|Year : 2020 | Volume
| Issue : 3 | Page : 184-190
The application of aspirin in pregnancy-related complications
Lu-Yu Ruan1, Zhen-Zhen Lai1, Hui-Li Yang1, Shao-Liang Yang1, Si-Yao Ha1, Jia-Wei Shi1, Hui-Hui Shen1, Ming-Qing Li2
1 Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
2 1Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011; NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 230032, China
|Date of Submission||08-Feb-2020|
|Date of Decision||29-Apr-2020|
|Date of Acceptance||30-Jun-2020|
|Date of Web Publication||29-Sep-2020|
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, No. 1326, Pingliang Road, Shanghai 200080
Source of Support: None, Conflict of Interest: None
Aspirin, one of the most widely applied medicines, not only possesses the effects on reducing fever, anti-vascular hyperplasia, and anti-inflammation, but also has the capacity of preventing platelet aggregation. So far, it is acceptable to adopt aspirin, especially low-dose aspirin (LDA), to prevent pregnancy-related complications, such as pregnancy complicated by antiphospholipid syndrome, systemic lupus erythematosus, or preeclampsia; unexplained recurrent spontaneous abortion; fetal growth restriction; and preterm birth. In this article, we reviewed the possible mechanism of action and applications of aspirin in these pregnancy-related complications.
Keywords: Abortion; Antiphospholipid Antibodies; Aspirin; Fetal Growth Restriction; Preeclampsia; Pregnancy; Preterm Birth; Systemic Lupus Erythematosus
|How to cite this article:|
Ruan LY, Lai ZZ, Yang HL, Yang SL, Ha SY, Shi JW, Shen HH, Li MQ. The application of aspirin in pregnancy-related complications. Reprod Dev Med 2020;4:184-90
|How to cite this URL:|
Ruan LY, Lai ZZ, Yang HL, Yang SL, Ha SY, Shi JW, Shen HH, Li MQ. The application of aspirin in pregnancy-related complications. Reprod Dev Med [serial online] 2020 [cited 2020 Oct 28];4:184-90. Available from: https://www.repdevmed.org/text.asp?2020/4/3/184/296548
| Introduction|| |
Aspirin, acetylsalicylic acid, is one of the most extensively used medicines. It exerts antipyretic (fever reducing), anti-analgesic, and anti-inflammatory effects and possesses antiplatelet properties. It was available as early as 1,500 years BC. At that time, Egyptians were the first to use myrtle bark to reduce pain and treat rheumatism. One thousand years later, Hippocrates identified that the leaves and bark of the willow had fever-relieving and pain-reducing properties. Subsequently, Buchner purified salicin and suggested that aspirin was its main antipyretic component in 1828. Then, alicylic acid was first synthesized from salicin by Piria in 1838. Following this, acetylsalicylic acid was extracted by Hoffman in 1897, making it stable and pure in chemistry. In 1899, acetylsalicylic acid was pharmaceutically described as a painkilling and anti-inflammatory compound. To date, it is popularly used in patients with coronaropathy and vascular diseases, placental vascular disease, and various types of cancers. In addition, low-dose aspirin (LDA) is often considered useful to treat pregnancy-related complications such as pregnancy complicated by antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), or preeclampsia (PE); preterm birth; unexplained recurrent spontaneous abortion (URSA); and fetal growth restriction (FGR).
The pathogenesis of most of these conditions is related to placental dysfunctions that may involve the enzymatic targets of aspirin. Different mechanisms may underlie different complications. The most known mechanisms are closely related to the metabolism of arachidonic acid at maternal–fetal interface, where many of the problems of pregnancy seem to arise. In general, via the action of the cyclooxygenase 1 (COX-1) enzyme, arachidonic acid is converted to prostanoids (prostacyclins, prostaglandins [PGs], and thromboxanes [TXs]). Classically, aspirin can inhibit the production of these molecules by inhibiting COX-1 enzyme, thereby reducing inflammation, which is the most recognized effect of aspirin. In addition, due to the presence of the reactive acetate group, aspirin can acetylate COX-2 to change its substrate specificity, resulting in the formation of the arachidonic acid product 15R-hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15R-HETE). The action of 5-lipoxygenase (5-LO) on 15R-HETE in leukocytes raises lipoxins (aspirin-triggered lipoxins [ATLs])., In APS women with antiphospholipid antibodies (aPLs), ATL has the ability to inhibit the influence of aPLs on trophoblast cells. In addition, aspirin depresses thromboxane A2 (TXA2) secretion, without altering PGI2 production, an action beneficial for PE prevention.
