Elpiniki Chronopoulou^1,2, Sadaf Shaikh^3, Claudia Raperport^2,4, Kate Brian^5, Grace Ogwel^2, Harish Bhandari^6, Bassel H Al Wattar^7,8, Efstathios Theodorou^1, Javier Zamora^9,10, Priya Bhide²

1 The Centre for Reproductive & Genetic Health (CRGH), Great Portland Street, London, W1W 5QS, UK,
2 Women’s Health Research Unit, Wolfson Institute of Population Health, Queen Mary University of London, Yvonne Carter Building, 58 Turner Street, London E1 2AB, UK,
3 King’s Fertility, the Fetal Medicine Research Institute, Windsor Walk, Denmark Hill, London, SE5 8BB, UK, 4. Whittington Health NHS trust, London, UK,
5 The Fertility Alliance, United Kingdom
6 Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals NHS Trust, Seacroft Hospital, York Road, Leeds LS14 6UH
7 Clinical Trials Unit, Anglia Ruskin University, Chelmsford, UK,
8 Beginings Assisted Conception Unit, Epsom and St Helier University Hospitals, London, UK,
9 Clinical Biostatistics Unit, Hospital Universitario Ramon y Cajal (IRYCIS), Madrid Spain,
10 CIBER Epidemiology and Public Health CIBERESP, Clinical Biostatistics, Madrid, Spain

Abstract

Intrauterine insemination (IUI) is a commonly offered fertility treatment for a variety of indications. There are multiple add-ons and variations to the IUI treatment protocol which are mostly offered empirically. The scope of this guideline is to review the existing literature aiming to offer evidence-based recommendations for their use in clinical practice. Standardising IUI treatment is important not only to optimise outcomes, but also to enable comparisons and future research in the field. This guideline assessed twenty-five different interventions to the standard IUI protocol. Add-ons and variations assessed included: follicular tracking, LH surge monitoring, types of IUI catheters, full bladder, slow insemination, operator experience, cervical mucus aspiration, endometrial scratch, hydrotubation, follicular phase stimulation, use of ovulation trigger, type of trigger and timing of trigger, use of intrauterine infusions prior to IUI, use of medications aiming to affect receptivity or uterine contractility during or after the IUI, double insemination, ultrasound guidance, bed rest and luteal phase support. The systematic literature search resulted in 154 randomised controlled trials (RCTs) with 34825 participants. Meta-analysis was performed for each research question when possible. There is a lack of well- powered RCTs with definitive conclusions in the literature, and as a result, most recommendations are based on low quality evidence; this must be emphasised in patient counselling. Future studies should take into account the background diagnosis and explore the efficacy of IUI add-ons for specific patient groups.

Introduction

Intra-uterine insemination (IUI) is a commonly offered fertility treatment. The UK Human Fertilisation and Embryology Authority (HFEA) data reported 7069 cycles of IUI using donor sperm in 2021 and more than 200,000 cycles were reported in Europe in 2019 and 150461 in 2020 (Smeenk et al., 2023; 2025). IUI has been used for treatment with donor sperm for single women, same sex couples or severe male factor infertility, treatment for couples for whom vaginal intercourse is not possible, HIV-discordant couples, unexplained infertility (UI), mild male factor, mild endometriosis, and anovulatory infertility in combination with ovulation induction.,

IUI is less invasive and safer than in vitro fertilisation (IVF). However, The NICE (National Institute for Health and Care Excellence) guidance (2013; updated 2017) does not recommend IUI treatment for UI, mild endometriosis or mild male factor. The rationale is that IUI is less successful than IVF and, when combined with ovarian stimulation, may be associated with higher multiple pregnancy rates (MPR) (Bahadur et al., 2015). This comes in contrast with guidance from the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) (Penzias et al., 2020; Romualdi et al., 2023) which suggest stimulated IUI as first line option for UI. The 2026 updated NICE guideline (March 2026) suggests that for people with UI, mild endometriosis or mild male factor fertility problems there should be a discussion regarding the treatment options including the benefits, risks and their individual preferences and consider up to four cycles of IUI with ovarian stimulation using gonadotrophins prior to IVF or offer directly IVF treatment (NICE, 2025).

The HFEA reported 12% live birth rate (LBR) for IUI with donor sperm (HFEA, 2023). In the UK, IUI with donor sperm declined by 4% from 2019 to 2023 due to increased use of IVF (preliminary data, HFEA, 2025). The same trends were noted in European data by ESHRE (Smeenk et al., 2023).

In the most standard/basic form of IUI, sperm preparations aim to separate better quality sperm from the ejaculate. The sperm is then deposited directly into the womb at the time of ovulation in a natural cycle. Numerous variations to the standard treatment protocol and add-ons have been proposed as strategies to increase success rates but their use remains variable and largely empirical.

There is wide variation in clinical practices for IUI across clinics globally and high variation in success rates and MPR. Consensus around best practice is an urgent requirement. The objective of this guideline is to provide evidence-based recommendations on clinical protocols for IUI treatment.

Materials and methods

Literature search

Standard IUI treatment was defined as a natural cycle IUI, without follicular phase stimulation or follicular tracking, without ovulation trigger, with a single, non-ultrasound guided insemination, and no other medication/intervention. Every additional intervention was considered an add-on or variation. Twenty-five different interventions were identified.

Two systematic literature reviews, one for standard IUI treatment, and one for IUI with add-on(s) were conducted based on Cochrane methodology using EMBASE, MEDLINE and CINAHL as well as the Cochrane Central register of trials from database inception to May 2025. For the purpose of this guideline, ‘standard IUI treatment’ was defined as natural cycle IUI, with no ovarian stimulation, no follicular tracking, no trigger, a single, non-ultrasound guided insemination, and no other medication/intervention. IUI treatment with any additional intervention was considered IUI with ‘add-on(s)’ and practice variations were considered as ‘variations’. Twenty-five different interventions were identified and assessed.

The reviews were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (Page et al., 2021) and have been registered on PROSPERO (registration number CRD42022300857 and CRD42022327131). The search strategies and results are included in supplementary material (Appendix S1-S5). The details of the screening and selection process are depicted in PRISMA flowcharts (Figure 1a,b,c). A literature search for add-ons performed previously (Chronopoulou et al., 2024), was updated by extending the earlier search to May 2025 (Figure 1b,c). The list of included studies and patient demographics are included in supplementary material (Appendix S6a-c).

Participants

Couples/single women undergoing one or more cycle(s) of IUI with any treatment protocol for any indication using partner or donor sperm.

Controls

Patients undergoing standard IUI treatment or IUI using a different variation or add-on intervention.

Variations

Pre-IUI: follicular tracking, LH surge monitoring.
During IUI: IUI catheters, full bladder, slow insemination, operator experience, cervical mucus aspiration.

