DISCUSSION
To our knowledge, this is the first study to explore the mediating effect of glucose level on the linking between advanced maternal age and offspring birthweight. We found the positive linear association between maternal age and macrosomia, and the total influence of maternal age on offspring birthweight was mediated 4% to 16% by preconception FPG level, which was more obvious among women with a history of adverse pregnancy outcomes (mediating 18%).
We confirmed that maternal age had a linear association with the risk of macrosomia, which was in line with most previous studies (28, 29). We noticed that a majority of studies defined various cutoff values of advanced maternal age taking all the adverse pregnancy outcomes into consideration, such as 35 or 40 years old (30, 31). In view of macrosomia, we firstly applied cubic restricted splines and found that the age of 30 years would be the reasonable cutoff value for advanced maternal age, which was consistent with Xiaolei’s definition with the join point regression (32).And, based on the cutoff value, women with advanced age would have a 66% increase in the risk of macrosomia.
We identified that the underlying pathway of the influence of advanced maternal age on offspring birthweight involved the preconception FPG level. Advanced maternal age was associated with higher preconception FPG level, which was consistent with the prior result that preconception diabetes mellitus had advanced age (24). E Cosson et.al proposed that the preconception hyperglycemia indicated the FPG was already increased during early pregnancy and might persist in late-pregnancy while insulin resistance increased (20), resulting the increasing risk for macrosomia (19). Salman et.al also reported that the pre-pregnancy impaired fasting glucose level was associated with increased risk for gestation diabetes mellitus (33), which indicating the mediating effect of glucose level might be persistent during pregnancy. Our study supported those prior results and confirmed the real relationship among preconception FPG level, maternal age and offspring birthweight. Notably, although the proportion of macrosomia among older reproductive-age women was low, the total effect would be large with the increasing number of delaying motherhood in China and the worse prognosis of macrosomia. In addition, it’s a challenge to monitor glucose level for women during pregnancy (34, 35), and the glycemic control before pregnancy among this risk group would be implication.
Interestingly, we further found that the mediating effect of glucose level was more obvious among older women with a history of adverse pregnancy outcomes. In our study, 94.2% adverse pregnancy outcomes were spontaneous and induced abortion. It was reported spontaneous abortion could increase the prevalence of insulin resistance, which resulting in the glucose intolerance and increasing the transport of glucose (36, 37). Similarly, induced abortion associated with metabolic syndrome such as glucose intolerance in women with age ≥ 40 years (38). Glucose intolerance in older women with a history of adverse pregnancy outcomes might to some extent explained the increased mediated effect of glucose level on birthweight of advanced maternal age. Our finding suggested that we should pay more attention to the preconception glycemic control before pregnancy for older women with a history of adverse pregnancy outcomes.
There are some limitations in our study. First, the 2-hour plasma glucose level and HbA1c concentration were not detected. Second, we did not get access to the glucose level during pregnancy. However, this may not change the mediating effect of glucose level since that the high glucose level indicated the increasing glucose level during early pregnancy (20). Third, the glycemic control status among reproductive-age women was unknown, which may underestimate the risk (24). Finally, the dietary patterns were not available, further study need to be explored.