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Does advanced paternal age affect outcomes following assisted reproductive technology? A systematic review and meta-analysis

Published:April 09, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.03.031

      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
      Fertility problems: assessment and treatment.
      ); 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 I.
      • Gunnell D.
      • Smith G.D.
      Advanced paternal age: How old is too old?.
      ). 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 H.
      Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment.
      ) with associated increasing risks of implantation failure, miscarriage secondary to oocyte aneuploidy (
      • Fragouli E.
      • Wells D.
      Aneuploidy in the human blastocyst.
      ), and obstetric and perinatal complications (
      • Oldereid N.B.
      • Wennerholm U.B.
      • Pinborg A.
      • Loft A.
      • Laivuori H.
      • Petzold M.
      • Romundstad L.B.
      • Söderström-Anttila V.
      • Bergh C.
      The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis.
      ). 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 A.N.
      • Urhoj S.K.
      Is advanced paternal age a health risk for the offspring?.
      ).
      Increasing paternal age has already been indicated to have negative implications for testicular function (
      • Handelsman D.J.
      • Staraj S.
      Testicular size: the effects of aging, malnutrition, and illness.
      ;
      • Sampson N.
      • Untergasser G.
      • Plas E.
      • Berger P.
      The ageing male reproductive tract.
      ), with direct effects on semen parameters, such as reduced sperm concentration and motility (
      • 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.
      ;
      • Eskenazi B.
      • Wyrobek A.J.
      • Sloter E.
      • Kidd S.A.
      • Moore L.
      • Young S.
      • Moore D.
      The association of age and semen quality in healthy men.
      ;
      • Jung A.
      • Schuppe H.C.
      • Schill W.B.
      Comparison of semen quality in older and younger men attending an andrology clinic.
      ;
      • Levitas E.
      • Lunenfeld E.
      • Weisz N.
      • Friger M.
      • Potashnik G.
      Relationship between age and semen parameters in men with normal sperm concentration: analysis of 6022 semen samples.
      ). 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 E.
      • Thonneau P.
      Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?.
      ;
      • Dunson D.B.
      • Colombo B.
      • Baird D.D.
      Changes with age in the level and duration of fertility in the menstrual cycle.
      ;
      • Ford W.C.L.
      • North K.
      • Taylor H.
      • Farrow A.
      • Hull M.G.R.
      • Golding J.
      Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men.
      ;
      • Hassan M.A.
      • Killick S.R.
      Effect of male age on fertility: evidence for the decline in male fertility with increasing age.
      ).
      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 E.
      • de Mouzon J.
      • Thépot F.
      • Thonneau P.
      French National IVF Registry (FIVNAT) Association. Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in France.
      ), with other smaller studies showing a reduction in fertilization and live birth rate in older men (
      • Aboulghar M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      ;
      • Belloc S.
      • Cohen-Bacrie P.
      • Benkhalifa M.
      • Cohen-Bacrie M.
      • De Mouzon J.
      • Hazout A.
      • Ménézo Y.
      Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination.
      ;
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ). 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 F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      ). Van Opstal and collaborators demonstrated that an advanced paternal age has an impact on embryo quality score in IVF treatment (
      • Van Opstal J.
      • Fieuws S.
      • Spiessens C.
      • Soubry A.
      Male age interferes with embryo growth in IVF treatment.
      ). 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 M.
      • Dal Canto M.
      • Guglielmo M.C.
      • Garcia D.
      • De Ponti E.
      • La Marca A.
      • Vassena R.
      • Buratini J.
      Sperm donation: an alternative to improve post-ICSI live birth rates in advanced maternal age patients.
      ), 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 J.
      • Garrido N.
      • Remohí J.
      • Pellicer A.
      • Meseguer M.
      Influence of paternal age on assisted reproduction outcome.
      ;
      • Sagi-Dain L.
      • Sagi S.
      • Dirnfeld M.
      Effect of paternal age on reproductive outcomes in oocyte donation model: a systematic review.
      ;
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      ). 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 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.
      ). 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.
      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).

      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, 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 M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      ;
      • Begueria R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      ; Bellver, 2008;
      • Capelouto S.M.
      • Nagy Z.P.
      • Shapiro D.B.
      • Archer S.R.
      • Ellis D.P.
      • Smith A.K.
      • Spencer J.B.
      • Hipp H.S.
      Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model.
      ;
      • 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.
      ;
      • 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.
      ;
      • Frattarelli J.L.
      • Miller K.A.
      • Miller B.T.
      • Elkind-Hirsch K.
      • Scott R.T.
      Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
      ;
      • Gallardo E.
      • Guanes P.P.
      • Simon C.
      • Remohi J.
      • Levy M.
      • Pellicer A.
      Effect of age on sperm fertility potential: oocyte donation as a model.
      ;
      • Garcia-Ferreyra J.
      • Luna D.
      • Villegas L.
      • Romero R.
      • Zavala P.
      • Hilario R.
      • Duenas-Chacon J.
      High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.
      ;
      • Garcia-Ferreyra J.
      • Hilario R.
      • Duenas J.
      High percentages of embryos with 21, 18 or 13 trisomy are related to advanced paternal age in donor egg cycles.
      ;
      • Ho J.
      • Noel M.
      • Kao C.N.
      • Mok-Lin E.
      • Cedars M.I.
      • Huddleston H.G.
      Semen parameters and paternal age do not affect fertilization rate or pregnancy outcomes in oocyte recipient cycles. Fertility and Sterility. P-33, e23.
      ;
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      ;
      • Kaarouch I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      ;
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ;
      • Kumtepe Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      ;
      • Luna M.
      • Finkler E.
      • Barritt J.
      • Bar-Chama N.
      • Sandler B.
      • Copperman A.B.
      • Grunfeld L.
      Paternal age and assisted reproductive technology outcome in ovum recipients.
      ;
      • Medina R.
      • Urbina M.T.
      • Benjamin I.
      • Lerner-Biber J.
      • Alvarez M.T.
      Paternal age and spontaneous abortion after IVF with donor eggs.
      ;
      • Meijerink A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      ;
      • Meyer L.
      • Zakarin L.
      • Reichman D.E.
      • Spandorfer S.
      • Rosenwaks Z.
      • Perelman R.O.
      • Cohen C.
      The effect of paternal age on shared recipient oocyte donation cycles. Fertility and Sterility. O-274, S81.
      ;
      • McPherson N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      ;
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      ;
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      ;
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ;
      • Whitcomb B.W.
      • Levens E.D.
      • Turzanski-Fortner R.
      • Richter K.S.
      • Kipersztok S.
      • Stillman R.J.
      • Levy M.J.
      Contribution of male age to outcomes in assisted reproductive technologies – addressing methodological challenges.
      ;
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      ;
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      ). 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.
      Table 1Study characteristics
      First author (year)Study typeStudy period and locationStudy groupsNumberFertility treatmentMaternal age(years)Paternal age(years)Cause of infertilityRisk of failure to conceiveSemen analysisSperm DFI
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      Retrospective cohort1992–2017

