The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial
BMC Women's Health
The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial
Janine G Smit 0
Jenneke C Kasius 0
Marinus JC Eijkemans
Carolien AM Koks
Ron Van Golde
Jurjen GE Oosterhuis
Annemiek W Nap
Gabrielle J Scheffer
Petra AP Manger
Dick BC Schoot
Arne M van Heusden
Walter KH Kuchenbecker
Denise AM Perquin
Eugenie M Kaaijk
Joop SE Laven
Marcel van Hooff
Leonie A Louwe
Jantien J Boomgaard
Corry H de Koning
Ineke CAH Janssen
Femke Mol 1
Ben WJ Mol 2
Helen L Torrance 0
Frank JM Broekmans 0
0 Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht , Utrecht , The Netherlands
1 Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre , Amsterdam , The Netherlands
2 Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam , Amsterdam , The Netherlands
Background: In in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment a large drop is present between embryo transfer and occurrence of pregnancy. The implantation rate per embryo transferred is only 30%. Studies have shown that minor intrauterine abnormalities can be found in 11-45% of infertile women with a normal transvaginal sonography or hysterosalpingography. Two randomised controlled trials have indicated that detection and treatment of these abnormalities by office hysteroscopy after two failed IVF cycles leads to a 9-13% increase in pregnancy rate. Therefore, screening of all infertile women for intracavitary pathology prior to the start of IVF/ICSI is increasingly advocated. In absence of a scientific basis for such a policy, this study will assess the effects and costs of screening for and treatment of unsuspected intrauterine abnormalities by routine office hysteroscopy, with or without saline infusion sonography (SIS), prior to a first IVF/ICSI cycle. Methods/design: Multicenter randomised controlled trial in asymptomatic subfertile women, indicated for a first IVF/ICSI treatment cycle, with normal findings at transvaginal sonography. Women with recurrent miscarriages, prior hysteroscopy treatment and intermenstrual blood loss will not be included. Participants will be randomised for a routine fertility work-up with additional (SIS and) hysteroscopy with on-the-spot-treatment of predefined intrauterine abnormalities versus the regular fertility work-up without additional diagnostic tests. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomisation. Secondary study outcome parameters are the cumulative implantation rate; cumulative miscarriage rate; patient preference and patient tolerance of a SIS and hysteroscopy procedure. All data will be analysed according to the intention-to-treat principle, using univariate and multivariate logistic regression and cox regression. Cost-effectiveness analysis will be performed to evaluate the costs of the additional tests as routine procedure. In total 700 patients will be included in this study. Discussion: The results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment. Trial registration: NCT01242852
Hysteroscopy; Subfertility; IVF
Despite the numerous advances in the field of in vitro
fertilisation (IVF) and intracytoplasmic sperm injection
(ICSI), the maximum implantation rate per embryo
transferred is still approximately 30%. Even if both ovum
pick-up and fertilization occur successfully in the
process of IVF, there is a large unexplained gap between
successful embryo transfer and occurrence of pregnancy.
Implantation failure presents a major clinical challenge
and is a cause of considerable stress to patients and
clinicians in assisted reproductive technology (ART). Besides
the psychological and physical burden of each IVF
treatment cycle, it also adds to the considerable costs
associated with fertility treatment . If progress is to be
made in improving implantation rates, a greater
understanding of the factors which determine successful
implantation is required.
Implantation failure could be due to the embryo,
uterine environment or a combination of both. Even minor
uterine cavity abnormalities, such as endometrial polyps,
small submucous myomas, adhesions, and septa are
considered to have a negative impact on the chance to
conceive through IVF . The prevalence of unsuspected
intrauterine abnormalities, diagnosed by hysteroscopy
prior to IVF, has been reported to be 1145% [3-13].
