The relationship between hypertensive disorders in pregnancy and endometriosis: a systematic review and meta-analysis

We obtained 14610 publications via the electronic search strategy (Web of Sciences: 6102; PubMed: 5945; Scopus; 2516; Cochrane Library: 47) from inception to 15 December 2023. Of these publications, 4734 duplicates were removed, and 9910 were subjected to title and abstract screening. Thirty articles were selected for eligibility at full-text review of which, 23 were eligible to be included in this review. Figure  1 shows the flowchart of the study. Fig. 1 The flow diagram of the systematic review for selection of the studie The flow diagram of the systematic review for selection of the studie Description of the studies is shown in Table  1 . The reviewed observational studies included cohort studies (13 papers), case–control studies (7 papers), and longitudinal design (3 papers). As far as the country of origin of the studies was concerned, four were performed in Italy [ 26 – 29 ], three in Japan [ 30 – 32 ], three in China [ 6 , 33 , 34 ], three in Australia [ 18 , 35 , 36 ], two in the UK [ 17 , 37 ], two in Denmark [ 38 , 39 ], two in the USA [ 40 , 41 ], one in France [ 42 ], one in Taiwan [ 10 ], one in Sweden [ 16 ], and one in Canada [ 43 ]. The number of participants in the studies varied from 40 to 1,429,585. In all studies, women of reproductive age were included. The diagnosis of endometriosis in the included studies was based on the results of laparoscopy, surgery, diagnosis code of International Classification of Diseases ICD 9—ICD10, or imaging. In this review, 133,941 women with endometriosis were compared with 8,932,888 healthy women in terms of hypertensive disorders of pregnancy. Table 2 shows the definitions of hypertensive disorders and endometriosis across all included studies. Table 1 Characteristics of studies included in the systematic review No Study Location Study type Age (y); mean ± SD No. of participants Gravidity of participants Main outcomes: N (%) Case Control Case Control Case Control 1 Brosens et al. 2007 [ 17 ] UK Retrospective case–control study 32 (21– 44) 33 (20– 44) 245 274 Nulliparous and multiparous Pre-eclampsia 2 (0.8%) 16 (5.8%) 2 Berlac et al. 2017 [ 38 ] Denmark National cohort study 31.4 30.4 11 739 615 533 Nulliparous and multiparous Hypertension 404 (2.1%) 18984 (1.8%) Pre-eclampsia 588(3.0%) 23 625 (2.2%) 3 Conti et al. 2015 [ 26 ] Italy Cohort study - - 219 1331 Nulliparous and multiparous Gestational hypertension 8 (3.7%) 77 (5.8%) Preeclampsia 5 (2.2%) 16 (1.2%) 4 Epelboin et al. 2021 [ 42 ] France Longitudinal study 31.7 ± 4.8 30.0 ± 5.3 31,101 4,083,732 Nulliparous and multiparous Preeclampsia 679 (2.18%) 64,288 (1.57%) 5 Farland et al. 2019 [ 40 ] USA Prospective cohort study 29.1 ± 5.3 29.1 ± 5.3 8,875 187,847 Nulliparous and multiparous Hypertensive disorders of pregnancy 541/5,665 (9.5%) 8,730/131,970 (6.6%) 6 Farland et al. 2022 [ 41 ] USA Cohort study 33.0 ± 4.03 34.54 ± 4.23 1,560 73,868 Nulliparous and multiparous PIH/Pre-eclampsia 213 (13.7%) 9,440 (10.5%) 7 Gebremedhin et al. 2023 [ 35 ] Australia Population-based retrospective cohort study 15–49 15–49 19,476 893,271 Nulliparous and multiparous Preeclampsia 1468 (7.5%) 54,098 (6.1%) 8 Glavind et al. 2017 [ 39 ] Denmark Danish cohort study 30–34 25–29 1,719 81,074 Nulliparous and multiparous Pre-eclampsia 89 (5.18%) 3519 (4.34%) 9 Hadfield et al. (2009) [ 18 ] Australia Population-based, longitudinal study 31.4 ± 5.1 28.3 ± 5.7 3239 205 640 Nulliparous and multiparous Gestational hypertension 352(10.9%) 23 186 (11.3%) Pre-eclampsia 103 (3.2%) 6564 (3.2%) 10 Harada et al. (2016) [ 30 ] Japan Prospective cohort study 15–45 15–45 330 8,856 Nulliparous and multiparous Pre-eclampsia 8 (2.4%) 281(3.1%) 11 Ibiebele et al. 2022 [ 36 ] Australia Population-based cohort study 32.0 ± 5.1 29.7 ± 5.7 13 406 556922 Nulliparous and multiparous Pregnancy hypertension 1378 (10.3%) 50 231 (9.0%) 12 Lin et al. 2015 [ 33 ] China Retrospective cohort study 32.8 ± 4.0 30.6 ± 3.5 249 249 Nulliparous—multiparous Pregnancy-induced hypertension 9 (3.6%) 11 (4.4%) 13 Liu et al. 