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21/24 Intrauterine insemination versus in vitro fertilisation for unexplained infertility commissioning brief




The aim of the Health Technology Assessment (HTA) Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research question

What is the clinical and cost-effectiveness of intrauterine insemination versus in vitro fertilisation (IVF) for unexplained infertility?

  • Intervention: Three cycles of gonadotrophin stimulated intrauterine insemination.
  • Patient group: Women under 40 years with a diagnosis of unexplained infertility, to fit with NICE recommendations. 
  • Setting: Fertility clinics. 
  • Comparator:  One cycle of IVF with standard ovarian stimulation and fresh and/ or frozen embryo transfer.
  • Study design: A randomised controlled trial with an internal pilot phase to test key trial processes such as recruitment and adherence. Clear stop/go criteria should be provided to inform progression from pilot to full trial. 
  • Important outcomes: Live birth. The gestational age is to be defined and justified by applicants.
  • Other outcomes: Patient acceptability; health related quality of life; cost-effectiveness; singleton live birth =37 weeks; gestational age at delivery; cycle cancellation; clinical pregnancy; multiple pregnancy; ectopic pregnancy; miscarriage; birthweight; neonatal outcome at 28 days after birth; time to pregnancy leading to live birth; ovarian hyperstimulation syndrome.
    Where established Core Outcomes exist they should be included amongst the list of outcomes unless there is good reason to do otherwise.
  • Minimum duration of follow-up: To be defined and justified by applicants.
  • Longer-term follow up: If appropriate, researchers should consider obtaining consent from participants to allow potential future follow up through efficient means (such as routine data) as part of a separately funded study.


Infertility is defined as the failure to conceive after 12 months or more of regular unprotected sex, affecting one in seven couples in the UK. Unexplained infertility is when tests and investigations do not find an obvious cause for a couple’s infertility, affecting about 30% of all infertile couples. A diagnosis of unexplained infertility has significant psychological and emotional impacts. Factors that influence the rate of successful conception without treatment include the age of the women, healthy weight, and smoking.

A therapeutic treatment for unexplained infertility is in vitro fertilisation (IVF). During IVF, an egg is removed from the woman's ovaries and fertilised with sperm in a laboratory. The fertilised egg, called an embryo, is then returned to the woman's womb to grow and develop. NICE guidelines recommend that 3 cycles of NHS funded IVF should be offered to women under the age of 40 who have been trying to get pregnant through regular unprotected sex for two years. However, the final decision about who can have NHS-funded IVF in England is made by local commissioning groups, and their criteria may be stricter than those recommended by NICE. The cost of IVF privately varies across clinics, but the average cost of one cycle of IVF is around £5000.

Whilst IVF can overcome unexplained infertility in some couples, it is an invasive and expensive treatment. The medications used during treatment have side effects and the procedure increases the risk of multiple pregnancies and ovarian hyperstimulation syndrome, where too many eggs develop in the ovaries making them large and painful, which can result in hospitalisation.

A less invasive, cheaper, alternative treatment is intrauterine insemination (IUI), where sperm are inserted into the uterus around the time of ovulation, increasing the chance of a sperm fertilising the egg. However, NICE recommended that IUI with or without ovarian stimulation should not be routinely offered for couples with unexplained infertility. The recommendation was based on poor quality evidence. Stakeholder surveys have indicated a general poor adherence to the guidelines with many clinicians continuing to use IUI treatment for unexplained infertility.

Since the NICE recommendation, there has been a single centre UK study with limited evidence to suggest that three cycles of IUI may offer the same likelihood of successful pregnancy as IVF. Several international studies have suggested that IUI may be more cost effective than IVF. Whilst there are some concerns that IUI may increase the risk of multiple pregnancies and births, there is evidence to suggest that controlled ovarian stimulation results in rates similar, or less than those following IVF treatment. Given the limitations and uncertainties in the current evidence and the continued use of both treatments in practice despite NICE guidance, there is a need for a large multicentre trial to provide rigorous evidence evaluating IUI treatment versus IVF for unexplained infertility.

Applications should be co-produced, demonstrating an equal partnership with service commissioners, providers and service users (or their advocates) in order to provide evidence and actionable findings of immediate utility to decision-makers and service users. Applicants may wish to consult the NIHR INVOLVE guidance on co-producing research.

Additional commissioning brief background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email

Making an application

If you wish to submit a Stage 1 application for this call, the online application form can be found on the funding opportunities page. To select this call, use the filters on the right of the screen or search using the call name and/or number.

Your application must be submitted on-line no later than 1pm on the 28 July 2021. Applications will be considered by the HTA Funding Committee at its meeting in September 2021.

Guidance notes and supporting information for HTA Programme applications are available by clicking the links.

Important: Shortlisted Stage 1 applicants will be given eight weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in January 2022.

Applications received electronically after 1300 hours on the due date will not be considered.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team. There may be unusual circumstances where the same person could be included on more than on application eg a lead from a named charity or a unique national expert in a condition.

For such exceptions (i) each application needs to state the case as to why the same person is included (ii) the shared co-applicant should not divulge application details between teams and (iii) both teams should acknowledge in their application that they are aware that one of their co-applicants is part of a competing application and that study details have not been shared.

Should you have any queries please contact us at