Abstract
Background
The objective of this study was to investigate the efficacy of low-dose aspirin (LDA) in preventing preeclampsia among pregnant women with polycystic ovary syndrome (PCOS), given the increased susceptibility of this population to preeclampsia development.
Methods
A retrospective cohort study was conducted on pregnant women with PCOS who delivered between January 1, 2018 and February 10, 2024 at our institution. Clinical characteristics and obstetric data were extracted from medical records. Propensity score matching (PSM) was employed to analyze the association between LDA use and PE incidence.
Results
The study cohort comprised 1522 pregnant women with PCOS. Among 395 pregnant women identified as high-risk for preeclampsia, 98 were administered LDA for preeclampsia prevention, while 297 did not receive LDA. Following PSM, no statistically significant difference was observed in preeclampsia risk between the LDA and non-LDA groups. Additionally, maternal and neonatal outcomes were comparable between the two groups.
Conclusions
This cohort analysis did not provide sufficient evidence to support the efficacy of LDA in preventing preeclampsia among PCOS patients at high risk for preeclampsia.
Keywords: Low-dose aspirin, PCOS, Preeclampsia, PSM, FGR
Introduction
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age, with an estimated prevalence of 5–15% [1]. The etiology of PCOS remains unidentified, and there are currently no established curative or preventive measures available [2]. PCOS has significant long-term implications for the metabolic, reproductive, and gynecological health of affected women. Individuals with PCOS exhibit an increased likelihood of developing hypertension, hyperlipidemia, insulin resistance, infertility, overweight or obesity, and type 2 diabetes [3]. Some women with PCOS may require assisted reproductive technology (ART), such as invitro fertilization (IVF) to achieve pregnancy. Furthermore, IVF, diabetes, hypertension, and obesity are all potential risk factors for preeclampsia (PE) [4]. Previous comprehensive studies have demonstrated that women with PCOS have a substantially elevated risk of PE [5, 6].
Prenatal medical research has long focused on PE, a potentially fatal pregnancy condition [7]. Furthermore, once PE develops, the only effective treatment is timely delivery, which adversely affects neonatal outcomes. To mitigate the risk of severe PE outcomes, preventive intervention is crucial for women at high risk of PE. Numerous studies have demonstrated the potential efficacy of LDA in preventing PE in high-risk pregnant women [8, 9]. Aspirin inhibits the production of prostaglandins and thromboxane, reduces inflammation and platelet aggregation, and selectively and irreversibly deactivates the cyclooxygenase-1 enzyme [10]. However, a recent randomized controlled trial conducted to evaluate the impact of LDA on PE in high-risk Chinese women revealed that a daily dosage of 100 mg of aspirin, administered between weeks 12 and 20 and continuing until week 34 of gestation, had no effect in reducing the incidence of PE in pregnant Chinese women with high-risk factors [11]. The question of whether LDA can reduce the risk of PE in pregnant women with PCOS who are particularly susceptible to PE remains unresolved.
Consequently, we utilized actual patient data to conduct a retrospective cohort study. We employed PSM to ensure comparability of the women’s baseline data. Our objectives were to evaluate the potential benefits of LDA use in pregnant women with PCOS and provide a theoretical framework for further investigation.
Methods
Study participants
The retrospective cohort study encompassed all women with PCOS who delivered infants at Fudan University Obstetrics and Gynecology Hospital in Shanghai, China from January 1, 2018 to February 10, 2024. These subjects were identified utilizing the hospital’s electronic medical record system, from which pertinent information on maternal characteristics, pregnancy outcomes and neonatal outcomes were extracted.
Criteria for women at high risk of developing PE
Pregnant women who met at least one of the following criteria were considered to be at high risk of developing PE [12]: (a) exhibited at least one high-risk clinical factor, specifically, a prior history of PE, diabetes mellitus (type 1 or 2), chronic hypertension, autoimmune disease, or kidney disease; or (b) presented with at least two intermediate risk factors, namely pre-pregnancy body mass index (pre-BMI greater than 30 kg/m2), advanced maternal age (35 years or older), family history of PE (mother or sister), nulliparity, ART and multiple pregnancy.
