For Healthcare Professionals Only
For some couples experiencing difficulties conceiving, fertility investigations identify a clear underlying cause. For others, standard investigations return within expected parameters, yet pregnancy still does not occur. When no identifiable cause is found following routine fertility assessment, a diagnosis of unexplained infertility may be given.
But unexplained does not necessarily mean unexplainable. Fertility is influenced by a complex interaction between reproductive, immune, nutritional and lifestyle factors, not all of which are captured by routine fertility testing. For healthcare professionals, this creates an opportunity to consider the wider clinical and nutritional picture, including nutrient status, thyroid health, co-existing conditions such as coeliac disease, the reproductive microbiome and oxidative stress.
What do we Mean by Unexplained Infertility?
Standard fertility investigations typically assess ovulation, tubal patency and semen parameters, with further investigations considered according to the clinical context.¹ However, these assessments cannot capture every biological process involved in successful conception. Fertilisation, embryo development and implantation involve complex molecular and cellular processes that are not fully assessed through routine fertility testing.
Nutritional Status: Looking Beyond Overt Deficiency
Adequate nutrient availability is fundamental to reproductive function. Micronutrients are involved in processes including DNA synthesis, cell division, energy metabolism, antioxidant defence and normal immune function, all of which have relevance during the preconception period. Importantly, nutritional inadequacy does not always present as overt clinical deficiency. Dietary restrictions, low energy intake, poor dietary diversity, gastrointestinal conditions and increased physiological requirements may all influence nutrient status.
Iron, folate, vitamin B12, vitamin D, iodine, zinc and selenium are among the nutrients that may warrant consideration depending on dietary intake, symptoms, medical history and existing blood results. For healthcare professionals, the aim is not to search indiscriminately for nutrient deficiencies in every patient with unexplained infertility, but to identify where dietary or clinical factors suggest nutritional status may warrant closer attention.
Coeliac Disease: A Potentially Overlooked Consideration
Coeliac disease is particularly relevant to unexplained infertility because it may be present without prominent gastrointestinal symptoms. It is an immune-mediated condition triggered by gluten in genetically susceptible individuals, causing inflammation and damage to the small-intestinal mucosa and potentially impairing nutrient absorption.
Evidence examining the prevalence of coeliac disease among women with infertility has produced mixed findings. Earlier research suggested an increased prevalence, while a more recent systematic review and meta-analysis found no significant increase compared with the general population.² Nevertheless, coeliac disease remains clinically relevant in unexplained infertility. Current NICE fertility guidance recommends considering serological testing for coeliac disease in people with unexplained subfertility.¹
From a nutritional perspective, damage to the intestinal mucosa can contribute to deficiencies in nutrients including iron, folate, vitamin B12, vitamin D and zinc, providing another potential consideration during the preconception period. Where coeliac disease is suspected, appropriate testing should take place while gluten is still being consumed rather than recommending a gluten-free diet empirically.
Thyroid Health, Autoimmunity and Fertility
Thyroid dysfunction is a recognised consideration in reproductive health, influencing menstrual function and ovulation. However, thyroid autoimmunity can also be present when TSH and circulating thyroid hormone concentrations remain within the reference range.³ Thyroperoxidase antibody (TPOAb) positivity has been associated with adverse fertility and pregnancy outcomes, although the relationship is complex and causality remains uncertain.³
Rather than viewing thyroid markers in isolation, relevant clinical context may include symptoms, menstrual and ovulatory function, family history, other autoimmune conditions and nutritional status. For healthcare professionals supporting couples with unexplained infertility, thyroid health may therefore form one part of the wider clinical picture, while recognising that current UK guidance does not recommend indiscriminate thyroid testing in asymptomatic fertility patients.¹˒³
The Reproductive Microbiome: An Emerging Area of Research
The reproductive microbiome is an emerging area of interest in fertility research. In women, the vaginal microbiome is commonly dominated by Lactobacillus species, which contribute to the maintenance of a low vaginal pH and help protect against potentially pathogenic organisms. Differences in vaginal microbial composition have been associated with infertility and reproductive outcomes. A 2024 systematic review and meta-analysis of women undergoing IVF found vaginal dysbiosis to be associated with a lower clinical pregnancy rate and higher risk of early pregnancy loss, although no significant difference in live birth rate was identified.⁴ More recent research continues to suggest differences in vaginal microbial composition between fertile and infertile women, but the evidence remains predominantly observational and causality has not been established.
