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Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis

Published:August 10, 2015DOI:https://doi.org/10.1016/j.rbmo.2015.07.012

      Abstract

      This systematic review investigated the effect of paternal obesity on reproductive potential. Databases searched were Pubmed, Ovid, Web of Science, Scopus, Cinahl and Embase. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool. Outcomes were: likelihood of infertility, embryo development, clinical pregnancy, live birth, pregnancy viability, infant development, sperm; concentration, morphology, motility, volume, DNA fragmentation, chromatin condensation, mitochondrial membrane potential (MMP), and seminal plasma factors. Thirty papers were included, with a total participant number of 115,158. Obese men were more likely to experience infertility (OR = 1.66, 95% CI 1.53–1.79), their rate of live birth per cycle of assisted reproduction technology (ART) was reduced (OR = 0.65, 95% CI 0.44–0.97) and they had a 10% absolute risk increase of pregnancy non-viability. Additionally, obese men had an increased percentage of sperm with low MMP, DNA fragmentation, and abnormal morphology. Clinically significant differences were not found for conventional semen parameters. From these findings it can be concluded that male obesity is associated with reduced reproductive potential. Furthermore, it may be informative to incorporate DNA fragmentation analysis and MMP assessment into semen testing, especially for obese men whose results suggest they should have normal fertility.

      Keywords

      Introduction

      Male infertility is a significant issue and constitutes approximately 50% of infertility cases (
      • Lamb D.J.
      • Lipshultz L.I.
      Male infertility: recent advances and a look towards the future.
      ). Defective sperm function affects about 1 in 20 men (
      • McLachlan R.I.
      • de Kretser D.M.
      Male infertility: the case for continued research.
      ) and constitutes the single most common cause of infertility (
      • Hull M.G.
      • Glazener C.M.
      • Kelly N.J.
      • Conway D.I.
      • Foster P.A.
      • Hinton R.A.
      • Coulson C.
      • Lambert P.A.
      • Watt E.M.
      • Desai K.M.
      Population study of causes, treatment, and outcome of infertility.
      ,
      • McLachlan R.I.
      • de Kretser D.M.
      Male infertility: the case for continued research.
      ). There is also increasing evidence of paternal non-genetic effects on the long-term health of the offspring transmitted through the gamete (
      • Fullston T.
      • Ohlsson Teague E.M.
      • Palmer N.O.
      • Deblasio M.J.
      • Mitchell M.
      • Corbett M.
      • Print C.G.
      • Owens J.A.
      • Lane M.
      Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content.
      ,
      • Linabery A.M.
      • Nahhas R.W.
      • Johnson W.
      • Choh A.C.
      • Towne B.
      • Odegaard A.O.
      • Czerwinski S.A.
      • Demerath E.W.
      Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study.
      ,
      • McPherson N.O.
      • Fullston T.
      • Bakos H.W.
      • Setchell B.P.
      • Lane M.
      Obese father's metabolic state, adiposity, and reproductive capacity indicate son's reproductive health.
      ,
      • Soubry A.
      • Schildkraut J.M.
      • Murtha A.
      • Wang F.
      • Huang Z.
      • Bernal A.
      • Kurtzberg J.
      • Jirtle R.L.
      • Murphy S.K.
      • Hoyo C.
      Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort.
      ). Therefore, understanding the factors influencing the health of sperm and the underlying mechanisms behind any resultant pathology is paramount.
      Obesity is a condition in which excess body fat is accumulated, and has been associated with multiple conditions such as diabetes, cardiovascular disease and certain types of cancer (
      • Proietto J.
      • Baur L.A.
      10: management of obesity.
      ). Obesity and its associated comorbidities present significant health concerns throughout the world. It is increasingly prevalent in the population of people trying to conceive (
      • Hyattsville M.
      United States health, 2008 with chartbook.
      ,
      • Visscher T.L.
      • Seidell J.C.
      The public health impact of obesity.
      ), with the prevalence of obesity in young men of reproductive age having tripled since the early 1970s (
      • Hyattsville M.
      United States health, 2008 with chartbook.
      ).
      Although it is clear that maternal obesity reduces fertility, in part through actions on the oocyte, which affect the viability of the resultant pregnancy (
      • Cai G.J.
      • Sun X.X.
      • Zhang L.
      • Hong Q.
      Association between maternal body mass index and congenital heart defects in offspring: a systematic review.
      ,
      • Papachatzi E.
      • Dimitriou G.
      • Dimitropoulos K.
      • Vantarakis A.
      Pre-pregnancy obesity: maternal, neonatal and childhood outcomes.
      ,
      • Pasquali R.
      • Patton L.
      • Gambineri A.
      Obesity and infertility.
      ), the potential role of male obesity in infertility has received comparatively little attention. This is surprising given the potential effect of male obesity on the molecular structure of maturing sperm and therefore subsequent embryo and fetal development. Further, the incidence of male infertility (at least in some geographical areas) is on the rise (
      • Katib A.
      Mechanisms linking obesity to male infertility.
      ,
      • Swan S.H.
      • Elkin E.P.
      • Fenster L.
      The question of declining sperm density revisited: an analysis of 101 studies published 1934–1996.
      ). This is coincident with a worldwide reduction in sperm quality, which to date is unexplained (
      • Andersson A.M.
      • Jorgensen N.
      • Main K.M.
      • Toppari J.
      • Rajpert-De Meyts E.
      • Leffers H.
      • Juul A.
      • Jensen T.K.
      • Skakkebaek N.E.
      Adverse trends in male reproductive health: we may have reached a crucial “tipping point”.
      ), but that some have postulated may in part be attributable to the increasing prevalence of overweight and obesity (
      • Finucane M.M.
      • Stevens G.A.
      • Cowan M.J.
      • Danaei G.
      • Lin J.K.
      • Paciorek C.J.
      • Singh G.M.
      • Gutierrez H.R.
      • Lu Y.
      • Bahalim A.N.
      • Farzadfar F.
      • Riley L.M.
      • Ezzati M.
      National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants.
      ,
      • Setchell B.P.
      Sperm counts in semen of farm animals 1932–1995.
      ). With an increase in the prevalence of obesity, it is necessary to broaden the understanding of the clinical significance of a male partner being overweight or obese. In general, male health is an under-researched area compared with female health, and there are broad knowledge gaps in the understanding of how the health of the male influences the viability of the sperm and subsequent pregnancy outcomes.
      The aim of this systematic review is to critically evaluate and synthesize the current evidence on the effects of paternal obesity on male reproductive potential. While some findings examining the effects of male obesity on reproductive endocrine state and sperm function are now available – specifically systematic reviews have been performed on the effect of paternal obesity on reproductive health as indicated by sperm count (
      • Sermondade N.
      • Faure C.
      • Fezeu L.
      • Shayeb A.G.
      • Bonde J.P.
      • Jensen T.K.
      • Van Wely M.
      • Cao J.
      • Martini A.C.
      • Eskandar M.
      • Chavarro J.E.
      • Koloszar S.
      • Twigt J.M.
      • Ramlau-Hansen C.H.
      • Borges Jr., E.
      • Lotti F.
      • Steegers-Theunissen R.P.
      • Zorn B.
      • Polotsky A.J.
      • La Vignera S.
      • Eskenazi B.
      • Tremellen K.
      • Magnusdottir E.V.
      • Fejes I.
      • Hercberg S.
      • Levy R.
      • Czernichow S.
      BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis.
      ), reproductive endocrine state (
      • Teerds K.J.
      • De Rooij D.G.
      • Keijer J.
      Functional relationship between obesity and male reproduction: from humans to animal models.
      ), and sperm count, concentration, volume, and motility in conjunction with the reproductive endocrine state (
      • MacDonald A.A.
      • Herbison G.P.
      • Showell M.
      • Farquhar C.M.
      The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis.
      ) – there has been no review of the effects of paternal obesity on primary fertility outcomes (i.e. attainment of pregnancy and live birth, infant development) or non-conventional parameters of semen quality (i.e. DNA fragmentation, mitochondrial membrane potential [MMP], chromatin condensation). The inclusion of these factors in this review will provide a more complete picture of the influence and mechanisms of obesity on male reproductive potential.

