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Review

The Prevalence of Gestational Diabetes Mellitus in Polycystic Ovary Disease—A Systematic Review, Meta-Analysis, and Exploration of Associated Risk Factors

by
Rajani Dube
1,*,
Taniqsha Bambani
1,
Sahina Saif
1,
Noha Hashmi
1,
Mohamed Anas Mohamed Faruk Patni
2 and
Noopur Ramesh Kedia
1
1
Department of Obstetrics and Gynecology, RAK College of Medical Sciences, RAK Medical & Health Sciences University, Ras al Khaimah P.O. Box 11172, United Arab Emirates
2
Department of Community Medicine, RAK College of Medical Sciences, RAK Medical & Health Sciences University, Ras al Khaimah P.O. Box 11172, United Arab Emirates
*
Author to whom correspondence should be addressed.
Diabetology 2024, 5(4), 430-446; https://doi.org/10.3390/diabetology5040032
Submission received: 13 July 2024 / Revised: 22 August 2024 / Accepted: 30 August 2024 / Published: 4 September 2024
(This article belongs to the Special Issue Women’s Special Issue Series: Diabetology)
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Abstract

:
Polycystic ovary syndrome (PCOS) is a common condition in reproductive-age women. Women with PCOS are at higher risk of pregnancy complications, including gestational diabetes (GDM). The prevalence of PCOS and GDM varies according to the diagnostic criteria used. The mechanism for the occurrence of GDM in women with PCOS is still unclear. Materials and Methods: A systematic search of the electronic database was done using keywords like PCOS and GDM to include studies between April 2008 and March 2023 where uniform diagnostic criteria were used. After assessing the risk of bias, studies with a high risk (of bias) were excluded, and a meta-analysis was conducted using relative risks and confidence intervals. Results and Discussion: Out of 1896 search results, 95 were selected for full-text review. The quality of the studies was scrutinized and a total of 28 studies were included as they fulfilled the inclusion criteria. The incidence of GDM in women with PCOS was found to be 10.55% (2.9–54.9%) from pooled data involving 1,280,245 women. The prevalence of PCOS in women diagnosed with GDM, based on pooled data from 36,351 women across retrospective studies, was found to be 2.47% (ranging from 1.5% to 50.1%). Selection predominantly included cohort studies, most commonly from China. The meta-analysis found that the risk of GDM is higher in women with PCOS than in those without PCOS (HR: 1.59, 95% CI: 1.27–1.91, p < 0.001). Family history of diabetes, ethnicity, high pre-pregnancy BMI, insulin resistance, gestational weight gain, use of assisted reproductive techniques, and multifetal gestation were found to be associated with GDM in women with PCOS. Conclusion: The prevalence of GDM in patients with PCOS is high, but the causality is complex. The newer predictive models are promising in clarifying the causative relationships, yet use various parameters with different cut-offs. There is a need for the development of universally acceptable parameters for the early prediction of GDM in women with PCOS.

