Fetal growth restriction (FGR) represents a significant obstetric challenge, affecting approximately 5–10% of pregnancies worldwide [1, 2]. It is diagnosed when a fetus fails to reach its inherent growth potential, most commonly defined as an estimated fetal weight below the 10th percentile for gestational age (GA) [3]. FGR is associated with a range of adverse perinatal outcomes, including higher risks of perinatal mortality, neonatal intensive care unit (NICU) admission, and long-term neurodevelopmental impairment (NDI).

The etiology of FGR is multifactorial, characterized by a complex interplay of maternal, fetal, and placental factors [1, 2, 4]. Maternal conditions such as hypertension, preeclampsia, malnutrition, and chronic underlying diseases can compromise placental function, leading to insufficient nutrient and oxygen delivery to the fetus. Fetal factors, including chromosomal abnormalities and congenital anomalies, also contribute to the development of FGR. Placental insufficiency, which disrupts the exchange of nutrients and gases, is widely recognized as the primary mechanism underlying FGR [2].

Current clinical practices for predicting FGR predominantly rely on routine fetal ultrasonography, including measurements of fetal biometry and Doppler assessments of uterine and umbilical arteries [5]. However, the accuracy of this method is influenced by factors such as maternal obesity, inaccurate estimation of GA, and operator subjectivity, which can lead to significant diagnostic errors. As a result, 75% of cases of idiopathic FGRs (IFGRs) go undetected until delivery, and the detection rate among low-risk pregnant women is only 15%. Limitations of ultrasound in predicting FGR also include operator dependency, limited sensitivity in low-risk populations, and relatively high false-positive rates. In recent years, several studies have shown that maternal serum biomarkers, such as pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PIGF), may also serve as predictors of FGR [6, 7, 8, 9]. Although these biomarkers provide some predictive value, their use alone in clinical settings remains constrained by insufficient sensitivity and specificity, and none of these measures can accurately predict FGR in the first trimester.

Recently, interest has increased in identifying novel biomarkers that allow timely interventions for mitigating adverse outcomes. In this context, the mannose-6-phosphate receptor (M6PR) has emerged as a promising candidate. M6PR is a multifunctional protein involved in several physiological processes, including lysosomal enzyme trafficking, insulin-like growth factor II (IGF-II)-mediated growth regulation, and modulation of signaling pathways critical for cellular function [10]. Emerging evidence suggests that M6PR plays a pivotal role in placental development and function, potentially influencing fetal growth trajectories [6, 11]. Zygmunt et al. [12] suggested that IGF-II/M6PR promotes the invasion of trophoblast cells into the uterus.

In a previous study, we performed RNA sequencing (RNA-seq) on five pairs of monochorionic diamniotic twins with selective FGR (sFGR) and three pairs of monochorionic diamniotic twins with normally grown fetuses (controls). The analysis revealed a significant upregulation of M6PR in the placental tissue of the sFGR group, suggesting a potential association between M6PR and sFGR. Since M6PR in the placenta can be released into the maternal blood, it may become a potential biomarker for the diagnosis of FGR and fetal monitoring [11]. Based on the role of M6PR in regulating placental function and our previous findings, the present study aimed to evaluate maternal serum M6PR levels during pregnancy as a potential predictive biomarker for FGR.

The present study evaluated maternal serum M6PR levels in late pregnancy as a novel biomarker to predict FGR. The results demonstrated a significant association between decreased M6PR levels and FGR in the third trimester, indicating its strong predictive value. However, serum M6PR concentrations during the first and second trimesters showed no significant alterations compared with the control group. In addition, reduced M6PR levels were significantly associated with both early-onset and late-onset FGR and idemonstrated significant predictive value. These results advance our understanding of the pathophysiology of FGR and support the development of early detection strategies.

