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Endometriosis increases the risk of gestational diabetes: a meta-analysis stratified by mode of conception, disease localization and severity – Scientific Reports


The PRISMA flow diagram of the review process is illustrated in Fig. 1. Out of the 330 full-text articles evaluated, 312 studies were excluded. In total, 18 studies23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40, involving N = 4,600,885 women, met the original inclusion criteria. Fifteen cohort studies23,24,25,26,27,28,29,31,32,34,35,36,38,39,40 (N = 4,600,016) and 3 case–control studies30,33,37 (N = 869) were included. Among the cohort studies, 10 were retrospective23,24,25,26,27,31,34,35,38,40 (with 2 of them27,31 employing a multicentric design), 2 were prospective32,36, 2 were based on a historical cohort28,29 and 1 was a nationwide study39. Out of the 3 case–control studies, 2 had a retrospective design30,33, while 1 was a prospective study37. A comprehensive summary of the characteristics of the included studies can be found in Table 1.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for study selection.

Table 1 Main characteristics of included studies (n = 18).

Risk of GDM in endometriosis patients versus controls

Studies overview

Out of the 1823,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40 studies included in the qualitative synthesis, two studies28,29 were based on the same historical cohort and study period, suggesting a high likelihood of data redundancy. Consequently, the quantitative synthesis was performed by omitting the study by Luke et al.28.

The population size of the included studies was highly variable: a total of N = 4,114,833 patients (n = 31,101 women with endometriosis and n = 4,083,732 controls) came from the largest study39 whereas only N = 88 women (n = 40 with endometriosis and n = 48 controls) were included in the smallest24.

In most of the included studies23,24,25,26,27,30,31,33,34,35,36,37,38, the diagnosis of endometriosis was based on surgical and histological confirmation of the disease. However, only two studies27,33,35 provided a complete description of the anatomical localizations of endometriosis lesions, whereas five studies24,33,34,37,38 reported data on endometriosis severity according to the revised American Fertility Society (r-AFS) staging system41. Notably, two studies focused exclusively on women with deep endometriosis (DE)26,31: one study26 included women with nodules surgically treated by segmental bowel resection, while another study31 evaluated women still exhibiting a posterior DE lesion of at least 2 cm on ultrasound assessment after a previous incomplete surgical excision.

In most studies, controls were defined as women without endometriosis; however, only one study36 performed a diagnostic laparoscopy to rule out the disease in controls. Regarding diagnosis of gestational diabetes, 8 studies23,25,27,31,32,35,38,40 used a positive oral glucose tolerance test (OGTT) as the criterion. Specifically, one study25 followed the Canadian Guidelines42, one32 followed the Japanese Guidelines43, one38 adhered to the Polish Guidelines44, and another40 followed the American Guidelines45. Interestingly, one study diagnosed gestational diabetes in cases and controls through self-administered questionnaires36; the Authors reported that, according to their previous large prospective cohort study, self-reported adverse pregnancy outcomes are validly reported, with a 94% confirmation rate for GDM46,47.

Quality assessment

The risk of bias assessment revealed that 8 studies23,25,32,35,36,37,38,40 were at low risk of bias, 826,27,28,29,30,31,33,34,39 had a moderate risk of bias, and the remaining one24 was at high risk of bias (Supplemental Fig. S1). According to the GRADE approach48, the overall quality of the evidence ranged from low to moderate.

Data analysis

The meta-analysis comparing endometriosis cases to controls, regardless the mode of conception, revealed a significantly increased risk of GDM in endometriosis (OR, 1.23; 95% CI 1.07–1.51; 17 studies; N = 4,599,449) with moderate heterogeneity (I2 = 53.43%) and non-significant publication bias (Egger’s: z = -0.75, p = 0.4557; Begg’s: z = -0.87, p = 0.4338) (Fig. 2a,b). Sensitivity analyses by omitting one study at time confirmed the robustness of the pooled risk estimate (Supplemental Fig. S2).

Figure 2
figure 2

Risk of GDM in endometriosis versus controls. Legend: Forest plot summarizing the results of the meta-analysis (a). Funnel plot for publication bias (b). Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus.