Therefore, it has been proposed that these abnormalities
should be diagnosed and treated in order to optimize
the condition of the uterine environment and thus the
outcome of IVF treatment. However, this
recommendation is not based on high quality evidence [3,5,7-10]. In
addition, the benefits of hysteroscopy in patients who
will undergo a first IVF/ICSI treatment have not yet
At present, the basic work-up for evaluation of the
uterine cavity prior to IVF consists of transvaginal
ultrasound, possibly followed by saline infusion sonography
(SIS), hysterosalpingography (HSG) or hysteroscopy. The
accuracy of HSG in assessment of the uterine cavity
integrity in subfertile patients has been reported to be
rather disappointing [14,15]. SIS is increasingly considered
to be useful in diagnosing intrauterine abnormalities. It
is an inexpensive, non-invasive diagnostic test, and has
been proven to be very accurate [16,17]. Yet
hysteroscopy is still considered to be the gold standard. It has
become easy to perform in an outpatient clinic without
anesthesia. Moreover, hysteroscopy enables diagnosis
and treatment of intrauterine pathology in the same
The NVOG (Dutch society of Obstetrics and
Gynaecology) as well as the ESHRE (European Society for
Human Reproduction and Embryology) and RCOG
(Royal College of Obstetricians and Gynaecologists) do
not recommend SIS nor hysteroscopy as initial
investigation prior to starting IVF [18-20]. It has been argued
that the significance of treating unsuspected intrauterine
abnormalities has not yet been proven.
So far, none of the guidelines considered the most
recent literature on this topic. In a retrospective cohort
analysis, Gera et al. compared the pregnancy rate after
operative hysteroscopy of patients with intrauterine
abnormalities at SIS to the pregnancy rate of patients with
a normal uterine cavity. A 31.6% increase in pregnancy
rate was observed after treatment of detected
abnormalities . Furthermore, two randomized trials reported
exceptional improvements in pregnancy rates after office
hysteroscopy and instant treatment of detected
pathology in patients after two failed IVF attempts.
Intervention resulted in a 913% increase in clinical pregnancy
rate in the subsequent IVF cycle [7,9]. These results
endorsed the findings of other, previously published
prospective studies [3,5]. Despite some methodological
weaknesses in the study design, the results of these studies
indicate a trend towards a beneficial effect of screening
hysteroscopy on IVF outcome. This finding, combined
with the observed high prevalence of intrauterine
abnormalities, has led to a general debate on the beneficial effect
of pre-IVF work-up of the uterine cavity.
The current study aims to clarify the additive value of
routine SIS and/or hysteroscopy prior to IVF/ICSI . Also,
patient preferences and the cost-effectiveness of these
tests as routine procedures for assessment of the uterine
cavity prior to starting IVF will be assessed.
The inSIGHT trial is a multicenter randomised
controlled trail (RCT). A total of twenty-five academic and
non-academic centers in the Netherlands will
participate. An economic analysis is incorporated to assess the
cost-effectiveness of the investigated tests as routine
procedures prior to IVF. Inclusion was started in May 2011.
This study will be conducted according to the
principles of the Declaration of Helsinki and in accordance
with the Medical Research Involving Human Subjects
Act (WMO). The study protocol has been approved by
the medical ethical review committee of the University
Medical Center Utrecht (MEC 10272) and by the board
of directors of all participating centers. The protocol is
registered at clinicaltrial.gov NCT01242852.
Recruitment, consent and randomisation
Women with an indication for a first IVF/ICSI treatment
cycle will be informed about this trial by their attending
physician. They will also receive written patient
information. One to two weeks after the first visit, the
coordinating investigator will counsel the woman. If a woman
agrees to participate in the study, informed consent will
be obtained and randomisation will be performed for
one of two strategies: routine infertility work-up
followed by immediate IVF (control arm) or the routine
work-up with additional diagnostic tests ((SIS and)
hysteroscopy) with on-the-spot treatment of intrauterine
pathology followed by IVF (intervention arm) (Figure 1).
Randomisation will be performed centrally by a
webbased randomisation program and will be stratified
according to recruiting center.