2023 [ 6 ] China Retrospective study 31.96 ± 4.38 31.75 ± 4.33 1026 2783 Nulliparous and multiparous Gestational hypertension 19 (1.85%) 60 (2.16%) Preeclampsia 38 (3.70%) 61 (2.19%) 14 Mekaru et al. 2013 [ 31 ] Japan Retrospective analysis 33.0 ± 3.8 33.6 ± 4.1 49 59 Nulliparous and multiparous Pregnancy-induced hypertension 6 (15%) 6 (12.5%) 15 Miura et al. 2019 [ 32 ] Japan Case–control study 34.2 ± 4.6 32.9 ± 5.2 80 2689 Nulliparous and multiparous Hypertensive Disorders of Pregnancy 4 (5.0%) 187 (7.0%) 16 Pan et al. 2017 [ 10 ] Taiwan Population-based longitudinal cohort study 31.77 ± 5.76 31.77 ± 5.76 2578 10312 Nulliparous and multiparous Gestational hypertension-preeclampsia 100 (3.88%) 168 (1.63%) 17 Saraswat et al. 2016 [ 37 ] UK National population-based cohort study 30.5 ± 5.2 27.2 ± 6.1 5375 8280 Nulliparous and multiparous Hypertensive disorders 350 (8.3%) 452 (6.7%) 18 Stephansson et al. 2009 [ 16 ] Sweden Population-based longitudinal study  35  35 13 090 1 429 585 Nulliparous and multiparous Pre-eclampsia 441 (3.37%) 41 377 (2.89%) 19 Porpora et al. 2020 [ 27 ] Italy Prospective cohort study 31(18–45) 29(18–42) 145 280 Nulliparous women Pregnancy induced hypertension 7 (5%) 16 (6%) Preeclampsia 3 (2%) 2 (1%) 20 Scala et al. 2019 [ 28 ] Italy Retrospect analysis 30.2 (26.8–33) 30.3(27–33) 40 80 Nulliparous and multiparous Preeclampsia 9 (7.5%) 6 (7.5%) 21 Uccella et al. 2019 [ 29 ] Italy Retrospective case–control study 34(22–45) 31(15–48) 118 1,690 Nulliparous women Hypertension/preeclampsia 13 (11%) 99 (5.9%) 22 Velez et al. 2022 [ 43 ] Canada Population-based cohort study 32.95 ± 4.88 30.03 ± 5.6 19,099 768,350 Nulliparous and multiparous Hypertensive disorder 1042 (5.5%) 37660 (4.9%) 23 Xie et al. 2023 [ 34 ] China Case–control study 30.96 ± 3.32 30.23 ± 2.98 188 188 Nulliparous and multiparous Hypertensive disorder in pregnancy 10 11 Table 2 Definition of hypertensive disorders and endometriosis in the included studies Study Gravidity of participants Definitions of PIH Definitions of endometriosis Brosens et al. 2007 [ 17 ] Nulliparous and multiparous Persistently raised blood pressure (140/90 mmHg) starting after the 20th week of gestation. Pre-eclampsia was defined as PIH with proteinuria (> 300 mg/24 h) Laparoscopy Berlac et al. 2017 [ 38 ] Nulliparous and multiparous International Classification of Diseases (ICD)-10 codes women who underwent surgical interventions for their disease before pregnancy Conti et al. 2015 [ 26 ] Nulliparous and multiparous Systolic blood pressure over 140 mmHg or diastolic blood pressure over 90 mmHg after 20 weeks of gestation. preeclampsia: hypertension developing after 20 weeks of gestation with proteinuria pathology following surgical removal of the lesions Epelboin et al. 2021 [ 42 ] Nulliparous and multiparous - The diagnosis of endometriosis was recorded if reported in previous hospitalizations since 2008 Farland et al. 2019 [ 40 ] Nulliparous and multiparous self-report Laparoscopy Farland et al. 2022 [ 41 ] Nulliparous and multiparous ICD 9 and 10 codes ICD9 and ICD10 codes Gebremedhin et al. 2023 [ 35 ] Nulliparous and multiparous ICD-9/ICD-9-CM ICD-9/10 th revision-Australian Modification) Glavind et al. 2017 [ 39 ] Nulliparous and multiparous using the relevant ICD-8 and ICD-10 from the Danish National Patient Registry laparoscopic surgery Hadfield et al. (2009) [ 18 ] Nuliparous and multiparous The ICD-10 codes used to define The ICD-10 codes used to define Harada et al. (2016) [ 30 ] Nuliparous and multiparous as persistently raised blood pressure ≥ 140/90 mmHg, occurring after > 20 weeks Preeclampsia with severe features was defined as severe blood pressure elevation and severe proteinuria Questionnaire Ibiebele et al. 2022 [ 36 ] Nuliparous and multiparous - Australian modification (ICD10-AM) Lin et al. 2015 [ 33 ] Nulliparous—multiparous Elevated blood pressure ≥ 140/90 mmHg after 20 weeks of gestation Preeclampsia is gestational hypertension with proteinuria confirmed histologically and visually at the surgical procedure Liu et al. 2023 [ 6 ] Nulliparous and multiparous ‘Hypertension in pregnancy’ was defined as a