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Sildenafil Citrate Added to Low Molecular Weight Heparin and Low Dose Aspirin in High-risk Pregnancy

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ClinicalTrials.gov Identifier: NCT04110444
Recruitment Status : Recruiting
First Posted : October 1, 2019
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Sahar MY Elbaradie, Fayoum University Hospital

Brief Summary:
Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of venous thromboembolism, systemic embolism in patients with mechanical heart valves and, in combination with aspirin, for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies Sildenafil citrate increases uterine blood flow and potentiates estrogen-induced vasodilatation. Intravaginal administration of Sildenafil in the success of in vitro fertilization describes no deleterious effects on mother and fetus

Condition or disease Intervention/treatment
High Risk Pregnancy Drug: Sildenafil

Detailed Description:

Pregnancy is considered an acquired hypercoagulable state due to increased concentration of coagulation factors, decreased levels of anticoagulants and decreased fibrinolytic capacity. Adverse pregnancy outcomes affect up to 15% of gestations and are the major cause of maternal and fetal morbidity and mortality. A poor perinatal outcome is expected in pregnancies with high vascular resistance in uterine circulation, but the pregnancies in which the resistance values are normalized in the later trimesters have a significantly better outcome.

For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. Moreover, in vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent.

In a normal pregnancy, the trophoblast produces nitric oxide (NO) which plays an important role in vasodilatation in the fetoplacental circulation to improve oxygen and nutritional supply to the fetus (9,10). Nitric oxide relaxes arterial and venous smooth muscle potently and might inhibit platelet aggregation and adhesion. Moreover, increased circulating phosphodiesterase (PDE) activity is suspected in women with preeclampsia. In pregnancies with fetal growth restriction and without preeclampsia, a reversible increased myometrial arterial tone by phosphodiesterase inhibition has been reported in vitro.

Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; Sildenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)-5 leading to cyclic guanosine monophosphate (cGMP) accumulation and enhances the relaxation elicited by exogenous and neural-released nitric oxide in corpus cavernous. Sildenafil citrate increases uterine blood flow and potentiates estrogen-induced vasodilatation. Intravaginal administration of Sildenafil in the success of in vitro fertilization describes no deleterious effects on mother and fetus. The Natural Killer Cells activity and endometrial thickness were significantly changed after vaginal Sildenafil therapy so it might be an interesting therapeutic option before conception in women with recurrent reproductive failure.

Reduced flow / increased resistance in uterine and umbilical arteries, indicative of reduced uteroplacental flow in pregnancies with fetal growth restriction, has been documented by non-invasive Doppler ultrasound velocimetry.

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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Sildenafil Citrate Added to Low Molecular Weight Heparin and Low Dose Aspirin to Improve Uteroplacental Perfusion in High-risk Pregnancy
Actual Study Start Date : January 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
sildenafile group A
received sildenafil citrate orally 20mg every 8 hours based on previous studies18,21 (Respatio tablet, pharma Egypt group) in addition to low molecular weight heparin daily according to the bodyweight at the booking visit (Clexane 20,40,60 mg, Sanofi eventis company) plus small dose of aspirin 75 mg (Aspocid 75mg tablet, CID pharmaceutical) once daily
Drug: Sildenafil
oral sildenafil t.d.s for high-risk pregnancies

control group B
received low molecular weight heparin as subcutaneous injection once daily plus low dose aspirin 75mg orally once daily in addition to placebo three times daily prepared by a local pharmacy from a domestic manufacturer



Primary Outcome Measures :
  1. change in abdominal circumference and estimated fetal weight after 2 weeks of therapy [ Time Frame: two weeks ]
    ultrasound assessment of fetal growth


Secondary Outcome Measures :
  1. amniotic fluid index 5-15 cm with minimum increase of 2 cm [ Time Frame: two weeks ]
    ultrasound assessment of amniotic fluid



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Ages Eligible for Study:   25 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
high-risk pregnant women of gestational age 28-37 weeks women with current preeclampsia, IUGR and oligohydramnios
Criteria

Inclusion Criteria:

  • high-risk pregnant women (women with current preeclampsia, IUGR and oligohydramnios)
  • gestational age 28-37 weeks
  • no major medical illness contraindicating sildenafil use (cardiovascular disease, sickle cell anaemia, retinopathy, hearing loss, liver diseases)
  • willingness to sign informed consent for study randomization

Exclusion Criteria:

  • gestational age less than 28 weeks
  • refusal of Doppler studies or sildenafil use
  • contraindication or allergy to sildenafil
  • those who can't present for monitoring visits or follow medication instructions
  • those with major medical illness including cardiovascular disease and diabetes mellitus
  • multiple pregnancies
  • suspected chromosomal or fetal congenital anomalies (documented by level II ultrasound examination)
  • users of any vasodilator agents
  • those who had maternal or fetal emergencies necessitating delivery at time of recruitment in the study or with diastolic blood pressure more than 110 mmHg
  • BMI is more than 34 that would impede accurate measurement of fetal biometry and Doppler parameters

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04110444


Locations
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Egypt
sahar M.Y elbaradie Recruiting
Fayoum, Egypt
Contact: sahar M.Y Elbaradie    +201001560674    sbaradie@gmail.com   
Sponsors and Collaborators
Fayoum University Hospital
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Responsible Party: Sahar MY Elbaradie, associate Professor, Fayoum University Hospital
ClinicalTrials.gov Identifier: NCT04110444    
Other Study ID Numbers: SMElbaradie
First Posted: October 1, 2019    Key Record Dates
Last Update Posted: July 23, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents