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Review
. 2023 Jun 24;28(1):197.
doi: 10.1186/s40001-023-01161-z.

The impact of early pregnancy metabolic disorders on pregnancy outcome and the specific mechanism

Xi-Zi Zhu #  1 , Zhi-Min Deng #  1 , Fang-Fang Dai  1 , Hua Liu  2 , Yan-Xiang Cheng  3
Affiliations
Review

The impact of early pregnancy metabolic disorders on pregnancy outcome and the specific mechanism

Xi-Zi Zhu et al. Eur J Med Res. .

Abstract

Miscarriage is the most common complication of pregnancy. The most common causes of early miscarriage are chromosomal abnormalities of the embryo, maternal endocrine abnormalities, organ malformations, and abnormal immune factors. Late miscarriages are mostly caused by factors such as cervical insufficiency. However, the causes of 50% of miscarriages remain unknown. Recently, increasing attention has been given to the role of metabolic abnormalities in miscarriage. In this review, we mainly discuss the roles of four major metabolic pathways (glucose, lipid, and amino acid metabolism, and oxidation‒reduction balance) in miscarriage and the metabolism-related genes that lead to metabolic disorders in miscarriage. Depending on aetiology, the current treatments for miscarriage include hormonal and immunological drugs, as well as surgery, while there are few therapies for metabolism. Therefore, we also summarize the drugs for metabolism-related targets. The study of altered metabolism underlying miscarriage not only helps us to understand the mechanisms involved in miscarriage but also provides an important basis for clinical research on new therapies.

Keywords: Amino acid metabolism; Glucose metabolism; Lipid metabolism; Miscarriage; Redox reactions.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The role of HIF-1α in abnormal glucose metabolism leading to abortion. A. Elevated lactate levels in metaphase macrophages activate the HIF-1α/SRC/LDHA pathway, enhancing INOS expression in a HIF-1α-dependent manner, which in turn promotes their M1 polarization, thereby disrupting immune tolerance and triggering abortion. AZD3965 can reverse. B. Insufficient accumulation of chorionic succinate promotes HIF-1α degradation via the PHD-VHL pathway, leading to a decrease in HIF-1α and thereby inhibiting angiogenesis, trophoblast migration, and glycolysis. C. Downregulation of the TGF-β/mTOR/HTF-1α pathway leads to inhibition of ATP-adenosine metabolism, resulting in a decrease in the number of CD39 + and CD73 + cells at the maternal–fetal interface. This inhibits trophoblast proliferation and invasion and reduces apoptosis and increases toxicity of dNK cells, which in turn leads to RSA. LA lactate, MCT the monocarboxylate transporter protein, AZD3965 MCT-1 inhibitor, HIF-1α the hypoxia-inducible factor 1α, ROS reactive oxygen species, SRC Proto-oncogene tyrosine-protein kinase SRC, LDHA lactate dehydrogenase A, INOS inducible nitric oxide synthase, EVT Extravillous trophoblasts, dNK decidual natural killer cells, TGF-β transforming growth factor-β, mTOR mammalian target of rapamycin, HGF hepatocyte growth factor
Fig. 2
Fig. 2
Abnormal amino acid metabolism and miscarriage. A. In the endometrium, a decrease in various amino acids can lead to the accumulation of uncharged tRNA, which in turn activates the GCN2/eIF2α/transcriptional activation factor 4 (ATF4) pathway, thereby inhibiting protein synthesis and inducing autophagy. B. At the maternal–fetal interface, meconium macrophages can promote trophoblast cell apoptosis by activating the PRMT3/ADMA/NO pathway and decreasing the concentration of NO in the meconium. SGC707 can reverse. C. Vitamin D deficiency can increase homocysteine levels by decreasing CBS, while inducing increased NK cell cytotoxicity and promoting inflammatory immune responses at the maternal–fetal interface. GCN2 the general control nonderepressible 2, eIF2αK4 eukaryotic translation initiation factor 2α kinase 4, ATF4 transcription activation factor 4, PRMTs type I protein L-arginine methyltransferases, SGC707 PRMT3 inhibitor, ADMA asymmetric dimethylarginine, NOS nitric oxide synthase, NO nitric oxide, CBS cystathionine beta-synthase, VitB6 Vitamin B6, VitD Vitamin D
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