Introduction
Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects up to 20% of women. The exact etiology is still not clear, but available data suggest that it is a polygenic disorder with epigenetic, developmental, and environmental components [1]. The diagnosis of PCOS is based on the presence of two out of three of the following: clinical or laboratory evidence of hyperandrogenism, ovulatory dysfunction including oligo- or anovulatory cycle, and the presence of polycystic ovary morphology on ultrasound [2]. PCOS is significantly associated with obesity, metabolic syndrome, diabetes, cardiovascular disease, and higher incidence of subfertility and pregnancy complications [3, 4]. One of the significant obstetrical morbidities is increased risk of preterm labor in the affected females; preterm labor is defined by the World Health Organization as delivery prior to 37 completed weeks of gestation [5]. Preterm birth is a serious cause of neonatal morbidity and mortality; it is responsible for approximately 1 million deaths annually and is a major public health concern worldwide [6].
The rate of adverse pregnancy outcomes such as gestational diabetes and preeclampsia is higher in females diagnosed with pre-pregnancy PCOS. In those women, an increased risk of preterm delivery has also been documented by many studies. Preterm delivery in women with pre-pregnancy PCOS cannot be explained by assisted reproductive technology (ART). These women may need increased surveillance during pregnancy and parturition [7, 8]. In women with PCOS, the associated maternal comorbidities such as advanced maternal age, obesity, glucose tolerance abnormalities, chronic hypertension, and fertility treatment may also contribute to risk of preterm delivery. However, there are few population-based studies examining pregnancy outcomes in women with PCOS [9]. It is believed that insulin resistance could alter glucose metabolism, leading to hormone imbalance and potentially predisposing to cervical incompetence in pregnant women with PCOS. Some studies have suggested a positive association, indicating that PCOS may predispose women to cervical incompetence, while others have reported no significant association [10]. The presence of obesity and other comorbidities in many women with PCOS may further compound these risks. Despite the growing interest in this association, evidence remains inconsistent, and the degree to which pre-pregnancy diagnosis of PCOS independently contributes to preterm labor is not fully established, especially in developing regions. Most available data originate from high-income countries, with limited research conducted in Middle Eastern or local populations.
This study aimed to investigate the association between pre-pregnancy PCOS and preterm labor and to assess the risk of neurodevelopmental disorders in those preterm neonates to provide better insight into pregnancy planning, antenatal care, and targeted interventions for at-risk women.
Patients and methods
Study design and setting
This prospective case-control study was carried out in the Labor Ward of the Department of Obstetrics and Gynecology and the Neonatal Care Unit at Azadi Teaching Hospital, located in Kirkuk City, Iraq. The study spanned a two-year period, from June 2023 to June 2025. It was carried out in accordance with the ethical principles of the Declaration of Helsinki. Oral informed consent was obtained from all participating pregnant women prior to enrollment.
A convenient sample of 200 pregnant women who presented with preterm labor was included. Preterm labor was defined as delivery occurring before 37 completed weeks of gestation, and diagnoses were confirmed by an obstetrician based on the presence of regular, effective uterine contractions and progressive cervical dilatation.
The study population was divided into two groups. Group A (cases) included preterm neonates born to mothers diagnosed with PCOS, based on the Rotterdam criteria, which require the presence of at least two of the following: oligo/anovulation, clinical and/or biochemical signs of hyperandrogenism, or polycystic ovaries on ultrasound. Group B (controls) consisted of preterm neonates born to mothers without a diagnosis of PCOS.
Eligible participants met the inclusion criteria of maternal age between 18 and 40 years, singleton pregnancy, and a confirmed diagnosis of PCOS prior to conception. Exclusion criteria included multiple gestation, fetal congenital or chromosomal anomalies, maternal smoking, Rh-negative women with alloimmunization, known uterine anomalies, medically indicated preterm delivery (such as due to preeclampsia, diabetes, or placenta previa), chronic systemic diseases including renal failure and autoimmune disorders, incomplete medical records, or refusal to participate in the study.
