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.