Non-Obstructive Azoospermia and Intracytoplasmic Sperm Injection: Unveiling the Chances of Success and Possible Consequences for Offspring
Abstract
:1. Introduction
2. Intracytoplasmic Sperm Injection (ICSI) Explained
3. Realistic Expectations in ICSI for Non-Obstructive Azoospermia
3.1. Factors Influencing Successful Sperm Retrieval in NOA Patients
3.1.1. Sperm Retrieval Technique
3.1.2. Other Clinical and Laboratory Factors
3.2. Factors Influencing Pregnancy Outcome with ICSI
3.2.1. Sperm Quality and Quantity
3.2.2. Laboratory Techniques
3.2.3. Fresh vs. Frozen-Thawed Sperm
3.2.4. Female Partner Health
4. Offspring Health
4.1. Miscarriage
Reference # | Study | Design | Study Group (n) | Control Group (n) | Outcome Measures | Findings | |
---|---|---|---|---|---|---|---|
NOA-ICSI | NOA-ICSI vs. Comparator | ||||||
[83] | Friedler et al., 1997 | Retrospective | Testicular sperm from NOA patients (18) by TESE Fresh sperm (9) Cryopreserved sperm (9) | NR | Miscarriage rate | Fresh sperm: Two twin pregnancies and four singleton pregnancies. One of the twin pregnancies resulted in a spontaneous miscarriage during the first trimester (1/6). Cryopreserved sperm: One twin pregnancy and one singleton pregnancy out of three ended in a spontaneous miscarriage during the first trimester (2/3). There was no statistically significant difference in miscarriage rates between the use of fresh and cryopreserved sperm. | NR |
[84] | Ben-Yosef et al., 1999 | Retrospective | Testicular sperm from NOA patients (25) by TESE Fresh sperm (14) Cryopreserved sperm (11) | NR | Miscarriage rate | Of the nine pregnancies achieved (four from fresh and five from cryopreserved spermatozoa), two were missed abortions (group not specified), one was ectopic, and six resulted in deliveries of healthy babies (three of each group). | NR |
[94] | Habermann et al., 2000 | Retrospective | TESE-ICSI cycles from NOA patients (12) Fresh sperm (3) Frozen-thawed sperm (9) | TESE-ICSI cycles from OA patients (34): Fresh sperm (9); Frozen-thawed sperm (25). | Miscarriage rate | TESE-ICSI cycles with fresh sperm of NOA patients: There was one pregnancy and one delivery of singletons. TESE-ICSI cycles with frozen-thawed sperm of NOA patients: There were six pregnancies and two miscarriages. | The miscarriage rates were similar between OA and NOA patients for fresh (25%, 1/4) and frozen-thawed sperm (30.8%, 4/9). |
[89] | Mercan et al., 2000 | Retrospective | Testicular sperm from NOA patients (291) By TESA (63) By TESE (228) | NR | Miscarriage rate | The miscarriage rates according to testicular sperm retrieval method were: TESA: 20.7% (6/29); TESE: 24.2% (16/66) (p = NS). | NR |
[72] | Friedler et al., 2002 | Retrospective | Testicular sperm from NOA patients (123) by TESE Fresh sperm (65 ICSI cycles) Frozen-thawed sperm (63 ICSI cycles) | Epidydimal sperm from OA patients (52) By PESA Fresh sperm (55 ICSI cycles) Frozen-thawed sperm (80 ICSI cycles) | ICSI outcomes | There was no significant difference between early miscarriage rate in NOA patients using testicular fresh sperm (15.7%, 3/19) compared to frozen-thawed testicular sperm (21%, 4/19). | The pregnancy rate/embryo transfer, early miscarriage rate, and ongoing/delivery pregnancy rates were similar in both groups using fresh or frozen-thawed sperm for ICSI for OA and NOA patients. |
[97] | Pasqualotto et al., 2002 | Retrospective | ICSI infants from NOA patients (68 cycles) by TESA | ICSI infants from OA patients (130 cycles) By PESA | Miscarriage rate | The miscarriage rate was higher in those in whom immotile vs. motile spermatozoa were retrieved (70% vs. 25.5%, p < 0.05). | NOA patients showed higher miscarriage rates (40%) than OA patients (28%) (p = 0.01). |
[98] | Pasqualotto et al., 2005 | Retrospective | TESA-ICSI cycles from NOA patients (102) | PESA-ICSI cycles from AO patients (155): Post-vasectomy (99); Congenital (25); Post-infection (31). | ICSI outcomes | From 102 TESA-ICSI cycles of NOA patients, 22 pregnancies were achieved, and 10 miscarriages occurred (45.6%). | No statistical difference was noted among groups despite NOA patients showing lower pregnancy rates. However, miscarriage rates were higher in NOA patients (45.6%) compared with other groups: Post-vasectomy (25.8%) Congenital (28.6%) Post-infection (28.6%) (p = NS) |
[76] | Giorgetti et al., 2005 | Prospective | TESE-ICSI cycles performed in NOA patients (99) SCO (16) MA (35) Hypo (48) | NR | Miscarriage rate | There was no significant difference between testicular histopathology groups in miscarriage rates: SCO: 1/5; MA: 3/13; Hypo: 2/17. From 35 pregnancies achieved with fresh embryos: Five spontaneous first-trimester miscarriage and one second-trimester miscarriage. From two pregnancies achieved with frozen-thawed embryos: No miscarriages were reported. | NR |