      Materials and methods

      A systematic review of the literature was performed to identify what effect paternal obesity has on male reproductive potential according to the methodologies of the JBI Database of Systematic Reviews and Implementation Reports (
      • The Joanna Briggs Institute
      The Joanna Briggs Institute Reviewer's Manual: 2011 Edition.
      ). An a priori published protocol was followed (
      • Campbell J.
      • Bakos H.
      The effect of paternal obesity compared with normal weight on semen quality, seminal plasma composition, embryo development, pregnancy outcomes and trans-generational effects in adult males: a systematic review protocol.
      ). The review was carried out to include both published and grey literature; however, ultimately only published studies were found. No date restrictions were applied, but language was restricted to English. Studies were retrieved up to March 2013, with an updated search performed in April 2015.

       Inclusion and exclusion criteria

      Studies carried out on male adults aged >18 years without history of reproductive disorders were included in the review. Studies that utilized frozen or donor sperm were excluded, as were those that focused on men who had been exposed to environmental toxicants such as pesticides. Data had to be reported with men categorised by body mass index (BMI), including a normal weight group (BMI ≤ 25) and an obese group (BMI ≥ 30). All types of quantitative research were eligible for inclusion in the review (with the exception of case series and reports).

       Outcomes of interest

      This systematic review considered studies that investigated the following outcomes: likelihood of infertility, in-vitro embryo development, clinical pregnancy, live birth, pregnancy viability, infant development, sperm; concentration, normal morphology, progressive motility, volume, DNA fragmentation, chromatin condensation, low mitochondrial membrane potential, and seminal plasma factors.

       Search strategy

      The search strategy utilized a three-step approach that has previously been described (
      • The Joanna Briggs Institute
      The Joanna Briggs Institute Reviewer's Manual: 2011 Edition.
      ). Included databases were Pubmed, Ovid, Web of Science, Scopus and Embase). A full list of keywords and indexing terms is provided in the supplementary materials, Appendix S1.

       Critical appraisal and data extraction

      Critical appraisal was carried out by two independent reviewers using a standardized checklist prior to inclusion in the review (
      • The Joanna Briggs Institute
      The Joanna Briggs Institute Reviewer's Manual: 2011 Edition.
      ). Disagreements between reviewers were resolved through discussion. Data was extracted from included papers using a standardized instrument (
      • Campbell J.
      • Bakos H.
      The effect of paternal obesity compared with normal weight on semen quality, seminal plasma composition, embryo development, pregnancy outcomes and trans-generational effects in adult males: a systematic review protocol.
      ,
      • The Joanna Briggs Institute
      The Joanna Briggs Institute Reviewer's Manual: 2011 Edition.
      ). Where data were missing or clarification was needed, authors were contacted by email.

       Data synthesis

      Data were entered into the statistical software JBI-MAStARI (The Joanna Briggs Institute) by double data entry to ensure the accuracy of the values. Meta-analysis was then performed, with effect sizes expressed as odds ratios (OR) or weighted mean differences (WMD) depending on whether the data were categorical or continuous, with variability expressed as 95% confidence intervals (CI). In one instance where the same outcome was assessed by different measures, the effects size was expressed as standardized mean difference (SMD). The fixed effects model was used unless a significant level of heterogeneity was found (as assessed by the standard chi-squared test), in which case the random effects model was used. Subgroup analysis was used to investigate the influence of data being collected from the clinical population as opposed to the general population on conventional semen parameters. In cases where categorical data were presented only as ORs rather than raw numbers or percentages the Cochrane systematic review tool “RevMan 5” (Cochrane) was utilized to perform meta-analysis by the inverse variance method.

