Gestational Diabetes Mellitus in the Setting of Polycystic Ovarian Syndrome: A Systematic Review

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy that arises in the 2nd and 3rd trimesters, leading to significant complications for the mother and her neonates, such as an increased rate of pregnancy-induced hypertension and miscarriages, while neonates may have a large birth weight, hypoglycemia, or macrosomnia. Numerous risk factors can lead to GDM; however, a significant one is polycystic ovarian syndrome (PCOS). PCOS is the most common endocrine pathology beginning before puberty, and due to significant hormonal changes, it is not diagnosed until after puberty. PCOS requires at least three of the following symptoms: hyperandrogenism, menstrual irregularities, or polycystic ovary morphology. While it is agreed that women with PCOS are at a significantly increased risk of GDM, no publication to our knowledge has evaluated the full relationship of GDM in the setting of PCOS. This paper aimed to assess this relationship and determine how it may differ for pregnant women with only GDM by determining the prevalence of GDM, the variations within phenotypes, the influence of fertilization methods, specific risk factors, maternal outcomes, and neonatal outcomes. The prevalence of GDM was significantly increased in women with PCOS compared to healthy controls, and some studies have found that phenotype A may be more likely to lead to GDM. Risk factors were similar to pregnant women with only GDM, but with GDM and PCOS specifically, preconception low sex hormone-binding globulin, increased BMI > 25 kg/m2, and preconception impaired glucose tolerance were specific. While maternal outcomes were similar to pregnant women with only GDM, women with GDM and PCOS were even more likely to develop pregnancy-induced hypertension and early miscarriage. Neonates from mothers with GDM and PCOS were more likely to have low birth weights compared to mothers with just GDM who had high birth weights. The evaluation of the relationship between GDM and PCOS allows for illumination of the need to evaluate influences that currently lack research, such as phenotype variation and influences of fertilization method. This also promotes the need to develop predictive algorithms based on risk factors to prevent these adverse outcomes for mothers and neonates.


Gestational diabetes mellitus
Pregnancy is generally associated with increased insulin resistance due to lactogen secretion, growth hormone, tumor necrosis factor-alpha, estrogen, and progesterone [1].The definition of gestational diabetes mellitus (GDM) is any grade of glucose intolerance at onset or first recognition in pregnancy and is classified by responsiveness to nutritional therapy (A1GDM) or requiring medication (A2GDM) [1,2].GDM is the most common medical complication of pregnancy and typically develops in the second and third trimesters of pregnancy, affecting between 2% and 10% of pregnancies in the United States [1,2].Screening includes evaluation of patient history, family history of type 2 diabetes mellitus, oral glucose tolerance test, and past medical obstetric outcomes [2].Screening occurs at 24-28 weeks with a 50-g, one-hour oral glucose tolerance test greater than 130 mL/dL [1,2].Two possible etiologies have been identified: pancreatic b-cell dysfunction or the hindered response to glycemic levels [1][2][3].Hindered response to glycemic levels is caused by significant insulin resistance due to hormonal releases such as lactogen, growth hormone, prolactin, and progesterone [1,2].Lactogen is released to induce metabolic changes and support preserving fetal nutritional status [2].Lactogen leads to variations and modifications at insulin receptors, reduced tyrosine kinase phosphorylation, and remodeling substrate-1 and phosphatidylinositol 3-kinase [2].GDM can be managed without medication with nutritional therapy or through medicines like insulin and metformin that achieve optimal glycemic control [1,2].
Maternal complications of GDM include preeclampsia, increased risk of cesarean delivery, and increased risk of developing type 2 diabetes mellitus [1,2].Fetal complications can occur, such as macrosomia, polycythemia, fetal hyperglycemia, neonatal hypoglycemia, shoulder dystocia, neonatal respiratory distress syndrome, and increased perinatal mortality [1,2].Women should be educated to self-monitor blood glucose levels up to four times a day, fasting, and one to two hours post meal to reduce the risk of GDM [1].Following delivery, fasting blood glucose is monitored for 24-72 hours and six weeks later to determine if the mother's hyperglycemic control is back to normal, and the oral glucose tolerance test is repeated every three years [1].Clinical risk factors include increased body weight, older age, reduced physical activity, cardiovascular disease, previous history, and PCOS [1,2].

Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) is a multifactorial disorder that is the most common endocrine pathology in females of reproductive age [4][5][6].Symptoms of PCOS begin during early pubertal years but can be challenging to diagnose due to the effects of puberty [4,6].It was initially discovered in 1935, and the prevalence now ranges from 5% to 15%, depending on what diagnostic criteria clinicians use [4].PCOS is a diagnosis of exclusion as many disorders, such as thyroid disease, non-classical congenital adrenal hyperplasia, and hyperprolactinemia, mimic the clinical features [4,5].It cannot be diagnosed with standard diagnostic tests like biopsy, blood test, and culture [5].PCOS, according to the Rotterdam criteria, is characterized by having two or more of the following: hyperandrogenism, irregular menstrual periods, and polycystic ovaries (PCO) [4][5][6].PCOS also consists of a variety of symptoms, with the most common being hirsutism, PCO, alopecia, irregular periods, and infertility [4].PCOS has also recently been divided into four phenotypes: A -hyperandrogenism, ovulatory dysfunction, and PCO morphology; B -hyperandrogenism and ovulatory dysfunction; C -hyperandrogenism and PCO morphology; D -ovulatory dysfunction and PCO morphology [6].
While the prevalence of PCOS is significant, it is widely underdiagnosed and usually requires more than one visit or visiting multiple physicians to be identified, typically in a one-year time frame [4].There are numerous comorbidities, such as infertility, obesity, type 2 diabetes mellitus, metabolic syndrome, impaired glucose tolerance, and depression in PCOS, but this list is not exhaustive [4,5].Almost all of the causes of PCOS are associated with functional ovarian hyperandrogenism, characterized by dysregulation in the secretion of androgen [4,5].Genes involving various points of steroidogenesis and androgenic pathways like LHCGR and EPHX1 have been identified to lead to PCOS, as twin studies show up to 70% heritability [4,5].Environmental factors such as obesity, bisphenol A toxin, and insulin resistance were found to influence the activation of these genes significantly [4,5].
First-line treatment involves lifestyle modification, such as calorie-restrictive diets and exercise, to address associated weight loss, hirsutism, regulation of the menstrual cycle, and impaired glucose tolerance [4,5].Hormonal contraceptives like oral contraceptives, patches, or vaginal rings are effective against the symptoms of PCOS [4,5].The progestin found in hormonal contraceptives decreases luteinizing hormone (LH) levels, indirectly decreasing ovarian androgen production and increasing sex hormone-binding globulin (SHBG) [4].Women with PCOS often have infertility, which can be treated with clomiphene citrate, which is a selective estrogen receptor modular and competitive inhibitor of estrogen receptors [4].Infertility can also be treated with assisted reproductive technology (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) when hormonal treatment fails [7,8].

Aim
Women with PCOS are considered a high-risk population that continues during pregnancy and are at a significantly increased risk of developing GDM.GDM has been shown to have significant effects on maternal and neonatal outcomes, typically affecting delivery time, birth weight, and neonatal health status.GDM risk can potentially be predicted and possibly prevented with predictor evaluation, but ongoing research is still trying to assess this possibility.However, it is essential to fully understand the association between PCOS and GDM, more than just the known increased risk.This paper aims to evaluate the prevalence of GDM with the variations in PCOS phenotypes, influences of fertilization methods, associated risk factors, and maternal and neonatal outcomes.We plan to evaluate the whole relationship and the impact of coexistence to highlight where research may be lacking and what may offer further insight into the development of GDM.

Review Methods
The present systematic review was performed with strict adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.This resulted in a methodical and calculated search of the current literature found in ScienceDirect, ProQuest, and PubMed between January 1, 2013, and November 1, 2023.The keywords used to conduct the search were "polycystic ovarian syndrome and gestational diabetes mellitus" and were chosen to acquire publications that covered an array of subtopics within this theme.The investigation was arranged around peer-reviewed experimental and observational publications.Publications in languages other than English, studies that were duplicates, and studies published before 2013 were excluded.After obtaining the publications after automatic screening, they were evaluated manually based on their title, abstract, study, and full-text availability.The preliminary investigation of the catalogs used resulted in 10,694 publications.The title and abstracts of the acquired publications were cross-references with the keywords and chosen subtopics, allowing for the publication list to be narrowed down and aligned with the aim of this review.A total of 50 publications were obtained according to the criteria mentioned below.

Inclusion Criteria
The publications were selected based on the following criteria: studies focusing on GDM in the presence of PCOS, peer-reviewed experimental or observational studies, studies performed on humans, full-text availability, and publications between 2013 and 2023.

Exclusion Criteria
The publications excluded from this review were based on the following criteria: articles written in languages other than English, duplications, and no full-text availability.The procurement algorithm using the stated inclusion and exclusion criteria is drawn out in Figure 1.The flowchart was adapted to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9].

