Pre-eclampsia is a pregnancy complication characterized by high blood pressure and damage to another organ system. It is a major cause of preterm birth and perinatal death. Aspirin is a non-steroidal anti-inflammatory drug, and low-dose aspirin has been proposed as an inexpensive prophylactic agent that can reduce the occurrence of pre-eclampsia in pregnant women with identifiable risk factors in European and Western populations. The bleeding risk associated with aspirin administration, for example, major bleeding, gastrointestinal bleeding, and fatal bleeding, usually concerns large doses of >300 mg daily. Less is known about risks associated with regular administration of doses <300 mg. There have always been concerns about the bleeding risk of aspirin administration during pregnancy, since normal pregnancy is associated with a change in hemostasis, including a significant increase in pro-coagulant activity and a decrease in physiological anticoagulants in maternal circulation to prevent major bleeding throughout gestation, labor, and the postpartum period.[3,4] Aspirin administration <100 mg daily can almost completely suppress platelet thromboxane A2 synthesis and thromboxane-dependent platelet aggregation, which results in the prolongation of the bleeding time and bleeding complications. Although some guidelines have announced the safety of aspirin <150 mg daily administration in pregnant women to prevent pre-eclampsia initiated after 12 weeks of gestation.[3,6,7] Some recent research also found that there is a high risk of bleeding during aspirin administration.[8-10] Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide, with a prevalence rate of approximately 6%. Definitions of PPH differ from country to country. According to the World Health Organization, PPH is defined as “blood loss from the birth canal in excess of 500 mL during the first 24 h after delivery.” In Western guidelines, PPH is defined as a cumulative blood loss of at least 1000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 h after the birth process. In Chinese guidelines, PPH is defined as blood loss of >500 mL following vaginal delivery, >1000 mL following cesarean delivery, and loss of blood coinciding with the need for transfusion within 24 h after delivery of the fetus or intrapartum loss.
The APPEC study is a large-population randomized controlled trial (RCT) in China evaluating the role of low-dose aspirin prophylactic treatment for pre-eclampsia. This study is a secondary analysis of data from the APPEC study to evaluate the bleeding risk of low-dose aspirin administration in the prevention of pre-eclampsia. In the APPEC study, eligible women with high-risk factors of developing pre-eclampsia according to their age, pre-pregnancy body mass index (pre-BMI), obstetrical histories, and medical histories were randomized to receive standard antenatal care plus aspirin (100 mg/day) or standard antenatal care only from the recruitment time (at 12–20 weeks of gestation) until 34 weeks of gestation or in the event of early delivery. PPH was defined according to the Chinese guideline in this study. Although maternal mortality due to PPH has decreased in recent years, the rate of PPH has increased. Being concerned about the subsequent PPH, most of the prophylactic use of low-dose aspirin would end several weeks before labor.
The objective of this study was to examine whether there is a potential bleeding risk and whether there exists a difference in the incidence of PPH according to maternal characteristics such as medical and obstetrical history after 100 mg aspirin in pregnant women with high-risk factors for developing pre-eclampsia.
This is a secondary analysis of the APPEC study. The study was approved by the Ethics Committee of the Peking University First Hospital (2016 ). The APPEC study is a multicenter, open-label RCT conducted at 13 tertiary hospitals in 11 provinces within China (2016–2018) designed to evaluate the effect of low-dose aspirin administered from early pregnancy in Chinese pregnant women with high-risk factors for developing pre-eclampsia.
The detailed methods used in this trial have been previously published. Briefly, this trial identified pregnant women with one of the following high-risk factors for developing pre-eclampsia: history of pre-eclampsia, diabetes mellitus (type 1 or 2), chronic hypertension, or at least two of the following intermediate risk factors, including obesity (pre-BMI ≥28 kg/m2), advanced maternal age (≥35 years), family history of pre-eclampsia (mother or/and sister), or nulliparity. Participants were randomized using a web-based computerized central randomization system in a 1:1 allocation ratio to receive standard antenatal care plus aspirin (100 mg/day) or standard antenatal care daily. Patient compliance was assessed by a combination of patients’ self-reports and physician evaluations at each antenatal visit and pill counts.