1. Introduction

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine conditions affecting women of reproductive age. Approximately 5% to 10% of women have the condition [1]. According to the population investigated and the diagnostic criteria employed, the prevalence can be 8% to 30% in reproductive-aged women, making it the most prevalent endocrinopathy in society [2,3,4]. In 2019, the prevalence of PCOS in the Middle East and northern Africa was 6,647,566 cases, with an age-standardized prevalence of 2079.7 per 100,000 women, representing a 37.9% increase in 29 years [5]. It is one of the main growing concerns among adolescents all over the world [6]. Amenorrhea, oligomenorrhea, obesity, infertility, and anovulation are among the common symptoms of PCOS [7]. Although alternative prediction models, including those based on anti-Müllerian hormone (AMH), body mass index (BMI), and serum hormone-binding globulin (SHBG) have been suggested, the most accepted diagnostic criteria is the Rotterdam criteria [8]. Diagnosis by Rotterdam criteria includes two of three of the following:
  • Oligo- or anovulation.
  • Clinical and/or biochemical signs of hyperandrogenism.
  • Polycystic ovaries.
This is in addition to the exclusion of other etiologies (e.g., congenital adrenal hyperplasia, androgen-secreting tumors, or Cushing’s syndrome) [9]. Most patients with PCOS can conceive after receiving treatment with menstrual cycle adjustment, ovulation induction, and assisted reproductive technology. Still, because of the influence of underlying diseases, although the pregnancy can be successful, the likelihood of complications during pregnancy is relatively high [10]. PCOS can cause various pregnancy complications, affecting the mother, fetus, and neonate. Complications include pregnancy-induced hypertension, preeclampsia, GDM, spontaneous preterm birth, and an increased necessity for a cesarean section. Regarding fetal outcomes, PCOS has also been correlated with elevated neonatal morbidity, prematurity, fetal growth restriction, birth weight variations (both large and small for gestational age), and transfer to a neonatal intensive care unit [11].
Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance induced by pregnancy, perhaps from exaggerated physiological changes in glucose metabolism [12,13]. It is a common complication in pregnancy, has a significant negative impact on pregnancy, and there is an increasing trend in its prevalence [14,15,16]. The prevalence of GDM can vary significantly depending on the diagnostic criteria used [17]. Different studies report a prevalence between 5.4% and 37.7% depending on the criteria used [18,19,20,21,22]. There is considerable controversy regarding the criteria used for the diagnosis of GDM. This is mainly because of the lack of a set of standard reference intervals. As GDM is influenced by genetics, ethnicity, lifestyle, and socioeconomic and societal factors, establishing standard global criteria is a challenge. The available diagnostic criteria proposed by different associations include those from the American Diabetes Association, World Health Organization, International Association of Diabetes and Pregnancy Study Group (IADPSG), the Australasian Diabetes in Pregnancy Society (ADIPS), Diabetes Canada, German Association for Gynecology and Obstetrics (DGGG), Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group, and a few others [23,24,25,26]. Commonly used diagnostic criteria for GDM are those of the ADA, IADPSG, and WHO, all using oral glucose-tolerance tests (OGTTs) [20,27,28] (Table 1).
There are various risk factors of GDM identified through previous research. Studies including 18,589 and 16,286 pregnant women in China reported risk factors of GDM as being advanced maternal age, higher prepregnancy body mass index (BMI), a family history of diabetes, weight gain during pregnancy, and habitual smoking [18,29]. Another study reported higher parity, history of GDM, and history of large-for-gestational-age babies as additional risk factors [30]. PCOS has been linked to an increased risk of GDM [31]. The proposed mechanism includes a rise of such hormones as estrogen, progesterone, and prolactin, which exacerbates the underlying insulin resistance (IR) present in women with PCOS, leading to GDM [2]. It has been reported in meta-analyses that women with PCOS are at a significantly higher risk of GDM (ranging from 2.8- to 3.7-fold) than those without PCOS [32,33,34,35]. However, there are significant inconsistencies among studies regarding diagnostic criteria. Moreover, in countries where risk-based screening is practiced, PCOS is considered a condition for GDM screening, but in countries with universal screening, the same protocol is used for women with and without PCOS [36].
The exact prevalence of GDM in PCOS women is still unknown due to differences in diagnostic criteria for both PCOS and GDM and the inability to rule out effects of confounders like ethnicity and obesity. In a few studies, having a first-degree relative with type 2 diabetes mellitus, serum levels of fasting glucose, fasting insulin, androstenedione, and SHBG levels before conception were identified as predictors of GDM [37]. Furthermore, a significant proportion of women with PCOS may have pre-gestational DM [38], and unless screened for earlier in the pregnancy, the prevalence of GDM will be inaccurate. Hence, through this systematic review, we aim to assess the gross prevalence of GDM among women diagnosed with PCOS. The objectives were to gather and analyze data from existing studies from databases to quantify the prevalence of GDM in women with PCOS and to identify potential confounding variables that may influence the association between PCOS and GDM.