[95] | Wu et al., 2005 | Retrospective | TESE-ICSI cycles performed in NOA patients (30) Fresh sperm (6) Frozen-thawed sperm (24) | TESE-ICSI cycles performed in OA patients (28) Fresh sperm (16) Frozen-thawed sperm (12) | Miscarriage rate | From six TESE-ICSI cycles with fresh sperm of NOA patients, there were two clinical pregnancies and no miscarriages reported (0%, 0/2). From 24 TESE-ICSI cycles with frozen-thawed sperm of NOA patients, there were 15 clinical pregnancies, and 5 miscarriages reported (33.3%, 5/15). | Both fresh and frozen-thawed TESE-ICSI cycles had similar spontaneous miscarriage rates (25% vs. 19.5%, p = NS) for OA and NOA patients. |
[85] | Konc et al., 2006 | Retrospective | TESE-ICSI cycles performed in OA and NOA patients (167) by TESE Fresh sperm (68) Frozen sperm (99) Motile sperm (50) Immotile sperm (117) | NR | Miscarriage rate | No difference was found in the abortion rates: Fresh sperm (10/20, 50%); Frozen sperm (7/22, 32%); Motile sperm (6/14, 43%); Immotile sperm (11/28, 39%) (p = NS). | NR |
[86] | Konc et al., 2008 | Retrospective | TESE-ICSI cycles from NOA patients Fresh/Motile sperm (30) Fresh/Immotile sperm (34) Frozen/Motile sperm (19) Frozen/Immotile sperm (74) | NR | Miscarriage rate | No differences were found in the abortion rates: Fresh/motile (4/10, 40%); Fresh/immotile (6/10, 60%); Frozen/motile (2/4, 50%); Frozen/immotile (6/18, 33%) (p = NS) | NR |
[90] | Ravizzini et al., 2008 | Retrospective | NOA patients (53) | NR | Miscarriage rate | From 32 patients with positive micro-TESE, 13 couples achieved clinical pregnancy, and none of them suffered a miscarriage. | NR |
[91] | Inci et al., 2009 | Retrospective | Micro-TESE-ICSI infants from NOA patients (87) Varicocele treated (66) Varicocele untreated (21) | NR | Miscarriage rate | The miscarriage rates did not differ significantly between treated varicocele (18.2%, 2/11) and untreated varicocele patients (0%, 0/2) (p = NS). | NR |
[99] | Semião-Francisco et al., 2010 | Retrospective | NOA patients (102) by TESA | OA patients: TESA (103) PESA (171) | Miscarriage rate | The miscarriage rates did not differ significantly between OA-TESA and NOA-TESA patients (p = NS). | The miscarriage rates were significantly higher for patients with OA who underwent TESA as compared to PESA (p = 0.038). |
[96] | Kalsi et al., 2010 | Retrospective | Testicular sperm from NOA patients (48) Fresh sperm (41) Frozen-thawed sperm (7) | Epidydimal sperm from OA patients (215): Fresh sperm (173) Frozen-thawed sperm (42) Testicular sperm from OA patients (43): Fresh sperm (28) Frozen-thawed sperm (15) | ICSI outcomes | In NOA patients, there was a difference between frozen-thawed sperm and fresh sperm concerning pregnancy rates, live birth rate, and miscarriage rate (p = NS). While with fresh sperm the miscarriage rate was 13.3% (2/15), using frozen-thawed sperm there was no miscarriage reported (0%, 0/4) (p = NS). | When comparing groups, there were no significant differences in fertilization, pregnancy, and live birth rates. |
[100] | He et al., 2010 | Retrospective | ICSI cycles performed in NOA patients (42) | ICSI cycles performed in OA patients (112) | ICSI outcomes | From 42 ICSI cycles of NOA patients, nine pregnancies were achieved (21.4%), and three miscarriages occurred (33.3%). | Although the clinical pregnancy rate was higher in OA patients compared with NOA patients (40.2% vs. 21.4%, p < 0.05), the miscarriage rates did not differ among the groups (15.6% vs. 33.3%, p = NS). |
[77] | Tehraninejad et al., 2011 | Prospective | NOA patients (134) Testicular sperm by micro-TESE | Oligozoospermic patients (314) Ejaculated sperm OA patients (180) Epidydimal sperm by PESA | Miscarriage rate | From 134 micro-TESE-ICSI cycles of NOA patients, the fertilization rate was 51.8%, the clinical pregnancy rate was 13.4%, and the miscarriage rate was 8%. | The frequency of miscarriage from men with NOA (8%) was similar compared to oligozoospermic (10.7) and OA (9.7%) patients (p = NS). |
[88] | Cavallini et al., 2011 | Retrospective | TESE-ICSI cycles performed in NOA patients (184) | NR | Miscarriage rate | From 184 ICSI cycles, 14 pregnancies were achieved, and 1 miscarriage occurred. | NR |
[87] | Boitrelle et al., 2011 | Retrospective | TESE-ICSI cycles performed in NOA patients (280) | NR | Miscarriage rate | Of the 38 pregnancies, three suffered a miscarriage before the first trimester of pregnancy. | NR |
[101] | Abdel Raheem et al., 2013 | Retrospective | TESE-ICSI cycles from NOA patients (77) Hypo (27) MA (20) SCO (18) | TESE-ICSI cycles from OA patients (60) | ICSI outcomes | There were no statistically significant differences in any of the ICSI outcomes measures (fertilization rate, embryo cleavage rate, clinical pregnancy rate, live birth rate, miscarriage rate) between different testicular histopathologies of NOA patients. | There were no statistically significant differences in any ICSI outcomes when using fresh and frozen-thawed sperm from OA or NOA patients. Additionally, ICSI outcomes did not differ between cycles that used or did not use pentoxifylline for motility enhancement. |
