Background
Low-dose aspirin has been the most widely studied preventive drug for preeclampsia. However, guidelines differ considerably from country to country regarding the prophylactic use of aspirin for preeclampsia. There is limited evidence from large trials to determine the effect of 100 mg of aspirin for preeclampsia screening in women with high-risk pregnancies, based on maternal risk factors, and to guide the use of low-dose aspirin in preeclampsia prevention in China.
Objective
The Low-Dose Aspirin in the Prevention of Preeclampsia in China study was designed to evaluate the effect of 100 mg of aspirin in preventing preeclampsia among high-risk pregnant women screened with maternal risk factors in China, where preeclampsia is highly prevalent, and the status of low-dose aspirin supply is commonly suboptimal.
Study Design
We conducted a multicenter randomized controlled trial at 13 tertiary hospitals from 11 provinces in China between 2016 and 2019. We assumed that the relative reduction in the incidence of preeclampsia was at least 20%, from 20% in the control group to 16% in the aspirin group. Therefore, the targeted recruitment number was 1000 participants. Women were randomly assigned to the aspirin or control group in a 1:1 allocation ratio. Statistical analyses were performed according to an intention-to-treat basis. The primary outcome was the incidence of preeclampsia, diagnosed along with a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg after 20 weeks of gestation, with a previously normal blood pressure (systolic blood pressure of <140 mm Hg and diastolic blood pressure of <90 mm Hg), and complicated by proteinuria. The secondary outcomes included maternal and neonatal outcomes. Logistic regression analysis was used to determine the significance of difference of preeclampsia incidence between the groups for both the primary and secondary outcomes. Interaction analysis was also performed.
Results
A total of 1000 eligible women were recruited between December 2016 and March 2019, of which the final 898 patients were analyzed (464 participants in the aspirin group, 434 participants in the control group) on an intention-to-treat basis. No significant difference was found in preeclampsia incidence between the aspirin group (16.8% [78/464]) and the control group (17.1% [74/434]; relative risk, 0.986; 95% confidence interval, 0.738–1.317; P =.924). Likewise, adverse maternal and neonatal outcomes did not differ significantly between the 2 groups. Meanwhile, the incidence of postpartum hemorrhage between the 2 groups was similar (6.5% [30/464] in the aspirin group and 5.3% [23/434] in the control group; relative risk, 1.220; 95% confidence interval, 0.720–2.066; P =.459). We did not find any significant differences in preeclampsia incidence between the 2 groups in the subgroup analysis of the different risk factors.
Conclusion
A dosage of 100 mg of aspirin per day, initiated from 12 to 20 gestational weeks until 34 weeks of gestation, did not reduce the incidence of preeclampsia in pregnant women with high-risk factors in China.
Introduction
Preeclampsia is a multisystem syndrome that affects 3%–5% of pregnant women. It is a major cause of maternal and perinatal mortality and morbidity. Lack of treatment may result in severe fatal complications of preeclampsia, including eclampsia, stroke, pulmonary edema, kidney failure, etc. Moreover, preeclampsia is associated with preterm birth, fetal growth restriction, and small for gestational age (SGA) newborns. Once preeclampsia develops, the only effective treatment is a prompt delivery, which results in adverse neonatal outcomes, especially when the delivery date is far from the due date (<34 weeks of gestation). Therefore, it is necessary to take preventive measures for women at high risk of preeclampsia to reduce these serious complications.
Why was this study conducted?
Guidelines concerning the aspirin preventive strategies for preeclampsia differ considerably from country to country. There are few pieces of evidence from large randomized controlled trials that have shown the effect of 100-mg aspirin for preeclampsia prevention in high-risk pregnant women. Aspirin use among high-risk pregnant women based on maternal risk factors needs to be verified. There is scarce evidence from large, randomized controlled trials, to guide the use of low-dose aspirin for preeclampsia prevention in high-risk pregnancies among Chinese women.
Key findings
In the women with high-risk pregnancies, low-dose aspirin did not reduce the incidence of preeclampsia compared with the control group; 16.8% (78/464) participants in the aspirin group and 17.1% (74/434) in the control group (relative risk, 0.986; 95% confidence interval, 0.738–1.317; P =.924).