systolic blood pressure of ≥ 140 mmHg or a diastolic blood pressure of ≥ 90 mmHg. When measured with semiquantitative urine dipsticks, proteinuria of at least 1 + in the presence of hypertension, with no evidence of urinary tract infection, was considered significant Diagnosis of endometriosis was done by laparoscopic examination, and the stage of endometriosis (was determined based on the revised American Society for Reproductive Medicine (rASRM) classification Mekaru et al. 2013 [ 31 ] Nulliparous and multiparous - laparoscopic evaluation Miura et al. 2019 [ 32 ] Nulliparous and multiparous - laparoscopy with histological confirmation Pan et al. 2017 [ 10 ] Nulliparous and multiparous International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) Surgical assessment by laparoscopy or laparotomy Saraswat et al. 2016 [ 37 ] Nulliparous and multiparous - surgically confirmed Stephansson et al. 2009 [ 16 ] Nulliparous and multiparous ICD-9 codes - Porpora et al. 2020 [ 27 ] Nulliparous women - surgical/histological or clinical /instrumental diagnosis of endometriosis Scala et al. 2019 [ 28 ] Nulliparous and multiparous Gestational hypertension and concomitant proteinuria Ultrasonographic diagnosis of endometriosis Uccella et al. 2019 [ 29 ] Nulliparous women - Pervious surgery Velez et al. 2022 [ 43 ] Nulliparous and multiparous - surgery with a diagnosis code of International Classification of Diseases ICD 9–617 or ICD10-N80 Xie et al. 2023 [ 34 ] Nulliparous and multiparous Increase in blood pressure of ≥ 140/ 90 mmHg after 20 weeks of gestation. Preeclampsia is gestational hypertension with proteinuria Histological examination Characteristics of studies included in the systematic review Definition of hypertensive disorders and endometriosis in the included studies as persistently raised blood pressure ≥ 140/90 mmHg, occurring after > 20 weeks Preeclampsia with severe features was defined as severe blood pressure elevation and severe proteinuria Elevated blood pressure ≥ 140/90 mmHg after 20 weeks of gestation Preeclampsia is gestational hypertension with proteinuria The relationship between gestational hypertension and endometriosis was investigated in 8 studies [ 6 , 18 , 26 , 27 , 31 , 33 , 36 , 38 ]. The evidence showed a positive and significant statistical relationship between the two mentioned variables (OR = 1.11, 95% CI: 1.06, 1.16; I 2  = 45%, P  < 0.0001; N  = 8) (Fig.  2 ). Due to the limited number of papers on the relationship between gestational hypertension and endometriosis, it was not possible to generate a funnel plot. Fig. 2 Forest plot showing the relationship between gestational hypertension and endometriosis between the two case and control group Forest plot showing the relationship between gestational hypertension and endometriosis between the two case and control group Twelve papers reported the relationship between pre-eclampsia and endometriosis [ 6 , 16 – 18 , 26 – 28 , 30 , 35 , 38 , 39 , 42 ]. As Fig.  3 shows, there is a positive relationship between pre-eclampsia and endometriosis (OR = 1.27, 95% CI: 1.23, 1.32; I 2  = 67%, P  < 0.00001; N  = 12). Because of high heterogeneity, we performed sensitivity analysis. By removing the effect of three studies [ 17 , 18 , 42 ] on the overall results, heterogeneity reached 44%, and still, the evidence indicated a statistically significant positive relationship between endometriosis and preeclampsia (OR = 1.26, 95% CI: 1.18, 1.36; I 2  = 37%, P  < 0.00001) (Fig.  4 ). Based on this, the chance of developing pre-eclampsia in the case group is 1.26 times that of the control group. In other words, the chance of developing pre-eclampsia in the case group is 26% higher than that in the control group. The distribution of points in the funnel plot (Fig.  5 ) as well as the Egger test results in Table  3 show that there is no publication bias ( P -value = 0.808). Fig. 3 Forest plot showing the relationship between pre-eclampsia and endometriosis between the two case and control group Fig. 4 Forest plot of sensitivity analysis showing the relationship between pre-eclampsia and endometriosis between the two case and