Infertility, Female, Premature Ovarian Insufficiency, PRP, Sterility, Female
Conditions
Keywords
poor ovarian response, low ovarian response, ICSI, IVF, ART, Platelet rich plasma, PRP
Brief summary
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.
Detailed description
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
BIOLOGICALautologous PRP (platelet rich plasma)
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.
OTHERSaline solution (NaCL) Injection
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.
Sponsors
University of Luebeck
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ovarian response | 34-36 hours following hCG administration at the end of ovarian stimulation | Number of retrieved COCs per intention-to-treat |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Live birth rate | at a follow-up time of 30 days after delivery | Incidence of the birth of at least one live newborn after 22 weeks of gestation |
| Hormone levels | Follow-up period of three months entailing monthly evaluation | 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) |
| Follicular response | On the day of triggering of final oocyte maturation or the day before | 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) |
| COCs and MII oocytes | Day 0 after follicle puncture | Mean number of retrieved COCs per protocol and mean number of metaphase II (MII) oocytes per protocol |
| Number of 2PN oocytes | Day 1 after follicle puncture | Mean number per protocol |
| Mean number and quality of embryos | Day 2-5 after follicle puncture | Grade a for cleavage stage embryo, \>=3BB for blastocyst |
| Biochemical pregnancy rate | 12-16 days after oocyte pick-up | Incidence of serum beta-hCG test \> 25 mIU/ml per ITT and PP |
| Clinical pregnancy rate | 4 weeks after embryo transfer | Incidence of gestational sac with heartbeat assessed by TVS per ITT and PP |
| Ongoing pregnancy rate | 8-10 weeks after embryo transfer | Incidence of at least one foetus with heart beat assessed by TVS |
| Still birth rate | after 22 weeks of gestation | Incidence of the delivery of a dead fetus |
| Gestational age | at the day of delivery | Gestational week estimated by calculating days from oocyte retrieval + 14 days |
| Weight of newborn | at the day of delivery | Birth weight measured in gram |
| Length of newborn | at the day of delivery | Birth length measured in centimeter |
| Incidence of birth sex | at the day of delivery | Incidence of female or male newborn |
| Incidence of multiple birth | at the day of delivery | Incidence of singleton/multiple newborns |
| Neonatal health | at a follow-up time of 30 days after delivery | major and minor congenital anomalies |
| Post procedure pain | on the day of follicle puncture | measured by a numerical rating scale from 0 (no pain) to 10 (worst pain) |
| Fertility Quality of Life Questionnaire | on the day of follicle puncture and embryo transfer | FertiQoL International is a validated relational scale to assess the relational domain regarding quality of life in women undergoing infertility treatment. For each question, the patient will check the response that is closest to her current thoughts and feelings. Scale reaches depending on the question from very dissatisfied to very satisfied, always to never or an extreme amount to not at all. |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | at a follow-up time after 1, 2 and 5 years | Incidence of adverse and serious adverse events with potential relationship to treatment |
| Miscarriage rate | early (week 7-12 weeks of gestation); late (between 12 to 22 weeks of gestation) | 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 |
Countries
Germany
Outcome results
None listed