Outcome measures
The primary outcome was the incidence of PE, defined as a blood pressure ≥ 140/90 mmHg associated with proteinuria (≥ 300 mg/day) after 20 weeks of gestation. The secondary outcomes included the incidence of placental abruption, postpartum hemorrhage (defined as ≥ 500 ml of blood loss for women who delivered vaginally or ≥ 1000 ml for women who delivered by cesarean section within 24 h of delivery), cesarean section rate, and fetal growth restriction (FGR) rate (birth weight below 10th percentile for singleton births).
Statistical analysis
Baseline characteristics of the two study groups were compared. Continuous variables were expressed as mean ± standard deviation, and t-test was utilized for comparison between groups with normal distribution; otherwise, Mann-Whitney U-test was employed for comparison. Categorical variables were expressed as number of cases and percentage, and the chi-square test (or Fisher’s exact probability method) was utilized for comparison between groups.
A 1:1 PSM was conducted to adjust for unmatched baseline characteristics, with exposure (LDA use vs. no LDA use) as the dependent variable, the covariates included the aforementioned risk factors for developing PE and blood pressure at the initial visit. The caliper was set at 0.05.
The outcomes were investigated using univariate logistic regression, and the relative risk (RR) with a 95% confidence interval (CI) were used to show the effect size of a comparison. Multivariable logistic regression models for PE, cesarean section, placental abruption, FGR, postpartum hemorrhage were developed with confounding factors included the abovementioned risk factors for developing PE. Subgroup analyses were also conducted. P < 0.05 was deemed statistically significant. All the statistical analyses were conducted with SPSS version 26.0 software (SPSS Inc., Chicago, USA).
Results
Baseline characteristics
This retrospective analysis encompassed 1522 individuals with PCOS, 36 cases were excluded due to non-compliance with the inclusion criteria. The study population consisted of 1091 pregnant women at low risk of preeclampsia and 395 pregnant women at high risk of preeclampsia. Of the 395 pregnant women classified as being at high risk for preeclampsia, 98 received LDA treatment from early pregnancy onwards, while 297 did not (Fig. 1).
Fig. 1.
Description of the study cohort
Before PSM, baseline attributes demonstrated significant heterogeneity. The LDA group exhibited a higher proportion of pregnant women with a pre-pregnancy body mass index (BMI) > 30 kg/m2 (n = 25, 25.5%) compared to the no-LDA group (n = 45, 15.2%, P = 0.02). Furthermore, the LDA group comprised a substantially higher percentage of twin pregnancies than the non-LDA group (27.6% vs. 16.8%, P = 0.02) (Table 1). After PSM, 97 pregnant women in each of the LDA and non-LDA groups were analyzed in a paired analysis, with a high degree of consistency in their characteristics (Table 2).
Table 1.
Baseline characteristics before propensity score matching
| No-LDA (N = 297) | LDA (N = 98) | P value | |
|---|---|---|---|
| Systolic pressure(mmHg) | 118.9 ± 12.3 | 124.6 ± 14.8 | 0.003 |
| Diastolic pressure (mmHg) | 74.6 ± 9.9 | 79.8 ± 11.7 | 0.02 |
| Pre-Pregnant BMI (kg/m2) | 23.9 ± 3.9 | 25.4 ± 4.5 | 0.06 |
| Pre-BMI ≥ 30 | 45(15.2%) | 25(25.5%) | 0.02 |
| Age(y) | 32.7 ± 3.8 | 32.6 ± 3.7 | 0.70 |
| Diabetes | 19(6.4%) | 7(7.1%) | 0.79 |
| Hypertension | 9(3.0%) | 9(9.2%) | 0.01 |
| Kidney disease | 4(1.3%) | 2(2.0%) | 0.62 |
| Autoimmune diseases | 6(2.0%) | 5(5.1%) | 0.10 |
| Primiparous | 259(87.2%) | 89(90.8%) | 0.33 |
| ART | 181(60.9%) | 52(53.1%) | 0.16 |
| Twins | 50(16.8%) | 27(27.6%) | 0.02 |
Table 2.