Data were collected directly by the researcher using a structured questionnaire developed from previously published literature [11, 12]. The maternal component of the questionnaire included age, obstetric history, PCOS diagnostic criteria, and insulin resistance assessment. Insulin resistance was measured using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), calculated using the formula: fasting insulin (μU/ml) multiplied by fasting glucose (mg/dl), divided by 405.
Neonatal data collected included gestational age at delivery, birth weight, Apgar scores at 1 and 5 minutes, duration of neonatal intensive care unit (NICU) admission, and morbidities such as intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and seizures. Findings from cranial ultrasound and magnetic resonance imaging (MRI), when indicated, were also recorded. An Apgar score below 4 was considered low. Cranial ultrasound was performed in the Radiology Department using a Philips Ultrasound system equipped with a sector (phased-array) transducer (7.5-10 MHz) through the anterior fontanelle using standard coronal and sagittal views. All examinations were performed by a single radiologist with 15 years of experience in neonatal cranial ultrasonography. It was used to diagnose IVH and classify it into four grades: Grade I, where bleeding is confined to the germinal matrix; Grade II, where bleeding extends into the ventricles without causing significant enlargement; Grade III, involving ventricular enlargement due to blood accumulation; and Grade IV, characterized by bleeding extending into the brain parenchyma surrounding the ventricles, also known as periventricular hemorrhagic infarction.
PVL was defined as a form of white matter brain injury typically associated with hypoxic-ischemic events and was diagnosed by cranial ultrasound, with MRI performed in selected cases. Seizures were identified either clinically or via electroencephalography and defined as episodes of abnormal, excessive electrical brain activity.
Neurodevelopmental evaluation of the neonates was conducted at 6, 12, and 24 months of age using the Denver Developmental Screening Test II (Denver II), which assesses gross motor, fine motor, language, and personal-social domains of development.
Statistical analysis was performed using JASP software (version 0.19.3, Intel build). The Shapiro-Wilk test was used to assess the normality of data distribution. Group comparisons were performed using Welch’s t-test for continuous variables and Fisher’s exact test for categorical variables. A prespecified parsimonious multivariable logistic regression was fitted for the outcome any Denver II neurodevelopmental delay, including five a-priori predictors: maternal PCOS (vs. non-PCOS), NICU stay (days), IVH (any vs. none), HOMA-IR (per unit), and Apgar score at 1 minute (per point). Effect sizes are reported as adjusted odds ratios (aOR) with 95% confidence intervals (CI). Model performance was assessed using the likelihood-ratio (LR) χ2 test, the area under the receiver-operating characteristic curve (AUC), and the Hosmer-Lemeshow goodness-of-fit test. All tests were two-sided with α = 0.05.
Ethical approval
The study protocol received approval from the Research Ethics Committee of the University of Kirkuk College of Medicine, and all necessary permissions were obtained from relevant health authorities. Neonatal complications were managed in line with established clinical guidelines with approval number 67 dated 27.03.2023.
Results
Among 200 preterm infants, including PCOS (n = 100) and non-PCOS (n = 100), maternal age did not differ between groups (28.78 ±6.27 vs. 28.60 ±5.80 years; p = 0.833). Mothers with PCOS had markedly higher HOMA-IR (4.726 ±1.454 vs. 2.028 ±0.713; p < 0.001).
Infants in the PCOS group had slightly lower gestational age (31.160 ±2.854 vs. 31.915 ±2.529 weeks; p = 0.049) and lower birth weight (1.547 ± 0.515 vs. 1.802 ±0.442 kg; p < 0.001). NICU stay was longer in the PCOS group (8.190 ±7.276 vs. 2.990 ±5.070 days; p < 0.001). Apgar scores were lower at 1 min (5.330 ±2.035 vs. 6.370 ± 1.419; p < 0.001) and 5 min (7.980 ±1.504 vs. 8.630 ±0.939; p < 0.001).
