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Intrauterine insemination: a United Kingdom survey on the adherence to NICE clinical guidelines by fertility clinics
Journal: BMJ Open
Manuscript ID: bmjopen-2015-007588
Article Type: Research
Date Submitted by the Author: 06-Jan-2015
Complete List of Authors: Kim, Dongah; University of Auckland, Obstetrics and Gynaecology Child, Tim; Oxford Fertility Unit, Farquhar, Cynthia; University of Auckland,
<b>Primary Subject Heading</b>:
Reproductive medicine
Secondary Subject Heading: Obstetrics and gynaecology
Keywords: Subfertility < GYNAECOLOGY, REPRODUCTIVE MEDICINE, Reproductive medicine < GYNAECOLOGY
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Title:
Intrauterine insemination: a United Kingdom survey on the adherence to NICE clinical
guidelines by fertility clinics
Authors: Dongah Kim, Tim Child, Cynthia Farquhar
Department of Obstetrics and Gynaecology, University of Auckland, Auckland 1142, New
Zealand Dongah Kim House Officer Oxford Fertility Unit, Oxfordshire OX4 2HW, United
Kingdom Tim Child Senior Fellow Department of Obstetrics and Gynaecology, University of
Auckland, Auckland 1142, New Zealand Cynthia Farquhar Professor
Correspondence to: Dongah Kim [email protected]
Word count for text only (excluding Article summary): 2722
Keywords: Intrauterine insemination, infertility, guideline.
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"the Corresponding Author has the right to grant on behalf of all authors and does grant on
behalf of all authors, an exclusive licence on a worldwide basis to the BMJ Publishing Group
Ltd to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL
products and sublicences such use and exploit all subsidiary rights, as set out in our licence."
All authors have completed the ICMJE uniform disclosure form and declare: no support from
any organisation for the submitted work, Mr Tim Child is a member of the NICE Guideline
Development Group and the Medical Director of Oxford Fertility Unit, a UK fertility clinic
offering both IUI and IVF.
'This research received no specific grant from any funding agency in the public, commercial or
not-for-profit sectors'
Dongah Kim affirms that this manuscript is an honest, accurate, and transparent account of
the study being reported; that no important aspects of the study have been omitted; and that
any discrepancies from the study as planned (and, if relevant, registered) have been
explained.
“The Corresponding Author has the right to grant on behalf of all authors and does grant on
behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in
all forms, formats and media (whether known now or created in the future), to i) publish,
reproduce, distribute, display and store the Contribution, ii) translate the Contribution into
other languages, create adaptations, reprints, include within collections and create
summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative
work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v)
the inclusion of electronic links from the Contribution to third party material where-ever it
may be located; and, vi) licence any third party to do any or all of the above.”
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Abstract
Objective
This study hypothesized that the adherence to the recent NICE guideline recommendation
that fertility clinics should not provide intrauterine insemination (IUI) would be low reflecting
the ongoing controversy surrounding this fertility treatment. The objective of this study was
to evaluate the awareness and response of UK fertility clinics to the recommendation.
Design
Online questionnaire survey addressing current clinical IUI practice, formal discussion of the
guideline recommendations and any alterations made since the recommendations.
Setting
Sixty-six UK fertility clinics licensed to provide IUI.
Participants
Forty-six fertility clinics, including six clinic groups which represent seventy percent of all
clinics and clinic groups licensed to provide IUI in April 2014 when the survey email was sent.
Results
Of the forty-six clinics who responded, ninety-six percent (44/46) of clinics continue to
offer IUI. Ninety-eight percent (43/44) of those offering IUI also use ovarian stimulation.
The most commonly used medications for ovarian stimulation are gonadotrophins
(96%), followed by clomiphene citrate (49%) and letrozole (19%). Seventy-eight percent
(36/46) of clinics had formally discussed the NICE guideline recommendations. Of these
clinics, seventeen clinics (47%) had made some changes to their practices; as a result
four clinics reported a reduction in the number of IUI cycles, six clinics had restricted the
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indications for IUI and five clinics had begun informing patients of the guideline
recommendations and two did not specify.
Conclusion
The majority of clinics were aware of the guideline recommendations however only a
relatively small proportion of clinics had made significant changes to their practice by
reducing the number of IUI cycles or restricting the clinical indications for IUI. The availability
of further evidence will assist NICE and clinicians in making recommendations on the use of
IUI. There is a need to address the specific reasons and barriers to adherence to the
recommendations.