Baseline characteristics after propensity score matching
| No-LDA (N = 97) | LDA (N = 97) | P value | |
|---|---|---|---|
| Systolic pressure (mmHg) | 122.1 ± 13.1 | 124.2 ± 14.5 | 0.29 |
| Diastolic pressure (mmHg) | 78.4 ± 10.9 | 79.6 ± 11.6 | 0.45 |
| Pre-Pregnant BMI (kg/m2) | 25.4 ± 3.7 | 25.3 ± 4.5 | 0.89 |
| Pre-BMI ≥ 30 | 21(21.6%) | 24(24.7%) | 0.61 |
| Age(y) | 32.4 ± 4.1 | 32.6 ± 3.7 | 0.77 |
| Diabetes | 5(5.2%) | 7(7.2%) | 0.55 |
| Hypertension | 5(5.2%) | 8(8.2%) | 0.39 |
| Kidney disease | 1(1.0%) | 2(2.1%) | 0.56 |
| Autoimmune diseases | 5 (5.2%) | 5(5.2%) | 1 |
| Primiparous | 95(97.9%) | 88(90.7%) | 0.06 |
| ART | 56(57.7%) | 51(52.6%) | 0.47 |
| Twins | 15(15.5%) | 26(26.8%) | 0.08 |
Main outcomes
Overall,13.8% (205/1486) of the participants developed PE. The incidence of PE was 23.5% (93/395) in the high-risk group and 10.3% (112/1091) in the low-risk group (OR 1.40, 95%CI 1.23–1.59, P < 0.01).
For the 194 PCOS patients at high risk of PE after PSM, the treatment effects regarding the outcomes are presented in Table 3. The incidences of maternal outcomes, including PE, postpartum hemorrhage, and cesarean section, were not significantly different between the LDA group and the no-LDA group. No significant differences in the occurrence of adverse neonatal or fetal outcomes were observed between the two groups. Subgroup analysis revealed no interaction between LDA use and the other risk factors. LDA did not alter the outcomes in adjusted models before and after PSM (Table 4).
Table 3.
Primary and secondary outcomes
| Before PSM | After PSM | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| No-LDA (297) | LDA (98) | RR (95%CI) | P value | AOR (95%CI) | No-LDA (97) | LDA (97) | RR (95%CI) | P value | AOR (95%CI) | |
| Primary outcomes | ||||||||||
| PE | 62 (20.9%) | 31 (31.6%) | 1.75 (1.05–2.91) | 0.03 | 1.40 (0.81–2.42) | 21 (21.6%) | 31 (32.0%) | 1.33 (0.92–1.91) | 0.11 | 1.41 (0.70–2.83) |
| PE delivery < 37w | 24 (8.1%) | 5 (5.1%) | 0.61 (0.22–1.64) | 0.32 | 0.53 (0.18–1.53) | 3 (3.1%) | 5 (5.2%) | 1.35 (0.55–3.33) | 0.72 | 0.84 (0.15–4.72) |
| PE diagnosed < 34w | 8(2.7%) | 3 (3.1%) | 1.14 (0.29–4.38) | 0.73 | 0.90 (0.21–3.86) | 1 (1.0%) | 3 (3.1%) | 2.02 (0.37–11.10) | 0.62 | 2.90 (0.22–37.53) |
| Secondary outcomes | ||||||||||
| Cesarean section | 175 (58.9%) | 67 (68.4%) | 1.50 (0.92–2.44) | 0.09 | 1.23 (0.71–2.10) | 60 (61.9%) | 66 (68.0%) | 1.14 (0.86–1.52) | 0.37 | 1.08 (0.55–2.12) |
| Placental abruption | 5(1.7%) | 1(1%) | 0.60 (0.06–5.21) | 1.00 | 0.62 (0.06–5.83) | 0 | 1 (1.0%) | - | - | - |
| FGR | 4(1.3%) | 5(5.1%) | 3.93 (1.03–14.97) | 0.04 | 3.45 (0.64–18.55) | 2 (2.1%) | 5 (5.2%) | 1.78 (0.55–5.79) | 0.44 | 4.16 (0.47–36.73) |
| Postpartum hemorrhage | 8(2.7%) | 2(2.0%) | 0.75 (0.15–3.60) | 1.00 | 0.77 (0.15–3.95) | 5(5.2%) | 2(2.1%) | 0.69 (0.42–1.13) | 0.44 | 0.33 (0.05–1.95) |
Adjusted OR: adjusted for a prior history diabetes mellitus, chronic hypertension, autoimmune disease, kidney disease, BMI, advanced maternal age, nulliparity, ART and multiple pregnancy
Table 4.
Association of LDA with PE in the subgroups according to maternal risk factors at enrollment
| Characteristic | OR(95%CI) | p | P for interactions |
|---|---|---|---|
| Overall | 0.59(0.31–1.12) | 0.11 | |
| Diabetes | 0.66 | ||
| Yes | 0.33(0.02–4.74) | 0.42 | |
| No | 0.62(0.32–1.20) | 0.15 | |
| Hypertension | 0.29 | ||
| Yes | 2.40(0.18–32.88) | 0.51 | |
| No | 0.55(0.27–1.10) | 0.09 | |
| Kidney disease | 1.00 | ||
| Yes | 0(0-) | 1.00 | |
| No | 0.61(0.32–1.16) | 0.11 | |
| Autoimmune diseases | 0.71 | ||
| Yes | 1(0.05–22.18) | 1 | |
| No | 0.57(0.29–1.11) | 0.09 | |
| BMI | 0.53 | ||
| < 30 | 0.52(0.24–1.13) | 0.09 | |
| ≥ 30 | 0.83(0.24–2.84) | 0.77 | |
| ART | 0.32 | ||
| Yes | 0.43(0.18–1.07) | 0.07 | |
| No | 0.84(0.33–2.13) | 0.71 | |
| Twins | 0.31 | ||
| Yes | 1.12(0.29–4.37) | 0.865 | |
| No | 0.51(0.24–1.06) | 0.07 | |
| Age | 0.28 | ||
| < 35 | 0.43(0.18–1.02) | 0.06 | |
| ≥ 35 | 0.89(0.33–2.43) | 0.82 | |
| Primiparous | 0.10 | ||
| Yes | 0.59(0.30–1.18) | 0.14 | |
| No | 1292379874.28(0-∞) | 0.10 |
Discussion
In this large, single-center retrospective cohort study, the incidence of PE in PCOS patients was observed to be 13.8%, which is consistent with previous studies [13]; however, no evidence was found to suggest that LDA use during pregnancy reduces the incidence of PE in PCOS patients with risk factors for PE. No statistically significant difference was observed between the two groups regarding other pregnancy-related disorders or fetal or neonatal outcomes. The subgroup interaction tests corroborated this conclusion.
A substantial body of evidence strongly suggests that compromised placental function may contribute to the development of PE [14, 15]. Identifying a single precise etiology of placental damage in women with PE presents a significant challenge. Research on the prevention of PE in pregnant women with high-risk factors for PE among those with PCOS remains limited.
According to a previous study, the placentas of women with PE exhibited increased levels of lipids [16] and oxidative stress indicators [17], these findings suggest several potential strategies for preventing PE, such as the utilization of vasodilators, anti-inflammatory medications, and blood lipid reduction [18, 19]. There is growing evidence that the clinical features of some PCOS-related insulin resistance may be detrimental to the development of the placenta and fetus by increasing the vascular tone of the uterine arteries [20], while decreasing the expression of placental angiogenic factor genes [21, 22]. The placental expression of insulin receptors is widely acknowledged [23], and insulin sensitizers can be employed to promote proper trophoblast migration and invasion, as well as normal signaling, which in turn can enhance uterine spiral artery remodeling [24]. These findings indicate a relationship between insulin resistance and placental damage-related disease outcomes, such as FGR, PE, and miscarriages [25]. Some studies have demonstrated that between weeks 12 and 19 of gestation, the clinically prevalent medication metformin, which can reduce insulin resistance during pregnancy, decreases uterine vascular impedance [26, 27]; however, metformin appears to have no function in preventing PE based on current clinical data [28].
