Interpretations
PE is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is a significant cause of maternal and perinatal morbidity and mortality, particularly when of early-onset. The basic pathophysiology of the condition is still poorly understood but there is evidence that poor trophoblast invasion of the decidua-myometrium with the suboptimal remodeling of the maternal spiral arteries and an imbalance of angiogenic / anti-angiogenic proteins leading to an inflammatory response, endothelium dysfunction, increased platelet aggregation predisposing to thrombosis and placental infarcts. Aspirin, at a daily dose as low as 60mg, selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation in pregnancy.19 Subsequent to this finding, large meta-analyses and systematic reviews have consistently shown LDA to be effective in reducing the incidence of PE,20-24 the benefits are generally modest and ideal candidates to receive LDA are not well-defined. Recently, the Aspirin for Evidence-based Preeclampsia Prevention (ASPRE) trial (in singleton pregnancy) has demonstrated that aspirin at a daily dose of 150 mg, initiated before 16 weeks of gestational age, and given at night to a high-risk population, identified by a combined first-trimester screening test, reduces the incidence of preterm pre-eclampsia by 62%.25 A secondary analysis of the ASPRE trial data also demonstrated a reduction in the length of stay in the neonatal intensive care unit by 68%, compared with placebo, mainly due to a reduction in births before 32 weeks of gestational age with preeclampsia.26
Different national guidelines have varying recommendations for low dose aspirin prophylaxis in twin pregnancy. The American College of Obstetrician & Gynecologist recommendations13recommends low dose aspirin (81mg/day) initiated between 12 weeks and 28 weeks (optimally before 16 weeks) until delivery, in multifetal gestations (as a high-risk factor). The NICE Guidelines published in the UK27 recommends prophylactic low dose aspirin (75 – 150mg/day) from 12 weeks until the birth of the baby if it is a first pregnancy, the mother is 40 years or older, has a pregnancy interval of 10 years, has a body mass index of> 35kg/m2 or a family history of pre-eclampsia in twin or triplet pregnancies. More recently, A prospective study in twin pregnancy randomizing women to 100mg/day aspirin versus placebo before 16 weeks noted an overall reduction in pre-eclampsia from 16% to 6% respectively (OR 0.32, 95%CI 0.12-0.82) (a result that was increased in the cohort of twin pregnancies with high hCG levels (threshold of 29.96iu/mL)).28
The efficacy of LDA for prophylaxis against the development of PE in singletons is proven, especially in ’high-risk pregnancies’, but the underlying mechanisms of action are unknown. As we know, PE was mainly induced by ischemia-hypoxia of the placenta. Soluble fms-like tyrosine kinase 1 (sFlt-1) would be released by trophoblast cells when the environment was anoxic, and ischemia-hypoxia would be aggravated by high levels of sFlt-1. Recently, several studies focused on the mechanism of aspirin acting on trophoblast cells. The release of sFlt-1 could be inhibited by aspirin through diverse pathways, and the ischemia-hypoxia of the placenta would be alleviated.29-32 It has been fully reported that the average sFlt-1 level and the sFlt-1/PlGF ratio were higher in twin pregnancies than singleton pregnancies and indicated that the more impairment to maternal vascular functions.33-35 Thus, for twin pregnancies, it is more essential to protect maternal vessels. The mechanism of aspirin mentioned above provides bases for the treatment of PE and SGA, but its efficacy in multiple gestations was still uncertain because of poor clinical evidence. A meta-analysis contained 6 RCTs and 898 pregnancies have shown that using LDA can significantly reduce the risk of PE in multiple gestations but it concluded the evidence was at low levels because of the limitation of each RCT.36 The occurrence of PE in our study was lower in LDA-treated mothers and the results were consistent with Euser et al.28
Whether the usage of aspirin could reduce SGA has been a matter of debate.36-38 Bergeron et al.36 focused on multiple gestations, concluded that the risk of SGA was not decreased by LDA (RR:1.09, 95% CI: 0.80-1.47). But in another meta-analysis for singletons, the early initiated LDA could reduce the odds of SGA (RR:0.47, 95% CI: 0.30-0.74).37 However, our data only presented a possible reduction of SGA by using LDA and this conclusion still needs further studies.
The onset of and PTB remains multifactorial with infection or inflammation, uterine overdistention, or endocrine and immunological disorders.39-41Ischemia of placenta and vascular disorders have also been shown to contribute to the pathogenesis of PTB.42, 43 Aspirin could down-regulate many inflammatory factors, and improve blood supply in the placenta; thus, aspirin could theoretically lower the incidence of PTB. And in clinical practice, aspirin showed strong benefits in singletons preventing PTB.10, 44, 45 In Andrikopoulou’s study, they found that LDA was associated with a decrease only in <34w PTB in singletons.10 Another RCT finished by Allshouse et al. investigated aspirin did not work in preventing PPROM or preterm birth in singletons.44 A recent double-blind RCT has proved LDA could reduce the risk of PTB and <34w PTB.45Although the evidence in singletons was strong, there was not sufficient evidence about LDA in protecting PTB in twins. Our findings suggested that LDA could decrease the occurrence of preterm birth, which was accorded with singleton RCT trials.