All women with primary or secondary infertility
scheduled for a first IVF/ICSI treatment cycle at one
of the participating hospitals who have a normal
transvaginal ultrasound are considered to be eligible
for inclusion. A normal transvaginal ultrasound is
defined as no visible intracavitary pathology (e.g.
submucous myomas, polyps or septa) and will be
performed in the follicular phase of the menstrual cycle.
Intramural myomas without impression or
deformation of the uterine cavity are incorporated in the
definition of a normal ultrasound. Exclusion criteria
are recurrent miscarriage, defined as 2 or more
miscarriages prior to the 20th week of gestation, prior
hysteroscopy treatment and intermenstrual blood loss.
twenty-five research hospitals the additional tests consist
of SIS and hysteroscopy. In all the other participating
hospitals the additional test will consist of solely a
SIS will be performed prior to the hysteroscopy on CD
39. A speculum will be inserted vaginally and up to
20 ml of sterile saline solution will be infused into the
uterine cavity through a catheter to distend the
endometrial cavity. A transvaginal transducer will be used to
scan the uterine cavity. The findings at SIS will be
recorded in a standardised manner on the case record
The hysteroscopy examination will be scheduled in the
early-mid follicular phase of a menstrual cycle (day 312).
The hysteroscopy examinator will be blinded for SIS
outcomes. A vaginoscopic approach will be used without
anesthesia in an outpatient setting. Only if the
examination cannot be accomplished due to patient intolerance,
the possibility of a paracervical block will be offered.
Hysteroscopy will be performed using a 5-mm outer-diameter
continuous flow hysteroscope with a 5 French working
channel and a 30 direction of view. The uterine cavity will
be distended by saline infusion. The endocervical canal,
uterine cavity, tubal orifices and endometrium will
be inspected methodically and findings recorded on
a standardized form. Intrauterine abnormalities will
be defined as endometrial polyps, septate uterus,
adhesions and chronic or acute endometritis. A
sample of the endometrium will be obtained for
IVF/ICSI (maximum of 3 cycles)
Figure 1 Flowchart inSIGHT study.
histological examination by a gentle biopsy with a
pipelle biopsy canulla or grasping forceps.
Therapeutic hysteroscopy will be performed in the same
hysteroscopy session if any of the predefined
intrauterine abnormalities is detected. It is left to the
judgement of the operator physician to decide to
perform a septum resection in a subsequent session
with laparoscopic observation. After the
hysteroscopy, the resected tissue will be examined
histologically by a pathologist for the presence of chronic or
To assess patient tolerance of SIS and a
diagnostic/therapeutic hysteroscopy, all patients will be asked to complete a
standardized questionnaire, containing questions about the
level of tolerance and acceptability of both procedures.
All randomised women, be it allocated to intervention
or control arm, will undergo IVF. In the intervention
group IVF treatment will be started within 3 months
after hysteroscopy. Rec-FSH or HMG combined with a
GnRH agonist protocol (Leuprolide or Triptorelin 100
microgram) or a GnRH antagonist protocol (Ganirelix/
Cetrorelix 0.25 mg/d) will be used. Final oocyte
maturation will be achieved by the administration of HCG
when 3 or more follicles of more than 16 mm are
present. Oocyte retrieval will be carried out 36 hours
after HCG administration. Luteal phase supplementation
consists of 600 mg natural micronised progesterone in
three separate dosages (UrogestanW/ProgestanW 100 mg
3x2/day) starting in the evening after oocyte retrieval
and continued until 18 days after ovum pick-up.
Withdrawal of individual patients
Subjects can abandon the study at any time for any
reason if they wish to do so without any consequences. The
investigator can decide to withdraw a subject from the
study for urgent medical reasons.
The primary endpoint of this study will be the
cumulative ongoing pregnancy rate resulting in live birth
achieved within 18 months of IVF/ICSI treatment after
Secondary study parameters/endpoints will be the
cumulative implantation and miscarriage rate within
18 months of IVF/ICSI treatment after randomisation,
cost calculations of SIS, hysteroscopy procedures and
the IVF treatment, patient preference and tolerance of
SIS and diagnostic/therapeutic hysteroscopy procedure
and presence of unexpected intracavitary abnormalities
(e.g. endometrial polyps, septate uterus, adhesions and
endometritis) prior to IVF/ICSI.