2. Materials and Methods

2.1. Selection Criteria

A systematic search of PubMed, Embase, MedRxiv, BioRxiv, Google Scholar, EBSCO Medline, Web of Science, and Scopus electronic databases was conducted. Medical subject handling terms (MeSH) and free-text term keywords like polycystic ovary syndrome and PCOS were used in combination with gestational diabetes, GDM, and diabetes to include studies between April 2008 and March 2023. A random-effect model was very helpful in pooling incidence in females associating PCOS to GDM using statistical analyses. The search consisted of only English-language articles, including cohorts, case–control studies, case reports, and case series. After a thorough screening, no randomized control trials were found.
Inclusion criteria
Studies fulfilling both 1 and 2 were included for review.
  • Studies reporting pregnant women with pre-pregnancy-confirmed PCOS by Rotterdam criteria.
  • Studies using either 100 g or 75 g oral glucose-tolerance test (OGTT) for screening GDM.
  • Studies including both PCOS and GDM.
Exclusion criteria
Exclusions consisted of duplicated studies, review articles, articles in languages other than English, single case reports, articles where the full text could only be purchased, and studies where PCOS and GDM were diagnosed with other criteria or self-reported. Conference abstracts, expert opinions, and critical appraisals were also excluded.

2.2. Quality Assessment and Bias

The quality of the studies was critically evaluated using Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews [39]. The bias was independently assessed by three reviewers (authors 1, 5, and 6). The study was considered to have a low risk of bias, with affirmative responses of more than 70%, moderate with 50–69%, and high with 49% or fewer affirmative responses. Studies demonstrating a high risk of bias were excluded from the study.

2.3. Statistical Analysis

The Statistical Package for Social Sciences (SPSS) version 29 was used for the analysis of data. The incidence and prevalence of GDM are reported as simple percentages in the pooled sample. The pooled relative risk was calculated from the pooled sample from studies with control groups and meta-analysis was conducted, with relative risk (RR), confidence intervals (CIs), and heterogeneity (I2) being calculated.

3. Results

3.1. Study Characteristics

After a thorough search, a total of 1896 results were retrieved. All the abstracts and study titles were screened and duplicates were removed. There were 1868 studies excluded as they either did not fit the inclusion criteria (1, 2, 3), were duplicates, animal studies, or other language studies, only abstracts were available, and PCOS and/or GDM were diagnosed with other criteria or were self-reported. Finally, after the quality assessment, 22 articles were included in the analysis for the prevalence of GDM in PCOS (prospective) and 6 articles for coexisting PCOS in GDM (retrospective).
The 28 eligible studies consisted of 6 prospective cohort studies, 15 retrospective cohort studies, five case–control studies, and two cross-sectional studies. There were studies from the Netherlands (3), China (8), Canada (2), Iran (3), and one each from India, Italy, South Korea, Sweden, Saudi Arabia, Mexico, Japan, Taiwan, Finland, the United Kingdom, and the United States of America (Supplementary Material Table S1). One of the studies involved women from three countries—Norway, Sweden, and Iceland. This screening process for inclusion and eligibility was carried out by three independent reviewers. Any disagreements were discussed, and the final study inclusions were agreed upon. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) show the final study inclusions (Figure 1).
The characteristics of the included studies are described in Supplementary Material Table S1. A total of 22 studies met the inclusion criteria for the incidence of GDM in women with PCOS (prospective). One study was conducted in two phases and on separate samples. In a total population of 1,280,245 women, the crude incidence was found to be 10.55% (2.9–54.9%) (Table 2).
After the calculation of the incidence of GDM by percentages from pooled data, the studies were further excluded if they did not have a control arm or showed a moderate risk of bias. Fifteen studies with a low risk of bias were assessed by meta-analysis to explore the risk of GDM among pregnant women with PCOS, incorporating a population of 1,257,526. These studies predominantly included cohort studies. The majority of the studies reported that the risk of GDM is higher in women with PCOS than in those without PCOS (HR: 1.59, 95% CI: 1.27–1.91, p < 0.001). A forest plot of a random-effect model was created to calculate the overall HR (I2 = 84%, p < 0.001) (Figure 2).
A funnel plot was generated to assess potential publication bias in the studies examining the risk of GDM among pregnant women with PCOS. The plot included 15 studies, incorporating a total population of 1,257,526. In this analysis, the funnel plot revealed slight asymmetry, suggesting a possible presence of publication bias (Figure 3).