      Results

       Study characteristics

      In total 30 studies were included in this systematic review. Thirty-five studies met the inclusion criteria, but five did not pass critical appraisal due to shortcomings in their statistical analysis or reporting (
      • Al-Ali B.M.
      • Gutschi T.
      • Pummer K.
      • Zigeuner R.
      • Brookman-May S.
      • Wieland W.F.
      • Fritsche H.M.
      • Aziz A.
      Body mass index has no impact on sperm quality but on reproductive hormones levels.
      ,
      • Al-Ali B.M.
      • Gutschi T.
      • Pummer K.
      • Zigeuner R.
      • Brookman-May S.
      • Wieland W.F.
      • Fritsche H.M.
      • Aziz A.
      Body mass index has no impact on sperm quality but on reproductive hormones levels.
      ,
      • Jamshidi L.
      Male obesity and sperm parameters in infertility.
      ,
      • Relwani R.
      • Berger D.
      • Santoro N.
      • Hickmon C.
      • Nihsen M.
      • Zapantis A.
      • Werner M.
      • Polotsky A.J.
      • Jindal S.
      Semen parameters are unrelated to BMI but vary with SSRI use and prior urological surgery.
      ,
      • Sekhavat L.
      • Moein M.R.
      The effect of male body mass index on sperm parameters.
      ) (Figure 1 Supplementary Table S1). The overall quality of included studies ranged from 4/9 to 8/9. The non-random recruitment of participants (appraisal criteria 1, Supplementary Table S1) was a characteristic failing of studies on this topic, with only two of the 35 utilizing any form randomized patient selection. The included studies were conducted in a range of different countries, including: the USA (9) (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ,
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ,
      • Hammoud A.O.
      • Wilde N.
      • Gibson M.
      • Parks A.
      • Carrell D.T.
      • Meikle A.W.
      Male obesity and alteration in sperm parameters.
      ,
      • Jokela M.
      • Elovainio M.
      • Kivimaki M.
      Lower fertility associated with obesity and underweight: the US National Longitudinal Survey of Youth.
      ,
      • Keltz J.
      • Zapantis A.
      • Jindal S.K.
      • Lieman H.J.
      • Santoro N.
      • Polotsky A.J.
      Overweight Men: clinical pregnancy after ART is decreased in IVF but not in ICSI cycles.
      ,
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • Roudebush W.E.
      Impact of body mass index values on sperm quantity and quality.
      ,
      • Linabery A.M.
      • Nahhas R.W.
      • Johnson W.
      • Choh A.C.
      • Towne B.
      • Odegaard A.O.
      • Czerwinski S.A.
      • Demerath E.W.
      Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ), Denmark (3) (
      • Aggerholm A.S.
      • Thulstrup A.M.
      • Toft G.
      • Ramlau-Hansen C.H.
      • Bonde J.P.
      Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Comment.
      ,
      • Petersen G.L.
      • Schmidt L.
      • Pinborg A.
      • Kamper-Jorgensen M.
      The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.
      ,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sorensen T.I.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      ), the UK (2) (
      • Pacey A.A.
      • Povey A.C.
      • Clyma J.A.
      • McNamee R.
      • Moore H.D.
      • Baillie H.
      • Cherry N.M.
      Modifiable and non-modifiable risk factors for poor sperm morphology.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ), Australia (2) (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ), Italy (2) (
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ), The Netherlands (2) (
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Hammiche F.
      • Laven J.S.
      • Twigt J.M.
      • Boellaard W.P.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.
      ), Brazil (1) (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ), China (1) (
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ), New Zealand (1) (
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      ), Hungary (1) (
      • Koloszar S.
      • Fejes I.
      • Zavaczki Z.
      • Daru J.
      • Szollosi J.
      • Pal A.
      Effect of body weight on sperm concentration in normozoospermic males.
      ), the Czech republic (1) (
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ), Argentina (1) (
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ), Norway (1) (
      • Nguyen R.H.
      • Wilcox A.J.
      • Skjaerven R.
      • Baird D.D.
      Men's body mass index and infertility.
      ), Turkey (1) (
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), Russia (1) (
      • Gutorova N.V.
      • Kleshchyov M.A.
      • Tipisova E.V.
      • Osadchuk L.V.
      Effects of overweight and obesity on the spermogram values and levels of reproductive hormones in the male population of the European north of Russia.
      ), and France (1) (
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ). A total of 115,158 participants were ultimately included in this systematic review, with a range of 81 to 47,835 participants per study. Twenty-one studies were carried out on data collected from participants attending an infertility clinic (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ,
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ,
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • Hammiche F.
      • Laven J.S.
      • Twigt J.M.
      • Boellaard W.P.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.
      ,
      • Hammoud A.O.
      • Wilde N.
      • Gibson M.
      • Parks A.
      • Carrell D.T.
      • Meikle A.W.
      Male obesity and alteration in sperm parameters.
      ,
      • Keltz J.
      • Zapantis A.
      • Jindal S.K.
      • Lieman H.J.
      • Santoro N.
      • Polotsky A.J.
      Overweight Men: clinical pregnancy after ART is decreased in IVF but not in ICSI cycles.
      ,
      • Koloszar S.
      • Fejes I.
      • Zavaczki Z.
      • Daru J.
      • Szollosi J.
      • Pal A.
      Effect of body weight on sperm concentration in normozoospermic males.
      ,
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • Roudebush W.E.
      Impact of body mass index values on sperm quantity and quality.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Pacey A.A.
      • Povey A.C.
      • Clyma J.A.
      • McNamee R.
      • Moore H.D.
      • Baillie H.
      • Cherry N.M.
      Modifiable and non-modifiable risk factors for poor sperm morphology.
      ,
      • Petersen G.L.
      • Schmidt L.
      • Pinborg A.
      • Kamper-Jorgensen M.
      The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.
      ,
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), while nine studies were carried out on the general population (
      • Aggerholm A.S.
      • Thulstrup A.M.
      • Toft G.
      • Ramlau-Hansen C.H.
      • Bonde J.P.
      Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Comment.
      ,
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ,
      • Gutorova N.V.
      • Kleshchyov M.A.
      • Tipisova E.V.
      • Osadchuk L.V.
      Effects of overweight and obesity on the spermogram values and levels of reproductive hormones in the male population of the European north of Russia.
      ,
      • Jokela M.
      • Elovainio M.
      • Kivimaki M.
      Lower fertility associated with obesity and underweight: the US National Longitudinal Survey of Youth.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Linabery A.M.
      • Nahhas R.W.
      • Johnson W.
      • Choh A.C.
      • Towne B.
      • Odegaard A.O.
      • Czerwinski S.A.
      • Demerath E.W.
      Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study.
      ,
      • Nguyen R.H.
      • Wilcox A.J.
      • Skjaerven R.
      • Baird D.D.
      Men's body mass index and infertility.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sorensen T.I.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      ) (Table 1).
      Figure thumbnail rbmo1415-fig-0001
      Figure 1Study identification and selection.
      Table 1Characteristics of included studies.
      StudyMethodsParticipants (sample size)ObeseNormal weightStudy authors' conclusionQuality
      • Aggerholm A.S.
      • Thulstrup A.M.
      • Toft G.
      • Ramlau-Hansen C.H.
      • Bonde J.P.
      Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Comment.
      Cross-sectionalParticipants had no vasectomy, known azoospermia or abnormalities of the reproductive organs (2139)BMI >30BMI 20.0–25.0Reduction in semen quality, if any, was marginal and below the detection limit of this study5/9
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      Cross-sectionalIVF patients. No significant symptoms of andrologic dysfunction (315)BMI >30BMI 20–24.9Increased paternal BMI is associated with decreased blastocyst development, clinical pregnancy rates and live birth outcomes6/9
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      Cross-sectionalMale partners of subfertile couples (483)BMI 30–34.9BMI 18.5–24.9Obesity was associated with increased sperm DNA damage, morbid obesity was associated with lower sperm count6/9
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      Cross-sectionalMale partners from couples undergoing ART, aged 18–55 without a history of vasectomy (114)BMI ≥30BMI 18.5–24.9Data suggest a possible deleterious effect of male obesity on the odds of having a live birth among couples undergoing ICSI6/9
