Comparative Effectiveness of Pharmacological Treatments for Fetal Growth Restriction: A Network Meta-Analysis

Background: Fetal growth restriction (FGR) is a prevalent pregnancy complication linked to adverse maternal and fetal outcomes. Effective pharmacological interventions are crucial to improving fetal growth and reducing complications. This study aimed to evaluate and compare the effectiveness of various pharmacological treatments for FGR using a network meta-analysis (NMA). Objective : This study aimed to evaluate and compare the effectiveness of various pharmacological treatments for FGR using a network meta-analysis (NMA). Search Strategy: Studies were identified through comprehensive searches in PubMed, Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. The search was updated until January 31, 2025. Selection Criteria: The study population consisted of singleton pregnancies at high risk of fetal growth restriction (FGR). Studies were excluded if they involved multiple pregnancies, fetal genetic abnormalities, or maternal conditions such as drug or alcohol abuse. Data Collection and Analysis: A systematic review and network meta-analysis were conducted following PRISMA guidelines. Main Results: LMWH and LMWH + LDA significantly reduced the incidence of IUGR (OR = 0.40, 95% CI = 0.26, 0.62 and OR = 0.37, 95% CI = 0.15, 0.93, respectively) compared to controls and LDA alone. LMWH treatment also significantly reduced the risk of pregnancy complications, including preeclampsia (OR = 0.21, 95% CI = 0.05, 0.93), preterm birth (OR = 0.61, 95% CI = 0.45, 0.81), miscarriage (OR = 0.42, 95% CI = 0.19, 0.91), and cesarean section (OR = 0.34, 95% CI = 0.18, 0.67). LMWH + LDA significantly improved live birth rates (OR = 7.08, 95% CI = 2.16, 23.22) and reduced the incidence of preeclampsia (OR = 0.22, 95% CI = 0.08, 0.59). Conclusions: LMWH and LMWH + LDA are effective in reducing IUGR, preventing preeclampsia, and improving live birth rates in high-risk pregnancies with FGR. These findings support the use of LMWH and LMWH + LDA as promising treatment options for FGR management. Comparative Effectiveness of Pharmacological Treatments for Fetal Growth Restriction: A Network Meta-Analysis Yanting Wei MMa#, Leilei Gong MDb#, Xin Yu MMb, Meng Wang MMa*, Xin Feng MMb* a Shijiazhuang Fourth Hospital, Shijiazhuang, China b Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China

Background: Fetal growth restriction (FGR) is a prevalent pregnancy complication linked to adverse maternal and fetal outcomes. Effective pharmacological interventions are crucial to improving fetal growth and reducing complications. This study aimed to evaluate and compare the effectiveness of various pharmacological treatments for FGR using a network meta-analysis (NMA).

This study aimed to evaluate and compare the effectiveness of various pharmacological treatments for FGR using a network meta-analysis (NMA). Search Strategy: Studies were identified through comprehensive searches in PubMed, Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. The search was updated until January 31, 2025. Selection Criteria: The study population consisted of singleton pregnancies at high risk of fetal growth restriction (FGR). Studies were excluded if they involved multiple pregnancies, fetal genetic abnormalities, or maternal conditions such as drug or alcohol abuse. Data Collection and Analysis: A systematic review and network meta-analysis were conducted following PRISMA guidelines. Main Results: LMWH and LMWH + LDA significantly reduced the incidence of IUGR (OR = 0.40, 95% CI = 0.26, 0.62 and OR = 0.37, 95% CI = 0.15, 0.93, respectively) compared to controls and LDA alone. LMWH treatment also significantly reduced the risk of pregnancy complications, including preeclampsia (OR = 0.21, 95% CI = 0.05, 0.93), preterm birth (OR = 0.61, 95% CI = 0.45, 0.81), miscarriage (OR = 0.42, 95% CI = 0.19, 0.91), and cesarean section (OR = 0.34, 95% CI = 0.18, 0.67). LMWH + LDA significantly improved live birth rates (OR = 7.08, 95% CI = 2.16, 23.22) and reduced the incidence of preeclampsia (OR = 0.22, 95% CI = 0.08, 0.59).

LMWH and LMWH + LDA are effective in reducing IUGR, preventing preeclampsia, and improving live birth rates in high-risk pregnancies with FGR. These findings support the use of LMWH and LMWH + LDA as promising treatment options for FGR management. Trial Registration: PROSPERO registration: CRD420251142968.

