Obesity and recurrent spontaneous abortion: the crucial role of weight management in pregnancy

Abstract

Recurrent spontaneous abortion (RSA), characterized by the loss of two or more pregnancies, impacts approximately 1–2% of couples and poses a significant challenge for individuals of childbearing age. The precise mechanisms underlying RSA remain incompletely understood. Concurrently, the global prevalence of obesity is on the rise, with obesity being closely associated with female reproductive disorders and infertility. This study initially examines the pathways through which obesity contributes to RSA, encompassing factors such as embryonic euploid miscarriage, endometrial development, immune function, among others. Furthermore, adipokines and the fat mass and obesity-related (FTO) are identified as potential contributors to RSA. The study also explores the enhancement of pregnancy outcomes through various weight management strategies, with a particular focus on the roles of dietary interventions, physical activity, and weight control during pregnancy. Obesity is closely related to RSA in multiple aspects. Additional clinical prospective and experimental studies are required to explore its precise pathogenesis. Through this review, we aim to provide strategies for improvement and treatment approaches for RSA related to obesity. Through this review, we suggest potential clinical management strategies and research avenues aimed at offering enhancements and therapeutic insights for miscarriages linked to obesity and its associated risk factors.

Introduction

The American Society for Reproductive Medicine (ASRM) defines RSA as a condition characterized by the occurrence of two or more clinical pregnancies resulting in loss [1]. This condition impacts approximately 1–2% of couples [2]. Major factors contributing to RSA include chromosomal abnormalities, anatomical structural irregularities, infections, immune system dysregulation, and endocrine disorders. Nevertheless, a significant proportion of RSA cases, approximately 50%, remain of unknown origin, termed as unexplained recurrent pregnancy loss. Despite extensive scholarly research in this area, challenges persist in fully understanding the causes and management of RSA.

As societal conditions advance, there is a global increase in the prevalence of obesity. This widespread issue has become a significant concern, impacting more than 2 billion individuals worldwide and resulting in over 3 million fatalities annually [3]. Projections based on current data suggest that by 2030, nearly 40% of the global population will be overweight, with approximately one-fifth falling into the obese category [4]. Obesity is recognized as a key risk factor for various non-communicable diseases and is closely linked to conditions such as type 2 diabetes, hypertension, coronary heart disease, acute pancreatitis, premature aging, and neurodegenerative disorders [5,6,7].

In the realm of reproductive health, researchers have noted that women with overweight may encounter a range of pregnancy complications, including birth defects, miscarriages, and neonatal illnesses, which can ultimately impact fertility rates. Studies indicate that obesity have detrimental effects on fertility by impeding ovulation, menstrual regularity, and natural conception. Obesity stands as an independent risk factor for recurrent miscarriages [8], with women with obesity exhibiting a notably higher rate of miscarriage compared to their counterparts with non-obesity [9]. As Body Mass Index (BMI) rises in pregnant individuals, there is a significant decrease in live birth rates [10].

This review aims to explore the mechanisms through which obesity contributes to RSA and heightens the risk of miscarriage by examining current scientific evidence on the adverse effects of maternal obesity on RSA. While male obesity receives less attention in this context due to the gender-specific nature of RSA, efforts have been made to synthesize existing research on the influence of male obesity on RSA. Additionally, the review outlines the positive effects of weight management on pregnancy outcomes for women with obesity, underscoring the advantages of controlling weight gain during pregnancy for the well-being of both mothers and fetuses.

The mechanism of obesity leading to RSA

Focusing on early embryo development, the review delves into six key aspects through which female obesity impacts the initiation and progression of RSA: (i) obesity and embryo euploid miscarriage; (ii) obesity and oocyte quality; (iii) obesity and endometrial development; (iv) obesity and maternal immune imbalance; (v) obesity and disrupted adipokine secretion; (vi) obesity-related genes (Fig. 1).

Fig. 1

Risk factors for obesity leading to RSA. In female obese patients, RSA may be related to six aspects: embryo euploid miscarriage, poor oocyte quality, endometrial dysplasia, maternal immune imbalance, adipokine secretion disorder, and obesity-related genetic abnormalities

Obesity and embryo euploid miscarriage

Chromosomal abnormalities in embryos are a common factor contributing to early miscarriage. Research indicates a link between obesity and a heightened occurrence of euploid miscarriages in women with RSA [11]. Tremellen et al. conducted an analysis on pregnancy outcomes post-transfer of confirmed euploid embryos in cryopreserved In Vitro Fertilization (IVF) cycles, noting a significantly elevated rate of pregnancy failures in obese individuals (41.9%) compared to lean (14.2%) and super-recombinant (29.1%) groups [12]. A recent multicenter review in 2021, involving 3,480 women categorized by weight, reported a 22.7% miscarriage rate in women with obesity, with 13.5% classified as clinical abortion [13]. Furthermore, in a separate study involving embryo transfers with known chromosomal outcomes, Among the 117 eligible patients who underwent abortions, women with obesity experienced a 58% frequency of euploid miscarriages, in contrast to 37% in women with non-obese, indicating a relative risk of 1.63 (95% confidence interval 1.08–2.47) [9].

