Unexplained Infertility, Explained?

Up to 30% of infertility cases remain classified as “unexplained” despite comprehensive reproductive evaluation. While this label often implies idiopathic dysfunction, it may instead reflect the limitations of current diagnostic frameworks, especially those that overlook chronic inflammation and microbial dysbiosis as contributors to reproductive failure.

Emerging evidence suggests that oral health, systemic inflammation, and shared microbial exposure between partners may play a meaningful and under-recognized role in fertility outcomes. This article explores the oral–systemic connection through a clinical lens, while reframing infertility as a shared biological process rather than an isolated female diagnosis.

Oral Inflammation as a Systemic Modifier of Reproductive Health

As we know, periodontal disease is a chronic inflammatory condition, characterized by sustained bacterial challenge and immune activation. Patients with untreated or poorly controlled periodontitis consistently demonstrate elevated systemic inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These mediators are known to interfere with hormonal signaling, endometrial receptivity, implantation, and immune tolerance.

 From a reproductive perspective, chronic inflammation has been implicated in:

    • Implantation failure
    • Early pregnancy loss
    • Suboptimal outcomes in assisted reproductive technologies

Notably, the presence of oral pathogens, such as Fusobacterium nucleatum within the placental tissues and amniotic fluid, provides compelling biological evidence for oral- reproductive microbial translocation. These findings challenge the long-held assumption that the mouth exists in isolation from reproductive physiology.

 Male Oral Health and Fertility: An Overlooked Contributor

Male factors contribute to approximately 40–50% of infertility cases, yet evaluation frequently remains limited to basic semen parameters. Increasingly, research links periodontal disease with reduced sperm motility, abnormal morphology, and increased sperm DNA fragmentation, which are all factors associated with fertilization failure and miscarriage risk.

 Proposed mechanisms include:

    • Oxidative stress driven by chronic oral inflammation
    • Immune-mediated tissue injury
    • Endothelial and vascular dysfunction

Oxidative stress is a well-established driver of sperm DNA damage and impaired spermatogenesis. These findings suggest that the oral inflammatory burden may meaningfully influence male reproductive potential, and that improving oral health could represent a modifiable preconception intervention.

Shared Oral Microbiomes and Couple-Based Risk

Microbiome research demonstrates that intimate partners often develop increasingly similar oral microbial profiles over time. Through intimate contact, shared environments, and daily habits, pathogenic oral bacteria may be bidirectionally transmitted, sustaining chronic inflammatory exposure within the couple unit. Salivary profiles often demonstrate striking microbial symmetry.

When one partner harbors untreated periodontal disease, the other may experience repeated microbial reinoculation—potentially explaining persistent fertility challenges despite treatment focused on a single individual.

This perspective supports a couple-based framework for fertility assessment, rather than assigning responsibility or pathology to one partner alone.

Saliva-Based Diagnostics in Preconception Care

 Saliva-based diagnostics offer a non-invasive, scalable method for assessing:

    • Oral pathogenic burden
    • Inflammatory biomarkers
    • Genetic susceptibilities associated with systemic inflammation

When integrated into preconception care, salivary testing may help clinicians identify modifiable inflammatory drivers earlier, allowing for targeted intervention before escalation to invasive or costly reproductive treatments. This proactive approach reframes fertility care from reactive treatment to preventive optimization, empowering couples with actionable data rather than delayed answers.

“Unexplained infertility” may not reflect true idiopathy, but rather diagnostic blind spots, particularly at the intersection of oral health, systemic inflammation, and shared microbial exposure.

Incorporating oral–systemic considerations into fertility evaluation offers an opportunity for earlier intervention, more comprehensive care, and interdisciplinary collaboration between dental and medical professionals. As evidence continues to evolve, oral health may play an increasingly important role in reproductive medicine, one that deserves both clinical attention and compassionate discussion.

References

    • Offenbacher S, et al. Periodontal disease and adverse pregnancy outcomes. Journal of Periodontology.
    • Kellesarian SV, et al. Association between periodontal disease and male infertility. Andrologia.
    • Tremellen K. Oxidative stress and male infertility. Human Reproduction Update.
    • Han YW. Fusobacterium nucleatum and adverse pregnancy outcomes. American Journal of Obstetrics and Gynecology.

Dr. Neusha Najafi
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