Romualdi, D., Ata, B., Bhattacharya, S., Bosch, E., Costello, M., Gersak, K., Homburg, R., Mincheva, M., Norman, R. J., Piltonen, T., Dos Santos-Ribeiro, S., Scicluna, D., Somers, S., Sunkara, S. K., Verhoeve, H. R., & Le Clef, N. (2023). Evidence-based guideline: unexplained infertility. Hum Reprod. https://doi.org/10.1093/humrep/dead150
Romualdi D, Ata B, Bhattacharya S, Bosch E, Costello M, Gersak K, Homburg R, Mincheva M, Norman RJ, Piltonen T, Dos Santos-Ribeiro S, Scicluna D, Somers S, Sunkara SK, Verhoeve HR, Le Clef N. Evidence-based guideline: unexplained infertility. Hum Reprod. 2023. doi:10.1093/humrep/dead150
Romualdi, D., et al. "Evidence-based guideline: unexplained infertility." Hum Reprod, 2023.
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No unexplained infertility recommendation has high-quality evidence
None of the 40 recommendations backed by evidence in this guideline has high-quality support. Of those, 31 have very low-quality support. The guideline covers couples with unexplained infertility. An ESHRE expert group wrote it.
Key Findings
The guideline makes 52 recommendations on defining, diagnosing and treating unexplained infertility: 40 evidence-based, 10 good practice points and two research-only.
Among the 40 evidence-based recommendations, 29 are strong and 11 are weak.
Graded by evidence, no recommendation reaches high quality. One is moderate, nine are low and 31 are very low.
The group names IUI with ovarian stimulation as first-line treatment, a strong recommendation that rests on very low-quality evidence.
The group advises against sperm DNA fragmentation testing and most other extra male tests when a WHO-criteria semen analysis is normal.
Interpretation
The guideline is a consensus document from a professional society. The authors used literature searches and expert agreement. They state that evidence for many tests and treatments was very limited, and that future studies may change their advice. Only English-language papers were searched. The group says HSG and HyCoSy miss mild endometriosis, adhesions and subtle tubal lesions. Good-quality data are insufficient to show that clinically relevant diagnoses go missing when laparoscopy is skipped in women at low risk for tubal pathology. The group recommends against routine diagnostic laparoscopy and advises counseling women at high risk for tubal pathology or endometriosis about it. The literature neglects the male partner, the group adds.
RRM Context
The guideline says the share of couples given this diagnosis depends on how much testing is done. Restorative reproductive medicine treats unexplained infertility as undiagnosed infertility. Evaluation comes before treatment. The first-line treatment here starts with no cause found. The guideline's text lists problems that standard imaging misses.
Our editorial summary of this paper, not the article's abstract.
Abstract
Guideline Group on Unexplained Infertility; Romualdi D(1), Ata B(2)(3), Bhattacharya S(4), Bosch E(5), Costello M(6)(7), Gersak K(8), Homburg R(9), Mincheva M(10), Norman RJ(7)(11), Piltonen T(12), Dos Santos-Ribeiro S(13), Scicluna D(14), Somers S(15), Sunkara SK(16), Verhoeve HR(17), Le Clef N(18).
Teede HJ et al., 2026·Lancet (London, England)·Free to read
Polyendocrine metabolic ovarian syndrome (PMOS), previously named polycystic ovary syndrome (PCOS), affects one in eight women. However, the term PCOS is inaccurate, implying pathological ovarian cysts, obscuring diverse endocrine and metabolic features, and contributing to delayed diagnosis, fragmented care, and stigma, while curtailing research and policy framing. Building on an international mandate for change, we outline an unprecedented, rigorous, multistep global consensus process for the name change. Funding and governance were established with engagement of 56 leading academic, clinical, and patient organisations. Using iterative global surveys (with responses from 14 360 people with PCOS and multidisciplinary health professionals from all world regions), modified Delphi methods, nominal group technique workshops, and marketing and implementation analyses, we identified principles prioritising scientific accuracy, clarity, stigma avoidance, cultural appropriateness, and implementation feasibility. An accurate new name was prioritised over retaining the PCOS acronym or a generic name. Implementation approaches prioritised evolution rather than transformation. Preferred terms were polyendocrine, metabolic, and ovarian, reflecting the condition's multisystem pathophysiology, and polyendocrine metabolic ovarian syndrome was the consensus new name. Accuracy was improved by omitting cysts and by capturing endocrine, metabolic, and ovarian dysfunction. A co-designed global implementation strategy, including a transition period, education, and alignment with health systems and disease classification, is under way.
