Table 1 Characteristics of the included studies
Study | settings | Design | Size | Participants | PRP preparation | Injection | control | outcome | Registration | Funding |
|---|---|---|---|---|---|---|---|---|---|---|
Aflatoonian 2021 [20] | Single center Iran | Quasi-experimental | 26 17 POR 9 POI | POI (ESHRE: onset < 40 years, oligo-/amenorrhea ≥ 4 months, and FSH > 25 IU/l. POR (Bologna criteria: age > 40 years, history of POR ≤ 3 oocytes in previous stimulation, and low ovarian reserve tests (AMH < 1.1 ng/ml) or AFC < 5) Exclusion criteria BMI < 18 or > 30 kg/m2 above 30 or less than 18, autoimmune diseases, thrombophilia, sex chromosome abnormality, STDs, tubal factor infertility, endocrine disorders, endometriosis, previous major lower abdominal surgery and pelvic adhesions, renal failure, malignancy, abnormal semen Iatrogenic POI hormonal therapy within 1 month before or after PRP | Protocol: Rooyagen, Tehran, Iran manufacturer’s instruction Volume: 20 ml of peripheral venous Blood and 3 ml acid citrate A anticoagulant solution Centrifugation: 1600g for 10 Min → 3 layers bottom RBCs, a buffy coat layer, and supernatant cellular Plasma. The plasma layer and buffy coat were transferred to another tube and centrifuged at 3500g for 5 min to achieve 3 ml PRP Platelets concentration: 3—5 times higher than basal blood. Storage: at 4°C for1 h. Activation with calcium gluconate in a 1:9 ratio | Timing: random in amenorrheic POI and Day 10 of cycle in oligomenorrheic POI and POR Technique: Transvaginal ultrasound guided multifocal intramedullary infusion of 1.5 ml using a 17-gauge single lumen needle into each ovary under minimal sedation. Most women received a 2nd injection of 3 mL PRP 3 months after the 1st injection (5 POR women received 1 injection only as spontaneous conception occurred after the 1st injection Follow up duration was 1 year following 1st PRP injection | Before and after assessment | CPR ChPR Miscarriage Ovarian reserve markers | RCT20180818040828N2 | Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran, under Grant Agreement No. 68876 |
Barad 2022 [21] | Single center USA | Quasi-experimental | 80 extremely low functional ovarian reserve 54 regular menstruating and 26 oligomenorrhea | Age 44 -54 years, Previous poor response in previous IVF cycles (oocytes ≤ 3), FSH > 12 mIU/ml and/or AMH < 1.2 ng/ml. Exclusion criteria: a history of active autoimmune disease, ongoing anticoagulant therapy, or evidence of infection, blood diseases, thrombocytopenia or cancer | Protocol: Regen Lab PRP Kit (RegenLab America Inc., Montreal, Canada Volume: 10 ml whole blood drawn into the Regen Lab PRP vacutainer with gel separator and citrate Centrifugation: Twice. First for 10min at 3800 relative centrifugal force (RCF) and again for 5min at 1500 RCF. This results in platelets pellet on top of the gel and 4—5ml plasma above the gel. The upper plasma removed, and the tube was inverted 25 times to resuspend the platelets in the remaining plasma | Timing: random in amenorrheic POI and Day 3–5 of cycle in others Technique: Sub-cortical injections of 0.1ml of the PRP were repeated 7 to 12 times per ovary until 1.5 ml had been administered to each ovary using 20-gauge needle under ultrasound guidance FSH, E2 and follicular growth were monitored every 3 days for 2 weeks then weekly for another 2 weeks then monthly. COH for IVF was started 1 month after the PRP injection | Before and after assessment | Ovarian reserve markers CPR LBR | NCT04275700 | intramural funds from The Center for Human Reproduction and the not-for-profit research Foundation for Reproductive Medicine |
