Low-Dose Aspirin for the Prevention of Preeclampsia in Polycystic Ovary Syndrome：A Retrospective Cohort Study

doi:10.21203/rs.3.rs-4364280/v1

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Low-Dose Aspirin for the Prevention of Preeclampsia in Polycystic Ovary Syndrome：A Retrospective Cohort Study

https://doi.org/10.21203/rs.3.rs-4364280/v1

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Background: We set out to investigate whether low-dose aspirin (LDA) is helpful in avoiding preeclampsia (PE) in polycystic ovary syndrome (PCOS), given that data indicate that these people are more likely to develop PE.

Methods: This was a retrospective cohort study of pregnancies with PCOS that delivered between January 1, 2018, and February 10, 2024 in our hospital. Clinical characteristics and obstetrical information were examined in the medical record. Propensity score matching (PSM) was utilized to analyze the association between LDA and PE.

Results: The study population consisted of 1522 PCOS pregnancies, 395 were at high risk of PE, including 98 took LDA for preventing PE and 297 who did not take LDA. After the PSM, there was no significant difference between the LDA group and no-LDA group in the risk of PE; Likewise, adverse maternal and neonatal outcomes did not differ between the two groups. None of the subgroup interaction tests were significant for the preventive impact of LDA on PE.

Conclusions: There was not enough evidence according to this cohort analysis to suggest that LDA can prevent PE in PCOS patients at high risk of PE.

Low-dose aspirin

PCOS

Preeclampsia

PSM

FGR

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting women in their reproductive years, with an estimated prevalence of 5 to 15%¹. As of right now, PCOS has no recognized etiology, and there are no reliable cures or prevention strategies available². Women with PCOS have long-term effects on their metabolic, reproductive, and gynecological health. Individuals who have PCOS are more likely to have high blood pressure, hyperlipidemia, insulin resistance, infertility, overweight or obesity, and type 2 diabetes³. In order to become pregnant, some PCOS women who ovulate seldom or never may need assisted reproductive technology (ART), such as in-vitro fertilization (IVF)⁴, while diabetes, hypertension, IVF and obesity are all risk factors for PE⁵. Previous comprehensive studies have discovered that women with PCOS have a much higher risk of PE^{6, 7}.

Prenatal medical research has long focused on PE, a potentially fatal pregnancy condition⁸.

Moreover, once PE appears, the only treatment that works is timely delivery, which has a detrimental influence on the outcomes of newborns. Preventive intervention is necessary for women who are at high risk of PE in order to decrease the chance of these serious outcomes. Several research studies have proven the potential advantage of LDA in avoiding PE in high-risk pregnant people ^{9, 10}. Aspirin inhibits the production of prostaglandins and thromboxane, reduces inflammation and platelet aggregation, and selectively and irreversibly deactivates the enzyme cyclooxygenase-1¹¹. However, a recent randomized controlled trial that looked at the effects of LDA on PE in high-risk Chinese women found that a daily dose of 100 mg of aspirin, started between weeks 12 and 20 and continued until week 34 of gestation, did not lower the incidence of PE in pregnant Chinese women with high-risk factors¹². The topic of whether aspirin can decrease PE in PCOS patients with high risk of PE pregnancies remains unsolved.

Therefore, we conducted a retrospective cohort study using actual patient data. We employed PSM to make sure that the maternal baseline data were comparable. Our objectives were to assess the possible advantages of LDA in PCOS pregnancies and offer a theoretical framework for further research.

1.Study Participants

The retrospective cohort included all PCOS pregnancies gave birth at Fudan University Obstetrics and Gynecology Hospital in Shanghai, China, between January 1, 2018, and February 10, 2024. The individuals were identified using the hospital's electronic medical record system, and relevant data on maternal characteristics, pregnancy outcomes, and newborn outcomes were extracted from their electronic records. The PCOS pregnancies had to meet the following requirements in order to be considered: gave birth, received regular exams, and had prenatal medical records documented at our hospital.

2. Definition of high risks of developing pre-eclampsia:

(a) at least one high-risk factor, namely, history of pre-eclampsia, diabetes mellitus (type 1 or 2), or chronic hypertension, autoimmune diseases, kidney disease; or (b) at least two of the following intermediate risk factors, including obesity (pre-pregnancy body mass index (pre-BMI) ≥ 28kg/m²), advanced maternal age (≥ 35 years), family history of pre-eclampsia (mother or/and sister) or nulliparity; pregnancy through assisted reproductive technology; non-single birth.