For different complications, there may be other underlying mechanisms that remain unknown. It is recommended to use LDA to treat these complications. However, the recommended dose and time to initiate treatment differ among different cases. Moreover, no consensus has been reached so far. Thus, controlled trials and clinical practice are needed to confirm the working hypotheses on the modes and degrees of aspirin action as well as to explore new therapies for reducing the rate of pregnancy-related complications.
| Aspirin and Pregnancy With Antiphospholipid Syndrome|| |
As one of the autoimmune diseases, APS is characterized by the existence of antibodies against specific normal body constituents, for example, PLs, lupus anticoagulant (LA), anti-β2-glycoprotein 1 antibodies, and anticardiolipin antibodies (ACAs), among other antibodies. According to a recent retrospective study, aPLs exist in 1%–5% of the population, although only a minority of this population has been diagnosed with APS.
Diagnosis of APS mainly includes laboratory criteria and clinical criteria. Laboratory criteria are for the existence in serum or plasma of LA, and the ACA of the immunoglobulin G (IgG) and/or IgM isotype or the anti-β2-glycoprotein I of the IgG and/or IgM isotype. Clinical criteria include vascular thrombosis and pregnancy morbidity, for example, fetal death, preterm birth, unexplained consecutive spontaneous pregnancy losses, and intrauterine growth restriction (IUGR).
The presence of aPLs leads to several clinical manifestations which are results of two main aspects of aPLs. On the one hand, aPLs can inhibit the growth, proliferation, differentiation, and migration of trophoblast cells.,, In addition, they can destroy the interaction of trophoblast cells with the uterine spiral arteries endothelium, leading to the fetal loss in the first trimester.,, On the other hand, aPLs may lead to endometrial inflammation, thrombosis, or both. aPLs activate the endothelium, platelets, and monocytes as well as the complement system, and inhibit anticoagulant proteins, resulting in the initiation of inflammatory phenomena. Furthermore, aPLs have a unique capacity to increase thrombosis formation in the arteries, veins, and small vessels. Thrombotic and inflammatory changes lead to placenta dysfunction, ultimately resulting in obstetrical manifestations, including PE, IUGR, and stillbirths in the third trimester.
At present, aspirin, especially LDA, is one of the generally used drugs for obstetric APS pregnant women. The underlying mechanism of LDA centers on the effects of aPLs. Classically, aspirin can block the effect of aPLs by inhibiting COX-1 enzyme, which reduces inflammation. In addition, lipoxins can prevent the influence of aPLs on trophoblasts. First, ATLs prevent the apL-induced decrease in trophoblast migration, likely by improving interleukin (IL)-6) production by trophoblast cells. Second, lipoxins can stabilize the interaction between trophoblasts and uterine spiral artery endothelium, which further enhances placental functions. However, the properties of rapid metabolism and inactivation of lipoxins make their use controversial in some clinical scenarios and difficult to study. Thus, the exact mechanism must be further explored. In summary, aspirin use is a potential therapy for an APS pregnant woman, but the exact mechanism of LDA actions must be further explored.
