Association Between SHBG Levels and Hypertensive Disorders of Pregnancy: A Systematic Review and Meta‐Analysis
Introduction The glycoprotein sex hormone binding globulin (SHBG) is primarily produced in the liver and functions as a critical regulator of sex hormone bioavailability by binding to circulating androgens and estrogens . SHBG plays a key role in maintaining hormonal balance,  and its levels are influenced by various physiological and pathological factors, including insulin resistance, inflammation, and hepatic function . During pregnancy, SHBG levels naturally rise substantially, with studies reporting baseline levels of approximately 40–60 nmol/L in non‐pregnant women, which increase to 100–150 nmol/L during the first trimester and peak between 200 and 400 nmol/L in the third trimester. These increases are attributed to heightened estrogen production and adaptive changes in liver metabolism. Recent research has highlighted deviations in these typical patterns of SHBG as potential indicators of adverse pregnancy outcomes [ , , ]. Specifically, altered SHBG levels have been implicated in hypertensive disorders of pregnancy (HDP), suggesting its utility as a biomarker for these conditions, which are of considerable global health significance. HDP, which include gestational hypertension (GH) and preeclampsia (PE), are major contributors to maternal and neonatal morbidity and mortality worldwide . These conditions affect approximately 5%–10% of pregnancies globally , with PE alone accounting for 3%–5% . GH is characterized by new‐onset hypertension after 20 weeks of gestation without proteinuria or systemic dysfunction , whereas PE is a more severe multisystem disorder marked by hypertension accompanied by proteinuria or signs of end‐organ damage, such as renal impairment, liver dysfunction, or thrombocytopenia . PE is responsible for 10%–15% of direct maternal deaths globally  and contributes to severe perinatal complications, including preterm birth, which occurs in up to 20% of affected pregnancies . Furthermore, the long‐term risks of hypertensive disorders include a two‐ to threefold increase in the likelihood of developing chronic hypertension and cardiovascular disease in later life. Despite these significant consequences, the pathogenesis of GH and PE remains incompletely understood, and reliable biomarkers for early detection and risk stratification are urgently needed. In recent years, an emerging body of evidence has explored the association between SHBG and HDP, although findings remain inconsistent. Several studies suggest that lower SHBG levels are associated with an increased risk of developing GH or PE , potentially due to the link between SHBG and metabolic disturbances, including insulin resistance and systemic inflammation. Conversely, some studies have reported no significant association or have proposed that altered SHBG levels may reflect comorbid conditions rather than directly contributing to hypertensive pregnancy disorders . These inconsistencies highlight the need for a comprehensive evaluation of the evidence to better understand the role of SHBG in the pathophysiology of GH and PE. Several mechanisms have been proposed to explain the association between altered SHBG levels and HDP. First, low SHBG levels are linked to metabolic disturbances, such as insulin resistance and systemic inflammation, which exacerbate vascular dysfunction and oxidative stress key drivers of placental insufficiency and hypertension . Second, SHBG regulates the balance of sex hormones, particularly estrogens and androgens , with lower SHBG levels leading to increased free androgens that promote vasoconstriction, endothelial dysfunction, and placental ischemia . Additionally, SHBG may influence angiogenic factors critical for placental development, with disruptions contributing to impaired uteroplacental blood flow . These mechanisms highlight SHBG's potential role in hypertensive disorders, although some suggest the association may reflect underlying metabolic or inflammatory conditions rather than a direct effect of SHBG. To address these knowledge gaps, this systematic review and meta‐analysis aim to evaluate the association between SHBG levels and HDP, with a specific focus on PE and GH. This study will synthesize the available evidence to determine the strength of these associations across diverse populations and explore the potential mechanisms underlying these relationships. By concentrating on PE and GH, this review seeks to clarify the role of SHBG in the development of these specific hypertensive pregnancy disorders and provide a foundation for future research and clinical applications. 

