Uterine artery doppler changes after vaginal administration of isosorbide mononitrate in patients with unexplained recurrent pregnancy loss

INTRODUCTION

Recurrence pregnancy miscarriage is a serious reproductive health problem, affecting 2% to 5% of couples. The incidence of RPL varies widely due to differences in the definitions and criteria used, as well as in population characteristics.¹ Known common causes of RPL are uterine abnormalities, antiphospholipid antibody syndrome, hormonal and metabolic disorders, and cytogenetic disorders. Other etiologies have been proposed but are still considered controversial, such as chronic endometriosis, hereditary thrombosis, deficiency of the luteal phase and high-level DNA fragmentation of sperm.² Nitric oxide (NO) is a gas and free radicals that are now known to play an important physiological role. NO is important in the endothelium-dependent regulation of blood flow and pressure and in the inhibition of platelet activation. Through this process, nitric oxide in the blood activates an enzyme called soluble guanylyl cyclase, which is activated thousands of times to produce the signaling molecule Cyclic GMP.³ NO plays an essential functional part in the vasculature by stimulating vasodilation, inhibiting platelet aggregation and adhesion to endothelial cells,

inhibiting smooth muscle proliferation, regulating apoptosis, and maintaining the integrity of the endothelial barrier.⁴ Transabdominal and transvaginal ultrasound, power and spectrum Doppler is a non-invasive tool for assessing physiological properties and blood flow during pregnancy.⁵

The study aimed to compare uterine-artery blood flow before and after the application of Isosorbide  mononitrate  as a nitric oxide donor during mid secretory-phase of menstrual-period for women with unexplained recurrent pregnancy-miscarriage.

PATIENTS AND METHODS

This study was conducted on  June 2021 to February 2022, 40 non-pregnant women who had repeated unexplained reports of pregnancy loss from patients attending Al-Azhar University Gynecology Clinic in Assuit. The study was included at ClinicalTrials.gov with the identification code: NCT05341856

Patients were then randomized into 2 groups using a computer-generated random sequence. Isosorbide mononitrate group (IMN group): (20 patients) complaining of unexplained RPL were inserted vaginally (IMN) with a 20 mg isosorbide mononitrate tablet into the posterior vault and mean values ​​of Doppler indices were taken in the after two specific uterine artery recorded hours of menstruation. of the manufacturer's recommended post-measured drug with maximum effect. Placebo group: (20 patients) complaining of unexplained LPR received a placebo placed in the posterior fornix and the middle uterine artery Doppler indices were remeasured two hours later.

Woman's age was ranged between 20-35 years, history of recurrent miscarriages (two or more consecutive miscarriages) with; Normal HSG or hysteroscopy, normal serum PRL, normal thyroid function, normal HbA1c, normal pelvic ultrasound, and negative tests for antiphospholipid antibody syndrome (LCA, lupus anticoagulant, and anti-B2 glycoprotein 1). Pregnancies, regular menstrual cycles within 3 months prior to the study, no hormonal contraceptive or intrauterine device, and no vasodilators were not included. Age younger or older than 20-35 years, nulliravidae, infertile women, induced abortion, systemic diseases affecting hemodynamic indices such as thrombocytopenia and thyrotoxicosis, cases of uterine abnormalities, uterine fibroids, polyps and adnexal masses were excluded.

All participants have checked; Correct medical history. Exploration: General Exploration, Belly, and VP. Tests: Routine tests (CBC, SBR, liver function, kidney function), 2D transvaginal ultrasound to assess the uterus and adnexa, and uterine artery Doppler examination to assess midmenstrual uterine blood flow using a 7.5 MHz transvaginal convex Probe (GE Healthcare - LOGIQ F6 device). The uterine arteries were identified transvaginally lateral to the cervix and measured and averaged in the parasagittal plane of the right uterine artery and left uterine artery. Pulsatility and resistance index were calculated.

The angle between the Doppler beam and the blood vessel was as close to 0 as possible. The study was approved by the Ethics Committee of AL Azhar University School of Medicine (Assuit). Receive verbal communications and communications from all participants.

Sample size were calculated with EpiInfo® version 3.01. Confidence interval set at 95%, statistical power at 80%, ratio of unexposed to exposed subjects at 1, percentage of unexposed subjects with result (assumed equal to Type I error 0.05), and percentage of exposed subjects with result specified at 50. The size was 30 patients for a total of 15 patients in each group. Assuming a 10% dropout rate and a 20% rejection rate, the sample size was increased to 40 patients, 20 patients in each group.

Data were analyzed using Statistical Program for the Social Sciences (SPSS) version 15.0. Quantitative data were expressed as mean ± standard deviation (SD) (for normally distributed data) and median (IQR) (for anomalously distributed data). Qualitative data were expressed as frequency and percentage. Paired t-test: Used to compare pre- and post-treatment means for the same group. t-significance test for independent samples: used when comparing two means (for normally distributed data). Mann-Whitney U test: Used to compare two means (for abnormally distributed data). Probability (P value): P0.05 was not significant.

RESULTS

S/D ratio was the lowest in isosorbide group compared to placebo group and the difference  was highly statistically significant(p-value < 0.001). No statistically  significant difference (p-value > 0.05) was  found between studied groups as regard resistance index after isosorbide mononitrate and placebo.Highly statistically  significant difference   (p-value < 0.001) was  found as regard  Pulsatility index in isosorbide mononitrate group (2.29 ± 0.19) when compared placebo  group (2.88 ± 0.19) after isosorbide mononitrate and placebo .

Table 1: Comparison between studied groups as regard Scio-demographic characteristics.

Table 2: Comparison between studied groups as regard clinical characteristics.

Table 3: Pre-treatment doppler indices of both group.

Fig. 1: Pre-treatment doppler indices of both group.

Table 4: Post -treatment doppler indices of both group.

Fig. 2: Post -treatment doppler indices of both group.

Table 5: Pre &post treatment uterine artery Doppler indices in isosorbide mononitrate group .

Fig. 3:  Pre &post treatment uterine artery Doppler indices in isosorbide mononitrate group .

Table 6: Pre &post treatment uterine artery Doppler indices in placebo group .

Fig. 4: Pre &post treatment uterine artery Doppler indices in placebo group.