As per the instructions,,, 75–100 mg/d (vs. 250–1,000 mg/d for pain or analgesia) is the most widely used dose of aspirin, hence LDA. However, different treatment plans are required for different cases. For women with APS who become pregnant for the first time, or women with previous normal pregnancies, or where pregnancy is complicated by aPL, with no history of pregnancy morbidity or thrombosis, there is no need for a specific treatment. They may be treated with LDA. For women without previous thrombosis but with a history of early miscarriage, LDA may be used as monotherapy or low-molecular-weight heparin (LMWH) in prophylactic doses. For women with previous miscarriage or of a history of pregnancy with PE or placental insufficiency, LDA plus prophylactic doses of LMWH are recommended. For APS women with previous thrombosis, LDA should be used alongside LMWH in therapeutic doses. Otherwise, for women who carry aPLs without manifestations, prophylactic doses of aspirin (75–100 mg daily) are needed. Beyond these situations, using LDA as monotherapy or with heparin should be addressed case wise. Whether LDA combined with unfractionated heparin or LMWH could improve the final results in situ ations of APS or first-trimester pregnancy loss is a debatable point that demands further investigation.,,
| Aspirin and Preeclampsia|| |
PE is of typical features by the presence of proteinuria and hypertension. Hypertension is defined as after 20 weeks of gestation, systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. In the absence of proteinuria, PE is usually defined by the presence of hypertension with another dysfunction such as thrombocytopenia, renal failure, liver insufficiency, pneumonedema, cerebral abnormality, or visual disturbances.,,
Placental dysfunctions are the key pathognomonic features of PE and are caused by poor trophoblast invasion and spiral artery remodeling, leading to inflammation and oxidative stress of endometrial cells. In turn, inflammation and oxidative stress result in further clinical manifestations of PE. There is, moreover, an association between aPLs and early severe PE, i.e., 20% of patients with severe PE are positive for aPLs.
LDA has long been used as a prophylactic therapy to prevent PE. However, whether it is effective in reducing the rate of PE remains controversial. It is widely accepted that LDA is useful for patients with high risk of PE., It is believed that using LDA may lead to a decreased incidence of PE in high-risk women for the condition. The underlying mechanism of LDA action mainly alters the balance between platelet TXA2 and endothelial PGI2. In general, arachidonic acid is converted by COX-1 into PGH2, whereas COX-2, induced by inflammatory, hypoxia, or oxidative stress, helps convert arachidonic acid first into PGH2 and then to PGI2 (and other PGs [PGE2, PGD2, and PGF2α]) in endothelial cells, and to TXA2 in platelets. TXA2 causes vasoconstriction, whereas PGI2 is responsible for vasodilation; PGE2 or PGF2α regulates blood pressure by vasoconstriction.
In normal pregnancy, the rate of TXA2 and PGI2 production is normal. However, in pregnant women with PE, there is a marked increase in TXA2 production, with a sharp drop in PGI2 production, accompanied by the rising levels of PGE2 and PGF2α., The resulting imbalance manifests in the clinical features of PE. Aspirin inhibits TXA2 and PGE2 secretion without altering PGI2 production. After conversion into salicylic acid, aspirin acetylates the reactive serine of COX enzyme and occupies substrate-binding sites that prevent arachidonic acid binding. However, because of the very short half-life of aspirin, the physiological state of the endothelium shows quick recovery. This ensures basal production of PGI2. In contrast, platelets, being anuclear and lacking controlled protein synthesis, cannot compensate for the covalent inactivation of the COX enzyme molecules present, resulting in the reduction of TXA2 in synthesis.
LDA regulates cytokine production and increases pro-angiogenic protein placental growth factor production to enhance the invasion and migration of trophoblast into the arteries.
It should be noted that the optimal dose and timing of aspirin administration remain controversial. When the dose is low, aspirin only inhibits COX-1; only at a relatively higher dose does aspirin restrain both COX-2 and COX-1. It appears that COX-2 is more important than COX-1 in pathological pregnancy; thus, aspirin dose should be carefully considered. Cumulative meta-analyses have confirmed that when aspirin is initiated no more than 16 weeks of gestation, with a daily dose of more than 100 mg, there is a significant beneficial effect among women at high-risk PE.,,,, In contrast, according to the guideline criteria of the US Preventive Services Task Force (USPSTF), it is proposed that LDA (81 mg/d) should be initiated in high PE risk women after 12 weeks of gestation. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine later added that for high PE risk patients, those with previous PE accompanied by adverse outcomes such as renal diseases, Type 1 or 2 diabetes, autoimmune diseases, chronic hypertension, or multifetal gestation, the application of LDA in 81 mg daily should be started at 12 weeks and no more than 28 weeks of gestation, optimally before 16 weeks. Regarding risk assessment, the USPSTF lists several high-risk factors and suggests that LDA should be used for women with more than one of these factors. Notably, obesity, nulliparity, age ≥35 years, and a family PE history are all moderate risk factors, and a history of uncomplicated term delivery is one of the low-risk factors. The USPSTF also recommends that for pregnant women with more than one of the above-mentioned moderate risk factors, LDA should be considered, whereas LDA is not suitable for those with only low-risk factors.
