Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.
BACKGROUND
Preeclampsia and small-for-gestational-age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low-molecular-weight heparin for the prevention of recurrence of preeclampsia and small-for-gestational-age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared.


OBJECTIVE
We sought to assess the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age pregnancy in women with a history of these conditions.


METHODS
This was an open-label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6+0and <16+0weeks if deemed to be at high risk of preeclampsia and/or small for gestational age based on their obstetric history. Eligible participants were randomly assigned in a 1-to-1 ratio to standard high-risk care or standard high-risk care plus enoxaparin 40 mg (4000 IU) by subcutaneous injection daily from recruitment until 36+0weeks or delivery, whichever occurred sooner. Standard high-risk care was defined as care coordinated by a high-risk antenatal clinic service, aspirin 100 mg daily until 36+0weeks, and-for women with prior preeclampsia-calcium 1000-1500 mg daily until 36+0weeks. In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks' gestation and later analyzed for soluble fms-like tyrosine kinase-1, soluble endoglin, endothelin-1, placental growth factor, and soluble vascular cell adhesion molecule 1. The primary outcome was a composite of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile. All data were analyzed on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000699268).


RESULTS
Between July 26, 2010, and Oct. 28, 2015, a total of 156 participants were enrolled and included in the analysis. In all, 149 participants were included in the outcome analysis (72 receiving standard high-risk care plus enoxaparin and 77 receiving standard high-risk care only). Seven women who miscarried <16 weeks' gestation were excluded. The majority of participants (151/156, 97%) received aspirin. The addition of enoxaparin had no effect on the rate of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile: enoxaparin 18/72 (25%) vs no enoxaparin 17/77 (22.1%) (odds ratio, 1.19; 95% confidence interval, 0.53-2.64). There was also no difference in any of the secondary outcome measures. Levels of soluble fms-like tyrosine kinase-1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high-risk care only.


CONCLUSIONS
The use of enoxaparin in addition to standard high-risk care does not reduce the risk of recurrence of preeclampsia and small-for-gestational-age infants in a subsequent pregnancy.
Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand; National Women's Health, Auckland City Hospital, Auckland, New Zealand. Electronic address: k.groom@auckland.ac.nz.
Katie M
KM
Groom
Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand; National Women's Health, Auckland City Hospital, Auckland, New Zealand.
Lesley M
LM
McCowan
Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand.
Laura K
LK
Mackay
Section of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand.
Arier C
AC
Lee
Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia; Department of Maternal-Fetal Medicine, Sunshine Hospital, Melbourne, Australia.
Joanne M
JM
Said
Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia; Pregnancy Research Center, Department of Maternal-Fetal Medicine, Royal Women's Hospital, Melbourne, Australia.
Stefan C
SC
Kane
Department of Obstetrics and Gynecology, University of Melbourne, Melbourne, Australia; Mercy Hospital for Women, Melbourne, Australia.
Susan P
SP
Walker
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Thijs E
TE
van Mens
Translational Obstetrics Group, Department of Obstetrics and Gynecology, Mercy Hospital for Women, University of Melbourne, Melbourne, Australia.
Natalie J
NJ
Hannan
Translational Obstetrics Group, Department of Obstetrics and Gynecology, Mercy Hospital for Women, University of Melbourne, Melbourne, Australia.
Stephen
S
Tong
Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand.
Larry W
LW
Chamley
Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand.
Peter R
PR
Stone
National Women's Health, Auckland City Hospital, Auckland, New Zealand.
Claire
C
McLintock
D000328:Adult; D000925:Anticoagulants / Q000627:therapeutic use*; D017984:Enoxaparin / Q000627:therapeutic use*; D005260:Female; D005317:Fetal Growth Retardation / Q000517:prevention & control*; D006801:Humans; D011225:Pre-Eclampsia / Q000517:prevention & control*; D011247:Pregnancy; D055815:Young Adult
D000925:Anticoagulants; D017984:Enoxaparin
enoxaparin; fetal growth restriction; intrauterine growth restriction; low-molecular-weight heparin; preeclampsia; randomized trial; small for gestational age