fetal growth restriction, intrauterine growth restriction, low molecular weight heparin, low-dose aspirin, pregnancy complications, network meta-analysis

Fetal Growth Restriction (FGR) is a condition characterized by inadequate fetal growth during pregnancy, often defined as a fetal weight below the 10th percentile for gestational age (1). It is a significant and common complication of pregnancy, with an estimated global prevalence of 3-10%, depending on the population studied and the diagnostic criteria used arise from a variety of causes, including placental insufficiency, maternal conditions such as hypertension or diabetes, infections, and genetic factors (2). It is with a wide range of adverse outcomes for both mothers and fetuses. In affected pregnancies, there is an increased risk of stillbirth, preterm birth, neonatal mortality, and long-term developmental complications for the child, including cognitive and motor delays. For mothers, likelihood of complications such as preeclampsia, cesarean delivery, and postpartum hemorrhage (3, 4). Beyond its medical implications, is a substantial economic burden on healthcare systems due to the need for intensive monitoring, preterm delivery, and long-term care for affected infants (5). Effective management of FGR is crucial, as it can significantly reduce the risk of adverse outcomes, improving both maternal and neonatal health and potentially reducing healthcare costs associated with these pregnancies. Currently, several pharmacological treatments are used to manage FGR, including anticoagulants, antiplatelet agents, and other drugs aimed at improving placental function. Among these, low-dose aspirin (LDA), low molecular weight heparin (LMWH), and unfractionated heparin (UFH) are commonly employed (6, 7). These treatments seek to improve uteroplacental blood flow and reduce thrombotic complications, potentially improving fetal growth. However, while these treatments show some promise, their effectiveness remains inconclusive, as results from individual studies are often conflicting. Additionally, the variety of treatment approaches complicates decision-making, as no single drug has been universally accepted as the most effective for treating FGR (8). Although some studies suggest these pharmacological interventions may improve fetal growth, systematic reviews and meta-analyses have demonstrated inconsistent findings across various settings (9). Despite these promising avenues, there is insufficient high-quality evidence to definitively recommend any specific therapeutic approach. A recent meta-analysis highlighted the efficacy of certain treatments but did not address the comparative effectiveness of different pharmacological strategies (10). The lack of robust, comparative evidence remains a significant gap in the literature, particularly concerning the effectiveness of different drug regimens in improving FGR outcomes. This study aims to address this gap by performing a network meta-analysis (NMA) to evaluate and compare the effectiveness of various pharmacological treatments for FGR. Unlike traditional pairwise meta-analyses, NMA allows for the simultaneous comparison of multiple treatments, even if some treatments have not been directly compared in individual studies (11). The primary objective of this research is to provide a comprehensive analysis of available treatment options, helping to identify the most effective pharmacological strategies for managing FGR. This will not only inform clinical decision-making but also contribute to the optimization of treatment protocols, ultimately improving maternal and fetal health outcomes in pregnancies complicated by FGR. By synthesizing evidence from a diverse range of studies, this analysis will offer valuable insights into the comparative effectiveness of different pharmacological interventions, addressing current shortcomings in the literature and providing a more nuanced understanding of their potential benefits.

2.1 Study Design This systematic review and network meta-analysis was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement and its extension for network meta-analysis in healthcare interventions (PRISMA-NMA) approval or consent for this meta-analysis was not required (12, 13), as this study was based on publicly available data from previously published studies. 2.2 Data Sources and Search Strategy A comprehensive literature search was conducted in PubMed, Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. The search was updated as of January 31, 2025. The search terms included: “fetal growth restriction,” “intrauterine growth restriction,” “pregnancy complications,” ” pharmacological interventions,” “heparin,” “aspirin,” and other related terms. The complete search strategy, including specific keywords and combinations, is detailed in Supplementary File 1. To ensure comprehensive inclusion, reference lists of relevant articles published in the last five years were also reviewed. Studies were selected for full-text review by two independent researchers, with discrepancies resolved by discussion or adjudication by a third reviewer. 