Gestational diabetes mellitus and development of intergenerational non-alcoholic fatty liver disease (NAFLD) after delivery: a systematic review and meta-analysis

Abstract

Background: It is known that gestational diabetes mellitus (GDM)-complicated pregnancies could affect maternal cardiometabolic health after delivery, resulting in hepatic dysfunction and a heightened risk of developing non-alcoholic fatty liver disease (NAFLD). Hence, this study aims to summarise existing literature on the impact of GDM on NAFLD in mothers and investigate the intergenerational impact on NAFLD in offspring.

Methods: Using 4 databases (PubMed, Embase, Web of Science and Scopus) between January 1980 and December 2023, randomized controlled trials and observational studies that assessed the effect of maternal GDM on intergenerational liver outcomes were extracted and analysed using random-effects meta-analysis to investigate the effect of GDM on NAFLD in mothers and offspring. Pooled odds ratio (OR) was calculated using hazards ratio (HR), relative risk (RR), or OR reported from each study, with corresponding 95% confidence intervals (CI), and statistical heterogeneity was assessed with the Cochran Q-test and I² statistic, with two-sided p values. The study protocol was pre-registered on PROSPERO (CRD42023392428).

Findings: Twenty studies pertaining to mothers and offspring met the inclusion criteria and 12 papers were included further for meta-analysis on intergenerational NAFLD development. Compared with mothers without a history of GDM, mothers with a history of GDM had a 50% increased risk of developing NAFLD (OR 1.50; 95% CI: 1.21-1.87, over a follow-up period of 16 months-25 years. Similarly, compared with offspring born to non-GDM-complicated pregnancies, offspring born to GDM-complicated pregnancies displayed an approximately two-fold elevated risk of NAFLD development (2.14; 1.57-2.92), over a follow-up period of 1-17.8 years.

Interpretation: This systematic review and meta-analysis suggests that both mothers and offspring from GDM-complicated pregnancies exhibit a greater risk to develop NAFLD. These findings underline the importance of early monitoring of liver function and prompt intervention of NAFLD in both generations from GDM-complicated pregnancies.

Funding: No funding was available for this research.

Keywords: Gestational diabetes mellitus; Intergenerational impact; Maternal postpartum; Non-alcoholic fatty liver disease; Offspring.

Fig. 1

Flow chart of systematic review literature searching scheme. Fig. 1A depicts the searching scheme of maternal postpartum NAFLD in women with a history of GDM; Fig. 1B depicts the searching scheme of offspring NAFLD born to a GDM-complicated pregnancy.

Fig. 2

Meta-analysis Results. Evidence of overall Odds Ratio (ORs) and 95% confidence interval (CI) of maternal GDM and maternal postpartum NAFLD (A) and offspring NAFLD (B), using unadjusted random-effects model. Heterogeneity was presented in both I² (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T² (reflecting the variance of the true effect sizes). Abbreviations: OR, odds ratio; CI, confidence interval; %, percentage.

Fig. 3

Subgroup analyses on maternal GDM and maternal postpartum NAFLD, stratified by study characteristics and adjustments. Evidence of overall Odds Ratio (ORs) and 95% confidence interval (CI) of maternal GDM and maternal postpartum NAFLD was reported in all subgroups, using unadjusted random-effects model. Heterogeneity was presented in both I² (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T² (reflecting the variance of the true effect sizes). Cochran's Q test is used to determine if there are differences of NAFLD within subgroups or between subgroups. p value < 0.10 for Q-test is considered significant. Abbreviations: CI, confidence interval; GDM, gestational diabetes mellitus; NAFLD, non-alcoholic fatty liver disease; T2D, type 2 diabetes; NOS, Newcastle–Ottawa Scale.

Supplementary Figure S1

Funnel plot regarding MA of maternal GDM and maternal NAFLD.

Supplementary Figure S2

Subgroup analysis of study adjustment in meta-analysis results of association between GDM and maternal postpartum NAFLD. Evidence of overall Odds Ratio (ORs) and 95% confidence interval (CI) of maternal GDM and maternal postpartum NAFLD was reported in all subgroups, using unadjusted random-effects model. Heterogeneity was presented in both I² (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T² (reflecting the variance of the true effect sizes). Cochran's Q test is used to determine if there are differences of NAFLD within subgroups or between subgroups. P value < 0.10 for Q-test is considered significant. Abbreviations: CI, confidence interval; BMI, body mass index, HDP, hypertensive disorder during pregnancy; HTN, hypertension; T2D, type 2 diabetes.

Supplementary Figure S3

Funnel plot regarding MA of maternal GDM and offspring NAFLD.