The primary outcome of the APPEC study was the occurrence of pre-eclampsia. The secondary outcomes of the APPEC study were maternal and neonatal. PPH was one of the secondary outcomes in the APPEC study. Further details of the enrollment criteria and exclusion criteria were published. We aimed to evaluate whether the administration of low-dose aspirin will increase the risk of PPH in this study.
Follow-up visit one is at the enrollment, follow-up visit two is at 12–26 weeks of gestation, follow-up visit three is at 20–28 weeks of gestation, follow-up visit four is at 28–34 weeks of gestation, follow-up visit five is at 34 weeks of gestation to delivery.
A platelet count <100 × 109/L or abnormal coagulation index would be considered a potential bleeding risk and associated with a tendency of bleeding. Patients were considered to have been at risk for bleeding if they had a platelet count <100 × 109/L just once at any of the five follow-up time points.
Baseline characteristics were calculated using Student's t-test, the chi-squared test, or Fisher's exact test as appropriate between two groups. The mean platelet count collected at five follow-up visits during pregnancy was compared using Student's t-test between two groups. We compared the incidence of potential bleeding risk using the chi-squared test between the two groups. The coagulation test results collected at follow-up visits one and five were compared at these two time points using the Student's t-test between two groups. Interactions were tested to assess whether the aspirin effect on the incidence of PPH differed between subgroups defined by maternal age (<35 years and ≥35 years), pre-BMI (<28 kg/m2 and ≥28 kg/m2), parity, gestational age at enrollment, and medical history including pre-eclampsia, chronic hypertension, and diabetes mellitus. In our analyses, increased PPH risk (relative risk [RR] aspirin/control) was estimated by separate analyses of different subgroups using logistic regression analysis. Adjustment using multivariable logistic regression models followed these analyses. We calculated crude RRs and adjusted RRs and their respective 95% confidence intervals (CIs) for the following maternal characteristics potentially associated with PPH: pre-BMI, maternal age, parity, chronic hypertension, diabetes mellitus, way of conception, way of delivery, and delivery week. We examined whether the test of interaction was significant at the 5% level. Since the number of post hoc test was seven, the P values should be compared to 0.05/7 = 0.007 to determine significance at the 5% level with a Bonferroni adjustment for multiple comparisons. The relation between pre-BMI and PPH was evaluated by binary logistic regression. Sensitivity analysis was conducted based on patients compliance to explore whether different compliance had an impact on PPH. Statistical analysis was performed in IBM SPSS Statistics version 22.0 (IBM, Armonk, NY, USA) and Stata version 11.0 (StataCorp, College Station, TX, USA) software.
Within the APPEC study group, 464 women received 100 mg of aspirin daily from the time of recruitment, and 434 women were as signed to the control group. Demographic characteristics did not differ between the aspirin and control group [Supplementary Table 1, https://links.lww.com/CM9/B506]. The overall rate of PPH was 5.9% (53/898). There was no significant difference in PPH incidence between the aspirin group and the control group (6.5% [30/464] vs. 5.3% [23/434], χ2 = −0.740, P = 0.459). The platelet count showed no statistically significant difference between the two groups at any of the five different time points during pregnancy, and there was a downtrend in the platelet count during pregnancy in both groups [Figure 1]. There was no significant difference between the two groups at a follow-up visit one and five on the coagulation index prothrombin time, activated partial thromboplastin time, fibrinogen, and D-Dimer. The bleeding risk was not significantly increased after aspirin administration (3.4% [16/464] vs. 3.0% [13/434], P = 0.701) [Table 1]. It can be inferred from the results that the prophylactic administration of low-dose aspirin for pregnant women with high-risk factors for developing pre-eclampsia will not increase the risk of PPH, decrease the platelet count, or disturb the balance of hemostatic.
Table 1 -
The coagulation index PT, APTT, FIB, and D-dimer of the two groups in follow-up visit 1 and 5.
|Follow-up visit point
||Aspirin group (n = 464)
||Control group (n = 434)
||PLT < 100 × 109/L∗, n (%)
∗Platelet count <100 × 109/L would be considered as an increased bleeding risk.APTT: Activated partial thromboplastin time; FIB: Fibrinogen; PLT: Platelet; PT: Prothrombin time.