WORD COUNT (ABSTRACT): 297
ARTICLE SUMMARY
Strengths and Limitations
• The survey was emailed to all but three of the eighty five UK fertility clinics
licensed to carry out intrauterine insemination.
• A response rate of 70% was achieved with the use of an electronic response
system and direct communication with the lead clinician or quality manager of
each clinic.
• A comparison of some important characteristics showed no major differences
between the survey participants and non-responding clinics.
• The timing of the survey was one year after the recommendations were
published in February 2013. Some of the survey data related in the 2013 year
may not have left sufficient time for the changes in practice to impact on the
data.
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Introduction
Intrauterine insemination (IUI) is a procedure typically used in the treatment of women
with unexplained infertility. It involves the placement of sperm directly into the uterus
at the time of ovulation, either in a natural menstrual cycle or following ovarian
stimulation. IUI has the advantages of being less invasive and more affordable than
other assisted reproduction techniques such as in- vitro fertilisation (IVF). However,
randomised controlled trials of IUI with and without stimulation compared with no
treatment have not provided convincing evidence of effectiveness of the procedure.1, 2
Pregnancy rates have been observed to be higher when IUI is combined with ovarian
stimulation however this has to be weighed up against the risks of ovarian hyper-
stimulation and multiple pregnancies.3
The latest National Institute for Health and Care Excellence (NICE) guideline on fertility
(2013) recommends that intrauterine insemination should not be routinely offered for
people with unexplained infertility, mild endometriosis or ‘mild male factor infertility’
who are having regular unprotected sexual intercourse.4 This is referring to the
treatment either with or without ovarian stimulation and acknowledges that IUI may
still be appropriate in situations where vaginal intercourse would not be suitable or
appropriate due to social, cultural or religious reasons. Instead the guidelines
recommend considering IVF as first line treatment after two years of expectant
management. A recent survey of fertility doctors in the UK with a response rate of 33%
found that 39% of respondents agreed with the recommendation that all patients with
unexplained subfertility should be offered IVF directly and 27% reported that they
would change their treatment strategy.5
This study hypothesized that the adherence to the recent NICE guideline
recommendations would reflect the ongoing controversy surrounding the use of
intrauterine insemination as a treatment for infertility. The objective of this
questionnaire survey was to evaluate the awareness and response of fertility clinics to
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the recommendation regarding IUI, in order to report on current practice in the United
Kingdom.
Method
An online questionnaire survey was used as it was simple and easy to distribute and
complete. The questionnaire was designed using an online survey software tool, Survey
Monkey. All clinics licensed to carry out intrauterine insemination were identified using
an advanced clinic search with the keyword ‘insemination’ on the Human Fertilisation
and Embryology Authority (HFEA) website. The clinic email address was obtained from
either the HFEA website, the clinic’s website or the clinic was directly rung when no
email address was acquired from these two locations. Of the 85 clinics identified, 82
clinics were contacted by email (3 clinics had no email addresses available and were not
contactable by phone on numerous occasions). Some of these clinics were noted to be
of the same clinic group. 8 such clinic groups were identified through clinic website
searches. Although an email was sent to each of the clinics, the answers were analysed
for consistency prior to a clinic group being collated as one for the purposes of this
study. At the end of the study period, a total of 66 clinics/ clinic groups were
approached by email.
A link to the survey was emailed with an explanatory cover letter. The clinics were
requested to identify themselves solely for the purpose of knowing which clinics had not
completed the survey although it was emphasized that all findings would be
anonymized. The questionnaire comprised of 7 short multiple choice questions with a
section for additional comments. The questionnaire was revised by three fertility
consultants and focused on whether the clinics were offering intrauterine insemination,
with or without ovarian stimulation, whether the guidelines have been discussed at a
clinic meeting and if any changes had been made to clinical practice. Ethical consent was
not required for this survey as the findings were kept anonymous and there was a link to
opt out of the survey. The survey was conducted from the 8th
April 2014, with an email
reminder sent out a week later and further links sent to alternative emails in the
remaining non-responders. The last of the completed surveys were received on the 2nd
June 2014. The clinic data available on the HFEA website was used to assess for
potential differences between the participants and non-responding clinics (Table 2).
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The data was anonymised and analysed on Excel. Descriptive statistics were calculated
only. A search was carried out on the HFEA website for the success rate of IUI with
partner sperm for each clinic to obtain the figures for the IUI cycles in 2013. The data
was obtained for 61 clinics, including the three clinics not contactable for the survey.