      Australia
      Idiopathic infertility undergoing IVF/ICSIn = 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 infertilityNSNSNS
      • 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.
      Retrospective cohortJanuary 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
      NSTotal 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 M.
      • Licata E.
      • Meneghini C.
      • Dal Lago A.
      • Fabiani C.
      • Amodei M.
      • Antonaci D.
      • Miriello D.
      • Corno R.
      • Liberanome C.
      • Bisogni F.
      • Paciotti G.
      • Meneghini A.
      • Rago R.
      Impact of paternal age on seminal parameters and reproductive outcome of intracytoplasmatic sperm injection in infertile Italian women.
      Retrospective cohortJanuary 2015



      April 2017

      Italy
      Couples undergoing ICSIn = 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%)
      NSTotal 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 M.K.
      • Park J.K.
      • Jeon Y.
      • Seok S.H.
      • Chang E.M.
      • Lee W.S.
      Effects of paternal age on human embryo development in in vitro fertilization with preimplantation genetic screening.
      Retrospective cohortJanuary 2016 – August 2017

      Korea
      Infertile patients undergoing IVFn = 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
      NSNSNSNS
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      Retrospective observational2010 – 2018

      China
      Infertile men with cryptozoospermia undergoing ICSIn = 35

      (men)

      n = 38

      (cycles)
      ICSI

      (100%):

      Ejaculated sperm (51.4%)

      TESA

      (48.6%)

      Autologous oocytes
      NSMean ± SD

      <35: 27.5 ± 3.3

      ≥35: 37.4 ± 1.8

      P-value < 0.001
      CryptozoospermiaNSSemen volume (ml)

      Mean ± SD

      <35: 10.5 ± 4.3

      ≥35: 7.9 ± 3.4

      P-value = 0.07
      NS
      • Capelouto S.M.
      • Nagy Z.P.
      • Shapiro D.B.
      • Archer S.R.
      • Ellis D.P.
      • Smith A.K.
      • Spencer J.B.
      • Hipp H.S.
      Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model.
      Retrospective2008 – 2015

      USA
      Vitrified oocyte donor IVF cyclesn = 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
      NSTotal 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%)
      Other variables not listed as having missing data had less than 2% of data missing.


      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)RetrospectiveJanuary 2012 – July 2016

      Peru
      IVF/ICSI donor egg cyclesn = 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)
      NSNSTotal 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 I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      ObservationalNS

      Morocco
      Couples undergoing IVF treatment for male factor infertilityn = 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 failureNSTotal 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 A.F.
      • Li R.H.
      • Yeung W.S.
      • Ng E.H.
      Effect of paternal age on semen parameters and live birth rate of in-vitro fertilization treatment: a retrospective analysis.
      Retrospective cohort2004 – 2014

      China
      Couples undergoing a first IVF cyclen = 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
      NSTotal 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 N.-Z.
      • Chen L.
      • Hu L.-L.
      • Dai W.
      • Bu Z.-Q.
      • Sun Y.-P.
      The influence of male age on treatment outcomes and neonatal birthweight following assisted reproduction technology involving intracytoplasmic sperm injection (ICSI) cycles.
      Retrospective cohortJanuary 2011 – January 2015

      China
      ICSI2474

      (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 infertilityNSTotal 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 N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      Retrospective cohort2009 – 2013

      Australia
      First IVF or ICSI or combined IVF and ICSI cyclesn = 3323

      (cycles)
      ICSI

      n = 2347

      IVF

      n = 841

      Split

      n = 135

      Autologous oocytes
      Median (range)

      34 (18–49)
      Median (range)

      36 (19–70)
      NSNSNSNS
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      Retrospective cohortJanuary 2008 – December 2013

      Korea
      TESE–ICSI in men with OA and NOATESE–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
      NSNSNS
      • Tatsumi T.
      • Ishida E.
      • Tatsumi K.
      • Okada Y.
      • Saito T.
      • Kubota T.
      • Saito H.
      Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following intrauterine insemination.
      Retrospective

      cohort
      April 2012 – May 2016

      Japan
      Women <40 years old undergoing IUIn = 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
      NSNSTotal 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 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.
      RetrospectiveJanuary 2010 – December 2015

      France
      Couples undergoing IVF/ICSIn = 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
      NSNSNSNS
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      RetrospectiveJanuary 2011 – November 2014

      USA
      Patients using IVF with PGT for aneuploidy or PGT for single-gene disordersn = 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
      NSNSNSNS
      • Ghuman N.K.
      • Mair E.
      • Pearce K.
      • Choudhary M.
      Does age of the sperm donor influence live birth outcome in assisted reproduction?.
      Retrospective cohort1991 – 2012

      UK
      First fresh donor insemination and IVF/ICSI cycles using donated spermn =

      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
      NSNSNSNS
      • Meijerink A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      Retrospective cohortJanuary 2001 – June 2013

      Netherlands
      First cycles of ARTn = 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)
      NSNSNSNS
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      Retrospective cohortJanuary 2007 – May 2015

      China
      ICSI cyclesn = 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%)
      NSTotal 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 J.
      • Luna D.
      • Villegas L.
      • Romero R.
      • Zavala P.
      • Hilario R.
      • Duenas-Chacon J.
      High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.
      Retrospective cohortJanuary 2012 – August 2015

      Peru
      Embryos obtained from IVF/ICSI cycles with donated oocytes in conjunction with PGTn = 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)
      NSNSTotal 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 J.
      • Noel M.
      • Kao C.N.
      • Mok-Lin E.
      • Cedars M.I.
      • Huddleston H.G.
      Semen parameters and paternal age do not affect fertilization rate or pregnancy outcomes in oocyte recipient cycles. Fertility and Sterility. P-33, e23.
      Retrospective cohort

      Abstract only
      2009–2013

      USA
      Infertile couples undergoing fresh oocytes transfer and severe male factor infertility excludedn = 255 patientsIVF

      Donor oocytes
      NS<40: n = 58

      40–45: n = 72

      45–50: n = 51

      >50: n = 33
      NSNSNSNS
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Liu J.
      Effect of paternal age on reproductive outcomes of in vitro fertilization.
      RetrospectiveJanuary 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
      NSNSNSNS
      • Begueria R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      Retrospective cohortFebruary 2007 – June 2010

      Spain
      Oocyte donor cycles with ICSIn = 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
      NSTotal 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 I.
      • Khoury J.
      • Abdallah M.E.
      • Warikoo P.
      • Hofmann G.E.
      The effect of paternal age on outcome in assisted reproductive technology using the ovum donation model.
      Retrospective cohort2002 – 2011

      USA
      Ovum donor cyclesn = 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)
      NSNSNSNS
      • Koh S.-A.
      • Sanders K.
      • Deakin R.
      • Burton P.
      Male age negatively influences clinical pregnancy rate in women younger than 40 years undergoing donor insemination cycles.
      Retrospective cohort1994 – 2011

      Australia
      Donor insemination cyclesn = 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)
      NSNSIndependent 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 Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      Retrospective cohortJanuary 1998 – August 2010