control group Fig. 5 Funnell plot of included studies to assess the potential publication bias Table 3 Egger test results for publication bias Beta (SE) Z P -value Egger test for pre-eclampsia -0.11 (0.47) -0.24 0.808 Forest plot showing the relationship between pre-eclampsia and endometriosis between the two case and control group Forest plot of sensitivity analysis showing the relationship between pre-eclampsia and endometriosis between the two case and control group Funnell plot of included studies to assess the potential publication bias Egger test results for publication bias Eight papers [ 10 , 29 , 32 , 34 , 37 , 40 , 41 , 43 ] assessed the overall occurrence of hypertensive disorders (combined gestational hypertension-preeclampsia) in women affected with endometriosis. The meta-analysis showed a statistically significant relationship between hypertensive disorders and endometriosis with high heterogeneity (OR = 1.17, 95% CI: 1.12, 1.22; I 2  = 93%, P  < 0.00001; N  = 8) (Fig.  6 ). To reduce heterogeneity, we omitted the effect of two papers [ 10 , 40 ] on the overall results. Heterogeneity reached eight percent, and a statistically significant relationship between the two variables was identified (OR = 1.13, 95% CI: 1.06, 1.21; I 2  = 8%, P  = 0.0001) (Fig.  7 ). In other words, the chance of developing hypertensive disorder in the case group is 13% higher than that in the control group. A funnel plot could not be generated due to the limited number of papers on the relationship between hypertensive disorders and endometriosis. Fig. 6 Forest plot showing the relationship between hypertensive disorders and endometriosis between the two case and control group Fig. 7 Forest plot of sensitivity analysis showing the relationship between hypertensive disorders and endometriosis between the two case and control group Forest plot showing the relationship between hypertensive disorders and endometriosis between the two case and control group Forest plot of sensitivity analysis showing the relationship between hypertensive disorders and endometriosis between the two case and control group The quality assessment of the included studies is shown in Table  4 . The median total quality score was 16 which represented moderate quality. Table 4 Quality assessment of the articles reviewed Study ID (Author, Year) Clarity External validity Internal validity Power Total score Bias Confounding Brosens et al. 2007 [ 17 ] 9 3 3 2 0 17 Berlac et al. 2017 [ 38 ] 7 3 3 3 0 16 Conti et al. 2015 [ 26 ] 7 2 3 2 0 14 Epelboin et al. 2021 [ 42 ] 9 3 3 3 0 18 Farland et al. 2019 [ 40 ] 9 3 4 3 0 19 Farland et al. 2022 [ 41 ] 9 3 4 3 0 19 Gebremedhin et al. 2023 [ 35 ] 8 3 3 3 0 17 Glavind et al. 2017 [ 39 ] 8 3 3 4 0 18 Hadfield et al. 2009 [ 18 ] 7 3 3 2 1 16 Harada et al. 2016 [ 30 ] 8 3 3 3 0 17 Ibiebele et al. 2022 [ 36 ] 9 3 3 3 1 19 Lin et al. 2015 [ 33 ] 9 1 3 2 0 15 Liu et al. 2023 [ 6 ] 7 3 4 2 0 16 Mekaru et al. 2013 [ 31 ] 7 1 4 2 1 15 Miura et al. 2019 [ 32 ] 9 3 4 3 0 19 Pan et al. 2017 [ 10 ] 9 3 4 3 1 21 Saraswat et al. 2016 [ 37 ] 9 3 4 3 1 21 Stephansson et al. 2009 [ 16 ] 9 3 4 3 1 20 Porpora et al. 2020 [ 27 ] 7 1 4 2 0 14 Scala et al. 2019 [ 28 ] 9 0 3 2 0 15 Uccella et al. 2019 [ 29 ] 5 0 3 1 0 9 Velez et al. 2022 [ 43 ] 9 3 3 3 1 19 Xie et al. 2023 [ 34 ] 8 2 4 3 1 18 Mean range 16 Quality assessment of the articles reviewed

This systematic review and meta-analysis of observational studies was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 19 ]. The protocol of this systematic review was registered in PROSPERO (Ref No: CRD 42024498946). In this review, we included studies published in databases from inception up to December 2023. Systematic searches were performed on PubMed, Scopus, Cochrane Library, and Web of Science using MeSH keywords and terms. The keywords used were “Endometriosis” along with “Preeclampsia” and “Hypertension of pregnancy”. The selection of relevant studies was according to the following inclusion criteria: observational studies (case–control, cross-sectional, or cohort) and studies published in English. Studies written in local languages or with qualitative, review, and