Abstract
Infertility affects more than 14% of couples, 30% being caused by male factor infertility. This meta-analysis includes 28 studies, selected according to PRISMA guidelines. Data were extracted from these studies to collate cycles separating paternal age at 30, 35, 40, 45 and 50 years (±1 year). Primary outcomes of interest were clinical pregnancy, live birth and miscarriage rates. Secondary outcomes were the number of fertilized eggs, cleavage-stage embryos and blastocysts, and embryo quality per cycle. Fixed-effects and random-effects models giving pooled odds ratios (OR) were used to assess the effect of paternal age. This meta-analysis included a total 32,484 cycles from 16 autologous oocyte studies and 12 donor oocyte studies. In autologous cycles, a statistically significant effect of paternal age <40 years was noted in clinical pregnancy (OR 1.65, 95% confidence interval [CI] 1.27–2.15), live birth (OR 2.10, 95% CI 1.25–3.51) and miscarriage (OR 0.74, 95% CI 0.57–0.94) rates. Paternal age <50 years significantly reduced miscarriage rate (OR 0.68, 95% CI 0.54–0.86), and increased blastocyst rate (OR 1.61, 95% CI 1.08–2.38) and number of cleavage-stage embryos (OR 1.67, 95% CI 1.02–2.75) in donor oocyte cycles, where maternal age is controlled. This is an important public and societal health message highlighting the need to also consider paternal age alongside maternal age when planning a family.
Key words
Introduction
Infertility is defined as an inability to achieve clinical pregnancy after 12 months or more of regular, unprotected sexual intercourse. A total of 1 in 7 couples in the UK are estimated to be affected by infertility, 30% of which is due to male factor infertility, with 25% of cases unexplained (
NICE 2013
); this can often have distressing and psychological consequences for patients. Many demographic studies have shown that fertility rates have fallen significantly over the years, with a delay in family planning observed in not only women, but also men. Figures in England and Wales have demonstrated that fathers aged 35–54 years accounted for 40% of live births in 2003, compared with only 25% in 1993 (Bray et al., 2006
). With childbearing increasingly delayed, it is crucial to understand the potential consequences of this for men as well as women.The damaging effects of increased maternal age on fertility have been well established with studies showing significantly reduced rates of conception over 40 years of age (
Leridon, 2004
) with associated increasing risks of implantation failure, miscarriage secondary to oocyte aneuploidy (Fragouli and Wells, 2011
), and obstetric and perinatal complications (Oldereid et al., 2018
). However, relatively little evidence exists on how paternal age can affect fertility in general. Similarly, the impact of paternal age on the health of the offspring has been less researched compared with maternal age. The adverse conditions most consistently associated with increased paternal age include musculoskeletal syndromes, cleft palate, acute lymphoblastic leukaemia and retinoblastoma, and neurodevelopmental disorders in the autism spectrum and schizophrenia (Andersen and Urhoj, 2017
).Increasing paternal age has already been indicated to have negative implications for testicular function (
Handelsman and Staraj, 1985
; Sampson et al., 2007
), with direct effects on semen parameters, such as reduced sperm concentration and motility (Bartolacci et al., 2018
; - Bartolacci A.
- Pagliardini L.
- Makieva S.
- Salonia A.
- Papaleo E.
- Viganò P.
Abnormal sperm concentration and motility as well as advanced paternal age compromise early embryonic development but not pregnancy outcomes: a retrospective study of 1266 ICSI cycles.
Journal of assisted reproduction and genetics. 2018; 35: 1897-1903
Eskenazi et al., 2003
; Jung et al., 2002
; Levitas et al., 2007
). Some studies have been able to demonstrate a paternal age effect specifically on fertility rates, where paternal age over 40 years has shown to significantly reduce fecundity and increase miscarriage rates (De La Rochebrochard and Thonneau, 2005
; Dunson et al., 2002
; Ford et al., 2000
; Hassan and Killick, 2003
).A larger proportion of research has focused on assisted reproductive technology (ART). De La Rochebrochard and colleagues found that, in couples undergoing IVF, the likelihood of conception was reduced in males aged over 40 years (
De La Rochebrochard et al., 2006
), with other smaller studies showing a reduction in fertilization and live birth rate in older men (Aboulghar et al., 2007
; Belloc et al., 2008
; Klonoff-Cohen and Natarajan, 2004
). Horta and co-workers looked at 2425 cycles of IVF/intracytoplasmic sperm injection (ICSI) in couples with idiopathic infertility, and found a negative effect of male age and female age on live birth rate for each additional year of age (Horta et al., 2019
). Van Opstal and collaborators demonstrated that an advanced paternal age has an impact on embryo quality score in IVF treatment (Van Opstal et al., 2021
). Mignini Renzini and colleagues undertook a multicentre retrospective cohort study of 755 ICSI cycles, and found that the use of sperm donors increased the live birth rate and reduced miscarriage rates in women with advanced maternal age (Mignini Renzini et al., 2021
), thus suggesting that this may be a strategy to improve the outcome of ICSI in this group. A factor to consider is the role of paternal age in the autologous control group compared with the sperm donation group.In contrast, some studies looking at fertilization, pregnancy, miscarriage and live birth rates have found no significant association with paternal age (
Bellver et al., 2008
; Sagi-Dain et al., 2015
; Spandorfer et al., 1998
). It is clear that more information is required to understand male factor infertility and its age-related effects, particularly given the conflicting results demonstrated.Objective
This meta-analysis aimed to assess the effect, if any, of paternal age on a wide range of reproductive outcomes following ART treatment.
Materials and methods
The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement 2020 checklist guidelines (
Page et al., 2021
). A literature search was performed using the PubMed, MEDLINE and Google Scholar databases for comparative studies up to and including June 2020. The objective of the search was to investigate the clinical significance of increasing paternal age on fertilization rates and pregnancy outcomes in ART. The following MESH search headings were used: ‘increased+paternal age+IVF’, ‘paternal age+IVF’, ‘paternal age+ICSI’, ‘paternal age+fertility treatment’ and ‘paternal age+ART’. The ‘related articles’ function was used to broaden the search and all citations identified were reviewed, irrespective of language. No studies investigating the effect of paternal age on ART outcomes were found before 1995. Therefore, the relevant studies were found between 1995 and 2020.- Page M.J.
- McKenzie J.E.
- Bossuyt P.M.
- Boutron I.
- Hoffmann T.C.
- Mulrow C.D.
- Shamseer L.
- Tetzlaff J.M.
- Akl E.A.
- Brennan S.E.
- Chou R.
- Glanville J.
- Grimshaw J.M.
- Hróbjartsson A.
- Lalu M.M.
- Li T.
- Loder E.W.
- Mayo-Wilson E.
- McDonald S.
- McGuinness L.A.
- Stewart L.A.
- Thomas J.
- Tricco A.C.
- Welch V.A.
- Whiting P.
- Moher D.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
BMJ. 2021; 372https://doi.org/10.1136/bmj.n71
Using these strategies, studies comparing ART outcomes across different paternal age groups were identified, and data regarding the outcomes of interest were extracted. The search strategy and included studies are shown in Figure 1.![Figure 1]()
Figure 1The search approach used to identify and select studies for inclusion (PRISMA flow chart).
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Data extraction
Three reviewers (S.M., S.S. and N.G.) independently extracted the data from each study. The following data were extracted: first author, year of publication, study design, study period, study country and study groups (fertility treatment, cause of infertility, maternal and paternal age groups). Quantitative data assessing fertility-related outcomes were also extracted: fertilization, cleavage, top-quality embryos, clinical pregnancy, live birth, miscarriage, congenital malformation and birthweight. Inclusion and exclusion criteria as well as paternal age group cut-off as per each study were collected. The Newcastle–Ottawa grading system was used to evaluate the quality of the studies (
Wells et al., 2009
).Wells, G., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., et al. The Newcastle Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in MetaAnalyses. 2009 [cited 2005 Jan 20]. Available from:http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
Inclusion and exclusion criteria
All comparative studies evaluating the effect of different paternal age groups on ART outcomes and reporting the incidence of pregnancy outcomes were included. ART defined as IVF treatment with or without ICSI was included in the meta-analysis. Studies that defined paternal age groups with cut-offs at 30, 35, 40, 45 and 50 years were included. In order to allow for standardization, those studies that reported a cut-off within a year of the specified paternal age groups were also included (30 ± 1, 35 ± 1, 40 ± 1, 45 ± 1 and 50 ± 1). Studies using donor and autologous eggs were included.
Those studies not reporting pregnancy outcomes as a rate per cycle were excluded. Finally, studies where paternal age groups were separated by more than 1 year of the specific age cut-offs as described above were not included.
Outcomes of interest
The primary outcomes of interest were the pregnancy, live birth and miscarriage rates per treatment cycle. Secondary outcomes of interest were the following incidence rates in the paternal age groups: (i) fertilization rate; (ii) cleavage rate embryos; (iii) blastulation rate; and (iv) number of top-quality embryos. Outcomes were analysed across different binary paternal age groups as reported above and separately for donor oocyte and autologous treatment cycles.
Statistical analysis
The odds ratio (OR) was used as the summary statistic to assess the effect of a particular age cut-off for each study. Consequently, all estimated odds ratios for a given outcome and age cut-off in the relevant studies were pooled (Siristatidis et al., 2013) to ensure the comprehensiveness of the analysis and maximization of the statistical power. In addition, sub-analyses were presented by type of effect measure, namely odds ratios within the subgroup of studies treating the general population as the reference.
The I2 statistic and the chi-squared test of heterogeneity were used to assess heterogeneity of treatment effects between studies. The degree of heterogeneity (I2) was categorized into low (25%), moderate (25–75%) and high (>75%). Both fixed-effects and random-effects models were used to calculate the pooled treatment effect in each meta-analysis (DerSimonian and Laird, 2015; Higgins et al., 2003).
Data were analysed using Stata (Stata Statistical Software Release 16; StataCorp, USA) and a result was regarded as statistically significant if P < 0.05.
Results
Using the literature search criteria previously described 46 studies were initially identified. Of these, 28 studies published between 1995 and 2020 were selected for the meta-analysis according to the stated selection criteria (
Aboulghar et al., 2007
; Begueria et al., 2014
; Bellver, 2008; Capelouto et al., 2018
; Chapuis et al., 2017
; - Chapuis A.
- Gala A.
- Ferrieres-Hoa A.
- Mullet T.
- Bringer-Deutsch S.
- Vintejoux E.
- Torre A.
- Hammah S.
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates.
Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4
Cito et al., 2019
; - Cito G.
- Coccia M.E.
- Picone R.
- Cocci A.
- Russo G.I.
- Garaffa G.
- Fucci R.
- Bertocci F.
- Borrani E.
- Basile V.
- Micelli E.
- Criscuoli L.
- Serni S.
- Carini M.
- Natali A.
Impact of advanced paternal age on the intracytoplasmic sperm injection outcomes in donor egg cycles.
Translational Andrology and Urology. 2019; 8: S22-S30
Frattarelli et al., 2008
; Gallardo et al., 1996
; Garcia-Ferreyra et al., 2015
; Garcia-Ferreyra et al., 2018
; Ho et al., 2015
; Horta et al., 2019
; Kaarouch et al., 2018
; Klonoff-Cohen and Natarajan, 2004
; Kumtepe et al., 2003
; Luna et al., 2009
; Medina et al., 2012
; Meijerink et al., 2016
; Meyer et al., 2012
; McPherson et al., 2018
; Nijs et al., 2011
; Park et al., 2018
; Spandorfer et al., 1998
; Tiegs et al., 2017
; Tsai et al., 2013
; Whitcomb et al., 2011
; Wu et al., 2016
; Yu et al., 2019
). Figure 1 is a PRISMA flow chart that illustrates the breakdown of the selected studies according to type of study. There was 100% agreement between the three reviewers regarding the data extraction. All the studies contained groups that were comparable in age.The characteristics of the included studies are summarized in Table 1. Quantitative data assessing fertility-related outcomes are reported in Table 2. Inclusion and exclusion criteria as well as paternal age group cut-off as per each study are listed in Table 3. Table 4 reports on the quality of studies included in the meta-analysis. Table 5 summarizes the overall findings as related to the primary outcomes (pregnancy rate, live birth rate and miscarriage rate) and secondary outcomes (fertilized embryo rate, cleavage-stage embryo rate, blastocyst rate and number of quality embryos). These findings were stated for the following paternal age cut-offs: 30, 35, 40, 45 and 50 years. Results for both fixed-effects and random-effects models are reported (Table 5). The significant results from these meta-analyses (fixed-effects model only) are presented in more detail below.
Degree of heterogeneity: Low, I2 < 25%; Moderate, I2 = 25–75%; High, I2 > 75%.Significant results shown in bold.References: 1.