Methods 2.1 Study Design This systematic review and meta‐analysis were conducted to compile and analyze existing research on the association between SHBG levels and HDP, specifically PE and GH. This study adhered to the guidelines outlined in the preferred reporting items for systematic reviews and meta‐analyses (PRISMA)  (Table ). Additionally, the study protocol was formally registered in the International Prospective Register of Systematic Reviews (PROSPERO). 2.2 Data Sources and Search Strategy A thorough search was performed across several electronic databases, including PubMed, EMBASE, and Web of Science, to identify studies published up to November 10, 2024. The search strategy incorporated a combination of free text keywords terms related to (“Sex hormones” or “sex hormone” or “Sex Hormone‐Binding Globulin [SHBG]”) AND (PE or “pre‐eclampsia” or “toxemia” or “edema‐proteinuria‐hypertension gestosis” or “GH” or “pregnancy‐induced hypertension” or “pregnancy hypertension” or “HDP”). No restrictions were imposed on the language or type of article to ensure comprehensive coverage. The detailed search strategy is presented in Table . 2.3 Eligibility Criteria Studies were included based on specific inclusion criteria. Only studies that investigated the association between SHBG levels and HDP, specifically PE and GH, were included. Participants were pregnant individuals with available data on SHBG levels, either measured directly or reported. Only studies that provided quantitative estimates, such as odds ratios (OR), risk ratios (RR), or sufficient data to calculate these metrics, were eligible. The primary exposure of interest was SHBG levels, with the outcomes being the presence or risk of PE or GH. The comparison group involved healthy pregnant women without elevated SHBG levels or those with normal SHBG levels, as specified by the studies. Studies published in peer‐reviewed journals were included. The exclusion criteria included case reports, conference abstracts, editorials, and review articles. Studies focusing solely on other pregnancy complications without specific data on SHBG or HDP were excluded. 2.4 Study Selection Two reviewers independently screened the titles and abstracts of identified studies to determine their eligibility. Full texts of studies deemed potentially relevant were subsequently retrieved and assessed by the same reviewers for inclusion. Any disagreements were resolved through discussion, with a third reviewer consulted if necessary to reach consensus. To streamline the study selection process, semi‐automated software (such as Nested‐Knowledge, MN, USA) was used to remove duplicates and assist with the screening process. 2.5 Data Extraction and Quality Assessment Data were gathered using a structured extraction form. The collected data included important study details such as author, year of publication, country of origin, sample size, study design, participant characteristics (e.g., age, gestational age), SHBG measurement methods, and reported effect sizes with their corresponding 95% confidence intervals (CIs). The data extraction procedure was carried out by two independent reviewers, and any disputes were settled through discussion or, if required, by consulting a third reviewer. The semi‐automated software's “tagging” feature (e.g., Nested‐Knowledge, MN, USA) facilitated the data extraction procedure. Utilizing the Newcastle‐Ottawa Scale (NOS), two assessors independently evaluated the quality of the included studies. The studies were assessed based on participant selection, comparability of study groups, and the methodology used to investigate the association between SHBG levels and HDP (Table ). 2.6 Data Synthesis and Statistical Analysis Data analysis was performed using R software version 4.4 to assess the relationship between SHBG levels and HDP, focusing on PE and GH. A random‐effects meta‐analysis was utilized to account for variability among studies. Results were reported as pooled effect sizes with 95% CIs. Heterogeneity among studies was evaluated using the I 2 statistic and Cochran's Q test, with I 2 values greater than 75% indicating substantial heterogeneity. Subgroup analysis was performed based on study design and type of HDP. The robustness of the results was tested through a leave‐one‐out sensitivity analysis. Sensitivity analysis was also performed excluding the study that included women with polycystic ovary syndrome (PCOS). Statistical significance was defined as a p‐value less than 0.05. 

Study Design This systematic review and meta‐analysis were conducted to compile and analyze existing research on the association between SHBG levels and HDP, specifically PE and GH. This study adhered to the guidelines outlined in the preferred reporting items for systematic reviews and meta‐analyses (PRISMA)  (Table ). Additionally, the study protocol was formally registered in the International Prospective Register of Systematic Reviews (PROSPERO). 

Data Sources and Search Strategy A thorough search was performed across several electronic databases, including PubMed, EMBASE, and Web of Science, to identify studies published up to November 10, 2024. The search strategy incorporated a combination of free text keywords terms related to (“Sex hormones” or “sex hormone” or “Sex Hormone‐Binding Globulin [SHBG]”) AND (PE or “pre‐eclampsia” or “toxemia” or “edema‐proteinuria‐hypertension gestosis” or “GH” or “pregnancy‐induced hypertension” or “pregnancy hypertension” or “HDP”). No restrictions were imposed on the language or type of article to ensure comprehensive coverage. The detailed search strategy is presented in Table . 