[102] | Celikten et al., 2013 | Retrospective | TESE-ICSI cycles of NOA patients (133) | PESA-ICSI cycles of OA patients (78) | ICSI outcomes | From 133 TESE-ICSI of NOA patients, 26 pregnancies were achieved (19.5%), and 16 miscarriages occurred (61.5%). | There were no significant differences in clinical pregnancy (16/78 vs. 26/133, p = NS) and miscarriage rates (10/16 vs. 16/26, p = NS) in OA and NOA patients. |
[103] | Karacan et al., 2013 | Retrospective | Testicular sperm from NOA patients (209) by micro-TESE Only motile spermatozoa | Testicular sperm from OA patients (128) by TESE Only motile spermatozoa | ICSI outcomes | The miscarriage rates for NOA patients were similar whether using fresh sperm (6.8%, 2/23), sperm used 24 h later (12.5%, 1/8), or frozen-thawed sperm (10%, 2/20), with no statistically significant differences (p = NS). | There were no statistically significant differences in any parameters (implantation rate and miscarriage) among the groups (p = NS). |
[82] | Madureira et al., 2014 | Retrospective | Testicular sperm from NOA patients with KS (65) by TESE: Fresh sperm (19) Frozen-thawed sperm (13) | NR | Miscarriage rate | The miscarriage rates of NOA patients with KS did not differ from using fresh sperm (16.7%, 2/12) compared with frozen-thawed sperm (0%, 0/4) (p = NS). | NR |
[92] | Karacan et al., 2014 | Retrospective | NOA patients (86) TESE (47) Micro-TESE (39) | NR | Miscarriage rate | From 12 clinical pregnancies, there was only 1 case of miscarriage using TESE sperm retrieval. The only pregnancy achieved by micro-TESE ended in full-term delivery. | NR |
[106] | Esteves et al., 2014 | Retrospective | Testicular sperm from NOA patients (151) by micro-TESE | Testicular sperm from OA patients (146) by TESA Ejaculated sperm from donors (40) | ICSI outcomes | From 48 infants delivered after ICSI with testicular sperm from NOA patients, 18 deliveries were singletons (58.1%), 9 were twins (29%), and 4 were triplets (12.9%). | The miscarriage rates did not differ among NOA (28.6%, 12/42), OA (23.9%, 16/67) patients and donor sperm (25%, 5/20) (p = NS). |
[93] | Hessel et al., 2015 | Retrospective | TESE-ICSI cycles (745) from NOA patients (61%) and OA patients (39%) Motile sperm (586) Immotile sperm—tail touch (159) | NR | Miscarriage rate | There was no significant difference in abortion rates between motile spermatozoa (24%) compared with tail touch spermatozoa (38%, p = 0.08). | NR |
[75] | Mazzilli et al., 2017 | Retrospective | TESE-ICSI of NOA patients (49) | TESA-ICSI of OA patients (34) ICSI infants with ejaculated sperm from: OAT (188); Moderate male factor (420); Normozoospermic (528). | ICSI outcomes | From 49 TESE-ICSI cycles of NOA patients, 7 pregnancies were achieved and 1 case of miscarriage (14.3%). | There were no statistically significant differences among groups in biochemical pregnancy and miscarriage rates. |
[104] | Bocca et al., 2017 | Retrospective | NOA patients (8) | OA patients (44) | Miscarriage rate | Miscarriage rates between OA and NOA groups were not significantly different (10.7% vs. 23.1%, p = NS). Maternal age <35 or >35 had no significant impact on these results (p = NS). | NR |
[109] | Okuyama et al., 2017 | Retrospective | NOA patients (388), including AZFc (28) and KS (83) | Cryptozoospermia (58) OA (272) | Miscarriage rate | The frequency of miscarriage from men with NOA was similar comparing fresh oocytes and fresh sperm/fresh oocytes and frozen-thawed sperm/frozen-thawed oocytes and fresh sperm (p = NS). | The frequency of miscarriage was similar comparing all groups (p = NS). |
[79] | Zhang et al., 2021 | Retrospective | NOA patients (65) who underwent 70 ICSI cycles 40 ICSI cycles with fresh spermatozoa (group A); 30 ICSI cycles with cryopreserved spermatozoa (group B). | NR | Miscarriage rate | There were significantly higher miscarriage rates in group B with cryopreserved spermatozoa (23.8%) than in group A with fresh spermatozoa (0%) (p = 0.009). | NR |
[105] | Vahidi et al., 2021 | Retrospective cross-sectional study | Testicular sperm from NOA patients (138) | Testicular sperm from OA patients (172) | Miscarriage rate | There was no difference in miscarriage rates between OA (7/172, 4.0%) and NOA (5/138, 3.6%) patients (p = NS). | |
[81] | Zhang et al., 2021 | Retrospective | Micro-TESE-ICSI cycles performed in NOA patients (347) KS (125) AZFc (64) Cryptorchidism (39) Mumps and orchitis (23) Idiopathic (96) | NR | Miscarriage rate | No differences were found in the miscarriage rates among all groups (p = NS). | NR |
[80] | Zhang et al., 2021 | Retrospective | Micro-TESE-ICSI cycles performed in NOA patients (344) Fresh sperm (234) Frozen-thawed sperm (110) | NR | Miscarriage rate | The miscarriage rate using fresh sperm was 6.0% (7/116) while the rate using frozen-thawed sperm was 14.9% (7/47) (p = 0.129). | NR |