3.2. Prevalence of PCOS in Women with GDM (Retrospective Studies)

There were six retrospective studies in this review that explored the prevalence of pre-pregnancy PCOS in women diagnosed with GDM. The pooled data show a prevalence of 2.47% (1.5–50.1%) of PCOS in women diagnosed with GDM through this review (Table 3).

3.3. Other Risk Factors in PCOS Contributing to the Development of GDM

There were a few studies that reported a combination of risk factors that are present in patients with PCOS and can lead to GDM in pregnancy with or without the presence of PCOS. These factors can be considered confounders when we assess the risk of GDM in PCOS (Figure 4).
Most of these studies either did not provide direct evidence through analysis, used different diagnostic criteria for diagnosis (of PCOS and/or GDM), or the conditions were self-reported. Through this review, the risk factors of GDM identified in women with PCOS were high BMI, preexisting insulin resistance (IR), advanced maternal age, use of assisted reproductive techniques (ART), multifetal gestation, South Asian and Chinese ethnicity, and a family history of diabetes in first-degree relatives (Table 4). However, an independent analysis of individual risk factors through multivariate analysis could not be carried out due to inadequate information on actual sample sizes and the nature of this review.

4. Discussion

Among the risk factors identified were high BMI, preexisting IR, advanced maternal age, use of ART, multifetal gestation, South Asian and Chinese ethnicity, and a family history of diabetes in first-degree relatives. In a previous meta-analysis, of 33 studies with a total sample of 2697, 954 were diagnosed with GDM. The estimated odds ratio of being diagnosed with GDM was 3.46 (95% CI: 2.80–4.27). However, here the effect of the presence of PCOS in either group was not explicitly analyzed [95]. In a recent meta-analysis of 33 studies exploring pregnancy and neonatal complications in women with PCOS conceived through ART, the OR of GDM was 1.51 (95% CI: 1.17–1.94). The study, however, did not include women with PCOS who conceived naturally or other confounders [96]. Another meta-analysis including a population-based registry from Massachusetts reported a 51% greater risk of GDM (CI: 1.38–1.65) in patients with PCOS. However, PCOS was identified by ICD codes and included subjects from a single site [97].

4.1. Risk of GDM in PCOS

Pregnancy is a diabetogenic state. The physiological changes in pregnancy to ensure an adequate supply of glucose for the fetus predispose women to develop GDM [94,98]. IR is a part of normal physiological change in pregnancy. Having a condition with preexisting IR increases the risk of GDM further [73,74]. Conversely, another study in Saudi Arabia showed no significant differences in IR between PCOS and GDM [61]. Several features present in PCOS patients confer a higher risk of GDM in affected women, namely, coexistent obesity, IR, hyperandrogenism, and excessive gestational weight gain [62,99,100,101]. As women with PCOS suffer from subfertility and are more likely to need assisted reproduction to conceive, they have a higher prevalence of multifetal gestation (due to ART), which can also lead to GDM [94,102].
There were a few studies where either or both PCOS and GDM were self-reported. The findings pointed to pre-pregnancy BMI and hyperandrogenism as predictors of GDM with or without PCOS [64,66]. A larger case–control study (both self-reported) involving 8612 women in Australia revealed a significantly higher risk of GDM in PCOS (11.2% vs. 3.8%; p < 0.001), with similar mean BMI between PCOS and non-PCOS women [85]. Similar results were seen in other self-reported studies where GDM was more prevalent in women with a family history of diabetes [90,103].

4.1.1. Family History of Diabetes, Ethnicity, and Occurrence of GDM

A family history of type 2 diabetes in first-degree relatives is considered a strong risk factor for GDM in pregnancy. In a study among pregnant women in Yemen, univariate analysis showed family history to be an independent significant predictor of GDM (p < 0.001) [90]. However, the PCOS diagnosis was self-reported and GDM was diagnosed by FBG and RBG. Studies also show a significantly higher prevalence of GDM in women with a family history of diabetes and among certain ethnic groups [56,104,105]. A cross-sectional study involving 231,618 women in Canada reported a higher prevalence of GDM in South Asian and Chinese women across all levels of BMI when compared with the general population [91]. A larger proportion of patients of Indian, Pakistani, or other Asian ethnicity in the PCOS group compared to the non-PCOS group was shown by another study in the United Kingdom [89]. Also, Asian women had the highest pregnancy weight gain with or without PCOS in another study, further increasing the influence of ethnicity on GDM occurrence [73].