Eligibility Criteria Studies were included based on specific inclusion criteria. Only studies that investigated the association between SHBG levels and HDP, specifically PE and GH, were included. Participants were pregnant individuals with available data on SHBG levels, either measured directly or reported. Only studies that provided quantitative estimates, such as odds ratios (OR), risk ratios (RR), or sufficient data to calculate these metrics, were eligible. The primary exposure of interest was SHBG levels, with the outcomes being the presence or risk of PE or GH. The comparison group involved healthy pregnant women without elevated SHBG levels or those with normal SHBG levels, as specified by the studies. Studies published in peer‐reviewed journals were included. The exclusion criteria included case reports, conference abstracts, editorials, and review articles. Studies focusing solely on other pregnancy complications without specific data on SHBG or HDP were excluded. 

Study Selection Two reviewers independently screened the titles and abstracts of identified studies to determine their eligibility. Full texts of studies deemed potentially relevant were subsequently retrieved and assessed by the same reviewers for inclusion. Any disagreements were resolved through discussion, with a third reviewer consulted if necessary to reach consensus. To streamline the study selection process, semi‐automated software (such as Nested‐Knowledge, MN, USA) was used to remove duplicates and assist with the screening process. 

Data Extraction and Quality Assessment Data were gathered using a structured extraction form. The collected data included important study details such as author, year of publication, country of origin, sample size, study design, participant characteristics (e.g., age, gestational age), SHBG measurement methods, and reported effect sizes with their corresponding 95% confidence intervals (CIs). The data extraction procedure was carried out by two independent reviewers, and any disputes were settled through discussion or, if required, by consulting a third reviewer. The semi‐automated software's “tagging” feature (e.g., Nested‐Knowledge, MN, USA) facilitated the data extraction procedure. Utilizing the Newcastle‐Ottawa Scale (NOS), two assessors independently evaluated the quality of the included studies. The studies were assessed based on participant selection, comparability of study groups, and the methodology used to investigate the association between SHBG levels and HDP (Table ). 

Data Synthesis and Statistical Analysis Data analysis was performed using R software version 4.4 to assess the relationship between SHBG levels and HDP, focusing on PE and GH. A random‐effects meta‐analysis was utilized to account for variability among studies. Results were reported as pooled effect sizes with 95% CIs. Heterogeneity among studies was evaluated using the I 2 statistic and Cochran's Q test, with I 2 values greater than 75% indicating substantial heterogeneity. Subgroup analysis was performed based on study design and type of HDP. The robustness of the results was tested through a leave‐one‐out sensitivity analysis. Sensitivity analysis was also performed excluding the study that included women with polycystic ovary syndrome (PCOS). Statistical significance was defined as a p‐value less than 0.05. 

