Impact of COVID-19 disease on the male factor in reproductive medicine – how-to advise couples undergoing IVF/ICSI

Search strategy

The relevant studies were searched from the electronic databases PubMed and MEDLINE, using the following keywords: ‘COVID sperm’, ‘SARS-CoV-2 sperm’, ‘COVID-19 sperm fertility’, ‘COVID insemination’, ‘SARS-CoV-2 IVF’, ‘sperm quality’. The search was last performed on 29 January 2023. Furthermore, the reference lists of the included studies were manually searched to find additional studies.

Eligibility criteria

Only studies with primary data were used. Case reports, case series, and reviews (systematic or narrative) were excluded. We also excluded studies focusing on females. Study selection/data extraction: two researchers (JS, VH) were involved in the data synthesis process. To process the data, we used Zotero (version 6.0.21, available at https://www.zotero.org/download/) to collect, organise, and cite research.

Is SARS-CoV-2 sexually transmitted?

Li et al. (2020a) tried to answer this question using RT-PCR assay to detect SARS-CoV-2 in semen. Semen testing showed that 6/38 patients (15.8%) had positive results for SARS-CoV-2, including 4/15 patients (26.7%) who were in the acute stage of infection and 2/23 patients (8.7%) who were recovering. Additionally, Delaroche et al. (2021) detected positive SARS-CoV-2 PCR in semen and seminal plasma fractions within 24 hours of a positive COVID-19 test in nasopharyngeal swabs, but only in one of 32 male participants. Viral cultures were all negative.

Twelve other studies (Holtmann et al. 2020; Best et al. 2021; Burke et al. 2021; Gupta et al. 2021; Guo et al. 2021a; Ma et al. 2021; Ruan et al. 2021; Scroppo et al. 2021; Temiz et al. 2021; Dipankar et al. 2022; Donders et al. 2022; Vahidi et al. 2022) could not detect SARS-CoV-2 virus in semen samples. For example, Ma et al. (2021) used qRT-PCR to detect the SARS-CoV-2 virus in semen samples receiving negative results for all 12 male study participants. The time between semen collection and disease onset ranged from 56 days to 109 days (with a median of 78.5 days). Just like Ruan et al. (2021) (no detection of viral nucleic acid in semen samples after approximately 80 days of the last RT-PCR positive pharyngeal swab), Gupta et al. (2021) could not identify SARS-CoV-2 virus in any of the semen samples within 7 days of symptom onset or 5 days of nasopharyngeal rRT-PCR test positivity.

In the study protocol of Temiz et al. (2021), they also used the RT-PCR test for semen analysis. The results revealed that none of the patients with COVID-19 had SARS-CoV-2 in their semen samples. During that period, no standard treatment protocol had been established.

Some (Guo et al. 2021a) established strict hygienic rules to avoid virus contamination before masturbation/ejaculation. In their study, they used the RT-qPCR assay to detect SARS-CoV-2. All patients tested positive for SARS-CoV-2 RNA in the pharyngeal swabs, but tested negative in semen specimens obtained by masturbation during the COVID-19-recovery-phase. The time interval from diagnosis to semen samples acquired is approximately 32 days. Also, others (Burke et al. 2021) instructed their participants to strict hygienic rules during sampling collection. No SARS-CoV-2 was detected in the semen samples in the median of 6 days time after COVID-19 diagnosis.

The time interval of 37 days post-COVID was examined using RT-PCR (Best et al. 2021). There was no RNA detected in any participant’s semen.

Twenty men in the acute stage and 20 men in the clinical recovery stage were examined and all tested SARS-CoV-2 negative (Vahidi et al. 2022). Some (Scroppo et al. 2021) divided their study participants into two groups (mild and moderate COVID-19 disease), where SARS-CoV-2 had not been detected in any semen samples, while others (Holtmann et al. 2020) did not detect SARS-CoV-2 RNA in semen samples from either recovered (n = 18) or acute infected (n = 2) subjects in the investigated time after the end of symptoms of 32.7 days on average using RT-PCR. Dipankar et al. (2022) collected two semen samplings. All semen samples collected in the first and second (74 days after) sampling were negative for SARS-CoV-2, tested with RT-PCR.

Donders et al. (2022) performed their study during the first and second wave of COVID-19 infection in Europe, where none of the men were vaccinated against COVID-19. SARS-CoV-2 RNA was detected in none of the 120 collected semen samples with the validated SpermCOVID PCR test (RT-PCR) at a mean of 52.7 ± 35.1 days post-COVID.