Risk of GDM in endometriosis patients versus controls including only ART pregnancies

In total, 7 studies23,28,29,30,33,37,40 met the inclusion criteria: 2 were retrospective cohort studies23,40, 2 were retrospective case–control studies30,33, 1 was a prospective case–control study37 and 2 were historical cohort studies28,29. Population sizes varied significantly: the total sample ranged from N = 92 women (n = 49 with endometriosis and n = 43 controls) in the smallest study23 to N = 2,307 women (n = 406 with endometriosis and n = 1,901 controls) in the largest29.

Most included studies23,29,30,33 considered ART cycles with pregnancies achieved through both fresh and frozen embryo transfers. One study included only fresh cycles37, and another included only frozen ART cycles40. For the majority of the included studies, we were able to extract data on our primary outcome specifically for male factor infertility controls23,29,33,40. General characteristics of the included studies are summarized in Table 1.

Quality assessment

Three studies23,37,40 were judged at low risk of bias, and three29,30,33 had a moderate risk of bias (Supplemental Fig. S1). The overall quality of the evidence, according to the GRADE approach48, was deemed low.

Data analysis

The meta-analysis failed to reveal significant differences in GDM risk between women with endometriosis and controls in the ART population (OR, 0.93; 95% CI 0.70–1.24; 6 studies; N = 3,778; p = 0.63) (Fig. 3a), with no heterogeneity (I2 = 0%). Symmetry was observed upon visual inspection of the funnel plot (Fig. 3b), and both Egger’s test (z = 1.76, p = 0.0787) and Begg’s test (z = 1.13, p = 0.2597) showed no evidence of a small-study effect. Subgroup analyses according to predefined moderators did not find any group difference in the pooled risk estimates (Supplemental Fig. S3).

Figure 3
figure 3

Risk of GDM in endometriosis versus controls, only pregnancies by ART. Legend: Forest plot summarizing the results of the meta-analysis (a). Funnel plot for publication bias (b). Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus.

Risk of GDM in endometriosis patients versus controls including only spontaneous pregnancies

Studies overview

Overall, only 3 studies24,29,39 could be included in this comparison: one was a retrospective cohort study24, one was a historical cohort29 and one was a nationwide cohort study39. The total population size was however quite large (N = 4,413,498).

Notably, the study population of Mekaru et al.24 also included conceptions through first-level infertility treatments (ovulation induction and intrauterine insemination). However, infertility treatments were reported to be comparable between the groups. Since conceptions through in-vitro fertilization (IVF) were excluded a priori, we did not consider any of the pregnancies evaluated by Mekaru et al.24 as obtained by ART. General characteristics of the studies included in this comparison are summarized in Table 1.

Quality assessment

Two studies were at moderate risk of bias29,39 and one had a high risk of bias24 (Supplemental Fig. S1). The overall quality of the evidence, according to the GRADE approach48, was deemed low.

Data analysis

The meta-analysis revealed a significantly increased risk of GDM in endometriosis women compared to controls in the natural conception population (OR, 1.08; 95% CI 1.04–1.12; 3 studies; N = 4,413,498; p < 0.001) (Fig. 4a), with no heterogeneity (I2 = 0%) and a non-significant small-studies effect (Egger’s: z = − 0.08, p = 0.934; Begg’s: z = − 1.04, p = 1.00) (Fig. 4b).

Figure 4
figure 4

Risk of GDM in endometriosis versus controls, only spontaneous pregnancies. Legend: Forest plot summarizing the results of the meta-analysis (a). Funnel plot for publication bias (b). Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus.

Risk of GDM in endometriosis patients comparing ART and natural pregnancies

Studies overview

Overall, 4 studies met the inclusion criteria29,34,38,39: one was a historical cohort29, two were retrospective cohort studies34,38, and the remaining was a nationwide cohort study39. Study populations were smaller than those in other comparisons performed, yet sample size varied considerably between studies: the largest study39 assessed a total of N = 38,035 patients (n = 6,934 endometriosis women who conceived by ART and n = 31,101 who conceived naturally), while the smallest38 included only N = 64 women (n = 36 endometriosis women with ART conceptions and n = 28 endometriosis women with natural conception).