To investigate the cost-effectiveness of SIS and
hysteroscopy as routine procedures prior to IVF treatment,
a cost analysis will be performed. The economic
evaluation is performed from a societal perspective.
Differentiation will be made between direct medical costs (all
health care sector costs), direct non-medical costs (costs
outside the health care sector that are affected by health
status or health care) and indirect costs of the fertility
treatment (costs of sick leave due to fertility treatment).
For medical costs, the process of care is divided into
three cost stages (cost of SIS, cost of hysteroscopy, cost
of IVF treatment), which can reoccur in case of repeat
treatment cycles. Costs will be computed from the
period of inclusion to the end of follow-up (18 months).
Health care utilisation in the fertility treatment
consists of visits to hospital, ultrasound, gonadotrophins,
oocyte retrieval, lab work of IVF (including various
laboratory tests) and hospital care. Volumes of health care
resources use will be measured prospectively alongside
the clinical study. At this stage, direct non-medical and
indirect costs may be generated if women are absent
from paid work, either for visiting the fertility clinic
during IVF treatment, or for sick leave associated with
physical or psychological side-effects of this treatment. The
Health and Labor Questionnaire  will be used to
document absence from paid work.
Sample size calculation
Based on the literature, the increase in ongoing pregnancy
in women with recurrent IVF failure after treatment of
predefined abnormalities of the uterine cavity is found to
be 932% in the subsequent IVF/ICSI cycles [5,7,9].
In a group of women 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.
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,
the prevalence of unsuspected intrauterine abnormalities
is considered to be 12% and the sensitivity of SIS
compared to hysteroscopy to be 95% . SIS and
hysteroscopy need to be performed in 160 women to achieve a
95% confidence interval of 10% (85100%). This means
that a total of 320 women need to be randomised in the
five hospitals in this study that perform SIS.
For each strategy, live birth rate as well as the average
costs per patient will be estimated and used to calculate
cost-effectiveness ratios. Incremental cost-effectiveness
ratios will be estimated for two strategies of additional
diagnostic/therapeutic procedures: SIS followed by
hysteroscopy if SIS is abnormal or no SIS but direct
hysteroscopy. These two strategies will be compared to no
additional investigations (routine fertility investigation
followed directly by IVF/ICSI). Robustness of the results
(costs and health outcomes) for various assumptions
and parameters estimates will be explored in sensitivity
analyses and visualized in ICER-graphs and
costeffectiveness acceptability curves.
SPSS and Excel will be used to perform the statistical
analysis. A probability less than 0.05 will be considered
to be significant. Data will be presented for the two arms
of the study group. Data will be expressed as means +/
standard deviation and proportions or rates. The analysis
will be by intention to treat.
Descriptive analysis will be used to assess the
prevalence of predefined minor intrauterine abnormalities at
SIS and office hysteroscopy. Comparisons between the
two arms of the randomised group will be done by
applying Chi-square testing to crude rates of cumulative
implantation and ongoing pregnancy and by using life
table analysis to account for the factor of time to
implantation or pregnancy. The difference in tolerability of
SIS will be compared to the tolerability of diagnostic and
therapeutic hysteroscopy making use of the Student
t-test analysis of the VAS score.
The relative contribution of predefined cavitary
abnormalities versus other predictive factors like female age
and duration of infertility will be assessed by univariate
and multivariate logistic regression and Cox regression.
