Men contribute half of the genetics of a pregnancy and suffer alongside their partners with loss, but they are so often left out of the research, the care, and the discussions surrounding miscarriage and recurrent pregnancy loss (RPL). This has been true for all aspects of infertility and reproduction for decades and plays into society’s assumption that reproduction is female-focused (and any issues with reproduction are the woman’s fault). More recently, at medical conferences and in medical journals, men’s health is being discussed in fertility and miscarriage, so we are starting to pay more attention to the other half, finally!
With lack of interest, there is a lack of research; and the role of men’s contribution to miscarriage risk is largely unknown. Part of the problem is there is little data and focus on testing to show how men’s health and genetics could play a role in miscarriage. Testing for men is largely focused on basic testing like a semen analysis and some genetic screening, but the best way to interpret these tests remains a controversial topic.
Paternal Risk Factors of Miscarriage
The one risk factor in men that may be associated with increased risk of miscarriage is age. The assumption that men are forever fertile while women’s fertility is intimately linked to age is not entirely true. As men get older, their fertility declines (1), and some studies have shown that their risk of miscarriage increases (2) despite their female partner’s age. Other studies, however, have not shown increased miscarriage risk with advanced paternal age (3). The association of paternal age and miscarriage is controversial and under investigation. Other risk factors contributing to male infertility include obesity, chronic illness, environmental toxins, and lifestyle factors, but these have not been studied thoroughly in association with miscarriage risk for a couple.
Testing the Male Partner in a Couple with Recurrent Pregnancy Loss
Karyotype for Men
This is the only test for men having recurrent miscarriages recommended by most expert guidelines (4). It is a blood test screening for a balanced translocation within chromosomes in the male partner of the RPL couple. A balanced translocation is a rare (3% of couples with RPL) genetic imbalance that does not affect the man’s health but puts the couple at a higher than usual miscarriage risk due to a high percentage of sperm carrying genetic imbalances that can lead to failed pregnancies. Men with a balanced translocation can have healthy babies because not all of the sperm are affected but the couple will have a higher chance of recurrent miscarriages due many of the man’s sperm having genetic imbalances. If a man is found to have a balanced translocation, options include either continuing to try naturally or to screen embryos for genetic mistakes before pregnancy which requires in vitro fertilization (IVF). Women can have balanced translocations too. If a balanced translocation is found in a couple they should review results with a genetic counselor to fully understand the implications and review options with a reproductive endocrinologist (fertility specialist) for next steps.
A standard semen analysis evaluates sperm parameters such as count, motility, and morphology (shape of the sperm). This analysis is routinely used as a part of an infertility evaluation for a couple since poor parameters could explain why a couple is not getting pregnant. The role of the semen analysis in a miscarriage evaluation, however, is controversial. Couples with miscarriages are conceiving, so one can assume there is an adequate amount of functioning sperm to allow conception, but are there parameters in a semen analysis that could explain miscarriage? ASRM says ‘No’ (4), but proponents for testing cite some small studies showing poor sperm parameters in couples with otherwise unexplained RPL (5). Although a semen analysis may reveal some abnormal sperm parameters, current reports do not reveal a direct link between abnormal sperm parameters and increased risk of miscarriage. Therefore, a semen analysis is not a standard test for a couple with multiple miscarriage so review with your doctor whether it’s right for you.
Sperm Aneuploidy Testing
Sperm can be tested for chromosome imbalances (aneuploidy) using fluorescent in situ hybridization (FISH). This test estimates the percentage of sperm with chromosomal abnormalities in a sample. It is assumed that a high percentage of sperm with chromosomal imbalances in a sperm sample would put a couple at a higher risk of miscarriages from chromosomal imbalances. This argument sounds appealing, but the downsides to this testing include the following:
- Not all the sperm can be tested – using information found in a small number of sperm means estimating and assuming what may be present in the whole sample.
- Not all the chromosomes are tested – usually only five chromosomes (13, 18, 21, X, and Y) are tested, leaving no information on the other 18 chromosomes.
Some studies have shown higher sperm aneuploidy rates in couples with RPL (6), but ASRM does not recommend routine testing of sperm aneuploidy in couples with RPL (4).
