Authors and Year | Study Design, Country, and Period of Enrollment | Participants and Main Inclusion Criteria | IVF-ET Cycle | Methods | Diagnostic Criteria of CE | Groups | Outcomes |
Cicinelli et al. 2015 [4] | Retrospective study ------ Italy ------- January 2009–June 2012 |
106 RIF patients undergoing IVF-ET cycle ------- -Unexplained infertility -Age < 40 years -At least 6 good quality embryos transferred in ≥3 previous IVF/ICSI cycles -Normal karyotype -FSH on day 3 ≤10 mUI/mL -BMI ≤ 30 kg/m2 -No previous surgery for myoma and/or endometriosis -No condition interfering with immune system -No antiphospholipid syndrome or thrombophilic condition -No antisperm antibodies |
-GnRH-ant with flexible or fixed scheme -rFSH (175–225 IU/day) -U-Hcg (10,000 UI) at follicle size 17 mm (≥2). -Egg retrieval 34 h after ovulation induction -≤3 embryos transferred (of which at least one with good quality) on day 3 of culture -Luteal phase support with vaginal progesterone |
-Diagnostic HSC -EB -HIS examination -Endometrial culture -Antibiotic therapy (when appropriate) -Control EB -IVF cycle |
1–5 plasma cells/HPF or discrete clusters of <20 plasma cells by CD138 staining | Group A: patients with cured CE (n = 46) Group B: patients with persistent CE (n = 15) |
-Clinical pregnancy rate -Ongoing pregnancy/live birth rate -Miscarriage rate |
Demirdag et al. 2021 [11] | Retrospective study ------ Turkey ------- September 2016–December 2019 |
1164 patients undergoing IVF-ET cycle (232 RIF) ------- -At least 4 good quality embryos transferred in ≥3 previous IVF/ICSI cycles -Age < 40 years -Normal karyotype -Normal uterine cavity -normal antiphospholipid antibody testing -no previous surgery for myoma and/or endometriosis -no male factors infertility - no autoimmune diseases, antiphospholipid antibody syndrome, endocrinological disorders |
Exogenous gonadotropins, rFSH alone or with hMG - GnRH antagonist cetrorelix at follicle size ≥14 mm or E2 > 300 pg/mL -rhCG (250 mcg) at follicle size 18 mm (≥2). -Egg retrieval 36 h after ovulation induction -1 to 2 top-quality embryos transferred on day 3 or 5 -Luteal phase support with vaginal progesterone |
-EB - HIS examination -Antibiotic therapy (when appropriate) -IVF cycle |
≥1 plasma cell/HPF | Group 1: patients with treated CE (n = 129) Group 2: patients without CE (n = 103) Group 3: patients undergoing the first IVF cycle (n = 932) |
-Implantation rate -Clinical pregnancy rate -Live birth rate |
Fan et al. 2019 [33] | Retrospective study ------ China ------- December 2016–July 2018 |
141 patients undergoing 1 IVF-ET cycle ------- -At least 2 high quality fresh embryos transferred in a previous IVF/ICSI cycle -Age 20–38 years BMI: 18–25 Kg/m2 - Normal uterine cavity -no endometriosis, adenomyosis, hydrosalpinx, fibroids |
- | -EB -HIS examination --IVF cycle |
Two methods: ≥1 plasma cell/section or ≥1 plasma cell/mm2 |
Group 1: <1 CD138+(n = 97) Group 2: ≥1 CD138+ (n = 44) |
-Implantation rate -Clinical pregnancy rate |
Hirata et al. 2021 [32] | Prospective study ------ Japan ------- June 2014–September 2017 |
53 patients undergoing IVF-ET cycle ------- -Age <41 years -Normal uterine cavity -Unexplained infertility - No history of RIF or RPL - No genetic disorders, endocrine diseases or autoimmune diseases |
-GnRH-a or GnRH ant protocol -oocyte retrieval and blastocyst freezing -Single blastocyst transfer within 90 days of endometrial tissue sampling with a hormone replacement cycle |
-Oocyte retrieval and blastocyst freezing -Diagnostic HSC -EB -HIS examination - single blastocyst transfer |
