The paternal role in pregnancy loss

Abstract

In this comprehensive review, the intricate relationship between paternal factors and pregnancy loss is examined. While pregnancy loss has historically been predominantly attributed to maternal factors, recent research underscores the significant contribution of the male partner. The review delves into various aspects of paternal influence, including paternal age, health, chromosome abnormalities, Y chromosome deletions, and sperm DNA fragmentation. Notably, advanced paternal age is found to be associated with an increased risk of recurrent pregnancy loss, shedding light on the importance of understanding the impact of aging on male fertility. Additionally, paternal health, particularly metabolic syndrome, emerges as a noteworthy factor contributing to pregnancy loss. Chromosome abnormalities in male partners, such as balanced translocations, and Y chromosome microdeletions are explored in the context of pregnancy loss risk. Moreover, the review highlights the growing body of evidence linking sperm DNA fragmentation and sperm protein abnormalities to spontaneous pregnancy loss, emphasizing the significance of sperm health in reproductive outcomes. Overall, this review provides a comprehensive overview of the multifaceted role of the male partner in pregnancy loss, calling for a more inclusive approach to pregnancy loss investigations that encompasses both maternal and paternal factors.

1 ∣. INTRODUCTION

Pregnancy loss is a distressing experience for couples attempting to conceive. Around 15%–25% of clinical pregnancies result in loss, but fortunately the occurrence of two or more consecutive events, known as recurrence, is relatively rare.¹ About 5% of women will experience two or more consecutive miscarriages, and only 1% will experience three or more consecutive losses. The diagnostic workup for pregnancy loss has traditionally focused on the female partner.² A multitude of factors may contribute to this condition, including uterine abnormalities, cervical incompetence, hormonal issues, infections, immunologic disorders, blood clotting abnormalities, and chromosomal anomalies.³ Advanced maternal age is also associated with an increased risk of miscarriage. Unfortunately, male factors are often neglected or overlooked in the evaluation of pregnancy loss. Indeed, current guidelines note only karyotype and sperm DNA fragmentation testing as avenues to evaluate for a male etiology. Recent research has highlighted potential etiologies and modifiable risk factors related to male health that provide additional opportunities to prevent these events (Figure 1). In this review, we will explore the current understanding of the male contribution to pregnancy loss, focusing on age, genetics, paternal health, and sperm quality.

FIGURE 1.

Paternal and maternal factors related to pregnancy loss.

2 ∣. PATERNAL AGE

The risk of adverse pregnancy outcomes, including pregnancy loss, is closely associated with advancing maternal age, which is typically defined as age ≥ 35 years.⁴ Recent data have further emphasized the reproductive risks of advancing maternal age. For example, a Norwegian study involving 421,201 pregnancies revealed that the proportion of pregnancies ending in miscarriage was the lowest among women aged between 25–29 years (10%), increased after 30 years, and ultimately 53% of pregnancies among women aged 45 or older resulted in miscarriage. There was also a strong correlation between previous miscarriages and an increased risk of recurrence; the risk of new miscarriage was 50% higher after a previous loss.⁵

Given that the male partner contributes half of the genetic material, it is crucial to comprehend the potential role of advancing paternal age in recurrent pregnancy loss (RPL). A 2019 meta-analysis by Fosse et al. evaluated 10 population-based cohort and case–control studies, and demonstrated that advanced paternal age beyond 40 years was significantly associated with an increased risk of spontaneous miscarriage, even after adjusting for maternal age. According to the study, fathers aged between 40–44 years had a 23% higher likelihood of contributing to the occurrence of spontaneous miscarriage before 20 weeks of gestation than fathers who were younger. Similarly, if the father’s age exceeded 45 years, the risk of pregnancy loss before 20 weeks increased by 43%, and before 13 weeks, it increased by 74%. The biological mechanism for this finding may be linked to sperm DNA integrity which will be discussed in detail later in this review. As it pertains to age, several studies have revealed that DNA fragmentation index (DFI), damage to the DNA, doubles between the ages of 20 and 60 years.⁶ For clinicians, understanding the risk of advanced paternal age can be beneficial in counseling patients trying to conceive and in cases where the cause of RPL remains unexplained or idiopathic and advanced paternal age is present.