Table 1Study characteristics
| First author (year) | Study type | Study period and location | Study groups | Number | Fertility treatment | Maternal age(years) | Paternal age(years) | Cause of infertility | Risk of failure to conceive | Semen analysis | Sperm DFI |
|---|---|---|---|---|---|---|---|---|---|---|---|
Horta et al., 2019 | Retrospective cohort | 1992–2017 Australia | Idiopathic infertility undergoing IVF/ICSI | n = 2425 (cycles) | Fresh IVF/ICSI cycles (100%) Autologous oocytes | Total: Mean (range) 37.1 (21–48) <30: n = 112 (4.6%) 30–34: n = 556 (22.9%) 35–39: n = 992 (40.9%) ≥40: n = 765 (31.5%) | Total: Mean (range) 46.6 (27.9–77.7) <40: n = 389 (16.0%) 40–44: n = 643 (26.5%) 45–49: n = 692 (28.5%) 50–54: n = 407 (16.8%) ≥55: n = 294 (12.1%) | Idiopathic infertility | NS | NS | NS |
Cito et al., 2019
Impact of advanced paternal age on the intracytoplasmic sperm injection outcomes in donor egg cycles. Translational Andrology and Urology. 2019; 8: S22-S30 | Retrospective cohort | January 2016 – December 2017 Italy | Infertile couples undergoing ICSI | n = 278 (couples) | ICSI with a donor egg and fresh ejaculated spermatozoa (100%) Donor oocytes | All oocyte donors: <25 (range 18–25) Recipients: Median ± SD (IQR) 42 ± 3.62 (29–50) | All men: Median ± SD (IQR) 44 ± 5.60 (31–70) | Male: Primary Female: Diminished ovarian reserve Poor response to ovarian stimulation Chromosome aberration Repeated failure of IVF cycles Premature ovarian failure | NS | Total sperm concentration (million/ml) Mean (range) ≤45: 32.0 (11.0–66.0) >45: 39.0 (14.5–79.0) P-value = 0.43 Total sperm motility (%) Mean (range) ≤45: 60.0 (50.0–70.0) >45: 52.5 (45.0–65.0) P-value = 0.02 Normal sperm morphology (%) Mean (range) ≤45: 5.0 (1.0–6.0) >45: 3.0 (1.0–5.0) P-value = 0.20 Semen volume (ml) Mean (range) ≤45: 4.0 (2.0–6.0) >45: 2.0 (1.0–4.0) P-value = 0.30 | NS |
Gallo et al., 2019
Impact of paternal age on seminal parameters and reproductive outcome of intracytoplasmatic sperm injection in infertile Italian women. Frontiers in Endocrinology. 2019; 10: 35 | Retrospective cohort | January 2015 – April 2017 Italy | Couples undergoing ICSI | n = 439 (couples) n = 543 (cycles) | ICSI (100%) Autologous oocytes | (Range) ≤35: (24–35) 36–40: (36–40) ≥41: (41–47) | (Range) ≤ 38: (25–38) 39–43: (39–43) ≥ 44: (44–64) | Primary infertility (67%) Secondary infertility (33%) | NS | Total sperm concentration (n/ml × 106) Mean (range) 25–38: 35.0 (0.1–250) 39–43: 36.7 (0.1–230) 44–64: 39.4 (0.1–210) Total sperm motility (%) Mean (range) 5–38: 32.2 (0–60) 39–43: 31.2 (0–60) 44–64: 32.4 (0–60) Abnormal forms (%) Mean (range) 25–38: 86.4 (65–100) 39–43: 87.4 (70–100)) 44–64: 86.7 (70–100) Semen volume (Ml) Mean (range) 25–38: 2.8 (0.2–0.8) 39–43: 2.7 (0.1–0.6) 44–64: 2.7 (0.2–0.9) | NS |
Kim et al., 2019 | Retrospective cohort | January 2016 – August 2017 Korea | Infertile patients undergoing IVF | n = 175 (cycles) | All fresh cycles ICSI (100%) Thawed embryo transfer cycles: IVF (27.1%) Half-ICSI (15.9%) ICSI (57%) PGT (100%) Autologous oocytes | Total females: Mean ± SD 36.0 ± 3.8 Female <35; male ≤38 Mean ± SD 32.0 ± 1.8 Female <35; male>38 Mean ± SD 33.42 ± 0.8 Female ≥ 35; male ≤38 Mean ± SD 36.9 ± 1.9 Female ≥35; male >38 Mean ± SD 39.3 ± 2.4 P-value < 0.001 | Total males: Mean ± SD 38.8 ± 5.0 Female <35; male ≤38 Mean ± SD 34.5 ± 2.4 Female <35; male>38 Mean ± SD 40.83 ± 2.4 Female ≥35; male ≤38 Mean ± SD 36.6 ± 1.9 Female ≥35; male >38 Mean ± SD 43.4 ± 4.0 P-value < 0.001 | NS | NS | NS | NS |
Yu et al., 2019 | Retrospective observational | 2010 – 2018 China | Infertile men with cryptozoospermia undergoing ICSI | n = 35 (men) n = 38 (cycles) | ICSI (100%): Ejaculated sperm (51.4%) TESA (48.6%) Autologous oocytes | NS | Mean ± SD <35: 27.5 ± 3.3 ≥35: 37.4 ± 1.8 P-value < 0.001 | Cryptozoospermia | NS | Semen volume (ml) Mean ± SD <35: 10.5 ± 4.3 ≥35: 7.9 ± 3.4 P-value = 0.07 | NS |
Capelouto et al., 2018 | Retrospective | 2008 – 2015 USA | Vitrified oocyte donor IVF cycles | n = 949 (females) | Vitrified oocyte donation IVF ICSI (100%): Fresh (94.5%) Frozen (4.2%) MESA/TESA (1.2%) Electrojaculate (0.1%) Donor oocytes | All oocyte donors (21–30) Recipients: Mean ± SD Total: 41.3 ± 4.5 ≤30: n = 24 (2.5%) 31–35: n = 107 (11.3%) 36–40: n = 268 (28.2%) 41–45: n = 431 (45.4%) 46–50: n = 113 (11.9%) ≥51: n = 6 (0.6%) | Total: Mean ± SD 41.5 ± 6.2 ≤30: n = 28 (3.3%) 31–35: n = 119 (14.0%) 36–40: n = 238 (27.9%) 41–45: n = 275 (32.2%) 46–50: n = 121 (14.2%) ≥51: n = 71 (8.3%) | Female: Diminished ovarian reserve and/or advanced reproductive age (>40) Recurrent pregnancy loss PCOS or other ovulatory dysfunction Tubal factor Endometriosis Single-gene mutation Multiple failed prior autologous IVF oocyte transfers Male factor | NS | Total sperm concentration × 106 (million/ml) <1: n = 4 (0.5%) 1–5.9: n = 24 (2.8%) 6–14.9: n = 70 (8.3%) 15–49.9: n = 301 (35.2%) ≥50: n = 448 (52.9%) Total sperm motility (%) <10: n = 13 (1.5%) 10–39.9: n = 150 (17.7%) ≥40: n = 683 (80.7%) Sperm morphology (%) <1: n = 15 (1.8%) 1–3.9: n = 165 (19.3%) >4: n = 554 (64.7%) Missing: n = 122 (14.3%) Semen volume (ml) <1.5: n = 146 (17.3%) 1.5–2.9: n = 365 (43.2%) ≥3: n = 334 (39.5%) | NS |
| Garcia–Ferreyra (2018) | Retrospective | January 2012 – July 2016 Peru | IVF/ICSI donor egg cycles | n = 52 (cycles) | IVF/ICSI donor egg cycles in conjunction with PGT Donor oocytes | All oocyte donors (20–30) Mean ± SD NS | (Range) ≤39: n = 16 (30–39) 40–49: n = 22 (40–48) ≥50: n = 14 (50–68) | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD ≤39: 125.4 ± 46.13 40–49: 95.4 ± 43.66 ≥50: 56.8 ± 50.69 Progressive motility (%) Mean ± SD ≤39: 30.3 ± 7.48 40–49: 28.1 ± 8.55 ≥50: 25.2 ± 9.07 Sperm morphology (%) Mean ± SD ≤39: 9.3 ± 5.44 40–49: 7.4 ± 3.84 ≥50: 5.5 ± 4.70 Semen volume (ml) Mean ± SD ≤39: 2.1 ± 1.19 40–49: 1.9 ± 1.31 ≥50: 1.9 ± 1.10 | Mean ± SD ≤39: 25.6 ± 15.63 40–49: 24.1 ± 14.49 ≥50: 33.6 ± 18.1 |
Kaarouch et al., 2018 | Observational | NS Morocco | Couples undergoing IVF treatment for male factor infertility | n = 83 (couples) | IVF ICSI Autologous oocytes | Mean ± SD <40: n = 42 33 ± 4.28 ≥40: n = 41 35 ± 3 P-value = 0.06 | Mean ± SD <40 n = 42 33 ± 4.28 ≥40 n = 41 44.8 ± 4.11 P-value = 0.01 | Male factor infertility including unexplained and previous IVF failure | NS | Total sperm concentration × 106 (million/ml) Mean ± SD <40: 24.3 ± 2.97 ≥40: 18.4 ± 2.64 P-value = 0.34 All: 21.4 ± 2.81; P-value = 0.20 Progressive motility (%) <40: 33% ≥40: 26% P-value = 0.16 All: mean ± SD 30% ± 0.22; P-value = 0.35 Sperm morphology normal (%) <40: 23% ≥40: 21% P-value = 0.45 All: mean ± SD 22% ± 0.14; P-value = 0.30 Semen volume (ml) Mean ± SD <40: 2.6 ± 1.1 ≥40: 2.4 ± 1.5 P-value = 0.37 All: mean ± SD 2.5 ± 1.3; P-value = 0.29 | Sperm DNA fragmentation <40: 25% ≥40: 41% P-value = 0.01 Sperm chromatin decondensation <40: 23% ≥40: 43% P-value = 0.01 Sperm aneuploidy <40: 4% ≥40: 14% P-value = 0.04 |
Lai et al., 2018 | Retrospective cohort | 2004 – 2014 China | Couples undergoing a first IVF cycle | n = 3549 (couples) | IVF (71.2%) ICSI (28.8%) Autologous oocytes | Mean (range) 36 (33–38) | Mean (range) 38 (35–42) | Tuboperitoneal factor Endometriosis Male factor Unexplained Mixed | NS | Total sperm concentration (million/ml) Mean (range) 47.9 (20.0–87.0) Progressive motility (%) Mean (range) 42 (28–53) Sperm morphology (normal) (%) Mean (range) 5 (3–8) Semen volume (ml) Mean (range) 3.1 (2.3–4.2) | NS |
Ma et al., 2018 | Retrospective cohort | January 2011 – January 2015 China | ICSI | 2474 (cycles) | ICSI (100%) Ejaculated (100%) Autologous oocytes | Total Mean ± SD (range) 29.10 ± 4.48 (20–38) ≤25: 24.27 ± 2.21 26–30: 27.23 ± 2.48 31–35: 31.28 ± 2.82 36–40: 34.86 ± 3.00 ≥41: 35.27 ± 3.19 | Total Number, mean ± SD (range) n = 2474 30.45 ± 5.50 (20–57) ≤25: n = 438 23.84 ± 1.11 26–30: n = 865 27.93 ± 1.39 31–35: n = 73 32.81 ± 1.41 36–40: n = 317 37.58 ± 1.37 ≥41: n = 124 44.12 ± 3.48 | Primary infertility | NS | Total sperm concentration (million/ml) Mean ± SD ≤25: 5.98 ± 18.02 26–30: 10.53 ± 27.88 31–35: 14.38 ± 40.70 36–40: 17.49 ± 28.40 ≥41: 22.22 ± 27.39 Progressive motility (%) Mean ± SD ≤25: 9.05 ± 15.31 26–30: 11.72 ± 16.76 31–35: 12.22 ± 15.53 36–40: 14.63 ± 17.47 ≥41: 16.07 ± 17.06 | NS |
McPherson et al., 2018 | Retrospective cohort | 2009 – 2013 Australia | First IVF or ICSI or combined IVF and ICSI cycles | n = 3323 (cycles) | ICSI n = 2347 IVF n = 841 Split n = 135 Autologous oocytes | Median (range) 34 (18–49) | Median (range) 36 (19–70) | NS | NS | NS | NS |
Park et al., 2018 | Retrospective cohort | January 2008 – December 2013 Korea | TESE–ICSI in men with OA and NOA | TESE–ICSI n = 452 (cycles) | TESE–ICSI OA n = 322 (71.2%) NOA n = 130 (28.8%) Autologous oocytes | Mean ± SD All: 33.8 ± 4.5 ≤30: 29.4 ± 3.4 31–35: 31.2 ± 2.9 36–40: 35.0 ± 3.6 41–45: 36.8 ± 4.1 ≥46: 38.4 ± 4.0 | Mean ± SD All: 37.3 ± 6.1 ≤30: n = 44; 29.0 ± 1.1 31–35: n = 151; 33.1 ± 1.4 36–40: n = 153; 37.8 ± 1.3 41–45: n = 53; 42.3 ± 1.3 ≥46: n = 51; 50.1 ± 3.1 | OA: Congenital bilateral absence of the vas deferens Failed vasectomy NOA: Hypospermatogenesis Reduction in degree of normal spermatogenesis and focal spermatogenesis with spermatid stage arrest Maturation arrest Spermatocyte stage arrest Sertoli cell-only syndrome Absence of germ cells | NS | NS | NS |
Tatsumi et al., 2018 | Retrospective cohort | April 2012 – May 2016 Japan | Women <40 years old undergoing IUI | n = 1576 (cycles) | IUI cycles with partner sperm only Autologous oocytes | Mean ± SD Pregnancy cycle: 35.9 ± 3.0 Non-pregnancy cycle: 36.6 ± 3.1 P-value = 0.002 Live birth cycle: 35.6 ± 3.1 Non-live birth cycle: 36.6 ± 3.1 P-value = 0.001 | Mean ± SD Pregnancy cycle: 38.0 ± 5.0 Non-pregnancy cycle: 39.1 ± 4.7 P-value < 0.001 Live birth cycle: 37.8 ± 5.1 Non-live birth cycle: 39.1 ± 4.7 P-value = 0.001 | NS | NS | Total sperm concentration (million/ml) Mean ± SD Pregnancy cycle: 6949 ± 4482 Non-pregnancy cycle: 6264 ± 4930 P-value= 0.028 Live birth cycle: 6700 ± 4496 Non-live birth cycle: 6289 ± 4925 P-value = 0.176 Total sperm motility (%) Mean ± SD Pregnancy cycle: 42.7 ± 17.7 Non-pregnancy cycle: 39.0 ± 18.6 P-value= 0.044 Live birth cycle: 42.3 ± 17.4 Non-live birth cycle: 39.1 ± 18.6 P-value = 0.132 Semen volume (ml) Mean ± SD Pregnancy cycle: 2.2 ± 1.4 Non-pregnancy cycle: 2.2 ± 1.3 P-value= 0.651 Live birth cycle: 2.1 ± 1.3 Non-live birth cycle: 2.2 ± 1.3 P-value = 0.470 | NS |
Chapuis et al., 2017
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates. Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4 | Retrospective | January 2010 – December 2015 France | Couples undergoing IVF/ICSI | n = 2491 (cycles) | IVF n = 859 (34.5%) ICSI n = 1632 (65.5%) Autologous oocytes | Effect of paternal age in IVF: mean ± SD 20–29: 29.39 ± 5.11 30–39: 34.22 ± 4.18 40–50: 37.08 ± 3.43 >51: 37.00 ± 5.77 P-value < 0.0001 Effect of paternal age in ICSI: mean ± SD 20–29: 27.54 ± 4.55 30–39: 32.69 ± 4.12 40–50: 36.72 ± 3.95 >51: 36.53 ± 4.90 P-value < 0.0001 | Mean ± SD NS 20–29 30–39 40–50 >51 | NS | NS | NS | NS |
Tiegs et al., 2017 | Retrospective | January 2011 – November 2014 USA | Patients using IVF with PGT for aneuploidy or PGT for single-gene disorders | n = 473 (patients) n = 573 (cycles of embryo transfers) | IVF with PGT IVF with PGT for single-gene disorders ICSI 189/573 (33%) Autologous oocytes | Mean ± SD 36 ± 5.0 | All: mean ± SD 39.9 ± 6.7 21–30: 28 ± 2.4 31–35: 34 ± 1.4 36–40: 38 ± 1.4 41–45: 43 ± 1.4 >45: 51 ± 5.3 | NS | NS | NS | NS |
Ghuman et al., 2016 | Retrospective cohort | 1991 – 2012 UK | First fresh donor insemination and IVF/ICSI cycles using donated sperm | n = 46,078 (women) | Fresh sperm donor insemination n = 38974 (84.6%) IVF/ICSI n = 7104 (15.4%) Autologous oocytes | Donor insemination 18–34: n = 25,925 (66.52%) 35–37: n = 6559 (16.83%) 38–50: n = 6490 (16.65%) IVF/ICSI 18–34: n = 3624 (51.01%) 35–37: n = 1359 (19.13%) 38–50: n = 2121 (29.85%) | Mean ± SD NS ≤20 21–25 26–30 31–35 36–40 41–45 | NS | NS | NS | NS |
Meijerink et al., 2016 | Retrospective cohort | January 2001 – June 2013 Netherlands | First cycles of ART | n = 7051 (cycles) | IVF n = 3752 (53.2%) ICSI n = 3299 (46.8%) Autologous oocytes | Median (range) <35: n = 3076 30.7 (20–42) 35–44: n = 3339 35.3 (21–44) ≥45: n = 636 36.8 (22–43) | Median (range) <35: n = 3076 32.0 (17–34) 35–44: n = 3339 38.3 (35–44) ≥45: n = 636 48.6 (45–73) | NS | NS | NS | NS |
Wu et al., 2016 | Retrospective cohort | January 2007 – May 2015 China | ICSI cycles | n = 2627 (cycles) | ICSI Ejaculated sperm n = 1946 (74.1%) PESA n = 489 (18.6%) TESA n = 192 (7.3%) Autologous oocytes | Mean ± SD Overall: 30.46 ± 3.83 <30: 26.67 ± 2.62 30–34: 30.08 ± 2.75 35–39: 32.77 ± 3.18 40–44: 33.99 ± 3.45 45–49: 33.43 ± 3.65 ≥50: 33.26 ± 3.72 | Mean ± SD Overall: 33.57 ± 5.35 <30: 27.42 ± 1.60 30–34: 32.03 ± 1.39 35–39: 36.69 ± 1.38 40–44: 41.42 ± 1.24 45–49: 46.43 ± 1.38 ≥50: 56.33 ± 7.77 | Male infertility (61.6%): Oligospermia Asthenozoospermia Teratozoospermia Female factors (10.1%) Both (28.2%) | NS | Total sperm concentration × 106 (million/ml) Mean ± SD <30: 26.4 ± 23.9 30–34: 28.1 ± 27.7 35–39: 27.7 ± 26.0 40–44: 33.6 ± 36.1 45–49: 34.6 ± 29.0 ≥50: 29.5 ± 35.9 Total: 28.5 ± 27.9 Progressive motility Mean ± SD <30: 23.2 ± 17.4 30–34: 21.9 ± 15.7 35–39: 23.5 ± 16.6 40–44: 22.2 ± 13.7 45–49: 23.1 ± 16.7 ≥50: 25.4 ± 12.1 Total: 22.7 ± 16.0 | NS |