      Taiwan
      Couples with azoospermia undergoing TESE and ICSIn = 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
      AzoospermiaNSNSNS
      • Gu L.
      • Zhang H.
      • Yin L.
      • Bu Z.
      • Zhu G.
      Effect of male age on the outcome of in vitro fertilization: oocyte donation as a model.
      Retrospective cohortJanuary 2004 – December 2009

      China
      Oocyte donation cycles and IVFn = 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
      NSNSNS
      • Medina R.
      • Urbina M.T.
      • Benjamin I.
      • Lerner-Biber J.
      • Alvarez M.T.
      Paternal age and spontaneous abortion after IVF with donor eggs.
      Retrospective cohort

      Abstract only
      Dates: NS

      Venezuela
      Couples undergoing IVFn = 260IVF

      Donor oocytes
      NS<34: n = 38

      35–38: n = 43

      >39: n = 179
      NSNSNSNS
      • Meyer L.
      • Zakarin L.
      • Reichman D.E.
      • Spandorfer S.
      • Rosenwaks Z.
      • Perelman R.O.
      • Cohen C.
      The effect of paternal age on shared recipient oocyte donation cycles. Fertility and Sterility. O-274, S81.
      Retrospective cohort

      Abstract only
      Dates: NS

      Germany
      Couples undergoing oocyte donation cyclesn = 332 couplesDonor oocytesNS<40

      40–49

      >50
      NSNSNSNS
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      Prospective cohortMay 2002 – July 2005

      Belgium
      Infertile patients undergoing first IVF or ICSI treatmentn = 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)
      NSNSTotal 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 B.W.
      • Levens E.D.
      • Turzanski-Fortner R.
      • Richter K.S.
      • Kipersztok S.
      • Stillman R.J.
      • Levy M.J.
      Contribution of male age to outcomes in assisted reproductive technologies – addressing methodological challenges.
      Retrospective cohortNS

      USA
      Anonymous oocyte donor cyclesn = 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
      NSNSTotal 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 E.H.
      • Dowling-Lacey D.
      • Bocca S.
      • Stadtmauer L.
      • Oehninger S.
      Impact of male age on the outcome of assisted reproductive technology cycles using donor oocytes.
      Retrospective cohort1998 – 2008

      USA
      Oocyte donation cycles with ICSI/IVFn = 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
      NSTotal 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 R.C.
      • Braga D.P.A.F.
      • Bonetti T.C.S.
      • Pasqualotto F.F.
      • Iaconelli A.
      • Borges E.
      Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.
      Retrospective observational (case–control)January 2002 – December 2007

      Brazil
      Couples undergoing ICSI cyclesn = 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
      NSNSTotal 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 M.
      • Finkler E.
      • Barritt J.
      • Bar-Chama N.
      • Sandler B.
      • Copperman A.B.
      • Grunfeld L.
      Paternal age and assisted reproductive technology outcome in ovum recipients.
      Retrospective cohortJanuary 2003 – December 2007

      USA
      All fresh ovum donation and IVF cyclesn = 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
      NSNSTotal 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 cohortJanuary 2003 – December 2006

      France
      IUI cyclesn > 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%)
      NSNS by paternal ageNS
      • Bellver J.
      • Garrido N.
      • Remohí J.
      • Pellicer A.
      • Meseguer M.
      Influence of paternal age on assisted reproduction outcome.
      Retrospective cohortJanuary 2000 – October 2006

      Spain
      IUI and IVF cycles ± donated oocytesTotal

      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
      NSIUI

      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
      NSTotal 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 I.
      • Gomez E.
      • Fernandez-Velencia A.L.
      • Landeras J.
      • Gonzalez R.
      • Coy P.
      • Gadea J.
      Effects of men and recipients’ age on the reproductive outcome of an oocyte donation program.
      Retrospective cohortJanuary 1996 – December 2006

      Spain
      Couples undergoing donor oocyte IVF cyclesn = 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
      NSTotal 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 J.L.
      • Miller K.A.
      • Miller B.T.
      • Elkind-Hirsch K.
      • Scott R.T.
      Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
      Retrospective cohortJanuary 2000 – July 2006

      USA
      Couples undergoing donor oocyte ART cyclesn = 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
      NSTotal 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 E.
      • Katz N.
      • Genkin L.
      • Girtler O.
      • Bocker J.
      • Bezdin S.
      • Barr I.
      Male age influences oocyte-donor program results.
      Retrospective cohortNS

      Israel
      Egg donation programme cycles and IVF treatmentn = 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)
      NSNSTotal 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
      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
      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
      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
      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
      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
      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
      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
      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 M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      Retrospective cohortJanuary 2001 – June 2006

      Egypt
      Subfertile couples undergoing ICSIn = 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
      NSTotal 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)Retrospective2000 – 2006

      France
      Couples treated by conventional IVF for bilateral tubal obstructionn = 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)
      NSNS
      Klonoff–Cohen (2004)Prospective1993 – 1998

      USA
      Couples undergoing IVF and GIFT couplesn = 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
      NSTotal 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 Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      Retrospective cohortDates: NS

      Turkey
      Infertile couples undergoing ICSIn = 919 ICSI cyclesICSI

      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 infertilityNSSperm 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 R.J.
      • Milligan R.C.
      • Sokol R.Z.
      The lack of influence of age on male fertility.
      Retrospective cohort1988 – 1998

      USA
      Couples undergoing IVF with donated oocytesn = 441

      (couples)

      n = 558

      (cycles)
      IVF

      Donor oocytes
      NSMean ± SD

      41.6 ± 7.2

      Range (22–64)
      NSNSTotal sperm count × 106 (million/ml)

      Mean ± SD

      207 ± 144

      Total motile sperm count × 106 (million/ml)

      Mean ± SD

      131 ± 103
      NS
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      Retrospective cohortSeptember 1993 – March 1995

      USA
      ICSI cyclesn = 821

      (cycles)
      ICSI

      (100%)

      Autologous oocytes
      Mean ± SD

      35.2 ± 4.5
      Mean ± SD

      38.4 ± 6.1
      NSNSTotal 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 E.
      • Guanes P.P.
      • Simon C.
      • Remohi J.
      • Levy M.
      • Pellicer A.
      Effect of age on sperm fertility potential: oocyte donation as a model.
      Retrospective cohortNS

      Spain
      Couples requiring oocyte donation and IVFn = 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
      NSTotal 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 C.
      • Ecochard R.
      • Bied V.
      • Lornage J.
      • Czyba J.C.
      Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age.
      Retrospective cohortSeptember 1987 – December 1992

      France
      Intrauterine artificial insemination with partner's spermn = 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
      NSNSNS
      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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      Studies included in the meta-analysis
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      NSNSNSNSClinical 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)
      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)
      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)
      NSNSMale ageing is negatively associated with clinical IVF/ICSI outcomes in couples with idiopathic infertility independent of female age
      • 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.
      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
      NSNSClinical 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
      NSNSPaternal age plays a significant role in determining outcomes of ICSI when oocytes are young and healthy
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      Fertilized embryos/total oocytes

      <35:

      242/359 (67.4%)

      ≥35:

      72/122 (59.0%)

      P-value = 0.09
      NSNSEuploid 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
      NSNSWhen 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 S.M.
      • Nagy Z.P.
      • Shapiro D.B.
      • Archer S.R.
      • Ellis D.P.
      • Smith A.K.
      • Spencer J.B.
      • Hipp H.S.
      Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model.
      NSNSNSNSClinical 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%)
      NSNormal

      ≤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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Garcia-Ferreyra J.
      • Hilario R.
      • Duenas J.
      High percentages of embryos with 21, 18 or 13 trisomy are related to advanced paternal age in donor egg cycles.
      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%)
      NSNSNSNSNSAdvanced 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 I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      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)
      NSClinical pregnancy/cycle

      <40: 28.6% (12/42)

      ≥40: 12.2% (5/41)

      Clinical pregnancy/transferred embryo

      <40: 32% (12/38)

      ≥40: 17% (5/29)
      NSMiscarriage/clinical pregnancy

      <40: 42% (5/12)

      ≥40: 60% (3/5)
      NSNSSperm 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 N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      2050/2215 (92.6%)NSNSNSClinical 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
      NSNSA 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      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
      NSNSGood-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
      NSNSNSFertilization 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 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.
      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
      NSClinical 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
      NSMiscarriage/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
      NSNSWithin 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      Fertilized embryos/total oocytes

      Overall: 6440/10106 (63.7%)

      Standard IVF:

      66 ± 17%

      ICSI:

      62 ± 15%
      NSBlastocysts/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
      NSNSIncreasing 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 A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      Fertilized embryos/total oocytes

      <35: 66.7%

      35–44: 66.7%

      ≥45: 66.7%
      NSNSGood-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%)
      NSNSNSNSNo 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 Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      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%)
      NSNSNSClinical 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)
      NSIncreased 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Garcia-Ferreyra J.
      • Luna D.
      • Villegas L.
      • Romero R.
      • Zavala P.
      • Hilario R.
      • Duenas-Chacon J.
      High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.
      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%)
      NSNSNSNSNSAdvanced 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 J.
      • Noel M.
      • Kao C.N.
      • Mok-Lin E.
      • Cedars M.I.
      • Huddleston H.G.
      Semen parameters and paternal age do not affect fertilization rate or pregnancy outcomes in oocyte recipient cycles. Fertility and Sterility. P-33, e23.
      Fertilized embryos/total oocytes

      <40: 64.2%

      40–45: 63.7%

      45–50: 58.9%

      >50: 63.3%
      NSNSNSClinical pregnancy/cycle

      <40: 45/58 (77.6%)

      40–45: 53/72 (73.6%)

      45–50: 37/51 (72.5%)

      >50: 26/33 (78.8%)
      NSMiscarriage/clinical pregnancy

      <40: 8/45 (17.8%)

      40–45: 14/53 (26.4%)

      45–50: 5/37 (13.5%)

      >50: 1/26 (3.8%)
      NSNSIndividual semen parameters and paternal age did not have significant effects on fertilization rate or pregnancy outcomes in oocyte recipient cycles
      • Begueria R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      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
      NSNSEmbryo 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%)
      NSNSPaternal 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 Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      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
      NSGood-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
      NSNSInsufficient evidence to demonstrate an unfavourable effect of advanced paternal age on the fertility outcome for TESE–ICSI
      First author (year)Rate of fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Medina R.
      • Urbina M.T.
      • Benjamin I.
      • Lerner-Biber J.
      • Alvarez M.T.
      Paternal age and spontaneous abortion after IVF with donor eggs.
      Fertilized embryos/total oocytes

      <34: 72%

      35–38: 61%

      >39: 78%
      NSNSNSClinical pregnancy/cycle

      <34: 24/38 (63%)

      35–38: 30/43 (70%)

      >39: 118/179 (66%)
      NSMiscarriage/clinical pregnancy

      <34: 4/24 (16.7%)

      35–38: 4/30 (13.3%)

      >39: 38/118 (32.2%)
      NSNSThere were no significant differences between groups in their fertilization, clinical pregnancy or implantation rates. Paternal age significantly affects the abortion rate
      • Meyer L.
      • Zakarin L.
      • Reichman D.E.
      • Spandorfer S.
      • Rosenwaks Z.
      • Perelman R.O.
      • Cohen C.
      The effect of paternal age on shared recipient oocyte donation cycles. Fertility and Sterility. O-274, S81.
      NSNSNSNSClinical 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%)
      NSNSPaired 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 M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      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
      NSNSNSClinical 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
      NSSingleton

      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 B.W.
      • Levens E.D.
      • Turzanski-Fortner R.
      • Richter K.S.
      • Kipersztok S.
      • Stillman R.J.
      • Levy M.J.
      Contribution of male age to outcomes in assisted reproductive technologies – addressing methodological challenges.
      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
      NSNSNSClinical 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%)
      NSNSIncreasing 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Luna M.
      • Finkler E.
      • Barritt J.
      • Bar-Chama N.
      • Sandler B.
      • Copperman A.B.
      • Grunfeld L.
      Paternal age and assisted reproductive technology outcome in ovum recipients.
      Fertilized embryos/total oocytes

      <40: 1951/3062 (63.7%)

      40–50: 2663/4414 (60.3%)

      >50: 845/1437 (58.8%)

      P-value < 0.05
      NSBlastocysts/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%)
      NSMiscarriage/clinical pregnancy

      <40: 17/143 (11.9%)

      40–50: 31/204 (15.2%)

      >50: 12/80 (15%)
      NSNSPaternal 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 J.
      • Garrido N.
      • Remohí J.
      • Pellicer A.
      • Meseguer M.
      Influence of paternal age on assisted reproduction outcome.
      Fertilized embryos/total oocytes

      Linear correlation

      IVF/ICSI

      r = 0.045

      P-value = non-significant

      Oocyte donation

      r = 0.056

      P-value = non-significant
      NSBlastocysts/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)
      NSMiscarriage/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)
      NSNSMale 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Frattarelli J.L.
      • Miller K.A.
      • Miller B.T.
      • Elkind-Hirsch K.
      • Scott R.T.
      Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
      NSCleavage-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%)
      NSNSAfter 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 M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      Fertilized embryos/total oocytes

      Mean ± SD

      ≥50: 64.9 ± 25.4

      <50: 66.7 ± 25.6

      P-value < 0.0001
      NSNSGood-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%)
      NSNSNSNSThere 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
      NSNSNSClinical 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 ageNSNo significant association with paternal ageAdvancing paternal age has a deleterious effect on IVF and GIFT outcomes
      First author (year)Rate of fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Kumtepe Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      Fertilized embryos/total oocytes

      <40: 5759/8203 (70.2%)

      >40: 1525/2265 (67.3%)
      NSNSGrade 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%)
      NSNSNSNSThe 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 S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      Fertilized embryos/total oocytes

      ≤39: 3342/4677 (71.5%)

      40–49: 1502/2109 (71.2%)

      ≥50: 211/308 (68.5%)