Compared to miscarriage in euploid pregnancies, the relationship between obesity and aneuploid pregnancy is less significant. The adverse effects of being overweight or obese on IVF and reproductive outcomes may not be directly linked to aneuploidy [14]. A study that looked back at a group of patients found that without taking maternal age into account, maternal BMI was significantly linked to a higher occurrence of aneuploidy, with rates of 51.5% in the obese category and 39.3% in the non-obese category. However, once age was factored in, BMI was not a reliable predictor of aneuploidy incidence [15]. This suggests that the detrimental effects of excess weight on IVF and reproductive outcomes may not be specifically tied to aneuploidy, a perspective supported by another retrospective study conducted by the Urian’ team [16].

The dominant perspective posits that obesity has a detrimental effect on embryonic chromosomes, primarily by influencing the quantity of chromosomal euploids, consequently elevating the risk of miscarriage. Nevertheless, the exact mechanism behind this phenomenon remains ambiguous, underscoring the need for additional research to explore the correlation between obesity and the quantity and configuration of both oocytes and embryonic chromosomes.

Obesity leading to abnormal oocytes quality

Oocytes are crucial in the embryonic development process, with the quality of oocytes significantly influencing the subsequent development of embryos. Leary et al. compared the morphology and developmental dynamics of embryos from healthy individuals with those from women with obesity and overweight. They found that oocytes from women with obesity and overweight were significantly smaller than those from women with a healthy BMI [17]. Furthermore these embryos often exhibit metabolic abnormalities, which could potentially jeopardize the health of the fetus and future generations. Additionally, embryos derived from oocytes of women with obesity and overweight also demonstrate lower developmental potential after IVF, with reduced blastocyst formation rates [18]. These results indicate that obesity increases the likelihood of reproductive system abnormalities by influencing the quality of oocytes. Subsequently, we will explore the precise mechanisms implicated in this phenomenon. We will discuss the impact and mechanisms of obesity on oocytes quality from four aspects: (i) Abnormal extracellular environment of oocytes; (ii) Telomere dysfunction; (iii) Stella levels decrease; (iv) Mitochondrial dysfunction (Fig. 2).

Fig. 2

Obesity leading to abnormal oocytes quality. A A high concentration of palmitic acid in follicular fluid induces ceramide accumulation and downregulates the AMPK/SIRT3 pathway, resulting in oocytes mitochondrial protein hyperacetylation and dysfunction. B Obesity can shorten the telomere length of oocytes, affect the development of embryos and fetuses, and consequently shorten neonatal telomeres. C Female mice knocked out for Stella could produce oocytes that appear normal, but the embryos were unable to reach the blastocyst stage. D Obesity leads to decreased mtDNA content and increased mitochondrial single nucleotide variations in oocytes, which can also result in mitochondrial dysfunction. Abbreviations: AMPK: adenosine 5’-monophosphate (AMP)-activated protein kinase; SIRT3: sirtuin 3; ATP: adenosine triphosphate; ROS: reactiveoxygenspecies; Stella KO: stella knockout mice; mtDNA: mitochondrial DNA; mtSNVs: mitochondrial nucleotide variations; MMP: membrane potential

Abnormal extracellular environment of oocytes

The maturation process of oocytes is a multifaceted phenomenon governed by various intrinsic and extrinsic factors within the ovarian environment. External elements such as follicular fluid (FF) and granulosa cells play a crucial role in providing essential nutrients and growth factors that facilitate the growth, maturation, and overall health of oocytes [19]. Granulosa cells contribute a diverse array of energy sources and nutrients to support the development and fertilization of oocytes [20]. Findings from in vitro fertilization-embryo transfer experiments demonstrated a decline in mitochondrial membrane potential, adenosine triphosphate levels, and mitochondrial DNA (mtDNA) copy number in granulosa cells of patients with obesity with polycystic ovary syndrome (PCOS) alongside an increase in reactive oxygen species levels. Notably, the formation of high-quality embryos, usable embryos, and high-quality blastocysts was significantly reduced in these patients [21]. Studies on mice subjected to a high-fat diet (HFD) have revealed an augmentation in corpus luteum count and heightened levels of estradiol and progesterone in the early stages of pregnancy. Treatment with oleic acid (OA) and palmitic acid (PA) resulted in a notable increase in estradiol and progesterone levels in luteinized KGN cells, suggesting that HFD-induced obesity during early pregnancy may compromise ovarian function and impact oocytes development [22]. Furthermore, consumption of a high-fat diet has been shown to upregulate the expression of miR-133a in adipose tissue and ovaries. miR-133a functions as a regulator, promoting apoptosis in granulosa cells by modulating the expression of anti-apoptotic and pro-apoptotic proteins, consequently leading to aberrant follicular development in obese mice [23].