[107] | Ping et al., 2022 | Retrospective | ICSI infants from NOA patients (84) | ICSI infants from extremely OZ (163) Severe OZ (174) Mild OZ (148) OA (155) Normozoospermia (210) | Miscarriage rate | NOA patients had a lower miscarriage rate (2/84; 3.3%), but the difference was not statistically significant (p = 0.44). Extremely OZ (9/163; 7.2%); Severe OZ (5/174; 3.9%); Mild OZ (7/148; 7.5%); OA (3/155; 2.7%); Normozoospermia (10/210; 6.2%). | |
[108] | Xu et al., 2023 | Retrospective | ICSI cycles from NOA patients (158) using testicular fresh sperm | ICSI cycles from OA patients (435) and oligoasthenozoospermia patients (92) using fresh testicular sperm | ICSI outcomes | From 158 TESE-ICSI cycles performed in NOA patients, the clinical pregnancy rate was 66.5% (105/158), and the live birth rate was 59.5% (94/158). | There were no significant differences between the three groups in terms of biochemical pregnancy rate, clinical pregnancy rate, live birth rate, or abortion rate. Miscarriage rates: Oligoasthenozoospermia 5.43% (5/92); OA 6.9% (30/435); NOA 5.06% (8/158) (p = NS). |
[78] | Elzeiny et al., 2024 | Retrospective | NOA-ICSI cycles (63) | NR | Neonatal outcomes | From 63 NOA-ICSI cycles, there were 39 clinical pregnancies, and 2 miscarriages reported. | NR |
4.2. Chromosomal Abnormalities
4.3. Congenital Malformations
4.4. Psychological and Neurological Development
Reference # | Study | Design | Study Group (n) | Control Group (n) | Outcome Measures | Findings | |
---|---|---|---|---|---|---|---|
NOA Infants | NOA-Infants vs. Comparator | ||||||
[127] | Palermo et al., 1999 | Retrospective | ICSI infants from NOA patients (22) | ICSI infants from OA patients (158) | Congenital malformation | Of 22 NOA-ICSI infants, only one child was born with a malformation (4.5%). | The incidence of congenital malformation did not vary according to the sperm origin or cause of azoospermia: OA: 1.3%; NOA: 4.5%. |
[128] | Scholtes et al., 1999 | Retrospective | ICSI infants (160) NOA (116) | OA (44) | Congenital malformation | From 36 live births, there was 1 case of congenital malformation (not specified). | NR |
[129] | Ludwig et al., 2003 | Retrospective | ICSI infants from: NOA patients (86); OA patients (68) | ICSI infants from OAT patients (1980) | Major congenital malformation | Of 112 NOA-ICSI infants, eight children were born with a major malformation (7.1%). | There were no differences between groups in major malformation: OAT: 8.7%; OA: 8.4%; NOA: 7.1%. |
[130] | Vernaeve et al., 2003 | Retrospective | ICSI infants with testicular sperm from NOA patients (83): Fresh sperm (72); Frozen-thawed sperm (11) | ICSI infants with testicular sperm from OA patients (216): Fresh sperm (189) Frozen-thawed sperm (27) | Congenital malformation | NOA-ICSI infants malformations: Major malformation: Polydactyly pre-axial fingers Bilateral cleft lip Minor malformation: Bilateral inguinal hernia in premature child | Among live-born children, major malformations rates were: NOA: 4% (2/54); OA: 3% (5/188); (RR: 1.4, 95% CI: 0.19–7.8). The rates of minor malformations were: NOA: 2% (1/54); OA: 4% (8/188) (RR: 0.4, 95% CI: 0.02–3.27). |
[131] | Vernaeve et al., 2004 | Retrospective | TESE-ICSI cycles performed in NOA patients (156): Orchidopexy (64); Unexplained (92) | NR | Congenital malformation | In the 15 live-born children in the orchidopexy group, one major (lipomeningocoele) and one minor (open ductus arteriosus) malformation were observed. No malformations were observed in the live-born children in the unexplained group. | NR |
[132] | Fedder et al., 2007 | Retrospective | ICSI infants from NOA patients (76) | ICSI infants from OA patients (282) | Congenital malformation | A total of 76 children were born to NOA patients, and none had any malformations. | There were no differences in congenital malformation among the groups: OA: 4.0%; NOA: 0%. |
[133] | Belva et al., 2011 | Prospective | ICSI infants from NOA patients (193) | ICSI infants from OA patients (474) | Congenital malformation | Of 168 NOA-ICSI infants, seven children were born with major malformation, of which three were genital malformation (cryptorchid testes and hypospadias). | There were no differences in congenital malformation among the groups: OA: 5.2%; NOA: 4.2%. |
[134] | Tavukcuoglu et al., 2013 | Retrospective | Micro-TESE-ICSI cycles from NOA patients (82): Fresh sperm (43) Frozen-thawed sperm (39) | NR | ICSI outcomes | There were no statistically significant differences in embryo quality, clinical pregnancy, live birth, and miscarriage rates when using fresh and frozen-thawed sperm in ICSI cycles from NOA patients. No congenital anomalies or major malformations were noted in both groups. | NR |
[135] | Oron et al., 2014 | Retrospective | ICSI infants (108) NOA (54) | OTA (54) | Fetal malformation | From 39 live births, there were 3 cases (7.6%) of fetal malformation (bilateral inguinal hernia, multiple malformations, polydactyl). | The fetal malformation rates were similar between the groups (p = NS). |