There is evidence that SARS-CoV-2 is detectable in seminal fluid during the acute phase of illness. A clear effect, however, was only found in two studies (Li et al. 2020a; Delaroche et al. 2021). Whereas Gacci et al. (2021) tested three patients (7%) positive in at least one sample (saliva, pre-ejaculation urine, semen and post-ejaculation urine), 40 patients (93%) tested negative for SARS-CoV-2 RNA in a median SARS-CoV-2-free time of 35 days. Of these three positive tested men none of their partners tested positive for SARS-CoV-2 in pharyngeal, vaginal or rectal swabs, although one of these three patients tested positive in semen and had unprotected vaginal, oral and anal sex with his stable partner. All the other studies (conducted after therapy and on average after 1 month after diagnosis) could not detect SARS-CoV-2 RNA in seminal fluid so it can be assumed that SARS-CoV-2 is no longer transmitted by sperm after 1 month at the latest.

To summarise this section, it can be said that the fact that SARS-CoV-2 is barely detectable in semen makes sexual transmission (other body secretions excluded) very unlikely, especially in the case of sperm donation.

Is sperm quality reduced – and if so, how long – after SARS-CoV-2 infection?

Temiz et al. (2021) evaluated the main sperm parameters: volume, pH, sperm counts, motility, percentage of normal morphology, and seminal leukocytes. The semen parameters, except semen morphology, were within normal limits. There were significantly fewer normally formed spermatozoa in the COVID-19 patients (1–1.5%) than in the control group (3%). This effect seems to be reversible, based on checking participants 4 months to 1 year post-COVID (Aksak et al. 2022). When tested COVID-19 negative, the sperm concentration was significantly higher. No statistically significant difference was detected between the groups for sperm morphology and motility. No proband in the COVID-19 negative group was azoospermic, while four men in the COVID-19 positive group were azoospermic. By 138 days post-COVID, there was no difference seen concerning sperm morphology (Ertaş et al. 2022). In addition, there was no significant difference in semen parameters between groups in terms of sperm concentration, semen volume, and advanced motility. However, the sperm count and total motility in men with COVID-19 disease were found to be significantly lower. A decreased sperm motility was also detected (Erbay et al. 2021), dividing the participants into two subgroups (mild and moderate symptoms). Motility and vitality significantly decreased in the mild symptomatic group, while the decrease in all semen parameters including semen volume was statistically significant in the moderate symptomatic group. It was observed that fever did not contribute to this effect. This could be confirmed with a semen analysis 3 months after COVID recovery, in which they found no significant association between sperm parameters and both the previous presence of fever or COVID-19 severity (Paoli et al. 2023).

The median of semen parameters from COVID-19-recovered men was within WHO 2010 fifth percentile (Cooper et al. 2010) with no significant difference compared to the normozoospermic controls and significantly better than infertile controls. The prevalence of oligozoospermia doubles in severe cases (12.7% vs 24%) but was not statistically significant. Also, others (Guo et al. 2021a) checked for total sperm count (TSC), as well as total motile sperm count (TMSC) and sperm morphology of the patients, finding their results to be within normal ranges. The median interval from diagnosis to providing semen samples was 32 days. A contrasting effect showing that SARS-CoV-2 can affect TSC and sperm concentration was detected after a similar period (approximately 37 days post-COVID) (Best et al. 2021). The sperm concentration and TSC of men were lower when tested positive. A follow-up was done approximately 90 days later in five men who completed the analysis. They had a similar TSC compared to the initial analysis. Some (Hu et al. 2022) performed a first analysis of sperm quality after a recovery time of 83 days as well as a second follow-up at 175 days. Neither significant difference in semen parameters between male recovered patients and control subjects nor significant difference in semen parameters between the first and the second follow-up was found. The TSC showed a significant decline after a recovery time of 90 days and an improving trend after a recovery time of approximately 150 days. The total sperm motility improved after a recovery time of 120 days. The sperm quality of COVID-19-recovered patients improved after a recovery time of nearly half a year. Others (Hamarat et al. 2022) checked for TSC before (7.74 ± 3.03 month) and post-COVID (2.35 ± 1.35 month). After the COVID-19 infection there was a significant decrease in total sperm count, the mean sperm concentration, and the mean percentage of samples with normal morphology. Guo et al. (2021b) assessed the semen samples at a median time of 76 days after the appearance of symptoms and 56 days after hospital discharge. Twenty-two of the 41 patients were also tested 84 days after hospital discharge. The median time between the first and second sampling was 29 days. The sperm concentration, total sperm count, and the percentage of progressively motile and motile spermatozoa in the patients were significantly lower at first sampling, while sperm vitality and morphology were not affected. At the second sampling, the sperm concentration, TSC, and number of motile spermatozoa per ejaculate were significantly increased while the percentage of morphologically abnormal sperm was reduced.

