Investigating the role of early low-dose aspirin in diabetes: A phase III multicentre double-blinded placebo-controlled randomised trial of aspirin therapy initiated in the first trimester of diabetes pregnancy

Abstract

BackgroundPreeclampsia, preterm birth and low birth weight represent key contributing factors to perinatal morbidity and mortality. Pregnancies complicated by type 1 and type 2 diabetes are at increased risk of these complications, which are purported to be largely attributed to placental dysfunction. Studies investigating a potential role for aspirin therapy in optimizing perinatal outcome have consistently failed to demonstrate a benefit among women with pre-existing diabetes, and yet widespread aspirin administration has become common practice in many centres. This study seeks to examine the effect of aspirin therapy, administered from the first trimester until 36 weeks gestation, on perinatal outcome in women with established pre-pregnancy diabetes. Our hypothesis is that aspirin therapy will reduce complications mediated by placental dysfunction, and improve perinatal outcomes.MethodsThis phase III double-blinded, placebo-controlled randomized clinical trial will be conducted in seven tertiary-level perinatology centres in Ireland. Consenting participants who meet all eligibility criteria will be allocated randomly to either aspirin 150 mg once daily or matching placebo, commenced between 11 + 0 and 13 + 6 weeks. Allocation will take place electronically using software by Clininfo with randomization tables provided by the trial biostatistician. The primary outcome will be a composite clinical measure of placental dysfunction (preeclampsia, preterm birth before 34 weeks, birthweight below the 10th centile or perinatal mortality). This trial has been set up such that it is parallel in design and is a superiority study. No participants have been recruited yet. The trial has been registered with Eudra Clinical Trials - EudraCT Number 2018-000770-29. Funding for this trial was granted by the Health research Board (HRB) 1/9/2017(DIFA-2017-026).DiscussionAspirin therapy has been investigated for the prevention of preeclampsia owing to its reduction on thromboxane production. Previous studies have failed to demonstrate a beneficial effect of aspirin on perinatal outcome amongst women with type I or type II diabetes. It is plausible that the failure to observe benefit to date, among the limited aspirin studies that have included participants with diabetes, may be a consequence of aspirin initiation too late in pregnancy to exert any effect on placentation. We believe that if aspirin is to be used for the prevention of placental dysfunction, it must be initiated before the second active phase of trophoblast invasion, which takes place from 14 weeks’ gestation onwards. No randomized trials investigating the role of aspirin in prevention of preeclampsia in pregnancies complicated by diabetes have previously initiated treatment in the first trimester, the gestational period at which it is most likely to exert an effect on placentation.

A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study

“…The results of the systematic review are shown in Figure S1. Of the 1475 potentially relevant studies, 67 16,17,23–87 fulfilled the inclusion criteria (Table 1). Two hundred and ten outcomes were extracted from the studies.…”

Aspirin for the prevention of pre‐eclampsia in women with pre‐existing diabetes: Systematic review

“…We suggest there is a need for further trials within this high-risk subgroup of women, particularly addressing issues around optimal aspirin dosage requirements and the possible implications of differing stages of disease, comorbidities and type 1 vs type 2 DM on effectiveness of prophylaxis. A multicentre phase III RCT in Ireland is underway and due for recruitment completion in early 2022, 40 of which we will eagerly await results.…”

Glycemic control and fetal growth of women with diabetes mellitus and subsequent hypertensive disorders of pregnancy

“…The study of the role of low-dose aspirin therapy in preventing preeclampsia that included a subgroup of pregnant women with preexisting DM failed to demonstrate a benefit among women with preexisting DM, and the women were all recruited in the second trimester [50]. In a recent phase III double-blinded, placebo-controlled randomized multicenter clinical trial conducted in Ireland, researchers examined the effect of low-dose aspirin therapy from the first trimester until 36 GW on perinatal outcome in women with established pre-pregnancy DM, hypothesizing that aspirin therapy will reduce complications mediated by placental dysfunction and improve perinatal outcomes [51]. Low-dose aspirin therapy to prevent the onset of preeclampsia in pregnant women with DM might decrease the onset of FGR as a second-order effect.…”