Cakiroglu 2020 [22] | Single center Turkey | Quasi-experimental | 311 POI POI (ESHRE criteria: oligo/amenorrhea for ≥ 4 months, FSH > 25 IU/l on two occasions 4 weeks apart and onset before 40 years of age | Inclusion criteria Age: 24—40 years, Infertility for > 1 year, and having at least one ovary Exclusion criteria were history of malignancy, genetic ovarian insufficiency, prior major lower abdominal surgery with pelvic adhesions, anticoagulant use for which plasma infusion is contraindicated, and current or previous IgA deficiency | Protocol: T-lab autologous platelet-rich plasma kit (T-Biotechnology Laboratory, Bursa, Turkey) Volume: 20 mL blood sample Centrifugation: at 830 g for 8 min. A 16 G needle connected to a 5 ml syringe was rotated into the buffy coat layer To collect 2–4 cc then a second tube was processed similarly. 4—8 cc PRP was collected and transferred to the resuspension tube and shaken gently for 30 – 60 s | Time: random in amenorrheic POI and within 10 days 1–10 of cycle end in others Technique: Within 2 h of preparation, PRP injection was performed transvaginally under ultrasound guidance and under sedation anesthesia into at least one ovary into the subcortical and stromal areas using a 35 cm 17 G single lumen needle Expectant management for 6 weeks to allow spontaneous pregnancy or menses | Before and after assessment | CPR LBR Ovarian reserve markers | No | None |
Cakiroglu 2022 [23] | Single center Turkey | Quasi-experimental | 510 POR using POSEIDON criteria | Inclusion criteria: Age 30 – 45 years, a history of infertility for at least 1 year, and at least one ovary. Exclusion criteria: history of malignancy, prior major lower abdominal surgery resulting in pelvic adhesions, anticoagulant use for which plasma infusion is contraindicated, and current or previous IgA deficiency | Protocol: T-lab autologous platelet-rich plasma kit (T-Biotechnology Laboratory, Bursa, Turkey) Volume: 20 mL blood sample Centrifugation: at 830 g for 8 min. A 16 G needle connected to a 5 ml syringe was rotated into the buffy coat layer To collect 2–4 cc then a second tube was processed similarly. 4—8 cc PRP was collected and transferred to the resuspension tube and shaken gently for 30 – 60 s | Time: within 10 days 1–10 of cycle end in others Technique: Within 2 h of preparation, PRP injection was performed transvaginally under ultrasound guidance and under sedation anesthesia into at least one ovary into the subcortical and stromal areas using a 35 cm 17 G single lumen needle Expectant management for 6 weeks to allow spontaneous pregnancy or menses | Before and after assessment | CPR LBR Ovarian reserve markers | NCT04237909 | None |
Farimani 2021 [24] | Single center Iran | Retrospective | 96 POR using POSEIDON criteria | Inclusion criteria: Any POR attending a single laboratory with the highest number of cases Exclusion criteria: Lack of follow-ups and incomplete laboratory results Diseases/disorders affecting the chance of fertility | Protocol: Shanghai protocol | Right after the first follicular puncture, the intra-ovarian PRP injection (2 ml) was performed under ultrasound guide followed by the second puncture for the second stimulation AMH, LH, E2 and FSH were measured after two menses | Before and after assessment | Ovarian reserve markers Oocyte retrieved CPR | No | None |
Melo 2020 [25] | Single center Venezuela | Prospective controlled, non-randomized comparative study | 83 low ovarian reserve 46 received PRP and 37 control | Inclusion criteria: Age ≥ 38 years Day 3 FSH > 12 mIU/mL AMH < 0.8 ng/m normal uterine cavity Exclusion criteria: Previous PID clinical/biochemical hyperandrogenism or polycystic ovaries tubal factor infertility, endometriosis, known platelet or thromboxane synthesis disorder known severe male factor | Volume: 5 blood collection tubes containing sodium citrate 3.8% were filled with 4.5 mL of blood each and centrifuged at 270 g for 10 min, then 100 μL of the platelet-rich supernatant were transferred from each of 4 of the original blood tubes and mixed with 0.1 mL of 10% calcium chloride The blood in the