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      Cross-sectionalMale partners of infertile couples. No known cause of spermatogenic failure or obstruction, retrograde ejaculate, obstructive azoospermia, Y chromosome deletion, or chromosomal abnormalities associated with infertility (1401)BMI >30BMI 20–25Semen quality was not statistically significantly affected by BMI in a cohort of male partners in subfertile couples5/9
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      Cross-sectionalMale partners of subfertile couples (330)BMI ≥30BMI 18.5–24.9Male obesity is associated with an increased risk of sperm DNA damage and lower sperm motility and thus reduced sperm quality5/9
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      Cross-sectionalCouples recruited from two different states where the male was 18 + and the female was 18–44 with no physician diagnosed infertility (501)BMI 30–34.9BMI <25.0The report suggests there is an inverse relationship between adiposity and sperm production6/9
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      Cross-sectionalMen presenting for semen analysis (305)BMI ≥30BMI <25Increased BMI values are associated with decreased mitochondrial activity and progressive motility and increased DNA damage7/9
      • Gutorova N.V.
      • Kleshchyov M.A.
      • Tipisova E.V.
      • Osadchuk L.V.
      Effects of overweight and obesity on the spermogram values and levels of reproductive hormones in the male population of the European north of Russia.
      Cross-sectionalVolunteers aged 23–58 years without acute disease or exacerbation of a chronic disease or STI (99)BMI ≥30.118.5 ≤ BMI < 25Higher spermatogenesis values were observed in men with excessive body weight versus men with normal body weight or obesity6/9
      • Hammiche F.
      • Laven J.S.
      • Twigt J.M.
      • Boellaard W.P.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.
      Cross-sectionalMale partners of subfertile couples (450)BMI ≥30BMI <25Sperm concentration and total motile sperm count in men of subfertile couples are detrimentally affected by a high BMI and cen=tral adiposity6/9
      • Hammoud A.O.
      • Wilde N.
      • Gibson M.
      • Parks A.
      • Carrell D.T.
      • Meikle A.W.
      Male obesity and alteration in sperm parameters.
      Cross-sectionalInfertility patients (472)BMI ≥30BMI <25Male obesity is associated with increased incidence of low sperm concentration and low progressively motile sperm count6/9
      • Jokela M.
      • Elovainio M.
      • Kivimaki M.
      Lower fertility associated with obesity and underweight: the US National Longitudinal Survey of Youth.
      LongitudinalA representative sample of Americans born between 1957 and 1974 (12,073)BMI >3018.5 ≤ BMI ≤ 24.9Obesity may be an important risk factor for infertility7/9
      • Keltz J.
      • Zapantis A.
      • Jindal S.K.
      • Lieman H.J.
      • Santoro N.
      • Polotsky A.J.
      Overweight Men: clinical pregnancy after ART is decreased in IVF but not in ICSI cycles.
      Cross-sectionalART patients (290 cycles)BMI ≥30BMI 18.1–24.9Overweight decreases clinical pregnancy4/9
      • Koloszar S.
      • Fejes I.
      • Zavaczki Z.
      • Daru J.
      • Szollosi J.
      • Pal A.
      Effect of body weight on sperm concentration in normozoospermic males.
      Cross-sectionalNormozoospermic patients attending an infertility clinic, no organic alterations of reproductive organs, no pathogenic bacteria or fungi (290)BMI 30.1–39BMI 20.1–25Obesity is associated with a lower sperm count in cases of normozoospermia6/9
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • Roudebush W.E.
      Impact of body mass index values on sperm quantity and quality.
      Cross-sectionalNormal healthy men aged 26–45 years, no previous surgery (520)BMI >30BMI 20–24Men present with BMI greater than 25 have fewer chromatin-intact normal-motile sperm cells per ejaculate4/9
      • Linabery A.M.
      • Nahhas R.W.
      • Johnson W.
      • Choh A.C.
      • Towne B.
      • Odegaard A.O.
      • Czerwinski S.A.
      • Demerath E.W.
      Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study.
      LongitudinalEuropean–American parents of infants enrolled in utero in the Fels longitudinal study (890)BMI ≥30BMI <25Infants of obese fathers had BMI growth curves distinct from those of normal weight fathers8/9
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      Cross-sectionalMale partners of infertile couples (222)BMI ≥30BMI 18.5–24.9Higher BMI and BMI class positively correlate with s-IL8, a reliable surrogate marker of prostate inflammatory disease6/9
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      Cross-sectionalMen presenting for semen analysis for any reason at participating fertility clinics, without definitive pathological conditions likely to affect sperm quality (511)BMI ≥30BMI 18.5–24.99The strength and consistency of the results of this study add to the growing evidence that any relationship between BMI and the semen parameters assessed in routine semen analysis, if present, is marginal5/9
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      Cross-sectionalMale partners of infertile couples (794)BMI 30–5018.5 ≤ BMI < 25Results support a deleterious effect of obesity on seminal quality, probably by alterations in the function of the epididymis6/9
      • Nguyen R.H.
      • Wilcox A.J.
      • Skjaerven R.
      • Baird D.D.
      Men's body mass index and infertility.
      LongitudinalPregnant couples between 1999 and 2005 where the woman was a native Norwegian speaker, living with the father of the child aged between 18 and 40 (26,303)BMI ≥3020 ≤ BMI ≤ 24.99Male adiposity is associated with increased infertility7/9
      • Pacey A.A.
      • Povey A.C.
      • Clyma J.A.
      • McNamee R.
      • Moore H.D.
      • Baillie H.
      • Cherry N.M.
      Modifiable and non-modifiable risk factors for poor sperm morphology.
      Cross-sectionalMale patients who visited a fertility clinic, a gynaecology clinic, an andrology laboratory, or made an appointment for a semen analysis and had been attempting conception for 12 months (1970)BMI >30BMI 18.5–24.99An individual's lifestyle has very little impact on sperm morphology6/9
      • Petersen G.L.
      • Schmidt L.
      • Pinborg A.
      • Kamper-Jorgensen M.
      The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.
      Cross-sectionalCouples receiving ART (12,566)BMI ≥30BMI 18.5–24.9Increased male BMI negatively influenced live birth after IVF treatments. With ICSI the association with BMI was less clear6/9
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sorensen T.I.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      LongitudinalCouples, excluding couples where the woman had a disease that could impact her BMI or fecundity (47,835)BMI ≥3018.5 ≤ BMI ≤ 24.99Couples have a high risk of being subfecund if they are both obese6/9
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      Cross-sectionalGeneral population. No chronic disease, genital disease, heavy smoking or regular alcohol consumption (990)BMI ≥30.0BMI 18.5–24.9The association between BMI and semen quality was found to be statistically significant even after adjusting for reproductive hormones6/9
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      Cross-sectionalCouples who had tried for 12 months or more to achieve pregnancy without success (153)BMI >30BMI <24.9The impact of elevated BMI on the parameters investigated (basic semen parameters, chromatin integrity and chromatin condensation) was not proven in this study4/9
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      Cross-sectionalCouples undergoing first fresh IVF cycles. Men with nonobstructive azoospermia were excluded (721)BMI ≥30BMI ≤24.99There was no overall association of male and female BMI, individually or in combination, with IVF success after taking into account several important confounding factors, such as male and female age, partner BMI and parity7/9
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      Cross-sectionalMale partners of couples attending an infertility clinic. No vasectomy surgery or azoospermia (2035)BMI >30BMI 18.5–24.99Obese men are more likely to have lower semen volume and fewer morphologically normal spermatozoa than men with normal BMI5/9
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      Cross-sectionalMen presenting for fertility assessment (81)BMI >30BMI 20–25Oxidative stress increased with increasing BMI as well as sperm concentration5/9
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      Cross-sectionalFresh ICSI cycles with autologous oocytes (155)BMI ≥ 30BMI 20–24.9Increasing paternal BMI has a negative influence on ICSI success, including clinical pregnancy rate and live birth rate6/9
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      Cross-sectionalGeneral population, healthy non-smoking (150)BMI 30.1–44.0BMI 19.0–24.9Healthy non-smoking obese men have worse conventional and nonconventional sperm parameters than normal weight controls7/9
      ART = assisted reproduction technology; BMI = body mass index (kg/m2); ICSI = intracytoplasmic sperm injection; STI = sexually transmitted infection.