Garcia-Ferreyra et al., 2015 | Retrospective cohort | January 2012 – August 2015 Peru | Embryos obtained from IVF/ICSI cycles with donated oocytes in conjunction with PGT | n = 32 (cycles) | IVF n = 14 (43.8%) ICSI n = 18 (56.3%) Donor oocytes | Oocyte donors (range) (21–28) Mean ± SD as per paternal age groups ≤39: 22.7 ± 1.53 40–49: 24.2 ± 1.4 ≥50: 24.1 ± 1.85 | (Range) ≤39: n = 5 (34–39) 40–49: n = 17 (40–47) ≥ 50: n = 10 (50–72) | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD ≤39: 90.1 ± 41.38 40–49: 101.5 ± 40.12 ≥50: 57.8 ± 51.62 Total sperm motility (%) Mean ± SD ≤39: 29.6 ± 11.55 40–49: 29.3 ± 7.05 ≥50: 21 ± 9.07 Sperm morphology (%) Mean ± SD ≤39: 11.3 ± 4.88 40–49: 7.9 ± 3.99 ≥50: 4.7 ± 3.51 Semen volume (ml) Mean ± SD ≤39: 3.2 ± 1.39 40–49: 2.1 ± 1.38 ≥ 50: 2 ± 1.15 | ≤39 17.4 ± 10.79 40–49 21.3 ± 13.48 ≥50 37.1 ± 17.61 |
Ho et al., 2015 | Retrospective cohort Abstract only | 2009–2013 USA | Infertile couples undergoing fresh oocytes transfer and severe male factor infertility excluded | n = 255 patients | IVF Donor oocytes | NS | <40: n = 58 40–45: n = 72 45–50: n = 51 >50: n = 33 | NS | NS | NS | NS |
Wu et al., 2015
Effect of paternal age on reproductive outcomes of in vitro fertilization. Plos One. 2015; https://doi.org/10.1371/journal.pone.0135734 | Retrospective | January 2007 – October 2013 China | IVF with embryo transfer | n = 9991 (cycles) | IVF Autologous oocyte | <30: n = 3327 30–34: n = 4587 35–38: n = 2077 | <30: n = 1751 30–32: n = 2410 33–35: n = 2486 36–38: n = 1903 39–41: n = 925 ≥42: n = 516 | NS | NS | NS | NS |
Begueria et al., 2014 | Retrospective cohort | February 2007 – June 2010 Spain | Oocyte donor cycles with ICSI | n = 4887 (cycles) | ICSI Frozen (75%) Fresh (25%) Donor oocytes | Mean ± SD 40.7 ± 4.7 Range (22–50) | Mean ± SD Overall: n = 5089 41.09 ± 6.77 <25: 22.60 ± 1.10 25–29: 27.89 ± 1.21 30–34: 32.43 ± 1.34 35–39: 37.12 ± 1.41 40–44: 41.96 ± 1.40 45–49: 46.60 ± 1.40 50–54: 51.62 ± 1.37 55–59:56.58 ± 1.34 ≥ 60: 63.65 ± 4.56 | Female: Failed IVF cycles with own oocytes Low ovarian reserve Poor oocyte quality Genetic or chromosomal abnormalities transmissible to offspring Spontaneous or iatrogenic menopause | NS | Total sperm concentration × 106 (million/mL) Mean ± SD Overall: 92.14 ± 156.38 <25: 66.11 ± 69.06 25–29: 90.86 ± 80.25 30–34: 86.78 ± 84.80 35–39: 87.53 ± 86.81 40–44: 87.62 ± 93.72 45–49: 97.62 ± 108.61 50–54: 127.60 ± 483.20 55–59: 99.05 ± 133.59 ≥60: 80.64 ± 80.73 Motility (%) Mean ± SD Overall: 19.39 ± 17.66 <25: 24.40 ± 9.28 25–29: 25.27 ± 22.17 30–34: 20.05 ± 17.64 35–39: 19.82 ± 17.46 40–44: 19.68 ± 17.87 45–49: 18.44 ± 16.98 50–54: 17.17 ± 17.14 55–59: 16.50 ± 17.39 ≥60: 14.35 ± 15.64 Semen volume (ml) Mean ± SD Overall: 3.67 ± 1.91 <25: 2.17 ± 1.16 25–29: 3.88 ± 1.74 30–34: 3.94 ± 1.88 35–39: 3.92 ± 1.94 40–44: 3.75 ± 1.95 45–49: 3.39 ± 1.77 50–54: 2.95 ± 1.80 55–59: 2.89 ± 1.67 ≥60: 2.46 ± 1.54 | NS |
Robertshaw et al., 2014 | Retrospective cohort | 2002 – 2011 USA | Ovum donor cycles | n = 237 (cycles) n = 110 (donors) | Ovum donation cycles Donor oocytes | Mean ± SD 26 ± 3.0 Range (21–31) | Mean ± SD 40 ± 7.0 Range (25–66) | NS | NS | NS | NS |
Koh et al., 2013 | Retrospective cohort | 1994 – 2011 Australia | Donor insemination cycles | n = 2142 (cycles) | Donor sperm insemination cycles Autologous oocytes | Mean ± SD 33.3 ± 0.9 Range (21–39) | Mean ± SD 36.4 ± 0.2 Range (19–69) | NS | NS | Independent t-tests >45 years Sperm concentration (t(1545) = 2.44 P-value = 0.015 Motile spermatozoa (t(1545) = 3.00 P-value = 0.003 | NS |
Tsai et al., 2013 | Retrospective cohort | January 1998 – August 2010 Taiwan | Couples with azoospermia undergoing TESE and ICSI | n = 184 (cycles) | ICSI TESE Autologous oocytes | Mean ± SD (per male age groups) 31–35: 31.0 ± 0.4 35–40: 33.4 ± 0.6 >40: 34.2 ± 0.9 | Mean ± SD NS 31–35 36–40 41–51 | Azoospermia | NS | NS | NS |
Gu et al., 2012 | Retrospective cohort | January 2004 – December 2009 China | Oocyte donation cycles and IVF | n = 70 (couples) n = 103 (cycles) | Oocyte donation cycles and IVF Donor oocytes | Mean ± SD 39.8 ± 6.9 Range (26–53) | Mean ± SD 41.5 ± 6.7 Range (26 to 57) | Diminished ovarian reserve Poor response to ovary stimulation Chromosome aberration | NS | NS | NS |
Medina et al., 2012 | Retrospective cohort Abstract only | Dates: NS Venezuela | Couples undergoing IVF | n = 260 | IVF Donor oocytes | NS | <34: n = 38 35–38: n = 43 >39: n = 179 | NS | NS | NS | NS |
Meyer et al., 2012 | Retrospective cohort Abstract only | Dates: NS Germany | Couples undergoing oocyte donation cycles | n = 332 couples | Donor oocytes | NS | <40 40–49 >50 | NS | NS | NS | NS |
Nijs et al., 2011 | Prospective cohort | May 2002 – July 2005 Belgium | Infertile patients undergoing first IVF or ICSI treatment | n = 278 (patients) | IVF n = 78 (28.1%) ICSI n = 96 (34.5%) Both n = 104 (37.4%) Autologous oocytes | Mean ± SD 31.9 ± 4.2 Range (20–46) | Mean ± SD 35.1 ± 4.9 Range (25–56) | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD ≤34: 40.79 ± 35.89 P-value = 0.73 35–39: 40.76 ± 34.25 P-value = 0.83 ≥40: 41.52 ± 31.71 P-value = 0.28 Motility (%) Mean ± SD ≤34: 52.59 ± 18.82 P-value = 0.68 35–39: 50.21 ± 16.97 P-value = 0.33 ≥40: 57.38 ± 13.01 P-value = 0.49 Sperm morphology (%) Mean ± SD ≤34: 5.36 ± 3.20 P-value = 0.027 35–39: 5.67 ± 2.98 P-value = 0.31 ≥40: 5.55 ± 2.94 P-value = 0.89 | Mean± SD ≤34 22.48 ± 11.80 P-value = 0.95 35–39 23.35 ± 12.32 P-value = 0.79 ≥40 24.57 ± 12.66 P-value = 0.3 |
Whitcomb et al., 2011 | Retrospective cohort | NS USA | Anonymous oocyte donor cycles | n = 1083 (couples) n = 1392 (cycles) | Treatment cycles using donor oocytes ICSI Donor oocytes | Per male age group Mean ± SD <30: 35.0 ± 7.4 30–34: 37.7 ± 4.9 35–39: 39.8 ± 4.0 40–44: 41.5 ± 3.2 45–49: 43.3 ± 3.6 50–54: 44.6 ± 3.1 ≥55: 44.1 ± 3.7 P-value < 0.001 | Mean ± SD NS <30 30–34 35–39 40–44 45–49 50–5 ≥55 | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD <30: 70.3 ± 44.8 30–34: 91.4 ± 66.1 35–39: 89.7 ± 61.3 40–44: 82.0 ± 66.9 45–49: 80.0 ± 58.2 50–54: 82.5 ± 66.5 ≥55: 92.4 ± 100.9 P-value = 0.61 Motility (%) Mean ± SD <30: 65.0 ± 12.2 30–34: 62.7 ± 17.9 35–39: 61.3 ± 18.2 40–44: 55.7 ± 18.9 45–49: 57.4 ± 16.9 50–54: 48.7 ± 17.5 ≥55: 37.7 ± 21.9 P-value < 0.001 Semen volume (ml) Mean ± SD <30: 3.1 ± 1.3 30–34: 3.0 ± 1.5 35–39: 3.1 ± 1.8 40–44: 2.5 ± 1.4 45–49: 2.5 ± 1.4 50–54: 2.4 ± 1.5 ≥55: 1.7 ± 1.3 P-value < 0.001 | NS |
Duran et al., 2010 | Retrospective cohort | 1998 – 2008 USA | Oocyte donation cycles with ICSI/IVF | n = 408 (couples) n = 519 (cycles) | Oocyte donation cycles ICSI n = 168 (32.4%) IVF n = 351 (67.6%) Donor oocytes | Oocyte donor (per male age groups): Mean ± SD 25–38: 26.5 ± 3.5 39–49: 26.6 ± 3.4 ≥50: 28.1 ± 3.6 Recipients: Mean ± SD 25–38: 35.8 ± 4.5 39–49: 42.5 ± 3.7 ≥50: 44.1 ± 8.1 | 23–38 n = 126 39–49 n = 348 ≥50 n = 45 | Poor fertilization/failure with IVF Unexplained infertility | NS | Total sperm concentration × 106 (million/ml) Mean ± SD 25–38:105.4 ± 111.8 35–39:104.1 ± 101.0 ≥50: 121.4 ± 17.6 Motility (%) Mean ± SD 25–38: 62.2 ± 17.6 35–39: 56.4 ± 20.4 ≥50: 41.8 ± 27.9 Semen volume (ml) Mean ± SD 25–38: 3.6 ± 1.6 35–39: 2.9 ± 1.7 ≥50: 2.2 ± 1.5 | NS |
Ferreira et al., 2010 | Retrospective observational (case–control) | January 2002 – December 2007 Brazil | Couples undergoing ICSI cycles | n = 1024 (couples) | ICSI 100% (fresh spermatozoa) Autologous oocytes | Mean ± SD Oligozoospermic 32.80 ± 4.86 Normozoospermic 34.23 ± 4.48 | Mean ± SD Oligozoospermic 36.85 ± 6.28 Normozoospermic 37.18 ± 6.12 | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD Oligozoospermic 7.03 ± 5.90 Normozoospermic 70.62 ± 46.95 Motility (%) Mean ± SD Oligozoospermic 41.07 ± 19.85 Normozoospermic 61.54 ± 13.02 | NS |
Luna et al., 2009 | Retrospective cohort | January 2003 – December 2007 USA | All fresh ovum donation and IVF cycles | n = 672 (cycles) | Fresh ovum donation and IVF/ICSI Donor oocytes | Mean ± SD Oocyte donor (per male age) <40: 26.2 ± 3.2 40–50: 25.9 ± 3.1 >50: 26.6 ± 3.4 Recipient (per male age) <40: 39.3 ± 5.1 40–50: 43.7 ± 3.0 >50: 45.5 ± 3 P-value <0.05 | Mean ± SD <40: n = 233 35.5 ± 2.9 40–50: n = 323 44.1 ± 2.9 >50: n = 116 54.3 ± 4.5 | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD <40: 75.5 ± 54.6 40–50: 76.2 ± 62.7 >50: 58.6 ± 56.5 P-value <0.05 Motility (%) Mean ± SD <40: 56.8 ± 14.2 40–50: 52.8 ± 16.1 >50: 42.9 ± 18.3 P-value <0.05 Semen volume (ml) Mean ± SD <40: 3.67 ± 8.5 40–50: 2.7 ± 1.5 >50: 2.1 ± 1.5 P-value <0.05 | NS |
| Belloc (2008) | Retrospective cohort | January 2003 – December 2006 France | IUI cycles | n > 17000 (cycles) | IUI Autologous oocytes | Mean ± SD NS <30 30–34 35–37 38–41 ≥42 | Mean± SD NS <30 30–34 35–39 40–44 ≥45 | Male: Semen (23.4%) Female: Cervical hostility (12.8%) Mixed semen and cervical problems (35.6%) Idiopathic infertility (20.3%) Multiple female aetiologies (7.9%) | NS | NS by paternal age | NS |
Bellver et al., 2008 | Retrospective cohort | January 2000 – October 2006 Spain | IUI and IVF cycles ± donated oocytes | Total n = 4902 cycles n = 2204 (IUI cycles) n = 1286 (IVF cycles) n = 1412 (IVF cycles with donated oocytes) | IUI (45.0%) IVF (26.2%) IVF with donated oocytes (28.8%) Autologous and donor oocytes | NS | IUI Mean 34.3 Range (25–56) 95% CI (34.2–34.5) IVF/ICSI Mean 34.8 Range (19–62) 95% CI (34.6–35.03) Ovum donation Mean 41.40 Range (25–71) 95% CI (41.08–41.70) | IVF: IUI failure Tubal pathology Infertility of unknown origin Ovum donation: Low ovarian response Premature ovarian failure Advanced female age Menopause Poor oocyte quality | NS | Total sperm concentration × 106 (million/ml) Mean ± SD IUI Mean (95% CI) Ejaculated: 94.43 (90.81–98.06) Post swim up: 12.29 (11.80–12.78) IVF/ICSI Mean (95% CI) Ejaculated: 72.75 (68.75–76.74 Post swim-up: 3.94 (3.17–4.70) Ovum donation Mean (95% CI) Ejaculated: 19.51 (17.63–21.39 Post swim-up: 1.08 (0.64–1.52) | NS |
Campos et al., 2008 | Retrospective cohort | January 1996 – December 2006 Spain | Couples undergoing donor oocyte IVF cycles | n = 662 (couples) n = 915 (cycles) | Oocyte donation cycles and IVF Donor oocytes | Mean ± SD Oocyte donors 25.03 ± 0.15 Range (18–36) Oocyte recipients:38.26 ± 0.17 Range (22–52) | Mean ± SD 39.10 ± 0.20 Range (21–61) | Female: Premature ovarian failure Menopause Genetic or chromosomal disorders Low response to ovarian stimulation Failure to achieve pregnancy after at least three cycles of ART Recurrent miscarriage | NS | Total sperm concentration × 106 (million/ml) Mean ± SD <39: 46.54 ± 1.71 ≥39: 49.36 ± 1.89 P-value = 0.27 Motility (%) Mean ± SD A+B grade (%) 39: 44.35 ± 0.93 ≥39: 37.36 ± 1.02 P-value <0.01 Sperm morphology normal (%) Mean ± SD <39: 12.42 ± 0.60 ≥39: 13.15 ± 0.76 P-value = 0.45 Semen volume (ml) Mean ± SD <39: 2.74 ± 0.09 ≥39: 2.56 ± 0.09 P-value = 0.17 | NS |
Frattarelli et al., 2008 | Retrospective cohort | January 2000 – July 2006 USA | Couples undergoing donor oocyte ART cycles | n = 1023 (couples/cycles) | IVF/ICSI with donor oocytes Donor oocytes | Mean ± SD Recipients 41.4 ± 4.7 Range (23–53) Donor 27.1 ± 3.5 Range (22–35) | Mean ± SD 41.8 ± 6.4 Range (26–74) | Diminished ovarian reserve Poor oocyte quality Poor embryo quality Age >44 years | NS | Total sperm concentration × 106 (million/ml) Mean ± SD Overall: 53.6 ± 60.6 ≤35: 58.3 ± 46.7 36–40: 54.6 ± 55.0 41–45: 59.4 ± 72.4 46–50: 53.3 ± 61.4 51–55: 51.0 ± 47.5 >55: 42.1 ± 39.9 P-value = 0.07 Motility (%) Mean ± SD Overall: 65.3 ± 35.0 ≤35: 69.0 ± 27.4 36–40: 67.1 ± 34.5 41–45: 68.5 ± 40.5 46–50: 57.7 ± 28.5 51–55: 52.3 ± 30.3 >55: 50.7 ± 16.8 P-value = 0.12 Semen volume (ml) Mean ± SD Overall: 3.1 ± 1.7 ≤35: 3.5 ± 1.5 36–40: 3.4 ± 1.9 41–45: 3.1 ± 1.6 46–50: 2.6 ± 1.6 51–55: 2.4 ± 0.7 >55: 1.6 ± 1.0 P-value <0.001 Sperm morphology normal (%) Mean ± SD Overall: 6.0 ± 2.9 ≤35: 6.1 ± 1.9 36–40: 6.4 ± 2.3 41–45: 6.0 ± 2.4 46–50: 5.5 ± 2.3 51–55: 5.1 ± 2.5 >55: 5.0 ± 2.0 P-value = 0.14 | NS |
Girsh et al., 2008 | Retrospective cohort | NS Israel | Egg donation programme cycles and IVF treatment | n = 484 (male patients) | Egg donation programme and IVF/ICSI Donor oocytes | Recipient 44.3 ± 6.81 Range (24–54) | Mean ± SD 45.9 ± 8.2 Range (25–60) | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD 26–30: 114 ± 65 31–35: 90 ± 58 36–40: 72 ± 51 41–45: 67 ± 37 46–50: 58 ± 38 51–55: 56 ± 37 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. 56–60: 16 ± 13 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. Progressive motility (%) Mean ± SD 26–30: 39 ± 27 31–35: 41 ± 26 36–40: 44 ± 24 41–45: 44 ± 23 46–50: 39 ± 22 51–55: 35 ± 18 56–60: 12 ± 19 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. Morphology (%) Mean ± SD 26–30: 14.8 ± 1.8 31–35: 13.7 ± 2.1 36–40: 13.6 ± 1.7 41–45: 12.9 ± 1.8 46–50: 12.1 ± 1.6 51–55: 11.2 ± 1.7 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. 56–60: 10.1 ± 1.9 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. Semen volume (ml) Mean ± SD 26–30: 4.8 ± 1.8 31–35: 4.5 ± 2.7 36–40: 4.1 ± 1.8 41–45: 3.2 ± 1.5 46–50: 2.9 ± 1.9 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. 51–55: 2.5 ± 1.0 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. 56–60: 2.3 ± 1.3 b Statistically different from the <40 years group. ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer. | NS |
Aboulghar et al., 2007 | Retrospective cohort | January 2001 – June 2006 Egypt | Subfertile couples undergoing ICSI | n = 454 (patients) | ICSI 100% Autologous oocytes | Mean ± SD As per male age ≥50: 33.2 ± 4.9 <50: 32.7 ± 4.8 | Mean ± SD ≥50: 53.9 ± 5.0 <50: 38.4 ± 5.8 | Male factor Unexplained Tubal factor Mixed Ovulatory factor | NS | Total sperm concentration × 106 (million/ml) Mean ± SD ≥50: 39.0 ± 26.3 <50: 46.0 ± 32.6 P-value = 0.05 Motility (%) Mean ± SD ≥50: 37.4 ± 20.4 <50: 46.4 ± 15.5 P-value < 0.0001 Morphology (abnormal) (%) Mean ± SD ≥50: 74.0 ± 11.5 <50: 81.3 ± 10.6 P-value = 0.019 | NS |