The use of aspirin has been associated with a significant reduction in preterm PE in high-risk pregnant women [8, 9], and in twin pregnancies [29]. However, in our investigation, we were unable to identify any evidence that pregnant women with high risk factors for PE experience a lower incidence of PE when administered LDA during pregnancy. According to current research [30], higher aspirin doses (150-162 mg) may demonstrate greater efficacy than lower doses (75–81 mg) in delaying the onset of PE. Similarly, it was observed that a 162 mg dose of aspirin exhibits superior effectiveness compared to an 81 mg dose in preventing severe preeclampsia in obese individuals [31]. These findings may be attributed to the enhanced inhibition of TbxB2 by 150 mg of aspirin compared to 75mg [12]. The patients in our study were administered 50-100 mg of aspirin daily rather than 150 mg. Consequently, we hypothesized that a higher aspirin dosage may be necessary to prevent PE and that 100 mg of aspirin might be insufficient to elicit the desired effect. Furthermore, our study’s definition of “high risk” was predicated solely on maternal clinical risk factors; however, additional research has demonstrated that the combination of maternal clinical risk factors, uterine artery pulsation index, mean arterial pressure, and placental growth factor levels can enhance the accuracy of screening for high-risk groups [32].
To the best of our knowledge, this study represents the first cohort trial to demonstrate that LDA use initiated in early pregnancy does not prevent adverse outcomes in pregnant women with PCOS at high risk of PE. This investigation has several limitations. Firstly, this cohort study was a retrospective observational analysis. Despite employing PSM to mitigate disparities between the groups, unquantified and residual confounding factors may potentially persist. Secondly, the findings should be interpreted with caution due to the low incidence of certain pregnancy outcomes, such as preterm PE. Thirdly, some women who experienced menstrual irregularities prior to pregnancy may have had undiagnosed PCOS due to delayed medical consultation. If such patients take aspirin orally during pregnancy, its efficacy in preventing PE may be diminished.
Conclusion
No decrease in PE was observed in pregnant women with PCOS who were at a heightened risk of PE, nor did it have any detrimental consequences on the mothers or their babies, due to LDA.
Acknowledgements
Not applicable.
Abbreviations
- PE
Preeclampsia
- LDA
Low Dose Aspirin
- PCOS
Polycystic Ovary Syndrome
- ART
Assisted Reproductive Technologies
- IVF
Invitro fertilization
- BMI
Body Mass Index
- PSM
Propensity score matching. FGR: Fetal Growth Restriction
Author contributions
LSL, ZXY and YY conducted the design of the study. LZZ and YY contributed to the acquisition of the data. LSL and ZXY contributed to the drafting of the article. LSL, PJN, WCJ, and LHY contributed to the analysis and interpretation of the data. GWR contributed to critically revising the article and provided final approval of the version to be submitted.
Funding
The study was funded by the National Natural Science Foundation of China (Grant No. 81971408), the Shanghai Municipal Health Commission (Grant No. 202240082), and the Science and Technology Commission of Shanghai Municipality (STCSM) (Grant No. 21Y11907800).
Data availability
The data used and analyzed during the current study are available upon reasonable request to the corresponding author.
Declarations
Ethics approval and consent to participate
The Fudan University Obstetrics and Gynecology Hospital Ethics Committee approved the study, and as the data were deidentified, informed permission was not necessary.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Shouling Luo and Xiaoyue Zhang equal contributions to this manuscript and are considered co-first authors
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Associated Data
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Data Availability Statement
The data used and analyzed during the current study are available upon reasonable request to the corresponding author.