Add-on interventions

Pre-IUI: endometrial scratch, hydrotubation, follicular phase stimulation, use of ovulation trigger, type of trigger, follicle size at the time of trigger, timing from trigger to IUI, use of human chorionic gonadotropin (hCG) intrauterine infusion, granulocyte colony-stimulating factor (G-CSF) intrauterine infusion or subcutaneous injection, platelet rich plasma (PRP) intrauterine infusion, Peripheral Blood Mononuclear Cells (PBMC) intrauterine infusion.

IUI stage: double insemination, ultrasound guidance during the procedure, oral or vaginal misoprostol at the time of IUI, administration of tocolytic agents.

Post IUI: intranasal oxytocin immediately after IUI, bed rest, luteal phase support, non-steroidal anti-inflammatory drugs (NSAIDs).

Primary outcomes

1. Live birth rate (LBR) / ongoing pregnancy rate (OPR); viable pregnancy beyond 12 weeks of gestation) per cycle/per woman randomised. LBR was primarily used and if not reported, OPR was used.

Secondary outcomes

1. Pregnancy rate (PR) (positive urine or blood pregnancy test).
2. Clinical pregnancy rate (CPR) (ultrasound confirmation of gestational sac +/- heartbeat).
3. Miscarriage rate (MR) (loss of pregnancy before 22-24 weeks of gestation).
4. MPR (ultrasound confirmation of at least two gestational sacs +/-heartbeats).

Included studies

Only RCTs were included. RCTs that randomised per woman and per cycle were included. Outcomes for the first treatment cycle only were included, where possible, when randomisation was per woman and multiple cycles were performed. Cumulative outcomes per woman were not assessed.

Excluded studies

• Studies assessing intracervical or intrafallopian sperm perfusion.
• Studies assessing interventions aimed to improve a baseline condition, rather than evaluate the efficacy of the IUI protocol.
• Studies assessing sperm preparation techniques.
• Studies comparing dosages or different brand names of medications.
• Literature not available in English.
• Abstracts only.
• Animal studies.

This guideline does not address

• The role of IUI compared with expectant management in UI.
• The role of IUI versus IVF in the management of UI.
• Definitions of UI.
• Ovulation induction strategies.
• Patient selection for IUI treatment.
• Sperm preparation techniques.
• Cumulative success rates of IUI.
• Cost-effectiveness of different interventions.

Data analysis

A narrative review was planned for all outcomes for every research question.

Meta‐analysis was planned for primary and secondary outcomes where adequate and appropriate data were available to produce pooled estimates of effect. A pairwise meta-analysis using a random effects model and inverse variance method was performed for each question. The pooled estimates for outcomes were presented as relative risk (RR) with 95% confidence intervals. Statistical significance was assumed when p < 0.05.

A random effects network meta-analysis within a frequentist setting was performed for the primary outcome for the comparison of follicular phase stimulation protocols. The interval plot results for each intervention compared with reference and the league table for all interventions against others were presented. To assess the superiority of the interventions included in the network meta-analysis, calculations were made for the probability of being the best, the mean rank, and the surface under cumulative ranking (SUCRA), which represents the percentage of an intervention that can be ranked first without uncertainty. For each treatment, all cumulative ranking probabilities (line plots of cumulative probabilities against ranks) were estimated. To test the presence of global inconsistency, a full design-by treatment interaction random effects model (global χ2 test) was used. If the null hypothesis of inconsistency parameters being equal to zero was not rejected, no inconsistency was confirmed. Then, local inconsistency estimates were presented using forest plots and side-splitting for direct and indirect estimates if available.

All analyses were performed using Stata V.15 or Revman V5.

Assessment of study quality and risk of bias (ROB)

Two authors independently assessed the studies for quality of evidence and risk of bias (ROB) and discrepancies, when identified, were resolved through discussion or by consulting a third author (PB) where necessary. ROB was assessed based on the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions as updated in March 2011 (Appendix S7, S8).

Recommendations

The recommendations made by the guideline development group (GDG) (the authors through consensus) have been graded according to the GRADE approach, as either ‘strong’ or ‘weak’ recommendations, or as ‘good practice points’ where limited evidence exists, and the recommendation is instead based upon the expertise of the GDG members (the authors). The authors considered clinically beneficial and hence recommended interventions which resulted in a relative increase in LBR by 30% (this was decided through consensus, considering average success rate of IUI for any indication to be 10%). This guideline was ratified by the British Fertility Society (BFS) after review by the BFS Executive Committee and Membership.

Variations

1. Follicular phase ultrasound monitoring

Most fertility clinics perform a baseline ultrasound scan before the start of treatment to identify pelvic pathology. There are no studies to assess the use of ultrasound monitoring for natural cycle IUI. The ESHRE 2023 guideline on UI suggests the use of urinary LH, ultrasound monitoring or mid luteal progesterone measurement for women with regular cycles to confirm ovulation. There are no studies assessing different methods of home ovulation tracking for natural cycle IUI (basal body temperature monitoring/tracking apps/cervical mucus observation/wearable and app-linked devices/saliva home testing kits), the vast majority of authors have used urine LH kits in the literature. NICE guidance (2013, updated 2017) advises against using basal body temperature charts to confirm ovulation because they do not reliably predict ovulation.

In women with unilateral tubal patency, follicular laterality may be a relevant consideration during monitored cycles; however, as no relevant RCTs were identified, no recommendation can be made regarding cycle selection based on laterality.

Recommendations

• Cycles without ultrasound monitoring can be offered for natural cycle IUI to patients with regular cycles and no pathology identified on baseline ultrasound scan. The first day of last menstrual period should be documented as the start of the IUI cycle. If the urine LH kits are not reliable (no peak/no positive result/constantly positive throughout the cycle), ultrasound tracking should be advised. (Consensus. Good practice point).

2. Timing of the IUI procedure in relation to the reported LH surge and urinary LH monitoring

Ovulation occurs at a mean of 32 hours from the first significant rise in serum LH and at a mean of 16.5 hours after the peak. The time of first significant rise rather than that of the peak in serum LH is a more reliable indicator to predict impending ovulation (World Health Organization, Task Force on Methods for the Determination of the Fertile Period, 1980). The definition of what constitutes the start of the LH surge/significant LH rise varies in the literature ranging between 10-20 mIU/ml and the LH surges that lead to ovulation are variable in terms of amplitude and duration (Park et al., 2007). The time lag of 6-12 hours between the serum and urine detection of LH should be taken into consideration, although good correlation exists between serum and urine LH levels (Frydman et al., 1984; Pattnaik et al., 2022). The reported amplitude and duration of the LH surge also vary. The sensitivity of urine LH kits varies and therefore kits with lower sensitivity may miss a low-amplitude LH surge. It is reported that most women begin their pre-ovulatory LH surge between midnight and 08.00am (Nulsen et al., 1987). It has been suggested that twice daily urinary testing may improve the efficacy of identification of the LH surge (Cahill et al., 1998), but if this is implemented, the working times of fertility units and the costs associated with home ovulation testing should be considered. No RCTs were identified that explored the frequency of home ovulation testing or the interval between positive result on home ovulation testing and IUI procedure.