| De La Rochebrochard (2006) | Retrospective | 2000 – 2006 France | Couples treated by conventional IVF for bilateral tubal obstruction | n = 1938 (couples) | IVF Autologous oocytes | Mean ± SD NS <30 30–34 35–37 38–40 >40 | Mean ± SD NS <30 30–34 35–39 >40 | Female: Totally sterile with bilateral tubal obstruction or absence of both tubes | Paternal age OR (95% CI) <30: 1.00 30–34: 1.52 (1.08–2.14) 35–39: 1.32 (0.92–1.89) >40: 1.70 (1.14–2.52) | NS | NS |
| Klonoff–Cohen (2004) | Prospective | 1993 – 1998 USA | Couples undergoing IVF and GIFT couples | n = 221 (couples) | IVF n = 136 (61.54%) GIFT n = 79 (35.75%) ZIFT n = 6 (2.71%) Autologous oocytes | Mean ± SD 36.81 ± 4.3 Range (26–49) | Mean ± SD 38.4 ± 5.68 Range (22–55) | Primary or secondary infertility: Tubal disease Endometriosis Immunological causes Male factor Unexplained infertility | NS | Total sperm concentration × 106 (million/ml) Mean ± SD 87.73 ± 85.11 Motility (%) Mean ± SD 46.95 ± 23.22 Morphology (abnormal) (%) Mean ± SD 36.95 ± 17.75 | NS |
Kumtepe et al., 2003 | Retrospective cohort | Dates: NS Turkey | Infertile couples undergoing ICSI | n = 919 ICSI cycles | ICSI Autologous oocytes | Paternal age <40: maternal mean age 30.7 ± 4.5 Paternal age ≥40: maternal mean age 36.2 ± 4.3 | <40 (n = 678) ≥40 (n = 241) | Male factor infertility | NS | Sperm concentration (million/ml) <40: 6.9 ± 1.1 >40: 6.9 ± 1.0 Progressive motility (%) <40: 18.9 ± 15.1 ≥40: 18.0 ± 16.7 Normal morphology <40: 1.8 ± 0.8 ≥40: 1.9 ± 1.5 | NS |
Paulson et al., 2001 | Retrospective cohort | 1988 – 1998 USA | Couples undergoing IVF with donated oocytes | n = 441 (couples) n = 558 (cycles) | IVF Donor oocytes | NS | Mean ± SD 41.6 ± 7.2 Range (22–64) | NS | NS | Total sperm count × 106 (million/ml) Mean ± SD 207 ± 144 Total motile sperm count × 106 (million/ml) Mean ± SD 131 ± 103 | NS |
Spandorfer et al., 1998 | Retrospective cohort | September 1993 – March 1995 USA | ICSI cycles | n = 821 (cycles) | ICSI (100%) Autologous oocytes | Mean ± SD 35.2 ± 4.5 | Mean ± SD 38.4 ± 6.1 | NS | NS | Total sperm concentration × 106 (million/ml) Mean ± SD ≤39: 22.7 ± 1.3 40–49: 24.7 ± 2.4 ≥50: 19.8 ± 4.5 P-value not significant Motility (%) Mean ± SD ≤39: 36.5 ± 0.9 40–49: 35.3 ± 1.4 ≥50: 34.9 ± 4.3 P-value not significant Morphology (%) Mean ± SD ≤39: 2.6 ± 0.1 40–49: 2.9 ± 0.2 ≥50: 2.8 ± 0.5 P-value not significant Semen volume (ml) Mean ± SD ≤39: 2.7 ± 0.1 40–49: 2.5 ± 0.1 ≥50: 2.1 ± 0.2 P-value <0.05 | NS |
Gallardo et al., 1996 | Retrospective cohort | NS Spain | Couples requiring oocyte donation and IVF | n = 240 (couples) n = 345 (cycles) | Oocyte donation and IVF Donor oocytes | All oocyte donors <35 Mean ± SD (per male age) ≤30: 32.7 ± 2.1 31–40: 29.3 ± 1.4 41–50: 30.8 ± 1.9 ≥51: 29.6 ± 2.2 Recipients Mean ± SD (per male age) ≤30: 29.8 ± 0.7 31–40: 35.1 ± 0.3 41–50: 40.8 ± 0.4 ≥51: 47.0 ± 1.5 P-value < 0.005 | Mean ± SD (NS) ≤30 31–40 41–50 ≥51 | Female: Low response Premature ovarian failure IVF failure Genetic Menopause Idiopathic Endometriosis Tubal | NS | Total sperm concentration × 106 (million/ml) Mean ± SD ≤30: 52.3 ± 10.6 31–40: 54.2 ± 4.5 41–50: 56.6 ± 7.3 ≥51: 57.2 ± 8.4 Motility A + B (fresh) Mean ± SD ≤30: 43.8 ± 6.2 31–40: 45.9 ± 2.1 41–50: 42.2 ± 3.1 ≥51: 40.7 ± 4.5 Motility A+B (post-capacitation) Mean ± SD ≤30: 62.2 ± 5.4 31–40: 62.8 ± 2.5 41–50: 66.1 ± 3.6 ≥51: 66.7 ± 5.2 Semen volume (ml) Mean ± SD ≤30: 3.1 ± 0.1 31–40: 2.6 ± 0.1 41–50: 2.3 ± 0.2 ≥51: 2.2 ± 0.2 | NS |
Mathieu et al., 1995 | Retrospective cohort | September 1987 – December 1992 France | Intrauterine artificial insemination with partner's sperm | n = 274 (couples) n = 901 (cycles) | Intrauterine artificial insemination Swim up migration n = 84 Centrifugation n = 814 Autologous oocytes | Mean ± SD 31.3 ± 4.5 Range (23–43) | Mean ± SD 33.7 ± 5.6 Range (23–57) | Female: Endometriosis Dysovulation Anovulation Abnormal post-coital test Poor cervical mucus penetration test abnormality Primary Cervical factor Male: Primary Non-specific semen Mixed idiopathic sexological indication | NS | NS | NS |
a Other variables not listed as having missing data had less than 2% of data missing.
b Statistically different from the <40 years group.ART, assisted reproductive technology; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IQR, interquartile range; IUI, intrauterine insemination; MESA, microsurgical epididymal sperm aspiration; NOA, nonobstructive azoospermia; NS, not specified; OA, obstructive azoospermia; OR, odds ratio; PCOS, polycystic ovary syndrome; PESA, percutaneous epididymal sperm aspiration; PGT, preimplantation genetic testing; TESA, testicular sperm extracted by testicular sperm aspiration; TESE, testicular sperm extraction; ZIFT, zygote intra-Fallopian transfer.
Table 2. Study outcomes relevant to pregnancy for paternal age groups
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
| Studies included in the meta-analysis | ||||||||||
Horta et al., 2019 | NS | NS | NS | NS | Clinical pregnancy/cycle OR (95% CI) <40: Ref. 40–44: 0.88 (0.65–1.20) 45–49: 0.77 (0.56–1.07) 50–54: 0.60 (0.40–0.89) a Statistically significant. aOR, adjusted odds ratio; ART, assisted reproductive technology; BMI, body mass index; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; NS, not specified; OR, odds ratio; PGT, preimplantation genetic testing; RC, xxxx; Ref., reference group; RR, xxxx; TESE, testicular sperm extraction. ≥55: 0.54 (0.35–0.84) a Statistically significant. aOR, adjusted odds ratio; ART, assisted reproductive technology; BMI, body mass index; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; NS, not specified; OR, odds ratio; PGT, preimplantation genetic testing; RC, xxxx; Ref., reference group; RR, xxxx; TESE, testicular sperm extraction. | Live birth/cycle <40: 108/387 (27.9%) 40–44: 149/642 (23.2%) 45–49: 122/692 (17.6%) 50–54: 58/407 (14.3%) ≥55: 52/294 (17.7%) | Miscarriage/clinical pregnancy OR (95% CI) <40: Ref. 40–44: 0.88 (0.48–1.63 45–49: 1.17 (0.62–2.20) 50–54: 1.54 (0.76–3.13) ≥55: 1.71 (0.75–3.93) | NS | NS | Male ageing is negatively associated with clinical IVF/ICSI outcomes in couples with idiopathic infertility independent of female age |
Cito et al., 2019
Impact of advanced paternal age on the intracytoplasmic sperm injection outcomes in donor egg cycles. Translational Andrology and Urology. 2019; 8: S22-S30 | Cycles with fertilized embryos/total cycles Mean ± SD Total: 77.1 ± 0.18 ≤45: 133/166 (80.1%) >45: 75/112 (67.0%) P-value: <0.01 | Cleavage-stage embryos/ total cycles Mean ± SD 93.0 ± 0.16 | NS | NS | Clinical pregnancy/cycle Total: 110/278 (39.6%) ≤45: 72/166 (43.37%) >45: 38/112 (33.93%) P-value = 0.26 | Live birth/cycle ≤45: 52/166 (31.33%) >45: 30/112 (26.79%) P-value = 0.28 | Miscarriage/clinical pregnancy ≤45: 20/72 (27.78%) >45: 8/38 (21.05%) P-value = 0.31 | NS | NS | Paternal age plays a significant role in determining outcomes of ICSI when oocytes are young and healthy |
Yu et al., 2019 | Fertilized embryos/total oocytes <35: 242/359 (67.4%) ≥35: 72/122 (59.0%) P-value = 0.09 | NS | NS | Euploid blastocysts/number of blastocysts analysed for PGT <35: 102/238 (42.9%) ≥35: 28/68 (41.2%) P-value = 0.08 | Clinical pregnancy/cycle <35: 20/26 (76.9%) ≥ 35: 6/12 (50%) Clinical pregnancy/transferred embryo <35: 20/35 (57.1%) ≥ 35: 6/15 (40%) P-value = 0.27 (clinical pregnancy/transferred embryo) | Live birth/cycle <35: 17/26 (65.4%) ≥ 35: 4/12 (33.3%) Live birth/transferred embryo <35: 17/35 (48.6%) ≥ 35: 4/15 (26.7%) P-value = 0.15 (live birth/transferred embryo) | Miscarriage/clinical pregnancy <35: 3/20 (15%) ≥ 35: 2/6 (33.3%) P-value = 0.56 | NS | NS | When paternal age is <35 years, use of ejaculated sperm can achieve a higher live birth rate When paternal age is ≥35 years, testicular sperm should be recommended for ICSI in men with cryptozoospermia as it offers better high-quality embryo and clinical pregnancy rates |
Capelouto et al., 2018 | NS | NS | NS | NS | Clinical pregnancy/cycle Total: 721/949 (76.0%) RR (95% CI) 36–40: 0.92 (0.81–1.06) 41–45: 0.93 (0.83–1.07) 46–50: 0.84 (0.70–0.99) ≥51: 0.93 (0.76–1.11) | Live birth/cycle Total: 526/949 (55.4%) ≤35: 84/147 (57.1%) 36–40: 133/238 (55.9%) 41–45: 157/275 (57.1%) 46–50: 63/121 (52.1%) ≥51: 40/71 (56.3%) | Miscarriage/clinical pregnancy Total: 108/949 (11.4%) | NS | Normal ≤35: 62/67 (92.5%) 36–40: 96/107 (89.7%) 41–45: 121/128 (94.5%) 46–50: 43/52 (82.7%) ≥51: 28/33 (84.8%) Low ≤35: 5/67 (7.5%) 36–40: 11/107 (10.3%) 41–45: 7/128 (5.5%) 46–50: 9/52 (17.3%) ≥51: 5/33 (15.2%) | Advancing male age, high BMI and poor sperm quality are not associated with outcomes in frozen donor oocyte IVF cycles |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Garcia-Ferreyra et al., 2018 | Fertilized embryos/total oocytes ≤39: 159/175 (90.9%) 40–49: 217/261 (83.1%) ≥50: 126/155 (81.3%) | Cleavage-stage embryos/fertilized embryos ≤39: 157/159 (98.7%) 40–49: 214/217 (98.6%) ≥50: 121/126 (96.0%) | Blastocysts/fertilized embryos ≤39: 76/159 (47.8%) 40–49: 104/217 (47.9%) ≥50: 53/126 (42.1%) | Good-quality embryos/cleavage-stage embryos ≤39: 122/157 (77.7%) 40–49: 169/214 (79.0%) ≥50: 100/121 (82.6%) | NS | NS | NS | NS | NS | Advanced paternal age increases global chromosomal abnormalities, and percentages of trisomy 21, 18 or 13 in embryos Such an effect is significantly important from the age of 50 years |
Kaarouch et al., 2018 | Fertilized embryos/total oocytes <40: 65% (300/462) ≥40: 56% (207/369) | Cleavage-stage embryos/fertilized embryos <40: 97% (291/300) ≥40: 94% (195/207) | Blastocysts/fertilized embryos <40: 33% (100/300) ≥40: 24% (47/195) | NS | Clinical pregnancy/cycle <40: 28.6% (12/42) ≥40: 12.2% (5/41) Clinical pregnancy/transferred embryo <40: 32% (12/38) ≥40: 17% (5/29) | NS | Miscarriage/clinical pregnancy <40: 42% (5/12) ≥40: 60% (3/5) | NS | NS | Sperm genome decay is detectable from around 38 years of age IVF outcomes are affected when spermatozoa from men over 40 years are used for ICSI Advanced paternal age effect on conventional sperm parameters, occurs from 43–44 years of age |
McPherson et al., 2018 | 2050/2215 (92.6%) | NS | NS | NS | Clinical pregnancy/cycle <40: 804/2344 >40: 25/277 | Live birth/cycle <40: 653/2344 >40: 18/277 | Miscarriage/clinical pregnancy <40: 151/804 >40: 7/27 | NS | NS | A negative association between paternal age and pregnancy rate or live birth was observed There is an additive effect to pregnancy and live birth rates when both partners are of advanced age |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Park et al., 2018 | Fertilized embryos/total oocytes Total: n = 3570/4972 (71.8%) ≤30: 419/577 (72.6%) 31–35: 1458/2059 (70.8%) 36–40: 1024/1445 (70.9%) 41–45: 378/507 (74.6%) ≥46: 291/384 (75.8%) P-value < 0.5 | NS | NS | Good-quality embryos/cleavage-stage embryos Total: 1534/2522 (60.8%) ≤30: 149/278 (53.6%) 31–35: 573/936 (61.2%) 36–40: 473/773 (61.2%) 41–45: 171/280 (61.1%) ≥46: 168/255 (65.9%) P-value < 0.5 | Clinical pregnancy/cycle ≤30: 16/44 (36.4%) 31–35: 51/151 (33.8%) 36–40: 54/153 (35.3%) 41–45: 17/53 (32.1%) ≥46: 10/51 (19.6%) Clinical pregnancy/transferred embryo Total 148/396 (37.4%) ≤30: 16/37 (43.2%) 31–35: 51/127 (40.2%) 36–40: 54/134 (40.3%) 41–45: 17/49 (34.7%) ≥46: 10/49 (20.4%) P-value < 0.5 | Live birth/cycle ≤30: 14/44 (31.8%) 31–35: 45/151 (29.8%) 36–40: 42/153 (27.5%) 41–45: 13/53 (24.5%) ≥46: 9/51 (17.6%) Live birth/transferred embryo Total 123/396 (31.1%) ≤30: 14/37 (37.8%) 31–35: 45/127 (35.4%) 36–40: 42/134 (31.3%) 41–45: 13/49 (26.5%) ≥46: 9/49 (18.4%) P-value < 0.5 | NS | NS | NS | Fertilization using TESE in obstructive azoospermia was not affected by the independent influence of paternal age; however, as maternal age increased concomitantly with paternal age, rates of pregnancy and delivery differed between those with paternal age <41 years and ≥46 years Therefore, paternal age ≥46 years old should be considered when applying TESE–ICSI in cases of obstructive azoospermia, and patients should be advised of the associated low pregnancy rates |
Chapuis et al., 2017
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates. Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4 | Fertilized embryos/total oocytes IVF 20–29: 64.01% (738/1153) 30–39: 67.66% (3542/5235) 40–50: 65.99% (1296/1964) >51: 42.47% (31/73) P-value < 0.0001 ICSI 20–29: 61.05% (1199/1964) 30–39: 65.20% (4882/7488) 40–50: 64.59% (1893/2931) >51: 70.35% (242/344) P-value = 0.0007 | Cleavage-stage embryos/fertilized embryos IVF (mean ± SD) 20–29: 699/738 30–39: 3306/3542 40–50: 1207/1296 >51: 29/31 P-value = 0.0048 ICSI (mean ± SD) 20–29: 958/1199 30–39: 4052/4882 40–50: 1591/1893 >51: 203/242 P-value = 0.3273 | Blastocysts/fertilized embryos IVF 20–29: 49.46% (365/738) 30–39: 54.97% (1947/3542) 40–50: 49.38% (640/1296) >51: 56.84% (17/31) P-value =0.0255 ICSI 20–29: 50.38% (604/1199) 30–39: 48.12% (2349/4882) 40–50: 47.02% (890/1893) >51: 46.28% (112/242) P-value = 0.5682 | NS | Clinical pregnancy/cycle IVF 20–29: 33/114 30–39: 204/524 40–50: 84/211 >51: 1/10 ICSI 20–29: 94/226 30–39: 389/949 40–50: 132/410 >51: 13/47 | NS | Miscarriage/clinical pregnancy IVF 20–29: 6/33 30–39: 38/204 40–50: 29/84 >51: NR ICSI 20–29: 16/94 30–39: 57/389 40–50: 27/132 >51: 6/13 | NS | NS | Within IVF cycles, the fertilization rate, mean number of embryos at days 2 and 3, mean number of embryos for prolonged culture and mean number of obtained blastocysts were significantly reduced in the age group >51 years compared with the other age groups Rate of clinical pregnancy also decreased but not significantly Within ICSI cycles, the pregnancy rate decreased significantly and early miscarriage rate was higher in the oldest paternal age group (>51 years) |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Tiegs et al., 2017 | Fertilized embryos/total oocytes Overall: 6440/10106 (63.7%) Standard IVF: 66 ± 17% ICSI: 62 ± 15% | NS | Blastocysts/fertilized embryos Mean ± SD Overall: 3972/6440 (61.7%) 21–30: 60 ± 24% 31–35: 66 ± 21% 36–40: 61 ± 23% 41–45: 62 ± 23% >45: 65 ± 23% P-value = 0.28 | Good-quality embryos/cleavage-stage embryos Mean ± SD Overall: 52 ± 24% 21–30: 51 ± 16% 31–35: 53 ± 24% 36–40: 51 ± 24% 41–45: 52 ± 24% >45: 51 ± 24% P-value = 0.96 | Clinical pregnancy/cycle Overall: 337/573 (58.8%) 21–30: 10/22 (45.5%) 31–35: 77/125 (61.6%) 36–40: 115/192 (59.9%) 41–45: 77/140 (55%) >45: 58/94 (61.7%) P-value = 0.51 | Overall: 315/573 (55.0%) | Miscarriage/clinical pregnancy Overall: 32/337 (9.5%) 21–30: 2/10 (20%) 31–35: 5/77 (6.5%) 36–40: 13/115 (11.3%) 41–45: 8/77 (10.4%) >45: 4/58 (6.9%) P-value = 0.55 | NS | NS | Increasing paternal age is associated with decreased fertilization. There was no effect on pregnancy or delivery rates after the transfer of a single euploid embryo No difference in outcome was seen when controlling for aneuploidy only or aneuploidy and oocyte age |