Despite the great advances in the field of IVF/ICSI,
implantation failure is still high. This not only causes
considerable stress to the woman but is also associated with
high costs of the fertility treatment. The uterine cavity is
considered to play an important role in successful
implantation. Even minor abnormalities, such as
endometrial polyps, submucous myomas, adhesions or septa, are
thought to impair the chance to conceive . Studies
have shown a high prevalence of unsuspected
intrauterine abnormalities prior to IVF [3-12,23]. In addition, two
RCTs reported improvement in pregnancy rates after
hysteroscopy in the subsequent IVF cycle in patients
with two previous failed IVF attempts. Currently,
hysteroscopy is not recommended as routine investigation
in the fertility work-up because of a lack of robust
evidence. The present inSIGHT study is a large randomised
controlled trial in which the effects on pregnancy rates
and costs of SIS and hysteroscopy will be studied. The
results of this study, which are expected in 2015, will
help to clarify the significance of hysteroscopy prior to
IVF: In vitro fertilisation; ICSI: Intracytoplasmic sperm injection; SIS: Saline
infusion sonography; HSG: Hysterosalpingography; NVOG: Nederlandse
Vereniging voor Obstetrie en Gynaecologie; ESHRE: European Society for
Human Reproduction and Embryology; RCOG: Royal College of Obstetricians
and Gynaecologists; RCT: Randomised controlled trial; CRF: Case Record
JS is responsible for the overall logistical aspects of the trial and drafted the
manuscript. JK, HT and FB have contributed to the development of the
protocol and study design. JK applied for a grant. FB and HT have overall
responsibility for the trial. CK, RvG, GE, AN, GS, PM, AH, MK, DS, AvH, WK, DP,
KF, EK, AS, JF, JL, MH, LL, JK, JB, CK, CJ, FM and BWM are responsible for
implementation of the study and inclusion of eligible patients. All authors
read and approved the final manuscript.
1Department of Reproductive Medicine and Gynaecology, University Medical
Center Utrecht, Utrecht, The Netherlands. 2University Medical Center Utrecht,
Julius Center for Health Sciences and Primary care, Utrecht, The Netherlands.
3Department of Obstetrics and Gynaecology, Maxima Medical Center,
Veldhoven, The Netherlands. 4Department of Obstetrics and Gynaecology,
Maastricht University Medical Center, University of Maastricht, Maastricht, The
Netherlands. 5Department of Obstetrics and Gynaecology, Medical Spectrum
Twente, Enschede, The Netherlands. 6Department of Obstetrics and
Gynaecology, Rijnstate Hospital, Arnhem, The Netherlands. 7Department of
Obstetrics and Gynaecology, Gelre Hospital, Apeldoorn, The Netherlands.
8Department of Obstetrics and Gynaecology, Diakonessen Hospital Utrecht,
Utrecht, The Netherlands. 9Department of Obstetrics and Gynaecology,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands. 10Department of Obstetrics and Gynaecology,
Ropcke-Zweers hospital, Hardenberg, The Netherlands. 11Department of
Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, The Netherlands.
12Department of Obstetrics and Gynaecology, Antonius Hospital,
Nieuwegein, The Netherlands. 13Department of Obstetrics and Gynaecology,
Isala Clinics, Zwolle, The Netherlands. 14Department of Obstetrics and
Gynaecology, Medical Center Leeuwarden, Leeuwarden, The Netherlands.
15Department of Obstetrics and Gynaecology, University Medical Center St
Radboud, Nijmegen, The Netherlands. 16Department of Obstetrics and
Gynaecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
17Department of Obstetrics and Gynaecology, Wilhelmina Hospital, Assen,
The Netherlands. 18Department of Obstetrics and Gynaecology, Gemini
Hospital, Den Helder, The Netherlands. 19Department of Obstetrics and
Gynaecology, Division of Reproductive Medicine, Erasmus MC, Rotterdam,
The Netherlands. 20Department of Obstetrics and Gynaecology, Sint
Franciscus Gasthuis, Rotterdam, The Netherlands. 21Department of
Gynaecology and Reproductive Medicine, Leids University Medical Center,
University of Leiden, Leiden, The Netherlands. 22Department of Obstetrics
and Gynaecology, Westfriesgasthuis, Hoorn, The Netherlands. 23Department
of Obstetrics and Gynaecology, Tergooi hospitals, Blaricum, The Netherlands.
24Department of Obstetrics and Gynaecology, Groene Hart Hospital, Gouda,
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