Low dose aspirin in thePrevention of Recurrent Spontaneous Preterm Labour
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To assess the effectiveness of low dose ASAstarted early in pregnancy as compared to placebo in the prevention ofrecurrent spontaneous preterm birth.
A multicenter double blind placebo controlled randomized trial
Women with a singleton pregnancy with a previousspontaneous preterm birth (in a singleton pregnancy), defined as birth at agestational age between 22 and 37 weeks. Spontaneous preterm birth is definedas a preterm birth following spontaneous contractions with intact membranes orbirth after preterm ruptured membranes. Indicated preterm births for maternalreasons such as preeclampsia or HELLP and for fetal reasons such as IUGR willbe excluded.
Eligible women will be randomized by a web-basedcentral randomization system for low dose ASA 80 mg one tablet a day versusplacebo one tablet a day, preferably taken in the evening. Patients will be counselledfor participation in the trial, comparing ASA use versus placebo, in whichadministration will be initiated between 8 and 16 weeks of gestation and willbe continued up to 36 weeks of gestation or up to (anticipated) preterm birth.
Local protocol for prevention of preterm labourderived from the national guidelines, such as cervical length measurement andif needed cerclage, or administration of progesterone, can be followedalongside the study protocol.
The primary outcome measure will be premature delivery, defined as a GAof less than 37 weeks.
Secondary outcomes will be a composite poor neonatal outcome (including bronchopulmonarydysplasia,periventricular leucomalacia> grade 1, intraventricular hemorrhage> grade 2, necrotizing enterocolitis, retinopathy of prematurity, cultureproven sepsis and perinatal death), number of days on ventilation support, daysof admission on the NICU,convulsions, asphyxia, proven meningitis, pneumothoraxand total days in hospital until 3 months corrected age. Furthermore pretermdelivery < 28 weeks, < 32 weeks, < 34 weeks of GA will be calculated,as well as growth restriction defined as birth weight < p10. Pretermdelivery will be analysed as spontaneous, induced or as a combination. Maternaloutcomes include maternal side effects maternal mortality, maternal morbidity(pregnancy-induced hypertension, preeclampsia, eclampsia, HELLP syndrome,pulmonary oedema, thromboembolic disease, or placental abruption), and majorante- orpost-partum haemorrhage.
Subgroup analyses will be performed for women with a previous preterm birth before andafter 32 weeks GA, contractions with intact membranes versus PPROM and for womentreated with progestagens versus no additional treatment.
A difference in reduction of recurrent PTB from36% to 23% (a reduction of 35%), can be detected if 406 patients are recruited(203 in each arm, beta-error 0.2; alpha-error 0.05).
An economic evaluation will be performed, theaim of the economic evaluation is to relate the costs of ASA in comparison withplacebo in a cost-effectiveness analysis (CEA). The economic evaluation will beperformed from a healthcare perspective. Missing cost and effect data will beimputed using multiple imputation. The primary outcome will be the costs(savings) per pre-term birth prevented. Costeffectiveness acceptability curvesshowing the probability that the intervention is cost-effective in comparisonwith usual care for a range of different ceiling ratios will also be estimated.Adjustment for confounders and effect modifiers will be done if necessary. In abudget impact analysis results from the economic evaluation will beextrapolated to the national level. The costs of ASA are very low, therefore incase of effectiveness, this treatment will in view of the high cost of pretermbirth, generate savings.
Preparation of the study will take 3 months.From data of the national perinatal registration of 2013 we calculated that ina there will be approximately 6850 pregnancies in women with a history ofspontaneous preterm birth in the Netherlands. Part of the women with a latepreterm birth will receive antenatal care from a primary care midwife. Allperinatal centers (n = 10) will participate in the trial, and at least 24secondary hospitals, we expect that approximately 20% will receive antenatalcare in a participating center. Based on our previous experience that 30% ofeligible women will participate in a placebo controlled trial, be included, weestimate that 200 women is reasonable number to be included per year. A maximum of 30 months therefore will beneeded to include all 406 patients. Follow-up and analysis will take 6 months.This makes a total duration of 36 months.
Dr. M.A. de Boer, gynecologist VUmc, Amsterdam(project leader)
Dr. M.A. Oudijk, gynecologist, AMC (principalinvestigator)
Dr. J.E.Bosmans, Assistant Professor, Departmentof Health Sciences and the EMGO Institute for Health and Care Research of theVU University in Amsterdam
Drs. Christiana Naaktgeboren, UMC Utrecht, firstname.lastname@example.org
Contact (researcher)Drs. Anna Landman, researcher,VUmc, email@example.com