4.1.2. PCOS and Insulin Resistance

It has been hypothesized that women with PCOS have basal IR and hence are more susceptible to developing GDM [75]. Fasting insulin levels as well as IR are high in patients with PCOS even in the presence of normal glucose levels [76,77]. In another study involving 83 women with PCOS (53 lean, BMI = 21.5 ± 1.8 kg/m2; 30 obese, BMI = 29.6 ± 3.7 kg/m2) and in 15 healthy women (BMI 21.6 ± 1.8 kg/m2), it was shown that basal blood glucose and fasting insulin levels were significantly higher in PCOS (both lean and obese) compared to the control group (p < 0.02; 0.000001). However, IR was higher only in obese PCOS (not in lean) compared to controls [78]. It has also been reported that IR is present in PCOS even with normal BMI [79]. When compared to diet alone, women with GDM treated with additional insulin sensitizers could achieve better glycemic control, and metformin has been used in PCOS patients to prevent GDM. This also points out the possible role of IR [80,81,84]. Despite these findings, IR in PCOS women cannot be completely explained by abdominal adiposity and is influenced by other factors associated with PCOS like abnormal insulin signaling, adipokine secretion, endothelial dysfunction, as well as defective lipid and steroid metabolism [82,83].

4.1.3. GDM and Obesity

There has been considerable debate about whether GDM risk is related to associated factors like obesity in patients with PCOS. Women diagnosed with PCOS are likely to be overweight or obese in 60% of cases [9]. It is also suggested that for every one-unit increment in BMI, the risk of PCOS increases by nearly 10% and that increased BMI is significantly associated with GDM but not PCOS [61]. A multicenter case–control study involving 1146 women with singleton pregnancies reported increased odds of GDM by 7% with each unit increase in pre-pregnancy, BMI and PCOS not being significant contributors to the diagnosis of GDM [62].
In a study involving 336 IVF cycles in women with PCOS, the participants were divided into obese PCOS, non-obese PCOS, obese non-PCOS, and non-obese non-PCOS. It was shown that GDM was significantly higher in the obese group (with or without PCOS) compared to women with or without PCOS having normal BMI [41]. Similar findings were reported in a previous study where GDM was significantly higher in women with higher pre-pregnancy BMI, but not increased in PCOS [46,68]. Furthermore, a secondary analysis of longitudinal studies looking at GDM risk factors like maternal age, ethnicity, BMI, smoking, and education reported that BMI trajectory was independently associated with GDM (OR 2.5) and stronger than PCOS (OR 1.89). However, the limitations included self-reported PCOS and BMI [67]. Previous meta-analyses reported that women with PCOS are at significantly higher risk of GDM compared to those without PCOS. When patients are age- and BMI-matched, the risk is significantly higher in normal and overweight women with PCOS [69,70]. In contrast, the risk of GDM in obese women (BMI > 30 kg/m2) with and without PCOS was similar in another study [71]. In countries with universal screening, the same protocol is used for women with and without PCOS. However, where risk-based screening is practiced, such as recommended by the National Institute for Health and Clinical Excellence guidelines in the UK, PCOS status is important to recognize alongside ethnicity, positive family history, and BMI [73,74]. A larger meta-analysis and meta-regression involving 63 studies also pointed out that increased maternal pregnancy complications including GDM in PCOS are independent of obesity. The odds of having GDM in PCOS patients were 2.89. The odds for GDM were greater for ovulatory, anovulatory, and hyperandrogenic phenotypes for PCOS. However, the included studies did not follow consistent parameters for GDM diagnosis [73,74]. It was also suggested that PCOS may not be an individual risk factor of GDM in the absence of high BMI [72].
Conversely, a two-phase cohort study involving more than 18,000 pregnant women showed an overall higher prevalence of GDM in women with PCOS. The risk was significantly higher in normal-weight subjects with PCOS than non-PCOS women (26.5% vs. 16.2%, p = 0.02). However, in the overweight/obese group, no difference in risk of GDM was observed between PCOS and non-PCOS subjects (p = 0.7). The second-phase independent cohort confirmed the risk of GDM associated with PCOS in normal-weight women (p < 0.0001) [52]. In another study of 1545 women with GDM, 21% were found to have PCOS. The researchers reported that these women were younger, had higher BMIs, and had an increased risk of additional pregnancy complications like preeclampsia [106]. It was seen in one study that IR was increased in women with PCOS and previous GDM compared with controls, but low-grade inflammation assessed by serum tumor necrosis factor alpha, highly sensitive C-reactive protein concentrations and white blood cell and neutrophil counts were increased only in women with PCOS compared with BMI-matched controls, thus indicating that chronic low-grade inflammation is unlikely to be responsible for the occurrence of GDM in patients with PCOS. However, it was a single study with only 20 women with PCOS and 18 with previous GDM [107]. Larger studies are required for better clarity on the association between GDM and chronic inflammation.

