BACKGROUND: Although spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has long been recognised as a major risk factor for miscarriage, being strongly related with fetal chromosomal abnormalities. The relation between paternal age and the risk of miscarriage is less evident, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to miscarriage. Previous meta-analyses showed associations between advanced paternal age and a broad spectrum of perinatal and paediatric outcomes. This is the first systematic review and meta-analysis on paternal age and spontaneous miscarriage.OBJECTIVE AND RATIONALE: The aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage.SEARCH METHODS: PubMed, Embase and Cochrane databases were searched to identify relevant studies up to August 2019. The following free text and MeSH terms were used: paternal age, father's age, male age, husband's age, spontaneous abortion, spontaneous miscarriage, abortion, miscarriage, pregnancy loss, fetal loss and fetal death. PRISMA guidelines for systematic reviews and meta-analysis were followed. Original research articles in English language addressing the relation between paternal age and spontaneous miscarriage were included. Exclusion criteria were studies that solely focused on pregnancy outcomes following artificial reproductive technology (ART) and studies that did not adjust their effect estimates for at least maternal age. Risk of bias was qualitatively described for three domains: bias due to confounding, information bias and selection bias.OUTCOMES: The search resulted in 975 original articles. Ten studies met the inclusion criteria and were included in the qualitative synthesis. Nine of these studies were included in the quantitative synthesis (meta-analysis). Advanced paternal age was found to be associated with an increased risk of miscarriage. Pooled risk estimates for miscarriage for age categories 30-34, 35-39, 40-44 and >= 45 years of age were 1.04 (95% CI 0.90, 1.21), 1.15 (0.92, 1.43), 1.23 (1.06, 1.43) and 1.43 (1.13, 1.81) respectively (reference category 25-29 years). A second meta-analysis was performed for the subgroup of studies investigating first trimester miscarriage. This showed similar pooled risk estimates for the first three age categories and a slightly higher pooled risk estimate for age category >= 45 years (1.74; 95% CI 1.26, 2.41).WIDER IMPLICATIONS: Over the last decades, childbearing at later ages has become more common. It is known that frequencies of adverse reproductive outcomes, including spontaneous miscarriage, are higher in women with advanced age. We show that advanced paternal age is also associated with an increased risk of spontaneous miscarriage. Although the paternal age effect is less pronounced than that observed with advanced maternal age and residual confounding by maternal age cannot be excluded, it may have implications for preconception counselling of couples comprising an older aged male.

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Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis

Sperm DNA integrity is crucial for fertilization and development of healthy offspring. The spermatozoon undergoes extensive molecular remodeling of its nucleus during later phases of spermatogenesis, which imparts compaction and protects the genetic content. Testicular (defective maturation and abortive apoptosis) and post-testicular (oxidative stress) mechanisms are implicated in the etiology of sperm DNA fragmentation (SDF), which affects both natural and assisted reproduction. Several clinical and environmental factors are known to negatively impact sperm DNA integrity. An increasing number of reports emphasizes the direct relationship between sperm DNA damage and male infertility. Currently, several assays are available to assess sperm DNA damage, however, routine assessment of SDF in clinical practice is not recommended by professional organizations. This article provides an overview of SDF types, origin and comparative analysis of various SDF assays while primarily focusing on the clinical indications of SDF testing. Importantly, we report four clinical cases where SDF testing had played a significant role in improving fertility outcome. In light of these clinical case reports and recent scientific evidence, this review provides expert recommendations on SDF testing and examines the advantages and drawbacks of the clinical utility of SDF testing using Strength-Weaknesses-Opportunities-Threats (SWOT) analysis.

Sperm DNA Fragmentation: A New Guideline for Clinicians.

