| Background:Aspirin has many pharmacological effects such as antipyretic,analgesic,anti-inflammatory,anti-platelet,and thrombosis inhibitor,and plays an important role in the treatment of many diseases.In recent years,low-dose aspirin(LDA,50-150 mg)has been found to be important in obstetrics for the prevention of adverse pregnancy outcomes in high-risk women,particularly for the prevention of hypertension-related disorders during pregnancy.Due to the potential for increased risk of hemorrhage and perforation of the gastrointestinal tract,the usage of LDA is not fully harmonized in different guidelines and different medical centers.For singleton pregnancies with high-risk factors for pre-eclampsia,many clinical studies demonstrate a positive effect of LDA on the prevention of adverse pregnancy outcomes.However,there is insufficient clinical evidence as to whether LDA should be used in specific populations with moderate to high-risk factors for pre-eclampsia.There are also some controversies as to whether LDA can prevent fetal growth restriction and preterm birth.The question of whether its use during pregnancy increases hemorrhage during labor and the postpartum period is also of great concern and is not yet definitive.Purpose:This study focuses on whether LDA can have a significant effect on the prevention of adverse pregnancy outcomes in two specific groups of pregnant women.Primiparous women are one of our priority groups because of their large population size and intermediate risk of pre-eclampsia,and because of the controversy over whether aspirin can reduce adverse pregnancy outcomes in this population.Twin pregnancies are characterized by a high risk of pre-eclampsia,but there is a lack of clear clinical evidence of an ameliorative effect of LDA on adverse pregnancy outcomes,which also warrants further exploration.Methods:This study focused on a primiparous population and a population of pregnant women with twin pregnancies.There are a large number of clinical studies on primiparous women,but the findings are variable and controversial.Therefore,we used a meta-analysis to examine whether LDA reduces the incidence of adverse pregnancy outcomes in healthy primiparous women,taking into account the available clinical evidence.In the absence of clinical studies in twin pregnancies,we conducted an observational cohort study to investigate whether low-dose aspirin improves adverse pregnancy outcomes in twin pregnancies.Firstly,we conducted a meta-analysis to determine whether low-dose aspirin improves adverse pregnancy outcomes in primiparous pregnancies by using the Embase,Pub Med,Medline,Cochrane Central Register of controlled trials,and Web of Science databases to identify relevant randomized controlled trials(RCTs).Inclusion criteria included:1)randomized controlled trial;2)blank or placebo used as control;3)healthy primigravida enrolled;4)outcome indicators including at least one of pre-eclampsia,preterm birth,or fetal growth restriction.Exclusion criteria:1)studies included non-healthy primigravida;2)studies that did not specify that the subjects were low-risk/healthy primigravida(i.e.,those that did not emphasize that their participants were"low-risk"were not considered for inclusion).Healthy primigravida were defined as pregnant women without a history of labor and free of hypertension,diabetes mellitus,and other systemic diseases that could affect pregnancy outcomes at the time of enrollment.We extracted the following information from the articles:author's name,year of publication,study design,randomization methods,blind method,type of control group,sample size,weeks of gestation in the randomized group,duration,dose,and compliance with aspirin therapy.The primary follow-up indicator was PE,while preterm labor,SGA,and postpartum hemorrhage were secondary follow-up indicators.The quality of our studies was assessed by the preferred reporting items of the systematic evaluation and meta-analysis(PRISMA)tool,and the quality of each included trial was assessed using the Cochrane Handbook.Assessments were carried out separately by two investigators and the final decision was then discussed.Funnel plots were used to assess publication bias and were completed by Review Manager 5.3 software.Individual relative risks(RRs)were calculated for each study using Review Manager5.3 software,and a pooled analysis with 95%confidence intervals(CIs)was performed using a random-effects model.We next conducted an observational cohort study of twin pregnancies with the following main methods:the study population was drawn from Medical Center 1 and Medical Center 2.The formal inclusion of observation subjects started from March 1,2016 until the cessation of inclusion in December 2018.Pregnant women who underwent documentation at the Medical Center 1 were routinely given 100 mg/day of aspirin starting at 12-16 weeks of gestation and served as the low-dose aspirin group(LDA group),while pregnant women with twin pregnancies at Medical Center 2 were routinely not given aspirin and served as the control group(NC group).The inclusion criteria for this study were:1)pregnant women aged between 18-45 years;2)pregnant women with twins as proven by ultrasound;3)gestational weeks not greater than 16+0weeks at the time of enrolment;4)able to sign and be aware of the informed consent form on their own.Exclusion criteria were:1)pregnant women who were about to be enrolled in the LDA group had contraindications to aspirin(e.g.allergy,active peptic ulcer,coagulation abnormalities,severe liver and kidney disease,etc.);2)those who had taken anticoagulants(including aspirin)in one month prior to enrollment.The primary follow-up outcome indicator for this study was PE,secondary outcome indicators included PTB and SGA,and the safety indicator was the incidence of PPH.For the outcome indicators,we mainly used propensity score matching as well as multi-factor logistic regression equations for statistical analysis.Conclusions:The meta-analysis of primiparous women showed that LDA significantly reduced the incidence of pre-eclampsia in low-risk primiparous women(RR:0.71,95%CI:0.50-0.99,P=0.05).The best protection against PE has achieved at LDA initiation>16 weeks and at doses?75 mg(RR:0.42,95%CI:0.24-0.77,P=0.004).LDA also significantly reduced the incidence of SGA at doses?75 mg(RR:0.77,95%CI:0.63-0.96,P=0.02).However,the incidence of preterm birth(RR:1.07,95%CI:0.87-1.33,P=0.33)and<34 weeks preterm birth(RR:0.91,95%CI:0.65-1.29,P=0.61)was not effectively reduced at this dose.Our study also found that LDA at doses between 60-100 mg did not significantly increase the risk of postpartum hemorrhage(RR:1.34,95%CI:0.96-1.89,P=0.09).A total of 932 pregnant women,277 in the LDA group and 655 in the control group,were followed up in the twin cohort study.After propensity score matching,235 pregnant women in the LDA group and 235 pregnant women in the control group were well matched and had similar demographic characteristics.Analysis of these 470 twin pregnancies showed a significant reduction in the incidence of PE in pregnant women with twin pregnancies at a dose of 100 mg/d of LDA(RR:0.42,95%CI:0.20-0.85,P=0.019).LDA also significantly reduced the PTB rate in twin pregnancies<34 weeks(RR:0.50,95%CI:0.29-0.86,P=0.013),but it could not reduce the incidence of SGA(RR:0.74,95%CI:0.55-1.00,P=0.063).Our results also show that LDA does not significantly increase the risk of postpartum hemorrhage at this dose of use(RR:0.89,95%CI:0.35-2.26,P=1.000).Sensitivity analyses showed that LDA was also effective in the prevention of PE and PTB and did not significantly increase the risk of postpartum hemorrhage.LDA could not significantly reduce the incidence of SGA,but a decreasing trend of SGA rate in the LDA group could be observed.To clarify the protective effect of LDA on SGA,further large clinical studies are still needed to explore.Discussion:LDA has a significant effect on the prevention of PE in both healthy primigravida and twin pregnancies and also has a role in the prevention of SGA in primigravida.The effect of LDA on the prevention of preterm labor was not significant in healthy primiparous women,but was significant in twin pregnancies.In this study,two different groups of pregnant women were studied and it is possible that LDA may have diverse clinical effects on these adverse pregnancy outcomes in different risk groups.It is also possible that the optimal dose and timing of LDA use may not be same in different maternal populations,and further clinical studies are needed to explore these issues. |
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