There was no evidence of heterogeneity in the incidence of PPH after aspirin administration in subgroups defined according to maternal age (<35 years and ≥35 years), pre-BMI (<28 kg/m2 and ≥28 kg/m2), parity, gestational age at enrollment, and medical history, including pre-eclampsia, chronic hypertension, and diabetes mellitus (present and absent), which indicated that there was not an increase of PPH risk after prophylactic administration of low-dose aspirin according to maternal characteristics and medical and obstetrical history [Table 2].
Table 2 -
RR for PPH in the aspirin group with 95% CI in different subgroups defined according to maternal characteristics and medical and obstetrical history.
||RR (95% CI)
||Adjusted RR (95% CI)
P values for interactions
|Obesity (pre-BMI ≥28 kg/m2)
|History of pre-eclampsia
|Gestational age at enrollment (weeks)
||>16 (305)≤16 (593)
||5/144 (3.5)25/320 (7.8)
||6/161 (3.7)17/273 (6.2)
||0.932 (0.291–2.988)1.255 (0.692–2.274)
||0.912 (0.272–3.062)1.289 (0.670–2.478)
∗The total number of the participants with or without the risk factor.
†Advanced age, maternal age ≥35 years. Data are presented as n or n/N (%).The P values should be compared to 0.007 to determine significance at the 5% level for multiple comparisons.CI: Confidence interval; PPH: Postpartum hemorrhage; Pre-BMI: Pre-pregnancy body mass index; RR: Relative risk.
We performed a sensitivity analysis based on adherence to aspirin intake. In the group with different adherence rates (≥70%, ≥80%, ≥90%), there was no difference in the incidence of PPH between the aspirin group (≥70%, 8.4%, 27/321; ≥80%, 8.7%, 25/288; ≥90%, 8.8%, 22/250) and the control group (5.3%, 23/434). Considering that aspirin-related bleeding risk is mainly due to failure to stop the drug on time, we analyzed the rate of PPH among women who did not stop taking aspirin 1 week before delivery. Forty-four patients in the aspirin group did not stop aspirin 1 week before delivery, and three of them experienced PPH. There was no difference in the incidence of PPH between them (RR = 1.287, 95% CI = 0.402–4.114; 6.8% [3/44] vs. 5.3% [23/434], P = 0.436) and the control group. A total of 290 patients in the aspirin group stopped aspirin 1 week before delivery, and 25 of them experienced PPH. There was also no significant difference in the incidence of PPH between them (RR = 1.627, 95% CI = 0.942–2.809; 8.6% vs. 5.3%, P = 0.055) and the control group. There was also no significant difference in the incidence of PPH between patients who did not stop aspirin 1 week before delivery and those who stopped aspirin 1 week before delivery (RR = 0.791, 95% CI = 0.249–2.510; 6.8% vs. 8.6%, P = 0.481).
We evaluated the relationship between maternal pre-BMI and PPH. We found that the incidence of PPH in obese participants (pre-BMI ≥28 kg/m2, 9.0%, 22/244) was significantly higher than that in other participants (pre-BMI <28 kg/m2, 4.7%, 31/654) (RR = 1.902, 95% CI = 1.124–3.219, P = 0.025). The influence of obesity on PPH was statistically significant (odds ratio [OR] = 1.074, 95% CI = 1.012–1.140, P = 0.018). This correlation was then tested separately in the aspirin and control groups since there was no difference of PPH incidence in the subgroup classified by pre-BMI (<28 kg/m2 and ≥28 kg/m2) between the aspirin and control groups. We found that the relationship between pre-BMI and PPH was only significant in the aspirin group, while the control group did not show a significant correlation (aspirin group, OR = 1.086, 95% CI = 1.004–1.175, P = 0.040; control group, OR = 1.060, 95% CI = 0.968–1.161, P = 0.209).
There is still no consistent agreement about whether the administration of low-dose aspirin during pregnancy would increase the risk of bleeding. Some research aimed to evaluate the relationship between the incidence of PPH and the prophylactic administration of low-dose aspirin showed that aspirin will not increase the risk of PPH and other bleeding events,[17-24] but some studies indicated that there was an increased risk of PPH.[9,10,25,26] Several studies have even found that the prophylactic effect of aspirin has a protective effect on PPH.[27,28] The secondary analysis of the APPEC study demonstrated that in pregnant women with high-risk factors for developing pre-eclampsia, the prophylactic administration of low-dose aspirin from 12 weeks to 20 weeks of gestation until 34 weeks of gestation or in the event of early delivery would not increase the incidence of PPH or decrease the incidence of PPH. There was no evidence of heterogeneity in the incidence of PPH in subgroups defined according to maternal characteristics. Administration of low-dose aspirin will not increase the risk of thrombocytopenia or disturb the balance of coagulation.