[106] | Esteves et al., 2014 | Retrospective | ICSI infants from testicular sperm by micro-TESE of NOA patients (151 cycles) ICSI infants from testicular sperm by TESA of OA patients (146 cycles) | ICSI infants from ejaculated sperm of donors (40 cycles) | Outcomes of neonates | In the group of NOA patients, two deliveries involved either perinatal death (2.1%, 1/48) or a malformation (cleft lip and palate) (2.1%, 1/48), leading to an overall adverse neonate outcome rate of 4.1%. | Among 24 neonates born from donor sperm, there were no cases of congenital malformations. By contrast, among 65 neonates born to OA patients, there was one case of perinatal death (1.5%, 1/65) and one case of malformation (1.5%, 1/65). However, the rates of congenital malformations and perinatal deaths did not significantly differ between the three groups (p = NS). |
[136] | Tsai et al., 2015 | Retrospective | ICSI infants (154); NOA (87) | OA (67) | Clinical outcomes | Only 1 case of heart minor anomaly and 1 case of heart major anomaly were reported in the NOA group. There were no musculoskeletal or urogenital system anomalies. | Neonatal outcomes were similar in the two groups, with comparable minor congenital anomalies (heart, musculoskeletal system, and urogenital system) and major congenital anomalies (heart major anomalies). |
[137] | Yu et al., 2018 | Retrospective | ICSI infants (225); NOA (44) | OA (126) Donor sperm (62) | Clinical outcomes | No baby was stillborn or had malformations in the NOA group. | One baby (2.2%) was stillborn due to megabladder in the donor sperm group. In the OA group, two pairs of twins (3.8%) died shortly after their premature birth (gestational age of 24 weeks and 28 weeks, respectively), and one baby (1.0%) had hypospadia. Live birth rates were significantly lower in the NOA group than in the donor sperm group (24.6% vs. 41.3%, p = 0.04) but not significantly lower than in the OA group (p = NS). Live birth rates were similar between the OA group and the donor sperm group. |
[81] | Zhang et al., 2021 | Retrospective | ICSI infants from NOA patients (769): KS (284)—125 cycles AZFc microdeletion (91)—64 cycles Cryptorchidism (52)—39 cycles Orchitis (23)—23 cycles Idiopathic (319)—96 cycles | NR | Congenital defects | No difference was found in birth defects among all groups (p > 0.05). Only three cases of birth defects were reported, all in the KS group. | NR |
[79] | Zhang et al., 2021 | Retrospective | ICSI infants from NOA patients (338): Fresh sperm (222) Cryopreserved sperm (116) | NR | Congenital defects | No difference was found in birth defects among the group with fresh or cryopreserved sperm. Only three cases were reported in the group with fresh sperm (3/108, 2.8%), while no case was reported in the group with cryopreserved sperm (0/40, 0%). | NR |
[63] | Lan et al., 2022 | Retrospective | ICSI infants from NOA patients (968) | NR | Clinical outcomes | From 140 live-birth deliveries, the birth defects rate was 1.43% (one case with cardiovascular malformation and the other with a cleft lip and palate). Singleton newborns of the frozen sperm group had higher height compared to the fresh sperm group (49.84 ± 2.04 cm vs. 48.50 ± 3.03 cm, p < 0.05). Among different etiologies of NOA, the highest rate of premature birth (50%) was observed in patients with Y chromosome AZFc microdeletions (p < 0.05). | NR |
[107] | Ping et al., 2022 | Retrospective cohort | ICSI infants from NOA patients (84) | ICSI infants from extremely OZ (163) Severe OZ (174) Mild OZ (148) OA (155) Normozoospermia (210) | Congenital defects | There were only two cases of major birth defects (both were patent foramen ovale): one in the NOA group (1/84; 1.6%) and the other in the normozoospermic group (1/210; 0.6%) (p = 0.34). | NR |
[138] | Romano et al., 2023 | Retrospective | ICSI infants from NOA patients (260) 446 COS cycles | ICSI infants from OA patients (290) 620 COS cycles | Congenital defects | Neonatal outcomes were similar in the two groups, with comparable gestational age and birth weight for single or twin pregnancies (p = 0.32). | OA: 7 cases of congenital defects (2 cases of persistently patent arterial duct of Botallo, hypospadias, bilateral clubfoot, right-side hemispondyl, cryptorchidism, and pharyngeal defects). NOA: 2 cases of congenital defects (intraventricular defect and hypospadias). |
[139] | Zhang et al., 2023 | Retrospective | ICSI infants from NOA (235) ICSI cycles with immotile sperm injection (101) with AOA | ICSI cycles with motile sperm injection (230) AOA (129) Non-AOA (101) | Clinical outcomes | From 141 live-birth deliveries, there were no early neonatal deaths or birth defect cases. | Neonatal outcomes, including singleton and twin birth rate, baby’s birth weight, and baby’s body length, were comparable among the three groups. |