3 ∣. PATERNAL HEALTH

The connection between maternal health and fetal development during pregnancy is a well-established field of study. Until recently, the potential influence of paternal health on pregnancy loss had garnered less attention and the literature was largely devoid of scholarship on this topic. In 2021, Kasman et al. conducted a retrospective study analyzing data from nearly 1 million pregnancies in the United States between 2009 and 2016 to explore this outcome with paternal metabolic syndrome. The definition of the metabolic syndrome for their work was characterized by a cluster of medical conditions including obesity, hypertension, dyslipidemia, and diabetes. Of note, they found a discernible stepwise association between paternal metabolic syndrome and an increased risk of pregnancy loss. As the number of metabolic derangements in the father increased, the risk of pregnancy loss exhibited a corresponding incremental rise. For instance, compared to metabolically fit fathers, men with one, two, or three metabolic conditions exhibited escalated risks of pregnancy loss by 10%, 15%, and 19%, respectively. Moreover, the research also confirmed a correlation between advanced paternal age and heightened pregnancy loss rates. Plausible mechanisms through which paternal health might impact pregnancy outcomes may be found in the genetic and epigenetic modifications in spermatozoa instigated by adverse health and lifestyle factors.^7-11 These changes to the spermatozoa may potentially affect the placental function, and contribute to the increased incidence of pregnancy loss. This new understanding of paternal health and the outcomes on pregnancy loss highlight the importance of considering both parents’ health status in counseling on the dynamics of pregnancy.¹²

4 ∣. CHROMOSOME ABNORMALITIES

Chromosome abnormalities denote a situation where the correct number of chromosomes is present but are structurally organized incorrectly. Balanced translocations, including Robertsonian or reciprocal translocations, are frequent chromosomal rearrangements of this nature.¹³ Robertsonian translocations are the most prevalent type, with an incidence of 1.2 per 1,000 live newborns.¹⁴ This type of translocation involves the fusion of two separate chromosomes, forming a new chromosome by discarding the two short arms and fusing together the two long arms.¹⁵ Unfortunately, spontaneous abortion of potential offspring is common in carriers of this abnormality due to gametes with unbalanced genetic material. This phenomenon is a well-known cause of miscarriage, and as a result the American Urologic Association guidelines recommend obtaining a karyotype for the male partner in couples who experience this problem.¹⁶ Fortunately, the overall prevalence of this condition is only 2.9% in couples who have experienced two or more pregnancy losses.¹⁷ For men who have been identified as carriers for this genetic abnormality, it is prudent to counsel that intracytoplasmic sperm injection (ICSI) with preimplantation genetic diagnosis (PGD) is often necessary to achieve a healthy embryo, with the understanding that pregnancy loss is still possible even with this technology.

5 ∣. Y DELETIONS

As previously discussed, genetic abnormalities within the male sex chromosome are known to cause male factor infertility. Three regions on the Y chromosome may develop microdeletions that have been termed azoospermia factor (AZF): AZFa, AZFb, and AZFc.¹⁸ Earlier research has demonstrated that these microdeletions are present in approximately 3%–5% of individuals with oligozoospermia and in 6%–16% of those with azoospermia.¹⁹ While the impact this genetic anomaly on sperm quality is well established, there is a growing body of the literature to suggest that these deletions may also be associated with pregnancy loss.

One of the earliest studies to suggest this association was Dewan et al. in 2006. They included 17 men from RPL couples, 18 men from couples who had experienced live births without any miscarriages, and 10 men from couples facing male factor infertility. Their study revealed that in the RPL couples, 82% (14 men) exhibited a microdeletion on the AZFc region.²⁰ A few years later Karaer et al. conducted a similar study with 43 men from couples with a history of 3 or more consecutive miscarriages and found that 7 men (16%) had microdeletions present.²¹ Finally, a more recent analysis in 2015 by Agarwal et al. recruited 59 couples with a history of RPL and 20 fertile controls with no miscarriage history and were able to perform Y chromosome microdeletion assays on 40 male partners of RPL and 20 controls. They found the frequency of Y chromosome microdeletion to be 32.5% (13/40) the RPL male partners.²²