3. Outcome measures

Primary outcome was the incidence of PE, PE was defined by blood pressure ≥ 140/90 mmHg associated with proteinuria (> 300 mg/day) after 20 weeks of gestational age. The secondary outcomes included the incidence of placental abruption, postpartum hemorrhage (defined as ≥ 500ml blood loss in vaginal delivery or ≥ 1000ml in cesarean delivery, within 24 hours of delivery); cesarean section rate, fetal growth restriction (FGR, birth weight < 10th percentile for singletons).

4. Statistical Analysis

The two research groups' initial features were contrasted. Numbers and percentages were used to represent categorical data, while mean ± standard values were used to represent continuous variables with normal distributions. The Fisher's exact test or Chi-square test were used to compare categorical variables, while the F test was used to analyze continuous variables.

To adjust the unmatched baseline characteristics, a 1:1 propensity score matching (PSM) was developed with the exposure (LDA vs no-LDA) as the dependent variable and all observed maternal characteristics as the independent variables, the caliper was set at 0.05. These covariates included these risks of developing PE and blood pressure at the first visit. The outcomes were investigated using logistic regression. Odds ratios (ORs) with 95% CIs were used to show the effect size of a comparison. Subgroup analyses were also performed. 2-tailed P < 0.05 was considered statistically significant. All statistical analyses were conducted with SPSS version 26.0 software (SPSS Inc., Chicago, USA).

Baseline characteristics

The current retrospective research comprised 1522 PCOS patients, 36 did not fit the inclusion criteria, 1091 individuals with low risk of PE and 395 individuals with high risk of PE made up the research population; The LDA group included 98 PCOS pregnancies with high risk of PE who received LDA and the no-LDA group included 297 PCOS pregnancies with high risk of PE who did not receive LDA (Table 1).

There were more BMI>28 cases in the LDA group (n =45, 15.2%) than in the no-LDA group (n=25, 25.5%, p =0.02). Additionally, there were significantly more twins in the LDA group (27.6% vs. 16.8%, p = 0.02) (Table 1). Finally, 97 pregnancies from the LDA group and 97 pregnancies from the no-LDA group were matched for analysis after PSM. All of the qualities were significantly associated (p > 0.05) (Table 2).

Main outcomes

Overall, 13.8% (205/1486) of the participants experienced 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).

In the 194 PCOS with high risk of PE after PSM, the treatment effects regarding the outcomes were shown in Table 3. The incidences of maternal outcomes, including PE,

postpartum hemorrhage and cesarean section showed no significant difference between the LDA and the no-LDA group. In addition, there was no difference in the incidence of neonatal or fetal outcomes, including preterm baby, FGR and neonatal weight between the two groups.

In order to assess the preventive impact of LDA on PE, as seen in Table 4, we conducted a subgroup analysis based on the risk variables at enrollment. The results indicated that there was no interaction between the trial groups and the risk factors.

In this large, single-center retrospective cohort study, the incidence of preeclampsia in PCOS patients was as high as 13.8%, which is consistent with previous studies¹³, but we did not discover any evidence that LDA during pregnancy reduced the incidence of PE in PCOS with risk factors for PE. There was no statistically significant difference between the two groups on other pregnancy-related disorders, or the outcomes of fetuses or neonates. The subgroup interaction tests supported the conclusion.