Bias
All publications procured were examined for bias through the GRADE (grading of recommendation, development, and evaluation) scale and were graded with a moderate bias rating.

Results
A total of 10,694 publications were populated: 71 were from PubMed, 1054 were from ScienceDirect, and 9569 were from ProQuest.Among the exclusions, 3452 were duplicate publications, and 6326 were published before 2013.This resulted in 9778 publications being excluded throughout the automatic screening algorithm, leading to 820 publications for manual screening.Publications were then examined manually based on their title, study, and full-text availability, resulting in 96 publications being chosen for eligibility for full-text examination.Ultimately, 48 publications were selected.
PCOS is a significant risk factor for developing GDM, and pregnant women with PCOS have a significantly increased prevalence of GDM.Pregnant women with GDM in the setting of PCOS were also discovered to have significantly increased BMI compared to controls with just GDM.Concerning PCOS phenotypes, phenotype A was more likely to increase GDM prevalence; however, when comparing all studies, this was insignificant.The influence of fertilization methods for women with PCOS was inconsistent, with some studies reporting that ART tends to reduce the prevalence of GDM.Still, IVF specifically increases the prevalence of GDM.There is a wide range of risk factors that lead to the development of GDM in the setting of PCOS, and while there is overlap with the development of GDM in healthy controls, low SHBG preconception was found to be a significant risk factor, along with BMI and preconception impaired glucose tolerance.Concerning maternal complications, there was a significantly increased risk of developing pregnancy-induced hypertension with a combination of GDM and PCOS, and there were some studies that found an increased rate of early miscarriage.Neonates were more likely to have low birth weight in mothers having GDM and PCOS, which is different from mothers solely having GDM as they were more likely to have neonates with high birth weights and macrosomnia.

Risk Factors That Increase the Incidence and Prevalence of Gestational Diabetes Mellitus
The development of GDM in pregnant women with PCOS is associated with numerous risk factors.Irregular menstrual patterns are a significant and independent risk factor for the development of GDM [10][11][12].The most common risk factor identified across the majority of studies is a high BMI of over 25 kg/m2 [12][13][14][15][16][17][18][19][20][21][22][23][24][25].Other associated risk factors include increased fast blood glucose, free androgen index, insulin resistance, cholesterol, blood pressure, testosterone concentrations, age, fasting insulin, HbA1c, presence of metabolic syndrome, short stature, lower high-density lipoprotein, and preconception impaired glucose tolerance [14,17,[19][20][21][22]24,[26][27][28][29].Another predictor of GDM is SHBG, which is shown to have a significantly negative association [19,21,25].Mumm et al., however, observed no difference in SHBG.Female fetal sex was also found to be a statistically significant risk factor for developing GDM by almost twofold [30].Having a greater first-degree family history of type 2 diabetes mellitus, family history of GDM, prior preterm birth, and early pregnancy loss can also contribute to the development of GDM [19,20,22,31].Ashrafi et al. found that a significant number of patients with PCOS who subsequently developed GDM had a history of hypothyroidism, suggesting it is a risk factor for, or at least a strong predictor of, developing GDM [10].

Maternal Complications Associated With Gestational Diabetes Mellitus
With GDM being present in the setting of PCOS, the question is whether or not there is an increased risk or presence of other pregnancy complications.Several recent studies observed that PCOS with GDM was found to be a significant risk factor and increases the incidence of pregnancy-induced hypertension compared to healthy controls with just GDM [27,[32][33][34][35][36].One study, however, found no significant increase in the incidence of pregnancy-induced hypertension [37].GDM with PCOS has also been found to increase the incidence of polyhydramnios, preterm premature rupture of membranes, and moderate or severe ovarian hyperstimulation syndrome [27,35,36].Being diagnosed with GDM in the 1st trimester in women with PCOS was also non-significantly associated with an increased rate of late miscarriage and a lower rate of live births [16,29].Yu et al., however, found that the overall incidence of abortion, spontaneous preterm birth, GDM, a hypertensive disorder in pregnancy, premature rupture of membranes, and macrosomia were significantly higher in the amenorrheic group compared to oligomenorrhea and regular menstrual cycles [12].

