Infertility Clinical Trial
Official title:
Local Uterine Application of Low Molecular Weight Heparin (LMWH) in Intra-cytoplasmic Sperm Injection (ICSI) a Randomised Controlled Pilot Study
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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