Low Dose Aspirin for Preventing Intrauterine Growth Restriction and Preeclampsia in Sickle Cell Pregnancy (PIPSICKLE): a Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 476
- 试验地点
- 16
- 主要终点
- Number of babies with birth weight below 10th centile for gestational age on the WHO INTERGROWTH-21st birthweight charts, stillbirth or fetal death or miscarriages divided by the total number of babies delivered.
研究概览
简要总结
Pregnancy in sickle cell disease (SCD) is fraught with many complications including preeclampsia (PE) and intrauterine growth restriction (IUGR). Previously, the investigators found an abnormality in prostacyclin-thromboxane ratio in sickle cell pregnant women, a situation that is also found in non-sickle pregnancies with PE and unexplained IUGR. Low dose aspirin (LDA) has been found to reduce the incidence of PE and IUGR in high-risk women due to its reduction of vasoconstrictor thromboxane whilst sparing prostacyclin, in effect "correcting" the ratio. It has been found to be safe for use in pregnancy and is recommended in obstetric guidelines for this use but has not been tested in sickle cell pregnancy. The investigators hypothesize that LDA would reduce the incidence of IUGR and PE in pregnant haemoglobin (Hb)SS women. The investigators also plan to build a machine-learning model to predict severe maternal outcomes in them.
The investigators propose a multi-site, randomized, controlled, double blind trial comparing a daily dose of 100mg aspirin with placebo, from 12 - 28 weeks gestation until 36 weeks. The study sites are three teaching hospitals in Lagos and Ile-Ife, and twelve general hospitals and one federal medical centre within Lagos state, with the coordinating centre at the College of Medicine, University of Lagos (CMUL), Idi-Araba, Lagos. A total of 476 eligible pregnant HbSS and HbSC women will be recruited consecutively and randomly assigned to either group using a web-based app, sealed envelope. Each study group will comprise 238 pregnant women with SCD.
All participants will be followed from recruitment till six weeks postpartum. They will have their body weight, blood pressure and haematocrit checked at each antenatal visit. Their full blood count, vital signs and oxygen saturation will be checked and recorded at each visit. Primary outcome measure will be birth weight below 10th centile for gestational age on INTERGROWTH 21 birthweight charts, and incidence of miscarriage or perinatal death. Analysis will be by intention to treat, and the main treatment effects will be quantified by relative risk with 95% confidence intervals, at a 5% significance level. The investigators plan to develop a prediction model to predict the risk of complications in these women using machine learning. The prediction outcome will be severe maternal outcomes comprising maternal near miss or death.
详细描述
STUDY RATIONALE Sickle cell disease (SCD) especially in pregnancy poses great burden and is thus designated a global public health problem by World Health Organization (WHO) and United Nations. In Nigeria, many SCD women die because of pregnancy complications. The physiological changes in pregnancy aggravate the severity of pregnancy complications in women with SCD. Maternal mortality ratio and perinatal mortality rate in Nigeria till date has remained high. Hypertensive disorders of pregnancy, which includes preeclampsia (PE) is a leading cause of maternal death and intrauterine growth restriction (IUGR) and low birth weight (LBW) are leading causes of perinatal deaths. Pregnancy outcomes in women with SCD follows a variable course and it is thus difficult to identify those who will develop complications during pregnancy. There is thus a need to develop cost-effective strategies to prevent complications in this category of women. However very few randomized controlled trials address their management, and guidelines for their treatment are supported by low quality evidence. Low dose aspirin (LDA) has been found to be beneficial in prevention of preeclampsia in non-SCD pregnant women. The NICE guideline lists several risk factors for preeclampsia for which LDA is recommended but no mention is made of women with SCD who are known to be at high risk of preeclampsia. This research is therefore targeted at determining if drugs such as LDA may be beneficial in reducing the contributions of this genetic condition to maternal and perinatal deaths in a low resource setting like ours, consequently saving economic as well as physical resources.