Results 3.1 Literature Search Database searches identified a total of 592 records across Embase (375 records), PubMed (95 records), and Web of Science (122 records). After removing 142 duplicate records, 450 records remained for screening. During the screening process, 404 records were excluded based on titles and abstracts that did not meet the inclusion criteria, leaving 46 full‐text articles for eligibility assessment. Upon full‐text review, 39 articles were excluded for the following reasons: 17 did not report relevant outcomes, seven were irrelevant to the study objectives, eight were review articles, and seven were case reports. Finally, eight studies [ , , – ] were included in the systematic review (Figure ). 3.2 Characteristics of Included Studies The included studies comprised investigations from diverse countries, including the USA, UK, Finland, Iran, and China (Table ). The study designs varied, encompassing cross‐sectional, case‐control, prospective cohort, prospective nested case‐control and Mendelian randomization approaches. Participants included pregnant individuals with a wide age range, from 20 years to over 40 years, with sample sizes ranging from 92 to over 300 000. Gestational ages at SHBG measurement ranged from 10 weeks to 27 weeks. Diagnostic criteria for HDP, including PE and GH, were based on standardized clinical methods. SHBG levels were measured using diverse techniques such as immunoradiometric assays, immunometric assays, competitive chemiluminescent immunoassays, and modular analyzers. Half of the studies did not report the method of SHBG analysis. This diversity in study design, population characteristics, and measurement methods reflects the broad range of methodologies employed to investigate the association between SHBG levels and HDP. The result from each studies is presented in Table . The quality assessment of these studies is presented in Table . 3.3 Association between SHBG and Risk of HDP The meta‐analysis of eight studies demonstrated that the OR for the association between SHBG levels and the risk of HDP was 0.875 (95% CI: 0.772–0.993, p = 0.037), based on the included studies. The analysis revealed substantial heterogeneity ( I 2 = 79%, Q = 37.69), indicating significant variability among the studies. OR estimates ranged from 0.550 to 1.040, with Wolf  reporting a lower OR of 0.550 (95% CI: 0.393–0.769), while Yu 2004 reported a higher OR of 1.040 (95% CI: 0.994–1.088) (Figure ). The pooled estimate was statistically significant, suggesting an association between higher SHBG levels and a lower risk of HDP. 3.4 Association between SHBG and Risk of PE The meta‐analysis of five studies demonstrated that the OR for the association between SHBG levels and the risk of PE was 0.890 (95% CI: 0.767–1.032, p = 0.1238), suggesting no significant association. The analysis revealed substantial heterogeneity ( I 2 = 79%, Q = 24.45), indicating considerable variability between studies. OR estimates ranged from 0.610 to 1.040, with Tamimi 2003 reporting a lower OR of 0.610 (95% CI: 0.391–0.952), while Yu 2004 showed a higher OR of 1.040 (95% CI: 0.994–1.088) (Figure ). 3.5 Association Between SHBG and Risk of GH The meta‐analysis of two studies demonstrated that the OR for the association between SHBG levels and the risk of GH was 0.729 (95% CI: 0.442–1.205, p = 0.217), based on the included studies. The analysis showed high heterogeneity ( I 2 = 88%, Q = 8.10), indicating substantial variability between studies. OR estimates ranged from 0.550 to 0.920, with Wolf 2002 (5) reporting a lower OR of 0.550 (95% CI: 0.393–0.779), while Wu 2024 (FinnGen Consortium) showed a higher OR of 0.920 (95% CI: 0.820–1.032) (Figure ). The pooled estimate was not statistically significant, suggesting no protective association between higher SHBG levels and a lower risk of GH ( p = 0.217). 3.6 Subgroup Analysis of Association between SHBG and Risk of HDP Subgroup analyses based on study design (Mendelian randomization, case‐control, prospective nested case‐control, prospective cohort, and cross‐sectional) revealed variability in the association between SHBG levels and the risk of HDP. The pooled OR for Mendelian randomization studies was 0.961 (95% CI: 0.895–1.031) with moderate heterogeneity ( I 2 = 37%), while case‐control studies showed a pooled OR of 0.990 (95% CI: 0.980–1.000) with no heterogeneity ( I 2 = 0%). Prospective nested case‐control studies demonstrated a stronger inverse association with a pooled OR of 0.624 (95% CI: 0.517–0.752) and no heterogeneity ( I 2 = 0%). Prospective cohort and cross‐sectional studies had pooled ORs of 0.817 (95% CI: 0.519–1.285) with moderate heterogeneity ( I 2 = 77%), and 1.040 (95% CI: 0.994–1.088), with no heterogeneity ( I 2 = 0%), respectively. Overall heterogeneity across subgroups remained substantial ( I 2 = 79%), and the test for subgroup differences was statistically significant ( p < 0.01), indicating that study design contributed to the observed heterogeneity (Figure ). 3.7 Sensitivity Analysis A leave‐one‐out sensitivity analysis was conducted to evaluate the robustness of pooled estimates for the association between SHBG levels and the risks of HDP and PE. For HDP, pooled ORs ranged from 0.871 to 0.990, and for PE, pooled ORs ranged from 0.885 to 0.994. In all cases, excluding any single study did not significantly change the overall effect size, confirming the stability of the potential association between SHBG levels and the reduced risk of both HDP and PE (Figures ). Additionally, we conducted a sensitivity analysis excluding the study by Xia et al.  which included women with PCOS, a potential source of bias. The pooled OR was found to be 0.852 (95% CI: 0.733–0.989, p = 0.03). This analysis revealed a significant association between higher SHBG levels and a reduced risk of HDP in healthy pregnant women, further supporting the robustness of the observed findings (Figure ). 

