Unexplained Infertility: An Update

Unexplained Infertility: An Update ABSTRACT Key Content - Unexplained infertility accounts for up to 30% of cases of infertility. - Potential causes for unexplained infertility have been proposed including reduced oocyte quality, poor endometrial receptivity, ovulatory PCOS, subclinical endometriosis and low semen quality. - Investigations for the diagnosis of infertility include assessment of ovulation, tubal patency, semen quality and uterine structure. - Predictive models such as the Hunault model can predict the likelihood of natural conception in those with unexplained infertility and can help guide management options which include expectant management, intrauterine insemination (IUI) (with or without ovarian stimulation) or in vitro fertilisation (IVF). - Current NICE guidance advises that couples with unexplained infertility are referred for IVF after 2 years of trying to conceive naturally. The recent ESHRE guidance supports IUI as a first-line treatment for those with unexplained infertility. There is some evidence that both IUI and IVF confer a benefit in those with a poor prognosis to natural conception; however, further good-quality research is required. Learning Objectives - To review current definitions and potential hypotheses for the causes of unexplained infertility. - To summarise the best practice for the investigation of the subfertile couple. - To summarise and review recent evidence on the treatment of unexplained infertility. 1 Introduction Infertility affects around 12%–15% of couples worldwide [1, 2]. Due to variations in diagnostics and population variation, the reported incidence of underlying causes varies hugely, but male factor infertility probably accounts for around 30% of cases. Female factors including ovulatory disorders, tubal factors and uterine disorders may account for 30%–50%. However, in around 30% of cases, the cause for infertility remains unexplained [3, 4]. The recent guidance from the European Society of Human Reproduction and Embryology (ESHRE) (2023) defines unexplained infertility for couples who have been unable to conceive after at least 12 months of regular, unprotected intercourse where testing has not revealed a cause; ‘infertility in couples with apparently normal ovarian function, fallopian tubes, uterus, cervix and pelvis, female age ≤ 40 years and with adequate coital frequency; and apparently normal testicular function, genito-urinary anatomy and a normal ejaculate’. Unexplained infertility is a frustrating diagnosis for patients and clinicians alike—a lack of clarity on the underlying obstacle to conception has proven a barrier to the development of new treatment strategies or consensus on a best-practice treatment plan. This paper will discuss the possible aetiologies underlying UI and the evidence behind different treatment strategies. 2 The Aetiology of Unexplained Infertility Unexplained infertility is an umbrella term applied to all couples who do not fit neatly into the other defined categories of infertility. It is unlikely to be a single pathology for all those diagnosed with unexplained infertility, and there may be multifactorial, subtle underlying causes for the infertility affecting these couples. The reported prevalence of unexplained infertility is therefore inversely related to the depth of investigation. The following factors are commonly proposed as contributors to unexplained infertility: 2.1 Oocyte Quality Oocyte quality plays an undeniably important role in conception; however, at present, it can only be analysed in vitro in the context of assisted reproductive technology (ART). Oocyte quality can be assessed by the ability of an oocyte to complete meiosis, undergo fertilisation by a single spermatozoon and continue normal embryonic development as an embryo, resulting in live birth. The main factor affecting oocyte quality is age, and it has been proposed that age > 37 should be used as an independent diagnostic criteria for unexplained infertility [5]. The mechanisms by which age impacts oocyte quality are multifactorial but have been linked to mitochondrial dysfunction, meiotic spindle dysfunction, free-radical production, cohesins, genomic instability and telomere attrition [6]. Higher live birth rates are seen in women aged < 35 undergoing in vitro fertilisation (IVF) for unexplained infertility compared to other causes, suggesting reduced oocyte quality is unlikely to be the cause in younger women (47% live birth rate vs. 38% for a known cause of subfertility) [7]. There is no absolute age cut-off for fertility, as it is a continuous decline until cessation of ovarian activity at the time of menopause, and there remains a small possibility of pregnancy for the first 12–24 months after the final menstrual period, depending on the age at which this is encountered. A reduction in oocyte quality may be accelerated by other factors such as oxidative stress and genetic mutations, but this is challenging to prove [8]. The zona pellucida and metaphase spindle structure can act as biomarkers indicative of oocyte function which can be tested via polarised light microscopy, harmonic generation microscopy, optical adherence microscopy and analysis of cytoplasmic velocity; however, these tests are not validated and require further research before being used in a clinical setting [9, 10]. 