      P-value = 0.044
      NSNSNSClinical pregnancy/cycle where female partner age ≤35

      ≤35: 172/310 (55.5%)

      36–39: 33/79 (41.8%)

      ≥40: 4/9 (44.4%)
      NSNSNSNSThe influence on pregnancy outcome after ICSI is related mostly to maternal and not paternal age
      • Gallardo E.
      • Guanes P.P.
      • Simon C.
      • Remohi J.
      • Levy M.
      • Pellicer A.
      Effect of age on sperm fertility potential: oocyte donation as a model.
      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
      NSGood-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%)
      NSMiscarriage/clinical pregnancy

      ≤30: 1/20 (5.0%)

      31–40: 8/89 (9.0%)

      41–50: 6/50 (12.0%)

      ≥51: 4/15 (26.7%)
      NSNSAge (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 M.
      • Licata E.
      • Meneghini C.
      • Dal Lago A.
      • Fabiani C.
      • Amodei M.
      • Antonaci D.
      • Miriello D.
      • Corno R.
      • Liberanome C.
      • Bisogni F.
      • Paciotti G.
      • Meneghini A.
      • Rago R.
      Impact of paternal age on seminal parameters and reproductive outcome of intracytoplasmatic sperm injection in infertile Italian women.
      Fertilized embryos/total oocytes

      Total: 536/543

      (99%)
      NSNSNSClinical pregnancy/cycle

      Total:

      123/536

      (23%)

      Correlation between male age and positive pregnancy test

      OR 0.98, CI 0.94–1.01
      NSNSNSNSMale 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Kim M.K.
      • Park J.K.
      • Jeon Y.
      • Seok S.H.
      • Chang E.M.
      • Lee W.S.
      Effects of paternal age on human embryo development in in vitro fertilization with preimplantation genetic screening.
      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
      NSNSEuploid 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%)
      NSMiscarriage/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%)
      NSNSThere was no significant relationship between paternal age and euploidy rate or clinical outcomes (e.g. implantation, ongoing pregnancy, abortion rates)
      • Lai A.F.
      • Li R.H.
      • Yeung W.S.
      • Ng E.H.
      Effect of paternal age on semen parameters and live birth rate of in-vitro fertilization treatment: a retrospective analysis.
      Spearman's correlation coefficient: –0.004

      P-value = 0.810
      NSNSNSClinical pregnancy/cycle

      1613/3168

      (50.9%)
      Live birth/cycle

      1227/3168

      (38.7%)
      Miscarriage/clinical pregnancy

      284/1613

      (17.6%)
      NSNSPaternal 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Ma N.-Z.
      • Chen L.
      • Hu L.-L.
      • Dai W.
      • Bu Z.-Q.
      • Sun Y.-P.
      The influence of male age on treatment outcomes and neonatal birthweight following assisted reproduction technology involving intracytoplasmic sperm injection (ICSI) cycles.
      NSNSNSNSClinical 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
      NSMean ± 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 T.
      • Ishida E.
      • Tatsumi K.
      • Okada Y.
      • Saito T.
      • Kubota T.
      • Saito H.
      Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following intrauterine insemination.
      NSNSNSNSClinical 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
      NSNSNSAdvanced paternal age alone does not adversely affect pregnancy or live birth rates or sperm parameters following IUI, after adjusting for confounding factors
      • Ghuman N.K.
      • Mair E.
      • Pearce K.
      • Choudhary M.
      Does age of the sperm donor influence live birth outcome in assisted reproduction?.
      NSNSNSNSNSLive birth/cycle

      Donor insemination overall: 9.54%

      IVF/ICSI overall: 22.76%
      NSExtremely low numbers of congenital abnormalities recorded (meaningful analysis not feasible)NSLive 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Liu J.
      Effect of paternal age on reproductive outcomes of in vitro fertilization.
      No significant difference in fertilization rate among different paternal age groups

      P-value > 0.05
      NSNSGood-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
      NSMiscarriage/clinical pregnancy

      No significant difference in miscarriage rate among different paternal age groups

      P-value > 0.05
      NSNSPaternal 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 I.
      • Khoury J.
      • Abdallah M.E.
      • Warikoo P.
      • Hofmann G.E.
      The effect of paternal age on outcome in assisted reproductive technology using the ovum donation model.
      NSNSNSNSClinical 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%)
      NSNSAdvanced 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      • Koh S.-A.
      • Sanders K.
      • Deakin R.
      • Burton P.
      Male age negatively influences clinical pregnancy rate in women younger than 40 years undergoing donor insemination cycles.
      NSNSNSNSClinical 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
      NSNSNSNSThis 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 L.
      • Zhang H.
      • Yin L.
      • Bu Z.
      • Zhu G.
      Effect of male age on the outcome of in vitro fertilization: oocyte donation as a model.
      Fertilized embryos/total oocytes

      Mean ± SD

      78.8% ± 18.6%
      NSNSNSClinical 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
      NSNSAgeing 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 E.H.
      • Dowling-Lacey D.
      • Bocca S.
      • Stadtmauer L.
      • Oehninger S.
      Impact of male age on the outcome of assisted reproductive technology cycles using donor oocytes.
      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
      NSNSNSClinical pregnancy/cycle

      Mean ± SD

      25–38: 0.31 ± 0.35

      39–49: 0.27 ± 0.34

      ≥50: 0.25 ± 0.31
      NSMiscarriage/clinical pregnancy

      Mean ± SD

      25–38: 0.15 ± 0.36

      39–49: 0.22 ± 0.36

      ≥50: 0
      NSNSAlthough 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 R.C.
      • Braga D.P.A.F.
      • Bonetti T.C.S.
      • Pasqualotto F.F.
      • Iaconelli A.
      • Borges E.
      Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.
      NSNSNSGood-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
      NSMiscarriage/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)
      NSNSFor 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 fertilizationRate of cleavage-stage embryoRate of blastocyst formationRate of top-quality embryosRate of pregnancyRate of live birthRate of miscarriageCongenital malformationsBirthweightObserved paternal age effect
      Belloc (2008)NSNSNSNSClinical pregnancy/cycle

      OR (95% CI)

      <35: 1.00

      35–44: 0.90 (0.75–1.09)

      ≥45: 0.81 (0.65–1.02)
      NSMiscarriage/clinical pregnancy

      OR (95% CI)

      <35: 1.00

      35–44: 1.71

      (1.14–2.54)

      ≥45: 1.75

      (1.06–2.90)
      NSNSAdvanced 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 I.
      • Gomez E.
      • Fernandez-Velencia A.L.
      • Landeras J.
      • Gonzalez R.
      • Coy P.
      • Gadea J.
      Effects of men and recipients’ age on the reproductive outcome of an oocyte donation program.
      Fertilized embryos/total oocytes

      Overall (mean % ± SD): 82.71 ± 0.59

      Range: (25–100)

