Metabolic Dysfunction-Associated Fatty Liver Disease and Subsequent Development of Adverse Pregnancy Outcomes

doi:10.1016/j.cgh.2021.11.007

Clinical Gastroenterology and Hepatology

Volume 20, Issue 11, November 2022, Pages 2542-2550.e8

https://doi.org/10.1016/j.cgh.2021.11.007 Get rights and content

Background & Aims

Recently, metabolic dysfunction–associated fatty liver disease (MAFLD), rather than nonalcoholic fatty liver disease (NAFLD), was proposed to better describe liver disease associated with metabolic dysfunction (MD). In this study, we attempted to investigate the impact of MAFLD on pregnancy complications.

Methods

The current study is a secondary analysis of a multicenter prospective cohort designed to examine the risk of NAFLD during pregnancy. In the first trimester, enrolled pregnant women were evaluated for hepatic steatosis by liver ultrasonography, and blood samples were collected for biochemical measurements. The study population was divided into 3 groups: no NAFLD, hepatic steatosis but without metabolic dysfunction (non-MD NAFLD), and MAFLD. The primary outcome was the subsequent development of adverse pregnancy outcomes, including gestational diabetes mellitus, pregnancy-associated hypertension, preterm birth, and fetal growth abnormalities.

Results

The study population consisted of 1744 pregnant women, including 1523 with no NAFLD, 43 with non-MD NAFLD, and 178 with MAFLD. The risk of subsequent development of adverse pregnancy outcomes was higher in MAFLD than in non-MD NAFLD (adjusted odds ratio, 4.03; 95% CI, 1.68–9.67), whereas the risk was not significantly different between no NAFLD and non-MD NAFLD. Among women with no NAFLD, the presence of MD increased the risk of adverse pregnancy outcomes. However, women with MAFLD were at higher risk for adverse pregnancy outcomes than women with no NAFLD without MD or those with no NAFLD with MD.

Conclusions

In pregnant women, MAFLD may be associated with an increased risk of subsequent adverse pregnancy outcomes.

Graphical abstract

Section snippets

Methods

The cohort included singleton pregnant women who were enrolled during their first trimester between October 2014 and August 2020 and followed up until delivery. After enrollment, baseline demographics and prepregnancy data were retrieved using questionnaires. At 10 to 14 weeks of gestation, participants underwent physical measurements and liver ultrasonography for evaluation of hepatic steatosis, and a fasting blood sample was collected for blood chemistry analysis. The study was approved by

Subject Population

During the study period, a total of 1922 pregnant women were enrolled. After excluding subjects with hepatitis B or C (n = 17), incomplete evaluation for MD (n = 11), withdrawal of consent (n = 43), previable birth (n = 14), and loss to follow-up evaluation (n = 93), the remaining 1744 pregnant women were included in the final analysis. According to the presence or absence of hepatic steatosis and MD, the study population was divided into 3 groups: no hepatic steatosis (no NAFLD, n = 1523);

Discussion

The principal findings of the current study were as follows: (1) among pregnant women, MAFLD was present in 10% of the study population, and among women with hepatic steatosis, MD was present in 81%; (2) the risk of subsequent development of adverse pregnancy outcomes was higher in women with MAFLD than in non-MD NAFLD women, whereas the risk was not significantly different between women without NAFLD and women with non-MD NAFLD; and (3) among women with no NAFLD, MD itself increased the risk

CRediT Authorship Contributions

Seung Mi Lee (Conceptualization: Equal; Formal analysis: Lead; Investigation: Equal; Writing – original draft: Lead; Writing – review & editing: Lead)

Young Mi Jung (Investigation: Equal; Writing – review & editing: Supporting)

Eun Saem Choi (Investigation: Supporting; Writing – review & editing: Supporting)

Soo Heon Kwak (Formal analysis: Supporting; Writing – review & editing: Supporting)

Ja Nam Koo (Investigation: Equal; Writing – review & editing: Supporting)

Ig Hwan Oh (Investigation:

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Cited by (10)