Neurological complications were more frequent with maternal PCOS: IVH (any grade) occurred in 28 vs. 10 neonates (p = 0.029), and seizures in 36 vs. 10 neonates (p < 0.001); PVL was present in 12 vs. 5 neonates (p = 0.076). Overall, any Denver II neurodevelopmental delay was observed in 45 neonates in the PCOS group versus 16 neonates of the non-PCOS group (p < 0.001) (Table I). In a prespecified parsimonious logistic model (outcome = any delay), maternal PCOS was independently associated with markedly higher odds of neurodevelopmental delay (aOR 6.32, 95% CI: 1.68–23.85; p = 0.006). Greater illness severity also predicted delay: longer NICU stay (aOR 1.15 per day, 95% CI: 1.05–1.25; p = 0.001) and lower Apgar score at 1 minute (aOR 2.60 per point, 95% CI: 1.85-3.64; p < 0.001). HOMA-IR showed a direct adjusted association (aOR 1.50 per unit, 95% CI: 1.02–2.21; p = 0.039). For IVH, the adjusted model yielded an aOR of 5.56 for any vs. none (95% CI: 1.73–25.00; p = 0.017). Model discrimination and calibration were good (LR χ2 (5) = 113.2; p < 0.001; AUC = 0.922; Hosmer-Lemeshow test p = 0.067) (Table II).
Table I
Comparison of maternal and neonatal characteristics between polycystic ovary syndrome (PCOS) and non-PCOS groups
Table II
Logistic regression results for predictors of neurodevelopmental disorders
[i] Model performance: LR χ2 (5) =113.2, p < 0.001; AUC = 0.921; Hosmer-Lemeshow p = 0.067.
aOR – adjusted odds ratio; CI – confidence interval;
HOMA-IR – Homeostasis Model Assessment of Insulin Resistance;
IVH – intraventricular hemorrhage; NICU – neonatal intensive care unit;
PCOS – polycystic ovary syndrome
Discussion
PCOS is one of the most prevalent endocrine disorders among women of reproductive age, affecting up to 20% of this population globally. Its pathogenesis is multifactorial, involving genetic, epigenetic, and environmental contributors [13]. Clinically, PCOS is associated with reproductive dysfunction, hyperandrogenism, and metabolic abnormalities including insulin resistance, obesity, and dyslipidemia [14, 15]. These features collectively contribute to an increased risk of pregnancy complications such as gestational diabetes, hypertensive disorders, and preterm labor [16]. Preterm birth remains a significant contributor to neonatal morbidity and mortality, especially in low- and middle-income countries, and is a recognized pathway to long-term neurodevelopmental disorders in affected infants [17, 18]. While the association between maternal PCOS and adverse obstetric outcomes has been increasingly documented, less attention has been directed toward the neurodevelopmental outcomes of offspring, especially preterm neonates. The challenge in the literature lies in the inconsistent evidence about whether PCOS, independently of confounding comorbidities such as obesity and diabetes, contributes to poor neurodevelopmental trajectories. Most existing studies have emerged from high-income settings, often in the context of ART, leaving a significant evidence gap in low-resource populations.
In our study, we investigated the relationship between maternal PCOS and neurodevelopmental outcomes in preterm neonates. The findings demonstrated a significantly higher risk of neurodevelopmental delay among preterm infants born to mothers with PCOS. Notably, fine motor, language, and gross motor delays were more frequent in the PCOS group, with a significant increase in NICU stay, lower birth weights, and higher incidence of IVH and seizures. These findings align with much research that has suggested an association between fetal neurodevelopmental abnormalities and maternal metabolic disorders [19–21]. Studies conducted by Neven et al. [22] and Velez et al. [23] have revealed that hyperinsulinemia and inflammation associated with PCOS may adversely affect fetal brain development and placental function. Our observation that insulin resistance, measured by HOMA-IR, was significantly higher in the PCOS group and directly correlated with neurodevelopmental outcomes supports this pathophysiological hypothesis. Similarly, the logistic regression model revealed that HOMA-IR and NICU stay duration were independent predictors of fetal neurodevelopmental delay. These findings are consistent with the study by Sigal et al. [24], which emphasizes the role of metabolic disturbances and neonatal stress in neurodevelopmental risk.
