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Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia
Letter to the Editors
ajog.org
Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia TO THE EDITORS: We read with interest the meta-analysis of Meher et al1 on antiplatelet therapy for the prevention of preeclampsia. While their results suggest modest benefits from aspirin, we believe the authors should have considered some methodological limitations and some aspects of perinatal diseases’ mechanisms in their analyses that could have led them to different conclusions. Only selected randomized trials published before 2005 were included. At that time, there was little scientific evidence about the optimal posology of aspirin during pregnancy. Therefore, most participants were taking only 60 mg of aspirin daily, which is probably insufficient, and potentially in the morning when aspirin has minimal effects.2 The results were stratified according to gestational age (16 weeks) and dosage (75 mg daily) but the authors did not report the combination of both (aspirin >75 mg 16 weeks). We recently demonstrated that the benefits of aspirin initiated 16 weeks of gestation was following a dose-response effect while the benefits were modest or absent when aspirin was initiated >16 weeks.3 The most important point that needs to be addressed is the selection of outcomes. Most obstetricians will define preterm birth (PTB) as a delivery <37 weeks and not <34 weeks. Recent literature stratified PTB into early onset (<32 or <34 weeks) and late onset (32-36 or 32-36 weeks) because of evidence showing that mechanisms of disease leading to PTB are different according to gestational age. Most cases of spontaneous early-onset PTB are associated with intraamniotic infection and inflammation and it is biologically unlikely that 60 mg of aspirin taken daily could prevent such cases. On the other hand, mechanisms leading to late-onset PTB are less well understood and it could be interesting to know whether low-dose aspirin could be beneficial. Similarly, most cases of preterm or early-onset preeclampsia are associated with deep placentation disorders that represent a failure of the physiological transformation of uterine spiral arteries, which typically occurs <16 weeks of gestation.4 We previously observed that aspirin initiated <16 weeks was beneficial to reduce the risk of preterm but not the term form of preeclampsia.5 For the benefit of readers and pregnant women, could the authors provide the relative risks of preterm preeclampsia (<37 weeks), early-onset preeclampsia (<34 weeks), and PTB
(<37 weeks) associated with aspirin started 16 weeks at a dose >60 or 75 mg? Stéphanie Roberge, PhD Suzanne Demers, MD, Msc, FRCSC Department of Obstetrics and Gynecology Faculty of Medicine Université Laval Quebec City, Quebec, Canada Harris Birthright Research Center of Fetal Medicine King’s College Hospital London, United Kingdom Emmanuel Bujold, MD, MSc, FRCSC Department of Obstetrics and Gynecology Faculty of Medicine Université Laval Quebec City, Quebec, Canada [email protected] The Canadian Institute of Health Research supported Dr Roberge (postdoctoral fellowship). The Fond de Recherche du Québec-Santé supported Drs Bujold (clinician scientist award) and Demers (MSc award) during the study. The current study was funded by the Jeanne and JeanLouis Lévesque Perinatal Research Chair at Université Laval, Quebec City, Quebec, Canada. The authors report no conflict of interest.
REFERENCES 1. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol 2017;216:121-8. e2. 2. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int 2013;30:260-79. 3. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol 2017;216:110-20.e6. 4. Ogge G, Chaiworapongsa T, Romero R, et al. Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia. J Perinat Med 2011;39:641-52. 5. Roberge S, Villa P, Nicolaides K, et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther 2012;31:141-6. ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2017.01.034
MONTH 2017 American Journal of Obstetrics & Gynecology
1
ajog.org
Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia TO THE EDITORS: We read with interest the meta-analysis of Meher et al1 on antiplatelet therapy for the prevention of preeclampsia. While their results suggest modest benefits from aspirin, we believe the authors should have considered some methodological limitations and some aspects of perinatal diseases’ mechanisms in their analyses that could have led them to different conclusions. Only selected randomized trials published before 2005 were included. At that time, there was little scientific evidence about the optimal posology of aspirin during pregnancy. Therefore, most participants were taking only 60 mg of aspirin daily, which is probably insufficient, and potentially in the morning when aspirin has minimal effects.2 The results were stratified according to gestational age (16 weeks) and dosage (75 mg daily) but the authors did not report the combination of both (aspirin >75 mg 16 weeks). We recently demonstrated that the benefits of aspirin initiated 16 weeks of gestation was following a dose-response effect while the benefits were modest or absent when aspirin was initiated >16 weeks.3 The most important point that needs to be addressed is the selection of outcomes. Most obstetricians will define preterm birth (PTB) as a delivery <37 weeks and not <34 weeks. Recent literature stratified PTB into early onset (<32 or <34 weeks) and late onset (32-36 or 32-36 weeks) because of evidence showing that mechanisms of disease leading to PTB are different according to gestational age. Most cases of spontaneous early-onset PTB are associated with intraamniotic infection and inflammation and it is biologically unlikely that 60 mg of aspirin taken daily could prevent such cases. On the other hand, mechanisms leading to late-onset PTB are less well understood and it could be interesting to know whether low-dose aspirin could be beneficial. Similarly, most cases of preterm or early-onset preeclampsia are associated with deep placentation disorders that represent a failure of the physiological transformation of uterine spiral arteries, which typically occurs <16 weeks of gestation.4 We previously observed that aspirin initiated <16 weeks was beneficial to reduce the risk of preterm but not the term form of preeclampsia.5 For the benefit of readers and pregnant women, could the authors provide the relative risks of preterm preeclampsia (<37 weeks), early-onset preeclampsia (<34 weeks), and PTB
(<37 weeks) associated with aspirin started 16 weeks at a dose >60 or 75 mg? Stéphanie Roberge, PhD Suzanne Demers, MD, Msc, FRCSC Department of Obstetrics and Gynecology Faculty of Medicine Université Laval Quebec City, Quebec, Canada Harris Birthright Research Center of Fetal Medicine King’s College Hospital London, United Kingdom Emmanuel Bujold, MD, MSc, FRCSC Department of Obstetrics and Gynecology Faculty of Medicine Université Laval Quebec City, Quebec, Canada [email protected] The Canadian Institute of Health Research supported Dr Roberge (postdoctoral fellowship). The Fond de Recherche du Québec-Santé supported Drs Bujold (clinician scientist award) and Demers (MSc award) during the study. The current study was funded by the Jeanne and JeanLouis Lévesque Perinatal Research Chair at Université Laval, Quebec City, Quebec, Canada. The authors report no conflict of interest.
REFERENCES 1. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol 2017;216:121-8. e2. 2. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiol Int 2013;30:260-79. 3. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol 2017;216:110-20.e6. 4. Ogge G, Chaiworapongsa T, Romero R, et al. Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia. J Perinat Med 2011;39:641-52. 5. Roberge S, Villa P, Nicolaides K, et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther 2012;31:141-6. ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2017.01.034
MONTH 2017 American Journal of Obstetrics & Gynecology
1