Background
The optimum time for commencing antiplatelet therapy for the prevention of preeclampsia
and its complications is unclear. Aggregate data meta-analyses suggest that aspirin
is more effective if given prior to 16 weeks’ gestation, but data are limited because
of an inability to place women in the correct gestational age subgroup from relevant
trials.
Objective
The objective of the study was to use the large existing individual participant data
set from the Perinatal Antiplatelet Review of International Studies Collaboration
to assess whether the treatment effects of antiplatelet agents on preeclampsia and
its complications vary based on whether treatment is started before or after 16 weeks’
gestation.
Study Design
A meta-analysis of individual participant data including 32,217 women and 32,819 babies
recruited to 31 randomized trials comparing low-dose aspirin or other antiplatelet
agents with placebo or no treatment for the prevention of preeclampsia has been published
previously. Using this existing data set, we performed a prespecified subgroup analysis
based on gestation at randomization to antiplatelet agents before 16 weeks, compared
with at or after 16 weeks, for 4 of the main outcomes prespecified in the Perinatal
Antiplatelet Review of International Studies protocol: preeclampsia, death of baby,
preterm birth before 34 weeks, and small-for-gestational-age baby. Individual participant
data for the subgroups were combined in a meta-analysis using RevMan software. Heterogeneity
was assessed with the I2 statistic. The χ2 test for interaction was used to assess statistically significant (P < .05) differences in treatment effect between subgroups.
Results
There was no significant difference in the effects of antiplatelet therapy for women
randomized before 16 weeks’ gestation compared with those randomized at or after 16
weeks for any of the 4 prespecified outcomes: preeclampsia, relative risk, 0.90, (95%
confidence interval, 0.79–1.03; 17 trials, 9241 women) for <16 weeks and relative
risk, 0.90 (95% confidence interval, 0.83–0.98; 22 trials, 21,429 women) for ≥16 weeks
(interaction test, P = .98); death of baby, relative risk, 0.89 (95% confidence interval, 0.73–1.09; 15
trials, 8626 women) for <16 weeks and relative risk, 0.92 (95% confidence interval,
0.79–1.07; 21 trials, 22,336 women) for ≥16 weeks (interaction test, P = .80); preterm birth prior to 34 weeks, relative risk, 0.90 (95% confidence interval,
0.77–1.04; 19 trials, 9155 women) for <16 weeks and relative risk, 0.91 (95% confidence
interval, 0.82–1.00; 25 trials, 22,117 women) for ≥16 weeks (interaction test, P = .91); and small-for-gestational-age baby, relative risk, 0.76 (95% confidence interval,
0.61–0.94; 13 trials, 6393 women) for <16 weeks and relative risk, 0.95 (95% confidence
interval, 0.84–1.08; 18 trials, 14,996 women) for ≥16 weeks (interaction test, P = .08).
Conclusion
The effect of low-dose aspirin and other antiplatelet agents on preeclampsia and its
complications is consistent, regardless of whether treatment is started before or
after 16 weeks’ gestation. Women at an increased risk of preeclampsia should be offered
antiplatelet therapy, regardless of whether they are first seen before or after 16
weeks’ gestation.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to American Journal of Obstetrics & GynecologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Antiplatelet agents for preventing pre-eclampsia and its complications.Cochrane Database Syst Rev. 2007 Apr 18; : CD004659
- CLASP: a randomized trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women.Lancet. 1994; 343: 619-629
- A randomized trial of low dose aspirin for primiparae in pregnancy. The Jamaica Low Dose Aspirin Study Group.BJOG. 1998; 105: 293-299
- Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomized trial for the prevention of pre-eclampsia and its complications.BJOG. 1998; 105: 286-292
- Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review.BMJ. 2001; 322: 329-333
- A meta-analysis of low-dose aspirin for the prevention of pregnancy-induced hypertensive disease.JAMA. 1991; 266: 260-264
- Aspirin for pre-eclampsia: beware of subgroup meta-analysis.Ultrasound Obstet Gynecol. 2013; 41: 479-485
- Antiplatelet agents for preventing pre-eclampsia and its complications.Cochrane Database Syst Rev. 2007; : CD004659
- Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data.Lancet. 2007; 369: 1791-1798
- Follow-up of children in the Italian Study of Aspirin in Pregnancy.Lancet. 1994; 343: 1235
- Low dose aspirin in pregnancy and early childhood development: follow up of the collaborative low dose aspirin study in pregnancy.BJOG. 1994; 102: 861-868
National Institute for Health and Care Excellence. Hypertension in Prenancy. Management of Hypertensive Disorders in Pregnancy. NICE clinical guideline no. 107. Issued 2010, updated January 2011. Available at: http://www.nice.org.uk/nicemedia/live/13098/50418/50418.pdf. Accessed May 8, 2015.
- Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. SOGC Practice Bulletin no. 307, May 2014. Executive Summary.Obstet Gynaecol Can. 2014; 36: 416-438
Lowe SA, Bowyer L, Lust K, et al. SOMANZ guideline for the management of hypertensive disorders of pregnancy 2014. Available at: https://somanz.org/documents/HTPregnancyGuidelineJuly2014. Accessed May 8, 2014.
- Report of the ACOG Task Force on Hypertension in Pregnancy.Obstet Gynecol. 2013; 122: 1122-1131
- WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia.World Health Organization, 2011 (Available at:) (Accessed May 8, 2015)
- Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis.Ultrasound Obstet Gynecol. 2013; 41: 491-499
- Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.Obstet Gynecol. 2010; 116: 402-414
- Antiplatelet agents for prevention of pre-eclampsia and its consequences: a systematic review and individual patient data meta-analysis.BMC Pregnancy Childbirth. 2005; 5: 7
- Low-dose aspirin in the prevention of pre-eclampsia: current evaluation.in: Teoh E.S. Ratnam S.S. Macnaughton M.C. Maternal physiology and pathology. The current status of gynaecology and obstetrics series. Parthenon Publishing Group Limited, Carnforth (United Kingdom)1992: 183-189
- Prevention of pre-eclampsia in high risk women with renal disease: a prospective randomized trial of heparin and dipyridamole.Nephrology. 1995; 1: 297-300
- ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnancies.BJOG. 1996; 103: 39-47
- Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial.Lancet. 1991; 337: 1427-1431
- Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the Essai Regional Aspirine Mere-Enfant study (ERASME) (Part 1).BJOG. 2003; 110: 475-484
- Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches.BJOG. 2002; 109: 161-167
- Idiopathic recurrent fetal growth retardation and aspirin-dipyridamole therapy.Am J Obstet Gynecol. 1989; 160: 763-764
Railton A, Davey DA. Aspirin and dipyridamole in the prevention of pre-eclampsia: effect on plasma 6 keto PGF1alpha and TxB2 and clinical outcome of pregnancy. Presented at the 1st European Congress on Prostaglandins in Reproduction, July 6-9, 1988, Vienna, Austria, page 48.
- Administration time-dependant influence of aspirin on blood pressure in pregnant women.Hypertension. 2003; 41: 651-656
- Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine Doppler at 23 weeks gestation.Ultrasound Obstet Gynecol. 2003; 22: 233-239
- Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women.N Engl J Med. 1993; 329: 1213-1218
August P, Helseth G, Edersheim TG, Hutson JM, Druzin M. Sustained release, low-dose aspirin ameliorates but does not prevent preeclampsia (PE) in a high risk population. In: Presented at the 9th International Congress, International Society for the Study of Hypertension in Pregnancy, March 15-18, 1994, Sydney, Australia, page 72.
