Het krijgen van herhaalde miskramen is een gezamenlijk probleem. De meeste bekende risicofactoren bij herhaalde miskramen zijn onderzocht bij de vrouw. Er is vergeleken met de vrouw weinig bekend van mannelijke risicofactoren bij herhaalde miskramen.

ESHRE Guideline group on RPL (2022)

Summary of literature

A meta-analysis investigating the association of advanced paternal age with spontaneous miscarriage during the first trimester of pregnancy showed that there is an increased risk for miscarriage for male age categories 30-34, 35-39 and 40-44 and this risk was higher for the ≥45 age category (du Fossé et al. 2020). In a large multicentered, parallel two group randomized trial (HABSelect) study of 2752 couples, Miller and colleagues found that the proportion of couples with clinical pregnancy that ended in miscarriage was lower in the group where sperm for ICSI with less DNA damage had been chosen using hyaluronan adherence (HA selection by PICSI) than in the standard ICSI group. The confidence interval for the absolute difference between groups was narrow (Miller et al, 2019). This reduction in miscarriage by selecting sperm with less DNA damage by PICSI has been observed in previous studies (Worrilow et al. 2013; Mokánszki et al. 2014).  As miscarriage reduction was a significant secondary outcome of the full HABSelect trial, samples 84 (n=1,247) selected for the mechanistic analysis were deliberately enriched for miscarriage 85 outcomes (n=92 or 7.7%) from a total of 154 miscarriages (5.6%) among all (n=2752) 86 couples randomized by stratified random sampling (West et al, 2022). Older women (>35 years) randomized to the trial’s experimental arm had the same live birth rates as younger women, with no increase in miscarriage rates with maternal age. This mechanism for this was most probably the avoidance of sperm with damaged DNA by using HA selection by PICSI (West et al. 2022). Moreover, the effects of male semen quality, occupational exposure, and lifestyle on RPL were examined based on semen analyses and detailed questionnaires from 68 RPL couples and 63 randomly selected healthy controls (Ruixue et al., 2013). Semen from men in the RPL group had significantly reduced viability, normal morphology and total progressive sperm motility and a higher mean percentage of DNA damaged sperm compared with those of controls. Furthermore, the risk of RPL was significantly increased when smoking, drinking and occupational exposure to environmental factors were superimposed (OR 11.965; 95% CI 1.49-95.62). It was concluded that in couples with RPL, male factors such as paternal age, sperm quality, occupational exposure, and lifestyle (smoking, alcohol consumption and soft drugs) should be assessed in addition to female factors (Anifandis et al. 2014; Jensen et al. 2014; Pacey et al. 2014; Miller et al. 2019; Smits et al. 2019; Montagnoli et al. 2021; West et al. 2022).

A systematic review and meta-analysis of 24 case-control and cohort studies on Chinese couples  including 1,690 male partners of women with RPL, and 1,337 male partners of fertile control women showed that male partners of women with RPL had a significantly lower level of sperm density (SMD=-0.53, 95%CI: – 0.75 to –0.30), sperm viability (standard mean deviation SMD=-1.03, 95%CI: – 1.52 to –0.54), sperm progressive motility rate (SMD=-0.76, 95%CI:-1.06 – -0.46), and normal sperm morphology rate (SMD= –0.56, 95%CI: – 0.99 to –0.12), and had a significantly higher rate of sperm deformity rate (SMD=1.29, 95%CI: 0.60 – 1.97), and sperm DNA fragmentation index DFI (SMD=1.60,95% CI: 1.04 to 2.17), when compared with the reference group. The 2 groups had no significant difference of semen volume (SMD=-0.03, 95%CI: -0.14 – 0.08) and semen pH value (SMD= –0.23, 95% CI: –0.50 to 0.05) (Li et al. 2021). Several other smaller studies have also compared sperm parameters of couples with RPL to fertile controls and found no differences in sperm volume  or sperm count (Sbracia et al. 1996; Gopalkrishnan et al. 2000; Bhattacharya 2008; Brahem et al. 2011; Imam et al. 2011; Talebi et al. 2012; Khadem et al. 2014. The percentage of motile sperm and percentage of sperm with normal morphology were reported to be lower in RPL men in some studies, while others found no difference. Three studies consistently reported higher DNA fragmentation in RPL men. Some studies have suggested a difference in sperm parameters between RPL couples that achieve a successful pregnancy and live birth rate, and couples that experienced an additional pregnancy loss, or failed to achieve pregnancy. One study reported differences in sperm concentration and motility between successful and unsuccessful couples (Sbracia et al., 1996).