       Fertility

       Likelihood of infertility

      Two studies were included in the meta-analysis of the effect of male obesity on the likelihood of a couple being infertile (failing to conceive after two or more years) (
      • Nguyen R.H.
      • Wilcox A.J.
      • Skjaerven R.
      • Baird D.D.
      Men's body mass index and infertility.
      ,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sorensen T.I.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      ). Couples with an obese male partner were found to be statistically significantly more likely to experience infertility than couples with a normal weight male (OR = 1.66, 95% CI 1.53–1.79, Supplementary Figure S1). Heterogeneity was non-significant and the fixed effects model was used. Another study investigated the relationship between being obese as a young adult (17 to 24 years) and the likelihood of having a child by 47 years (
      • Jokela M.
      • Elovainio M.
      • Kivimaki M.
      Lower fertility associated with obesity and underweight: the US National Longitudinal Survey of Youth.
      ). Men who were obese as young adults had an unadjusted risk ratio (RR) of having a child of 0.75 compared with normal weight men (95% CI 0.66–0.84), or (RR = 0.78, 95% CI 0.69–0.88) when data were adjusted for marital status.

       In-vitro embryo development

      Three studies reported on the effects of male partner obesity on embryo development (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ), but a meta-analysis could not be performed as none of the studies had outcomes in common. The first study found a statistically significant linear decrease in on-time and expanded blastocyst development with increasing BMI, but no significant differences for percentage of grade 1 or grade 2 embryos on day 3 (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ). In the second study embryo development was assessed as poor quality, accelerated cleavage, and slow cleavage on day 3 for 149 cycles. However, no significant differences were found between normal weight and obese men (
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ). In the final study, no difference was found between normal weight and obese (or morbidly obese) men for the percentage of day 5 embryos that were scored as highest quality (
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ).

       Clinical pregnancy from ART

      Five studies were included in the meta-analysis of the effect of male obesity on the OR of couples undergoing assisted reproduction technology (ART; IVF or intracytoplasmic sperm injection [ICSI]) achieving a clinical pregnancy (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ,
      • Keltz J.
      • Zapantis A.
      • Jindal S.K.
      • Lieman H.J.
      • Santoro N.
      • Polotsky A.J.
      Overweight Men: clinical pregnancy after ART is decreased in IVF but not in ICSI cycles.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ). Clinical pregnancy rates were reported as: heartbeat detected per oocyte retrieval (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ), ultrasound confirmation (giving no further details) per embryo transfer cycle (
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ), intrauterine gestational sac on transvaginal sonogram per cycle (
      • Keltz J.
      • Zapantis A.
      • Jindal S.K.
      • Lieman H.J.
      • Santoro N.
      • Polotsky A.J.
      Overweight Men: clinical pregnancy after ART is decreased in IVF but not in ICSI cycles.
      ), heartbeat detected per ICSI cycle (
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), and gestational sac and/or clinical recording of heartbeat (or documentation of birth or termination) per cycle (
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ). As
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      only presented data as OR, a meta-analysis was performed using the inverse variance method. Although Colaci et al. presented OR adjusted for maternal BMI and unadjusted OR the other four studies only presented unadjusted OR. As such, the unadjusted value was used in all cases to protect the homogeneity of the data. A non-statistically significant decrease in clinical pregnancy success rate was found for obese men compared with normal weight men (OR = 0.68, 95% CI 0.40–1.14, Figure 2). As data were significantly heterogeneous (P = 0.02) the random effects model was used.
      Figure thumbnail rbmo1415-fig-0002
      Figure 2Meta-analysis of the effect of obesity on the likelihood of clinical pregnancy from ART.

       Live birth from ART

      Five studies were included in the meta-analysis of the effect of male obesity on the OR of couples undergoing ART (IVF or ICSI) achieving a live birth (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ,
      • Petersen G.L.
      • Schmidt L.
      • Pinborg A.
      • Kamper-Jorgensen M.
      The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ). Live birth rate was reported according to: oocyte retrieval (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ), embryo transfer cycle (
      • Colaci D.S.
      • Afeiche M.
      • Gaskins A.J.
      • Wright D.L.
      • Toth T.L.
      • Tanrikut C.
      • Hauser R.
      • Chavarro J.E.
      Men's body mass index in relation to embryo quality and clinical outcomes in couples undergoing in vitro fertilization.
      ), treatment cycle (
      • Petersen G.L.
      • Schmidt L.
      • Pinborg A.
      • Kamper-Jorgensen M.
      The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.
      ), ICSI cycle (
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), and IVF cycle (
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ). For the same reasons as above the inverse variance method was used to meta-analyse unadjusted data. A statistically significant decrease in live birth success rate was found for obese men compared with normal weight men (OR = 0.65, 95% CI 0.44–0.97, Figure 3). Heterogeneity was non-significant and the fixed effects model was used. Additionally, for three studies (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • Hotaling J.M.
      • Carrell D.T.
      • Link M.
      • Hinkle S.N.
      • Kissell K.
      • Porucznik C.A.
      • Hammoud A.O.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), data were available that enabled the investigation of the difference between pregnancy rate (detection of a gestational sac) and live birth rate. It was found that the odds of having a non-viable pregnancy (pregnancy that did not result in a live birth) were significantly greater for couples with an obese male partner compared with normal weight partner (OR = 2.87, 95% CI 1.34–6.13, Supplementary Figure S2A), with an absolute risk difference of 10% (95% CI 3–18%, Supplementary Figure S2B). Heterogeneity was non-significant and the fixed effects model was used.
      Figure thumbnail rbmo1415-fig-0003
      Figure 3Meta-analysis of the effect of obesity on the likelihood of live birth from ART.

       Infant development

      The one study that was found that met the inclusion criteria and investigated the effect of paternal obesity on offspring development found that paternal obesity significantly altered infant BMI growth curves from birth to 3.5 years compared with normal weight fathers (P = 0.005) (
      • Linabery A.M.
      • Nahhas R.W.
      • Johnson W.
      • Choh A.C.
      • Towne B.
      • Odegaard A.O.
      • Czerwinski S.A.
      • Demerath E.W.
      Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study.
      ). This effect was still present after adjusting for maternal BMI (P = 0.02). Looking only at weight or length, the effect of paternal BMI did not reach significance. However, when the results were adjusted for maternal BMI the difference in offspring length between obese fathers and normal weight fathers was significant (P = 0.05).

       Conventional semen characteristics

       Sperm concentration

      Thirteen studies, nine of which were carried out in the clinical ART population (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • Hammiche F.
      • Laven J.S.
      • Twigt J.M.
      • Boellaard W.P.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ) and four in the general population (
      • Aggerholm A.S.
      • Thulstrup A.M.
      • Toft G.
      • Ramlau-Hansen C.H.
      • Bonde J.P.
      Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Comment.
      ,
      • Gutorova N.V.
      • Kleshchyov M.A.
      • Tipisova E.V.
      • Osadchuk L.V.
      Effects of overweight and obesity on the spermogram values and levels of reproductive hormones in the male population of the European north of Russia.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ), were included in the meta-analysis of the effect of male obesity on mean sperm concentration. An additional four studies were found that presented data in values that could not be incorporated into the meta-analysis (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ,
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ,
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      ). Due to the presence of significant heterogeneity the random effects model was used in the meta-analysis. No significant differences were found for sperm concentration overall or in either of the subgroups (Supplementary Figure S3).