The ACOG has made several other recommendations. Without risk factors, it is not proposed to apply LDA for the prior unexplained stillbirth, FGR, spontaneous preterm birth, or early pregnancy loss.
Regarding the harmful effects of LDA, it is considered that the use of LDA does not give rise to placental abruption, postpartum hemorrhage, or intracranial bleeding of the fetus; thus, LDA is considered relatively safe during pregnancy. However, aspirin allergy or aspirin-induced acute bronchospasm, hypersensitivity to other salicylates or nonsteroidal anti-inflammatory drugs, and presence of nasal polyps are the few absolute contraindications. Relative contraindications include a history of severe hepatic dysfunction, gastrointestinal bleeding, or active peptic ulcer disease. In summary, using LDA at the optimum time and dose for high or moderate PE risk women may be a suitable prophylactic therapy.
| Aspirin and Pregnancy Complicated by Systemic Lupus Erythematosus|| |
SLE has a characteristic of the overexpression of levels of Th2-derived cytokines, such as IL-10 and IL-6, which help stimulate the Th0 differentiating into Th2 cells. For many years, it has not been recommended for women with SLE, particularly with kidney involvement, to become pregnant. Although pregnancy is no longer impossible for SLE women, it is still considered a dangerous condition for both the fetus and mother due to the increased risk of SLE flare. During pregnancy, SLE activity is increased, which further increases the risk of several pregnancy-related complications, including PE, spontaneous abortion, and preterm birth, as well as kidney and heart diseases. The use of LDA is advised for all chronic renal disease pregnant women. Due to the higher PE risk in SLE patients, compared with those with normal pregnancy, the use of LDA is recommended. LDA should be used before conception and throughout pregnancy to decrease the risk of PE, especially for women with positive lupus nephritis or aPL titers. Women with SLE are similar to those with APS regarding the presence of aPLs. In addition, LDA may prevent cardiovascular events in women with SLE. Therefore, aspirin can be considered for all women with SLE. The use of LDA is primarily indicated for arterial thrombosis in women with SLE. However, whether the dose and time of aspirin use for women with SLE are the same as those for women with PE or with APS remains to be determined.
| Aspirin and Unexplained Recurrent Spontaneous Abortion|| |
Spontaneous abortion means fetal loss occurring no more than 28 weeks of gestation, with the weight of fetus being <1,000 g. When this happens no more than 12 weeks of gestation, it is defined as early abortion, and when it occurs after 12 weeks of gestation, it is defined as late abortion. Experiencing more than three miscarriages is classified as recurrent miscarriage. The definition of recurrent pregnancy loss (RPL) has not been agreed upon. According to the guidelines of the European Society of Human Reproduction and Embryology (ESHRE), RPL or RSA is the miscarriage of two or more pregnancies before 24 weeks of gestation. The Practice Committee of the American Society for Reproductive Medicine (ASRM) termed RPL as two or more unsuccessful pregnancies. However, the ASRM guideline does not mention a frequency limit. The guidelines of ESHRE and ASRM consider that two abortions, considering diagnostic findings as well, fully meet the standards of RPL. However, not all guideline group members of ESHRE agreed to this definition. The guideline of the Royal College Obstetricians and Gynaecologists considers that three abortions meet the definition of recurrence.
The risk factors involved in RSA are varied and include autoimmunity, coagulation, genetic abnormality, malnutrition, and other factors. APS is one of the most general incentives of RSA in the presence of aPLs. In women with RSA, the prevalence of aPLs is three times as that in normal women,, and aPLs are more likely to lead to late pregnancy abortion. In cases of RSA, aPLs may bind to trophoblasts to increase their apoptosis, decrease their fusion, and impair their invasion of trophoblasts; aspirin may contribute to treatment in such cases, as mentioned above.