2.3 Study Selection Studies eligible for inclusion were randomized controlled trials (RCTs) and observational cohort studies (both prospective and retrospective) published in English. The study population consisted of singleton pregnancies at high risk of fetal growth restriction (FGR), defined as women meeting at least one of the following criteria: a history of FGR in previous pregnancies, history of late pregnancy loss or recurrent early pregnancy loss, hypertensive disorders during pregnancy, or thrombophilic conditions (including both inherited and acquired thrombophilia). The interventions evaluated included unfractionated heparin (UFH), low molecular weight heparin (LMWH), low-dose aspirin (LDA), other antiplatelet agents, and pharmacological treatments such as phosphodiesterase inhibitors, nitric oxide donors, and statins, either alone or in combination. Studies comparing these interventions to placebo or no treatment (control groups) were included. The primary outcome was FGR, as defined by the authors of each study. Secondary outcomes included preterm birth, placental abruption, and fetal or neonatal death. Safety outcomes included bleeding complications, thrombocytopenia, and adverse events. Studies were excluded if they involved multiple pregnancies, fetal genetic abnormalities, or maternal conditions such as drug or alcohol abuse. 2.4 Data Extraction Study characteristics (e.g., authors, year of publication, patient demographics), intervention details, and outcome measures were independently extracted by two reviewers using EndNote X9 to manage references and avoid duplication. Data on continuous variables were extracted as mean and standard deviation, and for categorical variables, the number of events and total sample size were collected. In cases where necessary data were unavailable, the corresponding authors were contacted up to four times within a six-week period to request missing information. 2.5 Risk of Bias Assessment The risk of bias of included studies was evaluated using the Cochrane Risk of Bias Tool (RoB 2) for RCTs (14). This tool assesses the following domains: (a) sequence generation, (b) allocation concealment, (c) blinding of participants and outcome assessors, (d) incomplete outcome data, (e) selective reporting, and (f) other biases. Two independent reviewers performed the assessment, with discrepancies resolved by consensus or a third reviewer. For non-randomized studies, the Newcastle-Ottawa Scale (NOS) was used to evaluate methodological quality, with a score of ≥5 considered high quality for inclusion in the meta-analysis. 2.6 Data Analysis The network meta-analysis was conducted using a random-effects model to account for heterogeneity both within and between studies. Stata 17.0 (StataCorp LLC, Texas, USA) was used for all statistical analyses, and the network graph was generated using the ”network” and ”mvmeta” commands. The treatment effects for continuous outcomes were reported as mean differences (MD) with 95% confidence intervals (CIs), while for dichotomous outcomes, odds ratios (ORs) were calculated. Heterogeneity was assessed using the I 2 statistic, with thresholds for low (25%), moderate (50%), and high (75%) heterogeneity. Network consistency was evaluated using the node-splitting method and design-by-treatment models. The surface under the cumulative ranking (SUCRA) method was employed to rank interventions, where a higher SUCRA value indicated a more favorable treatment effect. To explore potential publication bias, we constructed funnel plots and conducted Egger’s test for asymmetry. A p-value of <0.05 was considered indicative of publication bias (15). 3. Results 3.1 Characteristics of Included Studies The initial electronic search identified 34240 records. After removing 22441 duplicate entries, 11799 articles underwent title and abstract screening. A total of 11625 studies were excluded based on title and abstract, and 169 articles were further assessed for full-text eligibility. Ultimately, 33 studies were included in this systematic review and network meta-analysis, comprising 5858 singleton pregnancies at high risk for FGR (16-48). The detailed characteristics of the included studies are provided in Supplementary File 2. Among the 33 studies, 25 were RCTs, 2 were non-randomized trials, 2 were retrospective cohort studies, and 4 were prospective cohort studies. These studies were published between 1985 and 2023, with a median publication year of 2014. Sample sizes ranged from 19 to 898 participants, with a median of 107 participants per study. The average age of the participants ranged from 26.2 to 37.5 years, with a median age of 30.4 years. The interventions evaluated included LDA (18 studies), LMWH (13 studies), LMWH + LDA (7 studies), dipyridamole + LDA (2 studies), UFH + LDA (2 studies), tadalafil (1 study), and controls (23 studies). 