The metabolites present in follicular fluid play a critical role in the maturation and growth of oocytes. In individuals with PCOS who are overweight or obese, a cluster of proteins associated with inflammation, immune response, and metabolic alterations has been identified in follicular fluid, which has a direct impact on oocytes development [24]. Elevated levels of inflammatory cytokines such as IL-6 and TNF-α have been observed in the follicular fluid of women with obesity, indicating an immune imbalance that could potentially harm developing oocytes [25]. Additionally, research has demonstrated a strong positive relationship between maternal BMI and the concentration of fatty acids in follicular fluid [26]. Increased levels of PA in follicular fluid have been found to trigger ceramide accumulation and suppress the AMPK/SIRT3 pathway in endometrial epithelial cells, resulting in heightened acetylation and functional impairment of mitochondrial proteins in oocytes [27] (Fig. 2A). Obesity has the capacity to disrupt oocytes metabolism and signaling pathways by influencing the functionality and metabolic status of granulosa cells, as well as the chemical composition of follicular fluid, potentially leading to developmental irregularities and reduced reproductive function. These discoveries underscore the significance of maintaining a healthy weight and metabolic profile for optimal fertility, and offer promising avenues for future therapeutic interventions.

Telomere dysfunction

Telomeres are essential in various stages of gametogenesis and embryogenesis, playing critical roles in chromosome orientation, synapsis, and segregation, all of which are vital for preserving genomic integrity and stability [28]. Research indicates a significant correlation between the length of telomeres in oocytes and embryonic development. Maternal obesity has been linked to telomere dysfunction, leading to chromosomal instability, reduced oocytes quality, and compromised embryonic developmental potential [29]. Studies by Antunes have demonstrated that women with overweight tend to have shorter telomeres in their oocytes compared to those with a normal BMI [30], underscoring the association between maternal weight and oocytes quality. Furthermore, investigations suggest a connection between the length of telomeres in newborns and the mother’s pre-pregnancy BMI. An increase in the mother’s pre-pregnancy BMI may result in a decrease in telomerse length in newborns, potentially impacting their future health and development [31]. In conclusion, these findings highlight the significance of telomeres in reproductive and developmental processes, as well as the influence of maternal obesity on oocytes quality and embryonic development through telomeres mechanisms (Fig. 2B).

Stella levels decrease

Stella, a well-known maternal factor, is present in primordial germ cells (PGCs) and serves a critical function during the initial stages of embryogenesis and cleavage [32]. It safeguards the distinct oocytes epigenome by preventing aberrant DNA methylation facilitated by DNMT1 and UHRF1 [33]. In mice subjected to a HFD, there was a notable decrease in Stella protein levels within oocytes. Introducing excess Stella in oocytes derived from mothers with obesity mitigated the developmental abnormalities observed in embryos. Remarkably, female mice lacking Stella produced seemingly normal oocytes that seldom progressed into blastocysts, displaying a phenotype akin to embryos from HFD mice [34] (Fig. 2C). In essence, obesity results in diminished Stella levels in oocytes, impeding embryonic development. Stella plays a safeguarding role in the epigenetic control of oocytes, and changes in Stella expression levels, prompted by obesity, have significant implications for embryonic development.

Mitochondrial dysfunction

Mitochondrial mass and mtDNA content massively increase during oocyte growth. They are highly dynamic organelles and oocyte maturation is accompanied by mitochondrial trafficking around subcellular compartments. Due to their key roles in generation of ATP and reactive oxygen species (ROS), mitochondrial defects have largely been linked with oocyte dysfunction [35]. Research studies have demonstrated that obese mouse oocytes cells exhibit various mitochondrial functional abnormalities, including decreased mitochondrial membrane potential, altered mitochondrial distribution, and structural irregularities, as well as defects in spindle/chromosome organization [36]. Marei et al. have reported that a high-fat die leads to a notable increase in mitochondrial inner membrane potential (MMP), reactive oxygen species levels, mitochondrial structural abnormalities, and endoplasmic reticulum (ER) swelling, while decreasing mitochondrial DNA (mtDNA) copy number [37]. These changes suggest that obesity may contribute to impaired mitochondrial function in egg cells. Furthermore, obesity can reduce mtDNA content in fully developed oocytes cells and cause mitochondrial nucleotide variations (mtSNVs), which can negatively affect mitochondrial function and oocytes cell quality [38] (Fig. 2D). Conversely, treatment with IGF2 in mature oocytes cells has been shown to enhance oocytes cell maturation and mitochondrial function, thereby alleviating the negative effects of obesity [36]. In conclusion, These animal studies highlight the detrimental influence of obesity on oocytes cell mitochondrial function, which can compromise oocytes cell maturation and female fertility.

Suboptimal oocytes quality is a notable element influencing adverse reproductive results in females with obesity. Efforts are underway to investigate approaches aimed at enhancing oocytes quality in this demographic. Antioxidant therapy is a prevalent intervention utilized to mitigate obesity-related oxidative stress and enhance oocytes quality. While existing studies predominantly concentrate on animal models, the Table 1 delineates prospective therapeutic avenues that could be relevant to human subjects. Despite the promising outcomes observed with current treatment modalities, additional research is imperative to substantiate their efficacy in clinical settings. The enhancement of oocytes quality in women with obesity necessitates further investigation and scholarly inquiry.