A substantial amount of data points to the possibility that compromised placental function contributes to PE^{14, 15}. It is difficult to identify a single, specific cause of placental damage in women with PCOS. Studies on preventing preeclampsia in pregnant women with high risk factors of PE in PCOS are still few. According to the study, the placentas of preeclamptic women exhibited increased levels of lipid¹⁶ and oxidative stress indicators¹⁷. These findings point to some possible strategies for preventing PE, such as using vasodilators, anti-inflammatory medications, and blood lipid reduction^{18, 19}. There is growing evidence that the clinical features of some PCOS-insulin resistance-may be harmful to the development of the placentas and fetus by Increasing the vascular tone of the uterine arteries²⁰, but decreasing the placental angiogenic factor genes^{21, 22}. It is commonly recognized that insulin receptors are expressed by the placenta²³, insulin sensitizers can help to promote appropriate trophoblast migration and invasion as well as normal signaling, which in turn can help to enhance uterine spiral artery remodeling²⁴. All of these findings point to a relationship between insulin resistance and placental damage-related diseases such as fetal growth restriction, PE, and miscarriages²⁵. Some studies found that between weeks 12 and 19 of gestation, the clinically prevalent medication metformin, which can reduce insulin resistance during pregnancy, decreased uterine vascular impedance^{26, 27}, but metformin appears to have no function in preventing PE based on current clinical data²⁸. Aspirin suppresses the formation of prostaglandins and thromboxane, decreases inflammation and platelet aggregation, and specifically and irreversibly inactivates the cyclooxygenase-1 enzyme ¹¹. The use of aspirin has been linked to a noteworthy decrease premature PE in high-risk pregnant women^{9, 10}, and in twin pregnancies²⁹. However, in our investigation, we were unable to discover any proof that pregnant women with high risk factors for PE would have a lower incidence of PE if they took LDA during their pregnancy. Recently, a randomized controlled trial that tested the effects of LDA on PE in high-risk Chinese women also discovered that a daily dose of 100mg of aspirin, started between weeks 12 and 20 and continued until week 34 of gestation, did not lower the incidence of PE in pregnant Chinese women with high-risk factors¹². The discrepancies in the results could be attributed to the dose of aspirin used, a third of pregnant women took 81 mg of aspirin daily with no discernible change in platelet function, while 150 mg of aspirin daily was advised based on dose dependence on treatment outcomes³⁰. Patients in our research, they took 50–100 mg of aspirin daily rather than 150mg. Thus, we reasoned that a higher aspirin dosage may be necessary to prevent PE and that 100 mg might not be sufficient to have the desired effect. Besides, our study's definition of "high risk" was based only on maternal risk factors; however, other research had demonstrated that integrating maternal clinical risk factors, uterine artery pulsation index, mean arterial pressure, and placental growth factor can improve the accuracy of screening high-risk groups³¹.

To our knowledge, this is the first cohort trial to demonstrate that early pregnancy-initiated LDA cannot reduce adverse outcomes in PCOS pregnancies with high risks of PE.

This study has several limitations. First, this cohort study is a retrospective observational analysis. Although we used propensity score matching to balance the differences between groups, unmeasured and residual confounding could still exist. Second, the findings need to be interpreted with caution because some pregnancy outcomes, such as preterm preeclampsia, had a low incidence. Third, our patients' socioeconomic and educational backgrounds are relatively decent. However, some women who experienced monthly irregularities prior to pregnancy may have missed cystic ovarian syndrome because they did not see a doctor in time, and if these patients take aspirin orally during pregnancy, its efficacy in preventing preeclampsia is reduced.

LDA did not decrease the frequency of PE in PCOS women who were at high risk of PE, nor did it have any adverse effects on mothers or neonates.

Ethics approval and consent to participate： The Fudan University Obstetrics and Gynecology Hospital Ethics Committee accepted the study, and as the data were deidentified, informed permission was not necessary.

Consent for publication：Not applicable

Availability of data and material：The data used and analyzed during the current study are available upon reasonable request to the corresponding author.

Competing interests：The authors declared that they have no conflict of interest to this work.

Funding：This work was supported National Natural Science Foundation of China (Grant No. 81471470 to W-R.G)

Authors' contributions: LSL conducted the design of the study, acquisition of data, and drafting of the article; PJN, YY, WCJ and LHY contributed to the analysis and interpretation of data; GWR contributed to revising the article critically and final approval of the article to be submitted.

Acknowledgements: Not applicable

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Tables 1 to 4 are available in the Supplementary Files section

No competing interests reported.

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You are reading this latest preprint version

Low-Dose Aspirin for the Prevention of Preeclampsia in Polycystic Ovary Syndrome：A Retrospective Cohort Study

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Version 1

Abstract

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Introduction

Methods

1.Study Participants

2. Definition of high risks of developing pre-eclampsia:

3. Outcome measures

4. Statistical Analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1