3.2 Network Meta-Analysis 3.2.1 Fetal and Neonatal Outcomes 3.2.1.1 Birth Weight The network meta-analysis for birth weight included 24 studies with 3490 participants, comparing the effects of various pharmacological treatments. Figure 2.1 illustrates the direct comparisons and sample size distribution across different treatment groups. Based on the Surface Under the Cumulative Ranking (SUCRA) values (Figure 4.1), the top three treatments for increasing neonatal birth weight were dipyridamole + LDA (78.1%), LMWH + LDA (73.5%), and LMWH (72.5%). However, as shown in Table 1.1, no significant differences were found between the treatments. 3.2.1.2 Fetal Death The network meta-analysis for fetal death included 8 studies with 1065 participants. Figure 2.2 shows the direct comparisons and sample size distribution. The SUCRA ranking (Figure 4.2) indicated that the top three treatments for reducing fetal death were controls (63.7%), LMWH (63.0%), and LMWH + LDA (57.4%). However, Table 1.2 reveals no significant differences between the treatments. 3.2.1.3 Live Birth The live birth network meta-analysis involved 8 studies with 1228 participants. Figure 2.3 presents the direct comparisons and sample size distribution. SUCRA values (Figure 4.3) showed that the top three treatments for increasing live birth rates were LMWH (89.6%), controls (71.0%), and LMWH + LDA (55.7%). As shown in Table 1.3, LMWH (OR = 15.55, 95% CI = 5.49, 43.99), controls (OR = 12.63, 95% CI = 4.00, 39.87), LMWH + LDA (OR = 7.08, 95% CI = 2.16, 23.22), and unfractionated heparin + LDA (OR = 4.20, 95% CI = 1.31, 13.44) significantly increased live birth rates compared to LDA. 3.2.1.4. Small for Gestational Age (SGA) The network meta-analysis for SGA included 12 studies with 2115 participants. Figure 2.4 illustrates the direct comparisons and sample size distribution. According to the SUCRA ranking (Figure 4.4), the top three treatments for reducing SGA occurrence were LMWH (85.8%), LMWH + LDA (63.1%), and controls (40.2%). However, Table 1.4 shows no significant differences between the treatments. 3.2.1.5. Intrauterine Growth Restriction (IUGR) The IUGR network meta-analysis included 15 studies with 1056 participants. Figure 2.5 displays the direct comparisons and sample size distribution. Based on the SUCRA ranking (Figure 4.5), the top three treatments for reducing IUGR occurrence were LMWH (87.7%), LMWH + LDA (87.1%), and controls (46.1%). Table 1.5 shows that LMWH significantly reduced IUGR compared to controls (OR = 0.40, 95% CI = 0.26, 0.62) and LDA (OR = 0.37, 95% CI = 0.15, 0.93). 3.2.2 Pregnancy and Delivery Outcomes 3.2.2.1. Placental Abruption The network meta-analysis for placental abruption included 13 studies with 2452 participants. Figure 3.1 displays the direct comparisons and sample size distribution. According to the SUCRA ranking (Figure 5.1), the top three treatments for reducing placental abruption were dipyridamole + LDA (74.4%), LMWH + LDA (72.9%), and LMWH (63.3%). Table 2.1 reveals that LMWH significantly reduced the incidence of placental abruption compared to controls (OR = 0.37, 95% CI = 0.14, 0.93). 3.2.2.2. Pre-eclampsia The network meta-analysis for pre-eclampsia included 22 studies with 3565 participants. Figure 3.2 shows the direct comparisons and sample size distribution. Based on the SUCRA ranking (Figure 5.2), the top three treatments for reducing pre-eclampsia were LMWH + LDA (83.6%), dipyridamole + LDA (80.8%), and unfractionated heparin + LDA (56.8%). Table 2.2 shows that LMWH + LDA significantly reduced pre-eclampsia compared to LDA (OR = 0.22, 95% CI = 0.08, 0.59), LMWH (OR = 0.21, 95% CI = 0.05, 0.93), and controls (OR = 0.10, 95% CI = 0.03, 0.35). 3.2.2.3. Preterm Delivery The network meta-analysis for preterm delivery included 20 studies with 3048 participants. Figure 3.3 presents the direct comparisons and sample size distribution. The SUCRA ranking (Figure 5.3) showed that the top three treatments for reducing preterm delivery were LMWH (74.3%), LMWH + LDA (67.0%), and LDA (53.2%). Table 2.3 shows that LMWH significantly reduced preterm delivery compared to controls (OR = 0.61, 95% CI = 0.45, 0.81). 3.2.2.4. Miscarriage The network meta-analysis for miscarriage included 14 studies with 2044 participants. Figure 3.4 displays the direct comparisons and sample size distribution. According to the SUCRA ranking (Figure 5.4), the top three treatments for reducing miscarriage rates were LMWH (87.6%), LMWH + LDA (56.8%), and controls (51.5%). Table 2.4 shows that LMWH significantly reduced miscarriage rates compared to controls (OR = 0.42, 95% CI = 0.19, 0.91) and LDA (OR = 0.13, 95% CI = 0.03, 0.53). 3.2.2.5. Cesarean Section The network meta-analysis for cesarean section included 8 studies with 1305 participants. Figure 3.5 shows the direct comparisons and sample size distribution. According to the SUCRA ranking (Figure 5.5), the top three treatments for reducing cesarean section rates were LMWH + LDA (85.5%), LMWH (57.2%), and controls (45.4%). Table 2.5 shows that LMWH + LDA significantly reduced cesarean section rates compared to LDA (OR = 0.34, 95% CI = 0.18, 0.67). 