remaining fifth tube was not mixed with calcium chloride to allow for quantification of the total number of platelets | Timing: between days 7 and 9 of the menstrual cycle Technique: 200 μL of PRP were injected into the cortex of each ovary using a single lumen aspiration needle under transvaginal ultrasound guidance and sedation. Each ovary was punctured once only, with the single lumen needle being inserted into the ovarian cortex superficially, and a total of 200-μL PRP injected into the subcortical area of the ovary Follow up of all women for 12 months was done | 37 no intervention | Ovarian reserve markers CPR LBR | No | None |
Navali 2022 [26] | 2 centers Iran | Quasi-experimental | 35 POR criteria ( AMH < 1.1 ng/mL, AFC < 5–7, a history of cycle cancellation due to < 3 oocytes retreived | Inclusion criteria: infertile women Age 30—42 years with at least one ovary and, and willing cooperate. Exclusion criteria: FSH > 25, current or previous IgA deficiency, genital or non-genital cancers, anticoagulants treatment, chromosomal ovarian failure, prior pelvic surgery resulting in pelvic adhesions, anemia, (hemoglobin < 10 g/dl), thrombocytopenia, (platelet count < 10 5/μ)l and did not receive the PRP injection | Protocol: Royagen kit (Co. SN: 312,569, Arya Mabna Tashkis, Iran) Volume: 20 mL blood sample Centrifugation: at 830 g for 8 min. A 16 G needle connected to a 5 ml syringe was rotated into the buffy coat layer To collect 2–4 cc then a second tube was processed similarly. 4—8 cc PRP was collected and transferred to the resuspension tube and shaken gently for 30 – 60 s | Antibiotic administration before oocyte pickup and 1 h before PRP injection Technique: After oocyte pick up about 2 cc of PRP injected into the cortex of both ovaries using a 35 cm 17 G single lumen needle with Doppler monitoring to prevent large vessel injury. After 2 months or 3 menses, patients received a new ovarian stimulation cycle with the same way and dose | Before and after assessment | Ovarian reserve markers M II oocytes | No | Women’s Reproductive Health Research Centre, Tabriz University of Medical Sciences (grant number: 65746) |
Pacu 2021 [27] | 2 centers Romania | Retrospective | 20 POR POSEIDON criteria | Inclusion criteria: Age 31—44 years Exclusion criteria: Male infertility, endocrine dysfunction, autoimmune diseases, thrombophilia, malignancies, infectious diseases, and a family history of neoplastic diseases | Protocol: EasyPRP kit; Neotec Biotechnology Ltd Volume: 60–80 venous blood Platelet count: 250,000–850,000 platelets/μl | Timing: between cycle day 3 and 5 Technique: 2–4 ml PRP at the level of the ovarian parenchyma, the approach of the ovary being at a distance from the vascular pedicle to avoid hemorrhagic accidents under general anaesthesia under ultrasonographic guidance (2 during laparoscpy) Follow up for 6 months was done | Before and after assessment | Ovarian reserve markers Cycle performance indicators | No | None |
Petryk 2020 [28] | Single center Ukraine | Quasi-experimental | 38 low ovarian reserve | Inclusion criteria: Age: 31–45 years Infertility with 2 or more failed oocyte recruitment during IVF cycles Have at least one normal ovary ≥ 1 ml volume Negative pregnancy test Exclusion criteria: significant chronic condition, cancer, or mental illness Ovarian or uterine lesions | Volume Two tubes. Each contains 8.5 ml venous blood + 1.5 trisodium citrate with citric acid and dextrose | Centrifugation: at a G-force of 800 for 3 min results in platelet-poor plasma which is then withdrawn into Falcon 15-ml conical centrifuge tubes. Recentrifugation for 15 min at room temperature at a G-force of 1400, the precipitate of platelets was obtained, and then 75% of the upper volume of PPP was withdrawn again. The platelet precipitate was resuspended in the remaining PPP resulting in 2 ml solution 0.7 ml of PRP was injected into each ovary with a concentration of 1,000,000 platelets per microliter (μl) using 25 G needle, 20 cm in length guided by ultrasound (In difficult cases, a laparoscopic-assisted approach was used) | Before and after assessment Follow up for 12 months was done | No | None | |
