Long-term outcomes following antenatal exposure to low-dose aspirin: study protocol for the 4-year follow-up of the APRIL randomised controlled trial.

INTRODUCTION: The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age. METHODS AND ANALYSIS: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design. ETHICS AND DISSEMINATION: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Uterine Fibroids Causing Preterm Birth: A New Pathophysiological Hypothesis on the Role of Fibroid Necrosis and Inflammation.

According to recent studies and observations in clinical practice, uterine fibroids increase the risk of preterm birth. There are several theories on the pathogenesis of preterm birth in the presence of fibroids. One theory proclaims that fibroid necrosis leads to preterm birth, though pathophysiological mechanisms have not been described. Necrotic tissue secretes specific cytokines and proteins and we suggest these to be comparable to the inflammatory response leading to spontaneous preterm birth. We hypothesize that fibroid necrosis could induce preterm parturition through a similar inflammatory response. This new hypothesis generates novel perspectives for future research and the development of preventative strategies for preterm birth. Moreover, we emphasize the importance of the recognition of fibroids and especially fibroid necrosis by clinicians during pregnancy.

The risk of preterm birth in women with uterine fibroids: A systematic review and meta-analysis.

BACKGROUND: Fibroids have been identified as a possible risk factor for preterm birth, however, the magnitude of this risk is unclear. Our objective was to determine the risk of total, spontaneous, and medically indicated preterm birth in women with fibroids. METHODS: A literature search was performed on 9 June 2021. We selected studies reporting on preterm birth in women with and without fibroids. Fibroids had to be diagnosed by routine ultrasound before or during pregnancy. Main outcomes were total preterm birth <37, <34, <32, and <28 weeks of gestation, and spontaneous and medically indicated preterm birth. Two authors independently performed study selection, data extraction and quality assessment. We performed quality assessment with the Newcastle-Ottawa scale. Meta-analyses were presented as Odds Ratios (ORs) with 95% Confidence Intervals (95%CIs). MAIN RESULTS: The search yielded 2078 unique articles of which 11 were included. Meta-analysis for preterm birth <37 weeks of gestation included 256,650 singleton deliveries: 12,309 with fibroids and 244,341 without fibroids. Women with fibroids had a higher rate of preterm birth (11.6% versus 9.0%; OR 1.66, 95%CI 1.29-2.14). Fibroids were also associated with preterm birth <34 (OR 1.88, 95%CI 1.34-2.65), <32 (OR 2.03, 95%CI 1.40-2.95) and <28 (OR 2.24, 95%CI 1.45-3.47) weeks of gestation. Data on type of preterm birth was limited: one study showed a significant association of fibroids with spontaneous preterm birth and another with indicated preterm birth. The main limitations of the included studies were the lack of correction for confounders, the risk of ascertainment bias due to possible underreporting of fibroids, and the substantial heterogeneity between studies. CONCLUSIONS: Our results suggest fibroids are associated with an increased risk of preterm birth, with a stronger risk at earlier gestational ages. We encourage further research to clarify the association between fibroids and preterm birth by systematic myometrial assessment in pregnancy. REGISTRATION: Prospero database [CRD42020186976].

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. METHODS AND FINDINGS: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. CONCLUSIONS: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. TRIAL REGISTRATION: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Radioembolization: Is Prophylactic Embolization of Hepaticoenteric Arteries Necessary? A Systematic Review.

PURPOSE: To study the effectiveness of prophylactic embolization of hepaticoenteric arteries to prevent gastrointestinal complications during radioembolization. METHODS: A PubMed, Embase and Cochrane literature search was performed. We included studies assessing both a group of patients with and without embolization. RESULTS: Our search revealed 1401 articles of which title and abstract were screened. Finally, eight studies were included investigating 1237 patients. Of these patients, 456 received embolization of one or more arteries. No difference was seen in the incidence of gastrointestinal complications in patients with prophylactic embolization of the gastroduodenal artery (GDA), right gastric artery (RGA), cystic artery (CA) or hepatic falciform artery (HFA) compared to patients without embolization. Few complications were reported when microspheres were injected distal to the origin of these arteries or when reversed flow of the GDA was present. A high risk of confounding by indication was present because of the non-randomized nature of the included studies. CONCLUSION: It is advisable to restrict embolization to those hepaticoenteric arteries that originate distally or close to the injection site of microspheres. There is no conclusive evidence that embolization of hepaticoenteric arteries influences the risk of complications.