representative U.S. survey. Future studies with large sample sizes and mechanistic studies are needed to confirm the risks of ADHD and LD.