We herein summarise the evidence concerning the impact of sperm DNA fragmentation in various clinical infertility scenarios and the advances on sperm DNA fragmentation tests. The collected evidence was used to formulate 41 recommendations. Of these, 13 recommendations concern technical aspects of sperm DNA fragmentation testing, including pre-analytical information, clinical thresholds and interpretation of results. The remaining 28 recommendations relate to indications for sperm DNA fragmentation testing and clinical management. Clinical scenarios like varicocele, unexplained infertility, idiopathic infertility, recurrent pregnancy loss, intrauterine insemination, in vitro fertilisation/intracytoplasmic sperm injection, fertility counselling for men with infertility risk factors and sperm cryopreservation have been contemplated. The bulk evidence supporting the recommendations has increased in recent years, but it is still of moderate to low quality. This guideline provides clinicians with advice on best practices in sperm DNA fragmentation testing. Also, recommendations are provided on possible management strategies to overcome infertility related to sperm DNA fragmentation, based on the best available evidence. Lastly, we identified gaps in knowledge and opportunities for research and elaborated a list of recommendations to stimulate further investigation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/and.13874

Sperm DNA fragmentation testing: Summary evidence and clinical practice recommendations.

Alcohol intake and cigarette smoking are the major lifestyle factors with negative impact on fertility. We were interested to evaluate the negative impact of these factors on oxidative stress (OS), enzymatic antioxidant activity (EAO) of spermatozoa and on its DNA damage. This study included 108 male infertile patients with normal range of sperm conventional parameters but with unexplained infertility in assisted reproductive technologies programme. Firstly, OS was analysed based on lipid peroxidation (MDA) and EAO which included catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR). Secondly, we evaluated DNA fragmentation by TUNEL assay and chromatin decondensation by aniline blue colouration. The whole lot was divided into four groups: control (nonalcoholic and nonsmoker patients), alcohol group, smoking group and alcohol-smoking group. The results showed, in three last groups compared to control an increased CAT, SOD and GR activities with high MDA level especially in smoking and alcohol-smoking group. The latter showed the highest values of DNA fragmentation and chromatin decondensation (31% and 39%) to exceed DNA damage normal range. Indeed, smoking and alcohol intake lead to increase EAO due to long-term unbalanced antioxidant/oxidation ratio with high OS which cause consequently sperm DNA damage calling in need by urgency to change the lifestyle behaviour.

Impact of alcohol and cigarette smoking consumption in male fertility potential: Looks at lipid peroxidation, enzymatic antioxidant activities and sperm DNA damage.

Sperm counts have shown a progressive decline across the world since the mid-1900s. Global rates of obesity have been climbing at a similarly alarming rate, suggesting that these two factors may be linked. However, studies examining the relationship between body mass index (BMI) and male fertility have produced conflicting results. These discrepancies among studies are commonly attributed to limitations that are inherent in human studies such as correlational data and confounding factors-limitations that are absent from animal studies. Hence, we conducted a systematic review and meta-analysis of animal studies that experimentally induced obesity with a high-fat diet and measured impacts on sperm traits and/or male fertility. Overall, we found strong, consistent evidence in animal studies that high-fat diets are detrimental for male fertility. Compared with controls, males fed a high-fat diet had smaller testes and sex accessory glands relative to body size, reduced semen quality, reduced mating success, and reduced fertilization success. This is the first time that experimental data of high-fat diet effects on male reproduction have been synthesized in a meta-analysis, and thus, our results provide novel insight to the complex question of how dietary-induced obesity affects male fertility. The strong negative effects detected in animal models suggest that the inconsistent results plaguing human studies are an artefact of limitations inherent in correlational studies rather than a true effect.

High-fat diets reduce male reproductive success in animal models: A systematic review and meta-analysis.

There is substantial evidence that paternal obesity is associated not only with an increased incidence of infertility, but also with an increased risk of metabolic disturbance in adult offspring. Apparently, several mechanisms may contribute to the sperm quality alterations associated with paternal obesity, such as physiological/hormonal alterations, oxidative stress, and epigenetic alterations. Along these lines, modifications of hormonal profiles namely reduced androgen levels and elevated estrogen levels, were found associated with lower sperm concentration and seminal volume. Additionally, oxidative stress in testis may induce an increase of the percentage of sperm with DNA fragmentation. The latter, relate to other peculiarities such as alteration of the embryonic development, increased risk of miscarriage, and development of chronic morbidity in the offspring, including childhood cancers. Undoubtedly, epigenetic alterations (ie, DNA methylation, chromatin modifications, and small RNA deregulation) of sperm related to paternal obesity and their consequences on the progeny are poorly understood determinants of paternal obesity-induced transmission. In this review, we summarize and discuss the data available in the literature regarding the biological, physiological, and molecular consequences of paternal obesity on male fertility potential and ultimately progeny health.