Four different diagnostic criteria: -≥1 plasma cell/10 HPFs -≥2 plasma cell/10 HPFs -≥3 plasma cell/10 HPFs -≥4 plasma cell/10 HPFs |
Based on the diagnostic criterion: (≥1; ≥2; ≥3, ≥4) Group A: patients with CE (26; 19; 14; 11) Group B: patients without CE (27; 34; 39; 42) |
-Clinical pregnancy rate -Live birth rate -Miscarriage rate |
Johnston-MacAnanny et al. 2010 [6] | Prospective study ------ USA ------- 2001–2007 |
518 RIF patients undergoing IVF-ET cycle 33 with an EB and 485 without an EB ------- -At least 1 good quality embryos transferred in ≥2 previous IVF/ICSI cycles |
-GnRH-a or GnRH ant protocol -rFSH alone or with hMG -U-Hcg (5000 or 10000 UI) at follicle size 17 mm (≥2). -Egg retrieval 35 h after ovulation induction -Luteal phase support with vaginal progesterone |
-EB -HIS examination -Antibiotic therapy (when appropriate) -Control EB -IVF cycle |
≥1 plasma cell/HPF | Group 1: patients with treated CE (n = 10) Group 2: patients without CE (n = 23) Group 3: RIF patients who did not have an EB (n = 485) |
-Clinical pregnancy rate -Ongoing pregnancy rate |
Kitaya et al. 2017 [12] | Prospective cohort study ------- Japan --- November 2011– July 2014 |
421 RIF patients undergoing up to three IVF-ET cycle ------- -IVF failure with three or more morphologically good cleavage-stage embryos and/or blastocysts transferred. -No intrauterine pathology |
- | -Diagnostic HSC -EB -HIS examination -Endometrial culture -Antibiotic therapy (when appropriate) -Control EB -IVF cycle |
ESPDI ≥ 0.25 The endometrial stromal plasmacyte density index (ESPDI) was calculated as the sum of the stromal CD138+ cell counts divided by the number of the HPF evaluated. | Group A: patients with cured CE (n = 116) Group B: patients with persistent CE (n = 4) Group C: patients without CE (n = 226) |
Clinical pregnancy rate -Ongoing pregnancy/live birth rate -Miscarriage rate |
Kuroda et al. 2020 [8] | Cross sectional study ------ Japan ------ June 2018– February 2020 |
88 infertile women ------ -No intrauterine pathology |
-clomiphene citrate or letrozole in combination with rFSH or hMG -hCG 250 μg or nasal buserelin acetate spray 600 μg at follicle size ≥17 mm (≥2) -Egg retrieval 35 h after ovulation induction -Conventional IVF or ICSI - All embryos were cryopreserved at blastocyst developmental stage ≥4 in the Gardner classification using the vitrification method -endometrium prepared for ET via a hormone replacement cycle |
-EB -IHC staining -ERA testing -Antiobiotic therapy (when appropriate) -Control EB -IVF cycle |
≥5 CD138+ plasma cells per 10 random stromal areas at ×400 magnification. |
Group A: non CE patients (n = 33); Group B: CE patients (n = 19) at ERA testing; Group C: cured-CE patients (n = 36) |
-hCG positive rate -Clinical pregnancy rate -Miscarriage rate -Ongoing pregnancy rate |
Li et al. 2021 [9] | Retrospective study ------ China ------ Between 2017 and 2018 |
716 infertile patients undergoing IVF-ET cycle ------- - <45 years; - endometrial scratching - previous antibiotic treatment for CE |
- | - endometrial scratching -EB -HIS examination -IVF |
Six different diagnostic criteria - 0 plasma cell/HPF in all of the 30 selected HPFs; -1 plasma cell/hpfs in at least 1 out of 30 selected HPFs; -2 plasma cell/HPFs in at least 1 out of 30 selected HPFs; -3 plasma cell/HPFs in at least 1 out of 30 selected HPFs; -4 plasma cell/HPFs in at least 1 out of 30 selected HPFs; -≥5 plasma cell/HPFs in at least 1 out of 30 selected HPFs; |
