Prevention of Preeclampsia and Intrauterine Growth Restriction With Aspirin Started in Early Pregnancy: A Meta-Analysis

OBJECTIVE: To estimate the effect of low-dose aspirin started in early pregnancy on the incidence of preeclampsia and intrauterine growth restriction (IUGR). DATA SOURCES: A systematic review and meta-analysis were performed through electronic database searches (PubMed, Cochrane, Embase). METHODS OF STUDY SELECTION: Randomized controlled trials of pregnant women at risk of preeclampsia who were assigned to receive aspirin or placebo (or no treatment) were reviewed. Secondary outcomes included IUGR, severe preeclampsia and preterm birth. The effect of aspirin was analyzed as a function of gestational age at initiation of the intervention (16 weeks of gestation or less, 16 weeks of gestation or more). TABULATION, INTEGRATION, AND RESULTS: Thirty-four randomized controlled trials met the inclusion criteria, including 27 studies (11,348 women) with follow-up for the outcome of preeclampsia. Low-dose aspirin started at 16 weeks or earlier was associated with a significant reduction in preeclampsia (relative risk [RR] 0.47, 95% confidence interval [CI] 0.34–0.65, prevalence in 9.3% treated compared with 21.3% control) and IUGR (RR 0.44, 95% CI 0.30–0.65, 7% treated compared with 16.3% control), whereas aspirin started after 16 weeks was not (preeclampsia: RR 0.81, 95% CI 0.63–1.03, prevalence in 7.3% treated compared with 8.1% control; IUGR: RR 0.98, 95% CI 0.87–1.10, 10.3% treated compared with 10.5% control). Low-dose aspirin started at 16 weeks or earlier also was associated with a reduction in severe preeclampsia (RR 0.09, 95% CI 0.02–0.37, 0.7% treated compared with 15.0% control), gestational hypertension (RR 0.62, 95% CI 0.45–0.84, 16.7% treated compared with 29.7% control), and preterm birth (RR 0.22, 95% CI 0.10–0.49, 3.5% treated compared with 16.9% control). Of note, all studies for which aspirin had been started at 16 weeks or earlier included women identified to be at moderate or high risk for preeclampsia. CONCLUSION: Low-dose aspirin initiated in early pregnancy is an efficient method of reducing the incidence of preeclampsia and IUGR.

[1]  George Davey Smith,et al.  Meta-analysis: Principles and procedures , 1997, BMJ.

[2]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[3]  R. Hermida,et al.  Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women. , 1997, Hypertension.

[4]  B. Couturier,et al.  Reproducibility of first trimester three-dimensional placental measurements in the evaluation of early placental insufficiency. , 2009, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC.

[5]  G. Chamberlain,et al.  Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension , 1990, The Lancet.

[6]  Geographic variation in the incidence of hypertension in pregnancy. World Health Organization International Collaborative Study of Hypertensive Disorders of Pregnancy. , 1988, American journal of obstetrics and gynecology.

[7]  Jonathan A C Sterne,et al.  Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. , 2001, BMJ.

[8]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[9]  B. Clayton,et al.  A VARIANT OF PHENYLKETONURIA , 1975, The Lancet.

[10]  L. Beilin.  Aspirin and pre-eclampsia , 1994, BMJ.

[11]  K. Nicolaides,et al.  Re: Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks' gestation. , 2003, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[12]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[13]  E. Kujansuu,et al.  Low dose acetylsalicylic acid in prevention of pregnancy‐induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches , 2002, BJOG : an international journal of obstetrics and gynaecology.

[14]  K. Nicolaides,et al.  Hypertensive disorders in pregnancy: combined screening by uterine artery Doppler, blood pressure and serum PAPP‐A at 11–13 weeks , 2010, Prenatal diagnosis.

[15]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[16]  L. Magee,et al.  Dalteparin for the prevention of recurrence of placental‐mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial , 2009, Journal of thrombosis and haemostasis : JTH.