Literature Search Database searches identified a total of 592 records across Embase (375 records), PubMed (95 records), and Web of Science (122 records). After removing 142 duplicate records, 450 records remained for screening. During the screening process, 404 records were excluded based on titles and abstracts that did not meet the inclusion criteria, leaving 46 full‐text articles for eligibility assessment. Upon full‐text review, 39 articles were excluded for the following reasons: 17 did not report relevant outcomes, seven were irrelevant to the study objectives, eight were review articles, and seven were case reports. Finally, eight studies [ , , – ] were included in the systematic review (Figure ). 

Characteristics of Included Studies The included studies comprised investigations from diverse countries, including the USA, UK, Finland, Iran, and China (Table ). The study designs varied, encompassing cross‐sectional, case‐control, prospective cohort, prospective nested case‐control and Mendelian randomization approaches. Participants included pregnant individuals with a wide age range, from 20 years to over 40 years, with sample sizes ranging from 92 to over 300 000. Gestational ages at SHBG measurement ranged from 10 weeks to 27 weeks. Diagnostic criteria for HDP, including PE and GH, were based on standardized clinical methods. SHBG levels were measured using diverse techniques such as immunoradiometric assays, immunometric assays, competitive chemiluminescent immunoassays, and modular analyzers. Half of the studies did not report the method of SHBG analysis. This diversity in study design, population characteristics, and measurement methods reflects the broad range of methodologies employed to investigate the association between SHBG levels and HDP. The result from each studies is presented in Table . The quality assessment of these studies is presented in Table . 

Association between SHBG and Risk of HDP The meta‐analysis of eight studies demonstrated that the OR for the association between SHBG levels and the risk of HDP was 0.875 (95% CI: 0.772–0.993, p = 0.037), based on the included studies. The analysis revealed substantial heterogeneity ( I 2 = 79%, Q = 37.69), indicating significant variability among the studies. OR estimates ranged from 0.550 to 1.040, with Wolf  reporting a lower OR of 0.550 (95% CI: 0.393–0.769), while Yu 2004 reported a higher OR of 1.040 (95% CI: 0.994–1.088) (Figure ). The pooled estimate was statistically significant, suggesting an association between higher SHBG levels and a lower risk of HDP. 

Association between SHBG and Risk of PE The meta‐analysis of five studies demonstrated that the OR for the association between SHBG levels and the risk of PE was 0.890 (95% CI: 0.767–1.032, p = 0.1238), suggesting no significant association. The analysis revealed substantial heterogeneity ( I 2 = 79%, Q = 24.45), indicating considerable variability between studies. OR estimates ranged from 0.610 to 1.040, with Tamimi 2003 reporting a lower OR of 0.610 (95% CI: 0.391–0.952), while Yu 2004 showed a higher OR of 1.040 (95% CI: 0.994–1.088) (Figure ). 

Association Between SHBG and Risk of GH The meta‐analysis of two studies demonstrated that the OR for the association between SHBG levels and the risk of GH was 0.729 (95% CI: 0.442–1.205, p = 0.217), based on the included studies. The analysis showed high heterogeneity ( I 2 = 88%, Q = 8.10), indicating substantial variability between studies. OR estimates ranged from 0.550 to 0.920, with Wolf 2002 (5) reporting a lower OR of 0.550 (95% CI: 0.393–0.779), while Wu 2024 (FinnGen Consortium) showed a higher OR of 0.920 (95% CI: 0.820–1.032) (Figure ). The pooled estimate was not statistically significant, suggesting no protective association between higher SHBG levels and a lower risk of GH ( p = 0.217). 