Pregnancy and Metabolic-Associated Fatty Liver Disease
2023, Endocrinology and Metabolism Clinics of North America
Transcriptional pathways linked to fetal and maternal hepatic dysfunction caused by gestational exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) in CD-1 mice
2022, Ecotoxicology and Environmental Safety
Citation Excerpt :
These biological processes are compromised in MAFLD (Eslam et al., 2020; Shao et al., 2020). Furthermore, MAFLD during pregnancy is associated with increased risk for preeclampsia, pregnancy-induced hypertension, and gestational diabetes mellitus (Lee et al., 2021). The ability to connect gene expression to phenotype is critical for establishing causal relationships between exposures and outcomes and for building confidence in toxicological mechanisms of action.
Per- and polyfluoroalkyl substances (PFAS) comprise a diverse class of chemicals used in industrial processes, consumer products, and fire-fighting foams which have become environmental pollutants of concern due to their persistence, ubiquity, and associations with adverse human health outcomes, including in pregnant persons and their offspring. Multiple PFAS are associated with adverse liver outcomes in adult humans and toxicological models, but effects on the developing liver are not fully described. Here we performed transcriptomic analyses in the mouse to investigate the molecular mechanisms of hepatic toxicity in the dam and its fetus after exposure to two different PFAS, perfluorooctanoic acid (PFOA) and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, known as GenX). Pregnant CD-1 mice were exposed via oral gavage from embryonic day (E) 1.5–17.5 to PFOA (0, 1, or 5 mg/kg-d) or GenX (0, 2, or 10 mg/kg-d). Maternal and fetal liver RNA was isolated (N = 5 per dose/group) and the transcriptome analyzed by Affymetrix Array. Differentially expressed genes (DEG) and differentially enriched pathways (DEP) were obtained. DEG patterns were similar in maternal liver for 5 mg/kg PFOA, 2 mg/kg GenX, and 10 mg/kg GenX (R²: 0.46–0.66). DEG patterns were similar across all 4 dose groups in fetal liver (R²: 0.59–0.81). There were more DEGs in fetal liver compared to maternal liver at the low doses for both PFOA (fetal = 69, maternal = 8) and GenX (fetal = 154, maternal = 93). Upregulated DEPs identified across all groups included Fatty Acid Metabolism, Peroxisome, Oxidative Phosphorylation, Adipogenesis, and Bile Acid Metabolism. Transcriptome-phenotype correlation analyses demonstrated > 1000 maternal liver DEGs were significantly correlated with maternal relative liver weight (R² >0.92). These findings show shared biological pathways of liver toxicity for PFOA and GenX in maternal and fetal livers in CD-1 mice. The limited overlap in specific DEGs between the dam and fetus suggests the developing liver responds differently than the adult liver to these chemical stressors. This work helps define mechanisms of hepatic toxicity of two structurally unique PFAS and may help predict latent consequences of developmental exposure.
MAFLD and Pregnancy: What are the Consequences?
2022, Clinical Gastroenterology and Hepatology
Reply
2022, Clinical Gastroenterology and Hepatology
The prevalence of metabolic dysfunction–associated fatty liver disease and its association on adverse pregnancy outcomes in women with gestational diabetes mellitus
2022, Diabetes Research and Clinical Practice
Citation Excerpt :
However, within this GDM cohort, the presence of MAFLD was not found to be associated with worse pregnancy outcomes. This is in contrast to prior studies which identified MAFLD as a potential risk factor for both adverse maternal and neonatal pregnancy outcomes, with a 2–3 fold higher risk of gestational hypertension and pre–eclampsia and a 2–fold increased risk of having both SGA or LGA neonates as well as pre–term birth and extreme prematurity (<32 weeks gestation) [26–28]. The lack of association of MAFLD with adverse pregnancy outcomes demonstrated in our study may be related to the predominance of participant recruitment occurring from a high–risk antenatal clinic, where closer monitoring and more intensive management is already in place for these at–risk group of women.
To determine the prevalence of metabolic dysfunction–associated fatty liver disease (MAFLD) and its association on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM).
380 women with GDM had a FibroScan® performed between 24 and 32 weeks. A Controlled Attenuation Parameter (CAP) ≥ 233.5 dB/m signified MAFLD. Gestational hypertension, pre–eclampsia and eclampsia contributed to a composite of adverse maternal outcomes. A composite of adverse neonatal outcomes included pre–term birth, hypoglycaemia, small/large–for–gestational age and admission to neonatal high dependency. Multiple logistic regression was used to determine independent associations with MAFLD.
147 (38.7 %) women had MAFLD. Higher pre–pregnancy BMI (median 28.4, IQR 24.7–33.0 kg/m² vs median 24.0, IQR 21.7–26.5 kg/m², p < 0.01) and rates of insulin therapy (62.2 % vs 40.7 %, p < 0.01) occurred in MAFLD over non–MAFLD women. MAFLD was independently associated with obesity (aOR 4.73 [95 % CI 2.53–8.86]) and insulin therapy (aOR 1.79 [95 % CI 1.12–2.85]). MAFLD and non–MAFLD women had comparable rates of adverse maternal (7.7 % vs 9.5 %, p = 0.56) and neonatal outcomes (75.4 % vs 68.8 %, p = 0.18).
Within this GDM cohort, almost 40% had FibroScan®–detected MAFLD in mid–to–late gestation. MAFLD was not associated with worse pregnancy outcomes.
Fatty liver indices and their association with glucose metabolism in pregnancy – An observational cohort study
2022, Diabetes Research and Clinical Practice
Citation Excerpt :
Metabolic dysfunction could be considered to be the underlying risk factor for both, the development of GDM and fatty liver disease; however, another Korean study found that pregnant women with MAFLD had an approximately twofold higher risk for developing GDM compared to women with no fatty liver disease but metabolic dysfunction, even after adjustment for age, prior history of GDM or family history of type II diabetes. This suggests that hepatic steatosis has an adverse impact on glycemic regulation in pregnancy, independently of the presence of metabolic dysfunction [32]. Some mechanistic studies suggest that increased ectopic lipid contents, specifically intracellular lipid metabolites, inhibit insulin signaling leading to hepatic insulin resistance [33].
Non-invasive hepatic steatosis indices can be used to assess the risk for metabolic (dysfunction) associated fatty liver disease (MAFLD). This may be helpful to detect metabolic disorders in pregnancy, specifically gestational diabetes (GDM). We aim to examine the association of these indices with parameters of glucose metabolism.
109 women underwent a metabolic characterization at 16 weeks of gestation and were classified according to the fatty-liver index (FLI) and hepatic-steatosis index (HSI) into low (G1), intermediate (G2) and high risk (G3). At 26 weeks, participants received an oral glucose tolerance test (OGTT) to assess insulin action, β-cell function and GDM status.
Both MAFLD indices were associated with impaired insulin sensitivity and compensatory increase of insulin release. G3 groups showed impaired insulin action. The higher circulating insulin concentrations were not able to compensate for insulin resistance in women with higher MAFLD scores, resulting in an increased risk of GDM (OR: 1.05, 95% CI 1.03 to 1.08, p < 0.001 for FLI). MAFLD scores were associated with fetal overgrowth.
Maternal MAFLD represents a high-risk obstetric condition. Hepatic steatosis indices are associated with impaired glucose regulation and may provide a useful tool for early risk assessment for impaired glucose metabolism.