Meijerink et al., 2016 | Fertilized embryos/total oocytes <35: 66.7% 35–44: 66.7% ≥45: 66.7% | NS | NS | Good-quality embryos/cleavage-stage embryos <35: 1642/3076 (53.4%) 35–44: 1678/3339 (50.3%) ≥45: 305/636 (48.0%) | Clinical pregnancy/cycle <35: 853/3076 (27.7%) 35–44: 792/3339 (23.7%) ≥45: 150/636 (23.6%) | NS | NS | NS | NS | No statistically significant differences between the paternal age groups were found with respect to the probability of an ongoing pregnancy after the first cycle respectively, compared with <35 years of age (control) Similar results were found with respect to paternal age and the availability of a top-quality embryo for transfer, biochemical pregnancy and miscarriage |
Wu et al., 2016 | Fertilized embryos/total oocytes Total: 1904/2627 (72.5%) <30: 430/589 (73.0%) 30–34: 756/1052 (71.9%) 35–39: 483/662 (73.0%) 40–44: 185/250 (74.0%) 45–49: 31/47 (66%) ≥50: 19/27 (70%) | NS | NS | NS | Clinical pregnancy/cycle Overall: 1274/2627 (48.5%) <30: 334/589 (56.71%) 30–34: 517/1052 (49.14%) 35–39: 288/662 (43.5%) 40–44: 105/250 (42.00%) 45–49: 19/47 (40.43%) ≥50: 11/27 (40.74%) | OR for a 5-year interval (95% CI) 0.916 (0.833–1.007) | OR for a 5-year interval (95% CI) 1.019 (0.823–1.263) | Congenital malformation/clinical pregnancy Overall: 0.80% (10/1249) <30: 0.30% (1/331) 30–34: 0.98% (5/510) 35–39: 1.41% (4/284) 40–44: 0% (0/105) 45–49: 0% (0/19) ≥50: 0% (0/11) | NS | Increased paternal age negatively influences the number of high-quality embryos but has no effect on pregnancy outcomes in couples undergoing ICSI cycles |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Garcia-Ferreyra et al., 2015 | Fertilized embryos/total oocytes ≤39: 48/58 (82.8%) 40–49: 169/207 (81.6 ≥50: 108/131 (82.4%) | Cleavage-stage embryos/fertilized embryos ≤39: 48/48 (100%) 40–49: 166/169 (98.2%) ≥50: 103/108 (95.4%) | Blastocysts/fertilized embryos ≤39: 26/48 (54.2%) 40–49: 83/169 (49.1%) ≥50: 29/108 (26.9%) | Good-quality embryos/cleavage-stage embryos ≤39: 40/48 (83.3%) 40–49: 144/169 (85.2%) ≥50: 76/108 (70.4%) | NS | NS | NS | NS | NS | Advanced paternal age increases the aneuploidy rates in embryos from donated oocytes, which suggests that genetic screening is necessary in those egg donor cycles with sperm from patients >50 years old |
Ho et al., 2015 | Fertilized embryos/total oocytes <40: 64.2% 40–45: 63.7% 45–50: 58.9% >50: 63.3% | NS | NS | NS | Clinical pregnancy/cycle <40: 45/58 (77.6%) 40–45: 53/72 (73.6%) 45–50: 37/51 (72.5%) >50: 26/33 (78.8%) | NS | Miscarriage/clinical pregnancy <40: 8/45 (17.8%) 40–45: 14/53 (26.4%) 45–50: 5/37 (13.5%) >50: 1/26 (3.8%) | NS | NS | Individual semen parameters and paternal age did not have significant effects on fertilization rate or pregnancy outcomes in oocyte recipient cycles |
Begueria et al., 2014 | Fertilized embryos/ total oocytes Mean ± SD Overall: 0.72 ± 0.22 <25: 0.64 ± 0.26 25–29: 0.71 ± 0.25 30–34: 0.71 ± 0.23 35–39: 0.72 ± 0.22 40–44: 0.72 ± 0.22 45–49: 0.73 ± 0.22 50–54: 0.73 ± 0.22 55–59: 0.74 ± 0.20 ≥60: 0.74 ± 0.24 | NS | NS | Embryo quality Mean ± SD Overall: 8.57 ± 1.05 <25: 8.57 ± 1.05 25–29: 8.57 ± 1.05 30–34: 8.57 ± 1.05 35–39: 8.57 ± 1.05 40–44: 8.57 ± 1.05 45–49: 8.57 ± 1.05 50–54: 8.57 ± 1.05 55–59: 8.57 ± 1.05 ≥60: 8.57 ± 1.05 | Clinical pregnancy/cycle <30: 45/131 (34.4%) 30–34: 248/598 (41.5%) 35–39: 555/1385 (40.1%) 40–44: 563/1446 (38.9%) 45–49: 327/817 (40.0%) >50: 190/509 (37.3%) | Live birth/cycle <30: 44/131 (33.6%) 30–34: 244/598 (40.8%) 35–39: 546/1385 (39.4%) 40–44: 548/1446 (37.9%) 45–49: 319/817 (39.0%) >50: 188/509 (36.9%) | Miscarriage/clinical pregnancy <30: 12/45 (26.7%) 30–34: 39/248 (15.7%) 35–39: 111/555 (20.0%) 40–44: 122/563 (21.7%) 45–49: 71/327 (21.7%) >50: 53/190 (27.9%) | NS | NS | Paternal age does not affect reproductive outcomes when the oocyte donor is <36 years of age, indicating that ICSI and oocyte quality can jointly overcome the lower reproductive potential of older semen |
Tsai et al., 2013 | Fertilized embryos/total oocytes 31–35: 545/612 35–40: 252/286 >40: 182/198 | Cleavage-stage embryos/fertilized embryos 31–35: 528/545 35–40: 245/252 >40: 175/182 | NS | Good-quality embryos/cleavage-stage embryos 31–35: 415/528 (78.6%) 35–40: 189/245 (77.1%) >40: 141/175 (80.6%) | Clinical pregnancy/cycle 31–35: 38/84 (45.2%) 35–40: 23/56 (41.1%) >40: 17/44 (38.6%) | Live birth/cycle 31–35: 35/84 (41.7%) 35–40: 19/56 (33.9%) >40: 14/44 (31.8%) | Miscarriage/clinical pregnancy 31–35: 7/38 >35–40: 4/19 >40: 3/17 | NS | NS | Insufficient evidence to demonstrate an unfavourable effect of advanced paternal age on the fertility outcome for TESE–ICSI |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Medina et al., 2012 | Fertilized embryos/total oocytes <34: 72% 35–38: 61% >39: 78% | NS | NS | NS | Clinical pregnancy/cycle <34: 24/38 (63%) 35–38: 30/43 (70%) >39: 118/179 (66%) | NS | Miscarriage/clinical pregnancy <34: 4/24 (16.7%) 35–38: 4/30 (13.3%) >39: 38/118 (32.2%) | NS | NS | There were no significant differences between groups in their fertilization, clinical pregnancy or implantation rates. Paternal age significantly affects the abortion rate |
Meyer et al., 2012 | NS | NS | NS | NS | Clinical pregnancy/cycle <40: 129/176 (73.3%) >40: 344/488 (70.5%) | Live birth/cycle <40: 89/176 (50.6%) >40: 262/488 (53.7%) | Miscarriage/clinical pregnancy <40: 40/129 (31%) >40: 82/344 (23.8%) | NS | NS | Paired analysis of 146 recipient couples revealed no statistically significant difference in day 3 implantation rate, day 5 implantation rate, total pregnancy rate or live birth rate |
Nijs et al., 2011 | Fertilized embryos/total oocytes Overall: 66.4 ± 21.6% P-value = 0.64 ≤34: 65.7 ± 21.4% P-value = 0.5 35–39: 69.2 ± 21.7% P-value = 0.23 ≥40: 62.6 ± 21.5% P-value = 0.32 | NS | NS | NS | Clinical pregnancy/cycle Overall: 126/278 (45.3%) P-value = 0.81 ≤34: 69/135 (51.1%) P-value = 0.77 35–39: 39/96 (41%) P-value = 0.98 ≥40: 18/47 (38.3%) P-value = 0.45 | Live birth/cycle Overall: 80/278 (28.7%) P-value = 0.49 ≤34: 43/135 (31.9%) P-value = 0.82 35–39: 25/96 (26.0%) P-value = 0.42 ≥40: 12/47 (25.5%) P-value = 0.40 | Miscarriage/clinical pregnancy Overall: 46/126 (36.5%) P-value = 0.49 ≤34: 26/69 (37.7%) P-value = 0.82 35–39: 14/39 (35.9%) P-value = 0.42 ≥40: 6/18 (33.3%) P-value = 0.40 | NS | Singleton Mean ± SD 3223 ± 635.6 g Twin Mean ± SD 2616 ± 333.4 g | Logistic regression analysis did not reveal any male age–related influences on sperm parameters, e.g. sperm concentration, motility or morphology No significant male age–related increase in DFI or immature chromatin was observed Elevated male age, after correcting for female age, was not related to lower fertilization rates or significant decreases in the chance of the birth of a healthy baby |
Whitcomb et al., 2011 | Fertilized embryos/total oocytes Mean ± SD <30: 10.8 ± 7.1 30–34: 11.1 ± 6.4 35–39: 10.4 ± 5.5 40–44: 10.3 ± 5.7 45–49: 10.3 ± 5.5 50–54: 11.0 ± 6.0 >55: 9.7 ± 5.8 P-value = 0.76 | NS | NS | NS | Clinical pregnancy/first treatment cycle <30: 16/21 (76.2%) 30–34: 80/119 (67.2%) 35–39: 205/287 (71.4%) 40–44: 222/341 (65.1%) 45–49: 132/207 (63.8%) 50–54: 49/78 (62.8%) >55: 20/30 (66.7%) P-value = 0.09 | Live birth/first treatment cycle <30: 13/21 (61.9%) 30–34: 66/119 (55.5%) 35–39: 174/287 (60.6%) 40–44: 191/341 (56.0%) 45–49: 119/207 (57.5%) 50–54: 41/78 (52.6%) >55: 17/30 (56.7%) P-value = 0.09 | Miscarriage/clinical pregnancy <30: 3/16 (18.8%) 30–34: 13/80 (16.3%) 35–39: 25/205 (12.2%) 40–44: 28/222 (12.6%) 45–49: 13/132 (9.8%) 50–54: 8/49 (16.3%) >55: 2/20 (10.0%) | NS | NS | Increasing male age is associated with semen parameters including volume and motility However, male age is not observed to have a statistically significant association with likelihood of live birth in donor cycles after adjustment for female recipient age |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Luna et al., 2009 | Fertilized embryos/total oocytes <40: 1951/3062 (63.7%) 40–50: 2663/4414 (60.3%) >50: 845/1437 (58.8%) P-value < 0.05 | NS | Blastocysts/fertilized embryos <40: 658/1078 (61%) 40–50: 811/1573 (51.6%) >50: 185/387 (47.8%) P-value < 0.05 | Good-quality embryos/cleavage-stage embryos <40: 1292/1951 (66.2%) 40–50: 1679/2663 (63.0%) >50: 520/845 (61.5%) P-value < 0.05 | Clinical pregnancy/cycle <40: 143/223 (61.1%) 40–50: 204/323 (63.2%) >50: 80/116 (69%) | NS | Miscarriage/clinical pregnancy <40: 17/143 (11.9%) 40–50: 31/204 (15.2%) >50: 12/80 (15%) | NS | NS | Paternal age may be inversely associated with reproductive outcome, as demonstrated by a decline in fertilization, blastocyst formation, implantation and cryopreservation rates with advancing age |
Bellver et al., 2008 | Fertilized embryos/total oocytes Linear correlation IVF/ICSI r = 0.045 P-value = non-significant Oocyte donation r = 0.056 P-value = non-significant | NS | Blastocysts/fertilized embryos Linear correlation IVF/ICSI r = 0.036 P-value = 0.020 Oocyte donation: r = 0.001 P-value = non–sig | Good-quality embryos/cleavage-stage embryos Linear correlation IVF/ICSI r = 0010 P-value = 0.0001 Oocyte donation: r = 0.027 P-value = 0.016 | Clinical pregnancy/cycle Overall: IVF/ICSI autologous oocyte cycles: 676/1286 (52.6%) 95% CI: (49.5–55.1) <30: 78/145 (53.8%) >30: 598/1141 (52.4%) <35: 349/659 (53.0%) >35: 327/627 (52.2%) <40: 627/1186 (52.9%) >40: 49/100 (49.0%) IUI: 396/2129 (18.6%) 95% CI: (16.4–19) Oocyte donation: 727/1412 (51.5%) 95% CI: (48.9–54.1) | NS | Miscarriage/clinical pregnancy Overall: IVF/ICSI: 103/676 (15.2%) 95% CI: (12.60–18.10) <30: 12/78 (15.4%) >30: 91/598 (15.2%) <35: 79/349 (22.6%) >35: 24/327 (7.3%) <40: 95/627 (15.2%) >40: 8/49 (16.3%) IUI: 85/395 (21.5%) 95% CI: (17.3–25.6) Oocyte donation: 135/726 (18.6%) 95% CI: (16.0–21.3) | NS | NS | Male age in the range studied slightly impairs semen quality, but this effect does not lead to a poorer outcome in assisted conception when the female partner is not of advanced age |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Frattarelli et al., 2008 | NS | Cleavage-stage embryos/ fertilized embryos Mean ± SD Overall: 11.1 ± 6.2 ≤35: 11.0 ± 6.6 36–40: 11.3 ± 6.5 41–45: 10.6 ± 6.0 46–50: 10.4 ± 5.7 51–55: 10.8 ± 5.5 >55: 11.6 ± 8.9 | Blastocysts/fertilized embryos Mean ± SD Overall: 5.0 ± 4.7 ≤35: 4.6 ± 5.6 36–40: 5.0 ± 5.0 41–45: 5.2 ± 5.2 46–50: 4.5 ± 4.3 51–55: 4.5 ± 4.9 >55: 3.0 ± 4.7 P-value < 0.05 | Good-quality embryos/cleavage-stage embryos Mean ± SD Overall: 6.6 ± 4.8 ≤35: 6.8 ± 5.4 36–40: 6.2 ± 5.1 41–45: 6.9 ± 4.5 46–50: 6.5 ± 4.5 51–55: 5.8 ± 3.7 >55: 7.3 ± 5.1 P-value = 0.54 | Clinical pregnancy/cycle ≤35: 109/145 (75%) 36–40: 225/312 (72%) 41–45: 243/315 (77%) 46–50: 113/162 (70%) >50: 65/92 (70.7%) | Live birth/cycle ≤35: 83/145 (57%) 36–40: 168/312 (54%) 41–45: 181/315 (57.5%) 46–50: 88/162 (54.3%) >50: 38/92 (41.3%) | Miscarriage/clinical pregnancy ≤35: 25/108 (23.1%) 36–40: 56/225 (25%) 41–45: 62/243 (25.5%) 46–50: 25/113 (22%) >50: 27/65 (41.5%) | NS | NS | After controlling for female age with use of the donor oocyte model, male age >50 years significantly affected pregnancy outcomes and blastocyst formation rates Semen volume and total motility decreased with increasing male age. Initial embryo morphology to cleavage stage was not affected |
Aboulghar et al., 2007 | Fertilized embryos/total oocytes Mean ± SD ≥50: 64.9 ± 25.4 <50: 66.7 ± 25.6 P-value < 0.0001 | NS | NS | Good-quality embryos/cleavage-stage embryos Mean ± SD ≥50: 5.1 ± 3.8 <50: 5.4 ± 3.5 | Clinical pregnancy/cycle ≥50: 86/227 (37.9%) <50: 83/227 (36.6%) | NS | NS | NS | NS | There was no significant difference in pregnancy rate between the two groups: ≥50/<50 There was also no significant difference in pregnancy rate between men aged ≥60 years compared with men aged 50–59 years Semen analysis showed significantly lower motility in the group ≥50 years (37.4 ± 20.4) versus <50 years There was a significantly higher fertilization rate in younger men, but this did not affect the pregnancy rate |
| Klonoff–Cohen (2004) | Fertilized embryos/total oocytes No significant association with paternal age | NS | NS | NS | Clinical pregnancy/cycle ≤35: 25/47 (53%) 36–40: 22/63 (34.9%) >40: 6/46 (13.0%) | Live birth/cycle ≤35:17/45 (37.8%) 36–40: 10/60 (16.7%) >40: 3/44 (6.8%) | No significant association with paternal age | NS | No significant association with paternal age | Advancing paternal age has a deleterious effect on IVF and GIFT outcomes |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Kumtepe et al., 2003 | Fertilized embryos/total oocytes <40: 5759/8203 (70.2%) >40: 1525/2265 (67.3%) | NS | NS | Grade 1 embryos transferred <40: 2.1 ± 1.2 >40: 2.3 ± 1.4 | Clinical pregnancy/cycle <40: 317/678 (46.8%) >40: 90/241 (37.3%) | NS | NS | NS | NS | The effect of male age on ART results in cases with male factor infertility is not a direct effect but a reflection of the negative impact of the parallel increase in the female age |
