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Resources for Health Care Professionals

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This study is designed to help women who have evidence of placental dysfunction either from ultrasound or biochemical testing. Women who are identified as having placental dysfunction are known to be at increased risk of certain adverse outcomes during their pregnancy, including intrauterine fetal growth restriction (IUGR), pre-eclampsia, and perinatal death.

As a staff member involved in the care of these women, we would like you to be familiar with the HEPRIN study, its aims, to be able to offer HEPRIN to eligible women, obtain consent and initiate recruitment into the trial.

BACKGROUND

The development of pregnancy complications such as pre-eclampsia and eclampsia, intrauterine growth restriction and placental abruption are thought to have a common origin related to abnormalities in the development and function of the placenta. These complications are worth preventing because they cause both maternal and perinatal morbidity and mortality. Whilst maternal ill-effects can occur with delivery at any gestation, most ill-effects upon the fetus are due to preterm birth. In these cases delivering before 32 weeks, the placenta is often small and damaged by vascular lessons such as villous infarction. This placental dysfunction may be detected in the pre-clinical phase through a triad of abnormalities of placental shape and maternal blood flow (detectable by ultrasound) and abnormal expression of feto-placental proteins in maternal blood. The early steps of placental development, namely promotion of uteroplacental blood flow to the implantation site by the extravillous trophoblast and the development of the chorio-allantoic placenta, are governed by the genetics of trophoblast development and render the pregnancy susceptible to hypertension and poor fetal growth. However in most instances the placenta is subsequently damaged by vascular pathology in the uteroplacental arteries and around the villi (resulting in multi-focal villous infarction), further compromising placental function and leading to maternal vascular injury and pre-eclampsia.

Heparin is an antithrombotic agent, acting to prevent the formation of blood clots. It is possible that antithrombotic agents may be able to prevent the development of vascular pathology, and therefore may be effective in reducing the risk or preventing the development of clinical complications related to placental dysfunction such as fetal death, pre-eclampsia or intrauterine growth restriction.

A systematic review of the literature identified a single randomized trial from China (Yu 2005), in which 107 women with an ultrasound diagnosis of IUGR were randomized to heparin or placebo in the third trimester of pregnancy. There were no reported cases of antepartum or post-partum hemorrhage, or maternal thrombocytopenia. There were no statistically significant differences identified for the outcomes preterm birth less than 37 weeks gestation (Heparin Group 5/68 versus Control Group 7/39; Relative Risk (RR) 0.41; 95% Confidence Intervals (CI) 0.14 to 1.20), or infant birth weight less than the 10th centile (Heparin Group 4/68 versus Control Group 6/39; RR 0.38; 95% CI 0.11 to 1.27). However, this sample size is small and underpowered to detect important differences in both maternal and infant health outcomes.

Limitations of the current evidence in the use of heparin for women with evidence of placental dysfunction

  • Limited reporting of any infant outcomes

  • Limited reporting of any maternal outcomes 

  • Lack of information about potential harmful effects for the woman and fetus from prolonged heparin therapy

Therefore, there is insufficient information to make recommendations about the benefits and harms of heparin therapy.

Aims of the HEPRIN trial

The aims of this randomised controlled trial are to assess whether the use of subcutaneous heparin in women with identified placental dysfunction during pregnancy will reduce the risk of intrauterine fetal death and other adverse pregnancy outcomes, improve maternal and infant health, without increasing maternal risks.

HYPOTHESIS

The primary hypothesis of this randomized trial is that the administration of heparin to women with identified placental dysfunction will reduce the risk of intra-uterine fetal death.

The secondary hypotheses of this randomized trail are that the administration of heparin to women with identified placental dysfunction will

  • Reduce the risk of maternal morbidity from pregnancy complications without adverse effects of therapy

  • Reduce the risk of infant morbidity from adverse outcomes

  • Improve maternal psychological well-being and satisfaction with care

  • Reduce the occurrence of pathologically identifiable placental thrombotic-ischaemic lesions.

INCLUSION CRITERIA

Women with:

  • Singleton pregnancy

  • 18+0 - 23+6 weeks gestation

  • Evidence of placental dysfunction in their current pregnancy as determined by two or more of the following

    • Abnormal ultrasonographic placental morphology

                 Any one of:

      • Thickness >4cm or >50% of length

      • Maximum placental length <10cm

      • Heterogeneous texture/echogenic cystic lesions

    • Abnormal uterine artery Doppler waveforms

      • Mean PI>1.45 (ignore notches)

    • Abnormal biochemical markers on first or second trimester maternal serum screening

                Any one of:

      • PAPP-A <0.35 MoM

      • AFP >2.0 MoM

      • Total hCG >4.0 MoM

      • Inhibin >3.0 MoM

EXCLUSION CRITERIA

Women with known positive thrombophilic screening; known lethal fetal anomaly; the presence of early onset fetal growth restriction prior to trial entry (defined as absent or reversed end diastolic flow on umbilical artery Doppler and fetal growth parameters more than 2 weeks smaller than predicted by gestational age); any contraindication to heparin therapy or continuation of the pregnancy (eg chorioamnionitis requiring delivery); clinical need for heparin therapy during pregnancy (eg previous venous thrombo-embolic episode). Women who present at greater than 23+6 weeks gestation will not be eligible for participation in this study.

TREATMENT

Heparin Group: Women randomized to the heparin group will receive specific instruction in the self-administration of subcutaneous heparin, and will receive a month’s supply of subcutaneous heparin and syringes. Women will be asked to self-administer 7500IU of un-fractionated heparin subcutaneously twice a day from randomisation until 34 weeks gestation or birth (whichever occurs first). Ongoing antenatal surveillance will be provided through the multidisciplinary Placenta Clinic or Maternal-Fetal Medicine Clinics of the collaborating hospitals, according to local standard practice.

Standard Care Group: Women randomized to the standard care group will receive ongoing antenatal surveillance provided through the multidisciplinary Placenta Clinic or Maternal-Fetal Medicine Clinics of the collaborating hospitals, but will not be administered medication.

PRIMARY STUDY ENDPOINT

The primary study outcome is:

  • Intrauterine fetal death (defined as fetal death prior to birth and after trial entry).

SECONDARY STUDY ENDPOINTS

The secondary study endpoints are:

  • Other adverse outcomes for the infant

  • Other adverse outcomes for the woman

  • Maternal emotional wellbeing

  • Placental histopathology

HOW CAN I INITIATE RECRUITMENT IN HEPRIN?

This can be achieved by

  1. Providing all women between 18 and 23+6 weeks gestation who are under your care and who fulfil the entry criteria (and none of the exclusion criteria) with the HEPRIN patient information sheet, and discuss their involvement in the trial.

  2. Women who are willing to take part in HEPRIN need to sign the HEPRIN consent form.

  3. Record entry details on the trial entry form in the HEPRIN folder.

  4. Telephone the central randomization service (Freecall number) at which time the woman will be randomized and her treatment allocated.

  5. If you require more information or assistance with this process, please contact Dr John Kingdom (MFM), Dr Rory Windrim (MFM), Dr Anne McLeod (Hematology) or Melissa Walker (mwalker@mtsinai.on.ca) the HEPRIN trial coordinator.

OTHER RESOURCES

  • Patient referral form

  • MD FAQs