Table 1 Drug therapy to improve oocytes quality

Obesity leading to impaired endometrial development

After the fusion of sperm and eggs, the zygotes must successfully implant within a specific timeframe. This process requires the endometrium, which is influenced by estrogen and progesterone from the corpus luteum, to exhibit receptivity. This critical phase is essential for the initiation of pregnancy. Endometrial receptivity, known as the “window of implantation”, denotes a hormonally regulated stage where the endometrial tissue temporarily transitions into a functional state to facilitate blastocyst implantation and the subsequent establishment of pregnancy [50]. The largest single cause of pregnancy loss is implantation error, with defective implantation rates in humans reaching up to 78%. Successful pregnancy establishment hinges on proper implantation, which requires a complex interplay between the endometrium and the blastocyst [51]. In addition, during pregnancy, the endometrium undergoes decidualization, a vital process for embryo implantation, pregnancy maintenance, and labor initiation [52]. The uterine decidua plays various roles, such as aiding in gas and nutrient exchange between the mother and fetus, immune regulation, trophoblast invasion, and placental development [53]. Deficiencies in endometrial decidualization can disrupt the interaction between the embryo and mother, leading to recurrent miscarriages [54]. Comstock et al. noted significant differences in endometrial transcriptomes between individuals with obesity and non-obesity, suggesting that these variances may contribute to a decreased implantation rate and a higher risk of miscarriage in women with obesity [55].

Bellver et al.’ study demonstrated that obesity negatively impacts the receptivity of the endometrium, potentially influencing the endometrial environment and resulting in a delayed Window of Implantation (WOI) and consequently poorer outcomes in Assisted Reproductive Technology (ART) [56]. A prospective cohort study demonstrated a correlation between BMI levels and the displacement rate of WOI, with percentages of 4.2% for normal weight individuals, 17.2% for those who are overweight, and 24.2% for patients with obesity. Following the clinical correction of displaced WOI through personalized embryo transfer (pET), there were no significant variations in pregnancy rate, implantation rate, or rates of pregnancy loss (6.7% vs. 13.2%) [57]. Weight reduction in obese women with polycystic ovary syndrome (PCOS) who are experiencing infertility could have a positive impact on endometrial receptivity [58]. At the animal level, studies have shown compromised endometrial receptivity in early-pregnancy mice due to maternal hyperinsulinemia on mouse models with hyperinsulinemia [59]. Additionally, obesity has been found to alter the transcriptional profile of sheep endometrium, leading to changes in gene expression during implantation, potentially contributing to obesity-related pregnancy complications [60] These findings suggest that obesity may increase miscarriage rates by affecting the duration of the implantation window. Strategies such as weight loss or interventions to correct the WOI may help mitigate some of the adverse pregnancy effects associated with obesity.

Furthermore, obesity has the potential to influence the decidualization process, which could result in miscarriage. Research conducted by Antoniotti et al. revealed that elevated levels of inflammation in the uterine cavity of individuals with obesity may trigger inflammatory signaling in endometrial epithelial cells. This activation can lead to endoplasmic reticulum stress, hindering decidualization and blastocyst implantation, as well as impeding trophoblast invasion, ultimately culminating in miscarriage and pregnancy complications [61]. In comparison to individuals with lower body weight, patients with obesity exhibited a significant reduction in the gene expression of PRL and IGFBP1, two markers associated with endometrial decidualization. Impaired autophagy flux in patients with obesity was also observed, prompting the authors to suggest that decreased autophagy might be accountable for compromised in vitro decidualization [62]. Studies involving animals and cells have demonstrated that the HFD can induce impaired decidualization in mice with obesity and metabolic syndrome [63]. HFD mice impair decidualization by disrupting glycolysis in the endometrium during early pregnancy [64]. Obesity can impede decidualization through various mechanisms, including inflammation, autophagy, fatty acids, and glycolysis. By affecting processes such as inflammation signaling, alterations in gene expression, impaired autophagy flux, and interference with metabolic pathways, obesity can disrupt the normal decidualization of the endometrium, potentially heightening the risk of RSA.

In brief, Obesity may shift the window of implantation and alter proper decidualization, which could potentially impact pregnancy outcomes.

Obesity leading to maternal immune imbalance

Obesity is commonly associated with chronic inflammation, characterized by significant alterations in the typical energy storage and endocrine functions of adipocytes. This condition is marked by heightened pro-inflammatory signaling, adipokine secretion, and cellular apoptosis [65]. Table 2 summarizes the changes in immune cells and their mechanisms in individuals with obesity. At a cellular level, obesity results in a reduction in anti-inflammatory Treg and Th2 cells, alongside an elevation in pro-inflammatory Th1 cells and CD8 + T cells. Furthermore, the balance between M2 and M1 macrophages is disrupted, with an increase in pro-inflammatory M1 macrophages [66]. Research indicates that the accumulation of pro-inflammatory macrophages is a central characteristic of obesity and a significant contributor to adipose tissue inflammation and associated complications [67].

During pregnancy, maintaining a delicate equilibrium between pro-inflammatory and anti-inflammatory cytokines is essential for successful implantation [68]. A review of immune cell alterations in individuals experiencing recurrent miscarriage is presented in Table 3. For instance, in cases of RSA, there is an elevated presence of Th17 cells and a reduced number of Treg cells in the decidua, suggesting a correlation between the Th17/Treg cells ratio modification at the maternal-fetal interface and the development of RSA [69]. Furthermore, obesity in pregnant women can lead to an upsurge in pro-inflammatory cells and factors, disrupting the balance between pro-inflammatory and anti-inflammatory cytokines, consequently leading to unfavorable pregnancy outcomes.