Ovulation (LH) tests are regulated as in vitro diagnostic (IVD) medical devices under the UK Medical Devices Regulations 2002 (as amended) and the EU IVDR (2017/746) (Ovulation tests as in vitro diagnostic medical devices, 2022). They must bear the UKCA (or CE) mark, indicating conformity with safety, analytical validity, and labeling requirements. Manufacturers must demonstrate that the product meets essential performance criteria such as sensitivity, specificity, and reproducibility. Clinical validation typically requires the LH kit to detect LH within a range of 20–40 mIU/mL, have ≥95 % agreement with laboratory immunoassay results in prospective testing, show inter-lot variability < 10 % and have clear visual readability and minimal false-positive rates.

Recommendations

• IUI should be performed between 24-36 hours after a reported positive urine LH surge at home testing. Once daily (early morning) urine LH testing is recommended. Commercially available urinary LH ovulation kits that are UKCA/CE marked or FDA-cleared and specify a sensitivity of 20–40 mIU/mL are considered reliable and meet accepted quality standards for detecting the pre-ovulatory LH surge. (Consensus. Good practice point).

3. Operator

Differences in success rates between different operators using similar catheters have been evaluated for embryo transfers (ETs) following IVF with equivocal results (Mizrachi & McQueen, 2022; Tyler et al., 2022). No similar trials were identified for IUI. Uterine contractility and the deposition of sperm in the uterine cavity for IUI is possibly not as important as for ET. The sperm can reach the fallopian tubes within five minutes from deposition in the vagina (Settlage et al., 1973) and expulsion of more than 40% of the volume infused into the cavity has been documented (Knutzen et al., 1992; Mansour et al., 1994).

Recommendations

• Operators should perform IUI after adequate training (Consensus, Good practice point). In the UK, the BFS offers an IUI training module within the Assisted Conception Training Framework. Competence should be demonstrated through structured assessment, in line with clinic policies and monitored via key performance indicators to ensure safety and consistent performance.

4. Full bladder

A full or half full bladder results in passive straightening of the anteverted uterus to facilitate introducing the IUI catheter through the cervical canal.

A single trial (460 participants) comparing the outcome of IUI performed in patients with a full or an empty bladder (Ayas et al., 2012) found that the PR was higher in the full bladder group (P=0.03, RR 1.95, 95% CI 1.048-3.637). The risk of difficulty in performing IUI was reported as being higher in the empty bladder group. The CPR was higher in the group of patients with easy IUI (RR 2.51, 95% CI 1.04-6.09). The quality of evidence was assessed as low.

Recommendations

• A full/half full bladder is recommended to facilitate the IUI procedure (Weak recommendation).

5. Aspiration of cervical mucus

Cervical mucus acts as a sperm reservoir, facilitating the slow release of sperm and sperm capacitation following intercourse (Katz, 1991). Hostile mucus has been proposed as a factor contributing to UI, and during the IUI, cervical mucus may be introduced into the uterine cavity and may have a negative effect on success rates.

We identified three trials exploring the removal of mucus prior to IUI (614 participants) (Azmodeh, 2012; Berjis, 2010; Vatsa et al., 2022). A meta-analysis was not possible as two trials did not report raw data, both of which individually reported an increase in PR with cervical mucus removal (Berjis 2010, Azmodeh 2012), compared to the third trial which reported no significant differences in CPR (Vatsa et al., 2022).

The quality of evidence was assessed as very low. Two studies (Berjis 2020, Azmodeh 2012) were conducted by the same groups, at the same centre and during similar time intervals. The patient populations in these two trials likely overlapped.

Recommendations

• Cervical mucus aspiration for IUI is not recommended (Consensus, Good practice point).

6. Slow-release insemination

It is hypothesised that slow sperm release (over 3-4 hours) provides low concentrations of sperm over a longer duration. This might mimic physiological sperm transportation from the cervix to the fallopian tube and prolong the period of potential fertilisation. No trials were identified comparing bolus insemination with other insemination durations.

We identified two trials (221 participants) comparing slow versus bolus insemination (Marschalek et al., 2020; Muharib et al., 1992). Both trials used a cross-over trial design and reported PRs. Both trials were included in the meta-analysis. No statistically significant difference was observed in PRs (RR 1.54, 95% CI 0.88-2.71) (Figure S1). Neither trial reported serious adverse effects.

The quality of evidence was assessed as very low.

Recommendation

• The use of slow-release sperm insemination over 3-4hours for IUI is not recommended (Weak recommendation, level of evidence -1). There is lack of evidence with regards to bolus insemination versus other insemination durations.

7. Catheter type

Soft catheters may improve success rates by minimising uterine contractions and trauma to the endometrium. Rigid catheters may facilitate easier negotiation of the cervical canal.

We identified four trials (932 participants) comparing soft versus rigid catheters for IUI (Fancsovits et al., 2005; Miller et al., 2005; Vermeylen et al., 2006; Vutyavanich et al., 2003). No difference was documented for LBR (RR 1.06, 95%CI 0.76-1.47) or CPR (RR 1.00, 95%CI 0.74-1.36) (Figure S2a-c). A single trial (Vermeylen et al., 2006) that reported miscarriage and multiple births did not report differences between groups.

The quality of evidence was assessed as low.

Recommendations

• The catheter types used for IUI should be based on operator preference, local policy and resources (Weak recommendation, level of evidence 1-).