       Normal morphology

      Nine studies were included in the meta-analysis of the effect of male obesity on the percentage of sperm with normal morphology (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ).
      Seven assessed morphology by World Health Organization (WHO) criteria (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), while two used Kruger's criteria (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ). Among the WHO studies five were conducted in the clinical ART population (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ), and two were conducted in the general population (
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ) (Supplementary Figure S4). Both of the studies that used Kruger's criteria were conducted in the clinical ART population (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ). An additional five studies were found that presented data in values that could not be incorporated in the meta-analysis (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ,
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ,
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      ,
      • Pacey A.A.
      • Povey A.C.
      • Clyma J.A.
      • McNamee R.
      • Moore H.D.
      • Baillie H.
      • Cherry N.M.
      Modifiable and non-modifiable risk factors for poor sperm morphology.
      ). Due to heterogeneity the random effects model was used in the meta-analysis of the WHO criteria studies, and a non-significant decrease in the percentage of sperm with normal morphology was found for obese men compared with normal weight men (Supplementary Figure S4). However, when analysis was restricted to the clinical ART population the decrease was statistically significant (WMD = −2.08%, 95% CI −3.25 to −0.92, Supplementary Figure S4). When Kruger's criteria studies were meta-analysed the results showed no significant difference (Supplementary Figure S5). Heterogeneity was non-significant and the fixed effects model was used.

       Progressive motility

      Twelve studies, nine of which were carried out in the clinical ART population (
      • Bakos H.W.
      • Henshaw R.C.
      • Mitchell M.
      • Lane M.
      Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
      ,
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • Hammiche F.
      • Laven J.S.
      • Twigt J.M.
      • Boellaard W.P.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ,
      • Umul M.
      • Kose S.A.
      • Bilen E.
      • Altuncu A.G.
      • Oksay T.
      • Guney M.
      Effect of increasing paternal body mass index on pregnancy and live birth rates in couples undergoing intracytoplasmic sperm injection.
      ) and three in the general population (
      • Gutorova N.V.
      • Kleshchyov M.A.
      • Tipisova E.V.
      • Osadchuk L.V.
      Effects of overweight and obesity on the spermogram values and levels of reproductive hormones in the male population of the European north of Russia.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ), were included in the meta-analysis of the effect of male obesity on the mean percentage of sperm in ejaculate that were progressively motile. Five additional studies could not be included in the meta-analysis due to data incompatibilities (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ,
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ,
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • Roudebush W.E.
      Impact of body mass index values on sperm quantity and quality.
      ,
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      ). Due to the presence of significant heterogeneity the random effects model was used in the meta-analyses, which showed a small but significant decrease in motility for obese men overall (WMD = −3.72%, 95% CI −7.11 to −0.33), with a non-significant trend for a decrease in the clinical population (Supplementary Figure S6). A potentially larger decrease was found in the general population; however, due to greater variance the effect was not significant.

       Ejaculate volume

      Ten studies, seven of which were carried out in the clinical ART population (
      • Duits F.H.
      • Van Wely M.
      • Van Der Veen F.
      • Gianotten J.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      ,
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • Hammiche F.
      • Laven J.S.
      • Twigt J.M.
      • Boellaard W.P.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Body mass index and central adiposity are associated with sperm quality in men of subfertile couples.
      ,
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ,
      • Shayeb A.G.
      • Harrild K.
      • Mathers E.
      • Bhattacharya S.
      An exploration of the association between male body mass index and semen quality.
      ) and three in the general population (
      • Gutorova N.V.
      • Kleshchyov M.A.
      • Tipisova E.V.
      • Osadchuk L.V.
      Effects of overweight and obesity on the spermogram values and levels of reproductive hormones in the male population of the European north of Russia.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Qin D.D.
      • Yuan W.
      • Zhou W.J.
      • Cui Y.Q.
      • Wu J.Q.
      • Ga E.S.
      Do reproductive hormones explain the association between body mass index and semen quality?.
      ), were included in the meta-analysis of the effect of male obesity on mean ejaculate volume. An additional three studies were found that presented data in values that could not be incorporated in the meta-analysis (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ,
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      ). Due to the presence of heterogeneity the random effects model was used in the meta-analyses which showed no significant differences in ejaculate volume for obese men overall or in the subgroup analyses (Supplementary Figure S7).

       Additional semen characteristics

       Sperm DNA fragmentation

      Four studies were included in the meta-analysis of the effect of male obesity on the percentage of sperm with DNA fragmentation (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ). Two studies assessed DNA fragmentation by TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL) staining (
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ), one used the sperm chromatin structure assay (SCSA) (
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ), and the fourth used the comet assay (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ). An additional study by Kort et al. assessed DNA fragmentation by the SCSA but did not provide population sizes (
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • Roudebush W.E.
      Impact of body mass index values on sperm quantity and quality.
      ). Chavarro et al. used the comet assay but presented data in median values (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ). Dupont et al. used TUNEL but presented data as median values and mean differences (
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ). Eisenberg et al. utilized the SCSA but presented data as median and dichotomized values (
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ). A statistically significant increase in the percentage of sperm with DNA fragmentation was found for obese men compared with normal weight men (WMD = 3.41%, 95% CI 2.08–4.75, Supplementary Figure S8). Heterogeneity between studies was non-significant, supporting the idea that although diverse methods were used to assess DNA fragmentation the effect being measured was the same, and meta-analysis was therefore appropriate (additional sensitivity analysis showed that the significant effect was retained when the random effects model was applied, and when the SMD method of meta-analysis was used, data not shown). Three of the studies that could not be included in the meta-analysis reported statistically significant increases in sperm with DNA fragmentation in obese compared with normal weight men (
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • Meeker J.D.
      • Hauser R.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      ,
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • Boubaya M.
      • Eustache F.
      • Clement P.
      • Briot P.
      • Berthaut I.
      • Levy V.
      • Cedrin-Durnerin I.
      • Benzacken B.
      • Chavatte-Palmer P.
      • Levy R.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      ,
      • Kort H.I.
      • Massey J.B.
      • Elsner C.W.
      • Mitchell-Leef D.
      • Shapiro D.B.
      • Witt M.A.
      • Roudebush W.E.
      Impact of body mass index values on sperm quantity and quality.
      ), while the fourth found no significant difference in median percentage DNA fragmentation (
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • Sundaram R.
      • Schisterman E.F.
      • Buck Louis G.M.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      ).