Table 2 Changes in immune cells in obese individual

Table 3 Immune cells changes associated with RSA

uNK cells

Uterine natural killer (uNK) cells represent a majority of early pregnancy uterine leukocytes, comprising 60–70% of the total population [109]. These cells are pivotal in regulating neovascularization, uterine artery remodeling, placental development, and immune responses during pregnancy [110]. Research indicates that IFN-γ, originating from uNK cells, plays a crucial role in facilitating uterine spiral artery remodeling [111]. Obesity is further associated with a notable decline in uNK cell numbers, resulting in impaired uterine artery remodeling. Additionally, in cases of obesity, uNK cells demonstrate an exaggerated response to platelet-derived growth factor (PDGF), causing excessive decorin expression that hampers trophoblast survival and impedes placental development, potentially causing placental damage [70]. In summary, obesity can diminish uNK cells quantities and disrupt uterine artery remodeling, thereby influencing pregnancy outcomes. The results suggest a relationship between obesity and the dysfunction of uNK cells, which may have negative implications for pregnancy outcomes.

T cells

During the early stages of embryo implantation, T cells constitute 3–10% of the white blood cells at the maternal-fetal interface [112]. Th17 cells primarily produce pro-inflammatory cytokines, while Treg cells mediate immunosuppression [113]. In the early stage of embryo implantation, the endometrium is in a pro-inflammatory environment, and the peripheral blood and decidua of RSA women exibit an increase in pro-inflammatory Th17 cells and a decrease in anti-inflammatory Treg cells [114]. In the third trimester, immunosuppressive T cells dominate, and Tregs are usually significantly increased at the maternal-fetal interface and in peripheral blood during this period [115]. Liao et al. found that women with a low Treg cells group in unexplained RSA (URSA) exhibited approximately five times the risk of RSA compared to women with normal Treg levels [116]. Research has also found that, compared with normal patients, the expression of Treg cells in RSA patients was decreased, while the expression of Th17 cells was increased [117]. Hence, the imbalance between Th17 and Treg cells is closely related to RSA. Both obese individuals and obese mouse models have shown an increase in Th17 cells and a decrease in Treg cells, indicating a similar trend in T cells alterations between individuals with obesity and RSA patients [76, 78, 79]. This implies that obesity may contribute to the progression of RSA by elevating the number of pro-inflammatory T cells.

Macrophages

Macrophages are the second-largest group of immune cells, comprising 20% of total leukocytes at the maternal-fetal interface [118]. They are involved in various functions such as antigen presentation, coordinating tissue remodeling and angiogenesis, inducing apoptosis of damaged cells, promoting trophoblast invasion, and inhibiting inflammation. Decidual macrophages are essential for fostering maternal and fetal immune tolerance [118, 119]. In pregnancies affected by obesity, there is a notable increase in the number of macrophages compared to those in normal-weight women, along with heightened expression of IL-6 and GRO-α proteins in the decidua [74]. Moreover, individuals with obesity demonstrate elevated levels of placental resident macrophages and increased expression of macrophage-related cytokines and specific factors like CD14, CD68, and EMR-1 [120], which are crucial for proinflammatory processes. In essence, macrophages play a critical role in obesity-induced RSA, as the obesogenic environment impacts pregnancy outcomes by enhancing pro-inflammatory macrophages and stimulating the release of pro-inflammatory cytokines.

Under the state of obesity, alterations in immune cell numbers and functions are associated with adverse pregnancy outcomes, such as RSA. NK cells, T cells, and macrophages can influence placental function and alter intrauterine inflammation, contributing to RSA. Understanding the physiological processes related to immune cells and obesity during pregnancy is vital.

Obesity leads to disrupted secretion of adipokines

Adipokines, which are bioactive peptides secreted by adipocytes, play a vital role in the regulation of energy, inflammation, and immune responses [121]. In cases of obesity, there is an upregulation of pro-inflammatory adipokines and a downregulation of anti-inflammatory adipokines. Optimal adipokine levels are fundamental for maintaining the integrity of the hypothalamic-pituitary-gonadal axis, regulating ovulation processes, achieving successful embryo implantation, and ensuring physiological pregnancies [122]. Pro-inflammatory adipokines consist of leptin, resistin, visfatin, and chemerin, while anti-inflammatory adipokines include adiponectin, omentin, and isthmin 1 [108, 123, 124]. This discussion will specifically focus on three adipokines that are closely associated with RSA.

Leptin, a significant hormone involved in the process of implantation, plays a crucial role in the regulation of placental development and endometrial receptivity [125]. Research conducted by Plowden revealed that elevated levels of leptin prior to pregnancy in women with a history of miscarriage were linked to decreased fertility, pregnancy, and live birth rates. This correlation was closely associated with BMI and leptin concentrations [126]. Additionally, Müller et al. discovered that the GTCC haplotype of the leptin receptor (LEPR) gene locus in patients with RSA was notably lower compared to that in healthy individuals [127]. Consequently, deviations in leptin levels and leptin receptors may result in impaired trophoblastic cell proliferation, leading to unfavorable pregnancy outcomes.