Add-on interventions

8. Endometrial scratch

An endometrial scratch may induce a healing cascade in the endometrium, facilitated by various chemicals such as cytokines and growth factors which may improve the implantation potential (Gnainsky et al., 2010) whilst also possibly promoting decidualisation of the endometrium. However, no single mechanism or chemical response can replicate the complex events around implantation (Siristatidis et al., 2014). Endometrial scratch has been studied as an add-on to IVF. The ESHRE guideline (2023) does not support its use for UI,

We included 18 trials (3269 participants) investigating the use of endometrial scratch in stimulated, single IUI (Abdelhamid, 2013; Ashrafi et al., 2017; Bahaa Eldin et al., 2016; El et al., 2015; Ghuman et al., 2020; Goel et al., 2017; Gupta et al., 2018; Hamdi et al., 2019; Hosseinimousa et al., 2024; Jafarabadi et al., 2020; Madhuri et al., 2022; Maged et al., 2016; Mardanian et al., 2018; Senocak et al., 2017; Soliman & Harira, 2017; Wadhwa et al., 2015; Yavangi et al., 2021; Zarei et al., 2014). Five trials included participants with UI (Ghuman et al., 2020; Hosseinimousa et al., 2024; Jafarabadi et al., 2020; Madhuri et al., 2022; Senocak et al., 2017). In five trials, the scratch was performed during the month preceding the IUI cycle and in ten trials it was performed during the follicular phase of the same cycle as the IUI. Seven trials used a Pipelle® catheter (Laboratoire CCD, Paris, France). Other methods of scratch included outpatient hysteroscopy (1 trial), Tao brush® (Cook Medical, Bloomington, IN, USA) (2 trials), embryo mucus aspiration catheter after cutting the tip of the catheter sheath (1 trial), Novak curette (2 trials), neonatal feeding tube (2 trials), vaginal cannula No.4 (1 trial), Karman’s cannula No.4 (1 trial). One did not provide the method of scratch.

All trials were included in the meta-analysis (Figures S2a-d). Endometrial scratch was found to increase the chance of OPR/LBR (RR 1.52, 95% CI 1.14 -2.03, 7 trials, NNT=19) and CPR (RR 1.75, 95% CI 1.47 – 2.11, 18 trials, NNT=11) without affecting the chances of miscarriage (RR 1.22, 95% CI 0.70 – 2.12, 12 trials) or MPR (RR 1.07, 95% CI 0.39 – 2.90, 6 trials).

The quality of evidence was assessed as low for LBR/OPR, moderate for CPR and very low for MR/MPR. The effect on MPR and MR could not be assessed based on the existing evidence. No significant side effects were reported in these trials. The existing evidence (of low quality) demonstrates a benefit for IUI cycles. These trials were not only assessing patients with UI. Hence, a possible beneficial effect may apply to the general population of patients going through IUI for mixed indications possibly by addressing underdiagnosed endometrial pathologies, the pathophysiology behind this effect should be further studied.

Recommendations

• The existing evidence suggests clinical benefit from the endometrial scratch (NNT=19). However, endometrial scratch cannot be recommended as standard practice for all. It is important to consider that endometrial scratch is an invasive intervention and outcomes should be interpreted with caution due to low quality of evidence. Endometrial scratch may be offered on a case-by-case basis after careful patient counselling balancing risks and benefits. (Weak recommendation, evidence level 1-).

9. Hydrotubation

Tubal flushing (hydrotubation performed prior to IUI) may improve outcomes for IUI due to mechanical effect (removal of debris/mucus/minor obstructions/adhesions) and immunological mechanisms (reduction of detrimental cytokines/inflammatory factors/sperm phagocytosis) (Nugent et al., 2002; Watson et al., 1994, Rasmussen et al., 1991).

We included three trials (523 participants) assessing the effect of perturbation/hydrotubation. The procedure was performed at the time of trigger injection (Yildiz et al., 2024) or after positive ovulation kit (Aboulghar et al., 2010; Edelstam et al., 2008). No benefit was demonstrated for any of the studied outcomes (Figure S3) (very low quality evidence).

Recommendations

• Hydrotubation/pertubation is not recommended before IUI to improve success rates (Weak recommendation, evidence level 1-).

10. Follicular phase stimulation

Stimulated IUI has been reported to increase the success rates and MPR mostly because of multifollicular growth (van Rumste et al., 2008). We identified three trials with 837 participants comparing stimulated and natural cycle IUI (Guzick et al., 1999; Huang et al., 2021; Steures et al., 2007).

Huang et al. (2021) compared letrozole vs no stimulation (single comparison, feasibility study) and did not demonstrate statistically significant difference between the two groups. Two multi-centre trials (Guzick et al., 1999; Steures et al., 2007) used gonadotrophins for subfertile couples. Steures et al. (2007) randomized 132 couples for three IUI cycles in 24 fertility units. The authors concluded that for poor prognosis couples with abnormal postcoital test resulting from a cervical factor or a male factor, the addition of controlled ovarian stimulation in the IUI regime did not provide additional benefit in success rates. Guzick et al. (1999) in another multicenter RCT randomized 465 couples for four cycles. The authors included women ≤40 years of age, with normal endometrial cavity, normal hormone profile and regular cycles, in phase endometrial biopsy and negative serum antisperm antibody test. Inclusion criteria for men included age ≤55 years, negative serum antisperm antibody test and presence of any motile sperm on screening semen analysis. The authors randomized participants in four groups; intracervical insemination, IUI, stimulated intracervical insemination and stimulated IUI. Stimulated IUI cycles were twice as likely to result in pregnancy compared with natural cycle IUI. Seventeen of the 18 sets of twins in this trial were in the superovulation groups. However, there is no separate data for IUI cycles and intracervical insemination cycles therefore the multiple pregnancy data from this trial could not be retrieved and are not included in the analysis.

The study design included cancellation policies (number of follicles/estradiol levels). Both trials were included in the meta-analysis which showed that ovarian stimulation with gonadotrophins increases the chance of LBR/OPR (RR 1.39, 95% CI 1.00–1.94, I2 = 0%) (NNT=19) without increasing MPR (RR 2.15, 95% CI 0.61–7.6, I2 = 59.6%) (Figure 3). The quality of evidence was assessed as very low.

Recommendations

• Stimulated IUI using gonadotrophins should be offered for infertile couples using partner’s sperm (Weak recommendation, evidence level 1-). The cycles should be monitored, and cancellation criteria should be in place to reduce risk of multiple pregnancy (Consensus. Good practice point).

11. Ovarian stimulation protocols

A 2021 Cochrane systematic review (Cantineau et al., 2021) of stimulation protocols for IUI in ovulatory women concluded that ovarian stimulation using gonadotrophins improves cumulative LBR compared with oral agents, based on low/moderate‐certainty evidence without significantly higher MPR. A recent systematic review and meta-analysis (Wessel et al., 2022) concluded that ovarian stimulation with gonadotrophins yields a significantly higher number of dominant follicles and significantly improved LBR for IUI in patients with UI (moderate-quality evidence) but may increase MPR, especially triplets (low quality evidence). Strict cancellation was reported to increase safety with regards to MPR without compromising success rates. A meta-analysis by van Rumste et al. (2008) summarises that multifollicular development is linked to higher PR in stimulated IUI. However, with three or more follicles, the risk of multiple pregnancy rises disproportionately, with little additional improvement in overall pregnancy outcomes. Therefore, the authors conclude that stimulated IUI should aim to stimulate no more than two follicles. If safety is the primary priority, targeting a single follicle is recommended.

