Semen Parameter Thresholds and Time-to-conception in Subfertile Couples

How High Is High Enough?

Sorena Keihani; Lauren E. Verrilli; Chong Zhang; Angela P. Presson; Heidi A. Hanson; Alexander W. Pastuszak; Erica B. Johnstone; James M. Hotaling

Disclosures

Hum Reprod. 2021;36(8):2121-2133. 

In This Article

Abstract and Introduction

Abstract

Study Question: What thresholds for total sperm count, sperm concentration, progressive motility, and total progressive motile sperm count (TPMC) are associated with earlier time-to-conception in couples undergoing fertility evaluation?

Summary Answer: Values well above the World Health Organization (WHO) references for total sperm count, concentration, and progressive motility, and values up to 100 million for TPMC were consistently associated with earlier time-to-conception and higher conception rates.

What is Known Already: Although individual semen parameters are generally not able to distinguish between fertile and infertile men, they can provide clinically useful information on time-to-pregnancy for counseling patients seeking fertility treatment. Compared to the conventional semen parameters, TPMC might be a better index for evaluating the severity of male infertility.

Study Design, Size, Duration: We used data from a longitudinal cohort study on subfertile men from 2002 to 2017 and included 6061 men with initial semen analysis (SA) in the study.

Participants/Materials, Setting, Methods: Men from subfertile couples who underwent a SA within the study period were included, and 5-year follow-up data were collected to capture conception data. Couples were further categorized into two subgroups: natural conception (n = 5126), after separating those who achieved conception using ART or IUI; natural conception without major female factor (n = 3753), after separating those with severe female factor infertility diagnoses. TPMC was calculated by multiplying the semen volume (ml) by sperm concentration (million/ml) and the percentage of progressively motile sperm (%). Cox proportional hazard models were used to report hazard ratios (HRs) with 95% CIs before and after adjusting for male age, the number of previous children before the first SA, and income. Using the regression tree method, we calculated thresholds for total sperm count, sperm concentration, progressive motility, and TPMC to best differentiate those who were more likely to conceive within 5 years after first SA from those less likely to conceive. We also plotted continuous values of semen parameters in predicting 5-year conception rates and time-to-conception.

Main Results and the Role of Chance: Overall, the median time to conception was 22 months (95% CI: 21–23). A total of 3957 (65%) couples were known to have achieved conception within 5 years of the first SA. These patients were younger and had higher values of sperm concentration, progressive motility, and TPMC. In the overall cohort, a TPMC of 50 million best differentiated men who were more likely to father a child within 5 years. Partners of men with TPMC ≥50 million had a 45% greater chance of conception within 5 years in the adjusted model (HR: 1.45; 95% CI: 1.34–1.58) and achieved pregnancy earlier compared to those men with TPMC < 50 million (median 19 months (95% CI: 18–20) versus 36 months (95% CI: 32–41)). Similar results were observed in the natural conception cohort. For the natural conception cohort without major female factor, the TPMC cut-off was 20 million. In the visual assessment of the graphs for the continuous semen parameter values, 5-year conception rates and time-to-conception consistently plateaued at higher values of sperm concentration, total sperm count, progressive motility, and TPMC compared to the WHO reference levels and our calculated thresholds. For TPMC, values up to 100–150 million were still associated with a better conception rate and time-to-conception in the visual assessment of the curves.

Limitations, Reasons for Caution: There was limited information on female partners and potential for inaccuracies in capturing less severe female infertility diagnoses. Also we lacked details on assisted pregnancies achieved outside of our healthcare network (with possible miscoding as 'natural conception' in our cohort). We only used the initial SA and sperm morphology, another potentially important parameter, was not included in the analyses. We had no information on continuity of pregnancy attempts/intention, which could affect the time-to-conception data. Finally, most couples had been attempting conception for >12 months prior to initiating fertility treatment, so it is likely that we are underestimating time to conception. Importantly, our data might lack the generalizability to other populations.

Wider Implications of the Findings: Our results suggest that a TPMC threshold of 50 million sperm provided the best predictive power to estimate earlier time-to-conception in couples evaluated for male factor infertility. Higher values of sperm count, concentration and progressive motility beyond the WHO references were still associated with better conception rates and time-to-conception. This provides an opportunity to optimize semen parameters in those with semen values that are low but not abnormal according to the WHO reference values. These data can be used to better inform patients regarding their chances of conception per year when SA results are used for patient counseling.