Adiponectin plays a crucial role in pregnancy and placental development by interacting with adiponectin receptors present in various tissues, which are vital for embryonic development and endometrial receptivity [128]. Research has demonstrated that women experiencing RSA exhibit significantly elevated serum adiponectin levels compared to a control group, while maintaining similar serum leptin levels [129]. At the animal level, studies have revealed that mice with adiponectin haploinsufficiency or homozygous mutations exhibit a notably reduced litter rate in comparison to wild-type mice [130]. Furthermore, the administration of recombinant adiponectin (rAPN) therapy has been shown to enhance pregnancy outcomes in aborted mouse models by augmenting the quantity and functionality of Treg cells and suppressing the quantity and functionality of Th17 cells [131]. These findings collectively underscore the critical role of adiponectin in preserving normal fertility in female mice.

Fatty Acid-Binding Protein 4 (FABP4), another adipokine, coordinates lipid transport in mature adipocytes. FABP4 regulates embryo implantation by altering uterine receptivity, and decreased expression of FABP4 in the endometrium may be related to pregnancy loss [132]. Animal experiments showed that FABP4 can also block blood vessel formation and lead to the obstruction of trophoblast vascular remodeling in early pregnancy [133]. Inhibition of FABP4 can reduce BMI and improve insulin resistance in obese mice [134]. Therefore, FABP4 is closely associated with obesity and pregnancy loss.

In brief, the roles and significance of leptin and adiponectin in pregnancy are crucial. Dysregulation of their levels and functions can result in trophoblast dysfunction and negative pregnancy consequences. Notably, deviations in leptin and adiponectin receptors have been linked to issues such as infertility and RSA. Furthermore, the presence of FABP4 has been correlated with conditions like obesity, insulin resistance, and pregnancy loss, suggesting that these elements could serve as potential targets for addressing infertility and enhancing pregnancy outcomes. Consequently, these discoveries offer valuable biological insights into the management and treatment of reproductive disorders related to obesity, underscoring the importance of weight control in enhancing fertility outcomes.

Obesity related genes FTO and RSA

In 2007, Dina et al. discovered that single nucleotide polymorphisms (SNPs) in the FTO gene region were associated with BMI and obesity risk, establishing FTO as the first locus explicitly linked to obesity [135]. The protein encoded by the FTO gene is an m6A demethylase, which can regulate m6A modifications on mRNA and thereby affect gene expression and metabolic pathways [136]. The activity of the FTO gene is associated with the signal transduction in the appetite control center, and its variation may cause increased appetite, which in turn influences the risk of obesity [137]. Experimental data obtained from animal models suggest that knockout of the FTO gene inhibited obesity and promoted energy expenditure, while overexpression of FTO increased food intake and obesity [138, 139]. Furthermore, overexpression of FTO can promote adipogenesis in 3T3-L1 preadipocytes and porcine intramuscular adipocytes [140]. Thus, the findings from both in vitro and in vivo studies indicate that FTO can facilitate fat accumulation and contribute to obesity. Recent studies have elucidated a relationship between the FTO and RSA. Andraweera et al. analyzed the peripheral blood of 202 patients with RSA in early pregnancy and found that the FTO rs9939609 SNPs may be associated with RSA [141]. Qiu et al. discovered that the downregulation of FTO in chorionic villi disrupts immune tolerance and angiogenesis at the maternal-fetal interface, leading to abnormal methylation, oxidative stress, and eventually RSA [142]. Another study revealed that FTO promotes MEG3 degradation by inhibiting MEG3 m6A modification in the trophoblast, thereby disrupting the MEG3-TGF-β regulatory axis. This disruption results in abnormal activation of the TGF-β signaling pathway, inhibiting cell invasion, and causing RSA [143].

The function of the FTO is not solely linked to the initiation of obesity but may also impact the susceptibility to RSA through its effects on embryonic development and immune function at the interface between the mother and fetus. Consequently, the FTO could potentially act as a crucial molecular bridge connecting obesity and RSA. Investigation into the FTO has the potential to enhance our comprehension of the molecular pathways involved in obesity and provide innovative approaches for the prevention and management of RSA.

The association between male obesity and RSA

In early pregnancy, the mother’s influence on the embryo is more pronounced than the father’s, but sperm also plays a crucial role in embryonic development, and abnormal sperm may lead to miscarriage. Hence, in this section, we briefly summarize some mechanisms by which obesity affects male reproductive health and may causes recurrent miscarriage. A retrospective multicenter case-control study suggests an association between increased sperm DNA fragmentation and idiopathic recurrent miscarriage [144], and the weight of the father is inversely related to the prognosis of future live births in couples with RSA [145]. Sperm DNA damage measured by the alkaline Comet has promise as a robust biomarker for sporadic and recurrent miscarriage after spontaneous or assisted conception, and may provide novel diagnoses and guidance for future fertility pathways [146]. Analysis of gene expression profiles has revealed a sex-specific response of the transcriptome to maternal and paternal obesity. Changes in the male blastocyst transcriptome were more pronounced than those in female blastocysts, and the impact of paternal obesity was greater than maternal obesity [147]. Paternal obesity can induce epigenetic and gene expression changes in sperm and the placenta. Epigenetic abnormalities in sperm can affect the expression of imprinted genes in the placenta and genes related to placental endocrine pathways [148]. Additionally, male obesity is linked to alterations in sperm DNA methylation profiles, which may compromise the reprogramming fidelity of sperm subsets and impede normal embryonic development [149]. Animal experiments have shown that the expression of SETD2 in the testis and sperm of male mice fed a high-fat diet for two months significantly increased. This alteration led to changes in DNA methylation levels, leading to increased apoptosis of blastocysts and a reduced total cell count in blastocysts [150]. FTO knockout mice exhibited an age-dependent decline in sperm concentration and serum testosterone levels [151]. Furthermore, the abundance of the MC4R gene in sperm was negatively correlated with sperm motility and positively correlated with biochemical pregnancy. The abundance of MC4R and GNPDA2 transcripts in sperm from men with asthenospermia and teratoospermia was higher than in normospermia [152].