2.2 Male Factors Male factor is infrequently considered as a contributor to unexplained infertility [11]. In addition to traditional semen analysis, there are many other more subtle factors affecting the ability of sperm to fertilise an oocyte successfully including deoxyribonucleic acid (DNA) fragmentation, oxidative stress levels and genetic factors including de novo mutations [12, 13]. Routine semen analysis does not assess other factors such as sperm function (using hemizona or acrosome function assays) and DNA fragmentation—possible subtle defects which may be contributing to unexplained infertility. The development of ICSI techniques has removed some of the need to understand and further investigate many abnormal semen analysis results [12] but should not detract from their consideration when seeking a cause for UI. 2.3 Subclinical Endometriosis It is well known that women with endometriosis are disproportionately represented in the infertile population, with an estimated 25%–50% [14] of infertile patients being diagnosed with endometriosis [15]. 25% of women with stage 1–2 endometriosis are asymptomatic and pain-free [16]—these women may be over-represented in an unexplained infertile population. Endometriosis frequently affects tubal patency but may also affect fertility through inflammatory pathways even when tubal patency is unaffected and endometriomas are not visible on ultrasound. Despite this, exclusion of endometriosis tends not to be included in standard diagnostic investigation panels for infertility. 2.4 Polycystic Ovarian Syndrome (PCOS) PCOS is the most common ovulatory dysfunction disorder associated with infertility [17] however, it may still be associated with infertility even when regular cycles are present [18], particularly in the obese population. Insulin resistance can be present in those with PCOS, both in the slim and obese phenotypes. Oocyte quality and maturity have been shown in ART studies to be adversely affected by molecular changes due to inflammation associated with obesity and insulin resistance [19]. In addition, there is evidence that obesity contributes to reduced endometrial receptivity, a process driven by dysregulation of various cytokines [20]. Women with PCOS may also be affected by progesterone resistance, reducing endometrial receptivity [21]. 2.5 Endometrial Receptivity There is currently no accurate test for detecting luteal phase defect or defective development of endometrial receptivity [22]. Having been a controversial topic for years, reduced progesterone production or response leading to reduced receptivity is now widely acknowledged as a possible cause for infertility [22, 23]. Tests have been developed to assess receptivity and the optimal timing of implantation within ART cycles, but no intervention has yet been shown to significantly improve treatment outcomes. Further research into the development of testing and treatment for this is ongoing. 2.6 Obesity and Lifestyle Factors Obesity has been shown to impact time to conception in young women with regular menstrual cycles, independent of PCOS. Mechanisms such as increased androgens, insulin, lipid and inflammation levels in serum have been suggested as possible causes which may impact oocyte quality [24, 25]. Stress, smoking status and alcohol intake may have a role to play in infertility; however, there is no current evidence that these levels differ between women with unexplained infertility compared to women with other subgroups of infertility and fertile populations [26]. 2.7 Summary The underlying cause of infertility has not been the focus of adequate research, and therefore, at present, the subtle defects impacting the chance of pregnancy are poorly understood, and treatments cannot be targeted towards correcting them. 3 Recent Hypotheses Recently published literature investigates the following additional possible causes: 3.1 Psychological Factors Some couples are affected by psychological barriers to conception including fear of conception, psychosexual disorders and lack of intercourse [27]. Underlying issues reported to impact fertility can include body image dysmorphia, impact of infertility on sexual desire and psychological sequelae of previous traumatic birth in secondary infertility. 3.2 Coeliac Disease The prevalence of coeliac disease is higher in the infertile population compared to the general population, particularly within the subgroup of unexplained infertility [28]. There is an average delay in diagnosis of 10 years for women with coeliac disease, with an average age at diagnosis being 40–50 years. A meta-analysis reported that women with unexplained infertility have a 6× increased risk of coeliac disease compared to the background risk (OR = 6; 95% CI, 2.4–14.6) [29]. 