The fact that there is no statistical difference concerning the seminal parameters in those patients with mild or moderate symptoms could be shown (Scroppo et al. 2021). Semen analysis was altered in 87% (13/15) of patients. Progressive motility was reduced in 73% of patients. Hypospermia was found in 27% of patients. There was increased viscosity in 80% of patients, with normal leukocyte counts in all collected samples. Holtmann et al. (2020) showed that patients with a moderate infection had a statistically significant impairment of sperm quality compared with men recovered from a mild infection and the control group. The individuals were divided into fever positive versus fever negative, regardless of their classification into mild and moderate and the semen was analysed. Although there were statistically significant differences regarding the complete motility, the number of immotile spermatozoa, and the volume and seminal values were all still in the normal range. Others (Pazir et al. 2021) divided the cohort into two subgroups as those with and without symptoms of fever. In the overall cohort, TMSC and total motility decreased significantly post-COVID, compared to the pre-infection values. Within the group with fever, no statistically significant difference was found between the pre- and post-infection semen parameters. In the group without fever, total motility significantly decreased post-COVID. Not only the studies mentioned above examined the effect of clinical types of COVID-19 on semen parameters, but also Ruan et al. (2021). Median interval between the last positive pharyngeal swab RT-PCR test and semen sample collection was approximately 80 days. Based on reference values, the semen characteristics of recovered COVID-19 men were within the lower reference limits. Total motility, sperm concentration, and TSC significantly declined compared with healthy controls. Different clinical types of COVID-19 have no significant difference in semen parameters, except for sperm concentration (descending trend). Men with a longer recovery time (>90 days) had a significantly lower TSC. This finding differs from the results of Gupta et al. (2021), where changes in motility and sperm count could not be found even during the active COVID-19 phase (within 7 days of symptom onset or 5 days of nasopharyngeal rRT-PCR test positivity in asymptomatic men). At the time of diagnosis of COVID-19, semen parameters showed a significant decrease in percentage of total motility, percentage of progressive motility, semen volume, and sperm morphology (Koç and Keseroğlu 2021). There was no significant difference in motility, concentration, or sperm count according to Vahidi et al. (2022), who compared men in the acute stage to men in the clinical recovery. However, a significant difference in the morphology and viability parameters could be observed (lower in men with acute disease).

Some (Li et al. 2020b) analysed semen from COVID-19 patients and showed that 39.1% (n = 9) had oligozoospermia, and 60.9% (n = 14) showed a significant increase in leukocytes in semen. Decreased sperm concentration and higher seminal levels of IL-6, TNF-a, and MCP-1, when compared to the control group, were observed. Leukocytes and cytokines could affect spermatogenesis and interfere with fertility. Also, others (Hajizadeh Maleki and Tartibian 2021) checked for markers of inflammation and oxidative stress. The semen parameters were evaluated at 10-day intervals for a maximum follow-up time of 60 days. The COVID-19 group revealed significantly higher levels of seminal plasma ACE2 enzymatic activity, TGF-β, TNF-α, IL-1β, IL-6, IL-8, IL-10, caspase-8, caspase-9, and caspase-3 activity, IFN-α, IFN-γ and reactive oxygen species, as well as lower levels of superoxide dismutase activity than those in the control group (P < 0.05). These perturbations tended to persist over time and were correlated with significant impairments in semen volume, sperm morphology, progressive motility, sperm concentration, and the number of spermatozoa. A similar period was examined by Dipankar et al. (2022), where 74 days after the first sampling, a second sampling was done. In the first sampling, semen volume, total motility, vitality, TSC, sperm concentration, percentage normal morphology, percentage cytoplasmic droplet, and fructose were significantly lower. In contrast, semen agglutination, DNA fragmentation index (DFI), liquefaction time, percentage head defect, semen viscosity, and leukocytes were increased. At the second sampling, these findings were reversed but not to the optimum level. All these findings were statistically significant (P < 0.05 for all). Thus, SARS-CoV-2 negatively affects semen parameters, including sperm DFI. In particular, the impact on the DFI was very high. DFI among all participants was more than 30% in the first sampling, with 27/30 participants showing DFI more than 30% during second sampling. The DFI was also examined and checked for sperm motility (low in 33.3%), morphology (defined as normal morphology <4%, poor sperm morphology in 16%), and DFI (assessed by sperm chromatin dispersion (SCD) test) (Ma et al. 2021). The higher the fragmentation value, the more DNA is damaged. In 4/12 patients with poor semen quality, the sperm DNA fraction percentage was increased (DFI 16.2%−23.7%). Also, a post-COVID loss of libido (25%) and a complaint about the loss of morning erection (8%) was reported. Sixteen percent had normal semen quality. Paoli et al. (2023) checked for DFI using the TUNEL assay. Three months after COVID-19 recovery, 80 patients were recruited and their mean percentage of DFI (14.1 ± 7.0%) was compared to the DFI of a normozoospermic control group published by Carlini et al. (2017) (12.8 ± 5.3%). These values were comparable. Additionally, there was no significant difference between subjects with or without fever or between COVID-19 severity groups. They only found a significant age-related correlation. Ruan et al. (2021) could not find differences checking DFI in individuals with recovery period <90 days versus >90 days after COVID-19 disease either, but the DFI in these post-COVID-19 patients in general was increased (mean DFI 18.41%).