       Sperm chromatin condensation

      Three studies contained data on the effect of male obesity on the percentage of sperm with decondensed chromatin (
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ). One assessed chromatin condensation by propidium iodide staining and found a statistically significant increase in the percentage of spermatozoa with decondensed chromatin in obese men compared with normal weight men (
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ), another used aniline blue staining and found a statistically non-significant increase (
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ), and the third used the SCSA and found a statistically non-significant decrease (
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • Markova P.
      • Rubes J.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      ). Due to the diversity of methods of staining and results obtained, meta-analysis was not undertaken.

       Sperm with low mitochondrial membrane potential

      Two studies were found that reported the percentage of sperm with low MMP for obese men compared with normal weight men (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ,
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ). In one study, MMP was assessed by JC1 staining (
      • La Vignera S.
      • Condorelli R.A.
      • Vicari E.
      • Calogero A.E.
      Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters.
      ), and it was demonstrated that the percentage of sperm in the ejaculate of obese men that had low MMP was statistically significantly increased compared with normal weight men. In the other deposition of DAB (diaminobenzidine) was used as a measure (
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • Cedenho A.P.
      • Bertolla R.P.
      • Fraietta R.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      ), and it was demonstrated that both the percentage of sperm with low MMP and the percentage of sperm with no MMP was statistically significantly increased in obese men compared with normal weight men. Due to the presence of heterogeneity and differences in how data were reported, the random effects model was used to assess standardized mean difference (SMD). A statistically significant increase in the percentage of sperm with low MMP was found for obese men compared with normal weight men (SMD = 0.91, 95% CI 0.30–1.53, Supplementary Figure S9).

       Seminal plasma factors

      Three papers reported on the effects of male obesity on the concentrations of different seminal plasma factors (
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ,
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ). However, each paper investigated different factors. As such, meta-analysis was not undertaken.
      In Tunc et al., a statistically significant positive correlation was found for increasing concentration of neopterin in seminal plasma and increasing BMI (
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ). In the study by Lotti et al., being obese was correlated with a statistically significantly increased concentration of interleukin-8 in seminal plasma compared with normal weight men (
      • Lotti F.
      • Corona G.
      • Colpi G.M.
      • Filimberti E.
      • Degli Innocenti S.
      • Mancini M.
      • Baldi E.
      • Noci I.
      • Forti G.
      • Adorini L.
      • Maggi M.
      Elevated body mass index correlates with higher seminal plasma interleukin 8 levels and ultrasonographic abnormalities of the prostate in men attending an andrology clinic for infertility.
      ). Martini et al. found a statistically significant negative correlation between increasing BMI and the seminal plasma concentration of alpha-glucosidase as well as a statistically significant positive correlation between BMI and seminal plasma concentration of fructose (
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • Molina R.I.
      • Mangeaud A.
      • De Cuneo M.F.
      • Ruiz R.D.
      Overweight and seminal quality: a study of 794 patients.
      ). Differences for citric acid were not statistically significant.