56 RCTs were identified (12156 participants) comparing ovarian stimulation protocols for IUI (Abdel Razik et al., 2017; Abunaila et al., 2020; Akbari et al., 2012; Al-Fozan et al., 2004; Al-Inany et al., 2010; Allegra et al., 2007; Asgharnia et al., 2022; Ayaz et al., 2018; Azmoodeh et al., 2015; Balasch et al., 1994; Barroso et al., 2006; Baysoy et al., 2006; Berker et al., 2011; Cantineau et al., 2011; Crosignani et al., 2006; Danhof et al., 2018; Dankert et al., 2007; Dansuk et al., 2015; Davar et al., 2006; Diamond et al., 2015; Duffy et al., 2006; Erdem et al., 2015; Ertunc et al., 2010; Fatemi et al., 2003; Fouda & Sayed, 2011; Ganesh et al., 2009; Gerli et al., 2000; Ghazizadeh et al., 2009; Gomez-Palomares et al., 2008; Gómez-Palomares et al., 2005; Gregoriou et al., 2008; Hendawy et al., 2011; Jain & Majumdar, 2016; Kamath et al., 2013; Karthik et al., 2018; Kaur et al., 2019; Lambalk et al., 2006; Lee et al., 2008; Moini et al., 2015; Nada et al., 2016; Peeraer et al., 2015; Pourali et al., 2017; Pourmatroud et al., 2013; Ragni et al., 2001; Ransom et al., 1996; Sengoku et al., 1994; Sh. Tehrani Nejad et al., 2008; Steward et al., 2011; Thyagaraju et al., 2022; Wadhwa et al., 2016; Weiss et al., 2018; Wu et al., 2007; Zadehmodares et al., 2012; Zarei et al., 2018; Zarei et al., 2015). Most trials did not differentiate results in terms of infertility diagnosis. Details and demographics of participants for all included trials are detailed in supplementary material. Inclusion criteria including age and BMI differed amongst trials (Appendix S6a).

For the purposes of this review, GnRH analogues were considered equevalent, hence Zikopoulos et al (2005) was excluded from the meta-analysis. As some studies assessed single comparisons, meta-analysis was not possible. The addition of isosorbide mononitrate 10 mg vaginal tablets from cycle day 5 until pregnancy test was assessed by a single pilot RCT (Abdel Razik et al. 2017). The authors concluded that this addition significantly improved CPR for stimulated IUI. One RCT compared stimulation with human menopausal gonadotrophin (HMG) +letrozole+tamoxifen vs hmg+letrozole+placebo (Pourmatroud et al., 2013) and one compared HMG+antagonist vs HMG+clomiphene (Karthik et al., 2018). Neither showed significant difference in success rates. A small RCT with 32 patients by Wu et al. (2007) compared the use of anastrozole vs clomiphene. The authors reported two pregnancies in the anastrozole group and none in the clomiphene group.

51 RCTs (11213 participants) were included in the network meta-analysis (Figures 4-6).

Sixteen studies with 5161 participants reported on LBR. Ovarian stimulation with gonadotrophins appears to yield significantly higher OPR compared to clomiphene (RR 1.24, 95% CI 1.06-1.44) and significantly higher LBR (RR 1.27, 95% CI 1.21-1.44). Gonadotrophins yield higher LBR compared to letrozole. The addition of GnRH analogues did not improve LBR compared to gonadotrophins alone. There was no statistically significant difference between letrozole and clomiphene for LBR but letrozole appeared to yield significantly higher OPR (RR 1.68, 95% CI 1.13-2.5).

The SUCRA for LBR was highest for combination treatment with clomiphene, letrozole and gonadotrophins, followed by combination of treatment with letrozole and gonadotrophins.

Thirty-one studies (7640 participants) reported on multiple pregnancy following the use of ovarian stimulation with IUI (Figures 5a,b). No significant differences were found with regard to MPR between different stimulation protocols.
Twenty-six trials (7060 participants) reported on MR, with no significant differences reported amongst different ovarian stimulation regimens (Figure S4).

The overall quality of included trials was moderate with a small number of studies demonstrating high ROB.

Recommendations

• If follicular phase stimulation is planned for IUI, gonadotropins are recommended for ovarian stimulation with or without oral agents (Strong recommendation). The cycle should be monitored. The dose of gonadotrophins should be individualised and the response should be monitored aiming for no more than two follicles. The decision on whether to proceed with an IUI cycle when more than two follicles are present involves clinical judgment and patient counselling balancing the benefit in success rates against the higher risk of multiple gestation. Cancellation criteria should be in place (Consensus. Good practice point). The use of GnRH analogues is not recommended in stimulated cycles (Weak recommendation, evidence level 1-). The dose and type of gonadotrophins, alternate days versus daily stimulation, duration of stimulation and different brand names of agents were not assessed in this guideline and should be decided based on clinical judgement and local policies (Consensus. Good practice point).
  The cost-effectiveness of stimulation strategies should be assessed which may influence patients’ decision between oral versus injectable agents. If oral agents are used letrozole may yield better results than clomiphene however the use of letrozole is currently off label and the evidence is insufficient therefore a recommendation cannot be made (Weak recommendation, evidence level 1-).

12. Ovulation trigger

A trigger injection can be used in IUI cycles, especially those where ovarian stimulation is used to induce follicle maturation and ovulation and to overcome the possible attenuation of the natural LH surge. HCG has a long-lasting effect compared to LH (Casper, 1996) and is used to sustain the corpus luteum function and to time the IUI for planning purposes. The use of GnRH agonist causes a release of FSH and LH which is shorter-lived and resembles the natural ovulation surge more closely than hCG. Both agonist and hCG triggers may also affect endometrial receptivity (Kolibianakis et al., 2005; Licht et al., 2007).

We included four trials (Kyrou et al., 2012; Lewis et al., 2006; Singh et al., 2019; Thomas et al., 2019) (942 participants) comparing outcomes following hCG trigger vs spontaneous ovulation. One investigated natural cycle IUI (Kyrou et al., 2012) and three investigated gonadotrophins (Singh et al., 2019; Thomas et al., 2019) or clomiphene (Lewis et al., 2006) stimulated cycles. All four trials were included in the meta-analysis (Figure S5).

No statistically significant difference was found for LBR/OPR (results from two trials) (RR 0.71, 95% CI 0.30–1.66, I2 = 72.1%) or CPR (RR 1.18, 95% CI 0.79–1.78, I2 = 0%). Two trials reported on MPR and MR without significant difference amongst the two groups.
We included six trials (Ha et al., 2019; Le et al., 2019; Shalev, 1995; Shalev et al., 1995; Soliman & Siam, 2014; Taheripanah et al., 2017) (1597 participants) comparing IUI outcomes following the use of hCG trigger vs agonist trigger (Figure S5). Two trials reported on OPR/LBR (RR 1.12, 95% CI 0.82–1.53, I2 = 0%) and six reported on CPR (RR 1.03, 95% CI 0.79–1.35, I2 = 33.3%) (moderate certainty evidence). No difference was found for any of the studied outcomes. One trial comparing hCG trigger vs FSH and hCG (Alborzi et al., 2024) reported a significant difference in CPR (16/40 vs 8/40) favouring the hCG+FSH group.