In the current study, IVH, notably Grade II, was significantly higher among neonates of PCOS mothers. This is consistent with research by Périsset et al. [25], who observed increased vulnerability of preterm white matter to hemorrhagic insults under conditions of oxidative and metabolic stress. IVH was also independently associated with increased odds of developmental delay in our regression model, consistent with prior evidence linking even lower-grade IVH to subtle but persistent cognitive and motor impairments [26].
Interestingly, although PVL and seizures were more prevalent in the PCOS group, they did not reach statistical significance as predictors in the adjusted regression model. Previous studies have shown that the sensitivity of cranial ultrasound in detecting early PVL may be limited, especially in mild or evolving cases [27]. Moreover, seizures may not always reflect underlying structural pathology and can be transient in the neonatal period [28].
Our finding of significantly lower Apgar scores in the PCOS group at both 1 and 5 minutes supports the evidence of increased perinatal compromise and aligns with studies by Fornes et al. [29] and Boldis et al. [30]. While some studies suggest that lower Apgar scores correlate with neurodevelopmental impairment [31], others suggest that their predictive value, particularly at 5 minutes, is limited when adjusted for gestational age and other clinical variables [32]. In our analysis, only the 1-minute score remained a significant predictor, consistent with recent data emphasizing the importance of early perinatal adaptation [33].
A novel observation from our study is the nearly sixfold increased odds of neurodevelopmental delay in neonates born to PCOS mothers (aOR = 6.32), independent of other clinical variables. This finding strengthens the emerging view that PCOS, even in the absence of ART or overt metabolic disease, may pose a direct risk to offspring neurodevelopment. However, this result diverges from some studies, such as those by Dubey et al. [34] and Kahn et al. [35], which reported an increased rate of neurodevelopmental disorders in offspring of PCOS mothers, primarily in term births. Our focus on preterm neonates – a higher-risk subset – may explain the stronger associations observed.
This study, while offering significant insights into the association between maternal PCOS and neurodevelopmental consequences in preterm neonates, has several limitations. The use of a convenience sample and the single-center design may restrict the generalizability of the findings. Furthermore, follow-up was restricted to 24 months, which may not fully capture long-term neurodevelopmental trajectories. The Denver II tool, in spite of its widespread use, serves as a screening measure and may not identify more subtle deficits. Additionally, the absence of advanced neuroimaging for all neonates and the lack of adjustment for certain confounding variables such as maternal BMI, socioeconomic status, and paternal factors may influence the results.
Despite these limitations, the findings highlight the need for increased clinical attention to pregnant women with PCOS. It is recommended that such women should receive frequent antenatal monitoring, with prompt screening for metabolic comorbidities and early identification for risk of preterm delivery, enabling timely intervention. Neonates of PCOS women require routine neurodevelopmental evaluation, and multidisciplinary follow-up should be considered. Future studies should aim for larger, multicenter designs with longer duration of follow-up and involve more comprehensive clinical and neuroimaging data to further elucidate these associations.
Conclusions
Pre-pregnancy maternal PCOS is independently associated with substantially increased odds of adverse neurodevelopmental outcomes in preterm neonates; longer NICU stay, higher HOMA-IR level, presence of IVH, and lower 1-minute Apgar further elevate risk. The findings support early screening and follow-up of infants born to mothers with PCOS, while larger studies are needed to clarify the unexpected directions for IVH and HOMA-IR after adjustment.