Restorative Care and Assisted Reproduction · Outcome Comparisons
Ganci D et al., 2026·Fertility and Sterility·Free to read
Restorative Reproductive Medicine (RRM) aims to restore fertility by diagnosing and treating the underlying causes of infertility. RRM is frequently promoted as an alternative to assisted reproductive technology (ART), despite uncertainty regarding its comparative effectiveness and safety. Where delayed childbearing and infertility are becoming more common, reliance on optimization of natural physiology alone may delay effective treatment and compromise reproductive outcomes. A systematic review of the current evidence comparing RRM to either ART or unassisted conception is, therefore, essential to inform clinical practice, guideline development, and shared decision-making for patients experiencing infertility. To assess the effectiveness and safety of RRM approaches, evaluated as a whole, rather than as individual components, compared with ART and medically unassisted conception in couples experiencing infertility. A systematic literature search of MEDLINE, Embase, CENTRAL and the Journal of Restorative Reproductive Medicine from inception to 28 November 2025. We included randomized control trials (RCTs) or nonrandomized comparative studies evaluating reproductive and safety outcomes of RRM as a unified treatment, compared with either ART or expectant management (attempted medically unassisted conception). Two reviewers independently screened titles, abstracts and full texts with disagreements resolved by a third reviewer. We retrieved 724 records, of which 16 studies underwent full-text review. No RCTs or comparative observational studies were identified. All 16 full-text studies were excluded for an ineligible study design (no control group); most were cohort studies in which all participants underwent RRM. Ten studies reported reproductive outcomes; nine of these made claims regarding the benefits or effectiveness of RRM. None of these claims were supported by the study designs used, as the lack of a comparison group precludes reliable estimation of treatment effects. Consequently, these studies cannot provide valid estimates of RRM success rates, nor permit any meaningful inference about its effectiveness relative to unassisted conception or ART. Large-scale RCTs or prospective cohort studies reporting effectiveness and safety outcomes are required to inform evidence-based fertility guidelines. There are no comparative studies to support reliable estimates of the safety and effectiveness of RRM compared with ART or medically unassisted conception for couples experiencing infertility.
Raperport C et al., 2024·BJOG : an international journal of obstetrics and gynaecology·Free to read
There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice. This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis. CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language. Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range. Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies. This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.
Mosorin ME et al., 2023·Acta Obstet Gynecol Scand·Free full text on PubMed Central
Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. MATERIAL AND This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.
Related research
Guideline Appraisal · Guideline Variation and Disagreement
Grande G et al., 2024·Human reproduction (Oxford, England)
Sir, We read with interest the guideline about unexplained infertility developed by the Guideline Group (GDG) on Unexplained Infertility of ESHRE (Romualdi et al., 2023). We appreciated the efforts to have clear, evidence-based recommendations on this important topic but would like to point out fundamental problems and misunderstandings on the approach to the male factor. Although we can agree on the definition of unexplained infertility made by the GDG as ‘infertility in couples with apparently normal ovarian function, fallopian tubes, uterus, cervix and pelvis, age ≤40 years and with adequate coital frequency; and apparently normal testicular function, genito-urinary anatomy, and a normal ejaculate’, substantial differences in the diagnostic approach for the female and male partner are then proposed to assess these features. In fact, a comprehensive evaluation of the female partner is recommended considering ovulation, ovarian reserve, tubal factor, uterine factor, and even vaginal microbiota, whereas the approach to the male partner is limited only to semen analysis. The entire following line of reasoning assumes that a normal semen analysis is sufficient to rule out male factor infertility and no further examination is needed. There are several problems with this approach. First of all, it is quite clear that a normal testicular function and genito-urinary anatomy cannot be determined by semen analysis only, but instead require a combination of, at least, history, physical examination, endocrine assessment, and ultrasound examination of the testes and seminal tract. For semen analysis, the GDG correctly refers to the World Health Organization (WHO) manual for semen analysis (6th edition) (World Health Organization, 2021) but misinterpreted it because the GDG does not recommend any other diagnostic procedure when ‘semen analysis according to WHO criteria is normal’. Not only did the GDG neglect to consider a broad approach to understand whether the testicular function and genito-urinary anatomy are normal, but also it made substantial misunderstandings on the role and significance of semen analysis and its relation with fertility. A main point is that the WHO manual does not define normal semen analysis (World Health Organization, 2021), simply because the so-called ‘reference values’, and in particular the fifth percentile reference, do not represent cut-off limits for fertility and infertility. These values represent the distribution of results from around 3500 presumed fertile men and they are ‘not sufficient to establish clinically useful decision limits’ (World Health Organization, 2021). WHO is very clear when stating that ‘reference values cannot be used to distinct limits between fertile and subfertile men’, ‘the lower fifth percentile of data from men in the reference population does not represent a limit between fertile and infertile men’, and ‘for an individual patient, a semen analysis is never prognostic of infertility’. Since, it is well known that natural fertility is possible with semen parameters below the fifth percentile and infertility with semen parameters above the fifth percentile, a ‘normal ejaculate’ cannot be defined. Therefore, there is a ‘problem in applying a dichotomous categorization to fertility that must be considered a continuum. It is also well known that there is a substantial overlap of semen examination results between fertile and infertile men’ (World Health Organization, 2021). Hence, the reference limits cannot be used as a specific limit between infertile and fertile men (Björndahl et al., 2023). Results of semen examination below the WHO reference values do not automatically mean that the problem of the couple resides in the male, and results above the limits do not always mean that the male partner of an infertile couple is undoubtedly fertile (Björndahl et al., 2023). Semen analysis is fundamental in the initial investigation of the male partner of an infertile couple, but its [truncated]
Quaas A et al., 2008·Rev Obstet Gynecol·Free full text on PubMed Central
Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.