Spandorfer et al., 1998 | Fertilized embryos/total oocytes ≤39: 3342/4677 (71.5%) 40–49: 1502/2109 (71.2%) ≥50: 211/308 (68.5%) P-value = 0.044 | NS | NS | NS | Clinical pregnancy/cycle where female partner age ≤35 ≤35: 172/310 (55.5%) 36–39: 33/79 (41.8%) ≥40: 4/9 (44.4%) | NS | NS | NS | NS | The influence on pregnancy outcome after ICSI is related mostly to maternal and not paternal age |
Gallardo et al., 1996 | Fertilized embryos/total oocytes ≤30: 182/266 31–40: 1187/1658 41–50: 614/843 ≥51: 129/176 | Cleavage-stage embryos/ fertilized embryos Mean ± SD ≤30: 172/182 31–40: 1097/1187 41–50: 565/614 ≥51: 117/129 | NS | Good-quality embryos/cleavage-stage embryos Mean ± SD (per male age) ≤30: 115/172 31–40: 765/1097 41–50: 411/565 ≥51: 112/117 | Clinical pregnancy/cycle ≤30: 20/31 (64.5%) 31–40: 89/195 (45.6%) 41–50: 50/98 (51.0%) ≥51: 15/21 (71.4%) | NS | Miscarriage/clinical pregnancy ≤30: 1/20 (5.0%) 31–40: 8/89 (9.0%) 41–50: 6/50 (12.0%) ≥51: 4/15 (26.7%) | NS | NS | Age (up to 64 years) did not affect sperm characteristics or their ability to fertilize human eggs. Similarly, embryo development in vitro, as well as implantation in recipient uteri was not affected by the age of the male providing the semen sample |
| Studies not included in the meta analysis | ||||||||||
Gallo et al., 2019
Impact of paternal age on seminal parameters and reproductive outcome of intracytoplasmatic sperm injection in infertile Italian women. Frontiers in Endocrinology. 2019; 10: 35 | Fertilized embryos/total oocytes Total: 536/543 (99%) | NS | NS | NS | Clinical pregnancy/cycle Total: 123/536 (23%) Correlation between male age and positive pregnancy test OR 0.98, CI 0.94–1.01 | NS | NS | NS | NS | Male age groups did not reveal any statistically significant differences in age-related semen parameters A statistically significant increase in the pregnancy rate of couples with older partner age difference and younger female age was observed A negative effect of male age was observed on the efficacy of the reproductive outcome as per a reduced number of type A embryos |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Kim et al., 2019 | Fertilized embryos/ total oocytes Female <35; male ≤38 730/1078 (67.7%) Female<35; male>38 157/222 (70.7%) Female≥35; male ≤38 417/587 (71%) Female≥35; male>38 793/1068 (74.3%) P-value = 0.39 | NS | NS | Euploid blastocysts/number of blastocysts analysed for PGT Female <35; male ≤38 100/210 (47.6%) Female <35; male >38 17/36 (47.2%) Female≥35; male ≤38 46/129 (35.7%) Female ≥35; male >38 56/196 (28.6%) P-value = 0.001 | Clinical pregnancy/cycle Female <35; male ≤38 21/58 (36.2%) Female <35; male >38 3/12 (25%) Female≥35; male ≤38 13/37 (35.1%) Female ≥35; male >38 17/68 (25%) Clinical pregnancy/transferred blastocysts Female <35; male ≤38 21/41 (51.2%) Female <35; male >38 3/8 (37.5%) Female ≥35; male ≤38 13/20 (65.0%) Female ≥35; male >38 17/38 (44.7%) | NS | Miscarriage/clinical pregnancy Female <35; male ≤38 1/21 (4.8%) Female <35; male >38 0/3 (0) Female ≥35; male ≤38 4/13 (30.8%) Female ≥35; male >38 7/17 (41.2%) Miscarriage/transferred blastocysts Female <35; male ≤38 1/41 (2.4%) Female <35; male >38 0/8 (0) Female ≥35; male ≤38 4/20 (20.0%) Female ≥35; male >38 7/38 (18.4%) | NS | NS | There was no significant relationship between paternal age and euploidy rate or clinical outcomes (e.g. implantation, ongoing pregnancy, abortion rates) |
Lai et al., 2018 | Spearman's correlation coefficient: –0.004 P-value = 0.810 | NS | NS | NS | Clinical pregnancy/cycle 1613/3168 (50.9%) | Live birth/cycle 1227/3168 (38.7%) | Miscarriage/clinical pregnancy 284/1613 (17.6%) | NS | NS | Paternal age is negatively correlated with some semen parameters, which show significant decline after 40 years old Paternal age is not predictive of live birth from IVF treatment |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Ma et al., 2018 | NS | NS | NS | NS | Clinical pregnancy/cycle Number of cycles (95% CI) ≤25: n = 438 (0.54–1.65) aOR = 0.95 P-value = 0.86 26–30: n = 865 (0.78–2.07) aOR = 1.27 P-value = 0.33 31–35: n = 730 (0.81–2.01) aOR = 1.28 P-value = 0.28 36–40: n = 317 (0.63–1.69) aOR = 1.03 P-value = 0.87 ≥41: n = 124 aOR = 1 | Live birth/cycle Number of cycles (95% CI) ≤25: n = 438 (0.74–2.26) aOR = 1.29 P-value= 0.36 26–30: n = 865 (0.95–2.57) aOR = 1.57 P-value = 0.07 31–35: n = 730 (1.02–2.60) aOR = 1.63 P-value = 0.03 36–40: n = 317 (0.81– 2.21) aOR = 1.34 P-value = 0.25 ≥41: n = 124 aOR = 1 | Miscarriage/ clinical pregnancy Number NS (95% CI) ≤25: (0.17–1.26) aOR = 0.46 P-value = 0.13 26–30: (0.23–1.29) aOR = 0.55 P-value = 0.17 31–35: (0.19–0.90) aOR = 0.41 P-value = 0.02 36–40: (0.28–1.48) aOR = 0.64 P-value = 0.30 ≥41: aOR = 1 | NS | Mean ± SD (g) ≤25: 3346 ± 487 26–30: 3377 ± 536 31–35: 3406 ± 504 36–40: 3381 ± 551 ≥ 41: 3409 ± 485 P-value = 0.847 | Paternal age is related to live birth and miscarriage rates However, it is not significant on clinical pregnancy rate Advanced paternal age may also affect the birthweight of twins |
Tatsumi et al., 2018 | NS | NS | NS | NS | Clinical pregnancy/cycle Males: ≥34: 33/358 (9.2%) 35–37: 28/217 (12.9%) 38–40: 25/473 (5.3%) 41–43: 13/294 (4.4%) 44–46: 5/131 (3.8%) ≥47: 7/103 (6.8%) P-value = 0.002 Females: ≥34: 46/511 (9.0%) 35–37: 29/298 (9.7%) 38–40: 36/767 (4.7%) P-value = 0.002 | Live birth/cycle Males: ≥34: 28/358 (7.8%) 35–37: 22/217 (10.1%) 38–40: 18/473 (3.8%) 41–43: 10/294 (3.4%) 44–46: 2/131 (1.5%) ≥47: 6/103 (5.8%) P-value = 0.001 Females: ≥34: 38/511 (7.4) 35–37: 22/298 (7.4) 38–40: 26/767 (3.4) P-value = 0.002 | NS | NS | NS | Advanced paternal age alone does not adversely affect pregnancy or live birth rates or sperm parameters following IUI, after adjusting for confounding factors |
Ghuman et al., 2016 | NS | NS | NS | NS | NS | Live birth/cycle Donor insemination overall: 9.54% IVF/ICSI overall: 22.76% | NS | Extremely low numbers of congenital abnormalities recorded (meaningful analysis not feasible) | NS | Live birth and miscarriage occurrence following assisted reproduction were not adversely affected by increasing sperm donor age up to 45 years |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Wu et al., 2015
Effect of paternal age on reproductive outcomes of in vitro fertilization. Plos One. 2015; https://doi.org/10.1371/journal.pone.0135734 | No significant difference in fertilization rate among different paternal age groups P-value > 0.05 | NS | NS | Good-quality embryos/cleavage-stage embryos Maternal age (<30) Mean ± SD <30: 3.2 ± 2.7 30–32: 3.2 ± 2.7 33–35: 3.1 ± 2.7 36–38: 3.1 ± 2.7 39–41: 3.3 ± 2.6 ≥42: 2.9 ± 2.8 P-value > 0.05 Maternal age (30–34) Mean ± SD <30: 3.0 ± 2.5 30–32: 2.9 ± 2.6 33–35: 2.9 ± 2.6 36–38: 3.0 ± 2.6 39–41: 2.8 ± 2.6 ≥42: 2.7 ± 2.5 P-value > 0.05 Maternal age (35–38) Mean ± SD <30: 2.6 ± 2.7 30–32: 2.6 ± 2.2 33–35: 2.5 ± 2.4 36–38: 2.6 ± 2.2 39–41: 2.5 ± 2.3 ≥42: 2.5 ± 2.2 P-value > 0.05 | Clinical pregnancy/cycle Maternal age groups <30: (55.8%) 30–32: (52.6%) 36–38: (47.7%) 39–41: (45.8%) P-value < 0.05 | NS | Miscarriage/clinical pregnancy No significant difference in miscarriage rate among different paternal age groups P-value > 0.05 | NS | NS | Paternal age had no significant effect on embryo quality at the cleavage stage or on miscarriage rate However, in the 31– 34-year maternal age group, paternal age had detrimental effects on implantation and pregnancy rates |
Robertshaw et al., 2014 | NS | NS | NS | NS | Clinical pregnancy/cycle 25–29: (100%) 30–34: (82.9%) 35–39: (88.5%) 40–44: (86.8%) 45–49: (87.8%) 50–54: (100%) ≥55: (44.4%) | Live birth/cycle 25–29: (90.9%) 30–34: (77.2%) 35–39: (76.5%) 40–44: (61.4%) 45–49: (57.0%) 50–54: (63.9%) ≥55: (47.6%) | Miscarriage/clinical pregnancy 25–29: (10.0%) 30–34: (7.3%) 35–39: (7.3%) 40–44: (25.0%) 45–49: (19.4%) 50–54: (33.3%) ≥55: (0.0%) | NS | NS | Advanced paternal age has an adverse impact on ART outcome. After adjusting for number and embryo grades transferred, a younger paternal age has a more favourable ART outcome |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
Koh et al., 2013 | NS | NS | NS | NS | Clinical pregnancy/cycle <40 (n = 1303) Ref. OR (95% CI) 40–44.9 (n = 427) 1.037 (0.737–1.460) 45–49.9 (n = 316) 0.574 (0.361–0.914) ≥50 (n = 96) 0.574 (0.259–1.269) P-value < 0.05 | NS | NS | NS | NS | This study reveals an adverse effect of male age on clinical pregnancy in women <40 years of age, not solely mediated by decreased sperm concentration or motility |
Gu et al., 2012 | Fertilized embryos/total oocytes Mean ± SD 78.8% ± 18.6% | NS | NS | NS | Clinical pregnancy/cycle ≤37: 9/29 (31.0%) >37: 25/74 (33.8%) P-value = 0.790 | Live birth/cycle ≤37: 9/29 (31.0%) >37: 18/74 (24.3%) P-value = 0.486 | Miscarriage/clinical pregnancy ≤37: 0/9 (0%) >37: 7/25 (28.0%) P-value = 0.075 | NS | NS | Ageing of the male has no significant impact on fertilization, pregnancy or live birth in oocyte donation cycles, but may be associated with pregnancy loss |
Duran et al., 2010 | Fertilized embryos/ total oocytes Mean ± SD 25–38: 0.86 ± 0.15 39–49: 0.82 ± 0.18 ≥50: 0.79 ± 0.23 P-value = 0.04 | NS | NS | NS | Clinical pregnancy/cycle Mean ± SD 25–38: 0.31 ± 0.35 39–49: 0.27 ± 0.34 ≥50: 0.25 ± 0.31 | NS | Miscarriage/clinical pregnancy Mean ± SD 25–38: 0.15 ± 0.36 39–49: 0.22 ± 0.36 ≥50: 0 | NS | NS | Although semen volume, sperm motility and fertilization rate decreased with advanced male age, embryo quality, clinical pregnancy, implantation, miscarriage and live birth rates were not affected |
Ferreira et al., 2010 | NS | NS | NS | Good-quality embryos/cleavage-stage embryos Multiple linear regression Oligozoospermic: P = 0.442 RC = 0.1822 Normozoospermic: P = 0.368 RC = 0.1725 | Clinical pregnancy/cycle Multiple linear regression Oligozoospermic: P = 0.008 RC = –0.7009 Normozoospermic: patients P = 0.752 RC = 0.0566 | NS | Miscarriage/clinical pregnancy Multiple linear regression Oligozoospermic: P = 0.128 OR = 0.92 95% CI (0.82–1.03) Normozoospermic: P = 0.916 OR = 1.00 95% CI (0.94–1.06) | NS | NS | For couples in which men are oligozoospermic, implantation rate could be impaired by increased paternal age In these couples, the chance of pregnancy decreases by 5% for each year of paternal age. The same effect is not observed in normozoospermic, men |
| First author (year) | Rate of fertilization | Rate of cleavage-stage embryo | Rate of blastocyst formation | Rate of top-quality embryos | Rate of pregnancy | Rate of live birth | Rate of miscarriage | Congenital malformations | Birthweight | Observed paternal age effect |
| Belloc (2008) | NS | NS | NS | NS | Clinical pregnancy/cycle OR (95% CI) <35: 1.00 35–44: 0.90 (0.75–1.09) ≥45: 0.81 (0.65–1.02) | NS | Miscarriage/clinical pregnancy OR (95% CI) <35: 1.00 35–44: 1.71 (1.14–2.54) ≥45: 1.75 (1.06–2.90) | NS | NS | Advanced maternal age had a negative effect on the pregnancy rate and was associated with increased miscarriage rate. An exactly parallel effect was found for paternal age The impact of increased age on necrospermia and sperm DNA structure is discussed as a probable direct cause of this paternal effect |
Campos et al., 2008 | Fertilized embryos/total oocytes Overall (mean % ± SD): 82.71 ± 0.59 Range: (25–100) P-value = 0.40 | NS | Blastocysts/fertilized embryos Overall (mean % ± SD): 5.63 ± 0.07 Range: (2–10) | NS | Clinical pregnancy/cycle Overall (mean %): 460/915 (50.27%) | NS | Miscarriage/clinical pregnancy Overall (mean %): 189/460 (41.1%) | NS | NS | Age has a detrimental effect on the reproductive outcome of oocyte donation cycles when both men and recipients are ≥ 39 years old |
Girsh et al., 2008 | NS | NS | NS | Good-quality embryos/cleavage-stage embryos Non-pregnant (26%) Pregnant (34%) P-value = 0.01 | NS | NS | NS | NS | NS | Sperm parameters are reduced by age; therefore an age-dependent effect could be a reason for failures in IVF cycles even in egg donation programme couples |
| De La Rochebrochard (2006) | NS | NS | NS | NS | NS | NS | NS | NS | NS | Paternal age over 40 years is an important risk factor for failure to conceive |
Paulson et al., 2001 | Fertilized embryos/ total oocytes Fertilization rate correlates with total sperm count r = 0.13 P-value=0.005 Fertilization rate did not correlate with male age | NS | NS | NS | There was no significant influence of male age on pregnancy success as per logistic regression | Live birth/cycle 32.7% | NS | NS | NS | Male ageing is associated with a significant decline in total sperm count; this change is not reflected in a decreased fertilization rate or decreased live birth rate in the oocyte donation model |
Mathieu et al., 1995 | NS | NS | NS | NS | Clinical pregnancy/couple (cumulative at 5 cycles per male ages) <30: n = 65 (51.7%) 30–34: n = 101 (40.3%) ≥35: n = 108 (25%) P-value = 0.03 | NS | NS | NS | NS | Multivariate analysis revealed the most significant factor contributing to a decreased likelihood of pregnancy was the age of the male partner (P = 0.01), followed by duration of infertility and dysovulation |
a Statistically significant.aOR, adjusted odds ratio; ART, assisted reproductive technology; BMI, body mass index; CI, confidence interval; DFI, DNA fragmentation index; GIFT, gamete intra-Fallopian transfer; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; NS, not specified; OR, odds ratio; PGT, preimplantation genetic testing; RC, xxxx; Ref., reference group; RR, xxxx; TESE, testicular sperm extraction.