3.3 Collapsing Zona Pellucida Women with unexplained infertility have been found to have more oocytes with collapsing zona pellucida during ART cycles. It has therefore been postulated that if this is occurring in vitro, this may also be happening in vivo, leading to a failure in conception [30]. 3.4 Imbalanced Adaptive Immunity Immunology involves a balancing act between cellular immunity components such as T cells, cytokines and autoantibodies amongst other factors. There is a suggestion that an imbalance of these factors could contribute to UI [31]. 3.5 Uterine Peristalsis Uterine peristalsis describes the contractility patterns of the smooth muscle of the myometrium. These patterns change during the menstrual cycle and during the late follicular phase, waves of contractions can be seen originating from the cervix towards the fundus of the uterus. It is thought that this contractility assists in rapid sperm transport and therefore fertilisation. Uterine pathology such as endometriosis, adenomyosis and leiomyomas affect peristalsis; however, patterns of uterine peristalsis may also differ in women with unexplained infertility compared to fertile women [32]. 4 Diagnostic Criteria One of the barriers to good-quality research and therefore progress towards better understanding and treating this condition is the heterogeneity between diagnostic tests applied to infertile couples, which leads to heterogeneity between populations assigned this diagnosis [33]. To meet the criteria suggested by ESHRE [34] and supported by the work in a systematic review on the diagnosis of unexplained infertility [33] as a minimum standard the following assessments are required before any diagnosis is applied. Assessment for infertility is far from standardised and the depth of testing applied to an individual or couple can alter not only their diagnosis but also their treatment options. 4.1 Evidence of Ovulation The detection of ovulation is challenging, and for many years successful ovulation has been assumed based on simple methods including a patient-reported history of regular menstrual cycles. Regular menstrual cycles suggest a high likelihood of a normally functioning hypothalamic–pituitary–adrenal–ovarian axis with successful ovulation. A history of regular menses is usually acceptable as a marker of ovulatory status [35] and ESHRE guidance suggests no confirmatory testing is required. Ultrasound follicle tracking and/or urinary ovulation prediction kits measuring luteinising hormone (LH) and sometimes estradiol are both reliable methods of assessing ovulation [34]. Basal body temperature testing (BBT) and endometrial biopsy have previously been used as methods of assessment of ovulation but are inaccurate and not now recommended [34, 36]. Mid-luteal serum progesterone level is another commonly used test of ovulatory function [36]. A 2015 study found that a single serum P > 5 ng/mL (15.9 nmol/L) had a specificity of 98.4 (95% CI 96.0–99.5) for ovulation as confirmed with ultrasound, cervical mucus testing and basal body temperature, with a sensitivity of 89.6 (95% CI 85.2–92.9) [37]. A recent study compared the accuracy of serum progesterone measurement combined with urinary LH monitoring with follicle tracking ultrasound for detecting ovulation. One study comparing LH surge measurement to ultrasound evidence of ovulation reported that a positive progesterone level 6 days after a detected LH surge was 79% accurate, with 80% sensitivity and 71% specificity [38] for the detection of ovulation. Progesterone levels can vary due to the pulsatile nature of its luteal production [39] and one single measurement of serum progesterone may not be useful for ruling out ovulation. In the United Kingdom, the NICE accepted cut-off is 30 nmol/L on day 21 of a 28-day cycle or 7 days after evidence of an LH surge measured in either serum or urine. 4.2 Semen Analysis Semen analysis is the primary test for male infertility. Evidence supports repeating an abnormal semen analysis to reduce the rate of false positive results in the diagnosis of male factor infertility. Various elements can be assessed including volume of ejaculate, total number of sperm, density of sperm (million/ml), motility of the sperm (progressive and non-progressive), sperm vitality and sperm appearance or percentage of ‘normal forms’. The World Health Organization 2021 laboratory manual for the examination of semen is recommended for standardisation of results, but relies on laboratories standardising their procedures in a compliant manner [40]. It is rare that any further testing is applied to men with normal results. In recent years, newer tests of sperm function have been developed including DNA fragmentation, hypo-osmotic swelling, acrosome reaction, sperm capacitation, hemizona binding assay, seminal reactive oxygen species, mitochondrial dysfunction, antisperm antibody and nuclear chromatin de-condensation (NCD) tests [41]. The utility of most of these is not yet proven, and they are therefore not widely offered. ESHRE guidance on unexplained infertility does not recommend testing DNA fragmentation since the evidence for its relevance or contribution to infertility if semen analysis is otherwise normal is limited [34]. An umbrella review of 22 systematic reviews demonstrated a weak association between DNA fragmentation and livebirth rate in one systematic review and no significance in a further 4. There were also weak or non-significant associations between DNA fragmentation and pregnancy, miscarriage, implantation, blastulation and fertilisation rates [42]. Further research is required before DNA fragmentation analysis is included in standard semen analysis processing. 