Ganzevoort, Wessel2; Alfirevic, Zarko3; von Dadelszen, Peter3; Kenny, Louise3; Papageorghiou, Aris3; van Wassenaer-Leemhuis, Aleid3; Gluud, Christian1; Mol, Ben Willem3; Baker, Philip N3
1 Copenhagen Trial Unit, Cochranecenteret Rigshospitalet, Rigshospitalet, The Capital Region of Denmark2 Department of Obstetrics and Gynecology, Academic Medical Centre, Room: H4-278, PO BOX 22660, 1100 DD Amsterdam, The Netherlands. email@example.com unknown
Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction - a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis
BACKGROUND: In pregnancies complicated by early-onset extreme fetal growth restriction, there is a high risk of preterm birth and an overall dismal fetal prognosis. Sildenafil has been suggested to improve this prognosis. The first aim of this review is to assess whether sildenafil benefits or harms these babies. The second aim is to analyse if these effects are modified in a clinically meaningful way by factors related to the women or the trial protocol. METHODS/DESIGN: The STRIDER (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction) Individual Participant Data (IPD) Study Group will conduct a prospective IPD and aggregate data systematic review with meta-analysis and trial sequential analysis. The STRIDER IPD Study Group started trial planning and funding applications in 2012. Three trials will be launched in 2014, recruiting for three years. Further trials are planned to commence in 2015.The primary outcome for babies is being alive at term gestation without evidence of serious adverse neonatal outcome. The latter is defined as severe central nervous system injury (severe intraventricular haemorrhage (grade 3 and 4) or cystic periventricular leukomalacia, demonstrated by ultrasound and/or magnetic resonance imaging) or other severe morbidity (bronchopulmonary dysplasia, retinopathy of prematurity requiring treatment, or necrotising enterocolitis requiring surgery). The secondary outcomes are improved fetal growth velocity assessed by ultrasound abdominal circumference measurements, gestational age and birth weight (centile) at delivery, and age-adequate performance on the two-year Bayley scales of infant and toddler development-III (composite cognitive score and composite motor score). Subgroup and sensitivity analyses in the IPD meta-analysis include assessment of the influence of several patient characteristics: an abnormal or normal serum level of placental growth factor, absent/reversed umbilical arterial end diastolic flow at commencement of treatment, and other patient characteristics available at baseline such as gestational age and estimated fetal weight. The secondary outcomes for mothers include co-incidence and severity of the maternal syndrome of pre-eclampsia, mortality, and other serious adverse events. DISCUSSION: Trials are expected to start in 2013-2014 and end in 2016-2017. Data analyses of individual trials are expected to finish in 2019. Given the pre-planned and agreed IPD protocol, these results should be available in 2020.