Gonadotrophin releasing hormone agonist with low dose human chorionic gonadotrophin co-triggers versus gonadotrophin releasing hormone agonist alone for reducing the risk of ovarian hyperstimulation in women with polycystic ovarian disease.

INTRODUCTION

Intracytoplasmic sperm injection (ICSI) usually applied for curing infertility attributable to tubal factor, important Infertility affects up to one in seven couples all over the world. Proportion of these couples may be able to ultimatelty conceive, but for the majority conception is unlikely without some form of medical intervention.¹

Infertility can be caused by a variety of factors such as gamete quality, congenital anatomical defects, and surgical problems. Infertility can also be caused by inadequate uterine blood flow, according to previous findings. ²

Despite recent advancement in ovarian stimulation protocols in IVF and embryo transfer procedures, the pregnancy rate has remained stagnant, with cycle pregnancy rates of no more than 40% and implantation rates per embryo transplanted being disappointingly low (15 percent ). ³

Ovarian hyper stimulation syndrome (OHSS) affects women who have recently received gonadotropin stimulation to achieve ovulation or have been treated with assisted reproductive technologies like in vitro fertilization. ⁴

Early OHSS is generally mild to moderate, and it appears three to seven days after hCG is given. Late OHSS is frequently severe and develops twelve to seventeen days after starting hCG therapy. Because pregnant hCG worsens the condition, the early form is caused by an exogenously injected hormone, whereas the late variety is caused by an implanting or implanted pregnancy.

OHSS is marked by ovarian enlargement and a shift of fluid from the intravascular compartment to the extravascular space. This occurs in response to the vasoactive substances that are secreted following human chorionic gonadotropin (hCG) trigger used prior to the egg retrieval. OHSS is graded based on the severity of the subjective symptoms as well as the clinical or laboratory findings. Mild OHSS requires no treatment, but supportive therapy is needed for the more severe cases. ⁵

The Aim was to compare gonadotrophin releasing hormone agonist with low dose human chorionic gonadotrophin co-triggers versus gonadotrophin releasing hormone agonist alone for decreasing the threat of severe form of ovarian hyperstimulation in women suffering polycystic ovarian illness.

PATIENTS AND METHODS

This rondamized control study designed compare (GnRHa) with  low dose human chorionic gonadotrophin co-triggers versus Gonadotrophin releasing hormone agonist alone for reducing the risk of  severe ovarian hyperstimulation  in women with polycystic ovarian disease under antagonist protocols  invitro-fertilization (IVF) /intracytoplasmic sperm injection (ICSI)  cycles.

 142 infertile women joining the ART department in the International Islamic Center for Population Studies and Research (IICPSR), Al-Azhar University Hospitals and private IVF centers.22 patients were missed during the study, only 120 completed the study, all of them were randomized and allocated in two groups: Dual group and GnRha alone group. Each group with 60 patients.

Diagnosis of the couples was confirmed by basic infertility work up and investigations.

The inclusion criteria: Age of patients from 18 to 42 years, estradiol level more than 4000pg/ml and ˃10 follicles in each ovary on day of triggering, women with documented polycystic ovarian disease according to Rotterdam criteria (PCOM, clinical or biochemical hyperandrogenism and anovulation) and normal uterine cavity (confirmed by ultrasound and\or Hystero salpingography (HSG), and\ or Hyteroscopy to exclude any anomalies).

The exclusion criteria:- The patients above 42 years old, uterine anomalies such as bicornuate uterus, rudimentary horn or uterine septum, patients with drug hypersensitivity to GnRH analogue and percutanous Epididymal Sperm Aspiration(PESA)or Testicular Sperm  Extraction {TESE)

All participants in this study exposed to complete history taking, general examination, abdominal examination as well as vaginal examination. All included couples patients counselled about the purpose and details of the programe. Full data collected from the eligible patients including detailed personal and menstrual history also general, abdominal and vaginal examinations as well as transvaginal ultrasound on 2nd day of the cycle. Examination were done for each studied patient using SIEMENS® ultrasound SONOLINE® sienna 8500 MT 7.5 MHZ vaginal angel 120° and 3.5-5.5 MHZ abdominal, to exclude the presence of ovarian masses, uterine myomas or endometrial polyp and counting the antral follicle count and using other ultrasonic machine in centre.

Hormonal Profiles Determination: On day three of the cycles preceding ovarian stimulation, blood sample (10 cc) was collected through vein puncture at early morning, samples were allowed to clot at room temperature for at least one hour. All samples were centrifuged, supernatant serum separated within 2 hours after withdrawal and stored at –20 0C until assay of basal hormones.

Serum FSH, LH, E2 and prolactin measured in sample collected with radioimmunoassay (RIA) using Gamma counter immunoassay analyzer.

Ovarian stimulation by Flexible antagonist protocols: All patients under Controlled Ovarian Hyperstimulation (COH) with: Flexible antagonist protocol started when the largest follicle reach 14mm with dose 250ug. (Cetrotide) with FSH / HMG Stimulation giving daily till triggering of ovulation, All patients randomized either to triggering of ovulation with GnRH agonist alone or activating of ovulation with GnRH agonist and low dose HCG 1500 iu.