Recommendations

• The use of a trigger may be considered for planning purposes, based on individual centres’ services and resources. No recommendation can be made regarding agonist vs hCG trigger (Weak recommendations, evidence level 1-).

13. Follicle Size at time of hCG trigger

In natural cycles, the spontaneous LH surge and ovulation occur at mean follicular diameters ranging between 17mm and 25 mm. When using an hCG trigger, oocyte maturity is gauged based on follicular size, and any associated inaccuracy in the timing of the trigger may affect outcomes.

A single RCT (612 participants) (da Silva et al., 2012) compared IUI outcomes in stimulated cycles with hCG trigger and luteal phase support with vaginal progesterone, when the trigger was administered when the leading follicle was 16-16.9mm or 18-18.9mm diameter. No significant difference in CPR or OPR was reported between the groups.

Recommendations

• There is insufficient evidence to support a recommendation as to the optimal follicular size for triggering ovulation in stimulated or natural cycles; the decision should be based on follicular growth, endometrial lining, cycle length and availability of services. (Consensus. Good practice point).

14. Interval between hCG trigger and IUI procedure

Ovulation is usually expected 36–48 h after hCG trigger (Edwards & Steptoe, 1974). Current practice varies considerably between centres, with some performing IUI on the day of the trigger and some after confirmed ovulation. ASRM recommends IUI within 24 – 36 hours after the administration of the trigger (Pfeifer et al., 2017).

We identified nine trials (1391 participants,2586 IUI cycles) that compared the timing of IUI following hCG trigger in heterogeneous patient groups with a variety of infertility backgrounds (Figure s7) (AboulGheit, 2010; Claman et al., 2004; Firouz et al., 2020; Kamel et al., 2015; Molaee et al., 2014; Rahman et al., 2011; Rijsdijk et al., 2019; Soliman, 2016; Weiss et al., 2015). Seven comparisons from six trials compared outcomes after delayed IUI (between 40-48 hours after hCG trigger) with those after standard IUI (between 32-36 hours after hCG trigger) (Claman et al., 2004, AboulGheit 2009, Weiss et al., 2014, Kamel et al., 2015, Soliman 2016, Firouz et al., 2020). Four comparisons assessed early IUI (two trials immediately after hCG trigger and two trials 24 hours after hCG trigger) compared to standard IUI (between 32-36 hours after hCG trigger) (AboulGheit 2009; Rahman et al., 2011; Molaee et al. 2014; Rijsdijk et al., 2019). Outcomes were not separately reported for the various indications.

Delayed IUI
A single trial (Weiss et al., 2014) (67 participants) reported outcomes in terms of LBR and found no significant differences between IUI performed at either 36, 42 or 48 hours post trigger (p=0.2021). Of the six trials that reported outcomes in terms of CPR (AboulGheit, 2010; Claman et al., 2004; Firouz et al., 2020; Kamel et al., 2015; Soliman, 2016; Weiss et al., 2015), two studies did not provide the data in the format required for a meta-analysis (AboulGheit, 2010; Claman et al., 2004). Neither trial reported significant differences between the groups. Five comparisons were included in the meta-analysis (Figures s7a,b), and the pooled estimate favoured a delayed IUI at 40-48 hrs as compared to IUI at 32-36 hours (RR 1.91, 95% CI 1.32-2.78). Four studies reported on PR (AboulGheit, 2010; Firouz et al., 2020; Kamel et al., 2015; Soliman, 2016). Meta-analysis demonstrated significantly higher PR in the delayed IUI group compared to IUI at 36 hours (RR 1.89, 95% CI 1.32-2.71).

Early IUI
Two trials (370 participants) (Rahman et al., 2011; Rijsdijk et al., 2019) reported outcomes in terms of LBR. The pooled estimate demonstrated significantly lower LBR with early IUI compared to IUI at 36 hours (RR 0.73, 95% CI 0.55-0.95). A single trial (Rijsdijk et al., 2019) that reported outcomes in terms of OPR found no significant differences between IUI performed either immediately after hCG trigger or 36 hours later. Of the two trials that reported outcomes in terms of CPR (AboulGheit, 2010; Rahman et al., 2011), one, AboulGheit (2010) did not provide the data in the format required for a meta-analysis. Neither trial found significant differences between the groups. Two trials that reported outcomes in terms of PR (AboulGheit 2009, Molaee 2014) were included in the meta-analysis, that demonstrated no difference between groups (OR 0.83, 95% CI 0.51-1.35) (Figures S7c,d).

The quality of evidence was assessed as moderate/low.

Recommendations

• IUI should be performed after 32-36 hours and up to 48 hours following the hCG trigger. Early IUI at less than 24 hours from trigger is not recommended (Weak recommendation, level of evidence -1).

15. Double insemination

The hypothesis that double insemination improves the outcome of IUI rests on the theoretical benefit of extending the fertilisation window . It is suggested that this may provide an advantage in cycles with multifollicular growth with different ovulation timings, and in cases where semen parameters are suboptimal. A Cochrane systematic review (Cantineau et al., 2003) that included six trials (Casadei et al., 2006; Liu et al., 2006; E. H. Y. Ng et al., 2003; Ragni et al., 1999; Silverberg et al., 1992; Zeyneloglu et al., 2002) showed statistically significant benefit of double insemination using partner’s sperm compared to single IUI (Peto odds ratio 1.8, 95% CI 1.4 – 2.4). The review was updated (Rakic et al., 2021) to include three further studies (Rahman et al., 2010; Bagis et al., 2010; Sorouri et al., 2016). Three RCTs reported outcomes in terms of LBR. No significant difference was found in LBR from double IUI for patients with UI or male factor (low quality evidence). The optimal timing of double insemination, number of dominant follicles, use of the ovulation trigger, and the relative invasiveness and cost-effectiveness of double compared with single insemination remain important unresolved uncertainties.