interventional designs, case report studies, congress presentations, or study protocols were excluded from this review. Furthermore, studies without a clear statement about the diagnosis of endometriosis, those lacking data on exposure or outcome, and those whose full text was not available were also excluded. All the included studies had a confirmed diagnosis of endometriosis either by the presence of lesions during surgery (with or without histological confirmation), by imaging modality, or by International Classification of Disease (ICD)-coded medical records in women who conceived spontaneously. Due to the higher risk of obstetric complications such as pregnancy-induced hypertension and preeclampsia associated with pregnancies conceived through ART [ 20 ], we excluded studies on these topics in order to eliminate their potential impact on the relationship between endometriosis and hypertensive disorders. Diagnosis of the gestational hypertension was defined as a systolic blood pressure of ≥ 140 mmHg or a diastolic blood pressure of ≥ 90 mmHg after 20 weeks of gestation or based on definition of International Classification of Diseases (ICD) 8, 9, 10 codes for gestational hypertensive disorders or etc. The case group in this study included pregnant women diagnosed with endometriosis at any stage or severity, while the control group consisted of pregnant women who had not been previously diagnosed with endometriosis. All the studies included in the review involved only women who had conceived naturally. Women who had become pregnant using in vitro fertilization were excluded from the study. Outcomes of this study were the hypertensive disorders of pregnancy including pre-eclampsia and gestational hypertension. FSH and SHF conducted a search on the databases and screened the titles and abstracts of the search results based on specific criteria. They independently extracted data from eligible full texts. In case of any discrepancies or conflicts, a third author was consulted to resolve the issue. Endnote X9 was used for screening and data extraction. A table was created for data extraction, and the following pieces of information were extracted: study author’s name, study location, study type, participants’ age, sample size of the control and case groups, definitions of PIH and endometriosis, and outcomes. FSH and SHF evaluated the quality of the studies included in the research using the checklist of Downs and Black (1998). The checklist comprised of twenty-seven questions that evaluated various areas. It included ten questions for assessing reporting bias, three for assessing external validity, seven for evaluating internal validity, six for assessing selection bias, and one question for assessing the power of the study [ 21 ]. The total quality score was classified as follows: a score of less than 14 was considered poor, a score between 15 and 19 was considered fair, and a score more than 20 was considered good [ 22 ]. We conducted a meta-analysis using Review Manager version 5.4 (RevMan 5.4; Cochrane Collaboration, Oxford, UK) and set the significance level at less than 0.05. Mean differences (MD) and 95% confidence intervals (95% CI) were used to compare variables between groups. We used a fixed-effect meta-analysis to combine the mean differences of each study and demonstrated effect sizes and 95% CI using forest plots. We measured heterogeneity using I 2 , where an I 2 value of 0–50% indicated low or moderate heterogeneity, and I 2  > 50% indicated substantial heterogeneity. We used the random effects model when I 2  > 50%. We conducted a sensitivity analysis to investigate potential sources of heterogeneity in case there was statistically significant heterogeneity across studies. In the sensitivity analyses, we systematically excluded one study at a time to test the strength of uncertainty in the meta-analysis [ 23 ]. We also statistically evaluated potential publication biases using funnel plots and Begg’s and Egger’s tests using STATA [ 24 ]. A funnel plot was used to assess publication bias whenever there were more than ten studies in the meta-analysis [ 25 ].

