inSIGHT trial

SIGnificance of routine Hysteroscopy prior to a first IVF Treatment cycle / 
the inSIGHT trial

Go to the inSIGHT website

Objective
The aim of the study is to assess whether diagnosing and treating unsuspected intrauterine abnormalities by additional diagnostic tests (saline infusion sonography (SIS) and/or routine office hysteroscopy) prior to a first IVF/ICSI treatment cycle improves IVF outcome and with that the cost-effectiveness of the fertility treatment.

The following specific research questions will be addressed:

• What exactly is the treatment benefit of intrauterine abnormalities by office hysteroscopy for the number of ongoing pregnancies resulting in live births in assisted reproductive therapy (ART) patients, indicated for a first IVF/ICSI treatment cycle?
• What exactly is the benefit of using SIS as a pre-selection tool to identify intrauterine abnormalities that can subsequently be treated by hysteroscopy in ART patients, indicated for a first IVF/ICSI treatment cycle?
• What are the costs of SIS and/or routine hysteroscopy prior to IVF?
• How do patients value and trade-off advantages and disadvantages of SIS and outpatient diagnostic and therapeutic hysteroscopy (patient preferences)?

Study design
Patients scheduled for a first IVF/ICSI treatment at one of the participating hospitals will undergo randomization for routine fertility work-up or routine work-up plus diagnostic tests to evaluate the uterine cavity (hysteroscopy alone or hysteroscopy in combination with SIS). If patients are randomized for the latter, a standard office hysteroscopy will be performed in the early-mid follicular phase of a cycle (day 3-9) 1–3 months before starting IVF/ICSI. On-the-spot-treatment of detected intrauterine abnormalities will be carried out during the hysteroscopy. In both study arms, IVF/ICSI treatment will be initiated and outcome during an eighteen months treatment period will be recorded. Also, the patients’ tolerance and preferences will be investigated. Finally, a cost-analysis based on the study results will be performed.

Study population
In total 738 patients indicated for a first IVF/ICSI treatment cycle at one of the participating hospitals will be included in this study.
Inclusion criteria:

• Women indicated for a first IVF/ICSI treatment
• Primary or secondary infertility
• Normal Transvaginal Ultrasound, performed in the follicular phase of the menstrual cycle

Exclusion criteria:

• Recurrent miscarriage
• Prior hysteroscopy treatments
• Meno-metrorrhagia (defined as any intermenstrual loss of blood)
  

Intervention
Consenting eligible patients will be randomized to one of two strategies: routine infertility work-up followed by immediate IVF (standard/control arm) or the routine work-up with additional diagnostic tests ((SIS and) hysteroscopy) with treatment of intrauterine pathology followed by IVF (experimental strategy/intervention arm).

Outcome measures
Main study outcome:

Cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomization (obtained in treatment cycles with fresh embryos as well as in subsequent cryo/thaw cycles).

Secondary study outcomes:

• Cumulative implantation rate and miscarriage rate achieved within 18 months of IVF/ICSI treatment after randomisation (obtained in treatment cycles with fresh embryos as well as in subsequent cryo/thaw cycles)
• Cumulative miscarriage rate within 18 months of IVF/ICSI treatment after randomization (obtained in treatment cycles with fresh embryos as well as in subsequent cryo/thaw cycles)
• Cost calculations of SIS, hysteroscopy procedures and the IVF treatment
• Patient tolerance of a SIS and diagnostic/therapeutic hysteroscopy procedure

Power/data analysis
In cases that are treated for the predefined abnormality, the increase in ongoing pregnancy after the subsequent cycle of IVF/ICSI is found to be 9-32% in patients with recurrent IVF failure (Oliveira et al., 2003; Demirol and Gurgan, 2004; Rama Raju et al., 2006).
In a group of patients indicated for a first IVF/ICSI treatment cycle, the difference in cumulative live birth rate after 18 months of IVF/ICSI treatment is estimated to be 10% between the patients with and without hysteroscopy (40 versus 30%). The number of patients needed to have 80% power (with alpha = 0.05) to detect such a difference is 350 per study arm. In order to allow for a "worst case scenario" dropout rate of 5%, a total of 738 patients (700/0.95), included in the proposed trial, will be required.
To be able to answer the question on the benefit of using SIS as a pre-selection tool the following sample size calculation for patients needing to have both SIS and hysteroscopy was made. From previous literature, we consider the prevalence of unsuspected intrauterine abnormalities to be 12% and the sensitivity of SIS compared to hysteroscopy to be 95%. To achieve a 95% confidence interval (CI) of 10% (85-100%) we would need to perform SIS and hysteroscopy in 160 patients. This means a total of 320 patients need to be randomized for SIS + hysteroscopy or routine work-up.

Subsidy
ZonMW

Contact
Drs. J.G. Smit / Prof. dr. F.J.M. Broekmans / dr. H.L. Torrance
UMC Utrecht,
Divisie Vrouw en Baby
Afdeling Voortplanting
Huispostnummer F05.126
Postbus 85500
3508 GA Utrecht
Tel. 088 -7551443
j.smit-6@umcutrecht.nl / f.broekmans@umcutrecht.nl / H.Torrance@umcutrecht.nl