Summary of systematic review evidence
Twelve trials (3588 participants) assessed double and single insemination (Bagis et al., 2010; Casadei et al., 2006; Gezginc et al., 2008; Liu et al., 2006; M Roopa, 2025; E. H. Ng et al., 2003; Ragni et al., 1999; Rahman et al., 2010; Ransom et al., 1994; Silverberg et al., 1992; Sorouri et al., 2016; Tonguc et al., 2010). Eleven trials reported outcomes in terms of CPR but only three reportedLBR/OPR (Figure S8). One study (Roopa, 2025) only reported on PR and was not included in the meta-analysis. There was no significant difference in CPR (RR 1.29, 95% CI 0.96–1.73, I2 = 49.2%) or LBR/OPR (RR 0.93, 95% CI 0.63–1.36, I2 = 0%). There was no significant difference between treatment groups in rate of miscarriage or MPR.

The timing of double insemination varied amongst the studies (18+40-42h, 12+34-36h, 34+60h, 24+48h, 18-24h, 36-48h).

The quality of evidence was assessed as low.

Recommendations

• Double insemination is not recommended to increase the success rate of IUI treatment. (Weak recommendation, evidence level 1-).

16. Ultrasound-guided IUI procedure

It is well established that transabdominal ultrasound guidance improves outcomes in IVF/ET cycles (Bede Tyler et al., 2022). Ultrasound guidance allows visualisation of the cervical canal reducing the number of attempts needed to navigate through the cervix, minimising injuries to the endometrium and cervical manipulation. By direct visualisation of the tip of the catheter, the operator is able to avoid touching the fundus and to minimise uterine contractions (Lesny et al., 1998). Whether or not this is important for IUI cycles is uncertain, since implantation takes place several days post insemination. Precise positioning of sperm suspension deposited in the uterine cavity is also less relevant in IUI than in IVF/ET cycles; expulsion of more than 40% of the volume infused into the cavity has been documented in the literature following mock uterine infusions (Knutzen et al., 1992; Mansour et al., 1994). The length of the procedure, the level of difficulty and patient discomfort are also important to consider.

Six trials (Bancquart J, 2015; Mubarak et al., 2019; Oruc et al., 2014; Polat et al., 2015; Ramón et al., 2009; Thanaboonyawat et al., 2021) were identified that explored the use of ultrasound guidance during the IUI procedure (Figure S9), including 1225 participants. Two RCTs reported outcomes in terms of OPR/LBR (RR 2.03, 95%CI 0.83–4.92, I2 = 0%). No significant difference was found in any of the clinical outcomes for ultrasound-guided procedures versus blind insemination.

The quality of evidence was assessed as very low.

Recommendations

• Routine use of transabdominal ultrasound guidance during IUI is not recommended, although it may prove useful in individual difficult cases (Weak recommendation, evidence level 1-).

17. Intrauterine hCG infusion +/- activated Peripheral Blood Mononuclear Cells (PBMC)

Intrauterine hCG infusion, which has been studied as an add-on to IVF/ET cycles (Bede Tyler et al., 2022) as a strategy to enhance endometrial receptivity, has been proposed as an add-on for IUI cycles. The evidence regarding the clinical benefit and the optimal timing for this infusion is limited.

Two trials (280 participants) investigated hCG infusion for IUI cycles (500 IU of hCG diluted in 0.5 ml normal saline). One (Wadhwa & Rani,2021) compared outcomes for patients who received intrauterine hCG infusion 3 minutes before IUI vs patients who received normal saline. The other (Hakimi et al.,2024) compared intrauterine hCG infusion at the time of the trigger injection (34-36h before IUI) vs no intervention. The studies found no significant difference for CPR (RR 1.79, 95% CI 0.72-4.49) (Figure S10a) or MR (RR 1.5, 95% CI 0.43-5.17) with or without hCG infusion (Figure S10b).

A single RCT (217 participants) was identified that assessed the intrauterine administration of PBMC+hCG two days post IUI (Joao et al., 2022) in patients undergoing IUI with partner’s sperm. No statistically significant difference was found for PR or CPR.

The quality of evidence was assessed as moderate/low.

Recommendations

• Intrauterine hCG infusion with or without PBMC as an add-on to IUI is not recommended (Weak recommendation, evidence level 1-)

18. Use of Granulocyte-Colony Stimulating Factor (G-CSF)

G-CSF is a cytokine involved in the regulation of immune responses, angiogenesis, and tissue remodeling and has been used in IVF/ET cycles to improve the endometrial thickness for patients with thin endometrium or recurrent implantation failure, in an attempt to maintain a local immune environment favorable for implantation (Rahmati et al., 2015). When administered as a subcutaneous injection, potential side effects include bone pain, allergic reaction, flu-like symptoms, leukocytosis and rarely thrombopenia and respiratory symptoms.

Three RCTs (620 participants) were identified reporting on the use of G-CSF for IUI cycles.Aramesh et al. (2022) randomised patients to receive 300mcg of G-CSF subcutaneously two days after the IUI procedure. Azizi et al. (2021) compared the same dose of G-CSF 12 hours before the trigger injection administered subcutaneously vs intrauterine infusion vs no G-CSF in patients with UI. Amooee et al. (2022), which aimed to target patients with a potential endometrial impairment, compared outcomes in patients with recurrent IUI failure, after administration of the same dose of G-CSF as an intrauterine infusion on the day of the trigger or after a saline infusion. Neither intrauterine nor subcutaneous administration of G-CSF resulted in benefit in terms of PR (Figures S11a-c). None of the studies reported LBR; while meta-analysis was not possible for OPR, no statistically significant differences were found in any of the studies.

The quality of evidence was assessed as moderate/low.

Recommendations

• The use of GCSF as an add-on to IUI is not recommended (Weak recommendation, level of evidence -1)

19. Bed rest

Spermatozoa have been shown to reach the fallopian tubes within five minutes of deposition in the vagina (Settlage et al., 1973), facilitated by progressive motility combined with uterine contractions, and they are known to survive for several days in the genital tract since pregnancy has been shown to result from intercourse as long as five days before ovulation (Suarez & Pacey, 2005; Wilcox et al., 1995). Traditionally bed rest following IUI has been offered. While simple and inexpensive, bed rest is a time-consuming intervention.

Three RCTs (984 participants) were included in the meta-analysis (Figure S12). There was no statistically significant difference in outcomes between 15-minute bed rest and immediate mobilisation following IUI in terms of OPR/LBR (RR 1.13, 95% CI 0.59 -2.15, I2= 87.0%) based on two trials (Custers et al., 2009; Van Rijswijk et al., 2016). The RCT by Saleh et al. (2000) was the only trial that reported outcomes in terms of CPR and showed a significant increase in CPR for patients who had 10min bed rest following IUI (16 vs 4 pregnancies) compared to immediate mobilisation.

The quality of evidence was assessed as very low/low.

Recommendations

• Bed rest following IUI is not recommended (Weak recommendation)

20. Tocolytics

Tocolytics have been used before and after IVF/ET to reduce uterine contractions (Tyler et al., 2022). No RCTs were identified addressing this question for IUI cycles.