Neonatal Outcomes With Gestational Diabetes Mellitus
Just like with additional maternal complications, the combination of GDM and PCOS must also lead to additional neonatal complications.The majority of studies found that neonates born to women with both PCOS and GDM were more likely to have fetal growth restrictions, leading to lower birthweight compared to neonates from mothers with just GDM [12,16,17,35,[38][39][40][41].A few studies, however, showed an increase in birthweight and macrosomnia [29,36,42].Amenorrheic menstrual cycles specifically were statistically correlated with macrosomnia in one study, though [12].Helseth et al. observed that within their 1st year of life, infants born to patients with PCOS and GDM exhibited less weight gain than control, but the difference was only approaching significance [17].
Neonatal hypoglycemia developed in 17% of infants born to patients with PCOS and GDM showed that the presence of PCOS with GDM, compared to GDM alone, is associated with a 3.2-fold increase in the risk of neonatal hypoglycemia development [32].Among patients with PCOS, the odds of developing neonatal jaundice and respiratory complications were significantly higher compared to the non-PCOS control group [43].ICU admissions differed among the three PCOS groups; however, after correction, this was not statistically significant [44].Among the four phenotypes of PCOS studied, no statistically significant differences were found in the incidence of neonatal birth weight, neonatal icterus, NICU admission, or neonatal death [45].While a good amount of studies found additional risks, several studies found no difference in Apgar, birth weight, and incidence of hypoglycemia, which was also seen in comparing fertilization methods [37,39,43,44,46].

Incidence of Gestational Diabetes Mellitus in Polycystic Ovarian Syndrome
PCOS is positively associated with and leads to an increased risk of developing GDM in pregnant women [14,24,26,[34][35][36]39,41,42,[46][47][48][49][50][51].One study found that there was a 2.7-fold increased risk of the development of GDM in pregnant women with PCOS [11].The current estimated prevalence of GDM in pregnant women with PCOS between studies was 26%, significantly higher than healthy controls [10,16,19,[21][22][23]26,27,35,38,40,41,44,47,[50][51][52][53][54][55].However, several studies observed that there was no significant difference in the incidence or prevalence of GDM between pregnant women with and without PCOS [13,15,31,52,56].When comparing whether or not women were amenorrheic or oligomenorrheic before pregnancy, there were conflicting results where one study found that the amenorrheic group was significantly more likely to develop GDM by 7.69%, while the other study found that oligomenorrhea was significantly associated with GDM concerning women with PCOS [12,14].Classically, women with PCOS tend to be overweight.This trend continued during pregnancy when GDM was diagnosed, with most studies observing that pregnant women with PCOS had a significantly higher BMI [13,18,23,33,43].Another interesting finding is that the implantation of an oocyte from a woman with PCOS into a woman without PCOS does not alter the baseline prevalence of GDM [46].

Phenotype Variation With the Prevalence and Incidence of Gestation Diabetes Mellitus
PCOS consists of four phenotypes A-D, but in general, it has been observed that pregnant women with PCOS consisting of hyperandrogenism and oligomenorrhea, such as A and B, were at an increased risk of developing GDM [47,48].Conclusions of which phenotype was more likely to develop GDM were split, with some studies observing that phenotype A was associated with the highest incidence of GDM with up to 27.5% of patients [26,28,44,45,53,57].In contrast, other studies found no significant difference [26,28,44,45,53,57].One study, however, determined that phenotype D was associated with the lowest incidence of GDM [45].Fasting blood glucose was also significantly higher in phenotype A than in D [45].Despite phenotype A possibly being associated with the highest risk of GDM, one study observed that fasting blood glucose was significantly higher in phenotype B, confirmed by glucose monitoring at three-hour oral glucose tolerance test (OGTT) [57].

Fertilization for Women With PCOS and Its Effects on Gestational Diabetes Mellitus
Women who suffer from PCOS may need to undergo assistance for fertilization to occur, and this can be through hormone regulation or IVF.Women with PCOS who underwent ovulation induction using clomiphene citrate and follicle-stimulating hormone (FSH) have a significant increase in the incidence of GDM developing during pregnancy [14].There was an increased probability of GDM among PCOS patients who underwent the artificial cycle method compared to those who completed the natural cycle method, but this was insignificant [39].Some studies observed that there was a decreased risk of developing GDM in women with PCOS who underwent ART, but this did not correlate with what studies have found about IVF and ICSI [41,42].Two studies found that there was a positive correlation between GDM development in women with PCOS who underwent IVF and ICSI [14,39].Zhang et al. went further into analyzing fertilization methods and the development of GDM and observed no difference in the incidence when comparing fresh and frozen embryos [25].One study, however, found that the use of ART did not significantly alter the incidence of GDM in women with PCOS [33].
The articles synthesized to compose this review can be found in Table 1.Regardless of the method of conception, the incidence of GDM was higher in women with PCOS compared to women without.PCOS was also associated with PIH, preterm delivery, and fetal growth restriction.