      P-value = 0.40
      NSBlastocysts/fertilized embryos

      Overall (mean % ± SD): 5.63 ± 0.07

      Range: (2–10)
      NSClinical pregnancy/cycle

      Overall (mean %): 460/915 (50.27%)
      NSMiscarriage/clinical pregnancy

      Overall (mean %): 189/460 (41.1%)
      NSNSAge has a detrimental effect on the reproductive outcome of oocyte donation cycles when both men and recipients are ≥ 39 years old
      • Girsh E.
      • Katz N.
      • Genkin L.
      • Girtler O.
      • Bocker J.
      • Bezdin S.
      • Barr I.
      Male age influences oocyte-donor program results.
      NSNSNSGood-quality embryos/cleavage-stage embryos

      Non-pregnant (26%)

      Pregnant (34%)

      P-value = 0.01
      NSNSNSNSNSSperm 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)NSNSNSNSNSNSNSNSNSPaternal age over 40 years is an important risk factor for failure to conceive
      • Paulson R.J.
      • Milligan R.C.
      • Sokol R.Z.
      The lack of influence of age on male fertility.
      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
      NSNSNSThere was no significant influence of male age on pregnancy success as per logistic regressionLive birth/cycle

      32.7%
      NSNSNSMale 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 C.
      • Ecochard R.
      • Bied V.
      • Lornage J.
      • Czyba J.C.
      Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age.
      NSNSNSNSClinical 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
      NSNSNSNSMultivariate 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 criteriaExclusion criteriaPaternal age groups (years)
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      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 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.
      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 M.
      • Licata E.
      • Meneghini C.
      • Dal Lago A.
      • Fabiani C.
      • Amodei M.
      • Antonaci D.
      • Miriello D.
      • Corno R.
      • Liberanome C.
      • Bisogni F.
      • Paciotti G.
      • Meneghini A.
      • Rago R.
      Impact of paternal age on seminal parameters and reproductive outcome of intracytoplasmatic sperm injection in infertile Italian women.
      1.Couples undergoing ICSI1.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 M.K.
      • Park J.K.
      • Jeon Y.
      • Seok S.H.
      • Chang E.M.
      • Lee W.S.
      Effects of paternal age on human embryo development in in vitro fertilization with preimplantation genetic screening.
      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 Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      1.All infertile men with cryptozoospermia who underwent ICSI1.Infertility caused by female factors

      2.Female partner with karyotype abnormalities
      <35

      ≥35
      • Capelouto S.M.
      • Nagy Z.P.
      • Shapiro D.B.
      • Archer S.R.
      • Ellis D.P.
      • Smith A.K.
      • Spencer J.B.
      • Hipp H.S.
      Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model.
      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 J.
      • Hilario R.
      • Duenas J.
      High percentages of embryos with 21, 18 or 13 trisomy are related to advanced paternal age in donor egg cycles.
      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 I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      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 A.F.
      • Li R.H.
      • Yeung W.S.
      • Ng E.H.
      Effect of paternal age on semen parameters and live birth rate of in-vitro fertilization treatment: a retrospective analysis.
      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 N.-Z.
      • Chen L.
      • Hu L.-L.
      • Dai W.
      • Bu Z.-Q.
      • Sun Y.-P.
      The influence of male age on treatment outcomes and neonatal birthweight following assisted reproduction technology involving intracytoplasmic sperm injection (ICSI) cycles.
      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 N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      1.First patient cycles of IVF, ICSI or a combination of both between 2009 and 20131.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 Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      1.Obstructive azoospermia and non-obstructive azoospermia1.Klinefelter syndrome

      2.Spinal cord injuries

      3.Y-chromosome deletions
      ≤30

      31–35

      36–40

      41–45

      ≥46
      • Tatsumi T.
      • Ishida E.
      • Tatsumi K.
      • Okada Y.
      • Saito T.
      • Kubota T.
      • Saito H.
      Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following intrauterine insemination.
      1.Couples undergoing IUI using the male partner's sperm1.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 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.
      1.All couples undergoing IVF or ICSI between 1 January 2010 and 31 December 20151.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 A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      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 N.K.
      • Mair E.
      • Pearce K.
      • Choudhary M.
      Does age of the sperm donor influence live birth outcome in assisted reproduction?.
      1.First fresh donor insemination and IVF/ICSI treatment cycles using donated sperm from the HFEA long-term anonymized data registry 1991–20121.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 A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      1.All first cycles of assisted reproductive treatment at the Radboud University Medical Centre (Radboudumc) between 1 January 2001 and 1 June 20131.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 Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      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 J.
      • Luna D.
      • Villegas L.
      • Romero R.
      • Zavala P.
      • Hilario R.
      • Duenas-Chacon J.
      High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.
      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 J.
      • Noel M.
      • Kao C.N.
      • Mok-Lin E.
      • Cedars M.I.
      • Huddleston H.G.
      Semen parameters and paternal age do not affect fertilization rate or pregnancy outcomes in oocyte recipient cycles. Fertility and Sterility. P-33, e23.
      1.IVF cycles with donor oocytes and fresh transfers1.Not fresh transfer

      2.Known donors

      3.Severe male factor infertility
      <40

      40–45

      45–50

      >50
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Liu J.
      Effect of paternal age on reproductive outcomes of in vitro fertilization.
      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 R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      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 I.
      • Khoury J.
      • Abdallah M.E.
      • Warikoo P.
      • Hofmann G.E.
      The effect of paternal age on outcome in assisted reproductive technology using the ovum donation model.
      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 cycles25–29

      30–34

      35–39

      40–44

      45–49

      50–54

      ≥55
      • Koh S.-A.
      • Sanders K.
      • Deakin R.
      • Burton P.
      Male age negatively influences clinical pregnancy rate in women younger than 40 years undergoing donor insemination cycles.
      1.Female recipients <40 years oldNS<40

      40–44.9

      45–49.9

      ≥50
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      1.Male patients diagnosed with azoospermia1. Men <31 years old31–35

      35–40

      >40
      • Gu L.
      • Zhang H.
      • Yin L.
      • Bu Z.
      • Zhu G.
      Effect of male age on the outcome of in vitro fertilization: oocyte donation as a model.
      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 R.
      • Urbina M.T.
      • Benjamin I.
      • Lerner-Biber J.
      • Alvarez M.T.
      Paternal age and spontaneous abortion after IVF with donor eggs.
      1.IVF with donor oocytes

      2.Egg donation model controlled for maternal age
      NS≤34

      35–38

      ≥39
      • Meyer L.
      • Zakarin L.
      • Reichman D.E.
      • Spandorfer S.
      • Rosenwaks Z.
      • Perelman R.O.
      • Cohen C.
      The effect of paternal age on shared recipient oocyte donation cycles. Fertility and Sterility. O-274, S81.
      NSNS<40

      40–49

      ≥50
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      1.Infertile patients undergoing a first IVF or ICSI treatment1.Testicular sperm cycles

      2.Cycles undergoing PGT
      ≤34

      35–39

      ≥40
      • Whitcomb B.W.
      • Levens E.D.
      • Turzanski-Fortner R.
      • Richter K.S.
      • Kipersztok S.
      • Stillman R.J.
      • Levy M.J.
      Contribution of male age to outcomes in assisted reproductive technologies – addressing methodological challenges.
      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 E.H.
      • Dowling-Lacey D.
      • Bocca S.
      • Stadtmauer L.
      • Oehninger S.
      Impact of male age on the outcome of assisted reproductive technology cycles using donor oocytes.
      1.Oocyte donors ≤35 years old1.Cycles involving sperm extraction