Subgroup Analysis of Association between SHBG and Risk of HDP Subgroup analyses based on study design (Mendelian randomization, case‐control, prospective nested case‐control, prospective cohort, and cross‐sectional) revealed variability in the association between SHBG levels and the risk of HDP. The pooled OR for Mendelian randomization studies was 0.961 (95% CI: 0.895–1.031) with moderate heterogeneity ( I 2 = 37%), while case‐control studies showed a pooled OR of 0.990 (95% CI: 0.980–1.000) with no heterogeneity ( I 2 = 0%). Prospective nested case‐control studies demonstrated a stronger inverse association with a pooled OR of 0.624 (95% CI: 0.517–0.752) and no heterogeneity ( I 2 = 0%). Prospective cohort and cross‐sectional studies had pooled ORs of 0.817 (95% CI: 0.519–1.285) with moderate heterogeneity ( I 2 = 77%), and 1.040 (95% CI: 0.994–1.088), with no heterogeneity ( I 2 = 0%), respectively. Overall heterogeneity across subgroups remained substantial ( I 2 = 79%), and the test for subgroup differences was statistically significant ( p < 0.01), indicating that study design contributed to the observed heterogeneity (Figure ). 

Sensitivity Analysis A leave‐one‐out sensitivity analysis was conducted to evaluate the robustness of pooled estimates for the association between SHBG levels and the risks of HDP and PE. For HDP, pooled ORs ranged from 0.871 to 0.990, and for PE, pooled ORs ranged from 0.885 to 0.994. In all cases, excluding any single study did not significantly change the overall effect size, confirming the stability of the potential association between SHBG levels and the reduced risk of both HDP and PE (Figures ). Additionally, we conducted a sensitivity analysis excluding the study by Xia et al.  which included women with PCOS, a potential source of bias. The pooled OR was found to be 0.852 (95% CI: 0.733–0.989, p = 0.03). This analysis revealed a significant association between higher SHBG levels and a reduced risk of HDP in healthy pregnant women, further supporting the robustness of the observed findings (Figure ). 

Discussion This systematic review aimed to assess the association between SHBG and HDP. The key results from this systematic review and meta‐analysis suggest a potential significant association between SHBG levels and the risk of HDP. Specifically, the cumulative pooled OR for HDP was 0.875 (95% CI: 0.772–0.993) indicating potential protective effect of higher SHBG levels against the development of HDP. These results point toward that individuals with higher SHBG levels have a reduced risk of developing HDP. In addition to the pooled OR, subgroup analyses further demonstrated variability based on study design and measurement techniques. While prior research supports the role of SHBG in mitigating metabolic dysregulation and inflammation, key contributors to hypertensive pregnancy disorders, our findings did not confirm a protective role in this context. In comparison to previous meta‐analyses, our study adds new dimensions to the understanding of SHBG's role in HDP. While prior reviews have primarily focused on broader metabolic markers, such as insulin resistance and inflammatory cytokines , or single‐study evaluations of SHBG levels , this meta‐analysis synthesizes data across multiple populations and study designs to specifically quantify the association between SHBG and HDP. Previous analyses have identified metabolic dysfunction as a key driver of hypertensive pregnancy complications , but limited attention has been given to SHBG as a specific biomarker. This study also emphasizes the variability in SHBG measurement techniques and highlights the need for standardization to improve its reliability as a biomarker. The substantial heterogeneity observed in studies assessing the association between SHBG and HDP reflects variations in study populations, measurement techniques, and diagnostic criteria. For HDP overall, the heterogeneity was high ( I 2 = 79%), indicating significant variability in the included studies. For PE, the heterogeneity was slightly lower ( I 2 = 79%), while for GH, the heterogeneity was the highest ( I 2 = 88%). Differences in gestational age at SHBG measurement, maternal age, body mass index, and other condition likely contributed to these variations. The variability in SHBG assay methods, such as chemiluminescent versus immunometric assays, may have also influenced the results. However, we could not perform subgroup analyses on these variable because of limited data. Despite this variability, the leave‐one‐out sensitivity analysis confirmed the robustness of the pooled estimates, supporting the reliability of these findings. Several mechanisms have been proposed to explain the association between altered SHBG levels and HDP. First, low SHBG levels are linked to metabolic disturbances, such as insulin resistance and systemic inflammation, which exacerbate vascular dysfunction and oxidative stress key drivers of placental insufficiency and hypertension . Second, SHBG regulates the balance of sex hormones, particularly estrogens and androgens , with lower SHBG levels leading to increased free androgens that promote vasoconstriction, endothelial dysfunction, and placental ischemia . Additionally, SHBG may influence angiogenic factors critical for placental development, with disruptions contributing to impaired uteroplacental blood flow . These mechanisms highlight SHBG's potential role in hypertensive disorders, although some suggest the association may reflect underlying metabolic or inflammatory conditions rather than a direct effect of SHBG. The results of this meta‐analysis carry several important clinical implications. First, they highlight the potential utility of SHBG as a biomarker for identifying individuals at risk of HDP early in pregnancy. Routine measurement of SHBG levels during antenatal care, in conjunction with other risk factors, could facilitate early risk stratification and targeted interventions. For instance, women with low SHBG levels may benefit from closer monitoring and early implementation of preventive strategies, such as dietary modifications or pharmacological treatments to reduce metabolic and vascular risk. Additionally, these findings emphasize the importance of addressing comorbid conditions like insulin resistance and obesity in reducing the overall burden of HDP. Finally, the role of SHBG in reflecting systemic metabolic health emphasizes the need for holistic antenatal care approaches that consider the interplay between hormonal, metabolic, and vascular factors. Despite providing valuable insights into the potential association between SHBG levels and the risk of HDP, this meta‐analysis has several limitations that warrant consideration. The included studies varied significantly in their design and population characteristics, with gestational ages at SHBG measurement ranging from as early as 10 weeks (mean = 10.5 weeks) to as late as 27 weeks. While random‐effects models were employed to account for heterogeneity, key moderating factors such as maternal age, body mass index, and comorbidities remain underexplored. We could not perform additional subgroup analyses due to limited availability on data on these variable reported by these studies. Additionally, unit conversions for SHBG levels could not be performed due to insufficient reporting in some studies, which may have impacted the comparability of results across studies. Although this analysis accounted for diverse SHBG measurement methods, including immunoradiometric assays, immunometric assays, chemiluminescent assays, and modular analyzers, potential variations in assay sensitivity and specificity may have influenced the pooled results. Furthermore, it is important to note that the included studies were predominantly observational in nature, which limits the ability to infer causality from the findings and highlights the need for longitudinal and interventional studies to confirm these associations. Additionally, most studies were conducted in regions such as the United States, the United Kingdom, and China, potentially limiting the generalizability of the findings to other populations with varying healthcare systems and demographic profiles. Future research should focus on standardizing gestational timing of SHBG measurement, exploring its relationship with maternal characteristics, and conducting longitudinal studies to establish temporal and causal links between SHBG levels and HDP. Expanding research to include more diverse populations and geographic regions will provide a more comprehensive understanding of SHBG's role in pregnancy and its utility as a biomarker for hypertensive disorders globally. 