Ultrasound: Transvaginal 2D color Doppler ultrasound done at the day of hCG injection to measure endometrial thickness, pattern, volume, RI, PI. All patients were asked to sit in a waiting area for at least twenty minutes before being scanned in order to reduce the possibility of any negative effects of physical activity on uterine blood flow. The examination was carried out with the patient in the lithotomy position, and colour Doppler Ultrasonography was used in conjunction with a 5-MHz trans-vaginal probe to get images. For this investigation, all scans were done by the same operator in order to avoid interobserver variability.

Oocyte preparation: Oocyte retrieval done 34-36 hours after hCG injection by trans-vaginal ultrasound-guided needle aspiration under general anesthesia. Follicular fluid was aspirated into sterile tubes. 

Sperm preparation: The World Health Organization's guidelines were followed while analyzing the sperm. A discontinuous Percoll gradient will be used to treat the sperm sample. A mini-Percoll gradient was utilized to generate motile spermatozoa in cases of severe oligoasthenozoospermia. ⁶ 

ICSI procedure: The ICSI procedure performed with very fine instruments under a microscope after the granulosa cells have been stripped away from the oocyte with enzymes, the oocyte is held in place by a holding pipet. The other pipet which is much smaller and sharper is used to pick up a single sperm. The smaller pipet is then brought into proper position and then inserted through the zona pellucida and into the cytoplasm of the oocyte where the sperm is injected.⁷

Embryo grading: Approximately 18 hours after ICSI procedure, the oocytes checked for signs of fertilization (two pronuclei or two distinct polar bodies).  

Embryo transfer: 2 to 5 days after oocyte retrieval, Up to 4 Grades A embryos per patient will be transferred according to the age of the patient, the indication for IVF, the count of previous attempts, and the number and quality of embryos available for transfer. All the embryo transfers were performed by senior physicians using soft ET catheter (Labotect) without ultrasonography guidance (Exept in difficult embryo transfer)

Detection, diagnosis and managment of OHSS

Outcomes: pregnancy rate, ongoing pregnancy rate and cycle cancellation and aspiration of ascetic fluid, ICU admission, morbidity and mortality

Ethical approval: Approval of Departmental and Ethical Committees were obtained from quality education assurance unit, Faculty of Medicine, Al-Azhar University Egypt.

Statistical analysis: the gathered data will be tallied and statistically examinedby SPSS program (Statistical Package for Social Sciences) software version 26.0, Microsoft Excel 2016 and MedCalC program software version 19.1. If the P value is less than 0.05, the result is significant; otherwise, it is non-significant. The p-value is a statistical indicator of the likelihood that a study's findings might have happened by chance.

RESULTS

      p≤0.05 is thought to be statically important, p≤0.01 is considered high statistically important, 

SD= standard deviation, *Mann-Whitney test and Chi-Square Test

Table 1: Comparison between the two groups concerning age

The age in dual group ranged from 38 to 42 years with mean ±SD was 38.23± 2.47 years while in GnRha alone  group the age ranged from 38 to 43 years with mean ±SD was 38.47± 2.30 years with no statistical important change (p=0.5828)between the two groups. Likewise, when it came to age groups, no significant variation existed among the two groups (p=0.588). Table (1)

      p≤0.05 is thought to be statically important,  p≤0.01 is considered high statistically important, 

SD= standard deviation, * Student T test

Table 2: Comparison between the two groups as per duration of infertility

The period of infertility in dual group ranged from 2 to 10 years with mean ±SD was 5.55± 2.04 years while in GnRha alone group the it ranged from 2 to 12 years with mean ±SD was 5.82± 1.82 years with no statistical substantial distinction between the two groups (p=0.451). Table (2)

      p≤0.05 is thought to be statically important, p≤0.01 is considered highly significantly important, 

SD= standard deviation, * Student T test

Table 3: Comparison among the two groups as per Antral follicle count, AMH andE2

In terms of Antral follicle count, there was no significantly wide variation groups (p= 0.285). In terms of AMH, there were no notable differences among 2 groups. (p= 0.262). As well, there was no important variation among the two groups concerning E2 (p= 0.646). Table (3)

      p≤0.05 is thought to be statically important, p≤0.01 is considered high statistically substantial, 

SD= standard deviation, * Mann-Whitney test

Table 4: Comparison between the two groups as per ICSI characteristics

There was variation with a statistical significance among the two groups concerning count of oocytes in M1 (p= 0.014). As well, there was notably change among the two groups concerning count of oocytes in M2 (p= 0.014). In regarding of the quantity of embryos frozen and transferred, there was no significantly substantial distinction among the two groups (p= 0.095 & 0.851 respectively). Table (4)

p≤0.05 is thought to be statically important p≤0.01 is considered high statistically significant, 

SD= standard deviation, OHSS: Ovarian hyperstimulation syndrome* Chi-Square Test ♦Fischer Exact test

Table 5: Comparison between the two groups as per outcome

There was no important change in prevalence of OHSS in dual group compared to GnRha alone group (p=0.243). In terms of ICU admission, no statistically substantial distinction between the two groups was not found. As well, In terms of clinical pregnancy, there was no significantly change between the two groups. (p= 0.184) and multiple pregnancy (p= 0.496). Table (5)