      2.Cycles including PGT
      23–38

      39–49

      ≥50
      • Ferreira R.C.
      • Braga D.P.A.F.
      • Bonetti T.C.S.
      • Pasqualotto F.F.
      • Iaconelli A.
      • Borges E.
      Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.
      1.All couples undergoing ICSI cycles using fresh spermatozoa1.Cycles in which fewer than four metaphase II oocytes were recoveredNS
      • Luna M.
      • Finkler E.
      • Barritt J.
      • Bar-Chama N.
      • Sandler B.
      • Copperman A.B.
      • Grunfeld L.
      Paternal age and assisted reproductive technology outcome in ovum recipients.
      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)NS1.Insemination cancelled if total living, motile sperm count was <0.5  ×  106 and >75% abnormal forms were present30

      30–34

      35–39

      40–44

      ≥45
      • Bellver J.
      • Garrido N.
      • Remohí J.
      • Pellicer A.
      • Meseguer M.
      Influence of paternal age on assisted reproduction outcome.
      IUI1. 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

      IVF1. 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 I.
      • Gomez E.
      • Fernandez-Velencia A.L.
      • Landeras J.
      • Gonzalez R.
      • Coy P.
      • Gadea J.
      Effects of men and recipients’ age on the reproductive outcome of an oocyte donation program.
      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 J.L.
      • Miller K.A.
      • Miller B.T.
      • Elkind-Hirsch K.
      • Scott R.T.
      Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
      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 E.
      • Katz N.
      • Genkin L.
      • Girtler O.
      • Bocker J.
      • Bezdin S.
      • Barr I.
      Male age influences oocyte-donor program results.
      1. Freshly ejaculated semen samples

      2. Oocyte donor age 20–26 years
      NS26–30

      31–35

      36–40

      41–45

      46–50

      51–55

      56–60
      • Aboulghar M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      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 H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      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 Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      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 R.J.
      • Milligan R.C.
      • Sokol R.Z.
      The lack of influence of age on male fertility.
      1. Initial screening analysis of sperm sample1. Cases involving ICSIAll participants

      >50
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      1. Consecutive ICSI cases

      2. Only male partners with female partners aged ≤35 years
      NS≤39

      40–49

      ≥50
      • Gallardo E.
      • Guanes P.P.
      • Simon C.
      • Remohi J.
      • Levy M.
      • Pellicer A.
      Effect of age on sperm fertility potential: oocyte donation as a model.
      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 C.
      • Ecochard R.
      • Bied V.
      • Lornage J.
      • Czyba J.C.
      Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age.
      1.All patients undergoing intrauterine artificial insemination with spermatozoa selected after in-vitro treatment of semenNS<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 biasComparability bias (controls for maternal age)Performance biasAttrition biasReporting bias
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      *********Fair
      • 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.
      **********Good
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      ******Poor
      • Capelouto S.M.
      • Nagy Z.P.
      • Shapiro D.B.
      • Archer S.R.
      • Ellis D.P.
      • Smith A.K.
      • Spencer J.B.
      • Hipp H.S.
      Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model.
      ********Good
      • Garcia-Ferreyra J.
      • Hilario R.
      • Duenas J.
      High percentages of embryos with 21, 18 or 13 trisomy are related to advanced paternal age in donor egg cycles.
      ********Good
      • Kaarouch I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      *******Fair
      • McPherson N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      *******Fair
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      *******Fair
      • 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.
      *******Fair
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      *******Fair
      • Meijerink A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      ********Fair
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      ********Fair
      • Garcia-Ferreyra J.
      • Luna D.
      • Villegas L.
      • Romero R.
      • Zavala P.
      • Hilario R.
      • Duenas-Chacon J.
      High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.
      ********Good
      • Ho J.
      • Noel M.
      • Kao C.N.
      • Mok-Lin E.
      • Cedars M.I.
      • Huddleston H.G.
      Semen parameters and paternal age do not affect fertilization rate or pregnancy outcomes in oocyte recipient cycles. Fertility and Sterility. P-33, e23.
      Poor
      • Begueria R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      ********Fair
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ********Fair
      • Medina R.
      • Urbina M.T.
      • Benjamin I.
      • Lerner-Biber J.
      • Alvarez M.T.
      Paternal age and spontaneous abortion after IVF with donor eggs.
      Poor
      • Meyer L.
      • Zakarin L.
      • Reichman D.E.
      • Spandorfer S.
      • Rosenwaks Z.
      • Perelman R.O.
      • Cohen C.
      The effect of paternal age on shared recipient oocyte donation cycles. Fertility and Sterility. O-274, S81.
      Poor
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      *******Fair
      • Whitcomb B.W.
      • Levens E.D.
      • Turzanski-Fortner R.
      • Richter K.S.
      • Kipersztok S.
      • Stillman R.J.
      • Levy M.J.
      Contribution of male age to outcomes in assisted reproductive technologies – addressing methodological challenges.
      *********Good
      • Luna M.
      • Finkler E.
      • Barritt J.
      • Bar-Chama N.
      • Sandler B.
      • Copperman A.B.
      • Grunfeld L.
      Paternal age and assisted reproductive technology outcome in ovum recipients.
      *********Good
      • Bellver J.
      • Garrido N.
      • Remohí J.
      • Pellicer A.
      • Meseguer M.
      Influence of paternal age on assisted reproduction outcome.
      *******Poor
      • Frattarelli J.L.
      • Miller K.A.
      • Miller B.T.
      • Elkind-Hirsch K.
      • Scott R.T.
      Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
      *********Good
      • Aboulghar M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      *******Fair
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      *******Fair
      • Kumtepe Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      *******Fair
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      *******Fair
      • Gallardo E.
      • Guanes P.P.
      • Simon C.
      • Remohi J.
      • Levy M.
      • Pellicer A.
      Effect of age on sperm fertility potential: oocyte donation as a model.
      *********Good
      Newcastle-Ottawa Quality Assessment according to