Author
PCOS is an independent risk factor for developing GDM.In the absence of PCOS, oligomenorrhea and hyperandrogenism are not associated with GDM.
However, an elevated risk of GDM was found among women with PCOS.Total testosterone and free testosterone levels were not significantly associated with GDM.
A positive association was found between PCOS and GDM.In patients with PCOS, amenorrhea was associated with a statistically significant higher incidence of GDM and macrosomia compared to patients with PCOS who had regular menstrual cycles or oligomenorrhea.Amenorrhea was also found to be associated with higher pregnancy complications.
Amenorrhea was an independent risk factor associated with adverse pregnancy outcomes in patients with PCOS who underwent IVF/ICSI.In patients with PCOS and GDM, compared to PCOS without GDM, significant differences were found in age, BMI, insulin resistance index, fasting insulin, testosterone, and SHBG levels.Additionally, the incidence of pregnancy and neonatal complications was significantly higher in the PCOS and GDM groups.
Given the significantly higher incidence of GDM in patients with PCOS, it is imperative to target the identified risk factors to reduce the occurrence of GDM. with PCOS and obese BMIs had a higher incidence of GDM associated with severe insulin resistance.
which worsens when patients also have higher BMI and poor insulin secretion.Some limitations to the study surround the lack of research determining phenotype variation and effects of fertilization methods.GDM is multifactorial and can be a dangerous complication of pregnancy, so evaluating many aspects associated with pregnancy is crucial to understanding and preventing the development of GDM.Some studies found hyperandrogenism itself may increase the risk of PCOS.Of the few studies observing phenotypic differences, this was mostly agreed upon, but the lack of research limits this significance.Fertilization should be evaluated more as the actual conception can influence the pregnancy, and it should be evaluated how assisted fertilization impacts pregnancy outcomes.

Conclusions
Several risk factors increase the risk of GDM in women with PCOS, such as a high BMI, older age, increased free androgen index, insulin resistance, preconception impaired glucose tolerance, decreased SHBG, family history of type 2 diabetes mellitus, and even hypothyroidism.Additional pregnancy complications can occur, with an increase in pregnancy-induced hypertension being the most noticeable.Increased pregnancy complications, in general, were found to be significantly higher in women who had prior amenorrhea compared to oligomenorrhea.Infants were also at an increased risk of being born with a decrease in birth weight and having a difference in weight gain during the 1st year of life.As known, PCOS is positively associated with an increased risk of GDM and, across all studies, has significant prevalence.These women also tend to be overweight with an increase in BMI.Some studies find that phenotype A was more likely to develop GDM than the other phenotypes.When it comes to fertilization, hormone therapy such as clomiphene citrate and FSH showed an increased risk of GDM, but there was an inconsistency with ART as some studies indicated a decreased prevalence.At the same time, others found that IVF may increase the prevalence of GDM.
GDM in the setting of PCOS greatly affects the pregnancy outcome and neonatal complications, and they do vary from patients with either just GDM or just PCOS.As seen, there are some traits of specific outcomes due to this pairing, such as a mother with PCOS and GDM tend to have low birth weight babies, even though GDM is associated with large gestational weight and further complications such as shoulder dystocia.There are a lot of factors involved in the development of this interaction.Because outcomes specifically due to the combination of PCOS and GDM can lead to significant consequences to both the mother and fetus, it is imperative to identify the unified risk factors that increase the chances of preventing this interaction from occurring.Further research should also focus on possibly creating a predictive model concerning predictors and risk factors before or at the beginning of pregnancy to implement treatment protocols to drastically reduce the occurrence of GDM.

FIGURE 1 :
FIGURE 1: Algorithm employed based on the inclusion and exclusion criteria.The flowchart was adapted to the PRISMA guidelines.

2023
Slouha et al.Cureus 15(12): e50725.DOI 10.7759/cureus.consisting of hyperandrogenism, menstrual dysfunction, and PCO and a significantly higher incidence of GDM compared to controls.High androgen levels were the significantly strongest predictor of developing GDM during pregnancy.PCOS with hyperandrogenism, menstrual dysfunctions, and polycystic ovaries is significantly correlated with GDM compared to healthy women and other phenotypes of PCOS patients.
Increased insulin resistance and MetS were found among those with hyperandrogenism and overweight, leading to an increased risk of GDM.GDM had a higher incidence in the PCOS group than the control group.Between both groups, there was a significant difference in the incidence of neonatal hypoglycemia, occurring more than twice as often in the PCOS group.
2% of women with PCOS developed GDM, and higher body mass, insulin resistance, fasting plasma glucose, elevated blood pressure, free androgen index, abnormal cholesterol, less gestational weight gain, and lower levels of SHBG were found to be risk factors.