Local Uterine Application of Low Molecular Weight Heparin (LMWH) in Intra-cytoplasmic Sperm Injection (ICSI)
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 1

Summary: 
      Heparin also has the ability to bind with and modulate a wide variety of proteins, which can
      influence a number of physiological processes involved in implantation & trophoblastic
      development. These processes include adhesion of the blastocyst to the endometrial surface &
      trophoblastic differentiation & invasion.

      A recent Cochrane review hinted towards research to study the possible effects of the local
      (uterine), & NOT SYSTEMIC application of heparin during Assisted reproductive technology
      (ART). Based on the above evidence the investigators hypothesize that low molecular weight
      heparin given intrauterine at mock embryo transfer after oocyte pick up will help improve
      pregnancy rates in patients undergoing ART.
    

Detailed description: 
      Following ethical approval of the committee of Egyptian IVF-ET center, a pilot prospective
      randomized controlled study will include 40 patients, in which the study arm (group A ) will
      be injected with LMWH intrauterine during mock embryo transfer, just after ovum pickup, while
      the control arm (group B) will be injected intrauterine with similar volume tissue culture
      media (G.2 plus ref. 10132, Vitrolife) also after ovum pickup. Admission into either group
      will be through randomization after inclusion & exclusion criteria have been met and before
      start of controlled ovarian stimulation protocol.

      The standard long gonadotrophin-releasing hormone (GnRH) agonist protocol will be used for
      patients with predicted normal response based on clinical & hormonal profile ; 1 mg of
      leuprolide acetate daily s.c injection (Lucrin ®; Abbott, Hoofddorp, The Netherlands) is
      applied from the mid luteal phase onward till the day of human chorionic gonadotropin (HCG)
      injection.

      Gonadotropins in the form of human menopausal gonadotropin (HMG) (Merional ®, IBSA, Institut
      Biochimique SA, Lugano, Switzerland) will be given by intramuscular injection (IM) from the
      2nd day of menstruation, The starting dose range from 150 to 450 IU depending on the basal
      follicle stimulating hormone (FSH) level, Antral follicle count (AFC) , Patient's age and
      body mass index (BMI).

      In all protocols, stimulation is monitored by trans vaginal ultrasonography and serial
      estradiol (E2) measurements starting from day 7 of the cycle and the gonadotropin dose is
      adjusted individually according to follicular response.

      After the development of at least three leading follicles≥18 mm, 10,000 unit of HCG
      (Choriomon, IBSA, Institut Biochimique SA) is given IM, and a trans-vaginal ultrasound-guided
      oocyte retrieval is performed 36 hours later.

      After scheduled oocyte pick up, a mock embryo transfer will be done using labotec catheter
      (Labotec, Gottingen Germany), and an injection of Enaoxaprin sodium (LMWH) (Clexane® Sanofi
      S.A Paris, France) will be given intrauterine in group A patients.

      LMWH is safe in pregnancy, category B drug , and given empirically sometimes in luteal phase
      and in early 1st trimester without reported problems, it has a half life of 4 Hours, and
      therefore it should not have any negative effects on developing embryos as it will not be
      present at the time of transfer while already performing it s desired effect on the
      endometrium.

      The dose of LMWH given was calculated comparatively according to the work done by our group
      Mansour et.al, 2011, where intrauterine administration 500 IU of HCG improved the
      implantation and pregnancy rates.

      Given the fact that this has not been attempted before, the best way to compare two different
      drugs is through biological activity. So if the investigators want to use 500 IU of LMWH, and
      knowing that In the in vitro purified system, enoxaparin sodium has a high anti Xa activity
      (approximately 100 IU/mg), so to get 500 IU of LMWH we need 5mg. Clexane 20mg is packed in a
      0.2ml syringe, And therefore the investigators need to inject 0.05ml intrauterine using
      labotec catheter. (1/4 OF THE ORIGINAL SYRINGES CONTENT..i.e 5mg).

      The control arm (group B) will be injected intrauterine with similar volume of tissue culture
      media (G.2 plus ref. 10132, Vitrolife) Oocytes are then fertilized in vitro using ICSI and
      after three to five days embryo transfer will be done using labotec catheter (Labotec,
      Gottingen Germany) with ultrasound guidance.

      Progesterone pessaries 400 mg twice daily (Cyclogest 400mg ®Actavis plc. Dublin, Ireland) is
      given as a luteal support starting from the day of embryo transfer and continued for 16 days
      after.

      Pregnancy is defined as the occurrence of a positive β-HCG >10 IU on day 12 after embryo
      transfer and a second higher value 2 days later, followed by ultrasonography confirmation of
      cardiac activity at 6 weeks gestation

      A third party not involved in the actual study will moniter progress of the results and
      record them. Study will be stopped if more than 10 consecutive patients fail to get pregnant
      in the LMWH group. If the pregnancy rate >25% in the intervention group by the end of 20
      cases, then recruitment willl continue till 60 patients are enrolled on each study arm.
    

Intervention name(s): Enaoxaprin sodium; tissue culture media
Intervention type(s): Drug; Drug
Intervention description(s): intrauterine administration after oocyte pickup as the main experimental intervention; intrauterine administration after oocyte pickup as placebo
Other intervention name(s): Clexane; (G.2 plus ref. 10132, Vitrolife)
Intervention MeSH terms: Enoxaparin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Low Molecular Weight (LMWH) Heparin ICSI Enaoxaprin sodium