Several studies addressing male factors and RPL have focused on male genetic defects. These range from markers of Y chromosomal deletions, sperm aneuploidy, sperm imprinted gene methylation, chromatin integrity and DNA damage. A systematic review and meta-analysis showed that the RPL patients’ partners had significantly higher rates of total sperm aneuploidy compared with the control group including partner of fertile women (Pu et al. 2020). The few studies on chromosomal anomalies were poorly powered and overall indicated no relationship with miscarriage (Bernardini et al. 2004; Carp et al. 2006; Bronet et al. 2012). Similarly, Y chromosome microdeletions were not associated with increased miscarriage rates in RPL couples (Kaare et al. 2008; Wettasinghe et al. 2010; Pereza et al. 2013). Sperm DNA shows more promise. Of the systematic reviews with meta-analysis, Robinson and colleagues interrogated 16 cohort studies (2969 couples) of which 14 were prospective (Robinson et al. 2012). In 15 out of 16 included studies, sperm DNA damage was assessed in couples undergoing IVF or ICSI, while one study focused on spontaneous conception. The meta-analysis showed a significant increase in miscarriage rates in men with high sperm DNA damage compared with those with low sperm DNA damage (RR 2.16; 95% CI 1.54-3.03). A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR 3.94; 95% CI 2.45-6.32) (Robinson et al. 2012). Similarly, Zhao and colleagues performed a systematic review in 2014 also including 16 cohort studies (3106 couples) showing that sperm DNA fragmentation had a detrimental effect on clinical outcomes (decreased pregnancy and increased miscarriage rates) after IVF/ICSI (Zhao et al. 2014). The studies used different sperm DNA damage test assays, endpoints were for different treatment types (IVF/ICSI/IUI), different aspects of DNA damage were measured and different thresholds for DNA damage were used. Further, female inclusion and exclusion criteria were imposed, and the definitions of miscarriage were not always coherent. Given a significantly increased RR despite these numerous confounding factors, both Robinson and Jing Zhao concluded that sperm DNA damage testing should be offered to couples following even a single miscarriage after fertility treatment (Robinson et al. 2012; Zhao et al. 2014).

Similar results were shown more recently. A meta-analysis of studies including 3992 ART patients showed a higher miscarriage rate in high-DFI group compared to the low-DFI group (RR=1.57 [1.18, 2.09], P<0.01) (Deng et al. 2019). Another systematic review and meta‐analysis of thirteen prospective studies showed that male partners of women with RPL have significantly higher SDF rates than male partners of fertile control women (mean difference MD: 11.9%, 95% CI 4.97 –18.86) (McQueen et al. 2019). Similarly, it was shown in a systematic review and meta-analysis including 2 prospective and 12 retrospective studies on RPL couples that the SDF levels were higher in RPL couples compared to fertile controls (MD: 11.98%, 95%CI 6.64- 17.32, p<0.001) (Tan et al. 2019) An altered methylation of sperm-imprinted genes (mainly, H19/IGF2 genes) was shown to be associated with SDF and pregnancy loss rates in a meta-analysis including 10 observational studies (Cannarella et al. 2021).  

There have also been original observational studies (Rogenhofer et al. 2017; Esquerré-Lamare et al. 2018; Dhawan et al. 2019; Ribas-Maynou et al. 2020; Zhu et al. 2020; Haddock et al. 2021; Le et al. 2021) and a large multi-centre randomized control study (Miller et al. 2019) that reported an inverse relationship between sperm isolated based on hyaluronan binding and pregnancy loss.

Further there have been four other international societies including the association between sperm DNA fragmentation and recurrent pregnancy loss with recommendations for testing of male partners presenting with this condition (American Society of Reproductive Medicine 2020 and American Urological Society, 2020 (Schlegel et al. 2021a, 2021b), European Association of Urology, Sexual and Reproduction Health(Salonia et al. 2021), and Society for Translational Medicine (Agarwal et al. 2017)). In addition, the most recent World Health Organisation manual for semen analysis recommends extended testing using sperm DNA fragmentation, where indicated (WHO laboratory manual 2021).

 A major cause of DNA damage is oxidative stress and this seems to be exacerbated by smoking, obesity and excessive exercise (Aitken et al. 2009; Hsu et al. 2009; Du Plessis et al. 2010; Aitken,Bakos 2021). Clinicians should advise male partners of couples presenting with RPL of these connections and suggest ways to prevent sperm DNA damage caused by unhealthy lifestyles (Sharma et al. 2013; Wright et al. 2014; Smits et al. 2019).

Recommendations

Justifications

Since 2017, several meta-analysis and observational studies showed that recurrent pregnancy loss rates were increased with abnormal SDF levels. Several assays have been described to measure sperm DNA damage and are available worldwide. Therefore, the guideline development group recommend assessing sperm DNA fragmentation in order to screen for male factor in couples with RPL. Sperm DNA damage is associated with advanced paternal age and caused by unhealthy lifestyles (such as smoking, obesity and excessive exercise). It is recommended that clinicians make couples aware of these risks and encourage the man addresses his unhealthy habits. Evidence shows that lifestyle modifications of the male partner could improve the clinical outcomes of couples experiencing RPL.

The results of the summary of literature were adapted from the international ESHRE guideline Recurrent Pregnancy Loss (2022). More details about the methodology of the ESHRE guideline on RPL (2022) can be found in “Annex 5: Methodology” of the ESHRE guideline and in the Manual for ESHRE guideline development, version 2013, which can be consulted at the ESHRE website. The evidence tables and literature studies can be found at the ESHRE website in Supplementary data files.