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Abstract Summary ecurrent unexplained spontaneous miscarriage is frustrating for patient and clinician which is defined as loss of three or more consecutive pregnancies before 20 weeks’ gestation. Multiple etiologies for recurrent unexplained spontaneous miscarriage have been reported including autoimmune, endocrine, anatomic, genetic factors. However, about 40%-50% of recurrent unexplained spontaneous miscarriage are of unknown etiology and are classified as URSM. There is some suggestion that unexplained miscarriages may be caused by an immune reaction as the fetus is secured from the humoral immunity during normal pregnancy, cellmediated immunity (cells and cytokines) was considered an important etiologic factor in URSM. Previously, it was reported that 37.1% of women with URSM have elevated peripheral blood NK cells. 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 as immunosuppressive drug and as miscarriages are often associated with thrombosis aspirin and low molecular weight heparin were used as the main treatment. In pregnant women treatment with Sildenafil citrate may improve blood flow to the placenta and fetus and is R Summary 128 currently being investigated as a treatment in fetal growth restriction. Sildenafil citrate plays a major role in vascular smooth muscle relaxation. Subsequently, it results in a decrease in vascular resistance which leads to an increase in uterine artery blood flow in early pregnancy, increase endometrial thickness and also decrease cytotoxic uterine Natural killer cells. The objective of this study was to assess the efficacy of sildenafil therapy in prevention of recurrent miscarriage. The current study is a randomized controlled study This study was conducted on 90 women recruited from Ain Shams Maternity hospital after they had received information on the purpose and course of the study from the medical investigator and had provided the written consent. The 90 participants were divided into two equal groups using simple random distribution technique, each group consists of 45 women, group A who received Sildenafil citrate and folic acid, group B received placebo and folic acid. 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 Summary 129 and IgM < 15 MPL measured by ELISA),Normal anti thyroid antibodies, Normal fasting 2hr postprandial blood glucose test, normal antinuclear antibody, 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 congenital anomaly, 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 in the previous pregnancies which are diagnosed sonographicaly or by history of previous cercelage, patient with antiphosphlipid syndrome, Cigarette smoking and alcohol. The 90 participants were divided into two groups using simple random distribution technique, group (A) received Sildenafil citrate and folic acid while group (B) placebo and folic acid. Each patient was subjected to Detailed history taking including: - Personal: name, age, occupation, address and relationship to the husband. Special habits of medical Summary 130 importance as smoking, alcohol abuse, sleep, diet, physical activity. - Menstrual: age of menarche, regularity, duration, painful or painless, amount of blood and LMP. - Obstetric history: number of parity, gravidity, first and second trimester history abortion, previous delivery (term or preterm), previous pregnancy complications as: ectopic, vesicular abortion, previous history of patulous cervix by history of previous cercelage or by ultrasound during previous pregnancies. - Medical history: chronic diseases as hypertension, diabetes, autoimmune disease and thyroid disorders and medication taking during pregnancy). - Physical examination including: - General examination: weight, height, blood pressure, pulse, respiratory rate, pallor, cynosis and lower limb edema. - pelviabdomenal examination for pelvic masses eg fibroid uterus and ovarian dermoid cyst. - Vaginal examination for cervical masses or vaginal septum. - Ultrasound examination: - Pelvic ultrasonography: to assess Ovarian masses or fibroid uterus. Summary 131 - All patients had undergone HSG to exclude uterine synachie, tubal obstruction and uterine anomalies. - 3D vaginal ultrasound to exclude congenital uterine anomalies such as (T shaped uterus, bicornate or septate uterus) if suspected by HSG. - Hysteroscopy to exclude uterine synachie and uterine Anomalies suspected by HSG. Laboratory investigations before pregnancy: - Complete blood count. - Fasting, 2 hour postprandial blood sugar HbA1c. - TSH, freeT3, T4. - Investigation to exclude other causes of recurrent miscarriage as (anticardolipin Abs, lupus anticoagulants) - Antithyroid Abs and Anti nuclear Abs. - When to start treatment: - Folic acid (0.5 mg) was started in a period of 3 months before conception in the two groups. - Sildenafil citrate was started preconception from the LMP starting from the last day of menses and repeated till the patient become pregnant; (dose: 25 mg; vaginal tablets, 4 times/day for 24 days) (El-Far et al., 2009). When patient become pregnant: - Assessment of gestational age by knowing LMP or first trimesteric ultrasound. Summary 132 Antenatal care: 8. Antenatal care visit every 2 weeks: 1st visit was after missed period. 9. Follow up for symptoms vaginal bleeding, hyperemesis, weight gain, pelvic pain during each visit. 10. Transvaginal ultrasound to determine the number, site of gestational sac at 6 weeks to determine fetal pole and fetal pulsation. 11. Measurement of nuchal fold thickness between 11 and 14 weeks. 12. Measurement of cervical canal length by transvaginal ultrasound at16 to18 weeks 13. Detailed anomaly scan at18 to21 week. 14. Uterine artery Doppler to measure uterine artery resistance index and pulsitility index at 20 weeks. Laboratory investigation during pregnancy at booking visit: Complete blood count. Blood group and RH. Viral markers hepatitis B, C and HIV. Rubella IgG Fasting, 2hr postprandial blood sugar. Lupus anticoagulant, anticardiolipin IgG, IgM if was not done before pregnancy. Summary 133 Antinuclear antibody test (ANA) if was not done before pregnancy. Complete urine analysis. There was no statistically significant difference between the study groups regarding demographic data (age, parity and BMI). There was also no statistically significant difference between both study groups regarding transvaginal measurement of cervical length. This study results showed a statistically significant decrease in group I from the group II according to uterine artery resistant index at 20 weeks Mean±SD (0.54±0.14 versus 0.66±0.24). This study showed a statistically significant decrease in group I from the group II according to uterine artery pulsatility index at 20 weeks Mean±SD (0.62±0.17 versus 0.77±0.12). This study showed a highly statistically significant difference between groups according to fetal viability till 20 weeks. Also this study showed beneficial effect of sildenafil citrate in the management of early recurrent unexplained pregnancy loss. In conclusion, our study showed that use of sildenafil citrate decrease rate of recurrent unexplained pregnancy loss |