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Flow parameters and fetal growth in the FRUIT-RCT: Fractionated heparin in women with Utero-placental Insufficiency and Thrombophilia

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for the full-text of this Thesis please e-mail the CMB: Introduction: Hypertensive disorders (HD) of pregnancy and small-for-gestational age (SGA) infants are the most common cause of utero-placental insufficiency and cause maternal and perinatal morbidity and mortality. HD and SGA infants often recur and are associated with inheritable thrombophilia. Aspirin reduces the risk of recurrence. Recently the FRUIT-RCT demonstrated that low-molecular-weight heparin (LMWH), when added to aspirin, did have a positive effect on the primary outcome recurrent early onset HD (HD <34 weeks) and had no effect on total HD. There was also no effect on the secondary outcome neonatal SGA. The FRUIT-RCT was performed with women with prior HD/SGA who delivered before 34 weeks and had inheritable thrombophilia. This study will focus on the secondary outcomes flow of the uterine artery, flow of the umbilical artery and fetal growth. Abnormal uterine and umbilical artery blood flows are reliable indicators for a change in fetal well being and maternal development of HD. Deflection of the fetal growth curve has major consequences for the neurodevelopment of the child. The fetal growth will be evaluated for different references (Skjaerven; based on a Norwegian population, used in the FRUIT-RCT, Visser; based on a recent Dutch population and Gardosi; based on customized parameters). In this study it will also be investigated whether there is a difference in the secondary outcome neonatal SGA if examined with the other two references (Visser and Gardosi). Objective: The aim of this study was to investigate whether the addition of LMWH to aspirin has an effect on the flow of the uterine and umbilical artery and on fetal growth, compared to treatment with aspirin alone. Another question is if the outcome neonatal SGA is different using various references. Participants and intervention: In an international multicenter randomized controlled trial, 139 women were included before 12 weeks gestation. Inclusion criteria were a previous delivery before 34 weeks of gestation with HD and/or a SGA infant and an inheritable thrombophilia. Ultrasound measurements were performed at 22-24 weeks, 28-30 weeks and 34-36 weeks gestational age; flow and growth development over time between the two study arms were examined. The intervention was either daily LMWH (dalteparin, 5000 IU weight-adjusted dosage) with aspirin 80 mg, or aspirin 80 mg alone. Results: There is no difference between both study arms in the flow of the uterine artery (P=0.317). Uterine artery flow was increased in 65% of the measurements, which is abnormal compared to the normal population. Women with an increased flow of the uterine artery, delivered in 93% accorded to Skjaerven and Visser and in 91% accorded to Gardosi a SGA infant. The flow of the umbilical artery did not differ between both study arms (P=0.451) as well. The fetal growth over time did not differ. This was found regardless which reference was used (Skjaerven P=0.681; Visser P=0.964; Gardosi P=0.237). No difference was found in the outcome neonatal SGA for the three different references. The total amount of SGA infants in the study population was notably higher than in a normal population: 26-34%, dependent on which reference was used. Conclusion: In this specific RCT population LMWH was added to aspirin versus aspirin alone. The addition of LMWH had no effect on uterine and umbilical flow or on fetal growth restriction (FGR). Because of the homogeneous population, it made no difference which of the three references was used for the outcomes FGR and neonatal SGA. The remarkable high prevalence of abnormal uterine artery flow and SGA underlines the recurrence of utero-placental insufficiency in this specific high-risk population.

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