Ovarian PRP (Platelet Rich Plasma) Injection for Follicular Activation

N/AActive Not RecruitingNCT05279560

University of Luebeck114 enrolled

Overview

The primary objective is to investigate the efficacy, defined as an increase in oocyte numbers upon ovarian stimulation, and safety of a single intra-ovarian PRP injection vs. saline solution (NaCl) injection (Placebo) transvaginally or laparoscopically for follicular activation in patients with child wish and with low ovarian reserve/expected poor ovarian response planning to undergo IVF or ICSI using own eggs. Pain score as numerical rating score and validated quality of life questionnaire will be requested after the procedure. Longterm follow-up of all participants will be performed 1, 2 and 5 years after end of study.

Age-related infertility and premature loss of ovarian reserve has become a major challenge for ART professionals as the the average age at first child wish has dramatically increased over time. Under physiological circumstances, most follicles in the human ovary remain dormant throughout the female life span and eventually become atretic, however, histological samples reveal that the follicular pool in the ovary is completely exhausted only as late as the early 70ies and that the ovary holds oogonial stem cells, which may have the ability to differentiate into functional follicles. The pressing problem for reproductive medicine is therefore the question how to reactivate some of the putative ovarian 'reproductive reserve' in those women with premature follicular depletion or those who wish to become pregnant at advanced age. Platelet rich plasma (PRP) is a blood-derived product, characterized by high concentrations of growth factors and chemokines. PRP is produced by centrifuging a small quantity of the patient's own blood and extracting the active, platelet-rich fraction. The platelet-rich fraction is applied to the human body typically by injection. PRP is used for therapeutic purposes in different medical areas ranging from orthopedics to plastic surgery, for its putative ability to stimulate and facilitate cell proliferation and thereby tissue differentiation and regeneration. In the context of reproductive medicine, PRP has been proposed to increase pregnancy rates after uterine flushing in women with recurrent implantation failure or thin endometrium. Intra-ovarian injection of PRP has been proposed to activate dormant ovarian follicles pre IVF-treatment in cases of idiopathic low ovarian reserve, premature ovarian insufficiency or ovarian depletion because of advanced maternal age. To date, there is no randomized placebo-controlled trial available that has evaluated intra-ovarian PRP injection in terms of efficacy and safety for premature ovarian failure, and, more specifically, also not in patients with depleted ovarian reserve/poor ovarian response (POR) who constitute a significant proportion of patients undergoing assisted reproduction.

Interventions

autologous PRP (platelet rich plasma)BIOLOGICAL

The required volume of PRP will be extracted from 60 ml of the patient's peripheral blood. Injecting PRP into the ovaries will be performed likewise to the standard operating procedure of oocyte retrieval. After centrifugation of the whole blood, 5ml PRP will be injected in each ovary intra-medullar and subcortical using a 17-gauge single lumen needle under sedation und under transvaginal ultrasound monitoring.

Saline solution (NaCL) InjectionOTHER

Injecting NaCL into the ovaries will be performed likewise to the standard operating procedure of oocyte retrieval. NaCL will be injected in each ovary intra-medullar and subcortical using a 17-gauge single lumen needle under sedation und under transvaginal ultrasound monitoring.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 42 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Serum AMH \< 0.5 ng/ml (at screening visit and in the absence of OC or sex-steroid intake) * Antral follicular count (AFC) in both ovaries ≤ 5 (at screening visit and in the absence of OC or sex-steroid intake) * Spontaneous cycle, menstrual cycle length 21-35 days * Body mass index (BMI) ≥18 kg/m2 and ≤38 kg/m2 * Both ovaries must be visible by transvaginal ultrasound examination * Both ovaries must be judged accessible by transvaginal puncture * Indication for IVF or ICSI treatment * Willingness to participate and provide written consent prior to initiation of any study-related procedures * The subject and male partner must agree to participate in the infant follow-up if she becomes pregnant * The subject must be able to communicate well with the investigator and research staff and to comply with the requirements of the study protocol. Exclusion Criteria: * ≥ four cumulus-oocyte-complexes (COCs) retrieved in a previous IVF cycles with a conventional stimulation protocol (within 6 months before enrollment) * Serum value of FSH ≥25 IU/l (within 12 months measured in the absence of OC or hormone replacement intake) * Thrombocytopenia defined as \< 100.000 platelets/µl at screening * Oral contraceptive or sex steroid intake within 1 month prior to enrollment * Presence of structural or numerical chromosomal abnormality in cytogenetic analysis * Relevant autoimmune disease * History of malignancy and systemic chemotherapy or pelvic radiation * Severe endometriosis (stage III-IV) * Ovaries located outside the inner pelvis * Presence of unilateral or bilateral hydrosalpinx * Relevant endocrine disorders such as hypothalamic-pituitary disorder or thyroid dysfunction (except substituted Hashimoto's thyroiditis or latent hypothyroidism) * Relevant thrombophilic disorder * Contraindication for pregnancy * Contraindication for transvaginal ovarian puncture (such as previous major lower abdominal surgery and known severe pelvic adhesion) * Uterine malformations or pathologies (such as sub mucosal fibroid(s), endometrial hyperplasia, endometrial fluid accumulation, or endometrial adhesions) * Mental disability or any other lack of fitness, in the investigator's opinion, to preclude subjects in or to complete the study

Outcomes

Primary Outcomes

Ovarian response

Number of retrieved COCs per intention-to-treat

Time frame: 34-36 hours following hCG administration at the end of ovarian stimulation

Secondary Outcomes

Hormone levels

Change from baseline in absolute and relative terms for Anti-Müllerian hormone (AMH), serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T) and antral follicle count (AFC)

Time frame: Follow-up period of three months entailing monthly evaluation

Follicular response

Number of follicles (classified and summarised for every ovary as follows: mean diameter 10.0 - 11.9 mm, 12.0 - 13.9 mm, 14.0 - 15.9 mm, 16.0 - 17.9 mm, 18.0 - 19.9 mm and larger 19.9 mm)

Time frame: On the day of triggering of final oocyte maturation or the day before

COCs and MII oocytes

Mean number of retrieved COCs per protocol and mean number of metaphase II (MII) oocytes per protocol

Time frame: Day 0 after follicle puncture

Number of 2PN oocytes

Mean number per protocol

Time frame: Day 1 after follicle puncture

Mean number and quality of embryos

Grade a for cleavage stage embryo, \>=3BB for blastocyst

Time frame: Day 2-5 after follicle puncture

Biochemical pregnancy rate

Incidence of serum beta-hCG test \> 25 mIU/ml per ITT and PP

Time frame: 12-16 days after oocyte pick-up

Clinical pregnancy rate

Incidence of gestational sac with heartbeat assessed by TVS per ITT and PP

Time frame: 4 weeks after embryo transfer

Ongoing pregnancy rate

Incidence of at least one foetus with heart beat assessed by TVS

Time frame: 8-10 weeks after embryo transfer

Miscarriage rate

Defined as spontaneous loss of a clinical pregnancy rate, where embryo(s) or fetus(es) is/are nonviable and is/are not spontaneously absorbed or expelled from the uterus or surgically removed

Time frame: early (week 7-12 weeks of gestation); late (between 12 to 22 weeks of gestation)

Still birth rate

Incidence of the delivery of a dead fetus

Time frame: after 22 weeks of gestation

Live birth rate

Incidence of the birth of at least one live newborn after 22 weeks of gestation

Time frame: at a follow-up time of 30 days after delivery

Gestational age

Gestational week estimated by calculating days from oocyte retrieval + 14 days