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: Conflicts of interest The authors disclose no conflicts.

: Funding This work was supported by the Seoul National University Hospital research fund (0320212200), and two National Research Foundation of Korea grants funded by the Ministry of Education, Science and Technology of the Korean government (2021R1A2C2005820 and 2021M3A9E4021818).

^b: Authors share co-corresponding authorship.

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Original ArticleHepatologyMetabolic Dysfunction-Associated Fatty Liver Disease and Subsequent Development of Adverse Pregnancy Outcomes

Background & Aims

Methods

Results

Conclusions

Graphical abstract

Section snippets

Methods

Subject Population

Discussion

CRediT Authorship Contributions

J Hepatol

J Hepatol

Clin Gastroenterol Hepatol

Lancet

J Hepatol

Ann Hepatol

Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes

Hepatology

Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients

Diabet Care

Nonalcoholic fatty liver disease: a feature of the metabolic syndrome

Diabetes

The NAFLD-MAFLD debate: eminence vs evidence

Liver Int

Non-alcoholic fatty liver disease in the first trimester and subsequent development of gestational diabetes mellitus

Diabetologia

Nonalcoholic fatty liver disease is a risk factor for large-for-gestational-age birthweight

PLoS One

The risk of pregnancy-associated hypertension in women with nonalcoholic fatty liver disease

Liver Int

A comparison of predictive performances between old versus new criteria in a risk-based screening strategy for gestational diabetes mellitus

Diabetes Metab J

Original Article
Hepatology
Metabolic Dysfunction-Associated Fatty Liver Disease and Subsequent Development of Adverse Pregnancy Outcomes