[17]  J. Thorp,et al.  Low-dose aspirin inhibits thromboxane, but not prostacyclin, production by human placental arteries. , 1988, American journal of obstetrics and gynecology.

[18]  F. de Wolf,et al.  Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. , 1987, British journal of obstetrics and gynaecology.

[19]  A. Seidler,et al.  Antiplatelet agents for preventing pre-eclampsia and its complications. , 2007, The Cochrane database of systematic reviews.

[20]  J. Golding,et al.  A randomised trial of low dose aspirin for primiparae in pregnancy , 1998, British journal of obstetrics and gynaecology.

[21]  G. Leslie,et al.  Low-Dose Aspirin in High-Risk Pregnancy? , 1997 .

[22]  Jean Golding,et al.  Geographic variation in incidence of hypertension in pregnancy , 1988 .

[23]  D. Arduini,et al.  First‐Trimester Placental Volume and Vascularization Measured by 3‐Dimensional Power Doppler Sonography in Pregnancies With Low Serum Pregnancy‐Associated Plasma Protein A Levels , 2009, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[24]  T. Chipato,et al.  A randomized controlled trial of low‐dose aspirin in women at risk from pre‐eclampsia , 1998, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[25]  M. Rogers,et al.  Calcium and low-dose aspirin prophylaxis in women at high risk of pregnancy-induced hypertension. , 1999, Hypertension in pregnancy.

[26]  A. Baschat,et al.  OC08.05: Impact of 1st trimester aspirin on population prevalence of pre‐eclampsia , 2009 .

[27]  G. Breart,et al.  Aspirin (100 mg) used for prevention of pre‐eclampsia in nulliparous women: the Essai Régional Aspirine Mère–Enfant study (Part 1) , 2003, BJOG : an international journal of obstetrics and gynaecology.

[28]  S. Uzan,et al.  PREVENTION OF PRE-ECLAMPSIA BY EARLY ANTIPLATELET THERAPY , 1985, The Lancet.

[29]  A. Ebrashy,et al.  Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial. , 2005, Croatian medical journal.

[30]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[31]  M. S. Patel,et al.  An introduction to meta-analysis. , 1989, Health Policy.

[32]  F. Parazzini,et al.  A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia. , 2004, European journal of obstetrics, gynecology, and reproductive biology.

[33]  G. Garewal,et al.  Effect of maternal low dose aspirin on neonatal platelet function. , 1998, Indian pediatrics.

[34]  J. Moutquin,et al.  Low-dose ASA response using the PFA-100 in women with high-risk pregnancy. , 2009, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC.

[35]  B. Sibai,et al.  Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. , 1998, The New England journal of medicine.

[36]  E. Kujansuu,et al.  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 , 1997 .

[37]  Jeffrey R. Wilson,et al.  CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women , 1994, The Lancet.

[38]  D. Ellwood,et al.  A Randomized Controlled Trial of Aspirin in Patients With Abnormal Uterine Artery Blood Flow , 1996, Obstetrics and gynecology.

[39]  R. Kreienberg,et al.  Effects of low‐dose aspirin on uterine and fetal blood flow during pregnancy: results of a randomized, placebo‐controlled, double‐blind trial , 2000, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[40]  R. Pijnenborg,et al.  Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. , 1980, Placenta.

[41]  R. Collins,et al.  Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre‐eclampsia and its complications , 1998, British journal of obstetrics and gynaecology.

[42]  R. Hermida,et al.  Administration time-dependent effects of aspirin in women at differing risk for preeclampsia. , 1999, Hypertension.

[43]  G. Remuzzi,et al.  Effect of low‐dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy‐induced hypertension , 1990, The New England journal of medicine.

[44]  M. Klebanoff,et al.  Low-Dose Aspirin to Prevent Preeclampsia in Women at High Risk , 1999 .

[45]  C. Lambalk,et al.  Lower incidence of hypertensive complications during pregnancy in patients treated with low-dose aspirin during in vitro fertilization and early pregnancy. , 2009, Human reproduction.

