Sildenafil Citrate in Early Unexplained Recurrent Pregnancy Loss

Effect of Preconceptional Sildenafil Citrate Treatment in Women With Early Unexplained Recurrent Pregnancy Loss: a Randomized Controlled Trial

Recurrent unexplained spontaneous miscarriage (RSM) is defined as three consecutive pregnancy loss prior to 20 weeks from the last menstrual period. 1% to 2% of women experience RSM. Treatment of URSM is a challenging issue. The currently available lines of treatment according to simplicity of use, reliability and degree of invasiveness include corticosteroids, sildenafil citrate, aspirin, heparin and immunoglobulins (besides good antenatal care), but up to now there are no prospective randomized studies, powerful enough, to determine a significant difference between these therapeutic protocols, with any of the above mentioned pharmacological agents.

Sildenafil Citrate (Viagra®), a vasodilator, is also described as an anti-inflammatory agent. While improving uterine blood flow in the proliferative phase, NO may have detrimental effects at the level of the endometrium during the implantation window. The NO- mediated release of cytokines such as tumour necrosis factor- from activated natural killer cells has been implicated as a cause of implantation failure.

Based on these observations, this study attempts was made to study uterine arteries and sub-endometrial blood flow during the luteal phase in normal fertile women and in patients with Unexplained recurrent miscarriage

Study Overview

• Status: Completed
• Conditions: Miscarriage, Recurrent
• Intervention / Treatment: Drug: Sildenafil Citrate; Drug: Folic Acid; Drug: Placebo Oral Tablet

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Abbaseya
    • Cairo, Abbaseya, Egypt, 002
      • Ain Shams Maternity Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Age: 20-35 years.
• BMI (20-30)
• History of three or more successive unexplained recurrent miscarriage.
• Normal uterine cavity by hystrography or hysteroscopy.
• No luteal phase defects by progesterone > 10 ng.
• Normal thyroid function (TSH, T3, T4)
• Normal lupus anticoagulant measured by activated partial throbmoplastine time (32-43 seconds).
• Normal anticardolipin (IgG < 20 gpl and IgM < 15 MPL measured by ELISA).
• Normal anti thyroid antibodies.
• Normal glucouse tolerance test.
• Normal parental karyotyping.

Exclusion Criteria:

• Age<20 or>35 year
• BMI<20 or>30
• Systemic diseases that might affect pregnancy such as diabetes or thyroid disorders or hypertension.
• History of consanguinity.
• Family history of chromosomal abnormalities (e.g. trisomy 21, trisomy 13, Turner's disease …etc.).
• History of autoimmune diseases, eg: systemic lupus.
• Congenital anomaly in uterine cavity as bicornate or septate uterus.
• Luteal phase defect and corpus luteum insufficiency.
• Uterine masses as fibroid or polyps.
• Patient with patuoles os.
• patient with antiphosphlipid syndrome.
• Cigarette smoking and alcohol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sildenafil group; Includes 45 women who received Sildenafil citrate (Respatio(R) 25mg tablets four times daily for 24 days preconceptionally starting first day of previous period) and folic acid (Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally).	Drug: Sildenafil Citrate; Respatio(R) 25mg tablets four times daily for 24 days preconceptionally starting first day of previous period; Drug: Folic Acid; Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally
Active Comparator: Control group; Includes 45 women who received placebo oral tablets (apparently identical to Respatio(R) 25mg tablets, four times daily for 24 days preconceptionally starting first day of previous period) and folic acid (Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally).	Drug: Folic Acid; Folic acid(R) 0.5mg tablets once daily for 3 months preconceptionally; Drug: Placebo Oral Tablet; Placebo tablet apparently identical to Respatio(R) 25mg tablets, taken four times daily for 24 days preconceptionally starting first day of previous period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miscarriage rate	number of spontaneous/missed miscarriages among the participants in both groups	24 gestational weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uterine artery resistance index	Uterine artery resistance index assessed by uterine artery Doppler study in ongoing pregnancies of both groups	At 24 gestational weeks
Uterine artery pulsatility index	Uterine artery pulsatility index assessed by uterine artery Doppler study in ongoing pregnancies of both groups	At 24 gestational weeks

Collaborators and Investigators

• Sponsor: Ain Shams University
• Investigators: Principal Investigator: Mohamed Yakout, MBBCh, M Yakout

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Actual): November 20, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: December 5, 2018
• First Submitted That Met QC Criteria: December 5, 2018
• First Posted (Actual): December 6, 2018

Study Record Updates

• Last Update Posted (Actual): December 6, 2018
• Last Update Submitted That Met QC Criteria: December 5, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pregnancy Complications; Recurrence; Abortion, Spontaneous; Abortion, Habitual; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Folic Acid
• Other Study ID Numbers: SURPL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No