Outcomes and Effectiveness · Outcomes by Diagnosis
In vitro fertilisation (IVF) is a widely accepted treatment for unexplained infertility (NICE 2004), which affects up to a third of all infertile couples. With estimated live birth rates (LBRs) per cycle varying from 33.1% in women aged under 35 years down to 12.5% in women aged between 40 and 42 years (HFEA 2011), its effectiveness has not been rigorously evaluated in comparison with other treatments. With increasing awareness of the role of expectant management, less-invasive procedures such as intrauterine insemination (IUI), and concerns about multiple pregnancies and costs associated with IVF, it is important to evaluate the effectiveness of IVF against other treatment options in couples with unexplained infertility. To evaluate the effectiveness and safety of IVF compared to expectant management, clomiphene citrate, IUI alone and intrauterine insemination plus controlled ovarian stimulation (IUI+SO). Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, first quarter), MEDLINE (1970 to July 2011), EMBASE (1985 to July 2011) and reference lists of articles were searched. Relevant conference proceedings were handsearched. Authors were contacted.
Selection Criteria: Randomised controlled trials (RCTs) were included. LBR per woman was the primary outcome.
Data Collection and Analysis: Two review authors independently assessed eligibility and quality of trials. MAIN Six RCTs were included in the final analysis. LBR per woman was significantly higher with IVF (45.8%) than expectant management (3.7%) (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, 1 RCT, 51 women). There were no comparative data for clomiphene citrate. There was no evidence of a significant difference in LBR between IVF and IUI alone (OR 1.96, 95% CI 0.88 to 4.36, 1 RCT, 113 women), 40.7% with IVF versus 25.9% with IUI. In studies comparing IVF versus IUI+SO, LBR per woman did not differ significantly between the groups among treatment-naive women (OR 1.09, 95% CI 0.74 to 1.59, 2 RCTs, 234 women) but was significantly higher in a large RCT of women pretreated with IUI + clomiphene citrate (OR 2.66, 95% CI 1.94 to 3.63, 1 RCT, 341 women). These three studies could not be pooled due to high heterogeneity (I(2) = 84%). There was no evidence of a significant difference in multiple pregnancy rate (MPR) or ovarian hyperstimulation syndrome (OHSS) between the two treatments (OR 0.64, 95% CI 0.31 to 1.29, 3 RCTs, 351 women; OR 1.53, 95% CI 0.25 to 9.49, 1 RCT, 118 women, respectively). AUTHORS' IVF may be more effective than IUI+SO. Due to paucity of data from RCTs the effectiveness of IVF for unexplained infertility relative to expectant management, clomiphene citrate and IUI alone remains unproven. Adverse events and the costs associated with these interventions have not been adequately assessed.
Outcomes and Effectiveness · Outcomes by Diagnosis
Wang R et al., 2019·The Cochrane database of systematic reviews·Free full text on PubMed Central
Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making. To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility. We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials. We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (or combined with ICSI). Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence. We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%. AUTHORS' There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.
Clinical Guidelines and Standards › Guidelines by Clinical Area › Fertility and Infertility Guidelines · Infertility › Evaluation › Unexplained Infertility · Assisted Reproduction › Procedures and Protocols › Intrauterine Insemination
Siladitya Bhattacharya, Robert J Norman, Terhi Piltonen, Harold R Verhoeve
S Bhattacharya, Bob Norman, Rob Norman, Bobby Norman, R Norman, T Piltonen, H Verhoeve
PMID 37599566 37599566 DOI 10.1093/humrep/dead150 10.1093/humrep/dead150 Romualdi et al. 2023, Romualdi 2023
Cite this article
Romualdi, D., Ata, B., Bhattacharya, S., Bosch, E., Costello, M., Gersak, K., Homburg, R., Mincheva, M., Norman, R. J., Piltonen, T., Dos Santos-Ribeiro, S., Scicluna, D., Somers, S., Sunkara, S. K., Verhoeve, H. R., & Le Clef, N. (2023). Evidence-based guideline: unexplained infertility. Hum Reprod. https://doi.org/10.1093/humrep/dead150
Romualdi D, Ata B, Bhattacharya S, Bosch E, Costello M, Gersak K, Homburg R, Mincheva M, Norman RJ, Piltonen T, Dos Santos-Ribeiro S, Scicluna D, Somers S, Sunkara SK, Verhoeve HR, Le Clef N. Evidence-based guideline: unexplained infertility. Hum Reprod. 2023. doi:10.1093/humrep/dead150
Romualdi, D., et al. "Evidence-based guideline: unexplained infertility." Hum Reprod, 2023.