Table 3Inclusion and exclusion criteria
| First author (year) | Inclusion criteria | Exclusion criteria | Paternal age groups (years) |
|---|---|---|---|
Horta et al., 2019 | 1.Couples with primary/secondary idiopathic infertility 2.Male partners classified as normozoospermic | 1.Endometriosis 2.Tubal factors 3.Polycystic ovarian syndrome 4.Ovarian hyperstimulation syndrome 5.Poor responders (≤3 mature oocytes) 6.Couples with more than 15 cumulus–oocyte complexes retrieved 7.Using cryopreserved gametes | <40 40–44 45–49 50–54 ≥55 |
Cito et al., 2019
Impact of advanced paternal age on the intracytoplasmic sperm injection outcomes in donor egg cycles. Translational Andrology and Urology. 2019; 8: S22-S30 | 1. Couples with primary male infertility or severe female infertility factor for at least 1 year 2.Egg donors <25 years old and screened 3.ICSI with fresh spermatozoa 4.Presence of normal or subfertile seminal parameters in at least two seminal analyses 5.Overall oocyte survival rate after warming of >85% | 1.Azoospermia 2.Hypogonadism 3.Varicocele 4.Retractile testes 5.Previous testicular torsion 6.Concomitant urogenital infections 7.Previous chemotherapy or radiotherapy 8.Haematological disorders 9.Chronic inflammatory disease 10.Drug therapy | ≤45 >45 |
Gallo et al., 2019
Impact of paternal age on seminal parameters and reproductive outcome of intracytoplasmatic sperm injection in infertile Italian women. Frontiers in Endocrinology. 2019; 10: 35 | 1.Couples undergoing ICSI | 1.Women who have stopped treatment due to OHSS 2.Male partners with azoospermia or severe oligoasthenoteratozoospermia requiring fine needle aspiration 3.Female partner requiring all oocytes to be cryopreserved 4.Female partner with a disorder (e.g. endometriosis, reduced ovarian reserve, recurrent miscarriage to endocrine ovulatory pathology) | ≤38 39–43 ≥44 |
Kim et al., 2019 | 1.Patients who underwent PGT 2.Patients who responded normally to ovarian stimulation | 1.Patients who did not undergo PGT 2.Patients who underwent day 3 embryo transfer | Female <35; male ≤38 Female <35; male >38 Female ≥35; male ≤38 Female ≥35; male >38 |
Yu et al., 2019 | 1.All infertile men with cryptozoospermia who underwent ICSI | 1.Infertility caused by female factors 2.Female partner with karyotype abnormalities | <35 ≥35 |
Capelouto et al., 2018 | 1.Oocyte donors from Reproductive Biology Associates between the ages of 21 and 30 years 2.Cycles in which the couple had at least one embryo transfer from a warmed oocyte cohort 3.Only the first embryo transfer from each warmed oocyte cohort 4.Blastocyst embryo transfers (post-fertilization day 5 or 6) | 1.Couples using a gestational carrier and couples in which the female recipient had uterine factor infertility (prior abdominal or laparoscopic myomectomy or a history of Asherman disease) 2.No fresh donor oocyte transfer cycles | ≤30 31–35 36–40 41–45 46–50 ≥51 |
Garcia-Ferreyra et al., 2018 | 1.Anonymous oocyte donors (20–30 years old) who underwent physical, gynaecological and psychological examinations in which no family history of hereditary or chromosomal diseases was noted 2.All participants with a normal karyotype who tested negative for sexually transmitted diseases 3.Recovered oocytes were assessed for nuclear maturity and only metaphase II oocytes were submitted to IVF/ICSI | NS | ≤39 years 40–49 years ≥50 years |
Kaarouch et al., 2018 | 1.Couples undergoing IVF treatment for male factor infertility (e.g. unexplained and previous IVF failure) 2.Women ≤39 years old | 1.Consumption of alcohol and/or tobacco 2.Azoospermia 3.Cryptospermia 4.Retrograde ejaculation 5.Partial ejaculate 6.Varicocele 7.History of exposure to gonadotoxins, e.g. chemotherapy, radiotherapy, pesticides 8.History of infection in the last 3 months 9.Antioxidant treatment 10.Infertile couples with female factor infertility | ≥40 <40 |
Lai et al., 2018 | 1.Only the first IVF cycles using ejaculated semen 2.Couples with total normal motile count, defined as sperm count with progressive motility and normal morphology (total count × % with progressive motility × % with normal morphology) | 1.PGT cycles 2.Cycles of donor sperm 3.Cycles with surgical sperm retrieval | <40 ≥40 |
Ma et al., 2018 | 1.Patients undergoing ICSI cycles with embryo transfers 2.Patients undergoing a first cycle 3.Female patients <38 years old 4.Patients who underwent GnRH agonist treatment using the long-acting protocol 5.Patients whose sperm origin was ejaculated spermatozoon 6.Patients in whom the cause of infertility was male factors | NS | ≤25 26–30 31–35 36–40 ≥41 |
McPherson et al., 2018 | 1.First patient cycles of IVF, ICSI or a combination of both between 2009 and 2013 | 1.Natural cycles 2.Cycles using donor oocytes, donor sperm, double-embryo transfer and embryo biopsy followed by PGT 3.Number of eggs collected ≤5 4.Missing patient data/no outcome data | NS |
Park et al., 2018 | 1.Obstructive azoospermia and non-obstructive azoospermia | 1.Klinefelter syndrome 2.Spinal cord injuries 3.Y-chromosome deletions | ≤30 31–35 36–40 41–45 ≥46 |
Tatsumi et al., 2018 | 1.Couples undergoing IUI using the male partner's sperm | 1.Samples that used precipitated semen or thawed semen 2.Cycles that involved double insemination 3.Cycles where the results of IUI were unknown 4.Cycles in women >40 years old 5.Donor sperm | ≥34 35–37 38–40 41–43 44–46 ≥47 |
Chapuis et al., 2017
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates. Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4 | 1.All couples undergoing IVF or ICSI between 1 January 2010 and 31 December 2015 | 1.ART cycles using surgically retrieved or frozen sperm 2.Cycles with PGT 3.Cycles using cryopreserved oocytes | 20–29 30–39 40–50 >51 |
Tiegs et al., 2017 | 1.Single thawed euploid embryo transfer cycles 2.Cycles in which paternal age was known 3.If a patient underwent multiple retrievals during this time, only the first retrieval was included in the baseline characteristic calculations 4.Cycles using both autologous and donor oocytes, with the age of the egg donor being used for analyses in these cases | 1.Cycles using donor sperm (as sperm donor ages were not available) | 21–30 31–35 36–40 41–45 >45 |
Ghuman et al., 2016 | 1.First fresh donor insemination and IVF/ICSI treatment cycles using donated sperm from the HFEA long-term anonymized data registry 1991–2012 | 1.Cycles with missing egg donor or sperm donor data, e.g. age 2.Treatment cycles involving gamete or zygote intra-Fallopian transfer, oocyte donation, frozen embryos or surrogacy | ≤20 21–25 26–30 31–35 36–40 41–45 |
Meijerink et al., 2016 | 1.All first cycles of assisted reproductive treatment at the Radboud University Medical Centre (Radboudumc) between 1 January 2001 and 1 June 2013 | 1.Couples who underwent assisted reproductive treatment in a modified natural cycle (n = 51) 2.Women who did not have embryo transfer because of risk of OHSS 3.Assisted reproductive treatment in oncology patients because of fertility preservation (n = 74) or for oocyte vitrification (n = 70) | <35 35–44 ≥45 |
Wu et al., 2016 | 1.ICSI cycles with embryo transfer between January 2007 and May 2015 2.Maternal age <39 years 3.First cycle performed in the centre 4.Agonist or antagonist protocols used | NS | <30 30–34 35–39 40–44 45–49 ≥50 |
Garcia-Ferreyra et al., 2015 | 1.Anonymous oocyte donors subjected to physical, gynaecological and psychological examinations in which no family history of hereditary or chromosomal disease was noted 2.Normal karyotype and negative screen for sexually transmitted disease | NS | ≤39 40–49 ≥50 |
Ho et al., 2015 | 1.IVF cycles with donor oocytes and fresh transfers | 1.Not fresh transfer 2.Known donors 3.Severe male factor infertility | <40 40–45 45–50 >50 |
Wu et al., 2015
Effect of paternal age on reproductive outcomes of in vitro fertilization. Plos One. 2015; https://doi.org/10.1371/journal.pone.0135734 | 1.IVF cycles with embryo transfer between January 2007 and October 2013 2.Agonist for pituitary downregulation 3.Female age <39 years old 4.Retrieved oocytes >4 5.Fresh embryo transfer 6.Embryo transfer performed on day 2 or day 3 | NS | <30 30–32 33–35 36–38 39–41 ≥42 |
Begueria et al., 2014 | 1.Oocyte donation cycles with ICSI 2.Oocyte donors 18–35 years old | 1.Semen from sperm donor 2.Semen obtained by testicular biopsy 3.Semen frozen prior to treatment for a medical condition | <25 25–29 30–34 35–39 40–44 45–49 50–54 55–59 ≥60 |
Robertshaw et al., 2014 | 1.Single donor recipient match (no donor sharing) 2.Blastocyst transfers only 3.All transfers performed under ultrasound guidance 4.All cycles using ejaculated sperm | 1. No testicular biopsy cycles | 25–29 30–34 35–39 40–44 45–49 50–54 ≥55 |
Koh et al., 2013 | 1.Female recipients <40 years old | NS | <40 40–44.9 45–49.9 ≥50 |
Tsai et al., 2013 | 1.Male patients diagnosed with azoospermia | 1. Men <31 years old | 31–35 35–40 >40 |
Gu et al., 2012 | 1.Donor cycles from women undergoing fertility treatment 2.All donors who achieved clinical pregnancy following IVF–embryo transfer cycles 2.Donors with: normal FSH <10 mIU/ml, basal antral follicle count >12, normal gonadotrophin responsiveness with peak oestradiol > pg/ml, serum HIV negative before and 6 months after oocyte retrieval | 1.Oocyte donation cycles using cryopreserved sperm 2.Oocyte donation cycles using ICSI | ≤37 >37 |
Medina et al., 2012 | 1.IVF with donor oocytes 2.Egg donation model controlled for maternal age | NS | ≤34 35–38 ≥39 |
Meyer et al., 2012 | NS | NS | <40 40–49 ≥50 |
Nijs et al., 2011 | 1.Infertile patients undergoing a first IVF or ICSI treatment | 1.Testicular sperm cycles 2.Cycles undergoing PGT | ≤34 35–39 ≥40 |
Whitcomb et al., 2011 | 1.Anonymous oocyte donors between 21 and 33 years old 2.BMI ≤28 kg/m2 3.Genetic risks 4.Endocrine evaluation 5.Urine drug test 6.STI screen | 1.Potential donors identified as being at high risk of infectious disease | <30 30–34 35–39 40–44 45–49 50–54 ≥55 |
Duran et al., 2010 | 1.Oocyte donors ≤35 years old | 1.Cycles involving sperm extraction 2.Cycles including PGT | 23–38 39–49 ≥50 |
Ferreira et al., 2010 | 1.All couples undergoing ICSI cycles using fresh spermatozoa | 1.Cycles in which fewer than four metaphase II oocytes were recovered | NS |
Luna et al., 2009 | 1.Donors <35 years old with normal baseline ovarian reserve testing 2.Recipients with normal uterine cavity and adequate endometrial development 3.Fresh ejaculated semen samples | 1.Cases using donor sperm, testicular sperm or aspirated sperm | <40 40–50 >50 |
| Belloc (2008) | NS | 1.Insemination cancelled if total living, motile sperm count was <0.5 × 106 and >75% abnormal forms were present | 30 30–34 35–39 40–44 ≥45 |
Bellver et al., 2008 | |||
| IUI | 1. Women under 38 years old 2. Tubal patency demonstrated by hysterosalpingography 3. Normal uterine scan 4. Normal basal hormonal concentrations 5. BMI <27 kg/m2 | 1. PCOS and endometriosis | ≤30 31 32 33 34 35 36 37 38–39 >39 |
| IVF | 1. Women under 38 years old 2. BMI <27 kg/m2 3. Normal uterine scan 4. Normal basal hormonal concentrations 5. First IVF cycle | 1. PCOS, hydrosalpinx or endometriosis 2. Severe oligozoospermia (<5 × 106/ml) | ≤30 31–32 33 34 35 36 37 38 39–40 >41 |
| Ovum donation | 1. BMI <27 kg/m2 2. Normal uterine scan 3. First oocyte donation cycle | 1. Endometriosis 2. Severe male factor infertility (<5 × 106/ml) | ≤34 35–37 38 39–40 41 42 43–44 45–46 47–49 >49 |
Campos et al., 2008 | 1. Donors 18–35 years old 2. Normal history and physical examination findings 3. Negative STI screen 4. Normal karyotype 5. No significant family history of hereditary or chromosomal diseases | 1. Severe male factor infertility | <39 ≥39 |
Frattarelli et al., 2008 | 1. Ovum donors ≤35 years old 2.Donors with normal FSH concentration (<12 mIU/ml) basal antral follicle count >8 and normal gonadotrophin responsiveness with peak oestradiol >500 pg/ml 3. Recipients with an embryo transfer ≥8 mm 4. All sperm obtained from ejaculation 5. Only one donor cycle per donor included | 1.No testicular biopsy or sperm aspiration procedures included | ≤35 36–40 41–45 46–50 51–55 >55 |
Girsh et al., 2008 | 1. Freshly ejaculated semen samples 2. Oocyte donor age 20–26 years | NS | 26–30 31–35 36–40 41–45 46–50 51–55 56–60 |
Aboulghar et al., 2007 | 1. Male partner aged ≥50 years 2Motile ejaculated spermatozoa in semen analysis on the day of oocyte retrieval 3. First ICSI cycle | 1. Couples with female partner ≥40 years old 2. Azoospermic men | ≥50 <50 |
| De La Rochebrochard (2006) | 1.Sterile female partners with bilateral tubal obstruction or absence of both tubes 2. Women treated with conventional IVF since 2000 | NS | <30 30–34 35–39 >40 |
Klonoff-Cohen and Natarajan, 2004 | 1.Couples with primary or secondary infertility, e.g. tubal disease, endometriosis, immunological causes, or male factor or unexplained infertility 2.All couples older than 20 years, married or cohabiting, and of white, African American, Asian or Hispanic background 3. Couples undergoing IVF or gamete intra-Fallopian transfer 4. Only fresh non-donor IVF cycles | 1.Women with pre-existing medical conditions, e.g. high blood pressure, diabetes, heart, thyroid, renal disease 2.Couples using donor sperm, oocytes, or surrogate uteri 3.Couples were eligible to participate once only in the study | ≤35 36–40 >40 |
Kumtepe et al., 2003 | 1. Only first cycle evaluated 2. ART for male factor infertility: two of the following: a. Sperm concentration <20 million/ml b. Progressive motility <25% c. Kruger strict criteria <5% normal forms | NS | <40 ≥40 |
Paulson et al., 2001 | 1. Initial screening analysis of sperm sample | 1. Cases involving ICSI | All participants >50 |
Spandorfer et al., 1998 | 1. Consecutive ICSI cases 2. Only male partners with female partners aged ≤35 years | NS | ≤39 40–49 ≥50 |
Gallardo et al., 1996 | 1. Donors <35 years old 2. Donors tested for HIV and hepatitis 3.Donors with no personal/family history of congenital malformation or hereditary diseases | 1. ICSI cycles | ≤30 31–40 41–50 ≥51 |
Mathieu et al., 1995 | 1.All patients undergoing intrauterine artificial insemination with spermatozoa selected after in-vitro treatment of semen | NS | <30 30–34 ≥35 |
ART, Artificial reproductive technology; BMI, body mass index; GnRH, gonadotrophin-releasing hormone; HFEA, Human Fertilisation and Embryology Authority; HIV, human immunodeficiency virus; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; NS, xxxxx; OHSS, ovarian hyperstimulation syndrome; PCOS, polycystic ovarian syndrome; PGT, preimplantation genetic testing; STI, sexually transmitted infection.
