Adverse Effects of Polycystic Ovary Syndrome on Pregnancy Outcomes in Women with Gestational Diabetes Mellitus: A Retrospective Study

Background : Polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) can both contribute to adverse maternal and neonatal outcomes. There is relatively limited research on the outcomes for women who have a history of both PCOS and GDM. Our study attempt to explore how the presence of comorbid PCOS affects pregnancy outcomes in women with GDM. Methods : Our study was a retrospective study of women diagnosed with GDM through a 75 g oral glucose tolerance test (OGTT) at our hospital from January 1, 2021, to December 31, 2022. We divided the participants into two groups, group +GDM/+PCOS and group +GDM/-PCOS, based on their history of PCOS. We compared clinical variables, delivery details and neonatal complications between the two groups. Results : Among the 149 women enrolled in the study with GDM, a total of 44 women were diagnosed with PCOS. Women with GDM and PCOS have higher plasma glucose level at 120 minutes (PG120) level (9.17 mmol/L vs 8.59 mmol/L, p = 0.001). The incidence of postpartum hemorrhage is higher in women with history of GDM and PCOS (2.9% vs 22.7%, p < 0.01). On regression analysis, plasma glucose level at 60 minutes (PG60) level (odds ratio (OR) 6.341, 95% confidence interval (CI) 1.69~23.76, p = 0.006) and PCOS (OR 36.105, 95% CI 3.89~335, p = 0.002) were identified as independent risk factors for postpartum hemorrhage. We also found that infants born to mothers with PCOS and GDM had lower Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) scores at 1 minute after birth ( p < 0.01). PCOS was also an independent risk factor for lower 1-minute APGAR scores on regression analysis ( β = –0.296, t = –3.852, p < 0.001). Conclusions : Women who co-presented with GDM and PCOS had worse postprandial blood glucose levels, higher rates of postpartum hemorrhage, and lower 1-minute APGAR scores in newborns. The management of PCOS should be promptly initiated, with close monitoring of blood glucose levels throughout pregnancy, and timely implementation of intervention measures to optimize obstetric and neonatal outcomes.


Introduction
Polycystic ovary syndrome (PCOS) is a prevalent hormonal disorder impacting women of reproductive age.It is characterized by a range of symptoms, among which irregular menstrual cycles are prominent, along with high levels of androgens in the body, and the occurrence of cysts on the ovaries [1].Many studies have highlighted that PCOS can significantly impact the development of gestational diabetes mellitus (GDM) during pregnancy.Women with PCOS face an elevated risk of developing GDM compared to those without PCOS [2,3].Both PCOS and GDM can impact adverse maternal and neonatal outcomes [4,5].Women with PCOS or GDM have a higher risk of experiencing preeclampsia, as well as an increased likelihood of preterm birth and neonatal hypoglycemia.Complications that have been explored in earlier research include a higher likelihood of preterm birth, preeclampsia, and increased Cesarean section rates among women with PCOS or GDM.Furthermore, infants born to mothers with both PCOS and GDM may face an elevated risk of experiencing neonatal complications, exhibiting a notably higher rate of admission to the neonatal intensive care unit (NICU) [6,7].
Research gaps in this area often include the need for more comprehensive investigations into the specific mechanisms linking PCOS with GDM.Studies focusing on maternal and neonatal outcomes for women with both PCOS and GDM remain relatively limited [8,9].This study aims to retrospectively assess how the presence of comorbid PCOS affects pregnancy outcomes in women with GDM.We seek to explore birth complications and neonatal outcomes in this specific population.The goal of our study is to unravel the complex relationship between adverse outcomes associated with both PCOS and GDM, guide clinical practices, enhance obstetric and neonatal outcomes through these measures, and provide comprehensive healthcare in the future.cluded a comprehensive assessment covering obstetric history, medical history, and demographic information.All women underwent follow-up prenatal monitoring and delivery in our hospital, and informed consent was obtained from all participating patients.The diagnosis of GDM involved pregnant women undergoing OGTT between 24 to 28 weeks of gestation.We defined GDM as having fasting plasma glucose level greater than 5.1 mmol/L, a onehour plasma glucose level greater than 10.0 mmol/L, and a two-hour plasma glucose level greater than 8.5 mmol/L, in accordance with the consensus guidelines in China [10].Information about their medical history, such as clinical symptoms, ultrasound, or endocrine results indicative of a potential PCOS diagnosis, was collected.We confirmed their diagnosis based on the relevant international PCOS diagnostic criteria.PCOS diagnosis was established if a women exhibited a minimum of two of the following three criteria: (1) oligo-anovulation (with menstrual cycle length >35 days and <8 menstrual cycles per year); (2) clinical or biochemical hyperandrogenism; (3) polycystic ovaries morphology, defined as having at least 25 small follicles (2-9 mm) in the entire ovary and/or an increased ovarian volume ≥10 mL; additionally, other potential etiologies were excluded.