3.3. Risk of Bias and Publication Bias Among the 25 RCTs included in the analysis, the overall risk of bias was assessed as low in 20 studies, with 4 studies showing some concerns and 1 study identified as having a high risk of bias. In terms of randomization, 23 studies exhibited low risk, while 1 study was rated with some concerns, and 1 study was deemed to have a high risk of bias. Regarding deviations from the intended interventions, all 25 studies had a low risk of bias. With respect to missing outcome data, 24 studies demonstrated a low risk of bias, while 1 study had a high risk. For outcome measurement, 23 studies were considered to have low bias, and 2 studies were assessed as having some issues. In terms of selective reporting of results, all 25 studies were rated as having a low risk of bias (Supplementary File 3). For non-randomized studies, the NOS was employed to assess methodological quality. Of the 7 studies evaluated, 3 received a score of 8, and 4 studies were scored 7. All studies received the maximum score for ”group selection” and ”outcome assessment.” Among the 7 studies, 3 studies scored 2 points for the ”comparability of groups” domain, while the remaining 4 studies scored 1 point. Publication bias was assessed using funnel plots (Supplementary File 4). The scatter plots around the vertical axis exhibited varying degrees of symmetry, suggesting the potential for publication bias. Specifically, Figures 4.3 and 4.10 show a relatively uniform distribution of points, indicating no significant bias, whereas funnel plots in Figures 4.1, 4.2, 4.4, 4.5, 4.6, 4.7, 4.8, and 4.9 display some degree of asymmetry, indicating the possibility of publication bias. The results of Egger’s test further supported these observations, with a p-value < 0.05 for pre-eclampsia, suggesting potential bias for this outcome. For the remaining outcomes, the Egger’s test p-values were all greater than 0.05, indicating no clear evidence of publication bias in the overall analysis. 4. Discussion This comprehensive network meta-analysis included 33 studies involving 5858 singleton pregnancies at high risk for FGR. The study systematically evaluated the effects of various pharmacological treatments on both fetal and neonatal outcomes as well as pregnancy and delivery outcomes. Several key findings emerged from this analysis: (1) Both LMWH and the combination of LMWH + LDA demonstrated significant efficacy in reducing the incidence of IUGR, indicating their potential in improving fetal growth. (2) LMWH treatment was found to significantly reduce the risk of several pregnancy complications, including placental abruption, preeclampsia, preterm birth, miscarriage, and cesarean section, highlighting its promise as a therapeutic choice for managing FGR-related complications. (3) LMWH + LDA exhibited particularly strong performance in preventing preeclampsia and increasing live birth rates, underscoring the additional benefits of this combination therapy in managing high-risk pregnancies. These findings are of great clinical importance, as they suggest that these pharmacological interventions can significantly improve both maternal and fetal health outcomes, offering valuable insights into the management of FGR and related complications in high-risk pregnancies. IUGR is a critical indicator of fetal health and a common complication of FGR. IUGR is associated with an increased risk of stillbirth, preterm birth, neonatal morbidity, and long-term developmental challenges, making it a central focus in the management of high-risk pregnancies (49). This study found that both LMWH alone (OR = 0.40, 95% CI = 0.26, 0.62) and the combination of LMWH + LDA (OR = 0.37, 95% CI = 0.15, 0.93) significantly reduced the incidence of IUGR compared to the control group and LDA alone. These findings are consistent with previous research, which has shown that LMWH, particularly when combined with LDA, provides significant benefits in reducing the risk of IUGR in high-risk pregnancies (50). LDA in preventing IUGR likely involve multiple factors related to placental perfusion and thrombosis prevention. LMWH, an anticoagulant, improves uteroplacental blood flow by preventing the formation of thrombi in the placental vasculature. This can result in enhanced oxygen and nutrient delivery to the fetus, thus reducing the risk of restricted growth (51). LDA, an antiplatelet agent, contributes to this effect by further improving uteroplacental blood flow through its action on platelet aggregation and endothelial function. Together, LMWH + LDA work synergistically to reduce thrombotic events, enhance placental circulation, and prevent the complications associated with FGR and IUGR (50). FGR is often associated with several pregnancy-related complications, which can adversely affect both maternal and fetal outcomes. Common complications in FGR pregnancies include placental abruption, preeclampsia, preterm birth, miscarriage, and cesarean delivery. These complications not only contribute to the high morbidity and mortality