Our results showed that the odds of gestational hypertension and preeclampsia were higher in women with endometriosis compared to those without endometriosis. This finding help physicians to apply effective strategies for the screening and early diagnosis of hypertensive disorders in pregnancy, which could reduce the risk of maternal and fetal morbidity during pregnancy. However, we recommend that more high-quality studies be conducted to prove the relationship between gestational hypertension and endometriosis. Also, there is a need to conduct longitudinal observational studies to investigate the effect of endometriosis on hypertensive disorders based on the severity, staging, and location of endometriosis. The effect of endometriosis on spontaneous versus induced pregnancies with assisted reproductive methods should also be compared and examined.

This systematic review aimed to evaluate the correlation between hypertensive disorders in pregnancy and endometriosis . We included 23 observational studies which had a moderate quality score on average. The pooled evidence in this meta-analysis showed that the odds of gestational hypertension and preeclampsia were higher in women with endometriosis when compared to those without endometriosis. Endometriosis is an important cause of infertility. Pathophysiological speaking, it is expected to affect pregnancy outcomes [ 14 ]. Hormonal and inflammatory changes that occur in pregnancy are essential to ensure proper decidualization and placentation. In addition, these changes are also necessary to maintain pregnancy and active labor at term. Similarly, in endometriosis, there are hormonal changes and inflammatory factors that can overlap with pregnancy changes, ultimately causing disruption in pregnancy processes [ 44 ]. Cytokines, proteases, and matrix metalloproteinases play a major role in proper decidualization, which is necessary for successful blastocyst implantation. In endometriosis, inflammatory pathways that are regulated by decidua cells may be changed, which could lead to impaired proper trophoblast invasion and implantation [ 44 ]. Studies conducted on the relationship between endometriosis and hypertension disorders have yielded conflicting results. Similar to our findings, a systematic review by Breintoft et al. (2021) showed that endometriosis due to placental dysfunction is associated with an increased risk of adverse pregnancy outcomes including gestational hypertension and preeclampsia [ 45 ]. Although our study focused on women who conceived spontaneously, the population in Breintoft et al. consisted of all women who conceived with ART or spontaneously. Also, the number of included studies was small in the mentioned study. A large population-based cohort study confirmed that there is a higher risk of preeclampsia in women with endometriosis compared to those without endometriosis [ 35 ]. It included a very large sample size, and its results support a significant association of endometriosis with an increased risk of preeclampsia and other outcomes including placenta previa and preterm birth. However, the results of a systematic review including more than one million women showed that endometriosis had no relationship with gestational hypertension or preeclampsia [ 46 ]. This is probably due to the limitations noted in that study, namely a) inconsistently adjusted confounding factors that applied among the multiple sets of data and b) diagnosis and management of pregnancy complications that could differ across the studies. In addition, in the mentioned review, the participants were women who had become pregnant after in vitro fertilization (IVF), but our study included women who had become pregnant spontaneously. Conversely, a cohort study involving 787,449 women with singleton pregnancies showed that endometriosis was associated with an increased risk of hypertensive disorders during pregnancy [ 43 ]. This finding may be explained by the fact that in women with endometriosis, changes in cytokines and thicker junctional zones of the myometrium cause inappropriate trophoblast invasion [ 44 , 47 ]. Since the conversion of spiral arteries in the myometrial junctional zone is a necessary process for the formation of normal placenta, various characteristics of the junctional zone of endometriosis patients can cause abnormal placental function and thus increase the risk of pregnancy-induced hypertension disorders [ 47 , 48 ]. This study has a significant strength because of the large number of studies reviewed and the large number of participants recruited, which increases the reliability of the conclusions. The accuracy of data was improved due to the absence of publication bias. Also, the diagnosis of endometriosis was confirmed in most cases using surgery and laparoscopy. To maintain consistency in the study results, we only included women who conceived naturally and excluded those who conceived through IVF. Despite these strengths, this study had a number of limitations. Unfortunately, there was insufficient data in most studies to perform subgroup analysis based on endometriosis extension, clinical severity, duration of the illness, staging, and women’s age and parity, which could be considered as confounding factors. Additionally, about 50% of pregnant women with ovarian or deep endometriosis may be unaware of their condition [ 49 ]. As a result, there could be a significant number of women with endometriosis who are misdiagnosed due to lack of awareness about their condition, potentially impacting research results. It is important to note that adenomyosis, a condition related to endometriosis where the endometrium invades the myometrium, was not taken into account in this review. In addition, the study with the greatest significance in this meta-analysis was the one conducted by Ibiebele et al. (2022) [ 36 ], which established a strong and positive relationship between gestational hypertension and endometriosis. Other studies included in the analysis did not demonstrate a significant relationship between the two conditions. Therefore, more high-quality studies are needed to prove the relationship between these two medical conditions.