4.3 Tubal Patency Tubal patency can be assessed in a number of different ways. Traditionally, hysterosalpingography (HSG) was the most commonly used investigation. Hystero-contrast-salpingography (HyCoSy) is now a recognised technique performed with dynamic ultrasound imaging which has good diagnostic sensitivity and specificity. Laparoscopy is another modality used to assess tubal patency; however, the risks involved are substantial compared to HSG and HyCoSy, and it is often only used first-line if history or symptoms suggest significant pelvic pathology. 21-68% abnormalities seen at laparoscopy are missed at HSG/HyCoSy; these are often cases of undiagnosed endometriosis [43]. However, for diagnosing tubal blockage alone, HyCoSy is comparable to laparoscopy and superior to HSG [44]. There is no consensus on whether tubal patency (ruling out tubal factor as the cause of subfertility) can include unilateral tubal patency. Confirmation of tubal patency by the methods described above does not assess tubal function. If the contralateral tube is blocked or has been removed due to infection, endometriosis, pelvic adhesions, ectopic pregnancy or other causes, it is not possible to rule out underlying tubal damage affecting the function of the remaining tube with the same aetiology. 4.4 Hormone Profile Most fertility assessments will involve the measurement of different female hormones. These often include LH, follicle-stimulating hormone (FSH), oestradiol, mid-luteal serum progesterone and anti-mullerian hormone. The evidence for the impact of abnormal hormone levels on female fertility in the presence of confirmed ovulatory function is limited. Abnormal thyroid hormones and prolactin can interfere with regular cycling, but treating the abnormality may improve pregnancy outcomes regardless of ovulatory status. 4.5 Uterine Cavity Assessment The uterine cavity can be affected by congenital or acquired abnormalities. Congenital anomalies include arcuate, septate, unicornuate, bicornuate and didelphi uteri. The evidence on the impact on fertility of endometrial polyps, uterine septae and even the major uterine anomalies is unclear. One large study discovered a 13.3% rate of uterine anomalies in women referred to a tertiary unit with subfertility. Despite this high rate of detection in the infertile population, the pregnancy outcomes of ART cycles in women with arcuate uteri (36/66 (54.5%) p = 0.09) and the major uterine anomalies (7/10 (70.0%) p = 0.11) were not significantly different to the case-matched controls with normal uterine cavities. However, miscarriage rates were higher in the major anomalies group (3/7 (42.9%); p = 0.05) [45]. Submucosal fibroids have been proven to affect the likelihood of pregnancy [46] and therefore should be excluded before making a diagnosis of unexplained infertility. Uterine cavity assessment can be undertaken during an ultrasound or tubal patency test (HSG/HyCoSY) and, therefore, should be easy to include in a routine fertility evaluation. 3D ultrasound is the gold standard for assessing the uterus and uterine cavity, but even a 2D ultrasound should be adequate to detect significant cavity defects. 4.6 Summary According to ESHRE and NICE, before diagnosing unexplained infertility, couples need a thorough history and investigations to assess ovulatory status, tubal patency, endometrial cavity and semen analysis. 5 Modelling Likelihood of Conception The likelihood of natural conception varies widely from couple to couple with unexplained infertility, and various prediction models have been proposed to help determine which couples should seek treatment rather than expectant management. All models have limitations, but can be helpful when managing expectations of couples seeking treatment, as well as guiding the timing of recourse to treatment. The Hunault model [47] is the most widely used and successful model when tested with external validation. This uses a logistic regression model to predict the likelihood of natural conception in the next 1 year. This model was revised by Bensdorp et al. [48] to include outcomes of pregnancies in the current relationship, tubal status, BMI, cycle length, baseline FSH, semen volume and sperm morphology to improve predictive accuracy (Table 1). The van Eekelen model uses similar information to predict spontaneous pregnancy at 6, 12 and 18 months [49]. | Parameter | Finding | Points | |---|---|---| | Woman's age | 21–25 years | 0 | | 26–31 years | 2 | | | 32–35 years | 6 | | | 36 or 37 years | 9 | | | 38 or 39 years | 11 | | | 40–41 years | 12 | | | Duration of subfertility | 1 year | 0 | | 2 years | 2 | | | 3 or 4 years | 5 | | | 5 or 6 years | 9 | | | 7 or 8 years | 13 | | | Type of subfertility | Primary | 6 | | Secondary | 0 | | | Motility in percent | ≥ 60% | 0 | | 40%–59% | 2 | | | 20%–39% | 4 | | | < 20% | 6 | | | Referral status | Secondary care | 0 | | Tertiary care | 4 | | | Post-coital test | Normal | 0 | | Abnormal | 14 | - Note: Total score = SUM (points for all six parameters). - Interpretation: - Minimum score: 0. - Maximum score: 55. - The higher the score, the lower the chances of spontaneous pregnancy. - Probability of spontaneous pregnancy = (0.0289 × ((score)2)) − (2.8016 × (score)) + 72.93. - Source: Models of Hunault et al. for Spontaneous Pregnancy Leading to Live Birth for a Subfertile Couple: 2-Sample Model|Medicalalgorithms.com. The McLernon model (now converted for use online as the OPIS calculator) can be used to predict livebirth following IVF/ICSI cycles both pre-cycle and post-IVF cycle. It uses maternal age, pregnancy history, duration of infertility as well as subtypes of infertility (tubal, male factor, ovulatory disorders, unexplained infertility) to predict live pregnancy outcomes after serial IVF cycles. 5.1 Summary Many couples with unexplained infertility will have good chances of natural conception. However, expectant management is often an unattractive option for couples, given the psychological stress associated with prolonged infertility. Active treatment options are currently expensive, invasive and time-consuming and careful counselling is required for couples choosing how to proceed with management of their infertility. 6 Current Treatment Consensus Common treatment options for unexplained infertility are expectant management, intrauterine insemination (IUI) and IVF/ICSI. Factors which may affect treatment choice include availability, effectiveness, safety, cost and emotional/physical/psychological burden. 6.1 Expectant Management Models such as Hunault and van Eekelen suggest that some couples with unexplained infertility have up to a 30%–40% chance of natural conception over 12 months. The likelihood of natural conception in couples with unexplained infertility does vary with female age and length of time trying to conceive, but the average probabilities of conceiving are around 2%–4% per cycle or 15% in 1 year [50]. Expectant management can include techniques to enhance chances of success such as timed intercourse with ovulation prediction—a Cochrane review of four RCTs (n = 1387) reported that timed intercourse improved live pregnancy rates (RR 1.35, 95% CI 1.06 to 1.71, I (2) = 0%, with very low level evidence) [51]. However, this evidence was of low to very low quality. A systematic review comparing the outcomes of timed intercourse, ovulation induction, IUI and IVF in women aged 18–40 with unexplained infertility suggested that timed intercourse was as effective as either superovulation with clomiphene citrate or gonadotrophins and IUI with ovarian stimulation [52]. A recent study compared the cumulative livebirth rates of women over 39 with unexplained infertility, either trying a year of expectant management, then up to 1 cycle of IVF or having 1 cycle of IVF immediately after diagnosis and found no statistically significant difference between the two groups (19.5% immediate versus 20.7% waiting, 95% CI −0.07 to 0.05) [53]. Of interest, 16% of the livebirths in the immediate treatment group resulted from natural conceptions. It is important to consider when counselling patients regarding management options what the negative impact on IVF outcomes might be if recommending delayed treatment. The latest HFEA data from 2023 suggests that per embryo transfer livebirth rates in the 38–39 age category were 25% and 17% in the age 40–42 category, dropping to 9% in those aged 43–44, illustrating the age-related decline in fecundity [54]. Spontaneous pregnancy rates decline with age and are illustrated below in Table 2. | Maternal age | Pregnant after 1 year/12 cycles | Pregnant after 2 years/24 cycles | |---|---|---| | 19–26 | 92% | 98% | | 27–29 | 87% | 95% | | 30–34 | 86% | 94% | | 35–39 | 82% | 90% | Expectant management is proposed in NICE guidance for at least 1 year in couples diagnosed with unexplained infertility. Contradictorily, the ESHRE guidance advises that there is a lack of good-quality research comparing expectant management to active fertility treatments and suggests that the decision to proceed to active fertility treatments should be ‘based on patient characteristics and preferences’. It is important when counselling patients to consider the impact of delaying IVF treatment on success rates if they do not conceive naturally. In the United Kingdom, eligibility criteria for NHS funding for fertility treatment also have varying upper age limits so consideration of this is also pertinent. 