associated with FGR but also complicate management during pregnancy. In this study, five common pregnancy complications were included, and the results demonstrated that LMWH treatment significantly reduced the risk of several complications, including placental abruption (OR = 0.37, 95% CI = 0.14, 0.93), preeclampsia (OR = 0.21, 95% CI = 0.05, 0.93), preterm birth (OR = 0.61, 95% CI = 0.45, 0.81), miscarriage (OR = 0.42, 95% CI = 0.19, 0.91), and cesarean section (OR = 0.34, 95% CI = 0.18, 0.67). These findings highlight the therapeutic potential of LMWH in reducing the risk of adverse pregnancy outcomes in women with FGR. These results are consistent with previous studies that have suggested LMWH’s beneficial effects on pregnancy complications in women at risk for FGR. For instance, LMWH has been shown to improve placental blood flow and prevent thrombotic events, which can mitigate the risks of placental abruption and preeclampsia—conditions that are closely linked to poor placental perfusion (52, 53). Additionally, LMWH’s anticoagulant properties may reduce the incidence of preterm birth and miscarriage by preventing the formation of clots in the uteroplacental vasculature, which can hinder fetal development. Cesarean section rates were also significantly reduced in LMWH-treated pregnancies, which may be attributed to the improved management of pregnancy complications and the reduction in adverse fetal outcomes. The mechanisms through which LMWH improves pregnancy outcomes in FGR patients likely involve its dual action as an anticoagulant and its impact on inflammation and placental function. By enhancing blood flow to the placenta and preventing clot formation, LMWH ensures better oxygen and nutrient delivery to the fetus, thus reducing the incidence of IUGR and associated complications (54). Furthermore, LMWH may modulate inflammatory pathways involved in the pathogenesis of preeclampsia, leading to better control of hypertensive disorders during pregnancy (52). Overall, these findings support the use of LMWH as an effective therapeutic strategy for managing FGR-related pregnancy complications and improving maternal and fetal health outcomes. Preeclampsia and live birth rates are two critical outcomes for pregnancies affected by FGR. Preeclampsia, a hypertensive disorder of pregnancy, is often associated with poor placental perfusion and an increased risk of adverse maternal and fetal outcomes, including preterm birth, fetal demise, and maternal morbidity. Live birth rates, on the other hand, directly reflect the success of the pregnancy and the health of both the mother and the infant. In this study, the combination of LMWH and LDA was found to significantly reduce the incidence of preeclampsia (OR = 0.22, 95% CI = 0.08, 0.59) and significantly increase live birth rates (OR = 7.08, 95% CI = 2.16, 23.22) compared to LDA alone. These results are consistent with previous studies that have demonstrated the combined benefits of LMWH and LDA in managing high-risk pregnancies (55). Research has shown that LMWH, as an anticoagulant, improves uteroplacental blood flow by preventing thrombosis, which can reduce the incidence of preeclampsia—a condition linked to impaired placental perfusion (56). Additionally, LDA, a commonly used antiplatelet agent, contributes to improving endothelial function and reducing inflammation, both of which are critical in preventing the development of preeclampsia. The combination of LMWH + LDA works synergistically to target multiple pathways involved in the pathogenesis of preeclampsia, thus improving pregnancy outcomes. The mechanisms underlying the observed benefits of LMWH + LDA in preventing preeclampsia and improving live birth rates are multifaceted. First, LMWH’s ability to enhance placental blood flow through its anticoagulant effect reduces the risk of placental dysfunction and the development of hypertensive disorders such as preeclampsia. By preventing thrombotic events and ensuring better placental oxygenation, LMWH helps to maintain a healthier intrauterine environment, which may improve fetal growth and viability (57). Second, LDA’s role in reducing platelet aggregation and modulating inflammatory responses further enhances uteroplacental circulation, preventing the pathological changes associated with preeclampsia (58). Together, LMWH and LDA form a complementary treatment approach that targets both thrombotic and inflammatory processes, providing a robust strategy for improving maternal and fetal health outcomes in high-risk pregnancies. LDA is commonly used in the management of FGR due to its antiplatelet properties, which are thought to improve uteroplacental blood flow and reduce the risk of thrombotic events that may contribute to fetal growth impairment. However, in this study, LDA alone ranked the lowest across multiple clinical outcomes, including the reduction of IUGR and the prevention of preeclampsia and miscarriage. These findings suggest that while LDA may have some benefits, its effectiveness is limited when used as a