Data Collection
We collected clinical variables including body mass index (BMI), age, glycemic parameters from the index OGTT, and the requirement of insulin therapy.We also collected delivery details and neonatal complications, including premature delivery, Cesarean section, neonatal hypoglycemia, Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score, and admission of the newborn to the NICU.Data pertaining to maternal characteristics and perinatal parameters were gathered through a thorough examination of the patients' medical records sourced from the obstetrics database maintained by the institution.This study received approval from the Institutional Review Board approval from The Fourth Affiliated Hospital of Soochow University (Protocol number: 231019).

Statistical Analysis
Statistical Package for Social Sciences (SPSS, IBM Corp. Released 2020.IBM SPSS Statistics for Windows, Version 27.0, Armonk, NY, USA) was used to perform statistical analysis.Prior to conducting statistical analyses, we assessed the normality of the data distribution using the Shapiro-Wilk/Kolmogorov-Smirnov test.Following the assessment, it was observed that the data did not exhibit a

Characteristics of Patients
In our research, no significant differences were observed between the two groups in terms of age, BMI, fasting plasma glucose level at 0 minutes (PG0), PG60, and the need for insulin therapy.In Table 1, we can see that the blood glucose levels two hours after the meal were significantly different between the two groups.PG120 was higher in the PCOS with GDM group.We can also observe from Table 1 that the proportion of primiparas in the PCOS combined with GDM group is higher (p = 0.016) (Table 1).

Patients Delivery Details and Neonatal Outcomes
The incidence of postpartum hemorrhage was significantly higher in the PCOS with GDM group when comparing pregnancy outcomes with the no-PCOS group (p < 0.001).However, no significant differences were observed in terms of gestational age and delivery mode between the two groups.We also found some interesting phenomenon when analyzing the outcome of the neonates, as the AP-GAR score at 1 minute after birth was lower in the PCOS with GDM group (p < 0.001).In our research, the neonatal birth weight of the PCOS with GDM group was higher than that of the GDM with no-PCOS group, but the difference was not statistically significant (p = 0.174).Similarly, the probability of neonatal specialist treatment was also increased in the PCOS+GDM group, but the difference was not statistically significant (p = 0.076) (Table 2).