Despite these suggestive findings, there are several publications to the contrary. Investigations conducted by Wettasinghe et al. in 2010 in Sri Lanka, Ghorbian et al. on and Iranian population in 2012, and Venkatesh et al. in 2011 in New Delhi did not identify Y chromosome microdeletions in cases of RPL.^23-25 These mixed outcomes highlight the multifaceted nature of pregnancy loss. Despite compelling evidence of correlation between Y-chromosome microdeletion and instances of RPL, there is likely a confluence of genetic and environmental influences that collectively shape the outcome and account for these mixed results. It remains to be determined, but consideration of Y-chromosome microdeletion analysis in cases, where the etiological basis of pregnancy loss remains elusive may offer a valuable avenue for patients seeking answers.

6 ∣. DNA FRAGMENTATION

In recent years, there has been growing interest in the role of sperm DNA fragmentation and its association with spontaneous pregnancy loss. Briefly, spermatozoa are packaged and protected by proteins that maintain the integrity of the genetic material. Portions of the DNA that are bound more loosely by these proteins can become susceptible to environmental or metabolic insults.²⁶ Additionally, it has been shown that the fragmentation of sperm chromatin demonstrates a continuous rise as it traverses from the testicle through the epididymis and vas deferens, reaching its pinnacle within the ejaculate.²⁷ Interventions such as dietary antioxidants and varicocoele repair have shown potential in reducing sperm DNA fragmentation.²⁸

There have been several meta-analyses attempting to demonstrate if a correlation exists between elevated levels of DNA damage in spermatozoa and the occurrence of miscarriage. Beginning in 2012, Robinson and colleagues analyzed 2,969 couples and compared partners demonstrating high DNA damage with those with low DNA damage.²⁹ Their findings revealed a link between sperm DNA fragmentation and sporadic miscarriage, with a relative risk of 2.16. In 2019, Mcqueen et al. performed a similar study that queried if a comparable correlation exists for instances of recurrent miscarriage.³⁰ They analyzed 579 male partners of women with RPL and 434 male partners of fertile women. For their meta-analyses they defined RPL as two or more, and fertile control women had successful pregnancies. They found that men with partners experiencing RPL had significantly higher DFI, a mean difference of 11.91, compared to those with fertile partners. These findings were reaffirmed in 2022 with an updated meta-analysis demonstrating again that couples experiencing unexplained recurrent miscarriage exhibit elevated levels of sperm fragmentation.³¹ Conversely, women whose partners had a lower DFI were found to have a higher likelihood of achieving a successful pregnancy.

7 ∣. PROTEOMICS

Recent research has shed light on the pivotal role of sperm proteins in fertilization and the early stages of the embryo development, revealing their impact on these critical processes. Notably, deviations in these proteins have been identified as contributing factors to increased rates of RPL.

Advancements in quantifying these proteins have significantly deepened our understanding of how both excessive and insufficient levels of specific proteins in spermatozoa affect the occurrence of pregnancy loss

Among the proteins discovered in higher concentrations, ATP citrate lyase, DEAD-box helicase 1, fatty acid synthase, and Histone 1.2 have been linked to RPL. Conversely, reduced levels of certain proteins, such as Hexokinase 1 (HK1) and RuvB-like helicase, have also exhibited associations with RPL.

The array of proteomic irregularities currently poses a clinical challenge due to their diverse interactions within sperm regulatory pathways. Nevertheless, this evolving body of knowledge holds promise in potentially identifying biomarkers for male infertility, until definitive treatments from these findings can be established.^32,33

8 ∣. CONCLUSION

In the realm of reproductive health, the occurrence of pregnancy loss presents profound emotional and psychological challenge for couples attempting to conceive. While the focus of diagnostic investigations has predominantly rested upon maternal factors, emerging research underscores the significance of the male partner’s contribution. Furthermore, these emerging findings warrant a paradigm shift in the investigation of pregnancy loss that includes not only maternal, but also a paternal health evaluation. Despite limitations within the existing literature and the need for additional research, the evolving comprehension of the paternal contribution to pregnancy underscores a substantial possibility for enhancing outcomes among couples grappling with pregnancy loss.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.