Group A: 0 CD138+/HPF in all of the 30 selected HPFs (n = 433); Group B: 1 CD138+/HPF in at least 1 out of 30 selected HPFs (n = 178); Group C: 2 CD138+/HPF in at least 1 out of 30 selected HPFs (n = 33); Group D: 3 CD138+/HPF in at least 1 out of 30 selected HPFs (n = 18); Group E: 4 CD138+/HPF in at least 1 out of 30 selected HPFs (n = 6); Group F: ≥5 CD138+/HPF in at least 1 out of 30 selected HPFs (n = 38); |
-Clinical pregnancy rate -Live birth rate -Miscarriage rate |
Xiong et al. 2021 [10] |
Retrospective study ------ China ------ June 2017–June 2018 |
640 infertile patients undergoing IVF-ET cycle ------- -No antibiotic treatments before the hysteroscopy - age < 40 years; -Normal basal hormone levels (FSH < 10 IU/L and E2 < 60 pg/mL); -BMI < 30 Kg/m2; -Normal parental peripheral karyotypes; -Frozen embryo transfer cycles within 6 months after antibiotic treatment - No RPL - no primary ovarian insufficiency - no previous surgery for myoma or endometriosis, - normal uterine cavity |
-GnRH a or GnRH ant protocol: -rFSH or hMG -GnRH a or GnRH ant mild stimulation protocol: oral clomiphene citrate 100mg/day + hMG from the fifth day -hCG (10,000 IU) or recombinant hCG (250 mg) when >3 follicles reached a mean diameter of 18 mm; - Oocyte retrieval was performed 36 h after hCG administration; -Luteal phase support with intra- muscular injection of progesterone (60 mg daily) or once daily vaginal progesterone combined with dydrogesterone (10 mg 3 times a day). |
-Diagnostic HSC -EB -HIS examination -Antibiotic therapy (when appropriate) -Control EB -IVF cycle |
≥1 plasma cell/HPF | Group 1: patients with CD138+/HPF = 0 (n = 88); Group 2: patients with CD138+/HPF 1–4 with antibiotic treatment (n = 116); Group 3: patients with CD138+/HPF 1–4 without antibiotic treatment (n = 199). ------- Group 1: patients with CD138+/HPF 0–4 (n = 403); Group 2: patients with cured CE (n = 211); ------- Group 1: patients with CD138+/HPF 0–4 (n = 403); Group 2: patients with persistent CE (n = 26); |
-Implantation rate -Clinical pregnancy rate -Live birth rate -Early pregnancy loss rate -Cumulative live birth rate |
Zhang et al. 2019 [34] | Prospective cohort study ------- China ------- February 2015–June 2017 |
298 RIF patients undergoing 1 IVF-ET cycle ------- -age < 35 years -≥three failed IVF-ET cycles or ≥6 high-quality embryo transferred -Normal uterine cavity -Normal parental peripheral karyotype. |
-rFSH (175–225 IU/day) -U-Hcg (10,000 UI) at follicle size 17 mm (≥2) -Egg retrieval 36 h after ovulation induction -≤3 embryos transferred (of which at least one with good quality) on day 3 of culture - Luteal phase support with intramuscular progesterone 60 mg daily |
-Diagnostic HSC -EB - HIS examination -intrauterine antibiotic therapy (when appropriate) -Control EB -IVF cycle |
≥1 plasma cell/HPF | Group 1: patients without CE (n = 126) Group 2: patients with cured CE (n = 85) Group 3: patients with persistent CE (n = 24) |
-Implantation rate -Clinical pregnancy rate -Live birth rate -Clinical loss rate |
BMI: body mass index; CE: chronic endometritis; E2: estradiol; EB: endometrial biopsy; ERA testing: endometrial receptivity array testing; ET: embryo transfer; FSH: follicle-stimulating hormone; GnRH-a: GnRH agonist; GnRH-ant: gonadotropin releasing hormone antagonist; HIS: histology; hMG: human menopausal gonadotropin; HPF: high power fields; HSC: hysteroscopy; ICSI: intracytoplasmatic sperm injection; IU: international unit; IVF: in vitro fertilization; RIF: recurrent implantation failure; RPL: recurrent pregnancy loss; rFSH: recombinant FSH; r-Hcg: recombinant human chorionic gonadotropin; U-Hcg: urinary human chorionic gonadotropin. |