The data was not available for 8 clinics. Eight clinics had data available for 2013 but are
no longer licensed to provide IUI.
Results
Forty-six of sixty-six (70%) clinics or clinic groups responded to the survey. There were a
total of 58 responses. Seven clinics provided more than one response and there were
five responses from within the same clinic groups. Four of the six clinic group
participants had more than one clinic respond to the survey. These responses were
found to have generally consistent answers prior to being collated into clinic groups.
Two clinic groups (one group consisting of two clinics and the other of three clinics) had
only one clinic respond, in which case their answers were taken as representative of the
clinic group. Responses were received from fertility clinics in England, Scotland,
Northern Ireland and Wales. Three clinic groups comprise of clinics in more than one
country. The majority of responses were from clinics in England, which has the largest
portion of clinics licensed to carry out IUI in the UK.
The key findings are shown in Table 1. The survey findings indicate that ninety-six
percent (44/46) of clinics are continuing to offer IUI. Ninety-eight percent (43/44) of
those offering IUI use ovarian stimulation. The most commonly used medications for
ovarian stimulation are gonadotrophins (96%), followed by clomiphene citrate (49%)
and letrozole (19%).
Seventy-eight percent (36/46) of clinics had discussed the NICE guideline
recommendations. The remaining clinics had either not considered the
recommendations (4), did not respond (2), did not know (2) or did not offer IUI (2). Of
those clinics who had discussed the guideline recommendations, seventeen clinics (47%)
had made changes to their practices; four clinics reported a reduction in the number of
IUI cycles, six clinics had restricted the indications for IUI and five clinics had begun
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informing patients of the guideline recommendations and two did not specify. Of the
twenty-five clinics who had not made any changes, two had not been offering IUI and
four had already made restrictions on the indications for IUI.
The clinical indications for IUI cycles in 2013 were unexplained infertility at 26 clinics,
endometriosis at 10 clinics and male factor infertility at 13 clinics and all three
indications at 9 clinics. Ten clinics did not answer the question. Two clinics noted that
the IUI cycles in 2013 were only offered for religious, social or cultural reasons and two
clinics offered IUI only for donor insemination and in the treatment of cancer patients. A
range of other indications for IUI were noted by the respondents and included couples
with psycho-sexual dysfunction, women with polycystic ovarian syndrome, couples who
required donor sperm, women with immunological factors and cervical factors, and
couples who wished to avoid IVF.
Table 2 reports on differences between the responding clinics and the non-responding
clinics and there were no significant differences detected.
Table 3 reports on the categories for the number of IUI cycles in each clinic. The majority
of clinics were doing less than 100 cycles of IUI a year and only 34% of clinics (of those
where the data was available) were doing more than 100 IUI cycles per year.
Table 4 shows the figures for the number of IUI cycles with partner sperm undertaken in
2013 and compares the data available on the HFEA website with the data available from
clinics who answered the specific question. The HFEA data shows that of the 5934 cycles
of IUI undertaken in 2013, 4970 cycles (84%) were stimulated. With the inclusion of the
eight clinics that are no longer licensed to carry out IUI, of the 6944 cycles of IUI
undertaken in 2013, 5950 cycles (86%) were stimulated.
Discussion
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The key finding of this survey is that while the majority of clinics were aware of the
recent guideline recommendations, only a relatively small proportion of clinics had
made significant changes to their practice by reducing the number of IUI cycles or
restricting the clinical indications for IUI. Several reasons as to why some clinics have not
made changes were given. Several clinics commented that there is continued funding
for IUI by local Clinical Commissioning Groups (CCGs). Interestingly, one respondent
commented that their own audit findings showed a success rate of up to 28% with IUI in
couples where the clinical indications included unexplained infertility, male factor
infertility and endometriosis. Another respondent commented that they disagreed with
the guidelines, questioning the evidence behind the recommendations. It was also
noted that some clinics were still offering IUI if it was preferred by patients, particularly
for self-funded patients or for patients who have only one cycle of IVF funded by NHS.
Some of these clinics commented that they were now informing patients of the
guideline recommendations however still continued to discuss and offer the treatment.