[78] | Elzeiny et al., 2024 | Retrospective | ICSI infants from NOA patients (108) | NR | Neonatal outcomes | From 63 couples who started ICSI, a total of 47 live offspring with no neonatal deaths or defects were reported. | NR |
5. Managing Patient Expectations
5.1. Genetic Considerations and Counseling
5.2. Reducing the Risk for Offspring: Pros and Cons of PGT-A
6. Future Directions
6.1. Advances in Testicular Sperm Retrieval
6.2. Stem Cell Therapy
6.3. Gene Editing Technologies
7. Conclusions
8. Review Criteria
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Reference # | Study | Design | Study Group (n) | Control Group (n) | Outcome Measures | Findings | |
---|---|---|---|---|---|---|---|
NOA-ICSI Infants | NOA-ICSI Infants vs. Comparator | ||||||
[110] | Martin et al., 2000 | Prospective | NOA patients (3) | Ejaculated sperm from fertile donors (18) | Sperm numerical abnormalities for chromosomes 13, 21, X, and Y, as well as the proportion of X- and Y-chromosome-bearing spermatozoa and diploidy | The frequency of disomy for chromosome 13, 21, and XY disomy was elevated but without statistical significance. | The only statistically significant difference between the infertile patients and control donors was for the proportion of YY disomy in which NOA patients had 0% compared to 0.06% in controls (p < 0.001) |
[111] | Bernardini et al., 2000 | Retrospective | NOA patients (3) OA patients (6) Patients with severe OAT (22) Patients with unexplained infertility (3) | Healthy donors (10) | Sperm aneuploidy for chromosomes X, Y, 1, and 17 | The frequency of spermatozoa aneuploidy, diploidy, and nullisomy for chromosomes 1 and 17 was significantly higher in NOA patients than in the other groups (unexplained infertility, OAT, and OA; p < 0.00001). The frequency of sex chromosome DNA-ploidy and nullisomy were also higher in NOA patients than in the other groups (unexplained infertility, OAT, and OA; p < 0.00001). | The frequency of spermatozoa aneuploidy, diploidy, and nullisomy for chromosomes 1 and 17 was significantly higher in NOA patients than in controls (p < 0.01). The frequency of sex chromosome DNA-ploidy and nullisomy were also higher in NOA patients than in controls (p < 0.01). |
[112] | Levron et al., 2001 | Retrospective | Testicular spermatozoa (9): NOA patients Testicular spermatozoa (10): OA patients Ejaculated spermatozoa (9): Oligoasthenoteratospermia patients | Ejaculated spermatozoa (6) from normal fertile donors | Sperm numerical abnormalities for chromosomes 18, X, and Y | The aneuploidy rates among the sperm were: 19.6% (30/153) of NOA patients; 8.2% (30/367) of OA patients; 13.0% (228/1751) of severe OAT; 1.6% (8/500) of controls. The disomy rates among groups were: 7.8% (12/153) in NOA patients; 4.9% (18/367) in OA patients; 6.2% (109/1751) in severe OAT; 1% (5/500) in controls. The disomy rates in groups of NOA, OA, and OAT patients were significantly higher than the controls (p < 0.001). In addition, the disomy rate was significantly higher in NOA and OAT patients than OA patients (p < 0.01). | NR |
[113] | Burrello et al., 2002 | Prospective | Testicular spermatozoa (6): NOA patients Epididymal spermatozoa (10): OA patients | Ejaculated spermatozoa (14) from healthy men | Sperm numerical abnormalities for chromosomes 8, 12, 18, X and Y | The frequency of total sex chromosome disomy was higher in testicular sperm (2.07%; range: 1.02 ± 6.25) than ejaculated sperm (0.43%; 0 ± 0.90%; p < 0.05), but not statistically different than epididymal sperm (1.38%; 0.75 ± 5.76); the frequency of autosome nullisomy was comparable among groups. The frequency of total autosome disomy (chromosomes 8, 12, and 18) was higher in epididymal (1.2%; 0 ± 4.09%) and testicular (2.23%; range: 0.96 ± 17.4%) spermatozoa compared to those in ejaculated spermatozoa (0.46%; 0.15 ± 0.65%; p < 0.05); the frequency of autosome nullisomy was comparable among groups. | The frequencies of sex chromosome and autosomes disomy were statistically higher in both testicular and epididymal spermatozoa compared to ejaculated spermatozoa. |
[114] | Mateizel et al., 2002 | Retrospective | Testicular spermatozoa (17): NOA patients | Testicular spermatozoa (26) from men with normal spermatogenesis | Sperm numerical abnormalities for chromosomes 18, X, and Y | There was no significant difference in numeric chromosomal abnormalities among the groups (8.2% vs. 5.6%, p = 0.076). Similarly, no differences were found in total disomy (2.5% vs. 3.7%, p > 0.05). | The proportion of sex chromosome aneuploidy was 5.8% in NOA patients and 4.5% in controls (p > 0.05). However, there was a significantly higher frequency of aneuploidy for chromosome 18 in NOA patients (3.2%) than the control group (1.3%; p = 0.016). The frequency of sex chromosome disomy was similar among groups (2.2% vs. 2.4%, p > 0.05). However, a higher frequency of disomy for chromosome 18 was observed in NOA patients (1.3%) than in the control group (0.3%; p = 0.05). Neither sex chromosome nullisomy frequency nor chromosome 18 nullisomy frequency were different between NOA patients and control. |