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Paternal obesity: how bad is it for sperm quality and progeny health?

INTRODUCTION Human sperm freezing is very widely used for male fertility preservation. This procedure consists in adding cryoprotectants to the spermatozoa followed by cooling and storing the spermatozoa at a subzero temperature. Many standardized cryopreservation media are available on the market. However, these media differ in their chemical composition and there are no sufficient data to optimize their classification. Therefore, the aim of this study was to compare five commercially available sperm cryopreservation media, which have not been compared together, in terms of motility, morphology and DNA integrity. MATERIALS AND METHODS One-hundred semen samples were obtained from 10 fertile participants and 90 infertile men. Each sample was evaluated before freezing for motility, morphology and DNA fragmentation index (DFI). Then, it was equally divided into five aliquots. Each aliquot was cryopreserved using one of the five media (A, B, C, D, and E). The same parameters were re-evaluated after the addition of the cryopreservation media in the fertile group, and after sperm thawing in fertile and infertile groups. RESULTS The results showed that the five selected cryopreservation media had negative effects on sperm motility and morphology per se. In the infertile group, the cryosurvival factor was significantly lower in cryomedium A when compared to the four other media (p < 0.001). In addition, a significantly higher percentage of sperm with coiled tail was detected in cryomedium E compared to cryomedium A (p < 0.05) and to cryomedium B (p < 0.001) after thawing, in the infertile group. Furthermore, the sperm DFI was significantly higher in cryomedia A (p < 0.001), B (p < 0.001), C (p < 0.01), D (p < 0.01) and E (p < 0.05) compared to that of the fresh semen derived from infertile participants. CONCLUSION This study indicates that the recovery rate of competent spermatozoa, after cryopreservation, is still critical in infertile men. Therefore, frozen semen sample should be used only when necessary.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/andr.12531

Cryopreservation media differentially affect sperm motility, morphology and DNA integrity.

Growing evidence suggests that paternal obesity may decrease male fertility potential. During infertility treatment with intra-cytoplasmic sperm injection (ICSI), a morphologically normal motile spermatozoon is injected into a mature egg, when possible. However, sperm motility and morphology per se do not reflect the sperm molecular composition. In this study, we aimed to assess the quality of motile spermatozoa in the context of obesity by analysing their conventional and molecular characteristics as well as their ability to promote early embryonic development. A prospective study was conducted on 128 infertile men divided into three groups: 40 lean, 42 overweight, and 46 obese men. Conventional sperm parameters (concentration, motility and morphology) and sperm molecular status (chromatin composition and integrity, 5-methycytosine (5-mC) and 5-hydroxycytosine (5-hmC) contents and oxidative stress level) were analysed on raw semen and/or on motile spermatozoa selected by density gradient or swim-up techniques. Morphokinetic analysis of the embryos derived from ICSI was performed using the Embryoviewer software. Our results showed that the motile sperm-enriched fraction from obese men exhibited higher levels of retained histones (p<0.001), elevated percentage of altered chromatin integrity (p<0.001), and decreased contents of 5-hmC (p<0.001), and 5-mC (p<0.05) levels as compared to that from lean men. Importantly, there were no statistically significant correlations between these molecular parameters and the percentages of morphologically normal motile spermatozoa. Regarding embryo morphokinetics, the CC1 (p<0.05) and CC3 (p<0.05) embryonic cell cycles were significantly delayed in the cleavage embryos of the obese group as compared to the embryos of the lean group. Our data is of particular interest because, besides demonstrating the negative impacts of obesity on motile spermatozoa molecular composition, it also highlights the possible risk of disturbing early embryonic cell cycles kinetics in the context of paternal obesity.

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Mira Hazzouri

Papers

Paternal obesity: how bad is it for sperm quality and progeny health?

Cryopreservation media differentially affect sperm motility, morphology and DNA integrity.

Adverse effects of paternal obesity on the motile spermatozoa quality.

High level of DNA fragmentation in sperm of Lebanese infertile men using Sperm Chromatin Dispersion test

Antioxidants modulation of sperm genome and epigenome damage: Fact or fad? Converging evidence from animal and human studies