Pregnancy is not solely the mother’s responsibility, the father also plays a significant role. In cases of RSA, alterations in DNA methylation levels may manifest in the sperm of fathers with obesity. These changes can result in placental epigenetic modifications and abnormal embryonic development. Obesity-related genes, such as FTO, MC4R, and GNPDA2, can also impact pregnancy outcomes by affecting sperm count and motility. For men with obesity, weight loss is a crucial step when seeking to improve fertility.

The significance of maintaining appropriate weight levels throughout pregnancy

Potential benefits of weight loss for patients with RSA

For infertile women with obesity who want to conceive, weight loss may be a solution to improving fertility. A systematic review and meta-analysis showed that bariatric surgery significantly reduced the rate of miscarriage in treated women (p = 0.01), RR 0.51,95% CI 0.30, 0.86 [153]. In addition, A retrospective cohort study showed that overweight infertile patients who lost 10% of their body weight had significantly higher pregnancy and live birth rates compared to those who did not lose weight [154]. However, this finding is not consistently supported by randomized controlled trials (RCTs). In obese women with PCOS who are infertile, weight loss positively affects endometrial receptivity, with 25% of women who successfully lose weight seeing an increased rate of natural pregnancy [58]. These data suggest that meaningful weight loss can improve the pregnancy and live birth rates among overweight infertile patients. Women who conceive naturally avoid IVF procedures, which alleviates significant psychological, physical, and financial burdens. Moreover, weight loss before pregnancy can also decrease the risk of adverse conditions during gestation. It has been observed that as the weight loss ratio increases, the incidence of hypertensive disorders during pregnancy, preterm delivery, stillbirth, and low birth weight tends to decline [155, 156]. Although some studies suggest that strengthening pre-pregnancy lifestyle intervention for weight loss does not improve fertility or birth outcomes [157, 158], some studies have shown that weight loss before pregnancy increases the risk of miscarriage [159], most current studies believe that if pregnant women control their weight at a healthy level before pregnancy, it is beneficial for both themselves and the fetus [160, 161]. Prepregnancy weight loss should be supervised by a clinician with specific expertise in obesity treatment. Weight loss may be required for longer intervals than those used in existing studies before attempting to conceive [162]. We advocate for women with obesity to lose weight before and during pregnancy, and to control their weight within a relatively normal range.

Managing weight during pregnancy through diet and exercise

Weight loss can help restore fertility in individuals with obesity and reduce the risk of RSA. Weight loss may improve fertility in individuals with obesity, although its effect on reducing the risk of RSA is not yet fully established. In addition to focusing on RSA, we also need to consider the impact of weight management on other pregnancy complications. Being overweight before pregnancy can increase the incidence of gestational diabetes, pregnancy complications, macrosomia, and preterm birth. Measures such as adopting healthier eating habits and engaging in regular physical exercise can enhance the mother’s health and optimize fetal development.

For patients with obesity, adjusting weight through diet is a fundamental aspect of disease management. For pregnant women with a pre-pregnancy BMI of ≥ 35 kg/m², individual assessment and dietary consultation by dietitians can help achieve and limit gestational weight gain, reduce the incidence of gestational diabetes mellitus, and decrease the likelihood of cesarean Sect. [163]. Following the implementation of a low glycemic index diet during pregnancy and a subsequent five-year follow-up, evidence emerged indicating a causal relationship between reduced gestational weight gain (GWG) during pregnancy and enhanced maternal well-being, as well as a decrease in overall weight gain. Pregnant women also experienced a change in their usual diet after delivery, showing a preference for foods rich in protein, with lower GI and lower GL energy [164]. Studies have shown that the Mediterranean diet can help improve diabetes, inflammatory diseases, cancer, and cognitive decline [165]. It can also reduce maternal anxiety and stress and improve sleep quality throughout pregnancy [166, 167]. There is evidence suggesting that diet is linked to inflammation, oxidative stress, and brain function, factors that may be associated with mental disorders. A study examining the relationship between dietary patterns and mental disorders in pregnant women in southern Brazil discovered that excessive consumption of sweets and sugars, as well as inadequate intake of fruits, were strongly linked to depression. Generalized anxiety, on the other hand, was associated with low consumption of beans [168]. These pieces of evidence clearly demonstrate that dietary habits and nutritional intake during pregnancy are crucial. Moderate energy intake and a balanced diet not only impact the mothe’s health and reduce the occurrence of complications during pregnancy but also benefit the growth and development of the fetus. Additionally, they can have long-term positive effects on the mother.

