DISCUSSION
cognitive and neuropsychological difficulties, fifty-nine 9-year-old, GDM, PCOS
GDM, POLYCYSTIC OVARY SYNDROME (PCOS)
In this follow-up study, which comprised one hundred fifty-nine 9-year-old children born to mothers with GDM, we found no statistically significant differences in cognitive or neuropsychological outcomes between the offspring of mothers who were treated with either metformin or insulin.It has been shown that metformin crosses the placentaTo our knowledge, this is the first report on the long-term cognitive and neuropsychological outcomes of children born to mothers with either metformin or insulin treatment of GDM. To date, in addition to previous studies of this cohort,Based on previous results, it seems that fetal exposure of metformin does not affect the motor, social, behavioral, linguistic, and cognitive development of children compared with insulin treatment, when examining children before school age. Mild cognitive and neuropsychological difficulties might become evident within age and increasing demands during school years. However, in this study, neurocognitive outcomes were similar in 9-year-old children between the metformin and insulin groups. The results of this study are in line with these studies and support the hypothesis of the safety of the antenatal metformin treatment of GDM for a child's development.It is important to observe that when metformin is used to treat polycystic ovary syndrome (PCOS), it is started during first trimester and may be continued throughout the pregnancy. Thus, possible long-term effects of metformin on offspring cognitive development might be found more likely in studies of pregnancies with PCOS mothers. As opposed to PCOS pregnancies, medication in GDM is usually started during the second or third trimester. However, in a Norwegian follow-up study of mothers with PCOS randomized to metformin or placebo treatment from the first trimester, the mean FIQ was similar in offspring aged 5 to 14 years (n = 93) in the metformin and placebo groups.A major strength of this study is that the 9-year-old offspring well represent the original cohort, which allows valid comparisons between the treatment groups. Moreover, the baseline data were similar between the 9-year-old study participants and the group of nonparticipants and between the 2 study sites. Currently, this follow-up cohort of one hundred fifty-nine 9-year-old offspring whose mothers received either metformin or insulin treatment of GDM is the largest published cohort comparing long-term effects of the medication on the cognitive and neuropsychological profiles of offspring. We consider the participation rate of 51% to be satisfactory, taking into account the long period of 9 years between birth and follow-up. In addition, neuropsychological assessment covered clinically essential functions of 9-year-old children and reflect the overall picture of their neurocognitive outcome. There were some limitations in this study. First, the neuropsychological assessments were performed by 5 psychologists or final-stage psychology students, although no differences in test score medians between the psychologists were found. Second, narrative memory test (NEPSY II) results were lower than average in both medication groups. This might be related to the ceiling effect further compounded by the exhaustion from prolonged examinations. Third, the children were examined at the age of 9 years, which led to a situation in which the studied children were in different grade levels, which might have affected the level of received educational support. Fourth, the suboptimal follow-up rate may have led to some potential differences not being detected between the treatment groups, and based on post hoc power analysis regarding FSIQ, the size of this follow-up cohort does not have power to find small differences between the groups. However, a large (10-point) difference in FSIQ could be excluded on the basis of our noninferiority power calculation.In conclusion, in this follow-up study of 9-year-old offspring of mothers with GDM randomized to metformin or insulin treatment during pregnancy, we found that metformin did not adversely affect either offspring's neurocognitive outcomes assessed by standardized tests or executive function assessed by teachers and parents. These results could obtain further confirmation by performing a follow-up study of this cohort at the end of the basic education at the age of 16 years.