A chromosome imbalance in the embryo is the most common cause of first trimester miscarriage (4). Some miscarriage genetic testing techniques reveal the parental origin of aneuploidy so that if a chromosomal imbalance is found in a miscarriage, we can identify whether the egg or the sperm made a mistake. A high percentage of chromosomally unbalanced sperm (aneuploidy) would seem to put a couple at risk for miscarriage, but one study looking at parental origin found sperm mistakes in only 7% of miscarriages tested in their sample (7). This means that in the miscarriages tested, 93% of the time the egg made the genetic mistake leading to a miscarriage from an unbalanced embryo and only 7% of the time the sperm made the mistake. The authors from this study suggest that even if a man in an RPL couple tests for high percentage of aneuploid sperm, that these sperm are likely weeded out of the selection process early, like at fertilization. If this is true, then testing for percentage of aneuploid sperm in an RPL couple may not be very helpful in counseling and guiding treatment.
A logical question from patients who read about this testing is: ‘Can we screen the sperm for chromosome imbalances before fertilization and decrease the chance of an embryo having a chromosome abnormality?’ This is an excellent question, and I wish we could; but it is not possible yet. Currently the FISH testing itself destroys the sperm, and for now, there is no technology available to screen for chromosomally normal sperm before fertilization with the egg. We can screen for chromosomal imbalances before pregnancy, but we can only screen embryos (once the egg and sperm have fertilized), and this requires in vitro fertilization (IVF).
DNA Fragmentation Testing
There are several different tests assessing DNA fragmentation in sperm, and its role in evaluation of male fertility and miscarriage is controversial. Theoretically, the higher the percentage of damaged DNA in sperm, the worse the sperm will function and the higher the risk of miscarriage. Higher percentages of DNA fragmentation have been seen in advanced paternal age, men with varicoceles (dilated veins in the scrotum), and toxic exposures, and some studies show higher DNA fragmentation in men with infertility (8), but results for men with miscarriages are inconsistent.
There are four different sperm DNA fragmentation tests:
- Sperm Chromatin Structure Assay (SCSA)
- Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick-End Labeling Assay (TUNEL)
- Comet Assay
- Sperm Chromatin Dispersion (Halo) Test
Sperm Chromatin Structure Assay (SCSA). In this test, the sperm is mixed with low pH media or heat to ‘stress’ the sperm, exposing DNA, and dye is added to the sample. The dye will attach to the fragmented DNA and not to intact DNA. A portion of the sperm (tens of thousands from the millions in the original sample) are put through a flow cytometer machine in which a beam of light shines on the DNA and transmits a wavelength from the light emitted from the samples (one wavelength for fragmented DNA and another for intact DNA). A computer calculates the totals and reports a DNA fragmentation index (DFI). In general, a DFI of less than 15% is reassuring and one greater than 30% is concerning for fertility (and possibly miscarriage) issues. The benefits of this test are that it can screen many sperm (although not all), and it has a standard protocol, which decreases variation between labs.
Terminal Deoxynucleotidyl Transferase-Mediated dUTP Nick-End Labeling (TUNEL) Assay. In this test, ‘nicks’ or free ends of DNA are detected in the sperm sample by attaching these ends to fluorescently stained nucleotides (like puzzle pieces fitting together). This allows the detection of single and double-stranded damage within the DNA. The cells can be assessed either microscopically or by flow cytometric analysis. A disadvantage of this assay is its many protocols, which make comparison between laboratories difficult.
Comet Assay. This test analyzes approximately 5000 sperm and can quantify the actual amount of DNA fragmentation per sperm. It measures more types of DNA fragmentation than the other tests (single strand breaks in DNA, double strand breaks in DNA, and sometimes altered base pairs).
Sperm Chromatin Dispersion (Halo) Test. This is a simple, inexpensive kit that measures the intact DNA in sperm. The appeal of this test is the low cost and simplicity, but studies showing its relevance to fertility and miscarriage are lacking.
The degree of efficacy of DNA fragmentation testing for couples with RPL is a controversial topic. Some studies show an association and others do not. One meta-analysis of 12 studies found that combining the findings in these multiple studies showed higher sperm DNA fragmentation in couples with RPL and suggests that this may be a cause for unexplained RPL (9). However, the studies used different assays for testing and different cut offs for considering what is normal and abnormal. Testing men in RPL couples for DNA fragmentation testing sounds appealing, but it is important to know that:
- There are several different types of tests, and they are not all equal in reproducibility, accuracy, and relevance.
- Standard ‘normal’ and ‘abnormal’ values have yet to be determined and confirmed.
- Research linking abnormal DNA fragmentation testing to miscarriage are limited to date.
Research is ongoing for DNA fragmentation, but for now, it is not a part of a routine RPL evaluation.
