PCOS’ clinical phenotype is the result of a metabolic imbalance characterized by insulin resistance and androgen excess [5] . In fact, it is this metabolic imbalance that interferes with endothelium dependent vasodilatory mechanisms leading to small vascular atrophy and accelerated atherogenesis [5] . Women of childbearing age with insulin resistance, are predisposed to developing gestational diabetes (GDM) and hypertensive disorders of pregnancy [6] . Complications associated with GDM include increased risk of preeclampsia, neonatal birth defects such as neural tube defects/hydrocephalus, caesarean section, and diabetes development later in life [6] . Complications associated with hypertensive disorders of pregnancy include fetal growth restriction, oligohydramnios, and preterm birth [7] . Several studies, including Fougner et al.’s cohort study, have investigated the relationship between PCOS and various obstetrical outcomes, with a documented statistically significantly increased risk of developing GDM, in addition to gestational hypertension, pre-eclampsia when compared to control populations [8] [9] . Peeve et al.’s retrospective cohort study found that in women with PCOS and multiple gestations, there is an increased likelihood of the adverse obstetrical outcomes mentioned prior [10] . Interestingly in women with PCOS undergoing IVF treatment there was no statistically significant difference in GDM development [11] .

Valgeirsdottir et al. have proposed a two-fold increased risk of preterm birth in patients with pre-existing PCOS [12] . Per Pan et al. pregnant females with pre-existing PCOS not on Metformin had a 10% higher incidence of preterm labor than those on Metformin, secondary to the medication’s anti-inflammatory effects [13] . In fact, PCOS is associated with a pro-inflammatory state secondary to low-grade adipose tissue-related systematic inflammation. Further, Liu et al. specifically listed pro-inflammatory factors associated with PCOS that increase in concentration during pregnancy such as: interleukin 1, 6, tumor necrosis factor, C-reactive protein, interleukin-18, monocyte chemoattractant protein-1, transforming growth factor-beta1 and nuclear factor-κβ [14] . Another etiology precipitating preterm labor in those with pre-existing PCOS is elevated AMH levels compared to those with term delivery, per Abdelsalam et al. and Kaing et al. [15] [16] . The concurrent preterm labor risk also elevates the risk of PPROM, per Qiu et al. [17] . Overall, those with PCOS have statistically significant rates of PPROM and congenital anomalies secondary to an increased pro-inflammatory state which is often compounded by elevated BMI [18] . Interestingly with multiple gestations, the baseline risk of PPROM is already increased secondary to the pregnancies, which overshadows risk of PCOS, per Mills et al. [18] .

A meta-analysis by Bahri et al. analyzing sixty-three studies found that PCOS was associated with higher rates of C/S while accounting for multiple confounding variables [19] . Further, Joham et al. cite an increased risk of C/S in women with PCOS as compared to their control counterparts. The authors note that PCOS is strongly correlated with obesity and central adiposity, which has an influence on the severity of clinical manifestation and outcomes [20] . In fact, an increased body mass index contributes to a slower first-stage labor progression, a possible indication for C/S [21] . Patients with greater BMIs tend to have more adverse pregnancy outcomes necessitating C/S from non-reassuring fetal heart tracing during induction/augmentation of labor to fetal macrosomia [21] . Again, a PRISMA-compliant systematic review and meta-analysis noted there was a significantly higher risk of C/S in PCOS patients, as compared to non-PCOS patients [22] . When Boomsma et al. stratified pregnant PCOS patients according to BMI, those with elevated BMI had an increased risk of C/S compared to those with low-normal BMIs [23] .

The only study that examined the relationship between PCOS and blood transfusion after delivery was done by Peeva et al. [10] . In this retrospective cohort study, Peeva et al. found that in women with PCOS and multiple gestations, there is an increased risk of post-partum hemorrhage, more likely requiring transfusion [10] . It is postulated that compounded risk factors for post-partum hemorrhage such as cesarean delivery, multiple gestations contribute to this outcome.

Interestingly, Peeva et al. identified that neonates born to mothers with PCOS, and multiple gestations are more likely to be small for gestational age (SGA) compared to singleton neonates born to mothers with PCOS [10] . However, conflicting data does exist as a recent systematic review by Bahri Khomami et al. provided evidence that there is no increased risk of large gestational age (LGA) or SGA in mothers with PCOS which is also supposed by Mills et al.’s large cohort study [18] [19] . Mann et al.’s descriptive study examining pregnancy outcomes in those with PCOS diagnosis in a tertiary care hospital in South India found that the increase for small for gestational age (SGA)/intrauterine growth restriction (IUGR), macrosomia were similar or lower compared to the general pregnant population [24] . With regard to fetal gestational size, it is thought that a contributing factor to possible LGA is hyperglycemia and BMI as evidenced through gestational diabetes, which PCOS patients have an increased penchant for developing. However, there is evidence that hyperandrogenism, yet another crucial component of PCOS, can restrict fetal growth by acting directly on placental functionality [25] .

The few studies conducted in the past two decades that investigated the relationship between PCOS and neonatal mortality indicate a positive relationship between these variables [26] - [28] , except for one study that only focused on twin births [29] . In a retrospective study using data from the Western Australia Data Linkage System, pregnancy and childbirth outcomes of PCOS individuals were investigated with a statistically significant correlation with perinatal mortality, which likewise correlates with the meta-analysis results from Boomsma et al. [23] [26] . A plausible justification for these adverse outcomes can potentially be linked to PCOS’ statistically significant impact on GDM, when poorly controlled can potentially lead to lethal fetal anomalies, even fetal macrosomia which can increase the risk of shoulder dystocia during delivery [23] . However, further research needs to investigate specific mechanistic pathways by which PCOS impacts neonatal mortality.

