Kate Navaratnam1, Ana Alfirevic2, Andrea Jorgensen3, Zarko Alfirevic4. 1. Centre for Women's Health Research, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L8 7SS, UK. Electronic address: Kate.Navaratnam@liverpool.ac.uk. 2. The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Brownlow Street, Liverpool, L69 3GL, UK. 3. Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, L69 3GL, UK. 4. Centre for Women's Health Research, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L8 7SS, UK.
Abstract
OBJECTIVES: Low-dose aspirin is recommended for prevention of pre-eclampsia in high-risk pregnant women. Current doses provide a conservative risk reduction and some individuals demonstrate 'aspirin non-responsiveness', with insufficient antiplatelet effects. We aimed to determine if aspirin non-responsiveness could be identified in women at high risk of pre-eclampsia and assess for potential associations with placentally-mediated adverse outcomes. STUDY DESIGN: Prospective cohort study. 180 women at high-risk of pre-eclampsia, by NICE criteria, prescribed 75 mg dispersible aspirin daily were recruited from antenatal clinics of Liverpool Women's Hospital between 17/01/14 and 31/03/16. Platelet function (Multiplate™ impedance aggregometry, VerifyNow™ and 11-dehydrothromboxane B2) and aspirin metabolites (nuclear magnetic resonance and liquid chromatography mass spectrometry) were assessed at 5 + 0-20 + 6 and 33 + 0-35 + 6 weeks. Pearson's chi-square test was used to assess for associations between longitudinal response to aspirin and (1) any pre-eclampsia (2) composite adverse placentally-mediated outcome (one, or combination of pre-eclampsia, placental abruption, IUGR and perinatal mortality). A Bonferroni correction was applied to correct for multiple analyses. RESULTS: 180 women were recruited, there were 4 withdrawals and no women were lost to follow-up. After 15 women delivered prior to the completion of follow-up, sufficient sample volumes for longitudinal platelet function and aspirin adherence testing were obtained from 156 women. There were no consistent aspirin non-responders in the cohort. 59% (n = 92) women exhibited normal response to aspirin, 34% (n = 53) variable response (switching response status between study visits) and in 7% (n = 11) response could not be determined as they exhibited lack of platelet response on a background of undetectable aspirin metabolites. There was no significant association between indeterminate or inconsistent (variable or indeterminate) response to aspirin and either pre-eclampsia (p = 0.59, p = 0.84) or composite outcome (p = 0.95, p = 0.65). CONCLUSIONS: When platelet function was assessed with COX-specific tests that measure the antiplatelet effects of low-dose aspirin and aspirin adherence is accurately accounted for aspirin non-responsiveness was not identified in pregnant women at high-risk of pre-eclampsia. Response to aspirin was not associated with placentally-mediated adverse outcomes. The high-degree of variable and indeterminate aspirin response indicates suboptimal adherence and/or dosing are more pressing factors to address to optimise aspirin effectiveness.
OBJECTIVES: Low-dose aspirin is recommended for prevention of pre-eclampsia in high-risk pregnant women. Current doses provide a conservative risk reduction and some individuals demonstrate 'aspirin non-responsiveness', with insufficient antiplatelet effects. We aimed to determine if aspirin non-responsiveness could be identified in women at high risk of pre-eclampsia and assess for potential associations with placentally-mediated adverse outcomes. STUDY DESIGN: Prospective cohort study. 180 women at high-risk of pre-eclampsia, by NICE criteria, prescribed 75 mg dispersible aspirin daily were recruited from antenatal clinics of Liverpool Women's Hospital between 17/01/14 and 31/03/16. Platelet function (Multiplate™ impedance aggregometry, VerifyNow™ and 11-dehydrothromboxane B2) and aspirin metabolites (nuclear magnetic resonance and liquid chromatography mass spectrometry) were assessed at 5 + 0-20 + 6 and 33 + 0-35 + 6 weeks. Pearson's chi-square test was used to assess for associations between longitudinal response to aspirin and (1) any pre-eclampsia (2) composite adverse placentally-mediated outcome (one, or combination of pre-eclampsia, placental abruption, IUGR and perinatal mortality). A Bonferroni correction was applied to correct for multiple analyses. RESULTS: 180 women were recruited, there were 4 withdrawals and no women were lost to follow-up. After 15 women delivered prior to the completion of follow-up, sufficient sample volumes for longitudinal platelet function and aspirin adherence testing were obtained from 156 women. There were no consistent aspirin non-responders in the cohort. 59% (n = 92) women exhibited normal response to aspirin, 34% (n = 53) variable response (switching response status between study visits) and in 7% (n = 11) response could not be determined as they exhibited lack of platelet response on a background of undetectable aspirin metabolites. There was no significant association between indeterminate or inconsistent (variable or indeterminate) response to aspirin and either pre-eclampsia (p = 0.59, p = 0.84) or composite outcome (p = 0.95, p = 0.65). CONCLUSIONS: When platelet function was assessed with COX-specific tests that measure the antiplatelet effects of low-dose aspirin and aspirin adherence is accurately accounted for aspirin non-responsiveness was not identified in pregnant women at high-risk of pre-eclampsia. Response to aspirin was not associated with placentally-mediated adverse outcomes. The high-degree of variable and indeterminate aspirin response indicates suboptimal adherence and/or dosing are more pressing factors to address to optimise aspirin effectiveness.