The study with the longest period after COVID-19 disease recovery was done by Shcherbitskaia et al. (2022). The researchers compared the DFI of 17 male samples 5 months post-COVID with 22 age-matched controls using TUNEL assay. They found a TUNEL > 15 in 47.06% of men post-COVID versus 40.91% of men without a SARS-CoV-2 infection in the past. In 52.94% of men after COVID-19 they found a TUNEL < 15, which shows that COVID-19 is not always associated with increased DFI. It was shown that increased DFI and diminished semen quality in men can be caused by an imbalance in semen pro- and antioxidant components after COVID-19.

Four subgroups were defined by Al-Alami et al. (2022), who recorded seminal fluid analysis (SFA) from 354 participants (first category): only vaccinated, infected and vaccinated, neither infected nor vaccinated, and only infected. In the second category, SFA from 49 subjects before and after their infection and/or vaccination was measured. There were no statistically significant differences in the SFA records in the first data category and the second. In addition, there were no statistically significant differences between the infected patients and the uninfected patients in terms of TSC, concentration, progressive motility, liquefaction, volume, normal forms existing within the semen, and viscosity. There was no significant difference between the four groups in terms of viscosity and liquefaction, concentration, TSC, volume, and progressive motility, whereas there was a significant difference in terms of normal forms existing within the semen.

A study used 118 samples for semen analysis (Donders et al. 2022). Sperm morphology was more affected than sperm motility after COVID-19 infection. Sperm concentration was the least affected. In this study, the reduced sperm quality lasted until 52.7 ± 35.1 days post-COVID. They also tested for COVID-19 antibody titers in serum. Sperm concentration and motility decreased with increasing serum antibody titers, while DNA damage increased. In addition, the global oligoasthenicteratozoospermia severity score was strongly correlated with higher antibody levels.

To sum up, the effect of SARS-CoV-2 on sperm quality seems to be reversible after approximately 3 months.

Does COVID-19 disease have any effects on the outcome of ART?

The effect of COVID-19 on the outcome of ART was examined in Jordan (Albeitawi et al. 2022) and in Wuhan, China (Wang et al. 2022). Previous COVID-19 infection did not affect IVF/ICSI, according to the Jordanian researchers, who observed clinical pregnancy rate, implantation rate, fertilisation rate, number of oocytes retrieved, number of mature oocytes, and number and quality of embryos at day 3. The Chinese study showed no significant difference in semen quality and a similar chance of pregnancy in terms of IVF outcomes. The motility and concentration of sperm did not significantly differ. However, it seemed that infected men had fewer sperm with normal morphology, while volume, semen concentration, total number of sperm per ejaculate, progressive motility, total number of progressive motility, complete motility, total number of complete motility, immotile, total number of immotile sperms did not differ. A decreased blastocyst formation rate and available blastocyst rate were observed in the exposed group. However, no significant difference was exhibited regarding the implantation rate, clinical pregnancy rate, biochemical pregnancy rate, early miscarriage rate, mature oocyte rate, cleavage rate, normal fertilisation rate, and high-quality embryo rate.

Unfortunately, by the time of writing no study had been made about the effect of COVID-19 disease on the outcome of intrauterine insemination (IUI).