The EPPI Trial - Enoxaparin for the Prevention of Preeclampsia and Intrauterine growth restriction - a open-label randomised controlled trial

Preeclampsia and intrauterine growth restriction (IUGR) are two of the most
common causes of maternal and perinatal morbidity and mortality. Preeclampsia
complicates approximately 5% of pregnancies and is the second most common cause
of direct maternal death in the Developed World. IUGR is more difficult to
define and measure but 10% of all infants will be born small for gestational
(SGA) by customised growth centiles. Women who have had previous preeclampsia
and/or IUGR are at significant risk of recurrence.

Of all preventative therapies which have been assed only aspirin therapy has
shown to lead to a modest reduction in preeclampsia and small for gestational
age (SGA) infants. Calcium also has shown to reduce preeclampsia rates in
women at high risk of preeclampsia.
Heparin acts as an anticoagulant but also has additional actions on placental
function and development that further make it a potential candidate for the
prevention of preeclampisa and IUGR. Unfractionated heparin (UFH) combined with
aspirin therapy has shown to prevent recurrent miscarriage in women with
Antiphospholipid syndrome (SGA). This has led to interest in the use of heparin
for the prevention of more types of placental mediated problems such as
preeclampsia and IUGR. However evidence suggesting significant benefits
associated with heparin treatment of these pregnancy complications is scarce.
Randomised controlled trials specifically aimed at women at risk of
preeclampsia and IUGR are required before advocating the introduction of
heparin, which is expensive and administered by injection, into clinical
practice. LMWH has several advantages over unfractionated heparin, including a
reduced risk of bleeding, more stable and predictable pharmacokinetics, reduced
risk of thrombocytopenia and a much lower risk of osteoporosis. The safety and
effectiveness of LMWH use in pregnancy has been reviewed and accepted.

Primary objectives:
To determine the difference in effect of prophylactic daily LMWH injections
with standard high risk antenatal care compared to standard high risk antenatal
care only for the prevention of preeclampsia and IUGR and to assess the size of
the effect in this population.

Secondary objectives:
To determine the effect of LMWH on
• uterine artery Doppler waveforms
• maternal serum markers and placental and angiogenic growth factors
• maternal serum treated trophoblast explants
• trophoblast deportation
and compare differences in those developing disease to those with
normal pregnancies.

A single centre open-label randomised controlled trial of LMWH therapy
(enoxaparin with as alternatives dalteparin or nadroparin) and highrisk
pregnancy surveillance vs highrisk pregnancy surveillance alone.

Enoxaparin (Clexane) 40 mg daily s.c. (alternatives: dalteparin (Fragmin)
5000IU once daily or nadroparin (Fraxiparin) 2850 IU once daily) will commence
at 6 weeks gestation or time of recruitment (whichever is later) up to a
gestation of 15+6 weeks. Commencement of treatment as close to 6 weeks as
possible. Injections will continue to 35+6 weeks.

If women are randomised to take the LMWH injections (enoxaparin, dalteparin or
nadroparin) they will be taught how to give themselfs daily injections starting
from the time they enter the study and the injections will continue until 36
weeks of pregnancy.
At the low, prophylactic, dose of LMWH, side-effects are very uncommon but
include bruising or skin reactions at the injection site. Rare side effects
include heparin induced thrombocytopenia, the chance of this occurring is less
than 0.1%. Osteoporosis does not occur at this dose.

Special extra blood tests at the time of joining the study, at 20 weeks and
again at 30 weeks will be performed. These tests will be perfomed at the same
time women have routine pregnancy blood tests.
A study investigator will perform an extra ultrasound in addition to the 20
week ultrasound at 24 weeks to measure the growth of the baby and assess blood
flow to the placenta. For some women this will be part of their routine
antenatal care. All other care during the pregnancy will be similar to that
given to women not taking part in the study who have comparable high-risk
pregnancies.