Differential Effects Of Pre-pregnancy And Gestational Diabetes Mellitus On The Risk Of Childhood And Adolescent Cancer In Offspring

Objective:Diabetes mellitus is the most common metabolic disorder in women during pregnancy.Diabetes mellitus during pregnancy can be divided into two types,one is diabetes mellitus diagnosed before pregnancy,which can be classified as type 1diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM).The other type of diabetes mellitus is gestational diabetes mellitus(GDM),which occurs in the middle and late stages of pregnancy.In recent years,studies have explored the association between maternal diabetes and childhood and adolescent cancers in the offspring,but the results were inconsistent.Therefore,I performed a systematic review to clarify the effects of pre-pregnancy diabetes and GDM on the risk of childhood and adolescent cancers in offspring,so as to provide scientific basis for reducing the adverse effects of maternal diabetes on the health status of offspring and improving maternal and infant health.Methods:We performed a comprehensive literature search in Pub Med,Embase,Web of science,CNKI and Wanfang Data databases from their inception to January 31,2021,to identify studies that investigated the association between maternal diabetes and risk of childhood and adolescent cancers in the offspring.Key terms in the literature search strategy were as follows:maternal diabetes,gestational diabetes mellitus,pre-pregnancy diabetes mellitus,childhood and adolescent cancers,pediatric cancers,adolescent cancer,offspring,cancers,tumor,neoplasms and malignancy,etc.In addition,references to relevant studies were manually searched.Newcastle-Ottawa Scale(NOS)guidelines was used to assess the quality of studies.Studies scoring 7-9were identified as high-quality,those with scores of 3-6 were considered moderate quality and the others were of low quality.The summary ORs and corresponding 95%CIs were calculated to examine the effect of maternal diabetes on the risk of childhood and adolescent cancers in the offspring.Since the risk of these diseases in the general population was low,all effect sizes(ESs)were interpreted as OR for simplicity.The Q test and the I~2 value was used to examine the heterogeneity of the included studies.I~2values of<25%,25-75%and>75%were defined as low,medium and high heterogeneity,respectively.Subgroup analysis and meta-regression were performed to explore the sources of heterogeneity.Our study used funnel plots to assess the publication bias in the included studies.Furthermore,Egger’s linear regression tests and Begg’s adjusted rank correlation test were also conducted and a P value of<0.05indicated potential publication bias.Results:As a result,20 literatures were included in this systematic review according to the inclusion/exclusion criteria.Of these studies,14 were case-control studies including a total of 23,015 cancer cases and 3,974,960 controls,and the remaining 6 were cohort studies with sample sizes ranging from 8,839 to 1,226,515.Preliminary analysis revealed a significantly increased risk of cancers in offspring of mothers with diabetes in pregnancy(OR,1.30;95%CI,1.10-1.53),but significant heterogeneity was observed(I~2=73.3%,P<0.001).Four studies did not report the specific type of maternal diabetes,with a pooled OR of 1.26(95%CI,1.05-1.51),suggesting a significantly increased risk of tumors in children of mothers with diabetes.Six studies reported the effect of GDM on the overall risk of childhood and adolescent cancers in their offspring,with a summary OR value of 1.15(95%CI,1.03-1.28).Six studies foucused on prepregnancy diabetes and the poolded OR was 1.55(95%CI,1.41-1.70).Meta-regression results showed that maternal diabetes type was one of the important sources of heterogeneity among the included studies(Adj R-squared=32.23%),and there was a statistically significant difference between prepregnancy diabetes and GDM(P=0.026).For specific types of cancer,both pre-pregnancy diabetes and GDM were associated with an increased risk of childhood leukemia(prepregnancy diabetes:OR,1.32,95%CI,1.13-1.55;GDM:OR,1.28,95%CI,1.04-1.57),especially acute lymphoblastic leukemia(pre-pregnancy diabetes:OR,1.56,95%CI,1.31-1.85;GDM:OR,1.30,95%CI,1.05-1.61).When pre-pregnancy diabetes and GDM were combined,meta-analysis results suggested that maternal diabetes was associated with a reduced risk of brain tumors in offspring(OR,0.59;95%CI,0.390.91).However,the association was not significant for pre-pregnancy diabetes and GDM.In addition,our study did not find an association between maternal diabetes and the risk of lymphoma,retinoblastoma,astrocytoma,germ cell tumors,hepatoblastoma,rhabdomyosarcoma and Wilms’tumor in the offspring.Conclusion:This study found that the risk of childhood and adolescent cancers was significantly higher in the children of diabetic mother compared to the children of women without diabetes.Children of pre-pregnancy diabetic mothers had a higher elevated risk of childhood tumors than did those of GDM mothers.Both pre-pregnancy diabetes and GDM are associated with an increased risk of leukemia in offspring,especially acute lymphoblastic leukemia.