Many researchers wonder whether LDA should be used as monotherapy or with heparin or with glucocorticoids. A randomized trial by Rai et al. demonstrated that low-dose aspirin (75 mg) combined with heparin (10,000 IU/day) showed a higher live birth rate than using aspirin as monotherapy in women with RSA induced by APA., In addition, combined therapy failed to achieve an improved pregnancy outcome if the dose of aspirin was too low (50 mg). Adding glucocorticoid or not remains controversial. Laskin et al. reported that aspirin with prednisone not only fails to improve live birth rate, but may also result in prematurity, gestational hypertension, and diabetes mellitus. In contrast, a study carried out by Geva et al. found that combining aspirin with prednisone before ovulation induction helped to decrease the rate of pregnancy loss, without increasing the risk of pregnancy complications. Clearly, more studies are needed to explore and evaluate efficient treatment.
The exact underlying cause in >50% of RSA cases is unknown; thus, it is termed unexplained or idiopathic URSA.
Currently, there are few effective treatments for URSA, making further treatment investigations vital for enhancing successful pregnancy in such cases. Because of the antiplatelet properties of aspirin, many researchers have wondered whether aspirin might be effective in raising successful pregnancy rate among URSA women. So far, aspirin may not be effective in woman with URSA as no evidence has been provided to approve the effectiveness of aspirin in these women. A randomized controlled trial showed no obvious difference between the effects of aspirin and placebo regarding live birth rates. de Jong et al. also found that irrespective of the existence of inherited thrombophilia, there was no obvious benefit of aspirin treatment in women with URSA. In addition, they investigated the effects of aspirin alone, LMWH alone, and aspirin with LMWH in women with URSA and found no significant difference compared with no treatment. Immune, coagulation, and nutrition were the main parameters examined; a combination of immunologic therapy, anticoagulant, and nutrition supplementation was taken into consideration. Aspirin depresses the aggregation of platelet and promotes coagulation; folic acid is beneficial for preventing neural tube malformation; and rednisone, a glucocorticoid, prevents maternal immune rejection. Administration of any these treatments alone did not raise the live birth rate of URSA women.,, On the contrary, a combination of aspirin (100 mg/day), prednisone (5 mg/day), and multivitamin triple therapy was related to a higher successful treatment rate, rather than the rate of a successful pregnancy, according to a cohort study by Ou et al. In their study, the combination group had the similar rate of a successful pregnancy (the number of pregnancies divided by the total number of women), but had a higher successful treatment rate (successful treatment was defined as the embryo and embryonic heart were obvious at 12 weeks of gestation, the thickness of nuchal translucency was no more than 2.5 mm, and the size was consistent with gestational day, along with no obvious malformations), making it a promising subject for research. However, the underlying mechanism and safety of combining multiple drugs to target various potential causes of URSA still remains unclear, more studies are needed to carry out.
| Aspirin and Fetal Growth Restriction|| |
FGR, also called IUGR, is defined as a fetus failing to fulfill its potential of growth., It is a common pregnancy-related complication and is associated with various pathologic outcomes, especially placenta-related diseases such as PE and stillbirth.,
Currently, a consensus has not been reached for the etiology and diagnostic criteria of FGR as it is difficult to measure fetus growth potential. In addition, one may not be able to differentiate between constitutionally small fetuses and FGR fetuses. FGR may be induced by several factors including placental insufficiency, maternal disease, fetal factors, and environmental toxins (e.g., smoking). The most common cause may be related to uteroplacental insufficiency, a condition related to inadequate placental formation or to placental inflammation, either of which may respond to the use of aspirin. Classically, aspirin suppresses COX-1 and COX-2 enzyme, causing a reduced production of PGs and TXs and further inhibition of platelet aggregation. In addition, aspirin induces vascular endothelial cells to release nitric oxide by acetylating endothelial nitric oxide synthase. In addition, aspirin reduces oxidative stress, injury, and inflammation by inducing the heme oxygenase-1 of endothelial cells to increase heme catabolism. For high FGR risk women, most guidelines and some experts advocate the use of aspirin at a 100–150 mg daily dose, and it is recommended to start this treatment at no more than 16 weeks of gestation.,,, In addition, some studies have indicated that the action on blood pressure by aspirin lies on the time of administration. Aspirin administration in the evening, rather than in the morning, is beneficial for reducing ambulatory blood pressure. Thus, initiated before 16 weeks of gestation, an evening dose of 100–150 mg aspirin may reduce the risk of FGR. However, it still remains controversial, according to the guideline from ACOG in 2018, in women showing FGR with the absence of risk factors for PE, it is not recommended to apply LDA as a preventive treatment for lack of evidence in women with isolated histories of FGR. In contrast, LDA may reduce the risk of FGR for women at risk of PE. Thus, there is short of evidences to support the application of aspirin to prevent FGR, therefore further study is required.,