Exercise during pregnancy has positive effects on both the mother and the fetus. Engaging in an exercise program has psychological benefits for pregnant women, such as reduced anxiety and depression, as well as improved well-being. Moderate-intensity aerobic exercise and exercise interventions have been shown to mitigate weight gain during pregnancy [169]. Moderate-intensity exercise and exercising during the second trimester can help control blood sugar levels [170]. In addition to reducing pregnancy weight and preventing gestational diabetes, researchers have found that pregnant women are more likely to regain their pre-pregnancy weight within six months after delivery [171]. From a psychological perspective, physical exercise during pregnancy and the postpartum period can improve the mental health of pregnant women and reduce the probability of postpartum depression [172]. In the absence of medical or obstetric complications, the American College of Obstetricians and Gynecologists recommends 30 min of aerobic exercise per day for physical and mental health during pregnancy [173]. In the third trimester of pregnancy, pregnant women often experience poor sleep due to symptoms such as uterine enlargement, bladder compression, and back pain. Engaging in prenatal yoga practice has been shown to effectively improve the sleep quality of pregnant women in the third trimester [174]. The main benefits of exercise for pregnant women include improved physical condition, weight control, shorter labor time, faster postpartum recovery, and prevention of gestational diabetes, gestational hypertension, preeclampsia, and preterm birth.

However, these studies primarily rely on association analysis, without having clearly established causal relationships. Future research should delve deeper into the causal relationships and their intensity, aiming to provide more definitive evidence.

A women-centered approach is essential to advance weight management strategies. In clinical practice, we have found women seek practical advice delivered in a sensitive and respectful manner, rather than a sole focus on the risks of obesity during pregnancy. Weight control becomes more challenging, particularly for individuals who need to improve their nutrition during pregnancy. Women with obesity must manage their weight gain within a certain range during pregnancy, necessitating strict monitoring. Whether through dietary intervention, intensive exercise, or a combination of both, these strategies positively impact pregnancy outcomes.

How clinicians should evaluate and manage patients with obesity and RSA

RSA is a complex disease that often involves multiple medical factors and lifestyle influences. For patients with obesity, clinicians should evaluate and manage RSA by considering a combination of the following factors. For patients with obesity, clinicians should evaluate and manage RSA by considering a combination of factors while being mindful of the stigma and bias that these patients may face within the healthcare system. It is crucial to ensure a full and unbiased evaluation, not just assuming that miscarriage is secondary to body size. It is well-established that obesity is associated with an increased risk of miscarriage. Therefore, patients with obesity should actively take steps to lose weight to reduce this risk. The endocrine environment of obese patients may affect the risk of miscarriage. PCOS, a gynecological disease closely related to obesity, is closely associated with RSA [175]. Additionally, the evaluation of markers of glucose/insulin metabolism as well as the levels of vitamin D as important step to be included in the diagnostic work-up of RPL women [176]. Immune factors may also play a pivotal role in RSA. Clinicians should identify patients with or without immune system diseases during clinical consultations and treatments and actively address the primary diseases [177]. In addition, genetic factors may cause RSA, and clinicians should conduct genetic tests on both spouses to rule out possible genetic factors [178]. In conclusion, clinicians should develop personalized evaluation and management programs tailored to the specific conditions of patients, taking into account genetic, endocrine, immune, and other factors to reduce the risk of RSA.

Summary and future perspectives

This review delves into the association between obesity and RSA, highlighting that obesity is more likely to result in euploid miscarriages rather than aneuploid miscarriages. Obesity can negatively impact oocytes quality, influencing embryo implantation, and hinder decidualization, consequently affecting the rate of embryo implantation. Moreover, obesity can disrupt the balance of endometrial immune cells and cytokines, perturb adipocytokines released by adipocytes, and disturb the expression of specific obesity-related genes. These factors collectively contribute to the initiation and progression of RSA. Additionally, male obesity can compromise sperm quality, thereby diminishing fertility. Therefore, the influence of male obesity on fertility necessitates consideration. Given the escalating concern of obesity, interventions aimed at reducing the weight of women with obesity through dietary modifications, physical activity, and potentially medication are anticipated to enhance fertility outcomes in RSA patients.

In clinical practice, it is imperative for physicians to conduct a thorough assessment of the patien’s weight and ascertain potential causes of previous miscarriages. Tailored evaluation and management strategies should be devised to mitigate the risk of RSA. The correlation between obesity and RSA is multifaceted, necessitating further investigation through clinical and experimental research to elucidate its precise pathogenesis. Individuals with obesity encounter challenges in conception and are predisposed to unfavorable pregnancy outcomes. Additional research is warranted to elucidate the involvement of obesity in the pathogenesis of RSA and the associated regulatory mechanisms, with the goal of implementing prospective therapeutic interventions.

As a systemic disease, obesity triggers numerous mechanisms that impact female reproductive health. At present, there is no ideal treatment for obesity and obesity-induced RSA. Studying the effects of obesity on RSA and its underlying mechanisms holds significant social and clinical value for improving pregnancy outcomes. This article reviews the impact of obesity on female RSA and fertility. It examines the association between obesity and RSA as well as the influence of weight management on pregnancy. The aim is to provide insights for research, prevention, and treatment of RSA in women with obesity.