The seminal microbiome is also attracting increasing attention. Semen contains diverse microbial communities, and differences in their composition have been associated with semen quality. Systematic reviews have reported associations between particular microbial profiles and sperm concentration, motility and morphology, although findings between studies are heterogeneous and the clinical significance remains uncertain.⁵
Research in this area is still evolving, and these associations do not currently establish a role for routine reproductive microbiome testing or microbiome-targeted interventions in unexplained infertility. However, the vaginal and seminal microbiomes provide another example of biological factors that are not captured by standard fertility investigations and may contribute to our evolving understanding of what currently falls under the umbrella of ‘unexplained’ infertility.
Oxidative Stress, Inflammation and Fertility
Oxidative stress occurs when the production of reactive oxygen species exceeds the body’s antioxidant defences. While reactive oxygen species have physiological roles in reproduction, excessive oxidative stress can damage cellular lipids, proteins and DNA and has been investigated in relation to sperm and oocyte quality, fertilisation, embryo development and implantation.⁶
Nutrition and lifestyle can influence oxidative and inflammatory balance. A dietary pattern rich in vegetables, fruit, wholegrains, nuts, seeds, legumes, oily fish and unsaturated fats provides antioxidants, polyphenols, fibre and essential fatty acids alongside a broad range of micronutrients. Omega-3 fatty acids, particularly EPA and DHA found in oily fish, have attracted interest in reproductive health, with research investigating their relationship with both female and male fertility.⁷˒⁸
Smoking, excessive alcohol intake, poor sleep and other lifestyle factors may also contribute to oxidative stress. Rather than focusing on individual ‘antioxidant’ or ‘anti-inflammatory’ foods, supporting an overall nutrient-dense dietary and lifestyle pattern may be more meaningful during the preconception period.
Looking Beyond Standard Fertility Testing: Bringing the Pieces Together
One of the challenges of unexplained infertility is that there may not be a single factor to identify and ‘fix’. Fertility reflects the interaction of multiple biological systems, and influences across nutrition, immune function, oxidative balance and reproductive physiology may collectively contribute to the overall picture.
It is also important to consider both partners. Routine semen analysis provides valuable information about sperm concentration, motility and morphology, but it cannot capture every aspect of sperm function or reproductive health. Current NICE guidance, for example, does not recommend routine sperm DNA fragmentation testing, highlighting the limits of what standard fertility investigations currently assess.¹ Male preconception health, including nutrition and lifestyle, therefore remains relevant even where routine semen parameters fall within expected ranges. Individualised, couple-centred preconception care can help ensure that the focus does not fall solely on the female partner.
Alongside a nutrient-dense diet, targeted preconception supplementation can help support nutritional intake during this period. Proceive Max Women and Proceive Max Men provide advanced nutritional support for women and men navigating a more complex fertility journey, including those who have been trying to conceive for more than 12 months or are preparing for fertility treatment. For couples who do not regularly eat oily fish, Proceive Conception Omega 3 can also provide EPA and DHA alongside their preconception supplement. The purpose of nutritional support is to help provide a strong nutritional foundation for conception and pregnancy while appropriate clinical investigation and fertility treatment continue.
Key Takeaways for Healthcare Professionals
- Unexplained infertility is a diagnosis of exclusion and does not necessarily mean that no contributing factors exist.
- Routine fertility investigations cannot capture every biological process involved in conception, embryo development and implantation.
- Nutritional status may warrant consideration even in the absence of overt nutrient deficiency.
- NICE recommends considering serological testing for coeliac disease in people with unexplained subfertility.¹
- Thyroid health and autoimmunity may form part of the wider clinical picture where clinically appropriate.
- The vaginal and seminal microbiomes represent emerging areas of fertility research, but evidence does not currently support routine microbiome testing or targeted intervention.