Of all, 2 studies29,39 included ART cycles with pregnancies obtained by both fresh and frozen embryo transfers; the remaining two studies34,38 did not mention if ART cycles included only fresh or only frozen embryo transfers or both. Notably, data from Warzecha et al.38 for natural conception also included first-level infertility treatments (intrauterine insemination). General characteristics of the included studies are summarized in Table 1.

Quality assessment

Overall, one study was at low risk of bias38, while the remaining three were at moderate risk of bias29,34,39 (Supplemental Fig. S1). The overall quality, as judged by the GRADE approach48, was considered low or very low.

Data analysis

The meta-analysis failed to find any significant difference in GDM risk in pregnancies of patients affected by endometriosis with different modes of conception (ART versus natural) (OR, 0.97; 95% CI 0.89–1.06; 4 studies; N = 39,193; p = 0.51), with no heterogeneity in pooling data (I2 = 0%) (Fig. 5a). Symmetry of funnel plot and non-significant tests for small-studies effect (Egger’s: z = 1.06, p = 0.287; Begg’s: z = 1.02, p = 0.308) showed absence of significant publication biases (Fig. 5b).

Figure 5
figure 5

Risk of GDM in endometriosis pregnancies by ART versus endometriosis spontaneous pregnancies. Legend: Forest plot summarizing the results of the meta-analysis (a). Funnel plot for publication bias (b). Abbreviations: ART = assisted reproductive techniques; CI = confidence interval; GDM = gestational diabetes mellitus.

Risk of GDM in patients with deep endometriosis versus all other localization of endometriosis

Studies overview

Overall, only 2 studies33,35 provided data on the prevalence of GDM in DE compared to all other localizations of endometriosis (ovarian and/or superficial and/or DE with concomitant ovarian and/or superficial lesions). Both had a retrospective design; one was a cohort study35 and one was a case–control study33. The overall study population was relatively small (N = 350). Interestingly, the prevalence of DE in the original study populations was 15.3% in the study by Mannini et al.35 and 43.4% in that by Jacques et al.33. General characteristics of the included studies are summarized in Table 1.

Quality assessment

Of the two included studies, one was at low risk of bias35 and the other was at moderate risk of bias33 (Supplemental Fig. S1). The overall quality of the evidence, according to the GRADE48 approach, was judged as very low.

Data analysis

The meta-analysis failed to show a significant difference in the risk of GDM in pregnant patients with different localizations of endometriosis: DE versus other disease localizations (OR, 0.67; 95% CI 0.32–1.40; 2 studies; N = 350; p = 0.29), with no heterogeneity (I2 = 0%) (Fig. 6). Relative symmetry was observed on visual inspection of the funnel plot (data not shown); however, due to the very low number of publications, publication bias could not be entirely ruled out.

Figure 6
figure 6

Risk of GDM in deep endometriosis versus all other localization of endometriosis. Legend: Forest plot summarizing the results. Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus.

Risk of GDM in stage III-IV versus stage I-II endometriosis

Studies overview

Overall, only two studies provided complete data on the prevalence of GDM according to endometriosis severity33,38. One was a retrospective cohort study38 and the other was a retrospective case–control study33. The total study population was very small (N = 175). The prevalence of stage III–IV endometriosis patients according to the r-AFS classification41 was similar in the two study populations: 57.81% in Warzecha et al.’s cohort38 and 46.85% in Jacques et al.’s sample33. General characteristics of the two included studies are summarized in Table 1.

Quality assessment

One study was at low risk of bias38, and the other study was at moderate risk of bias33 (Supplemental Fig. S1). Due to the very low number of publications available, the overall quality of the evidence, as judged by the GRADE approach48, was considered very low.

Data analysis

The meta-analysis found a significantly increased risk of GDM in patients with stage III-IV disease severity compared to stage I-II (OR, 3.20; 95% CI 1.20–8.54; 2 studies; N = 175; p = 0.02). Patients with advanced stages of the disease showed more than threefold increase in the risk of the outcome, with no study heterogeneity (I2 = 0%) (Fig. 7). Relative symmetry was observed upon visual inspection of the funnel plot (data not shown), demonstrating non-significant evidence of publication bias despite the very low number of publications available.

Figure 7
figure 7

Risk of GDM in stage III–IV versus stage I–II endometriosis. Legend: Forest plot summarizing the results. Abbreviations: CI = confidence interval; GDM = gestational diabetes mellitus.



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