| Aspirin and Preterm Birth|| |
Preterm birth means fetus is born no more than 37 weeks of gestation, which is a main complication affecting many pregnancies. Preterm birth contributes to perinatal morbidity and mortality, and further leads to several chronic medical complications.,,,
Numerous clinical data indicate that using LDA may decrease the preterm birth rate, especially before 16 weeks of gestation, probably because LDA cut downs the risk of FGR, PE, and other diseases caused by placental dysfunction. Additional, compelling evidence shows that PGs play a key role in the initiation and progression of labor for inducing myometrial contractility and regulating extracellular matrix metabolism related to cervical ripening. In general, chorion acts as a protective barrier to preventing primary PGs from passing to the underlying myometrium or decidual tissue, with the high activity of 15-hydroxyprostaglandin dehydrogenase (PGDH). However, the low activity of PGDH in preterm labor may result in barrier damage, ultimately provoking premature birth. Although the relation between PGDH and aspirin is unclear, this may provide a new idea to study.
LDA may also be effective in spontaneous preterm labor,, but it is difficult to make a distinction between its effect on medically indicated preterm birth with its positive actions on PE and other diseases and spontaneous preterm birth, which requires further study. One study found that LDA is related with a decreased spontaneous preterm birth rate for women without other pregnancy complications before 34 weeks of gestation, which suggests a new, but unstudied, treatment option. It has been reported that LDA may also prevent recurrent spontaneous preterm birth. The function of aspirin on reversing placental abnormality is associated with the benefit of aspirin for medically indicated preterm birth as mentioned above; however, aspirin may exhibit an additional effect on spontaneous preterm birth as some researchers speculate that the aspirin may exert its anti-inflammatory role throughout the pregnancy, providing a new option for the underlying mechanism of aspirin's effect on spontaneous preterm birth. Controlled trials and clinical practice are needed to confirm these hypotheses and explore other therapies for reducing overall preterm birth rate.
| Summary and Perspective|| |
Aspirin inhibits platelet aggregation and is, therefore, widely used to treat many pregnancy-related complications such as APS, PE, SLE, FGR, and preterm birth. Current clinical researchers have found that aspirin may improve the pregnancy outcomes complicated by APS, PE, and SLE; FGR; and preterm birth. Nevertheless, the exact underlying mechanism remains unclear, especially the effect of aspirin on the functional cells at the maternal–fetal interface, such as trophoblasts, endothelial cells, or other immunological cells. As is well known, aspirin is an inhibitor of COX-1/COX-2, and thereby disturbs the metabolism of arachidonic acid, which plays a pivotal role in aspirin efficiency. Aspirin reduces the production of TXA2 and PGE2, thereby decreasing the rate of TXA2 and PGI2 production during PE. In addition, aspirin acetylates COX-2, changing its substrate specificity, so it generates 15R-hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15R-HETE) rather than prostanoids. With the action of 5-lipoxygenase (5-LO) on leukocytes, aspirin raises lipoxins (ATLs), which diminish the effect of aPL in APS women, ultimately improving the live birth rate. Accumulating studies indicate that COX-2, rather than COX-1, may be more closely linked with pathological pregnancy. In summary, the biological functions of aspirin at the maternal–fetal interface require further study. More insight into the underlying mechanisms of aspirin's effects will further clarify and improve the rationale and standardization of aspirin treatment for pregnancy-related complications.
Financial support and sponsorship
This study was supported by the Program of the National Natural Science Foundation of China (No. 31970798, 31671200); Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (CX2017-2); and the Program for Zhuoxue of Fudan University, China.
Conflicts of interest
There are no conflicts of interest.
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