- Low-dose aspirin to prevent preeclampsia in women at high risk.N Engl J Med. 1998; 338: 701-705
- A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia.Int J Gynecol Obstet. 1998; 60: 129-135
- A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow.Obstet Gynecol. 1996; 87: 74-78
- A prospective randomized placebo-controlled trial of low dose aspirin for prevention of intra uterine growth retardation.Chin Med J. 1996; 109: 238-242
- Calcium and low-dose aspirin prophylaxis in women at high risk of pregnancy-induced hypertension.Hypertens Pregnancy. 1999; 18: 165-172
- Effect of low dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries—a prospective longitudinal study on a high risk population with persistent notch in the uterine arteries.Eur J Ultrasound. 1997; 5: 17-30
- The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies.N Engl J Med. 1989; 321: 351-356
- Low-dose aspirin therapy to prevent preeclampsia.Am J Obstet Gynecol. 1993; 168: 1083-1093
Kincaid-Smith P. Trial to evaluate the role of aspirin (60 mg) in the prevention of idiopathic intrauterine growth retardation and pregnancy induced hypertension in primigravid women with abnormal uterine artery waveforms on Doppler examination at 22–24 weeks gestation. Personal communication, Oct. 30, 1991.
- Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Italian Study of Aspirin in Pregnancy.Lancet. 1993; 341: 396-400
- Low-dose aspirin in high-risk pregnancy.Hypertens Pregnancy. 1997; 16: 229-238
- A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia.Eur J Obstet Gynecol Reprod Biol. 2004; 112: 142-144
- Low-dose aspirin for preventing preeclampsia and its complications: a meta-analysis.J Clin Hypertens. 2015; 17: 567-573
- The existence of publication bias and risk factors for its occurrence.JAMA. 1990; 263: 1385-1389
- Low-dose aspirin reduces uteroplacental vascular impedance in early and mid gestation in IVF and ICSI patients: a randomized, placebo controlled double-blind study.Ultrasound Obstet Gynecol. 2008; 32: 687-693
- Effects of aspirin on placenta and perinatal outcomes in patients with poor obstetric history.Arch Gynecol Obstet. 2006; 274: 209-214
- Aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function.Obstet Gynecol. 2011; 118: 1021-1028
- Effects of low-dose aspirin on uterine and fetal blood flow during pregnancy: results of a randomized, placebo-controlled, double-blind trial.Ultrasound Obstet Gynecol. 2000; 15: 19-27
- Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.Placenta. 1983; 4: 397-413
- Priming and remodelling of human placental bed spiral arteries during pregnancy-a review.Placenta. 2005; 26: S31-S36
- Prevention of gravidic endothelial hypertension by aspirin treatment administered from the 8th week of gestation.Hypertens Res. 2011; 34: 1116-1120
- Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial.Croat Med J. 2005; 46: 826-831
- Effect of aspirin for prevention of preeclampsia in women with abnormal ultrasonic findings in uterine artery.Feyz J Kashan Univ Med Sci. 2011; 15: 98-104
- Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials.BJOG. 2013; 120: 64-74
- Lower incidence of hypertensive complications during pregnancy in patients treated with low-dose aspirin during in vitro fertilization and early pregnancy.Hum Reprod. 2009; 24: 2447-2450
- The effect of low-dose acetylsalicylic acid (ASA) on control of hypertensive in pregnancy.Hypertens Pregnancy. 2006; 25: 148
- Evaluation of the effect of metformin and aspirin on utero placental circulation of pregnant women with PCOS.Iran J Reprod Med. 2012; 10: 265-270
- Aspirin consumption during the first trimester of pregnancy and congenital abnormalities: a meta-analysis.Am J Obstet Gynaecol. 2002; 187: 1623-1630
- Competing risks model in early screening for preeclampsia by biophysical and biochemical markers.Fetal Diagn Ther. 2013; 33: 8-15
Article info
Publication history
Published online: October 31, 2016
Accepted:
October 11,
2016
Received in revised form:
October 2,
2016
Received:
April 18,
2016
Footnotes
The authors report no conflict of interest.
Identification
Copyright
© 2016 Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsiaAmerican Journal of Obstetrics & GynecologyVol. 216Issue 6
- PreviewWe 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.
- Full-Text
- Preview