What does this add to what is known?
A dosage of 100 mg of aspirin per day, initiated from 12 to 20 gestational weeks until 34 weeks of gestation, did not reduce the incidence of preeclampsia in pregnant women with high-risk factors in China.
A variety of drugs, including low-dose aspirin, low-molecular-weight heparin, antioxidants, calcium, proton-pump inhibitors, metformin, and statins, have been reported to have beneficial effects on the prevention and treatment of preeclampsia. Among these drugs, low-dose aspirin was reported to be the most promising prophylactic agent. , The major effect of aspirin is dependent on cyclooxygenase, which inhibits thromboxane A2 production in platelet and subsequently reverses the preeclampsia patients’ thromboxane A2/prostaglandin I2 imbalance, thereby improving placental function by favoring systemic vasodilatation and inhibiting the platelet aggregation, which is abnormally activated in preeclampsia. , The prophylactic use of low-dose aspirin for preeclampsia was suggested for the first time in 1978 in a case report. Since the first evidence from a randomized trial reported aspirin’s obstetrical efficacy in 1985, numerous studies have reported the potential value of low-dose aspirin in preeclampsia prevention among high-risk pregnancies. In 2004, a Cochrane meta-analysis reported that the administration of antiplatelet agents in high-risk women could reduce the rate of preeclampsia by 19%. Guidelines from the World Health Organization (WHO) and several countries, including the United States, the United Kingdom, Canada, French and Australia, also recommended the use of low-dose aspirin to prevent preeclampsia in women with high-risk pregnancies.
Guidelines concerning the aspirin preventive strategies for preeclampsia differ considerably from country to country. There is no standardized protocol regarding aspirin use because the dosage, initial timing of medication, and screening methods of the high-risk population vary among the guidelines from different countries, including China. A published randomized controlled trial involved >3000 participants and concluded that 100 mg of aspirin did not reduce the incidence of preeclampsia among the low-risk population. Apart from this one, there was little evidence from large randomized controlled trials that had shown the effect of 100-mg aspirin on preeclampsia in high-risk pregnant women. Moreover, most randomized controlled trials focused on Caucasian or Black populations, thus lacking evidence on Asian populations. There is little evidence from large randomized controlled trials to guide the use of low-dose aspirin in preeclampsia prevention in the Chinese pregnant women. Further, aspirin use in high-risk pregnancies based on maternal risk factors needs to be verified. Considering the above reasons, we aimed to conduct this trial to explore the effect of 100 mg of aspirin on screened women with high risk factors to prevent preeclampsia in the Chinese population. Furthermore, through this study, we could provide evidence for the recommendation of aspirin use among the Chinese population.
Therefore, we conducted a large randomized controlled trial (RCT) in China to evaluate the role of low-dose aspirin in preeclampsia prevention, filling a critical gap in the literature and ultimately leading to effective policy recommendations for clinical practice.
Materials and Methods
Study design
Between December 2016 and March 2019, we conducted an RCT (the Low-Dose Aspirin in the Prevention of Pre-Eclampsia in China [APPEC] study), where women with clinical risk factors associated with preeclampsia were enrolled from 13 hospitals in China. These hospitals were from 11 cities and provinces of Beijing, Henan, Guangdong, Shanghai, Jiangsu, Shandong, Hunan, Gansu, Shaanxi, Shanxi, and Chongqing. We compared 2 groups of pregnant women with high risk of preeclampsia—aspirin group, who took aspirin (from 12 to 20 weeks of gestation until 34 weeks of gestation) at night before going to bed, with a control group who received no treatment in high-risk pregnant women.