Sfakianoudis 2020 [29] | Single center Greece | Quasi-experimental | 120 women 30 POR (Bologna Criteria) 30 POI (Age < 40 years, Amenorrhea for ≥ 4 months, and FSH > 25 IU/L) 30 perimenopase (Age < 40 years and Menstrual cycle irregularities) 30 menopausal (Age 45–55 years, Amenorrhea for ≥ 12 months, and FSH > 30 IU/L) | Inclusion criteria: BMI 18.5 – 30 kg/m2 Exclusion criteria: autoimmune disorders, STDs, infectious diseases, tubal factor infertility, chronic inflammatory diseases, endometriosis, chronic endometritis, and endocrine disorders such as thyroid dysfunction, hypothalamic-pituitary disorders, previous reproductive tract surgeries, anemia, thrombophilia, current cancer or a medical history of familiar cancer and abnormal semen | Protocol: a RegenACR®-C Kit (Regen Laboratory, Le Mont-sur-Lausanne, Switzerland) PRP was prepared earlier on the day of administration. 60 mL of the patient’s peripheral blood was required in order to yield the required volume of PRP Platelet count 1,000,000 platelets/ µL Intramedullary injected on multiple sites in both ovaries with the patient under inhaled minimal sedation. The technique included penetration across the central part of each ovary respectively, gradual infusion of 4 mL of activated PRP, via a 17-gauge single lumen needle attached to the transvaginal probe transducer | Timing: random in amenorrheic POI and menopausal and Day 3 of cycle in POR and perimenopausal women. Immediately in women not receiving HR and stop HR for 6 months for women receiving HR Follow up for 3 months was done | Before and after assessment | Ovarian reserve markers Spontaneous pregnancy | No | None |
Sills 2020 [30] | Single center USA | Quasi-experimental | 182 POR | Inclusion criteria: had at least one ovary, infertility of > 1yr duration, at least one prior failed (or canceled) IVF cycle, or amenorrhea for at least three months Exclusion criteria: ongoing pregnancy, current or previous IgA deficiency, chromosomal ovarian insufficiency, prior major lower abdominal surgery resulting in pelvic adhesions, anticoagulant use for which plasma infusion is contraindicated, psychiatric disorder ongoing malignancy, or chronic pelvic pain | Volume: 8–10 mL whole blood was collected by peripheral venipuncture Centrifugation: 1500g × 5 min Processed blood was then fractionated, and erythrocytes were trapped beneath while lower density components settled atop the separator gel. Less than 3 mL of supernatant (corresponding to relatively platelet-poor plasma fraction) was then aspirated off the top of each column before recapping the vial for gentle tube inversion/resuspension PRP activation was achieved with calcium gluconate | 10cc syringes were used to divide activated PRP samples into two equal portions and maintained at room temperature, then attached to a 35cm single lumen 19G needle assembly (Rocket Medical; Washington, UK). The injection apparatus was modified for office PRP administration by bypassing the Falcon tube collection port to allow direct injection into ovarian stroma under transvaginal ultrasound guidance. The ovaries were aligned with the needle guide to avoid intervening vascular or other structures and the needle was quickly advanced without rotation deep into the central ovary. Once tip placement was confirmed, activated substrate was slowly introduced as the needle was withdrawn across the previously traversed ovarian cortex. The final ~ 1mL of sample was deposited just under the ovarian capsule | Before and after assessment Follow up for 3 months was done | Ovarian reserve markers | NCT03178695 | None |