Recommendations

• Tocolytics are not recommended for IUI cycles (Consensus. Good practice point).

21. Misoprostol

Misoprostol is a prostaglandin E1 analogue which has been used vaginally at the time of IUI with the aim of potentially enhancing immunomodulation, uterine contractility and isthmic tubal relaxation (Aitken & Kelly, 1985; Coutinho & Maia, 1971; Skibinski et al., 1992) since the washed sperm used for IUI is deprived of natural prostaglandins. Of the three trials examining the use of misopristol in IUI identified, Brown et al. (2001) found significant benefit from 400mcg vaginal misoprostol on the day of IUI for clomiphene stimulated cycles in terms of PR. The authors did not document increase in pain score or significant side effects following misoprostol administration. The other two trials (Moslemizadeh et al., 2009; Zahiri Sorouri et al., 2015) showed no benefit in terms of PR or CPR. A large multicentre, double blinded RCT (Billiet et al., 2008), which was excluded from the meta-analysis due to cross over design, found no benefit from vaginal misoprostol at the time of IUI for PR and the authors reported high rates of side effects.

Three RCTs (550 participants) were identified exploring the effect of vaginal misoprostol following IUI on CPR (Figure S13). There was no statistically significant difference in CPR with the use of misoprostol vs placebo (RR 1.20, 95% CI 0.66-2.20). Two of these RCTs used 200μg (Moslemizadeh et al., 2009; Zahiri Sorouri et al., 2015) and one used 400μg (Brown et al., 2001) misoprostol as a single dose administered vaginally.

The quality of evidence was assessed as very low.

Recommendations

• The use of misoprostol is not recommended in IUI cycles (Weak recommendation, level of evidence -1)

22. Oxytocin

One RCT (86 participants) (Ochsenkühn et al., 2010) compared the effect of 8 IU intranasal oxytocin immediately after IUI vs placebo. No significant difference was found on PR (very low-quality evidence)

Recommendations

• The use of oxytocin in IUI cycles is not recommended (Weak recommendation).

23. Luteal phase support

Progesterone is essential to support implantation and early pregnancy. A large meta-analysis of eleven RCTs concluded that there is benefit from progesterone supplementation in stimulated IUI cycles in terms of LBR/OPR (Chronopoulou et al., 2024). Two RCTs (Gupta et al.; Leppänen et al., 2022) were not included in the meta-analysis as they did not use vaginal progesterone. Gupta et al. (2024) used oral dydrogesterone 10 mg twice daily for 17 days following IUI which did not improved outcomes. Leppänen et al. (2022) used a single dose of GnRH agonist in the luteal phase, which was not shown to improve LBR.

The results of the meta-analysis (Figure 6) suggest that the use of vaginal progesterone support in stimulated IUI cycles significantly increases LBR/OPR (RR 1.37, 95% CI 1.09–1.72, I2 = 4.9%, NNT=29) as well as CPR (RR 1.37, 95% CI 1.15– 1.62, I2 = 0%, NNT=21) without affecting the chance of miscarriage (RR 1.13, 95% CI 0.69–1.86, I2 = 0%) or multiple pregnancy (RR 1.05, 95% CI 0.49–2.27, I2 = 0%). Four trials (Ebrahimi et al., 2010; Erdem et al., 2009; Karadag et al., 2016; Schwarze et al., 2013) only included couples with UI, with the remainder including patients with mixed indications. The dose of progesterone varied between 200mg and 800mg per day for pessaries; the gel preparation (90mg of progesterone) was used once daily. Two trials in this meta-analysis evaluated clomiphene-stimulated cycles, but neither found a benefit from progesterone support (Kyrou et al. 2010; Karadag et al. 2016). The other trials evaluated outcomes in cycles with ovarian stimulation using gonadotrophins with or without oral agents (letrozole or clomiphene).

The quality of evidence was assessed as moderate to low.

Recommendations

• Vaginal progesterone support is recommended in gonadotrophin-stimulated IUI cycles (Strong recommendation). Insufficient data are available to make a recommendation concerning dose and duration (Consensus. Good practice point). Insufficient data are available to make a recommendation for natural cycles IUI or for stimulated IUI using letrozole or clomiphene (Consensus. Good practice point).

Non-steroidal anti-inflammatory medications (NSAIDs)

NSAIDs have been proposed as an add-on following IUI with the aim of reducing the uterine contractility and the inflammatory response.
One double blind

RCT (260 participants) compared the use of piroxicam (10mg daily on days 4-6 after IUI) vs placebo in patients with UI (Zarei et al., 2016). While the PR was significantly higher for patients who received piroxicam (low quality evidence), this did not result in higher OPR.

Recommendations

• The use of NSAIDs after IUI is not recommended (Weak recommendation)

Conclusion and recommendations for future research

Despite its historical association with modest success rates, IUI remains a safe and effective fertility treatment and is a prerequisite for IVF eligibility for NHS funding in certain patient populations. This guideline assessed 25 different interventions (add-ons/variations) to the standard IUI protocol (154 RCTs with 34825 participants). The results suggest it is clinically beneficial to use endometrial scratch, ovarian stimulation with gonadotrophins, vaginal progesterone as luteal phase support for gonadotrophin stimulated cycles and half full/full bladder to facilitate the procedure. In terms of timing of the procedure, IUI should be performed 32-48 hours post trigger (if a trigger is used) or 24-36 hours after a reported positive urine LH surge. Urine LH testing is recommended once daily (early morning). Depending on service availability and patient preference, follicular phase monitoring, trigger and ultrasound guidance can also be considered to facilitate the cycle. In view of the findings that overall, the quality of evidence for many interventions was low, and that the existing studies are not well powered to assess MPR/MR, provision of information counselling to patients is essential, during which the risks and benefits of each add-on or variation under consideration can be explored.

The existing RCTs assessing IUI add-ons and variations have not stratified their results according to indication for IUI, limiting the ability to draw conclusions for specific patient subgroups such as UI. Cumulative success rates are not addressed in this guideline as most authors report results per cycle and in clinical practice patients are keen to know the success rate per cycle of treatment. There is inconsistency in the inclusion criteria in the existing RCTs, in terms of patient selection and sperm parameters (Starosta et al., 2020). Patient selection is crucial as the inclusion of cases with severe male factor infertility or unilateral tubal patency may influence outcomes. In addition, methodological variables, including sperm preparation techniques and duration of abstinence, can further influence results (Lemmens et al., 2016). Several questions are not addressed by the current literature and well-designed, adequately powered trials are needed. Future research should reduce heterogeneity and report outcomes according to indication to enable solid conclusions and evidence-based recommendations for patient subgroups.

Disclosure statement: The authors have no competing interests to declare.

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