Endometriosis is a chronic gynecological disease characterized by the presence and growth of estrogen-dependent endometrial structures outside the uterine cavity, particularly on ovaries, fallopian tubes, pelvic peritoneum, and uterosacral ligaments [ 1 ]. Pelvic pain and infertility are the most common symptoms of affected women, occurring in 10–15% of women of reproductive age [ 2 ]. In the diagnosis of endometriosis based on ESHER guidelines, the presence of clinical symptoms, along with symptoms detected in clinical examinations and imaging (MRI and ultrasound) are used, and in case of suspicion of peritoneal endometriosis, laparoscopy is used for definitive diagnosis along with histological examination [ 3 ]. Clinical symptoms of endometriosis include abnormal bowel movements, intestinal dysfunction, dyspareunia, lower abdominal pain, severe dysmenorrhea, and infertility [ 4 ]. On the other hand, the prevalence of psychological disorders such as anxiety and depression is reported high in affected women [ 5 ]. Surgical excision of the lesion is a common treatment method that can alleviate pain and greatly enhance quality of life [ 6 ]. Of course, in some cases, recurrence of the disease has been reported [ 7 ]. Hypertensive disorders of pregnancy (chronic hypertension, gestational hypertension, and pre-eclampsia) are so prevalent throughout the world and can lead to serious consequences for both the mother and the baby [ 8 ]. The global prevalence of this disorder is almost 116 per 100,000 women of reproductive age. However, it varies depending on the region [ 9 ]. Current risk factors for hypertensive disorders include primigravida, increasing age, pre-pregnancy obesity, twin or multiple pregnancy, and some chronic diseases like polycystic ovarian syndrome (PCOs), overt diabetes, chronic kidney disease (CKD), and autoimmune disease [ 10 ]. Although the relationship between endometriosis and hypertensive disorders is not clearly defined, these two conditions seem to follow the same pathophysiological mechanisms. Endometriosis is known as an immunological and chronic inflammatory disease [ 11 ]. It has been shown that the concentration of immunological and inflammatory factors such as macrophages, natural killer cells (NK cells), cytokines, B and T lymphocytes, growth factors, and angiogenesis stimulants is higher in women with endometriosis [ 10 , 12 ], which can impede maternal and fetal adaptation with the normal changes of pregnancy. Additionally, a variety of immune cells and mediators have been associated with the onset of preeclampsia, a condition in which oxidative stress is linked to activation of the maternal inflammatory response. Immune cells such as regulatory T cells, macrophages, NK cells, and neutrophils are known to contribute significantly to the pathology of preeclampsia [ 13 ]. The interference caused by inflammatory and immunological responses can have a detrimental effect on trophoblast invasion and placental implantation that occurs by affecting the decidua and the placenta, which are crucial components of the process [ 14 ]. Defects in placental invasion or inappropriate remodeling of uterine spiral arteries can lead to blood pressure disorders in pregnancy [ 15 ]. Therefore, it seems that inflammatory and immunological factors play a role in pathogenesis of these two conditions and that they can affect each other. However, the evidence regarding the link between hypertensive disorders of pregnancy and endometriosis seems to be conflicting. While some studies have shown a significant association between the two [ 16 ], others have suggested the opposite [ 17 ]. Moreover, some have found no relationship between these two conditions [ 18 ]. This disparity in results may stem from differences in study methodologies, sample sizes, endometriosis severity and location, or the presence of selection bias. Therefore, it is important to elucidate the role of endometriosis as a predictor of subsequent hypertensive disorders in patients with endometriosis who conceived spontaneously. The aim of the current systematic review was to investigate the potential link between hypertensive disorders during pregnancy and endometriosis.