Epigenetics and Sperm Function
Epigenetics is the study of the impact and influence of the structures around the raw genetic content of DNA that influence which genes are used and how they function. There are some newer tests available evaluating the epigenetics and the function of sperm in relation to infertility, but this is very new and has not been studied in relation to miscarriage risk to date.
In the field of reproduction, we all want to find a way to evaluate the male partners in an RPL couple. Currently, the only expert-recommended test for men in an RPL couple is a karyotype screening for a balanced translocation. Other potential male-focused testing involves sperm tests that have been designed to evaluate male infertility, including sperm aneuploidy testing, DNA fragmentation, and epigenetics in the sperm. These sperm tests are varied, research into their prediction of miscarriage risk is conflicting, and we are left wondering, ‘What next?’
Many men in RPL couples ask for testing and are frustrated when I review what’s available. They see their female partner go through a battery of tests of anatomy, hormones, genetics, and immune system, and the men are offered very little. We review all options, and I focus on what they can do to optimize their health and support their partner.
Interventions for Men in a Couple With RPL
Testing for men with RPL is limited and its efficacy is controversial, but there are still steps men can take to improve their overall health and well-being, which may decrease the risk of miscarriage for the couple. Although research is limited on men’s role in miscarriage, lifestyle changes that can improve one’s overall health would likely improve both sperm function and DNA function.
Consider these life style modifications to improve overall well-being:
- Maintain an Ideal Weight – Obesity has been associated with poor sperm parameters and decreased fertility in men (10). Obesity impacts all areas of health, so getting to an ideal body weight in a steady, safe manner that you can maintain is an excellent goal.
- Nutrition – Eat more non-processed, fresh, organic, whole food.
- Exercise – Regular cardiovascular and strengthening exercises are good, but there is some evidence to support that high impact, intense, competitive-level training may decrease sperm parameters (11). Exercise is wonderful, but everything is better in moderation.
- Limit Toxin Exposure – Think about your food, shampoos, lotions, cologne, and plastics exposure since environmental and reproductive toxins affect men (12).
- Quit Smoking – Eliminate smoking and all tobacco use, even smokeless tobacco or vaping (13).
- Limit or Eliminate Caffeine – One study showed an increased risk of miscarriage if either partner (woman or man) consumed more than two caffeinated beverages daily (14)
- Limit or Eliminate Alcohol - Some research shows that alcohol affects sperm parameters (15), but there are no universal guidelines for how much is too much. Alcohol is associated with dependency, weight gain, sleep difficulties, and many health issues. It can be enjoyed occasionally, but should not be a part of everyday life and should be used in limited quantities. Patients who drink daily are nervous when I recommend reducing or eliminating alcohol, but when they try it, they usually report back feeling better than ever.
- Avoid Marijuana – With the legalization of marijuana in many states, its use will most likely continue to rise. Many patients are not surprised when I recommend quitting smoking or limiting alcohol, but they can be surprised when I recommend limiting or eliminating marijuana. There is a general assumption in society that marijuana is natural and healthy and better for health than alcohol or other drugs. But marijuana has been associated with poor sperm parameters and decreased fertility (16), and I do not recommend using it while trying to conceive.
- Consider a High-Quality Multivitamin – Sperm parameters may be improved with a multivitamin, which may help replace some nutrients missing from a man’s diet. A balanced, varied diet full of protein, fresh vegetables, and fruit is the best way to meet our nutritional needs, but a multivitamin full of antioxidants may be beneficial. The efficacy of supplements and vitamins for the improvement of sperm function is debated among experts. Studies are weak and results vary.
The emotional impact of miscarriage and RPL is immense for the couple together, but it’s easy for the man’s emotional well-being to be ignored. The physical toll of miscarriage is a burden carried by women, but the emotional toll is shared and can be felt in a different way by men (17). For men, they often want an answer to the problem or a solution they can focus on and help fix. Miscarriage is gray, not black and white, and the lack of control or direct path to the end goal of a baby can be frustrating for all involved, especially men. Men can often feel guilty watching their female partners go through the physical demands of miscarriage – the changes in their body, the procedures, and the testing. Providers and the field of reproduction tend to focus on women with miscarriage – they are the patients who have the pregnancies – and men can feel like they are watching from the sidelines.
Men are grieving in this process as well, and everyone needs to remember that. Both the men and the women in an RPL couple need to focus on their self-care.
At this time, there is little research into testing and treatment for men in an RPL couple, but this is starting to change. In the meantime, while we are still investigating men’s contribution to miscarriage risk, we cannot ignore their role in the journey for the couple. Men should be a part of the consults for the RPL couple, their questions should be answered, and they can be encouraged to optimize their health both physically and emotionally to improve their overall well-being with the hopes of decreasing miscarriage risk.