Strengths and Limitations of the survey
The survey was emailed to all but three of the fertility clinics licensed to carry out
intrauterine insemination in the United Kingdom. The response rate was 70%, which is
better than other similar surveys exploring guideline awareness and adherence to
recommendations. A similar recently published survey focused on the management of
women with unexplained subfertility and also included whether doctors would change
practice according to the NICE guidelines.5 A total of 420 members of the British Fertility
Society were contacted by email and a disappointing response rate of 33% was
reported. Another UK survey conducted in 2012 assessed the management of infertility
in women aged 40 and over.6 Sixty-nine fertility clinics offering IVF and IUI were
contacted by email and better response rate of 64% was achieved.6 A postal survey
evaluated clinician attitudes to IUI and was sent to 150 fertility clinics in the UK.7A
response was received from 101 practitioners; the survey did not specify whether the
responses were from different clinics. The reasons for the better response rate in our
own survey were the use of an electronic response system and that we communicated
directly with the lead clinician or quality manager of each clinic.
It is expected that there would be non-responders to the survey, however the response
rate of 46 of the 66 clinics emailed (70%) was sufficient to draw conclusions. It is
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possible that those who responded were the motivated clinics, in which case the
findings would be an overestimation of the actual awareness and adherence to the
guidelines. However, a comparison of some important characteristics showing no major
differences between the survey participants and non-responding clinics is reassuring
that the clinics who responded are representative. (Table 2)
Another potential form of response bias is that the responders may have selected what
they believed to be ‘right’ answers, which would also lead to an overestimation. The
anonymity of the findings was emphasized in the cover letter and survey in an attempt
to minimise this. The cover letter specifically requested for the email to be forwarded to
the most appropriate person, however it can only be inferred that the personnel from
each clinic who completed the survey were knowledgeable about the actual practice in
their clinic, aware of whether discussions took place and of any changes made. It is
assumed that the practice protocols and any changes are generally followed through by
the consultants within each clinic. In the two clinic groups where there was only one
response, it is assumed that the answers are representative of the practice within the
clinic groups. A comparison between answers within the other clinic groups (the largest
consisting of six clinics where three clinics responded) showed general consistency,
however it is still possible that they are not reflective of practice in all the clinics within a
group. If this assumption is inaccurate it would have a relatively minor effect on the
findings considering the small total number of clinic groups.
The timing of the survey was one year after the recommendations were published in
February 2013. Some of the survey data related in the 2013 year may not have left
sufficient time for the changes in practice to impact on the data. However, the majority
of the survey questions were not related to the 2013 year but more focused on the
practice changes made.
The survey findings are generalizable to fertility clinics throughout the UK. The NICE
guidelines recommend the level of funding for fertility treatment in England and Wales.
Relationship between evidence and recommendations
The NICE guideline recommendations were based on studies that showed no evidence
of a benefit in terms of live birth rates with IUI compared to expectant management. 1, 2
However the Steures et al study (2006) involved couples with mild unexplained
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infertility with a probability of pregnancy greater than 30%.1 The Bhattacharya et al
study (2008) showed no improvement in live birth rates with unstimulated IUI in couples
with unexplained infertility.2 It has been previously suggested that the success rate of
IUI remains controversial due to the influence of multiple factors.7 These include the
timing, localization, preparation of sperm, use of ovarian stimulation, the number and
size of the follicles and techniques used when carrying out the procedure. Considering
the lack of robust evidence to support the guidelines and the range of factors that
influence the efficacy of IUI, it is not surprising that the survey findings indicate a variety
of different attitudes towards the use of IUI.
Some clinics noted that they are still discussing and offering IUI due to patient
preference over IVF. The European Society of Human Reproduction and Embryology
Capri Workshop in December 2009 suggested that for couples with a better chance of
conception, it is more likely that ovulation induction is equally effective to IUI. For
couples with lower chances of conception, IVF would more likely be effective over IUI.
They concluded that although IUI may be more affordable and less demanding, IVF is
more effective in the treatment of infertility.8 This is supported by the findings of the
recent FORT-T trial (the Forty and Over Treatment Trial), which compared two cycles of
IUI with controlled ovarian stimulation using clomiphene citrate or FSH versus
immediate IVF (2014).9 This randomised controlled trial involved 154 older couples
(females aged between 38 and 42 years) with unexplained infertility and a reasonable
chance of conception. In these couples, immediate treatment with IVF was the most
efficient option with higher live birth rates and fewer treatment cycles. The previous
Fast Track and Standard Treatment (FAST-T) trial had suggested that for young couples
with unexplained infertility, proceeding to IVF after three cycles of IUI with clomiphene
citrate was more cost effective than continuing with further three cycles of IUI with FSH
(2010).10
Although there is some evidence to suggest that IVF is more effective
compared to IUI, there is a need for further randomised controlled trials to support the
recommendation of direct treatment with IVF. In addition to the issue of efficacy, the
survey respondents highlighted affordability and funding for IVF as influencing clinical
practice and guideline adherence. In implementing the guideline, clinicians may also
need to be able to confidently convince patients and deny requests for IUI.