monotherapy in managing FGR. One potential explanation for LDA’s suboptimal performance in this analysis is its single mechanism of action. LDA primarily works by inhibiting platelet aggregation, thereby improving endothelial function and reducing inflammation. While this may help in improving placental perfusion, LDA alone may not be sufficient to address the multifactorial pathophysiology of FGR. FGR is often associated with placental insufficiency, thrombotic events, and systemic inflammation, and these factors may require more comprehensive treatment strategies (58). For instance, the combination of LDA with LMWH not only reduces thrombosis but also improves blood flow by enhancing placental circulation, leading to more favorable outcomes. The lack of synergy when LDA is used alone may explain its lower effectiveness compared to combination therapies. Furthermore, it is possible that the variability in the dosage and treatment duration of LDA across the studies included in this analysis contributed to the suboptimal ranking. Different doses of LDA may have varying effects on pregnancy outcomes, and some studies may not have utilized the most effective dosage for optimizing placental blood flow. The absence of a standardized treatment regimen for LDA in FGR management complicates its effectiveness and may have contributed to the observed variation in results (59). In contrast, combination therapies, such as LMWH + LDA, offer a more comprehensive approach by targeting multiple mechanisms involved in FGR and its associated complications, which could explain the superior outcomes observed in this study. This study presents several notable strengths that contribute to the robustness of the findings. First, the use of a NMA allowed for the simultaneous comparison of multiple pharmacological interventions for FGR, including both those that have been directly compared in studies and those that have not. This comprehensive approach provides a more nuanced understanding of the comparative effectiveness of various treatments, offering insights that would be impossible to obtain from traditional pairwise meta-analysis. Second, this analysis synthesized data from a substantial number of studies, providing a large, diverse dataset that enhances the generalizability of the findings. This extensive evidence base strengthens the conclusions drawn from the analysis and provides a comprehensive assessment of the therapeutic options available for managing FGR. However, several limitations must also be considered when interpreting the results. First, despite the large number of studies included, the clinical heterogeneity among the studies was high, which may have affected the generalizability of the findings. Differences in patient populations, such as varying inclusion criteria and maternal comorbidities, as well as variations in treatment protocols (e.g., dosage and duration of therapy), could have introduced biases that influence treatment outcomes. Although we attempted to control for some of these variables through stratified analyses, the potential for residual confounding remains. This heterogeneity underscores the need for more standardized clinical protocols and larger, well-controlled trials to confirm the efficacy of pharmacological interventions in FGR. Second, while the studies included in this meta-analysis were predominantly RCTs, the inclusion of non-randomized studies and observational data introduces a potential risk of bias. While observational studies are valuable for examining real-world clinical outcomes, they are inherently subject to confounding factors that can distort the relationship between treatment and outcomes. The inclusion of these studies, though necessary for providing a more comprehensive view of the available evidence, may limit the internal validity of the findings. Future research should focus on conducting high-quality RCTs to provide more definitive evidence regarding the efficacy of these treatments. Finally, the lack of data on long-term maternal and fetal outcomes represents a significant gap in the current literature. While this study provides valuable insights into short-term pregnancy-related outcomes such as fetal growth and preeclampsia, the long-term effects of these treatments on maternal cardiovascular health, infant development, and potential lifelong complications remain unclear. Further research should aim to assess the long-term safety and efficacy of pharmacological interventions for FGR to provide a more complete understanding of their benefits and risks. 5. Conclusion This network meta-analysis provides a comprehensive evaluation of pharmacological treatments for FGR, highlighting the significant benefits of LMWH and its combination with LDA in improving fetal outcomes. LMWH alone and LMWH + LDA were found to significantly reduce the incidence of IUGR, preeclampsia, and other pregnancy complications, while improving live birth rates. These findings support the use of LMWH and LMWH + LDA as promising therapeutic strategies for managing high-risk pregnancies with FGR. Despite the strengths of this study, further high-quality randomized controlled trials are needed to standardize treatment protocols and explore long-term maternal and fetal outcomes, ensuring optimal management of FGR and its associated complications. This work was supported by the National Natural Science Foundation of China [grant 82204698].