4.1.4. GDM and Gestational Weight Gain

Weight gain in pregnancy, especially in the first 20 weeks, is a significant contributor to abnormal OGTT in the next 10 weeks and the need for insulin therapy [108]. Lean or overweight PCOS women gain more weight during pregnancy compared with women without PCOS with the same BMI [85,86,87]. This weight gain mainly occurs in the second and third trimesters in overweight women with PCOS [84] and this gain in the latter half is significantly associated with pregnancy complications, including GDM [50,88]. However, this trend is not observed in obese women with PCOS [86]. Women after childbirth are more likely to retain the GWG and be overweight or obese in subsequent pregnancies and develop GDM [109,110]. Hence, isolated pregnancy weight gain is not conclusive of GDM occurrence in the context of PCOS and should be analyzed in view of pre-pregnancy BMI [52,111].

4.1.5. GDM and ART

It has been reported that ART can increase the risk of developing GDM. As women with PCOS are more likely to need ART for conception, this can be an important factor. In a previous study exploring GDM in 60 women with PCOS conceived after ovulation induction, it was concluded that the risk of GDM was not higher in PCOS women compared to age- and BMI-matched non-PCOS controls [90]. However, there were variable diagnoses of PCOS in this study. When the risk of GDM is compared between different ART procedures, it was reported that GDM is significantly more common in in vitro fertilization/intracytoplasmic sperm injection and intrauterine insemination groups compared to spontaneous conception group, despite all the three groups being similar in age, pre-pregnancy BMI, and weight gain in pregnancy. However, this study excluded women with PCOS [93].
Women with PCOS are more likely to receive ART and conceive at a higher maternal age, and the chances of multifetal gestation are higher in PCOS and ART. In a recent study involving large samples of 13,732 ART mothers and 386,660 non-ART mothers, it was reported that at advanced maternal age (≥40 years), the prevalence of GDM was higher in the ART group compared to non-ART [94]. Having a twin pregnancy also increased the risk of GDM significantly compared to singleton pregnancies. However, there was no significant difference in the likelihood of GDM among mothers who had twins between ART and non-ART groups. In the younger age group (<40 years), there were higher odds of GDM for ART singleton mothers compared with non-ART singleton mothers. The BMI, smoking status, PCOS, and type of ART procedure were not reported for most of the subjects in this study [94].

4.2. Prevalence of PCOS in GDM

A few of the retrospective studies reported the prevalence of PCOS among women diagnosed with GDM [61,63,64]. A retrospective cohort study involving 34,686 women with GDM found that 1.5% of these women also had PCOS compared to 1.2% of women without GDM [63]. It points out the possibility of additional risk of developing diabetes in women who develop GDM in pregnancy. Factors in women with PCOS likely contribute to the development of metabolic diseases like diabetes and hypertension outside pregnancy, which do increase the risk of GDM during pregnancy.