Participants
Inclusion criteria were as follows: (1) age ≥18 and <55 years; (2) singleton pregnancy; (3) live fetus at the gestational age of 12 to 20 weeks; (4) definition of high risk of developing preeclampsia: (a) at least 1 high risk factor, namely, history of preeclampsia, diabetes mellitus (type 1 or 2), or chronic hypertension; or (b) at least 2 of the following intermediate risk factors, including obesity (prepregnancy body mass index [pre-BMI] ≥28 kg/m 2 ), advanced maternal age (≥35 years), family history of preeclampsia (mother or/and sister) or nulliparity; (5) ability to undergo all procedures listed in the protocol; (6) a written informed consent for participation in the study. The exclusion criteria included (1) allergy to aspirin; (2) asthma; (3) peptic ulcers; (4) no tolerance to this study because of severe heart, liver, or renal disease; (5) autoimmune diseases; (6) mental disorders; (7) history of alcohol or drug abuse within 6 months; (8) in-vitro fertilization; (9) previous registration in another drug trial within the previous 3 months. This study was approved by the ethics committee of the Peking University First Hospital. We registered the study protocol in the clinical trials registry database ( ClinicalTrials.gov ) on June 10, 2016.
Definitions of risk factors for preeclampsia
Chronic hypertension was defined as hypertension (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) predating the pregnancy or recognized at before 20 weeks of gestation. Advanced maternal age was defined as maternal age ≥35 years. We divided a pre-BMI into 4 groups according to the WHO expert consultation for the Asian population : group A: underweight (BMI, <18.5 kg/m 2 ); group B: normal weight (BMI, 18.5–23.9 kg/m 2 ); group C: overweight (BMI, 24.0–27.9 kg/m 2 ); and group D: obesity (BMI, ≥28 kg/m 2 ). Parity status, diabetes mellitus (type 1 or 2), history of preeclampsia, and family history of preeclampsia (mother or sister) were also recorded.
Procedure
Participants were identified during their first antenatal care visit (before 20 weeks of gestation) at our study sites. The patients were enrolled at obstetrics clinics, and a brief assessment card was used to identify eligible women. Recruitment strategies depended on local hospitals and included recruitment advertisements, online news, advertisements in training classes for pregnant women, and screening by a doctor. Pregnancy was confirmed via transabdominal B-mode ultrasound. Blood pressure was measured by well-trained nurses using a mercury sphygmomanometer, with patients’ arms well supported at the level of the patients’ heart and an appropriate-sized adult cuff, after they were seated comfortably and quietly, after 5 minutes of rest. Two measurements of blood pressure were performed within 1-minute intervals, and the average readings was recorded. Then the investigators evaluated the risk factors and baseline conditions of the pregnant women, and those who met the eligibility criteria were enrolled in the study. Trial information was provided both verbally and with a written information sheet. Eligible women were encouraged to consider their involvement in the study and discuss participation with their partners or family members before providing written consent. All participants were free to withdraw from the study at any time if they wished, and appropriate ongoing antenatal care was arranged for all participants according to their clinical risks.
Participant data were collected from a paper case report form and then entered into an electronic case report form (eCRF) ( http://bjdx.clinicalcloud.com.cn/Login.aspx ) for further data sorting. To ensure high-quality trial conduct, data typing, entries, and permitted ranges of answers to every question on the eCRFs were restricted to the web-based system. We also arranged regular meetings to ensure project implementation. Data monitors visited each study site periodically to verify the accuracy of the collected data.
Participants were randomized using a web-based computerized central randomization system, which is the interactive Web Response System ( http://bjdx.clinicalcloud.com.cn/Login.aspx ), in a 1:1 allocation ratio. They were assigned a randomization code, which determined the women who received 100 mg of aspirin daily and those who did not.
Study outcomes
The primary outcome of this study was the incidence of preeclampsia. Preeclampsia was defined according to the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin, number 222. Preeclampsia was diagnosed with SBP ≥140 mm Hg or DBP ≥90 mm Hg on at least 2 occasions 4 hours apart, developing after 20 weeks of gestation with previously normal blood pressure (SBP <140 mm Hg and DBP <90 mm Hg), and accompanied by proteinuria. Any of the following criteria were used for diagnoses of proteinuria: protein in urine is ≥300 mg per 24 hours of urine collection (or can be extrapolated from a timed collection), protein to creatinine ratio is ≥0.3 mg/dL, dipstick reading 2+ (used only if other quantitative methods are not available), and new-onset vital organ damage. The secondary outcomes included the incidence of preeclampsia delivery before 34 weeks of gestation, before 37 weeks of gestation, and at or after 37 weeks of gestation; the incidence of gestational hypertension; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; placental abruption; postpartum hemorrhage (defined as ≥500 mL blood loss in vaginal delivery or ≥1000 mL in cesarean delivery, within 24 hours of delivery); and fetal distress. Neonatal outcomes included preterm birth (delivery at or after 28 weeks of gestation and before 37 +0 weeks of gestation); miscarriage, stillbirth, or neonatal death; fetal death with preeclampsia; perinatal death; fetal malformation; low birthweight (birthweight <2500 g); very low birthweight (birthweight <1500 g); SGA (birthweight <10th percentile for singletons) ; Apgar score and neonatal intensive care unit (NICU) admission.