M6PR is an important cell membrane receptor that mainly recognizes and transports enzymes labeled with mannose-6-phosphate (M6P). These enzymes are synthesized in the endoplasmic reticulum and then transported to lysosomes to perform their functions. M6PR ensures normal cell metabolism and function through its role in enzyme binding and transport from the Golgi apparatus to the lysosome [17]. Two types of M6PRs have been reported. The mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGFII receptor, M6P/IGF2-R) binds the M6P ligand and the IGF2 receptor. Cation-dependent mannose-6-phosphate receptor (CD-M6PR) requires a bivalent cation to bind the M6P ligand but not bind IGF2-R [18, 19]. M6P/IGF2-R is also known as a cation-independent M6P receptor (CI-M6PR) because it binds its ligand without require ions [20, 21, 22]. The molecular weight of CD-M6PR is 46 kDa, and the molecular weight of CI-M6PR is 250 kDa [22, 23]. M6PR mediates the transport of M6P-labeled enzymes from the Golgi to the lysosome, a key process in its biological function. This process is key for cellular metabolism and the clearance of intracellular substances. M6PR internalizes bound enzymes into the cell through endocytosis and subsequently delivers them to the endoplasmic reticulum or lysosome, where they perform their functions [24]. M6PR also plays a role in cell signaling, affecting cell growth, differentiation, and metabolism. Dysfunction of M6PR is associated with a various diseases, including lysosomal storage disorders (e.g., Gaucher disease and Fabry disease), as well as certain types of cancer [25, 26, 27, 28].

A decrease in M6PR may impact fetal growth by disrupting intracellular transport, particularly in the delivery of enzymes and nutrients essential for cell growth. Reduced expression of M6PR can impair the transport of nutrients and enzymes, thereby affecting normal fetal growth and development. In addition to its in substance transport, M6PR may also play a role in cell signaling. Decreased M6PR expression may affect cellular responses to growth factors and other signaling molecules, which in turn affect fetal growth regulation. M6PR dysfunction can impair lysosomal function, increasing the risk of apoptosis. Such cell death may compromise fetal tissue development and organ formation. M6PR is associated with cellular antioxidant capacity, and a decrease in M6PR levels may lower cellular resistance to oxidative stress, thereby increasing the risk of fetal damage. The placenta is the main structure supporting fetal growth, and a decrease in M6PR may impair placental cell function, thereby disrupting nutrient and gas exchange between mother and fetus. Reduced M6PR may also affect the expression of growth-related genes, potentially leading to FGR.

The decrease in M6PR may impair cellular nutrient uptake and utilization, thereby adversely affecting fetal growth. The mammalian target of rapamycin (mTOR) pathway is a key regulator of cell growth and metabolism, controlling cell growth, proliferation, protein synthesis, and autophagy [29, 30]. During embryonic development, precise regulation of the mTOR pathway is essential, as its abnormal activation or inhibition can result in FGR [31, 32, 33, 34]. When M6PR is reduced, it may impair lysosomal function and disrupt cellular nutrient processing and utilization. Under these conditions, cells may fail to maintain normal mTOR pathway activity. Inhibition of mTOR results in reduced expression of cyclin D and cyclin-dependent kinase 4 (CDK4), restricting cell growth and proliferation and affecting normal fetal development [35, 36, 37]. Combined with the alterations in the mTOR pathway, we speculated that the reduction in M6PR may form a feedback loop, thereby further exacerbating FGR. This potential mechanism may involve complex cellular signaling, leading to impaired placental function and compromised maternal nutrient supply to the fetus. In summary, our findings suggest a potential link between decreased M6PR, mTOR pathway dysregulation, and the pathogenesis of FGR. Investigating these mechanisms could enhance our understanding of the pathophysiological processes underlying FGR and provide novel insights for its prevention and treatment.