4.3. Predictors of GDM in PCOS Patients

In a recent study, the authors used a nomogram model to predict the occurrence of GDM in 434 pregnant women with PCOS. Overall, 23.9% developed GDM (n = 104) and the significant predictors of GDM were first-trimester hemoglobin A1c, advanced maternal age (≥35 years), total cholesterol levels, low-density-lipoprotein cholesterol levels, systolic blood pressure, family history, BMI, and testosterone (p < 0.05) [56]. Earlier studies reported the level of serum SHBG concentrations before conception as the most significant predictor of GDM in women with PCOS [40,51]. Factors in PCOS that were significantly independently predictive of GDM were age ≥ 30 years, BMI ≥ 24 kg/m2, increased IR (≥22.69), increased fasting insulin (≥22.71 mIU/L), testosterone (≥2.85 nmol/L), androstenedione (≥6.63 nmol/L), and SHBG (<64.22 nmol/L), but positive family history of DM was not a significant predictor of GDM in women with PCOS in another recent systematic review [54]. While some factors, such as pre-pregnancy BMI and smoking, are modifiable, other risk factors like ethnicity and family history of DM are non-modifiable [112].
Strengths and limitations—The scope of this study is limited by the absence of any randomized control trials due to the nature of the condition. Also, this lack of consistency and comprehensiveness of risk factors in the studies posed a challenge when attempting to perform a meta-analysis within the scope of this review. This review was not registered with the PROSPERO trial registry. However, the inclusion of studies with set criteria for diagnosis of PCOS and GDM addresses the lacunae of inconsistent diagnosis in other reviews. Including studies with low risk of bias and risk-factor analysis were the strengths of this review. In addition, the proposal with methodology and search strategy was reviewed by the institutional research board and was approved before the commencement of the research.

5. Conclusions

The prevalence of GDM in patients with PCOS is high, but the causality is complex. Although distinct entities in themselves, both GDM and PCOS are interrelated. The association between them is likely due to similar etiopathogenetic pathways through metabolic syndrome, ethnicity, IR, hormonal changes, subfertility, advanced age at conception, fertility treatments, and resultant multifetal gestation. The newer predictive models are promising in clarifying the causative relationships, yet use various parameters at different cut-offs. Conditions like advanced maternal age at pregnancy, use of assisted reproduction, obesity, and PCOS are on the rise worldwide. Hence, there is a need for the development of universally acceptable parameters for the early prediction of GDM in women with PCOS and prospective, blinded cohort studies for the exclusion of confounding variables.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/diabetology5040032/s1. Table S1—Details of included studies; Table S2—PRISMA checklist.