      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
      Autologous and donor refers to oocytes, age refers to paternal age threshold.
      Pooled OR95% CII2Degree 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.
      low asterisk Degree of heterogeneity: Low, I2 < 25%; Moderate, I2 = 25–75%; High, I2 > 75%.Significant results shown in bold.References: 1.
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      ; 2.
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      ; 3.
      • 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.
      ; 4.
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      ; 5.
      • Bellver J.
      • Garrido N.
      • Remohí J.
      • Pellicer A.
      • Meseguer M.
      Influence of paternal age on assisted reproduction outcome.
      ; 6.
      • Begueria R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      ; 7.
      • Whitcomb B.W.
      • Levens E.D.
      • Turzanski-Fortner R.
      • Richter K.S.
      • Kipersztok S.
      • Stillman R.J.
      • Levy M.J.
      Contribution of male age to outcomes in assisted reproductive technologies – addressing methodological challenges.
      ; 8.
      • Gallardo E.
      • Guanes P.P.
      • Simon C.
      • Remohi J.
      • Levy M.
      • Pellicer A.
      Effect of age on sperm fertility potential: oocyte donation as a model.
      ; 9.
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      ; 10.
      • Meijerink A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      ; 11.
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ; 12.
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ; 13.
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ; 14.
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      ; 15.
      • Capelouto S.M.
      • Nagy Z.P.
      • Shapiro D.B.
      • Archer S.R.
      • Ellis D.P.
      • Smith A.K.
      • Spencer J.B.
      • Hipp H.S.
      Impact of male partner characteristics and semen parameters on in vitro fertilization and obstetric outcomes in a frozen oocyte donor model.
      ; 16.
      • Medina R.
      • Urbina M.T.
      • Benjamin I.
      • Lerner-Biber J.
      • Alvarez M.T.
      Paternal age and spontaneous abortion after IVF with donor eggs.
      ; 17.
      • Frattarelli J.L.
      • Miller K.A.
      • Miller B.T.
      • Elkind-Hirsch K.
      • Scott R.T.
      Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles.
      ; 18.
      • McPherson N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      ; 19.
      • Kaarouch I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      ; 20.
      • Kumtepe Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      ; 21.
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      ; 22.
      • Ho J.
      • Noel M.
      • Kao C.N.
      • Mok-Lin E.
      • Cedars M.I.
      • Huddleston H.G.
      Semen parameters and paternal age do not affect fertilization rate or pregnancy outcomes in oocyte recipient cycles. Fertility and Sterility. P-33, e23.
      ; 23.
      • Meyer L.
      • Zakarin L.
      • Reichman D.E.
      • Spandorfer S.
      • Rosenwaks Z.
      • Perelman R.O.
      • Cohen C.
      The effect of paternal age on shared recipient oocyte donation cycles. Fertility and Sterility. O-274, S81.
      ; 24.
      • Luna M.
      • Finkler E.
      • Barritt J.
      • Bar-Chama N.
      • Sandler B.
      • Copperman A.B.
      • Grunfeld L.
      Paternal age and assisted reproductive technology outcome in ovum recipients.
      ; 25.
      • 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.
      ; 26.
      • Aboulghar M.
      • Mansour R.
      • Al-Inany H.
      • Abou-Setta A.M.
      • Aboulghar M.
      • Mourad L.
      • Serour G.
      Paternal age and outcome of intracytoplasmic sperm injection.
      ; 27.
      • Garcia-Ferreyra J.
      • Luna D.
      • Villegas L.
      • Romero R.
      • Zavala P.
      • Hilario R.
      • Duenas-Chacon J.
      High aneuploidy rates observed in embryos derived from donated oocytes are related to male aging and high percentages of sperm DNA fragmentation.
      ; 28.
      • Garcia-Ferreyra J.
      • Hilario R.
      • Duenas J.
      High percentages of embryos with 21, 18 or 13 trisomy are related to advanced paternal age in donor egg cycles.
      .

      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;
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ;
      • Meijerink A.M.
      • Ramos L.
      • Fleischer K.
      • Veltman J.A.
      • Hendriks J.C.
      • Braat D.D.
      Influence of paternal age on ongoing pregnancy rate at eight weeks’ gestation in assisted reproduction.
      ;
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      ;
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      ;
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ;
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      ;
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      ). 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 2
      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).

      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 (
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ;
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ;
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      ). 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 3
      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.

      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 M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ;
      • Yu Y.
      • Wang R.
      • Xi Q.
      • Zhang H.
      • Jiang Y.
      • Li L.
      • Liu R.
      • Zhang X.
      Effect of paternal age on intracytoplasmic sperm injection outcomes in crytozoospermic men.
      ). 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;
      • 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.
      ;
      • Kaarouch I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      ;
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ;
      • Kumtepe Y.
      • Yakin K.
      • Kahraman S.
      • Sertyel Demra
      • Vaniloglu F.
      • Cengiz S.
      • Donmez E.
      Male age is not an independent factor to affect the outcome of assisted reproductive techniques.
      ;
      • McPherson N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      ;
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      ;
      • Spandorfer S.D.
      • Avrech O.M.
      • Colombero L.T.
      • Palermo G.D.
      • Rosenwaks Z.
      Effect of parental age on fertilization and pregnancy characteristics in couples treated by intracytoplasmic sperm injection.
      ;
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ;
      • Wu Y.
      • Kang X.
      • Zheng H.
      • Liu H.
      • Huang Q.
      • Liu J.
      Effect of paternal age on reproductive outcomes of intracytoplasmic sperm injection.
      ). 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 4
      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.

      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 (
      • Klonoff-Cohen H.S.
      • Natarajan L.
      The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer.
      ;
      • Horta F.
      • Vollenhoven B.
      • Healey M.
      • Busija L.
      • Catt S.
      • Temple-Smith P.
      Male ageing is negatively associated with the chance of live birth in IVF.ICSI cycles for idiopathic infertility.
      ;
      • McPherson N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      ;
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Park Y.S.
      • Lee S.H.
      • Lim C.K.
      • Choi H.W.
      • An J.H.
      • Parl C.W.
      • Lee H.S.
      • Lee J.S.
      • Seo J.T.
      Paternal age as an independent factor does not affect embryo quality and pregnancy outcomes of testicular sperm extraction-intracytoplasmic sperm injection in azoospermia.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ). 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 5
      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.

      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 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.
      ;
      • Kaarouch I.
      • Bouamoud N.
      • Madkour A.
      • Louanjli N.
      • Saadani B.
      • Assou S.
      • Aboulmaouahib S.
      • Amzazi S.
      • Copin H.
      • Benkhalifa M.
      • Sefrioui O.
      Paternal age: Negative impact on sperm genome decays and IVF outcomes after 40 years.
      ;
      • McPherson N.O.
      • Zander-Fox D.
      • Vincent A.D.
      • Lane M.
      Combined advanced paternal age has an additive negative effect on live birth rates – data from 4057 first IVF/ICSI cycles.
      ;
      • Nijs M.
      • De Jonge C.
      • Cox A.
      • Janssen M.
      • Bosmans E.
      • Ombelet W.
      Correlation between male age, WHO sperm parameters, DNA fragmentation, chromatin packaging and outcome in assisted reproduction technology.
      ;
      • Tiegs A.W.
      • Sachdev N.M.
      • Grifo J.A.
      • Mc Culloh D.H.
      • Licciardi F.
      Paternal age is not associated with pregnancy outcomes after single thawed Euploid blastocyst transfer.
      ;
      • Tsai Y.
      • Lan K.
      • Kung F.
      • Lin P.
      • Chiang H.
      • Lin Y.
      • Huang F.
      The effect of advanced paternal age on the outcomes of assisted reproductive techniques among patients with azoospermia using cryopreserved testicular spermatozoa.
      ). 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 R.
      • Garcia D.
      • Obradors A.
      • Poisot F.
      • Vassena R.
      • Vernaeve V.
      Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers?.
      ;