The participants’ compliance in our study was assessed by patients self-reporting in a diary and physician evaluating at each antenatal visit. The adherence was calculated as a percentage of the number of tablets taken indeed to the total number of tablets expected to take.
Statistical analysis
According to previous studies, the preeclampsia incidence in pregnant women with high risk factors was at least 20%. We supposed a relative reduction of at least 20% in the intervention group (leading to an incidence of 16%). For 80% power (β) and a level of significance set at 5% (α), 446 participants were required in each group. Thus, the total number of women required for this study was 892. Considering 10% withdrawal or loss to follow-up, 981 women needed to be recruited. Thus, we set a sample size of 1000 women (500 per group) for the study.
Statistical analyses were performed using an intention-to-treat basis. Data were analyzed using the SPSS 20.0 software (IBM Corp, Armonk, NY). Logistic regression analysis was used to determine the significance of the between-group difference in preeclampsia occurrence and other adverse maternal and neonatal outcomes. The treatment effect was quantified as the relative risk (RR) with a 95% confidence interval (CI) in the aspirin group. Interaction analysis was also performed. The level of statistical significance was set at P <.05.
Results
Trial participants
The first participant was recruited on December 7, 2016. From December 2016 to March 2019, 1000 women were assessed for eligibility. A total of 10 women were excluded because of randomization error (n=2) and for not meeting the inclusion criteria (n=8) ( Figure ). Thus, 990 women were randomized to either the aspirin group (n=496) or the control group (n=494). There were 32 women in the aspirin group and 60 women in the control group who withdrew from the study. These participants did not want their data to be published. Thus, data from a total of 898 women were analyzed. The baseline characteristics of these individuals are summarized in Table 1 , showing that the 2 groups were well matched at the baseline. In our study, 23 patients were lost to follow-up, 9 in the aspirin group (2 patients withdrew consent and 7 were out of contact), and 14 in the control group (1 patient withdrew consent and 13 were out of contact). The 23 patients had baseline information, and we included these patients in the analysis on the intention-to-treat basis.
| Characteristic | Aspirin group (n=464) | Control group (n=434) |
|---|---|---|
| Age (y) | 32.88±4.62 | 32.78±4.46 |
| Advanced age a (%) | 175 (37.7) | 161 (37.1) |
| Height (cm) | 161.33±5.33 | 160.74±5.07 |
| Prepregnancy weight (kg) | 66.21±12.99 | 66.03±12.11 |
| Prepregnancy BMI (kg/m 2 ) | 25.38±4.43 | 25.53±4.35 |
| Obese (prepregnancy BMI ≥28 kg/m 2 ) (%) | 122 (26.3) | 122 (28.1) |
| Primiparous (%) | 155 (33.4) | 153 (35.3) |
| Chronic hypertension (%) | 241 (51.9) | 200 (46.1) |
| Preexisting diabetes (%) | 108 (23.3) | 110 (25.3) |
| History of preeclampsia (%) | 162 (34.9) | 136 (31.3) |
| Family history of preeclampsia (%) | 19 (4.1) | 18 (4.1) |
| Gestational age (wk) | 14.62±5.99 | 14.60±4.98 |
| Diastolic blood pressure (mm Hg) b | 82.12±12.66 | 81.60±12.18 |
| Systolic blood pressure (mm Hg) b | 128.64±16.26 | 128.05±16.11 |
a Advanced age is when maternal age was ≥35 years
b Blood pressure was measured at first antenatal care before 20 weeks of gestation.