Author Contributions

Conception and design: T.B., S.S., N.H., N.R.K. and R.D. Proposal writing: T.B. and N.R.K. Acquisition of data: T.B., S.S., N.H. and R.D. Analysis and/or interpretation of data: R.D., M.A.M.F.P. and N.R.K. Drafting the manuscript: R.D., T.B., S.S., N.H. and M.A.M.F.P. Revising the manuscript critically for important intellectual content: R.D. and M.A.M.F.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. PRISMA flowchart for study inclusion.
Figure 1. PRISMA flowchart for study inclusion.
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Figure 2. Forest plot.
Figure 2. Forest plot.
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Figure 3. Funnel plot.
Figure 3. Funnel plot.
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Figure 4. Risk factors of GDM in women with PCOS.
Figure 4. Risk factors of GDM in women with PCOS.
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Table 1. Diagnosis of GDM.
Table 1. Diagnosis of GDM.
OGTT (75 g)
Threshold for GDM DiagnosisFasting
(mmol/L (mg/dL))		1 h *
(mmol/L (mg/dL))		2 h **
(mmol/L (mg/dL))
ADA5.1 (92.0)10.0 (180.0)8.5 (152.0)
IADPSG5.1 (≥92.5)10.0 (≥180.0)8.5 (≥153.0)
WHO5.1–6.9 (92.0–125.0)≥10.0 (180.0)8.5–11.0 (153.0–199.0)
OGTT—oral glucose tolerance test; * plasma glucose after 1 h of glucose intake; ** plasma glucose after 2 h of glucose intake.
Table 2. Incidence of GDM in women with PCOS.
Table 2. Incidence of GDM in women with PCOS.
Author
(Reference)		Sample SizeIncidence of GDM
n (%)		Prevalence of PCOS (n)Serial Number
Altieri et al. [40]5163 (20%)151
Veltman-Verhulst et al. [41]5021 (42%)502
Han A R et al. [42]33610 (2.9%)3363
Roos N et al. [43]1,195,123125 (3.3%)37874
Reyes-Munoz et al. [44]10414 (26.9%)525
de Wilde et al. [37]32641 (21.6%)1896
Ashrafi et al. [45]702104 (44.4%)2347
de Wilde et al. [46]7222 (30.5%)728
Sawada et al. [47]11312 (24.5%)649
Pan et al. [48]7629636 (20.46%)310910
Xiao et al. [49]238964 (18.1%)35211
Rees et al. [50]27,204253 (4.4%)906812
Xia et al. [51]9431 (32.9%)9413
Zheng et al. -1 [52]56639 (26.5%)242 14 A
Zheng et al. -2 [52]18,106135 (22.09%)87714 B
Fougner et al. [53]791297 (41.1%)72215
Li et al. [54]19647 (23.98%)19616
Patnaik et al. [55]1029 (17.6%)5117
Ouyang et al. [56]434104 (24%)43418
Wang et al. [57]81479 (54.9%)14419
Sterling et al. [58]39411 (15.5%)7120
Liu et al. [59]767837 (9.7%)38121
Qiu et al. [60]16,506272 (14.49%)187622
Total1,280,2452366 (10.55%)22,416
Table 3. Prevalence of PCOS in women with GDM.
Table 3. Prevalence of PCOS in women with GDM.
Serial NumberReference GDM (n)PCOS (n)
1[61]12515
2[62]1014174
3[63]34,686520
4[64]17144
5[65]261131
6[66]9415
Total36,351899
Table 4. Factors in PCOS women associated with GDM.
Table 4. Factors in PCOS women associated with GDM.
Serial NumberFactor (Reference)Evidence (Reference)
1.High BMI
[41,46,52,62,67,68,69,70,71,72] 		High BMI increases PCOS [41]
High BMI causes GDM, but not PCOS [46,61,62,67,68,69,70,71,72]
Normal BMI with PCOS had a higher risk of GDM than obese [52]
2.IR
[73,74,75,76,77,78,79,80,81,82,83,84]		IR was higher in obese PCOS only [78]
IR was higher even with a normal BMI [79]
Use of insulin sensitizers in patients with PCOS [80,81,82,83,84]
3.Gestational weight gain (GWG) [50,73,85,86,87,88]GWG is higher in certain ethnicities [73]
Overweight women have higher GWG [50,85,86,87]
4.Ethnicity and family history [56,73,89,90,91]GWG is higher in certain ethnicities [73]
GDM and PCOS both have a higher prevalence in certain ethnicities [50,82,83,84,85,86,87,88,89]
5.Multifetal gestation, ART
[92,93,94]		GDM is not higher in PCOS conceived with ART if age- and BMI-matched [90]
GDM is higher with ART compared to spontaneous conception and in multifetal gestation following ART [93,94]
[ART = Assisted Reproductive Techniques].
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Dube, R.; Bambani, T.; Saif, S.; Hashmi, N.; Patni, M.A.M.F.; Kedia, N.R. The Prevalence of Gestational Diabetes Mellitus in Polycystic Ovary Disease—A Systematic Review, Meta-Analysis, and Exploration of Associated Risk Factors. Diabetology 2024, 5, 430-446. https://doi.org/10.3390/diabetology5040032

AMA Style

Dube R, Bambani T, Saif S, Hashmi N, Patni MAMF, Kedia NR. The Prevalence of Gestational Diabetes Mellitus in Polycystic Ovary Disease—A Systematic Review, Meta-Analysis, and Exploration of Associated Risk Factors. Diabetology. 2024; 5(4):430-446. https://doi.org/10.3390/diabetology5040032

Chicago/Turabian Style

Dube, Rajani, Taniqsha Bambani, Sahina Saif, Noha Hashmi, Mohamed Anas Mohamed Faruk Patni, and Noopur Ramesh Kedia. 2024. "The Prevalence of Gestational Diabetes Mellitus in Polycystic Ovary Disease—A Systematic Review, Meta-Analysis, and Exploration of Associated Risk Factors" Diabetology 5, no. 4: 430-446. https://doi.org/10.3390/diabetology5040032

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