The aim of this clinical trial is to determine whether daily administration of 100mg LDA from 12 - 28 weeks of gestation till 36 weeks, reduces the risk of IUGR, PE, perinatal deaths or miscarriages and other complications (sickling and non-sickling related) in pregnant HbSS women compared with the use of placebo.
OBJECTIVES
- To determine the effect of the use of LDA during pregnancy in HbSS and HbSC women on the risk of IUGR, perinatal death or miscarriage.
- To determine the effect of the use of LDA during pregnancy in HbSS and HbSC women on the risk of other maternal complications including PE, preterm delivery, number of vaso-occlusive crises, need for blood transfusion, urinary tract infections, respiratory tract infections, acute chest syndrome, retained placenta, placental abruption, and vaginal bleeding.
METHODOLOGY Study design A multi-centre parallel, double blind, superiority randomized controlled trial, with women allocated in a 1:1 ratio into two groups, namely low dose aspirin (LDA) group and placebo group.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double blind design. An unblinded pharmacist does the drug packaging and has the code for drug identification. All other members of the research team and patients are blinded and do not know what each drug is.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Age 18 years and above
- •Singleton fetus
- •Women whose genotypes are Haemoglobin SS or SC.
- •28 weeks gestation or less at recruitment, estimated from the last menstrual period or by an early ultrasound scan.
排除标准
- •Women with associated medical conditions in pregnancy e.g., HIV infection, diabetes mellitus, hypertension, renal disease, sickle nephropathy
- •Multiple pregnancy
- •Hypersensitivity to aspirin
- •History of blood transfusion in the last 3 months
- •Women who participated in the PIPSICKLE trial during their previous pregnancy.
研究组 & 干预措施
Intervention
Low dose aspirin (LDA) group will receive 100mg aspirin daily taken at once just before bedtime from 12 weeks gestational age or enrollment till 36 weeks gestational age.
干预措施: Low-dose aspirin (Drug)
Control
Placebo group will receive one tablet of the placebo which has same shape, size, thickness and colour as the LDA daily taken at once just before bedtime from 12 weeks gestational age or enrollment till 36 weeks gestational age.
干预措施: Placebo (Other)
结局指标
主要结局
Number of babies with birth weight below 10th centile for gestational age on the WHO INTERGROWTH-21st birthweight charts, stillbirth or fetal death or miscarriages divided by the total number of babies delivered.
时间窗: up to seven days after delivery.
Intrauterine growth restriction, perinatal death or miscarriage as a composite outcome.
次要结局
- Number of women that die at any gestational age during pregnancy or within 42 days after delivery from any cause arising from the pregnancy or its management but not from incidental or accidental causes, divided by the total number of participants.(To be measured from randomization until date of death or 6 weeks post-delivery whichever comes first,)
- Number of participants who will develop preeclampsia defined as hypertension and significant proteinuria after 20 weeks gestational age divided by the total number of participants.(To be measured from date of randomization if greater than 20 weeks up till 6 weeks post-delivery if present)
- Number of women delivered before 37 weeks gestational age divided by the total number of participants randomized.(up to preterm delivery.)
- Number of participants who will develop thromboembolism divided by the total number of participants.(To be measured from randomization until date of death or 6 weeks post-delivery whichever comes first,)
- Number of babies who died from 28 weeks gestational age up to seven days post delivery (comprising all still births and early neonatal deaths divided by total births reported as percentage.(from 28 weeks gestational age till seven days post delivery)
- Mean number of sickle cell crises in participants in each arm.(from enrolment till six weeks postpartum.)
- Number requiring blood transfusion.(from enrolment till six weeks postpartum.)
- Number of women with urinary tract infection in each arm.(from enrolment till six weeks postpartum.)
- Number of women with lower respiratory tract infection (pneumonia) in each arm.(from enrolment till six weeks postpartum.)
- Number of women with acute chest syndrome in each arm.(from enrolment till six weeks postpartum.)
- Number of women with retained placenta in each arm.(from enrolment till six weeks postpartum.)
- Number of women with placenta abruptio in each arm.(from enrolment till six weeks postpartum.)
- Number of participants with adverse drug events.(from enrolment 36 weeks gestational age.)