Primary outcome
Overall, 16.9% (152/898) of the participants developed preeclampsia. The incidence of preeclampsia was 16.8% (78/464) in the aspirin group and 17.1% (74/434) in the control group (RR, 0.986; 95% CI, 0.738–1.317; P =.924) ( Table 2 ).
| Aspirin group (n=464) | Control group (n=434) | Relative risk (95% confidence interval) | P value | |
|---|---|---|---|---|
| Primary outcome | ||||
| Preeclampsia (%) | 78 (16.8) | 74 (17.1) | 0.986 (0.738–1.317) | .924 |
| Secondary outcomes | ||||
| Preeclampsia delivery at <34 gestational wk (%) | 24 (5.2) | 28 (6.5) | 0.802 (0.472–1.361) | .413 |
| Preeclampsia delivery at <37 gestational wk (%) | 46 (9.9) | 46 (10.6) | 0.935 (0.635–1.378) | .735 |
| Preeclampsia delivery at ≥37 gestational wk (%) | 32 (6.9) | 28 (6.5) | 1.070 (0.655–1.745) | .790 |
| Gestation hypertension (%) | 29 (6.2) | 31 (7.1) | 0.875 (0.536–1.427) | .593 |
| HELLP syndrome (%) | 4 (0.9) | 0 | — | — |
| Placental abruption (%) | 45 (9.7) | 40 (9.2) | 1.053 (0.702–1.577) | .805 |
| Postpartum hemorrhage (%) | 30 (6.5) | 23 (5.3) | 1.220 (0.720–2.066) | .459 |
| Fetal distress (%) | 35 (7.5) | 31 (7.1) | 1.056 (0.663–1.681) | .818 |
Secondary outcomes
The treatment effects regarding the secondary outcomes are shown in Tables 2 and 3 . The incidences of maternal outcomes, including preeclampsia at different delivery weeks of gestation (<34 weeks, <37 weeks, and ≥37 weeks), gestational hypertension, HELLP syndrome, placental abruption, and fetal distress, showed no significant difference between the aspirin and the control group. The incidence of postpartum hemorrhage between the aspirin and control groups was not significantly different (6.5% [30/464] vs 5.3% [23/434]; RR, 1.220; 95% CI, 0.720–2.066; P =.459). In addition, there was no significant difference in the incidence of neonatal or fetal outcomes, including preterm baby, fetal or neonatal mortality, fetal abnormality, low birthweight, very low birthweight, SGA, or NICU admission between the aspirin and control groups.
| Aspirin group (n=464) | Control group (n=434) | Relative risk (95% confidence interval) | P value | |
|---|---|---|---|---|
| Gestational age at delivery (wk) a | 37.46±3.20 | 37.28±3.40 | — | .416 |
| Preterm birth b (%) | 79 (17.0) | 79 (18.2) | 0.935 (0.705–1.241) | .644 |
| Miscarriage, stillbirth, or neonatal death (%) | 50 (10.8) | 55 (12.7) | 0.850 (0.593–1.218) | .377 |
| Fetal death with preeclampsia (%) | 7 (1.5) | 11 (2.5) | 0.595 (0.233–1.522) | .273 |
| Perinatal death (%) | 5 (1.1) | 9 (2.1) | 0.520 (0.176–1.538) | .237 |
| Fetal malformation (%) | 13 (2.8) | 19 (4.4) | 0.640 (0.320–1.280) | .207 |
| Neonatal birthweight a , g | 3015.07±744.67 | 3022.94±771.75 | — | .884 |
| Low birthweight a (%) | 74 (17.5) | 60 (15.3) | 1.140 (0.835–1.558) | .409 |
| Very low birthweight (%) a | 24 (5.7) | 27 (6.9) | 0.822 (0.483–1.399) | .470 |
| SGA a , c (%) | 81 (19.1) | 63 (16.1) | 1.189 (0.881–1.603) | .257 |
| Apgar score a | ||||
| 1 min | 9.31±1.12 | 9.40±0.97 | — | .225 |
| 5 min | 9.81±0.60 | 9.86±0.58 | — | .330 |
| NICU admission (%) | 107/424 (25.2) | 77/392 (19.6) | 1.285 (0.992–1.664) | .057 |
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