Conclusion This meta‐analysis suggests a potential association between higher SHBG levels and a reduced risk of HDP, including GH and PE. These findings emphasize the importance of incorporating SHBG measurement into routine antenatal care to identify women at higher risk of HDP and implement early interventions. Additionally, public health initiatives are essential to raise awareness about the role of SHBG as a potential biomarker for pregnancy complications, promoting its use in clinical practice and supporting targeted strategies to improve maternal and fetal health outcomes. 

Ajay Malvi: Conceptualization, Methodology, Writing—Original Draft, Mahalaqua Nazli Khatib: Data Curation, Writing—Review & Editing, Roopashree R: Formal Analysis, Investigation, Mandeep Kaur: Resources, Data Curation, Manish Srivastava: Supervision, Project Administration, Amit Barwal: Visualization, Investigation, G. V. Siva Prasad: Methodology, Validation, Pranchal Rajput: Software, Formal Analysis, Rukshar Syed: Investigation, Data Curation, Kamal Kundra: Conceptualization, Resources, Vinamra Mittal: Validation, Writing—Review & Editing, Muhammed Shabil: Project Administration, Zaid Khan: Resources, Supervision. Writing—Review & Editing, Amit Kumar: Resources, Supervision, Pancham Cajla: Visualization, Supervision, Ganesh Bushi: Data Curation, Writing—Review & Editing, Rachana Mehta: Data Curation, Methodology, Prakasini Satapathya: Conceptualization, Supervision, Shilpa Gaidhane: Writing—Original Draft, Visualization, Renu Sah: Project Administration, Resources. 

The authors declare no conflicts of interest. 

Not applicable. 

Not applicable since this is a review and not involved any human. 

The author declares no conflicts of interest. 

Supporting information 