[46]  P. Kyle,et al.  Flow Cytometric Detection of Activated Platelets in Pregnant Women Prior to the Development of Pre-Eclampsia , 1995, Thrombosis and Haemostasis.

[47]  R. Ruano,et al.  Prevention of preeclampsia with low-dose aspirin -- a systematic review and meta-analysis of the main randomized controlled trials. , 2005, Clinics.

[48]  O. Dapunt,et al.  Low-dose aspirin in primigravidae with positive roll-over test. , 1992, Gynecologic and obstetric investigation.

[49]  Y. Lacasse,et al.  Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis. , 2009, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC.

[50]  J. Dungan.  Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data , 2008 .

[51]  J. Newnham,et al.  Low Dose Aspirin for the Treatment of Fetal Growth Restriction: A Randomized Controlled Trial , 1995, The Australian & New Zealand journal of obstetrics & gynaecology.

[52]  G. Cutter,et al.  Low-dose aspirin therapy to prevent preeclampsia. , 1993, American journal of obstetrics and gynecology.

[53]  B. Sibai,et al.  Prevention of preeclampsia with low‐dose aspirin in healthy, nulliparous pregnant women , 1993, The New England journal of medicine.

[54]  C. Wolf‐peeters,et al.  The human placental bed: electron microscopic study of trophoblastic invasion of spiral arteries. , 1980, American journal of obstetrics and gynecology.

[55]  R. Collins,et al.  ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women , 1996, British journal of obstetrics and gynaecology.

[56]  Aeilko H. Zwinderman,et al.  Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis , 2008, Canadian Medical Association Journal.

[57]  Douglas G Altman,et al.  Systematic reviews in health care: Assessing the quality of controlled clinical trials. , 2001, BMJ.

[58]  A. Flahault,et al.  Effect of aspirin in pregnant women is dependent on increase in bleeding time. , 1999, American journal of obstetrics and gynecology.

[59]  H. Wallenburg,et al.  LOW-DOSE ASPIRIN PREVENTS PREGNANCY-INDUCED HYPERTENSION AND PRE-ECLAMPSIA IN ANGIOTENSIN-SENSITIVE PRIMIGRAVIDAE , 1986, The Lancet.

[60]  H. Honest,et al.  Aspirin for Prevention of Preeclampsia in Women With Historical Risk Factors: A Systematic Review , 2003, Obstetrics and gynecology.

[61]  Preeclampsia and fetal growth. , 2001 .

[62]  D. Barker.  The developmental origins of chronic adult disease , 2004, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[63]  K. Nicolaides,et al.  Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks' gestation. , 2004, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[64]  V. Söderström-Anttila,et al.  Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. , 1997, Human reproduction.

[65]  W. B. Robertson,et al.  The physiological response of the vessels of the placental bed to normal pregnancy. , 1967, The Journal of pathology and bacteriology.

[66]  L. Vatten,et al.  Preeclampsia and Fetal Growth , 2000, Obstetrics and gynecology.

[67]  James J. Walker,et al.  Pre-eclampsia , 2000, The Lancet.

[68]  R. Abbate,et al.  DIFFERENTIAL INHIBITION OF PROSTACYCLIN PRODUCTION AND PLATELET AGGREGATION BY ASPIRIN , 1979, The Lancet.

[69]  A Metin Gülmezoglu,et al.  WHO analysis of causes of maternal death: a systematic review , 2006, The Lancet.

[70]  P. Bradley,et al.  Sexual expression in paraplegia. , 1991, BMJ.

[71]  R. Frydman,et al.  Severe preeclampsia is associated with high inhibin A levels and normal leptin levels at 7 to 13 weeks into pregnancy. , 2003, American journal of obstetrics and gynecology.

[72]  D. Henderson-smart,et al.  Antiplatelet agents for preventing pre-eclampsia and its complications. , 2007, The Cochrane database of systematic reviews.