Ultimately, this cross-sectional study aims to clarify and add to what has been established between PCOS and varying obstetrical outcomes that we deem as necessary for further investigation.

PCOS contributes to maternal morbidity including statistically significant increased risk of hypertensive and diabetic disorders during pregnancy, C/S, PPROM, and neonatal mortality.

We suggest that PCOS primes a state of insulin resistance that increases the risk for the development of GDM. Pregnancy increases the risk of insulin resistance, as patients gradually enter the third trimester, insulin sensitivity declines to 50% which is attributed to increased levels of estrogen, human placental lactogen, estrogen [28] . However, published data is contradictory about the significance of the relationship between PCOS and GDM. Asrafi et al. posit that increased insulin resistance in PCOS has differing clinical effects on patients based on ethnicity and specific environmental factors such as body weight which impacts insulin functionality [29] . Holte et al. have provided further evidence that women with PCOS and GDM had higher serum levels of VLDL triglycerides and cholesterol than women with normal ovaries; yet again, priming insulin resistance [30] . Furthermore, Holte et al. surmised that women with PCOS and GDM had an imbalance of activity between beta cells and insulin sensitivity [30] . Despite the contradictory research on the relationship between PCOS and the development of GDM, physiologically it seems that PCOS baseline alters insulin sensitivity and receptivity which adds to the already impaired insulin response during pregnancy.

Further, we provide evidence that there is a significant relationship between PCOS and hypertensive disorders of pregnancy. Though the pathophysiologic rationale for PCOS has not been thoroughly elucidated itself, one hypothesis between PCOS and pre-eclampsia posits that DNA damage inherent within individuals who are obese with PCOS, predisposes them [31] [32] . Further, the deranged metabolic environment within PCOS may cause altered placentation and endovascular changes both within and outside of the placenta, predisposing patients to premature delivery and preeclampsia [32] [33] . As stated previously, metabolic imbalance caused by insulin resistance and androgen excess interferes with endothelium dependent vasodilatation mechanisms causing small vascular hypertrophy and accelerated atherogenesis. It is important to highlight that PCOS compounds the risk of the presence of other metabolic derangements which augments the risk of elevated blood pressure during pregnancy.

Linkage between neonatal mortality and PCOS is due to an overall increased risk of maternal diabetes and maternal obesity. Our findings corroborate this relationship. Based on the results of this study, PCOS increases the risk of gestational diabetes and it has been proposed that maternal androgen excess in utero is a predominant risk factor for fetal growth impairment which may negatively impact fetal outcome [34] . Further, Kristensen et al. provided evidence that elevated BMI among women with PCOS contributes to a higher incidence of perinatal mortality [35] .

The increase in C/S can be attributed to elevated BMI, as it is an independent risk factor for labor dystocia. The relationship between PCOS and C/S is conflicting [23] [32] . Again, the risk for blood transfusion post-delivery in the setting of a history of PCOS is not statistically significant; however, general factors that may increase post-partum hemorrhage are heightened in this population such as multiple gestation, pre-eclampsia, fetal macrosomia, maternal obesity [10] .

Persistent low-grade inflammation associated with PCOS increases PPROM rates through increased inflammatory factors mentioned prior [18] . Our data corroborates this relationship.

The risk for small gestational age (at 2 standard deviations) for PCOS diagnosed 3 months before pregnancy is significantly decreased. Conflicting data exists between these variables as LGA is largely attributed to gestational diabetes development versus SGA being attributed to increased hyperandrogenism which can possibly interfere with placental functionality [23] .

A strength of our study is the sheer volume of data obtained from across the United States of America through the CDC comparing PCOS and specific obstetrical outcomes. This wealth of data adds to and will progress the relationship between PCOS and adverse obstetrical outcomes which can be utilized as integral part of physician-patient counseling.

A drawback of this paper is hypertensive disorders of pregnancy are grouped together in the data analysis and the dataset covers a select number of adverse obstetrical outcomes. As a result, we are unable to delineate specific risks associated with the spectrum of specific hypertensive disorders of pregnancy. Lastly, there is an aspect of selection bias as participants may have an incorrect diagnosis of PCOS at the time of survey completion. This may impact the true sample size and statistical implications of the study as patients may not have been accurately diagnosed.

Despite the revelations gathered from our study, there still remains much unknown about the link between PCOS and the above obstetrical outcomes, necessitating further investigation. Specifically, the mechanistic rationale behind why PCOS contributes to the aforementioned obstetrical outcomes is an area of great conflict that needs more research. We have been able to provide preliminary evidence, through the use of the CDC PRAMS dataset, that PCOS plays a significant role in obstetrical outcomes such as an increased risk of development of diabetes, hypertensive disorders, in addition to an increased risk of neonatal mortality, C/S, PPROM. Interestingly PCOS is protective against small for gestational age fetuses in those diagnosed during pregnancy. We suggest that clinicians discuss with PCOS patients, who either plan to become pregnant or are currently pregnant, the associated adverse obstetric outcomes as outlined above.

We would like to thank the PRAMS Working Group, which includes the PRAMS Team, Division of Reproductive Health, CDC and the following PRAMS sites for their role in conducting PRAMS surveillance and allowing the use of their data. The general PRAMS methodology and protocol have been reviewed and approved by the CDC institutional review board. In addition, state PRAMS projects undergo review by the local institutional review board of record for the local health departments.