The relationship between maternal pre-BMI and PPH is still under debate. The incidence of PPH is increasing and maternal obesity is also increasing worldwide.[30,31] Maternal obesity is a risk factor for developing pre-eclampsia. Date from several population-based studies have also found that maternal obesity is associated with an increased risk of PPH.[32-35] However, some research found that obesity is associated with a reduced risk of severe PPH due to the hypercoagulability state of obese women in pregnancy.[36,37] Some research found that maternal body mass index had no significant association with PPH.[38-40] Our analysis of pre-BMI and PPH demonstrated that obese people tend to have a higher incidence of PPH. However, further analysis indicated that this relationship was only significant in the aspirin group. In the control group, there was no significant correlation between pre-BMI and PPH.
The platelet count showed no significant difference between the two groups at any of the five time points in the study, indicating that the administration of low-dose aspirin did not reduce the platelet count. There was a downtrend in the platelet count during pregnancy in both groups, which was consistent with the trend of a decreasing trend of platelets during pregnancy in other research.[41-43]
The results of our study may help strengthen the argument that there was no increased risk of PPH after prophylactic administration of aspirin in pregnant women with a high risk of developing pre-eclampsia. Subgroup analysis demonstrated that in all subgroups, there was no difference in the incidence of PPH after aspirin administration. The platelet count and coagulation index were not disturbed after low-dose aspirin administration. The findings of our study were biologically plausible. We also found that the incidence of PPH was significantly correlated with maternal pre-BMI, and further analysis demonstrated that this correlation was only significant in the aspirin group. Obesity is an intermediate-risk factor for developing pre-eclampsia. The results of our study may provide evidence that for pre-eclampsia high-risk pregnant women with high BMI, there would be an increased risk of PPH after aspirin administration. Therefore, more attention should be given to these women. However, researchers have also found that the preventative effect of low-dose aspirin in obese pregnant women may not be as efficient as in normal pregnant women. Therefore, in the consideration of an increased risk of PPH in pregnant obese women after aspirin administration, whether it is safe or whether there is truly a need to increase aspirin dosage or frequency is still under discussion. For obese women who want to become pregnant, appropriate weight loss can not only reduce their risk of developing pre-eclampsia but can also reduce the risk of bleeding when aspirin is needed during pregnancy.
Limitations of this study include the fact that the APPEC study was not specifically designed to evaluate the impact of low-dose aspirin on PPH and hemostatic changes. Participants in our study were pregnant women with different high-risk factors for developing pre-eclampsia, so there were considerable differences in maternal characteristics among the study population.
Considering that a higher dosage of 150 mg aspirin was recommended in the ASPRE study, an insufficient dosage of aspirin may affect the risk of PPH in our study. Three RCTs which implemented aspirin dosages of 150 mg have been reported.[45-47] Two of them reported no potential bleeding harm with 150 mg aspirin,[46,47] and one of them did not report PPH outcomes. In our further studies, we can explore whether choosing an early initiation and applying a higher aspirin dosage may affect the risk of PPH.
The APPEC study aimed to evaluate the effect of low-dose aspirin in Chinese pregnant women with high-risk factors. The statistical power for detecting the effects of smaller subgroups of data upon a secondary outcome was inevitably poor, and only the larger interaction effects were likely to be detected. This problem was exacerbated by the multiple comparisons. However, the consistency of different groups was reassured by the estimated OR.
For pregnant women at high risk of developing pre-eclampsia, administration of low-dose aspirin did not increase the risk of PPH, regardless of the characteristics (obese, advanced age, chronic hypertension, diabetes, pre-eclampsia, gestational age, etc.), medical, or obstetrical history of the women. After administration of aspirin, the risk of PPH has a positive correlation with body mass index, which means obese pregnancies would have an increased risk of developing PPH after aspirin administration.
We thank all the doctors, nurses in the APPEC study, and the patients who participated in this trial.
This work was supported by grants from the Major Program of the National Natural Science Foundation of China (No.81490745) and the State Key Development Program for Basic Research of China (No.2015CB943304).
Conflicts of interest
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