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Table 1 Results of League Table for Fetal and Neonatal Outcomes Table 1.1 Birth Weight | 43.05 (-350.43,436.53) | LMWH + LDA | ||||| | 50.82 (-299.34,400.98) | 7.77 (-296.65,312.19) | LMWH | |||| | 185.77 (-350.27,721.81) | 142.72 (-367.41,652.85) | 134.95 (-314.25,584.15) | Tadalafil | ||| | 211.14 (-111.71,534.00) | 168.09 (-56.62,392.80) | 160.33 (-44.85,365.50) | 25.37 (-432.64,483.39) | LDA | || | 353.14 (-275.96,982.25) | 310.09 (-274.74,894.93) | 302.33 (-275.28,879.93) | 167.37 (-540.66,875.41) | 142.00 (-397.94,681.94) | UFH + LDA | | | 306.77 (-18.67,632.22) | 263.72 (-17.01,544.45) | 255.95 (113.28,398.62) | 121.00 (-304.94,546.94) | 95.63 (-72.75,264.01) | -46.37 (-611.96,519.21) | CON | Table 1.2 Fetal Death | 1.01 (0.23,4.50) | LMWH | ||| | 0.72 (0.01,45.98) | 0.71 (0.01,58.79) | LMWH + LDA | || | 0.41 (0.01,11.46) | 0.41 (0.01,15.55) | 0.57 (0.05,6.99) | LDA | | | 0.19 (0.00,11.64) | 0.19 (0.00,14.93) | 0.27 (0.01,8.60) | 0.46 (0.04,5.19) | Dipyridamole + LDA | Table 1.3 Live Birth | 1.23 (0.75,2.01) | CON | ||| | 2.20 (0.45,10.65) | 1.78 (0.34,9.32) | LMWH + LDA | || | 3.70 (0.78,17.59) | 3.00 (0.59,15.41) | 1.68 (0.54,5.21) | UFH + LDA | | | 15.55 (5.49,43.99) | 12.63 (4.00,39.87) | 7.08 (2.16,23.22) | 4.20 (1.31,13.44) | LDA | Table 1.4 SGA | 0.78 (0.26,2.35) | LMWH + LDA | || | 0.64 (0.36,1.12) | 0.82 (0.29,2.32) | CON | | | 0.46 (0.20,1.09) | 0.60 (0.30,1.20) | 0.73 (0.34,1.55) | LDA | Table 1.5 IUGR | 1.11 (0.22,5.53) | LMWH + LDA | ||||| | 0.40 (0.26,0.62) | 0.36 (0.08,1.70) | CON | |||| | 0.37 (0.15,0.93) | 0.33 (0.09,1.24) | 0.92 (0.41,2.08) | LDA | ||| | 0.32 (0.10,1.04) | 0.29 (0.06,1.29) | 0.79 (0.26,2.38) | 0.86 (0.42,1.80) | Dipyridamole + LDA | || | 0.24 (0.04,1.40) | 0.22 (0.02,2.17) | 0.60 (0.11,3.30) | 0.65 (0.10,4.33) | 0.76 (0.10,5.74) | Tadalafil | | | 0.21 (0.03,1.62) | 0.19 (0.03,1.20) | 0.53 (0.07,3.84) | 0.58 (0.09,3.51) | 0.67 (0.09,4.69) | 0.88 (0.06,12.03) | UFH + LDA | Table 2 Results of League Table for Pregnancy and Delivery Outcomes Table 2.1 Placental Abruption | 1.10 (0.10,12.40) | LMWH + LDA | ||| | 0.69 (0.11,4.23) | 0.63 (0.06,6.72) | LMWH | || | 0.38 (0.09,1.58) | 0.34 (0.05,2.43) | 0.54 (0.14,2.06) | LDA | | | 0.25 (0.05,1.19) | 0.23 (0.03,2.02) | 0.37 (0.14,0.93) | 0.68 (0.26,1.72) | CON | Table 2.2 Pre-eclampsia | 1.53 (0.05,47.21) | Dipyridamole + LDA | |||| | 0.43 (0.06,3.25) | 0.28 (0.01,13.26) | UFH + LDA | ||| | 0.22 (0.08,0.59) | 0.15 (0.01,3.86) | 0.52 (0.07,3.96) | LDA | || | 0.21 (0.05,0.93) | 0.14 (0.01,3.63) | 0.50 (0.05,5.00) | 0.96 (0.33,2.84) | LMWH | | | 0.10 (0.03,0.35) | 0.06 (0.00,1.51) | 0.22 (0.03,2.01) | 0.43 (0.19,0.98) | 0.45 (0.22,0.92) | CON | Table 2.3 Preterm Delivery | 0.96 (0.40,2.30) | LMWH + LDA | ||| | 0.83 (0.51,1.35) | 0.87 (0.42,1.79) | LDA | || | 0.66 (0.13,3.30) | 0.69 (0.15,3.08) | 0.79 (0.17,3.68) | UFH + LDA | | | 0.61 (0.45,0.81) | 0.63 (0.28,1.45) | 0.73 (0.50,1.08) | 0.92 (0.19,4.51) | CON | Table 2.4 Miscarriage | 0.45 (0.05,3.76) | LMWH + LDA | |||| | 0.42 (0.19,0.91) | 0.93 (0.11,7.72) | CON | ||| | 0.38 (0.04,3.37) | 0.85 (0.16,4.43) | 0.91 (0.10,8.08) | UFH + LDA | || | 0.32 (0.03,3.55) | 0.71 (0.03,15.93) | 0.77 (0.08,7.44) | 0.84 (0.04,19.74) | Dipyridamole + LDA | | | 0.13 (0.03,0.53) | 0.29 (0.06,1.43) | 0.31 (0.07,1.30) | 0.34 (0.06,1.81) | 0.41 (0.03,5.95) | LDA | Table 2.5 Cesarean | 0.53 (0.09,3.23) | LMWH | ||| | 0.48 (0.08,2.86) | 0.91 (0.65,1.29) | CON | || | 0.31 (0.04,2.30) | 0.58 (0.05,7.37) | 0.63 (0.05,7.88) | UFH + LDA | | | 0.34 (0.18,0.67) | 0.65 (0.12,3.51) | 0.71 (0.14,3.71) | 1.12 (0.17,7.57) | LDA | Title of figures Figure 1: PRISMA Flow diagram of the search process for studies. Figure 2: Network of Treatment Comparisons for Fetal and Neonatal Outcomes. Figure 3: Network of Treatment Comparisons for Pregnancy and Delivery Outcomes. Figure 4: Ranking of Treatment Strategies Based on Probability of Impact on Fetal and Neonatal Outcomes. Figure 5: Ranking of Treatment Strategies Based on Probability of Impact on Pregnancy and Delivery Outcomes. Information & Authors Information Version history Peer review timeline Published Frontiers in Pharmacology Version of Record15 Apr 2026Published Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 250views 77downloads Citations Download citation Yanting Wei, Leilei Gong, Xin Yu, et al. Comparative Effectiveness of Pharmacological Treatments for Fetal Growth Restriction: A Network Meta-Analysis. Authorea. 25 November 2025. DOI: https://doi.org/10.22541/au.176407946.62988459/v1 DOI: https://doi.org/10.22541/au.176407946.62988459/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.