Study Funding/Competing Interest(S): None.

Trial Registration Number: N/A.

Introduction

Semen analysis (SA) is usually the first and often the only test used to evaluate the reproductive function of a male partner in couples seeking infertility counseling (Practice Committee of the American Society for Reproductive Medicine, 2015). The World Health Organization (WHO) recommendations are commonly used to interpret SA results (World Health Organization, 2010). To define the lower threshold for semen parameters, the most recent WHO-5 criteria use the 5th percentile of semen values derived from a population of men whose partners conceived a child within 12 months of stopping contraceptives (World Health Organization, 2010). These thresholds, however, do not strongly correlate with fertility outcomes and cannot be reliably used to differentiate fertile from infertile men (Nagler, 2011). Moreover, several studies have shown an increased probability of pregnancy with semen parameter values well above the WHO reference levels (Guzick et al., 2001; Slama et al., 2002; Herrera et al., 2020).

While the overall ability of semen parameters to differentiate fertile from infertile men remains limited (Polansky and Lamb, 1988; Guzick et al., 2001; van der Steeg et al., 2011), specific semen parameters, individually or in combination, might provide information on male factor severity and help in predicting time-to-conception (Ayala et al., 1996; Slama et al., 2002; Buck Louis et al., 2014; Barratt et al., 2017). Infertility is commonly defined as the inability to conceive after 1 year of unprotected intercourse (Practice Committee of the American Society for Reproductive Medicine, 2015). However, more than half of couples undergoing an infertility evaluation will achieve a successful pregnancy within 2–3 years either spontaneously or with the help of therapies such as IUI or IVF (Ayala et al., 1996; Jouannet et al., 1988; Buck Louis et al., 2014). Thus, longitudinal studies with adequate follow-up time are needed to assess the relations between semen parameters and time-to-conception, rather than conception success. Time to conception is a more clinically meaningful parameter for counseling patients seeking fertility treatment.

The concept of total motile sperm count (TMC), or more accurately total progressive motile sperm count (TPMC), was first introduced in the 1970s as a better way to assess the severity of male factor infertility by combining information on semen volume, sperm concentration, and progressive motility (Smith et al., 1977; Borges et al., 2016). Smith et al. (1977) were among the first groups to investigate the relation between TPMC and pregnancy rates in a small group of infertile couples and suggested that male partners with lower TPMC contributed to lower couple pregnancy rates. Further studies reinforced the idea that TPMC has a better correlation with natural pregnancy rates than other individual semen parameters (Small et al., 1987; Ayala et al., 1996; Hamilton et al., 2015). TPMC is also correlated with IUI success and might be useful in selecting patients for IUI over IVF (Brasch et al., 1994; Huang et al., 1996; Borges et al., 2016; Madbouly et al., 2017), although the results are still debated (Ombelet et al., 2014; Mankus et al., 2019; Zanetti et al., 2019). In 2015, Hamilton et al. (2015) compared different ranges of TPMC values in predicting natural pregnancy in couples with unexplained or male factor infertility. In the absence of a validated classification, the authors used arbitrary thresholds to define five TPMC groups and considered a TPMC >20 million as normal, according to the Dutch national fertility guidelines at the time. They recommended three prognostic groups, namely TPMC <5 million, 5–20 million, and >20 million (Hamilton et al., 2015). As a result, TPMC is now more widely used to assess male fertility, with a threshold of 20 million sperm commonly referred to as 'normal' in both research studies (Borges et al., 2016; Hajder et al., 2016; Blickenstorfer et al., 2019) and clinical practice (Michigan Medicine, Pacific Fertility Center, Utah Center for Reproductive Medicine). However, the methodology and the evidence underpinning these thresholds remain unclear and population-based data are lacking to define the optimal TPMC threshold for fertility prediction.

We hypothesized that higher values of semen parameters are associated with higher conception rates and earlier time-to-conception in men undergoing fertility evaluation. We examined the associations between individual semen parameters and time-to-conception within 5 years of obtaining a semen sample and aimed to define the ranges and thresholds best associated with time-to-conception in a population-based setting.

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