Discussion
PCOS is a prevalent gynecological endocrine disorder among women of childbearing age, with an incidence rate of 5% to 10% [11].The typical pathophysiological features include an increase in androgens, persistent anovulation, and insulin resistance.Clinical manifestations mainly involve obesity, hirsutism, menstrual irregularities, and infertility [12].The incidence of GDM in our country is showing a trend of increasing occurrence and affecting younger individuals each year.Additionally PCOS is identified as an independent risk factor for GDM.GDM and PCOS are both linked with adverse pregnancy and neonatal outcomes [13][14][15][16].Despite the prevalence of both conditions, there remains a paucity of research and discussion regarding the impact of GDM on the effects and results experienced by both mothers with PCOS and their newborns.
We observed that women with both GDM and PCOS had a higher blood PG120 on OGTT.Many studies have already revealed the impact of PCOS on GDM.A nationwide population-based study found a history of PCOS as a noteworthy and independent risk factor for development of GDM.PCOS is typically associated with insulin resistance, which is closely related to the occurrence of GDM during pregnancy [17].Our study also confirms their findings.These findings underscore the additional influence of PCOS on blood glucose regulation in women with GDM.It highlights the necessity of closely monitoring both glycemic parameters throughout pregnancy.Our study reveals that a history of PCOS exacerbates postprandial blood glucose levels in women with GDM, but does not significantly impact fasting blood glucose levels.According to the collections of menstrual and reproductive histories, as well as past medical histories, most of PCOS women in our study had received treatment before pregnancy, which might be one of the possible explanations to the study results.
In our study, although the neonatal birth weight of the PCOS with GDM group was higher than that of the GDM group, there was no statistically significant difference between two groups.If the sample size were larger, further analysis could be conducted.Numerous studies have confirmed the association between high blood glucose and macrosomia.In GDM, there is an increased transfer of blood glucose across the placenta, which enters the fetal circulation.Excess glucose in the fetus circulation is stored as body fat, leading to macrosomia, also known as "large-forgestational-age" [18].These conclusions are also consistent with our research findings.The results of our study have found that GDM with PCOS patients had a higher incidence of postpartum hemorrhage.Additionally, PG60 ≥10.0 mmol/L and a history of PCOS were the independent risk factors of postpartum hemorrhage.The larger the birth weight, the more likely it is to lead to prolong labor.Along with that, the likelihood of requiring vaginal assistance during delivery increases, and there may even be a need for an emergency Cesarean section.There is a higher risk of vaginal tissue tearing.In the case of macrosomic deliveries, the likelihood of experiencing postpartum bleeding and injuries to the genital tract is approximately three to five times higher compared to deliveries with normalsized babies.Moreover, there is a heightened risk of uterine atony, characterized by ineffective contraction of the muscles of the uterus, leading to significant bleeding and postpartum hemorrhage [19].A retrospective cohort study indicated women with PCOS experienced a higher incidence of postpartum hemorrhage [20].Furthermore, a meta-analysis conducted in China shows a correlation between PCOS during and elevated rates of pregnancy complications, underscoring PCOS as an important risk factor for pregnancy complications [21].We can infer that PCOS exacerbates the high blood glucose conditions of GDM women, increasing the incident rate of postpartum hemorrhage.
GDM is linked to higher rates of adverse outcomes for newborns [22,23], these complications include macrosomia (larger-than-average baby), respiratory distress syndrome (RDS), neonatal hypoglycemia, hospitalization in the NICU, and intrauterine growth restriction [24][25][26].As widely reported in literature [27,28], we also found an increased occurrence of negative outcomes in newborns among women with both GDM and PCOS.The APGAR score, a clinical evaluation conducted at 1 minute and 5 minutes post-birth, is a method used to gauge the well-being of a newborn.It considers factors like skin color/tone, heart rate, reflexes, muscle tone, and respiration.The APGAR scores can serve as indicators for anticipating enduring neurological challenges in infants [29,30].We found signifi-cant differences in the APGAR score at 1 minute.Furthermore, the percentage of newborns from mothers with both GDM and PCOS having an APGAR score below 10 at 1 minute was notably higher.Some studies have indicated that women with GDM and PCOS exhibited a greater occurrence of NICU admissions due to hypoglycemia [31].The prognosis of the fetus is often associated with an increased incidence of admissions to the NICU, making NICU admissions a frequently used indicator for adverse pregnancy outcomes [29,30].However, these adverse neonatal outcomes did not reach statistical significance in our study.
Despite our efforts, there are several limitations in our study.Given the retrospective nature of our study, it is possible that cases of PCOS may have been undetected or misdiagnosed.While some patients were directly asked about their diagnosis of PCOS, for others, the diagnosis and/or history of symptoms related to PCOS may have been inferred from their general medical history.Furthermore, the scarcity of cases in our study may result in the lack of statistical power needed to identify potential influencing factors.Future studies may benefit from a larger sample size.The lack of data on pre-pregnancy PCOS management, especially the duration of metformin treatment, prevents our ability to assess the effects of metformin therapy for PCOS on maternal and fetal outcomes.Additionally, insufficient follow-up data related to postpartum OGTT prevents us to analyze the combined effects of concurrent GDM and PCOS in postpartum women.

Conclusions
In conclusion, our research of women with GDM revealed marked contrasts in postprandial blood glucose, postpartum hemorrhage, and neonatal APGAR scores in the presence of PCOS.Women with co-existing GDM and PCOS had worse postprandial blood glucose levels, higher rates of postpartum hemorrhage, and lower 1-minute AP-GAR scores in newborns.Additionally, in regression analyses, postprandial blood glucose and PCOS were independent risk factors for postpartum hemorrhage in GDM women, which demonstrates the impacts of these factors on the health of both mothers and infants.The significance of regular prenatal follow-up, vigilant monitoring of blood pressure and glycemic control in women with GDM and PCOS is underscored by our findings, aiming to optimize obstetric and health results in newborns.