[115] | Palermo et al., 2002 | Prospective | Testicular spermatozoa (5): NOA patients Epididymal spermatozoa (8): OA patients | Ejaculated spermatozoa (14) Healthy men | Sperm numerical abnormalities | The sperm aneuploidy rate was 11.4% in NOA men, 1.8% in OA patients, and 1.5% in ejaculate controls. | The incidence of chromosomal abnormalities in the NOA patients was significantly higher than in the OA and control groups (p = 0.0001); the most predominant abnormality in NOA men was sex chromosome disomy (37.5%), followed by nullisomy (32.1%). |
[116] | Martin et al., 2003 | Prospective | NOA patients (6) | Ejaculated sperm from fertile donors (18) | Sperm numerical abnormalities for chromosomes X and Y | The frequency of sex chromosomal disomy for XY, YY, and total sex chromosome disomy and diploidy was higher compared with control donors, but only YY disomy reached statistical significance (p = 0.02). | One NOA patient had a frequency of 3.8% XY disomy and 4.3% diploidy, 13-fold and 7-fold higher than control donors, respectively. |
[117] | Silber et al., 2003 | Retrospective | Embryos derived from 19 TESE-ICSI cycles of NOA patients (100) | Embryos derived from 111 cycles of ICSI with ejaculated sperm from oligozoospermic patients (830) | Embryo numerical abnormalities for chromosomes 13, 15, 16, 18, 21, 22, X and Y | The rates of normal embryos were higher in the oligozoospermia-ICSI group than TESE-ICSI group (41.8% vs. 22%, p < 0.001). In addition, the rates of mosaic embryos were higher in the TESE-ICSI group than in the oligozoospermia-ICSI group (53% vs. 26.5%, p < 0.001). The rates of aneuploidy per chromosome were similar in both groups, including 2.9% and 1% rates of sex chromosome aneuploidy in oligospermia-ICSI and TESE-ICSI groups. | NR |
[118] | Rodrigo et al., 2004 | Prospective | NOA patients (13) OA patients: Testicular sperm (7) Epididymal sperm (2) | Normozoospermic patient: Ejaculated sperm (5) | Sperm numerical abnormalities for chromosomes 13,18, and 21 and sex chromosomes X and Y | Fresh and frozen-thawed testicular sperm samplers showed similar incidences of chromosomal abnormalities for chromosomes 13, 18, 21, and sex chromosomes in NOA patients. | Testicular samples from NOA patients showed significantly higher rates of diploidy (p < 0.0001) and disomy chromosomes 13 (p < 0.0001) and 21 (p < 0.001) and for sex chromosomes (p < 0.0001) than those of the control group. The incidence of diploidy and disomy for sex chromosomes rates was higher in the testicular samples from NOA patients when compared to testicular samples from OA patients. |
[119] | Ma et al., 2006 | Retrospective | Testicular sperm from NOA patients (3) | Testicular sperm from OA patient (1) | Sperm numerical abnormalities | The overall aneuploidy, sex aneuploidy, sex disomy, and sex nulisomy of the NOA patients were higher than those of control (p < 0.05). | NR |
[120] | Sun et al., 2008 | Prospective | Testicular sperm from NOA patients (7) | Ejaculated sperm from a control group after vasectomy reversal (6) | Sperm numerical abnormalities for chromosomes 9, 21 and sex chromosomes X and Y | The frequency of disomy for chromosome 21 (p = 0.001), XX (0.004), and YY (0.04) was significantly elevated in NOA patients compared with controls. | NR |
[121] | Magli et al., 2009 | Retrospective | OAT men (134 cycles, of which 76 were severe OAT), OA men (29 cycles), and NOA men (27 cycles) | Normozoospermic men (105 cycles) | Embryo numerical abnormalities for chromosomes 13, 15, 16, 17, 18, 21, 22, X and Y | The frequency of abnormal embryos was significantly lower in normozoospermic patients (55%) than in OA (62%, p < 0.025) and NOA (69%, p < 0.005). | NR |
[122] | Rodrigo et al., 2011 | Prospective | Testicular sperm from: OA patients (16); NOA patients (19) | Ejaculated sperm from fertile donors (10) Testicular sperm from fertile donors (10) | Sperm numerical abnormalities for chromosomes 13, 18, 21, X and Y; Implantation and ongoing pregnancy rates in ICSI cycles | Testicular sperm from fertile donors showed a higher incidence of diploidy (0.27% vs. 0.10%; p < 0.0001) and disomy for chromosomes 13 (0.16% vs. 0.07%; p < 0.05) and 21 (0.25% vs. 0.12%; p < 0.01), and sex chromosomes (0.34% vs. 0.21%; p < 0.05) than ejaculated sperm from fertile donors. Sperm chromosomal abnormalities were higher in surgically retrieved gametes from azoospermic men (12.5% in OA and 68.4% in NOA) than in ejaculated sperm from fertile donors. No differences in the percentage of genetically abnormal sperm were observed when surgically retrieved sperm from azoospermic patients were compared with testicular sperm from fertile donors. ICSI reproductive outcomes in NOA patients resulted in a significantly lower fertilization rate and poorer embryo quality than in OA patients. The ongoing pregnancy rate per ICSI cycle was lower for NOA than OA patients (21.4% vs. 38.1%). | NR |