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Conclusion
The purpose of the NICE guidelines is to optimise the quality of care by assisting
clinicians and patients in making appropriate and safe decisions. This survey reflects the
continued variation in the practice of IUI in the UK and a general poor response to the
guidelines. There is a need for more high quality trials such as the FORT-T trial, INeS
trial11
and the ongoing TUI study12
. The availability of further evidence will aid NICE and
clinicians in making recommendations on the use of IUI as a treatment for infertility.
Adherence to the guidelines will also improve when there is a reflection of the
recommendations in the funding by the local CCGs. Further studies that evaluate the
specific reasons and barriers to adherence to the guideline will also help.
Acknowledgments
We would like to thank all the individuals who took the time to complete the survey.
Other individuals who provided invaluable assistance are Ursula Foley, University of
Auckland, Karen Kumar, Oxford Fertility Unit, Mr Andrew Bond, Oxford Fertility Unit and
Clare Lewis-Jones, Infertility Network UK.
Data sharing
Clinic responses on the electronic response system, Survey Monkey and data on Excel
spreadsheets are kept by Dongah Kim.
Competing Interest
Mr Tim Child is a member of the NICE Guideline Development Group and the Medical Director
of Oxford Fertility Unit, a UK fertility clinic offering both IUI and IVF.
Contributorship
Cynthia Farquhar and Tim Child were involved in the conception and design of the study.
Dongah Kim and Tim Child were involved in data acquisition. Dongah Kim and Cynthia Farquhar
carried out data analysis and interpretation. All three authors revised the work.
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Broekmans FJ, et al. Intrauterine insemination with controlled ovarian
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2. Bhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, et al.
Clomifene citrate or unstimulated intrauterine insemination compared with
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controlled trial. BMJ 2008;337:a716.
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insemination for unexplained subfertility. Cochrane Database Syst Rev 2012;(4)
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Obstet Gynaecol 2008;28(7):738–741.
8. ESHRE Capri Workshop Group. Intrauterine insemination discussed by the ESHRE
Capri Workshop Group 2009. http://www.eshre.eu/ (accessed August 30 2014).
9. Goldman MB, Thornton KL, Ryley D, Alper MM, Fung JL, Hornstein MD, et al. A
randomised clinical trial to determine optimal infertility treatment in older
couples: the Forty and Over Treatment Trial (FORT- T). Fert Steril 2014;101:1574-
81.
10. Reindollar RH, Regan MM, Neumann PJ, et al. A randomized clinical trial to
evaluate optimal treatment for unexplained subfertility: the fast track and
standard treatment (FASTT) trial. Fert Steril 2010;94:888-899.
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11. Bensdorp AJ, Slappendel E, Koks C, Oosterhuis J, Hoek A, Hompes P, et al. The
INeS study: prevention of multiple pregnancies: a randomised controlled trial
comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained
or mild male subfertility [abstract]. BMC Womens Health 2009;9:35 doi:
10.1186/1472-6874-9-35.
12. Liu E, Armstrong S, Farquhar C. The intrauterine insemination with stimulation in
women with unexplained infertility study. ACTRN12612001025820. Date
registered 24/09/2012.
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Table 1: Survey responses from fertility clinics in the United Kingdom
Question Total (%) Yes (%) No (%) Don’t know (%) Did not answer (%)
1) Is your clinic offering intrauterine insemination? 46 44/46 (96) 2/46 (4) 0 (0) 0 (0)
2) If yes, are you offering intrauterine insemination with
ovarian stimulation?
44 43/44 (98) 0 (0) 0 (0) 1/44 (2)
3) If yes, which of the following medications are used? *
Gonadotropins
Clomiphene citrate
Letrozole
43
43
43
41/43
21/43
8/43
1/43
21/43
34/43
0
0
0
1/43
1/43
1/43
4) Has the 2013 NICE clinical guideline 156 been discussed
at a clinic meeting? **
46 36/46 (78) 6/46 (13) 2/46 (4) 2/46 (4)
5) Have any alterations in your clinic practice been made
since this recommendation? ***
46 17/46 (37) 25/46 (54) 2/46 (4) 2/46 (4)
6) What were the clinical indications for the IUI cycles in
2013? ****
Unexplained infertility
Endometriosis
Male factor infertility
Cervical factor infertility
Immunological factor infertility
Only for religious, social, cultural reasons
Only for donor insemination and cancer patients
Question not answered
26/44
10/44
13/44
6/44
1/44
2/44
2/44
10/44
*Note: More than one option possible. One clinic uses Tamoxifen.
