Aspirin for the prevention of spontaneous preterm birth
Authors:   , Landman Anadeijda Johanna Elisabeth Marguerita Christina 
Published: January 2023

Chapter 2 comments on the secondary analysis of the MFMU trial assessing low-dose aspirin compared to placebo in nulliparous women. They found a significant reduction in spontaneous preterm birth <34 weeks of gestation. The treatment effect was independent of the time of initiation of therapy (<16 vs ≥16 weeks), while, in the case of preeclampsia, previous studies have shown that it is best to start aspirin prophylaxis before 16 weeks of gestation.

In Chapter 3, we presented the results of the APRIL trial: a multicentre, double-blinded, placebo-controlled randomised trial evaluating low-dose aspirin 80 mg for the prevention of recurrent preterm birth <37 weeks of gestation. 387 women with a singleton pregnancy and a previous spontaneous preterm birth of a singleton between 22 and 37 weeks of gestation were included. The preterm birth rate was 21.2% in the aspirin group and 25.4% in the placebo group; this was not statistically significant (RR 0.83, 95% CI 0.58-1.20, p=0.323).

We performed a cost-effectiveness analysis alongside the APRIL trial, as described in Chapter 4. The mean costs per patient in the aspirin group (€7,076) were lower than in the placebo group (€7,175); mean difference -€99 (95% CI -€2,385 to €2,325). Overall, there was a modest, non-significant, reduction in the occurrence of preterm birth and in health care costs.

In Chapter 5, we compared the effect of aspirin 80 mg and placebo on three platelet function tests (VerifyNow®, Chronolog LTA and Thromboxane B2) in the second (18-22 weeks) and third trimester (28-32 weeks) of pregnancy. A total of 11 women participated: 6 in the aspirin group and 5 in the placebo group. All three platelet function tests showed a markedly reduced platelet activity in the aspirin group compared to the placebo group in the second and third trimester. We concluded aspirin 80 mg has a clear inhibitory effect on platelet function during pregnancy.

In Chapter 6, we performed a systematic review of randomised controlled trials assessing long-term outcome of children who were exposed to low-dose aspirin versus placebo or no treatment during pregnancy. Individual trials reported reduced post-neonatal mortality at 12 months and improved motor function at 18 months. No differences were found in mortality rate; the proportion of children with short stature or low weight; or respiratory, hearing or visual problems at 18 months.

The follow-up age of available randomised controlled trials is limited to 18 months when infants are still at a very early stage of development. Therefore, we are performing follow-up of children born from the APRIL trial at the corrected age of four years. The study protocol is described in Chapter 7. The main outcomes are mildly abnormal (neuro)development as assessed by the Ages and Stages Questionnaire and mildly abnormal behaviour as assessed by the Strengths and Difficulties Questionnaire.

In Chapter 8, we developed a first-trimester prognostic model for spontaneous preterm birth of singletons <37 weeks of gestation in a prospective multicentre cohort of 3695 women. The model included the following predictors: history of preterm birth, nulliparity, maternal age, smoking during pregnancy, a family history of preterm birth, and vaginal blood loss in the first trimester. Model performance after internal validation was poor (AUC 0.69).

Chapter 9 presents the results of a systematic review and meta-analysis evaluating the risk of preterm birth among women with uterine fibroids compared to women without fibroids. Women with fibroids had a higher rate of preterm birth compared to women without fibroids (11.6% versus 9.0%; OR 1.66, 95% CI 1.29-2.14). We encourage further research to clarify this association through prospective and systematic myometrial assessment by ultrasound in early pregnancy.