[123] | Vialard et al., 2012 | Retrospective | Testicular sperm from: KS patients (10) NOA patients with normal karyotype (19) OA patients (22) | Normal sperm analysis (11) | Sperm numerical abnormalities for chromosomes 18, X, and Y by FISH | The aneuploidy rates were higher in KS patients (5.3%) than in NOA patients with normal karyotypes (4.0%; p = 0.0089). However, both rates were higher than OA patients (0.65%) and controls (0.58%) (p < 0.0001). | Gonosome aneuploidy (X and Y) frequency were similar between KS and NOA patients (3.48% and 2.39%, respectively), but these rates were significantly higher than those patients with OA and controls (0.49% and 0.44%, respectively) (p < 0.0001). The same was true for chromosome 18 abnormalities frequencies (1.43%, 1.19%, 0.15%, 0.10% for KS, NOA, OA, and controls, respectively) (p < 0.0001). |
[124] | Vozdova et al., 2012 | Prospective | Testicular sperms from NOA patients (17) | Ejaculated sperms from normozoospermic donors (10) | Sperm numerical abnormalities for chromosomes X, Y, 13, 15, 16, 18, 21 and 22 by FISH | The frequency of disomy (2.32%) and diploidy (0.80%) was significantly higher in testicular sperm from men with NOA than in ejaculated sperm of normozoospermic donors (disomy: 0.62%; diploidy: 0.29%; p < 0.001 and p = 0.031, respectively). | NR |
[125] | Weng et al., 2014 | Retrospective | Embryos derived from 11 ICSI cycles of NOA patients by TESE (54) Embryos derived from 11 ICSI cycles of OA patients by MESA (58) | Embryos derived from 101 ICSI cycles of ejaculated sperm (460) | Embryo numerical abnormalities for chromosomes 8, 9, 13, 14, 15, 16, 17, 18, 20, 21, 22, X and Y | The rates of complex abnormalities were not statistically different between the MESA and TESE groups. The aneuploidy rate in each studied chromosome was not different among these three groups. The rate of abnormality in sex chromosomes did not differ from the rate of autosomal chromosomes, and there was no difference in the rates of abnormality between the X and the Y chromosomes. | There was a higher incidence of complex chromosomal abnormality in MESA-derived embryos than in TESE and ejaculated embryos. |
[126] | Cheung et al., 2019 | Prospective | Testicular sperms from NOA patients (4) | Epididymal sperms from OA patients (2) Ejaculated sperms from non-azoospermic infertile men (16) | Sperm numerical abnormalities for chromosomes 15, Y | Aneuploidy rates were higher in the ejaculated group (11.1%) compared to the epididymal sperm group from OA men (1.8%) and testicular sperm group from NOA men (1.5%) (p < 0.0001). | NR |
Reference # | Study | Design | Study Group (n) | Control Group (n) | Outcome Measures | Associations | |
---|---|---|---|---|---|---|---|
NOA-ICSI Infants | NOA-ICSI Infants vs. Comparator | ||||||
[140] | Tsai et al., 2011 | Retrospective | TESE-ICSI infants (60) from NOA and OA patients | Children born after ICSI using freshly ejaculated sperm from men with severe OAT (21) | Perinatal outcomes and development of children assessed at the age of 1–7 years | No evidence of differences in the development of children after TESE-ICSI or ICSI using sperm from men with severe OAT. | No significant psychomotor or intellectual development delays were observed in all ICSI infants. |
[136] | Tsai et al., 2015 | Retrospective | ICSI infants (154); NOA (87) | OA (67) | Clinical outcomes | Children’s development outcomes were evaluated using a preschool developmental screening Table until 60 months of age. Items assessed: child’s feeding and sleeping behavior; posture; coordination; memory; problem-solving skills; language skills; socialization. | The general health of the children conceived using ICSI was satisfactory, with none showing major handicap in psychomotor or intellectual development. |
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Majzoub, A.; Viana, M.C.; Achermann, A.P.P.; Ferreira, I.T.; Laursen, R.J.; Humaidan, P.; Esteves, S.C. Non-Obstructive Azoospermia and Intracytoplasmic Sperm Injection: Unveiling the Chances of Success and Possible Consequences for Offspring. J. Clin. Med. 2024, 13, 4939. https://doi.org/10.3390/jcm13164939
Majzoub A, Viana MC, Achermann APP, Ferreira IT, Laursen RJ, Humaidan P, Esteves SC. Non-Obstructive Azoospermia and Intracytoplasmic Sperm Injection: Unveiling the Chances of Success and Possible Consequences for Offspring. Journal of Clinical Medicine. 2024; 13(16):4939. https://doi.org/10.3390/jcm13164939
Chicago/Turabian StyleMajzoub, Ahmad, Marina C. Viana, Arnold P. P. Achermann, Isadora T. Ferreira, Rita J. Laursen, Peter Humaidan, and Sandro C. Esteves. 2024. "Non-Obstructive Azoospermia and Intracytoplasmic Sperm Injection: Unveiling the Chances of Success and Possible Consequences for Offspring" Journal of Clinical Medicine 13, no. 16: 4939. https://doi.org/10.3390/jcm13164939