- Men are half of the equation in a couple that is having recurrent miscarriages, but research is lacking and understanding their contribution is limited.
- Factors in men that may increase risk of miscarriage for a couple include advanced age, obesity, chronic illness, environmental toxins, and lifestyle factors, but there is little evidence to support these claims.
- The only test recommended by expert groups for a man in a RPL couple is a blood test for karyotype to evaluate for a balanced translocation (genetic issue found in 3-5% of couples with RPL).
- Other tests like semen analysis, aneuploidy testing in sperm, DNA fragmentation, and epigenetic testing have limited research and limited utility at this time.
- Lifestyle factors that focus on improving a man’s overall health and well-being may be beneficial in decreasing miscarriage for the couple.
- The emotional impact of RPL on men is important to remember and address.
- Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF. Effects of increased paternal age on sperm quality, reproductive outcome, and associated epigenetic risks to offspring. Reprod Biol Endocrinol 2015; 19;13:35.
- de la Rocehbrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage; results of a multicenter European study. Hum Reprod. 2002 Jun;17(6):1649-56.
- Ghuman NK, Mair E, Pearce K, Choudhary M. Does age of sperm donor influence live birth outcome in assisted reproduction? Hum Reprod 2016;31:582-90.
- Evaluation and treatment for recurrent pregnancy loss: a committee opinion. Fertil Steril 2012;98:1103-11.
- Zidi-Jrah I, Hajlaoui A, Mougou-Zerelli S, Kammoun M, Meniaoui I, Sallem A, Brahem S, Fekih M, Bibi M, Saad A, Ibala-Romdhane S. Relationship between sperm aneuploidy, sperm DNA integrity, chromatin packaging, traditional sperm parameters, and recurrent pregnancy loss. Fertil Steril 2016;105:58-64.
- Ramasamy R, Scovell JM, Kovac JR, Cook PJ, Lamb DJ, Lipshultz LI. Fluorescence in situ hybridization detects increased sperm aneuploidy in men with recurrent pregnancy loss. Fertil Steril. 2015;103:906-909.
- Robinson WP, Bernasconi F, Lau A, McFadden DE. Frequency of meiotic trisomy depends on involved chromosome and mode of ascertainment. Am J Med Genet 1999;84:34-42.
- Simon L, Proutski I, Stevenson M, Jennings D, McManus J, Lutton D, Lewis SE. Sperm DNA damage has negative association with live birth rates after IVF. Reprod Biomed Online 2013;26:68–78.
- Robinson L, Gallos ID, Conner SJ, Rajkhowa M, Miller D, Lewis S, Kirkman-Brown J, Coomarasamy A. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod 2012;10:2908–2917.
- Bieniek JM, Kashanian JA, Deibert CM, Grober ED, Lo KC, Brannigan RE, Sandlow JI, Jarvi KA. Influence of increasing body mass index on semen and reproductive hormonal parameters in a multi-institutional cohort of subfertile men.Fertil Steril 2016;106:1070-1075.
- Jóźków P, Rossato M. The impact of intense exercise on semen quality. Am J Mens Health 2016 In press.
- Estill MS, Krawetz SA. The Epigenetic Consequences of Paternal Exposure to Environmental Contaminants and Reproductive Toxicants. Curr Environ Health Rep. 2016;3:202-13.
- Sharma R, Haarlev A, Agarwal A, Esteves SC. Cigarette Smoking and Semen Quality: A New Meta-analysis Examining the Effect of the 2010 World Health Organization Laboratory Methods for the Examination of Human Semen. Eur Urol 2016 In press.
- Buck Louis GM, Sapra KJ, Schisterman EF, Lynch CD, Maisog JM, Grantz KL, Sundaram R. Lifestyle and pregnancy loss in a contemporary cohort of women recruited before conception: The LIFE Study. Fertil Steril 2016;106:180-8.
- Opuwari CS, Henkel RR. An update on oxidative damage to spermatozoa and oocytes. Biomed Res Int. 2016;2016:9540142. doi: 10.1155/2016/9540142.
- du Plessis SS, Agarwal A, Syriac A. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. J Assist Reprod Genet. 2015;32:1575-88.
- Kong GW, Chung TK, Lai BP, Lok IH. Gender comparison of psychological reaction after miscarriage-a 1-year longitudinal study. BJOG 2010;117:1211-9.