- Oxidative stress provides a potential mechanism linking nutrition, lifestyle and reproductive health in both partners.
- Unexplained infertility should be approached as a couple-centred issue, with male preconception health remaining relevant even where routine semen parameters are within expected ranges.
- A nutrient-dense dietary pattern alongside appropriate preconception supplementation can help provide a strong nutritional foundation while clinical investigation and treatment continue.
Frequently Asked Questions
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What is unexplained infertility?
Unexplained infertility may be diagnosed when no identifiable cause is found following routine fertility assessment. Standard investigations can assess factors including ovulation, tubal patency and semen parameters, but they cannot capture every biological process involved in successful conception.
-
Does unexplained infertility mean there is no underlying contributing factor?
Not necessarily. Fertility is influenced by a complex interaction between reproductive, immune, nutritional and lifestyle factors, not all of which are captured by routine fertility testing.
-
Why might nutritional status warrant consideration in unexplained infertility?
Nutritional inadequacy does not always present as overt clinical deficiency. Dietary restrictions, low energy intake, poor dietary diversity, gastrointestinal conditions and increased physiological requirements may all influence nutrient status. For healthcare professionals, the aim is not to search indiscriminately for nutrient deficiencies in every patient with unexplained infertility, but to identify where dietary or clinical factors suggest nutritional status may warrant closer attention.
-
Why might coeliac disease be considered in unexplained infertility?
Coeliac disease may be present without prominent gastrointestinal symptoms and can potentially impair nutrient absorption. Current NICE fertility guidance recommends considering serological testing for coeliac disease in people with unexplained subfertility.
-
What is the relationship between the reproductive microbiome and fertility?
Differences in vaginal and seminal microbial composition have been associated with fertility and reproductive outcomes. However, research is still evolving and these associations do not currently establish a role for routine reproductive microbiome testing or microbiome-targeted interventions in unexplained infertility.
-
Why should both partners be considered in unexplained infertility?
Routine semen analysis provides information about sperm concentration, motility and morphology but cannot capture every aspect of sperm function or reproductive health. Male preconception health, including nutrition and lifestyle, therefore remains relevant even where routine semen parameters fall within expected ranges.
References
- National Institute for Health and Care Excellence. Fertility problems: assessment and treatment. NICE guideline NG257. London: NICE; 2026.
- Glimberg I, Haggård L, Lebwohl B, Green PHR, Ludvigsson JF. The prevalence of celiac disease in women with infertility – a systematic review with meta-analysis. Reprod Med Biol. 2021;20(2):224–233.
- Dhillon-Smith RK, Boelaert K, Jeve YB, Maheshwari A, Coomarasamy A. Subclinical hypothyroidism and antithyroid autoantibodies in women with subfertility or recurrent pregnancy loss. BJOG. 2022;129(12):e75–e88.
- Maksimovic Celicanin M, Haahr T, Humaidan P, Skafte-Holm A. Vaginal dysbiosis – the association with reproductive outcomes in IVF patients: a systematic review and meta-analysis. Curr Opin Obstet Gynecol. 2024;36(3):155–164. doi:10.1097/GCO.0000000000000953.
- Gomes IA, Monteiro PB, de Moura GA, et al. Microbiota and seminal quality: a systematic review. JBRA Assist Reprod. 2023;27(3):507–513. doi:10.5935/1518-0557.20230008.
- Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reprod Biol Endocrinol. 2012;10:49.
- Salas-Huetos A, Arvizu M, Mínguez-Alarcón L, et al. Women’s and men’s intake of omega-3 fatty acids and their food sources and assisted reproductive technology outcomes. Am J Obstet Gynecol. 2022;227(2):246.e1–246.e11. doi:10.1016/j.ajog.2022.03.053.
- Hosseini B, Nourmohamadi M, Hajipour S, et al. The effect of omega-3 fatty acids, EPA, and/or DHA on male infertility: a systematic review and meta-analysis. J Diet Suppl. 2019;16(2):245–256. doi:10.1080/19390211.2018.1431753.