6.2 Intrauterine Insemination (IUI) The evidence for the use of IUI in unexplained infertility is inconclusive. IUI can be performed in cycles with or without ovarian stimulation. Evidence is mixed for gonadotrophins and clomiphene and lacking for use of letrozole stimulation or unstimulated unexplained infertility. The most recent Cochrane review of intrauterine insemination for unexplained infertility combined the results of 15 trials (n = 2068). They compared IUI, IUI with ovarian hyperstimulation and conservative management. For most subgroups analysed, there was no evidence that IUI improved livebirth rates without unacceptably high multiple birth rates compared to conservative management or timed intercourse. IUI vs timed intercourse in stimulated cycles: OR 1.59, 95% CI 0.88 to 2.88. IUI vs timed intercourse in natural cycles: OR 1.60, 95% CI 0.92 to 2.78. IUI in stimulated cycle vs IUI in natural cycle: OR 2.07, 95% CI 1.22 to 3.50. For couples with a low chance of natural conception, IUI combined with ovarian stimulation medication ‘probably’ improves livebirth rates. However, the quality of these individual studies was low and further research is required [55]. The National Institute for Health and Care Excellence (NICE) guidance does not accept IUI as a treatment for unexplained infertility, whereas the ESHRE guidance supports its usage as a first-line treatment. 6.3 In Vitro Fertilisation (IVF) IVF is able to overcome issues with sperm and egg transport, sperm–egg interaction, ovulation dysfunction, tubal and cervical factors [15, 56, 57]. Therefore, it is an attractive option for couples with an undefined cause of infertility. However, IVF is not universally accessible and is not only expensive and invasive but has also been associated with significant risks including multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) (Table 3). | Age group | 18–34 | 35–37 | 38–39 | 40–42 | 43–44 | |---|---|---|---|---|---| | Pregnancy rate | 41% | 34% | 25% | 17% | 9% | Current NICE guidance states that patients with unexplained infertility can be considered for IVF after 2 years of trying to conceive, with an update expected that suggests consideration of four cycles of IUI with gonadotrophin stimulation first. ESHRE guidance suggests that IUI should be used as a first-line treatment and that the decision to treat with IVF should be individualised for the couple. A recent meta-analysis included eight randomised controlled trials (RCTs) comparing IVF with IUI + controlled ovarian stimulation (COH) for unexplained infertility and demonstrated that IVF was associated with a higher livebirth rate (RR 1.53, 95% CI 1.01–2.32, p < 0.00001). However, analysis of results for women under 38 who had not previously received fertility treatment showed no benefit to IVF (RR 1.01, 95% CI 0.88–1.15, I2 = 0%, three RCTs), whereas a subgroup analysis of women over the age of 38 showed a significant benefit for IVF (RR 2.15, 95% CI 1.16–4.0, I2 = 42%, 1 RCT) [58]. A Cochrane review has been published comparing expectant management with IUI + COH, IUI alone and IVF in a network meta-analysis (10 RCTs, n = 2725). This study found no significant differences in outcomes for any of these treatments when compared with expectant management. When only considering couples with a poor prognosis for natural conception, there was a benefit to IUI (OR 4.48, 95% CI 2.00 to 10.1) and IVF (OR 4.99, 95% CI 2.07 to 12.04) treatment, but no clear difference between these two treatment options (OR 1.11, 95% CI 0.78 to 1.60) [59]. 6.4 Summary It appears that there is not enough evidence to support the usage of IVF as a first-line treatment for couples with unexplained infertility. Management decisions should be made on a case-by-case basis, as there may well be subgroups within the unexplained infertility population who would benefit from faster access to IVF and others who have equal chances of a livebirth from expectant management or IUI with or without COH. 7 Conclusion Unexplained infertility is an umbrella term describing couples with infertility for whom no clear cause has yet been found. A variety of hypotheses have been proposed as potential causes for unexplained infertility; it is widely accepted that it is unlikely that all of those with unexplained infertility will have a single unifying underlying pathological process. Little progress has been made towards better understanding the aetiology of unexplained infertility, hindering the determination of the best treatment plans. Standardising the diagnostic tests applied before the diagnosis is made will help in the accurate comparison of treatment options and more meaningful meta-analysis of trial results. In the meantime, a holistic approach starting with a detailed history, appropriate testing and possibly the application of prediction models is a good starting point and expectant management, IUI or IVF, when used appropriately, offer these couples an overall excellent chance of achieving their desired family. Author Contributions C.R. performed the research, wrote the original manuscript and then edited the re-drafted version. R.F.-L. transformed the original manuscript into the current format, and P.B. supervised and corrected both original and new versions. All authors edited the final manuscript before submission. Conflicts of Interest The authors declare no conflicts of interest.