Although current serological biomarkers provide some utility in predicting FGR, their clinical application remains limited due to suboptimal performance. In contrast, M6PR represents an emerging biomarker that may offer improved specificity and sensitivity, as well as directly reflect the underlying pathophysiology of FGR, warranting further investigation and validation. The AUC, which ranges from 0.5 (no discrimination) to 1.0 (perfect discrimination), is an important metric to evaluate the classification performance of the model. In this study, the model predicted third trimester FGR with an AUC of 0.736, showing good ability to distinguish the control group from the non-control group. The sensitivity was 0.812, indicating that the model had a high accuracy in identifying the non-control group, such as third trimester FGR patients, while the specificity was 0.785. This also indicates that the accuracy of the model is relatively high when excluding controls, such as healthy individuals. Such performance metrics are promising for clinical applications, especially for screening and early intervention of patients in third trimester patients. In the detailed analysis of model performance, we examined not only the AUC value of the model but also the positive and negative prediction rates, which are critical to evaluate the potential of the model in clinical diagnosis. The positive prediction rate was 0.791, which meant that when the model predicted a non-control group, it was correct 79.1% of the time, which provided strong decision support for clinicians. At the same time, the negative prediction rate of 0.807 indicated that when the model predicts a control group, it was accurate 80.7% of the time, further enhancing its reliability in ruling out the disease. The false positive and false negative rates revealed the types of errors that may occur in the prediction process of the model. The false positive rate was 0.215, indicating a 21.5% chance that the model would misclassify a control case as non-control, which could lead to unnecessary further testing or treatment. The false negative rate was 0.188, which meant that there was 18.8% chance that the model would miss non-control group cases, which needed special attention in clinical practice. The Youden index was 0.598, reflecting the combined sensitivity and specificity of the model. It reflected the ability of the model to distinguish between different disease states and provided a quantitative measure of its overall performance.

Previous studies have evaluated other biomarkers for FGR prediction. For instance, elevated levels of soluble fms-like tyrosine kinase-1 (sFlt1, also known as VEGFR1) in maternal blood were reported to be associated with FGR [38, 39]. The sensitivities were 0.64 and 0.89, and the specificities were 0.54 and 0.62, respectively. The AUC of ROC was 0.777, and the NPV was 0.98. However, the PPV was only 0.17. Maternal plasma soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were both increased between the 22 and 29 weeks of gestation. The sensitivity and specificity of sICAM-1 were 0.42 and 0.16, respectively, and those of sVCAM-1 were 0.16 and 0.03, respectively [40, 41]. In conclusion, M6PR is a superior marker to predict the occurrence and progression of FGR in the third trimester. Compared with other markers, it offers irreplaceable advantages and is more suitable for clinical diagnosis.

Currently, the role of M6PR in the pathological mechanisms of FGR remains unclear. Future research should focus on the pathways through which M6PR influences placental function and fetal growth. Exploring the interplay between M6PR and other growth factors, inflammatory markers, and placental morphogenesis may provide a more comprehensive understanding of its role in FGR. Moreover, combining M6PR with a panel of emerging biomarkers and applying advanced statistical models, such as machine learning algorithms, may further enhance predictive accuracy and facilitate personalized approaches to FGR management. M6PR emerges as a promising novel biomarker for the prediction of early- and late-onset FGR in maternal serum during the third trimester. However, its efficacy in predicting FGR in the first and second trimesters remains limited. Continued investigation into M6PR and its integration with comprehensive biomarker panels could pave the way for more effective strategies in the prevention and management of FGR, ultimately improving perinatal outcomes.

This study demonstrated that maternal serum M6PR levels were significantly lower during the third trimester in patients with FGR. M6PR alone demonstrated superior predictive performance for early-onset FGR, with an AUC of 0.723, whereas the AUC for late-onset FGR was 0.645. These findings highlight the potential of M6PR as a biomarker for predicting FGR and its subtypes, suggesting that it could be incorporated into serological screening strategies for FGR.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

WL, PS designed the research study. XB and YC performed the research. WL, ZG and YH analyzed the data. YL and YH participated in data collection and processing. YL, SZ and LZ contributed to the study design and to revision of the manuscript. JX, JL and ZC contributed to data collection. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Research ethics approvals were granted at the Medical Ethics Committee of Maternity and Child Healthcare Hospital of Nanshan District (approval reference number NSFYEC-KY-2021047) and conducted in accordance with the Declaration of Helsinki. All participants provided informed consent prior to inclusion in the study.

We thank the peer reviewers for their constructive comments and the clinical records team for assistance with data retrieval.

This project was funded by Nanshan district health system science and technology major project (NSZD2023067), Supported by Sanming Project of Medicine in Shenzhen Nanshan (No.202407).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/CEOG45923.