Stojkovska 2019 [31] | Single center Macedonia | Pilot comparative study | 40 POR (ESHRE criteria) 20 PRP 20 control | Inclusion criteria: Age 53–42 years Normal semen analysis IVF completed with ET Exclusion criteria: Genetic or chromosomal ovarian insufficiency, immunoglobulin A deficiency, large surgical repairs of pelvic floor with severe pelvic adhesions, the use of anticoagulants, psychotropic medicaments, psychiatric disorders, carcinomas or a history of chronic pelvic pain, present infection, haemoglobin < 11 g/L or platelets < 150 × 103/μL | Protocol: Regen PRP, (Regen Laboratory, Mont-sur-Lausanne, Switzerland) Under strict aseptic conditions and optimum temperature regulations (21–24°C), PRP was prepared according to the manufacturer’s guidelines | The volume immediately above the erythrocyte layer was collected. Calcium gluconate was used as an activator. After activation, in a period less than 2 min, approximately 3–5 ml of the PRP was injected into the ovaries under transvaginal ultrasound guidance 30 cm single lumen 17G aspiration needles under propofol intravenous anaesthesia | 20 POR no intervention | FR IR CPR LBR | No | None |
Tandulwadkar 2020 [32] | Single center India | Quasi-experimental | 20 POR POSEIDON Group 3 and 4 (AFC < 5 and AMH < 1.1 ng/ml) | Inclusion criteria: Age 20–45 years Normal karyotype Normal semen parameters Exclusion criteria: Autoimmune diseases POI due to chemotherapy or radiotherapy Active viral infections | 20 ml of peripheral blood in the heparinized syringe was taken and 2 ml of PRP was prepared after double centrifugation. This was mixed with 16 ml of ABMDSCs | Intraovarian instillation under general anesthesia of 6 ml (in younger patients with good volume of ovaries) or 4 ml (in women with inadequate ovarian volume) of ABMDSC’s per ovary at multiple sites along the long axis of the ovary starting from caudal end and continued by withdrawing the specially designed needle up to the cranial end into the main stroma. Injection was done under ultrasonographic guidance in 8 women and laparoscopically in 12 women | Before and after assessment All patients were followed up weekly for 6 weeks then underwent COS using minilong agonist protocol, | Ovarian reserve markers | No | None |
Tulik 2022 [33] | Single center Turkey | Retrospective | 71 women 50 POR (Bologna criteria 2 or more of age > 40 years; poor ovarian response in previous IVF cycles (≤ 3 oocytes retrieved; and abnormal ovarian reserve tests 21 POI ESHRE criteria at least 4 months of amenorrhea, FSH > 25 U/L and age < 40 years | Inclusion criteria: BMI 18–30 kg/m2 Exclusion criteria: endocrine disorders (thyroid dysfunction, hyperprolactinemia, diabetes mellitus, Addison disease, congenital adrenal hyperplasia, Cushing syndrome); corrected or present uterine anomalies; and azoospermia | Protocol: T-Biotechnology, Bursa, Turkey 20 mL of blood is collected from each patient into two tubes. Tubes are centrifuged at 1500 g for eight minutes. Approximately 2 mL of plasma is gathered above the newly formed buffy coat layer from each tube through a 16 G needle into a 5 mL syringe. Plasma obtained from the tubes is transferred into a single re-suspension tube and gently agitated for 30–60 s to prepare the PRP solution for use | A total of 4 mL of PRP solution was obtained per patient and divided into two equal portions to inject into each ovary. Patients were sedated for ovarian injection. The procedure was carried on with a 35 cm long 17 G needle under transvaginal ultrasound guidance. 2 mL of solution was injected into the stromal region of each ovary within two hours of PRP preparation | Before and after assessment AFC, menstrual pattern, and serum hormones were assessed monthly for at least 6 months | Cycle performance indicators (FR,IR,CPR,LBR, cancellation rate, no oocytes) | No | None |