Table 4Summary of the Newcastle-Ottawa Quality Assessment results
| First author (year) | Selection bias | Comparability bias (controls for maternal age) | Performance bias | Attrition bias | Reporting bias |
|---|---|---|---|---|---|
Horta et al., 2019 | **** | * | ** | ** | Fair |
Cito et al., 2019
Impact of advanced paternal age on the intracytoplasmic sperm injection outcomes in donor egg cycles. Translational Andrology and Urology. 2019; 8: S22-S30 | **** | ** | ** | ** | Good |
Yu et al., 2019 | *** | * | ** | Poor | |
Capelouto et al., 2018 | *** | ** | * | ** | Good |
Garcia-Ferreyra et al., 2018 | *** | ** | * | ** | Good |
Kaarouch et al., 2018 | *** | * | * | ** | Fair |
McPherson et al., 2018 | *** | * | * | ** | Fair |
Park et al., 2018 | *** | * | * | ** | Fair |
Chapuis et al., 2017
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates. Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4 | *** | * | * | ** | Fair |
Tiegs et al., 2017 | *** | * | * | ** | Fair |
Meijerink et al., 2016 | *** | * | ** | ** | Fair |
Wu et al., 2016 | *** | * | ** | ** | Fair |
Garcia-Ferreyra et al., 2015 | *** | ** | * | ** | Good |
Ho et al., 2015 | Poor | ||||
Begueria et al., 2014 | *** | * | ** | ** | Fair |
Tsai et al., 2013 | *** | * | ** | ** | Fair |
Medina et al., 2012 | Poor | ||||
Meyer et al., 2012 | Poor | ||||
Nijs et al., 2011 | *** | * | * | ** | Fair |
Whitcomb et al., 2011 | *** | ** | ** | ** | Good |
Luna et al., 2009 | *** | ** | ** | ** | Good |
Bellver et al., 2008 | *** | ** | ** | Poor | |
Frattarelli et al., 2008 | *** | ** | ** | ** | Good |
Aboulghar et al., 2007 | *** | * | * | ** | Fair |
Klonoff-Cohen and Natarajan, 2004 | *** | * | * | ** | Fair |
Kumtepe et al., 2003 | *** | * | * | ** | Fair |
Spandorfer et al., 1998 | *** | * | * | ** | Fair |
Gallardo et al., 1996 | *** | ** | ** | ** | Good |
Newcastle-Ottawa Quality Assessment according to
Wells et al., 2009
.Wells, G., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., et al. The Newcastle Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in MetaAnalyses. 2009 [cited 2005 Jan 20]. Available from:http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
Table 5Summary of meta-analyses performed according to fixed effects (reported first) and random effects (reported second) models
| Outcomes | Pooled OR | 95% CI | I2 | Degree of heterogeneity * Degree of heterogeneity: Low, I2 < 25%; Moderate, I2 = 25–75%; High, I2 > 75%. Significant results shown in bold. References: 1. Park (2018); 2. Tiegs (2017); 3. Chapuis (2017); 4. Wu (2016); 5. Bellver (2008); 6. Begueria (2014); 7. Whitcomb (2011); 8. Gallardo (1996); 9. Yu (2019); 10. Meijerink (2016); 11. Tsai (2013); 12. Nijs (2011); 13. Klonoff-Cohen (2004); 14. Spandorfer (1998); 15. Capelouto (2018); 16. Medina (2012); 17. Frattarelli (2008); 18. Mcpherson (2018); 19. Kaarouch (2018); 20. Kumtepe (2003); 21. Horta (2019); 22. Ho (2015); 23. Meyer (2012); 24. Luna (2009); 25. Cito (2019); 26. Aboulghar (2007); 27. Garcia-Ferreyra (2015); 28. Garcia-Ferreyra (2018). |
|---|---|---|---|---|
| Primary outcomes | ||||
| Autologous (age <30 years) Pregnancy (n = 5)1–5 Miscarriage (n = 3)2,3,5 | 1.11 1.11 0.89 0.89 | 0.83–1.47 0.83–1.47 0.61–1.30 0.61–1.31 | 70 70 0 0 | Moderate Moderate Low Low |
| Donor (age <30 years) Pregnancy (n = 3)6–8 Live birth rate (n = 2)6,7 Miscarriage (n = 3)6–8 | 0.99 0.80 0.85 0.85 1.22 1.28 | 0.73–1.35 0.65–2.26 0.61–1.19 0.60–1.19 0.69–2.14 0.73–2.27 | 59.3 59.3 0 0 0 0 | Moderate Moderate Low Low Low Low |
| Autologous (age <35 years) Pregnancy (n = 10)1,2,4,5,9,10–14 Live birth rate (n = 5)1,9,11–13 Miscarriage (n = 5)2,5,9,11,12 | 1.31 1.31 1.59 1.74 1.38 1.38 | 1.15–1.51 1.13–1.51 1.27–2.01 1.15–2.62 0.69–2.76 0.69–2.76 | 47 51 38 50 76 76 | Moderate Moderate Moderate Moderate High High |
| Donor (age <35 years) Pregnancy (n = 4)6,7,16,17 Live birth rate (n = 4)6,7,15,17 Miscarriage (n = 4)6,7,16,17 | 1.04 1.04 1.05 1.05 0.84 0.88 | 0.91–1.20 0.91–1.20 0.92–1.19 0.92–1.19 0.67–1.07 0.64–1.21 | 0 0 0 0 33 33 | Low Low Low Low Moderate Moderate |
| Autologous (age <40 years) Pregnancy (n = 12)1–5,11–14,18–20 Live birth rate (n = 6)1,11–13,18,21 Miscarriage (n = 7)2,3,5,11,12,18,19 | 1.66 1.65 2.19 2.10 0.74 0.81 | 1.30–2.13 1.27–2.15 1.83–2.63 1.25–3.51 0.57–0.94 0.57–1.15 | 77 79 81 81 32 32 | High High High High Moderate Moderate |
| Donor (age <40 years) Pregnancy (n = 8)6–8,16,17,22–24 Live birth rate (n = 5)6,7,15,17,23 Miscarriage (n = 8)6–8,16,17,22–24 | 1.06 1.06 1.05 1.05 0.87 0.88 | 0.97–1.15 0.97–1.15 0.96–1.15 0.96–1.15 0.75–1.01 0.70–1.10 | 0 0 0 0 44 44 | Low Low Low Low Moderate Moderate |
| Autologous (age <45 years) Pregnancy (n = 4)1,2,4,10 Live birth rate (n = 2)1, 21 | 1.17 0.97 1.68 1.68 | 1.01–1.37 0.40–2.36 1.38–2.03 1.38–2.03 | 30 94 0 0 | Moderate High Low Low |
| Donor (age <45 years) Pregnancy (n = )6,7,17,22,25 Live birth rate (n = 5)6,7,15,17,25 Miscarriage (n = 5)6,7,17,22,25 | 1.10 1.10 1.08 1.08 0.91 1.02 | 0.99–1.22 0.99–1.22 0.97–1.19 0.97–1.19 0.76–1.08 0.74–1.40 | 0 0 0 0 52 52 | Low Low Moderate |
| Autologous (age <50 years) Pregnancy (n = 3)3,4,26 | 1.20 1.28 | 0.90–1.61 0.81–2.03 | 49 49 | Moderate |
| Donor (age <50 years) Pregnancy (n = 6)6–8,17,22,24 Live birth rate (n = 4)6,7,15,17 Miscarriage (n = 6)6–8,17,22,24 | 1.03 1.00 1.16 1.19 0.68 0.66 | 0.89–1.20 0.81–1.23 0.99–1.35 0.96–1.49 0.54–0.86 0.46–0.98 | 28 28 37 37 46 46 | Moderate Moderate Moderate |
| Secondary outcomes | ||||
| Autologous (age <30 years) Fertilization rate (n = 3)1,3,4 | 0.95 0.95 | 0.81–1.11 0.81–1.11 | 67 67 | Moderate Moderate |
| Non-donor (age <35 years) Fertilization rate (n = 4)1,4, 9,11 Top-quality embryos (n = 4)1,9,10,11 | 0.92 0.92 1.07 1.03 | 0.64–1.31 0.64–1.31 0.99–1.16 0.88–1.21 | 89 89 58 58 | High High Moderate Moderate |
| Autologous (age <40 years) Fertilization rate (n = 7)1,3,4,11,14,19,20 Cleavage-stage embryos (n = 3)3,11,19 Blastulation rate (n = 2)3,19 Top-quality embryos (n = 2)1,11 | 1.03 1.03 0.97 1.12 1.14 1.25 0.58 0.58 | 0.93–1.14 0.93–1.14 0.87–1.09 0.76–1.64 1.05–1.23 0.92–1.70 0.24–1.40 0.24–1.40 | 70 70 34 34 61 61 88 88 | Moderate Moderate Moderate Moderate Moderate Moderate High High |
| Donor (age <40 years) Fertilization rate (n = 4)8,24,27,28 Cleavage-stage embryos (n = 2)8,28 Top-quality embryos (n = 4)8,24,27,28 | 1.15 1.15 1.16 1.16 0.98 0.98 | 0.90–1.46 0.90–1.46 0.84–1.61 0.84–1.61 0.75–1.28 0.75–1.28 | 73 73 0 0 71 71 | Moderate Moderate Low Low Moderate Moderate |
| Autologous (age <45 years) Fertilization rate (n = 2)1,4 Top-quality embryos (n = 2)1,10 | 0.87 0.96 0.97 0.97 | 0.70–1.08 0.62–1.49 0.66–1.43 0.66–1.43 | 63 63 83 83 | Moderate Moderate High High |
| Donor (age <50 years) Fertilization rate (n = 4)8,24,27,28 Cleavage-stage embryos (n = 3)8,27,28 Blastulation rate (n = 3)24,27,28 Top-quality embryos (n = 4)8,24,27,28 | 1.11 1.12 1.67 1.86 1.61 1.61 0.75 0.75 | 1.00–1.24 1.00–1.24 1.02–2.75 0.95–3.63 1.08–2.38 1.08–2.38 0.33–1.69 0.33–1.69 | 0 0 25 25 72 72 92 92 | Low Low Low Low Moderate Moderate High High |
a Autologous and donor refers to oocytes, age refers to paternal age threshold.
Park et al., 2018
; 2. Tiegs et al., 2017
; 3. Chapuis et al., 2017
; 4. - Chapuis A.
- Gala A.
- Ferrieres-Hoa A.
- Mullet T.
- Bringer-Deutsch S.
- Vintejoux E.
- Torre A.
- Hammah S.
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates.
Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4
Wu et al., 2016
; 5. Bellver et al., 2008
; 6. Begueria et al., 2014
; 7. Whitcomb et al., 2011
; 8. Gallardo et al., 1996
; 9. Yu et al., 2019
; 10. Meijerink et al., 2016
; 11. Tsai et al., 2013
; 12. Nijs et al., 2011
; 13. Klonoff-Cohen and Natarajan, 2004
; 14. Spandorfer et al., 1998
; 15. Capelouto et al., 2018
; 16. Medina et al., 2012
; 17. Frattarelli et al., 2008
; 18. McPherson et al., 2018
; 19. Kaarouch et al., 2018
; 20. Kumtepe et al., 2003
; 21. Horta et al., 2019
; 22. Ho et al., 2015
; 23. Meyer et al., 2012
; 24. Luna et al., 2009
; 25. Cito et al., 2019
; 26. - Cito G.
- Coccia M.E.
- Picone R.
- Cocci A.
- Russo G.I.
- Garaffa G.
- Fucci R.
- Bertocci F.
- Borrani E.
- Basile V.
- Micelli E.
- Criscuoli L.
- Serni S.
- Carini M.
- Natali A.
Impact of advanced paternal age on the intracytoplasmic sperm injection outcomes in donor egg cycles.
Translational Andrology and Urology. 2019; 8: S22-S30
Aboulghar et al., 2007
; 27. Garcia-Ferreyra et al., 2015
; 28. Garcia-Ferreyra et al., 2018
.Meta-analysis: primary outcome
Pregnancy rate in autologous oocyte cycles (paternal age cut-off 35 years)
Ten out of 28 studies reported on the overall pregnancy rate at a paternal age cut-off of 35 years in autologous oocyte cycles (Bellver, 2008; ![Figure 2]()
Klonoff-Cohen and Natarajan, 2004
; Meijerink et al., 2016
; Nijs et al., 2011
; Park et al., 2018
; Spandorfer et al., 1998
; Tiegs et al., 2017
; Tsai et al., 2013
; Wu et al., 2016
; Yu et al., 2019
). The incidence of overall clinical pregnancy at paternal age <35 years was 40.0% (2531/6320) and at paternal age >35 years was 32.6% (2191/6722). The meta-analysis demonstrated that the odds of pregnancy were significantly greater if paternal age was <35 years (OR 1.31, 95% confidence interval [CI] 1.13–1.51; Figure 2). There was a moderate degree of heterogeneity (I2 = 51%).
Figure 2Forest plot depicting pregnancy rate in autologous cycles for paternal age group <35 years versus >35 years. For each study, the odds ratio (OR) point estimate is shown as a solid diamond, with the horizontal lines extending from it depicting its 95% confidence interval (CI). The area of the shaded box is proportional to the weight given to a study. The red dotted line through the centre of the diamond indicates the value of the overall OR estimate and the horizontal points of the diamond represent the limits of the 95% CI for the OR. The black vertical line is the line of null effect (OR = 1).
00229-2&id=gr2.jpg){kind=link}
Live birth rate in autologous oocyte cycles (paternal age cut-off 35 years)
Five studies reported the live birth rate per treatment cycle in autologous oocyte cycles (![Figure 3]()
Klonoff-Cohen and Natarajan, 2004
; Nijs et al., 2011
; Park et al., 2018
; Tsai et al., 2013
; Yu et al., 2019
). The incidence of overall live birth (per treatment cycle) was 35.3% (171/485) at paternal age <35 years and 24.5% (151/616) at paternal age >35 years. The meta-analysis demonstrated that the odds of live birth were significantly greater if paternal age was <35 years (OR 1.74, 95% CI 1.15–2.62; Figure 3). There was a moderate degree of heterogeneity (I2 = 50%).
Figure 3Forest plot depicting live birth rate in autologous oocyte cycles for paternal age group <35 years versus >35 years. CI, confidence interval; OR, odds ratio.
00229-2&id=gr3.jpg){kind=link}
Miscarriage rate in autologous oocyte cycles (paternal age cut-off 35 years)
When focusing on the miscarriage rate per clinical pregnancy, the incidence of miscarriage was 21.7% (122/563) at paternal age <35 years and 11.5% (78/676) at paternal age >35 years (Bellver 2008;
Nijs et al., 2011
; Tiegs et al., 2017
; Tsai et al., 2013
; Yu et al., 2019
). The meta-analysis demonstrated that the odds of miscarriage were not significantly reduced if paternal age was <35 years (OR 1.38, 95% CI 0.69–2.76). There was a high degree of heterogeneity (I2 = 76%).Clinical pregnancy rate in autologous oocyte cycles (paternal age cut-off 40 years)
A total of 12 out of 28 studies reported on the overall clinical pregnancy rate at a paternal age cut-off of 40 years in autologous oocyte cycles (Bellver, 2008; ![Figure 4]()
Chapuis et al., 2017
; - Chapuis A.
- Gala A.
- Ferrieres-Hoa A.
- Mullet T.
- Bringer-Deutsch S.
- Vintejoux E.
- Torre A.
- Hammah S.
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates.
Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4
Kaarouch et al., 2018
; Klonoff-Cohen and Natarajan, 2004
; Kumtepe et al., 2003
; McPherson et al., 2018
; Nijs et al., 2011
; Park et al., 2018
; Spandorfer et al., 1998
;Tiegs et al., 2017
; Tsai et al., 2013
; Wu et al., 2016
). The overall incidence of overall clinical pregnancy at paternal age <40 years was 44.0% (4363/9922) and at paternal age >40 years was 34.5% (741/2145). The meta-analysis demonstrated that the odds of a clinical pregnancy were significantly greater if paternal age was <40 years (OR 1.65, 95% CI 1.27–2.15; Figure 4). There was a high degree of heterogeneity (I2 = 79%).
Figure 4Forest plot depicting pregnancy rate in autologous oocyte cycles for paternal age group <40 years versus >40 years. CI, confidence interval; OR, odds ratio.
00229-2&id=gr4.jpg){kind=link}
Live birth rate in autologous oocyte cycles (paternal age cut-off 40 years)
Six of the 28 studies reported the live birth rate per treatment cycle in autologous oocyte cycles (![Figure 5]()
Klonoff-Cohen and Natarajan, 2004
; Horta et al., 2019
; McPherson et al., 2018
; Nijs et al., 2011
; Park et al., 2018
; Tsai et al., 2013
). The overall incidence of live birth (per treatment cycle) was 28.4% (1011/3555) at paternal age <40 years and 17.6% (450/2551) at paternal age >40 years. The meta-analysis demonstrated that the odds of live birth were significantly greater if paternal age was <40 years (OR 2.10, 95% CI 1.25–3.51; Figure 5). There was a high degree of heterogeneity (I2 = 81%).
Figure 5Forest plot depicting live birth rate in autologous oocyte cycles for paternal age group <40 years versus > 40 years. CI, confidence interval; OR, odds ratio.
00229-2&id=gr5.jpg){kind=link}
Miscarriage rate in autologous oocyte cycles (paternal age cut-off 40 years)
When focusing on the miscarriage rate per clinical pregnancy at paternal age <40 years, the incidence of miscarriage was 17.4% (439/2530) at paternal age <40 years and 21.0% (101/480) at paternal age >40 years (Bellver, 2008;
Chapuis et al., 2017
; - Chapuis A.
- Gala A.
- Ferrieres-Hoa A.
- Mullet T.
- Bringer-Deutsch S.
- Vintejoux E.
- Torre A.
- Hammah S.
Sperm quality and paternal age: effect on blastocyst formation and pregnancy rates.
Basic and Clinical Andrology,. 2017; https://doi.org/10.1186/s12610-016-0045-4
Kaarouch et al., 2018
; McPherson et al., 2018
; Nijs et al., 2011
; Tiegs et al., 2017
; Tsai et al., 2013
). The meta-analysis demonstrated that the odds of miscarriage were significantly reduced if paternal age was <40 years (OR 0.74, 95% CI 0.57–0.94). There was a moderate degree of heterogeneity (I2 = 32%).Miscarriage rate in donor oocyte cycles (paternal age cut-off 50 years)
When focusing on the miscarriage rate per clinical pregnancy at paternal age <50 years in donor oocyte cycles, the incidence of miscarriage was 18.7% (695/3723) at paternal age <50 years and 24.0% (107/445) at paternal age >50 years (
Begueria et al., 2014
;