      Discussion

      The meta-analyses performed in this systematic review have provided clear evidence that human paternal obesity negatively affects reproductive potential, as shown by significantly reduced fertility in the general population and reduced rates of live birth from ART, as well as increased rates of nonviable pregnancy. A non-significant decrease in rate of clinical pregnancy from ART was also found, which requires additional studies for firm conclusions to be drawn. To the authors' knowledge this systematic review is the first instance where these primary fertility outcomes have been assessed by meta-analysis to demonstrate the negative effect that male obesity has on reproduction. Unfortunately, the majority of studies meta-analysed did not present values adjusted for maternal BMI, leaving open the possibility that these findings could be influenced by assortative mating. Additionally, these findings are based on observational research, and therefore show correlation and not causation. However, that paternal obesity is responsible for decreased fertility is supported by experimental studies performed in animal models (
      • Fullston T.
      • Ohlsson Teague E.M.
      • Palmer N.O.
      • Deblasio M.J.
      • Mitchell M.
      • Corbett M.
      • Print C.G.
      • Owens J.A.
      • Lane M.
      Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content.
      ,
      • Mitchell M.
      • Bakos H.W.
      • Lane M.
      Paternal diet-induced obesity impairs embryo development and implantation in the mouse.
      ). Furthermore, there is evidence from both animal and human models that improving the metabolic health of obese males (through exercise and/or controlled diet) can improve fertility (
      • Faure C.
      • Dupont C.
      • Baraibar M.A.
      • Ladouce R.
      • Cedrin-Durnerin I.
      • Wolf J.P.
      • Levy R.
      In subfertile couple, abdominal fat loss in men is associated with improvement of sperm quality and pregnancy: a case-series.
      ,
      • Hakonsen L.B.
      • Thulstrup A.M.
      • Aggerholm A.S.
      • Olsen J.
      • Bonde J.P.
      • Andersen C.Y.
      • Bungum M.
      • Ernst E.H.
      • Hansen M.L.
      • Ernst E.H.
      • Ramlau-Hansen C.H.
      Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men.
      ,
      • McPherson N.O.
      • Bakos H.W.
      • Owens J.A.
      • Setchell B.P.
      • Lane M.
      Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth.
      ).
      The physiological cause of the reduction in reproductive potential found by this review is less clear, with the conventional semen parameters ejaculate volume and concentration showing no statistically significant differences between obese and normal weight men, while the difference found for motility was small. This supports the previous findings of
      • MacDonald A.A.
      • Herbison G.P.
      • Showell M.
      • Farquhar C.M.
      The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis.
      , who found no significant association between paternal obesity and mean sperm count, motility and ejaculate volume. It should be noted that sperm concentration is known to have a highly skewed distribution, which may make WMD a suboptimal measure. Supporting this, in a recent meta-analysis where the authors had access to the primary data of all included studies and could classify participants as normospermic, oligospermic or azoospermic, it was shown that obese men were significantly more likely to be oligo- or azoospermic (
      • Sermondade N.
      • Faure C.
      • Fezeu L.
      • Shayeb A.G.
      • Bonde J.P.
      • Jensen T.K.
      • Van Wely M.
      • Cao J.
      • Martini A.C.
      • Eskandar M.
      • Chavarro J.E.
      • Koloszar S.
      • Twigt J.M.
      • Ramlau-Hansen C.H.
      • Borges Jr., E.
      • Lotti F.
      • Steegers-Theunissen R.P.
      • Zorn B.
      • Polotsky A.J.
      • La Vignera S.
      • Eskenazi B.
      • Tremellen K.
      • Magnusdottir E.V.
      • Fejes I.
      • Hercberg S.
      • Levy R.
      • Czernichow S.
      BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis.
      ). However, there were semen parameters reported on in this systematic review that did show significant differences; normal morphology, DNA fragmentation and low MMP were all negatively impacted by paternal obesity. The loss of mitochondrial membrane potential and increased DNA fragmentation in spermatozoa are associated with high concentrations of reactive oxygen species (ROS) (
      • Wang X.
      • Sharma R.K.
      • Gupta A.
      • George V.
      • Thomas A.J.
      • Falcone T.
      • Agarwal A.
      Alterations in mitochondria membrane potential and oxidative stress in infertile men: a prospective observational study.
      ,
      • Zribi N.
      • Chakroun N.F.
      • Elleuch H.
      • Abdallah F.B.
      • Ben Hamida A.S.
      • Gargouri J.
      • Fakhfakh F.
      • Keskes L.A.
      Sperm DNA fragmentation and oxidation are independent of malondialdheyde.
      ). High ROS concentrations have been associated with reduced fertilization and impaired embryonic development (
      • Dada R.
      • Shamsi M.B.
      • Venkatesh S.
      • Gupta N.P.
      • Kumar R.
      Attenuation of oxidative stress and DNA damage in varicocelectomy: implications in infertility management.
      ,
      • Gharagozloo P.
      • Aitken R.J.
      The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy.
      ,
      • Tunc O.
      • Thompson J.
      • Tremellen K.
      Development of the NBT assay as a marker of sperm oxidative stress.
      ,
      • Zribi N.
      • Chakroun N.F.
      • Elleuch H.
      • Abdallah F.B.
      • Ben Hamida A.S.
      • Gargouri J.
      • Fakhfakh F.
      • Keskes L.A.
      Sperm DNA fragmentation and oxidation are independent of malondialdheyde.
      ), and have consistently been shown to increase with obesity (
      • Bakos H.W.
      • Mitchell M.
      • Setchell B.P.
      • Lane M.
      The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model.
      ,
      • Hirao K.
      • Maruyama T.
      • Ohno Y.
      • Hirose H.
      • Shimada A.
      • Takei I.
      • Murata M.
      • Morii T.
      • Eguchi T.
      • Hayashi M.
      • Saruta T.
      • Itoh H.
      Association of increased reactive oxygen species production with abdominal obesity in type 2 diabetes.
      ,
      • Tunc O.
      • Bakos H.W.
      • Tremellen K.
      Impact of body mass index on seminal oxidative stress.
      ). Importantly, ROS concentrations and DNA fragmentation are also associated with pregnancy loss (
      • Dada R.
      • Shamsi M.B.
      • Venkatesh S.
      • Gupta N.P.
      • Kumar R.
      Attenuation of oxidative stress and DNA damage in varicocelectomy: implications in infertility management.
      ,
      • Gharagozloo P.
      • Aitken R.J.
      The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy.
      ,
      • Imam S.N.
      • Shamsi M.B.
      • Kumar K.
      • Deka D.
      • Dada R.
      Idiopathic recurrent pregnancy loss: role of paternal factors; a pilot study.
      ) and therefore could be the cause of the increased frequency of non-viable pregnancies found for obese men in this meta-analysis. Findings for DNA fragmentation were the strongest as the meta-analysis was based on four studies, with an additional three studies similarly reporting significant increases in DNA fragmentation with paternal obesity. This has potential clinical implications as a case series study found that overweight and obese men from couples with idiopathic infertility and high sperm DNA fragmentation who undertook a weight loss intervention had reduced rates of DNA fragmentation and all subsequently conceived spontaneously or with minimal assistance (intrauterine insemination) (
      • Faure C.
      • Dupont C.
      • Baraibar M.A.
      • Ladouce R.
      • Cedrin-Durnerin I.
      • Wolf J.P.
      • Levy R.
      In subfertile couple, abdominal fat loss in men is associated with improvement of sperm quality and pregnancy: a case-series.
      ). The finding that paternal obesity was associated with decreased normal morphology was only made in the clinical population when morphology was assessed by WHO criteria. When studies were carried out in the general population, or using Kruger's criteria, the difference in mean sperm morphology for obese and normal weight men became non-significant. As there were only two included studies that assessed sperm morphology in the general population or that used Kruger's criteria, these findings require further investigation before firm conclusions can be made. Interestingly, a study on weight loss carried out in obese men found that sperm morphology was significantly improved in men with the greatest weight loss (
      • Hakonsen L.B.
      • Thulstrup A.M.
      • Aggerholm A.S.
      • Olsen J.
      • Bonde J.P.
      • Andersen C.Y.
      • Bungum M.
      • Ernst E.H.
      • Hansen M.L.
      • Ernst E.H.
      • Ramlau-Hansen C.H.
      Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men.
      ). Finally, the percentage of sperm with low MMP increased with paternal obesity. This finding was based on only two studies, but both reported statistically significant effects. As such, it is relatively unlikely that further replication will alter the conclusion that paternal obesity is associated with increased rates of sperm with low MMP. These findings suggest that the reduced reproductive potential that has been shown to be associated with paternal obesity may be mediated by increased rates of sperm with DNA fragmentation, abnormal morphology and low MMP. This suggests that the assessment of conventional semen parameters typically carried out in fertility clinics may be insufficient to detect the cause of some obese men's failure to conceive. As such, it may be useful for pathology laboratories to incorporate DNA fragmentation analysis and/or MMP assessment into their semen testing regimen, especially for obese men whose semen analyses otherwise suggest they should have normal fertility.
      The main strength of this systematic review is its numerous novel findings. It is not only the first review to use meta-analysis to investigate the relationship between paternal obesity and primary reproductive outcomes (fertility, clinical pregnancy after ART, live birth after ART, and pregnancy viability), it is also the first systematic review to go beyond conventional semen parameters and meta-analyse sperm morphology, DNA fragmentation, and low MMP.
      One limitation of the current review was the high degree of heterogeneity that existed between studies for many measures – which necessitated the use of the random effects model for many meta-analyses and reduced statistical power. Although heterogeneity between observational studies is expected, it is still interesting and suggests differences in the conduct of individual studies. Furthermore, for several outcomes – seminal plasma factors, sperm chromatin condensation and embryo development – meta-analysis could not be performed owing to the included studies not reporting comparable data. Additionally, only one study was found which met the inclusion criteria and reported on the effect of paternal obesity on infant development (
      • Linabery A.M.
      • Nahhas R.W.
      • Johnson W.
      • Choh A.C.
      • Towne B.
      • Odegaard A.O.
      • Czerwinski S.A.
      • Demerath E.W.
      Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study.
      ). As the health of the next generation is of the utmost importance, this is a key limitation, especially as the potential for paternal obesity to influence development beyond fertilization is strongly indicated by the increased rate of non-viable pregnancy that has been found.
      In conclusion, this systematic review has demonstrated that the reproductive potential of obese men – as indicated by fertility, rate of live birth from ART, and pregnancy viability – is reduced relative to that of normal weight men. The data suggest that this may be due to decreased normal morphology, and increased rates of DNA damage and low MMP. If this observation is upheld by further investigation it has clinical implications for the diagnosis of infertility in obese men.

      Acknowledgements

      The authors acknowledge and thank the following for their assistance in the creation of this systematic review by providing data and clarification when contacted in relation to included articles: Francesco Lotti, Mario Maggi, Alex J. Polotsky, Julia Keltz, Gitte L. Petersen, John M. Twight, Regine P.M. Steegers, Madelon van Wely and Ozlem Tunc.

      Appendix. Supplementary material

      The following is the supplementary data to this article:

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      Biography

      Dr Jared M Campbell is an early career researcher currently working with the Joanna Briggs Institute to improve evidence-based health care. He previously undertook his PhD in embryology and has worked as a technician in an andrology laboratory.