** 2/6 clinics that did not discuss the guideline were not offering intrauterine insemination.
*** 2/25 clinics that had not made alterations were not offering intrauterine insemination.
****More than one clinical indication for the IUI cycles possible.
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Table 2: Comparison of characteristics of responding and non-responding clinics
*Note: (%) is the percentage of the total number of responding clinics, non-responding clinics or total. Percentages do not
necessarily sum up to 100% due to rounding.
Characteristic Responding clinics Non-responding clinics Total
Type of patients, n (%)
Private patients only
NHS and private
NHS patients only
Total
6 (13)
37 (80)
3 (7)
46
4 (20)
11 (55)
5 (25)
20
10 (15)
48 (73)
8 (12)
66
Clinic groups 6 (13) 2 (10) 8
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Table 3: The total number of IUI cycles in each clinic in 2013.
Note: The figures for the ‘Number of women who began IUI cycles in 2013’ indicate the number of clinics that began IUI
cycles for the number of women shown. Source: HFEA Website 2013.
Total number of IUI cycles in each clinic in 2013 Number of responding clinics Number of non-responding clinics
0 1 0
1-50 17 8
51-100 6 6
101-150 4 1
151-200 3 1
201-250 5 1
251-300 3 1
≥ 301 1 0
Only DI data or no data available 6 2
Total 46 20
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Table 4: The number of IUI cycles with partner sperm in the UK during 2013.
2013 IUI figures Clinics who answered specific question HFEA data
Total number of cycles 2146 (24 clinics) 5934 (61 clinics)
Total number of stimulated cycles 1830 (24 clinics) 4970 (61 clinics)
Total number of unstimulated cycles 316 (23 clinics) 964 (61 clinics)
Clinical pregnancy rate
- Per stimulated cycle of IUI
- Per natural cycle of IUI
Median 12%, range (0-28%)
Median 8.5%, range (0-100%)
Median 10.6%, range (0-24.2%)
Median 0%, range (0-100%)
HFEA data source: HFEA website 2013.
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STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross-sectional studies
Section/Topic Item
# Recommendation Reported on page #
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1, 3
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 3,4
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4, 5
Objectives 3 State specific objectives, including any prespecified hypotheses 5
Methods
Study design 4 Present key elements of study design early in the paper 3
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
collection
6
Participants
6
(a) Give the eligibility criteria, and the sources and methods of selection of participants 5
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
6, tables 1, 2, 3.
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
6, 7
Bias 9 Describe any efforts to address potential sources of bias 9, tables 2, 3.
Study size 10 Explain how the study size was arrived at 5
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
6
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 6
(b) Describe any methods used to examine subgroups and interactions
(c) Explain how missing data were addressed
(d) If applicable, describe analytical methods taking account of sampling strategy
(e) Describe any sensitivity analyses
Results
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Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow-up, and analysed
5, 6
(b) Give reasons for non-participation at each stage
(c) Consider use of a flow diagram
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
6, 7, tables 2, 3
(b) Indicate number of participants with missing data for each variable of interest Table 1
Outcome data 15* Report numbers of outcome events or summary measures 7, 8, tables 1, 4
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
6, 7, 8, tables 1, 4
(b) Report category boundaries when continuous variables were categorized
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses
Discussion
Key results 18 Summarise key results with reference to study objectives 8
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
8, 9
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
11
Generalisability 21 Discuss the generalisability (external validity) of the study results 10
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
2
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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Intrauterine insemination: a United Kingdom survey on the adherence to NICE clinical guidelines by fertility clinics
Journal: BMJ Open
Manuscript ID: bmjopen-2015-007588.R1
Article Type: Research
Date Submitted by the Author: 14-Apr-2015
Complete List of Authors: Kim, Dongah; University of Auckland, Obstetrics and Gynaecology Child, Tim; Oxford Fertility Unit, Farquhar, Cynthia; University of Auckland,
<b>Primary Subject Heading</b>:
Reproductive medicine
Secondary Subject Heading: Obstetrics and gynaecology
Keywords: Subfertility < GYNAECOLOGY, REPRODUCTIVE MEDICINE, Reproductive medicine < GYNAECOLOGY
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Title
Intrauterine insemination: a United Kingdom survey on the adherence to NICE
clinical guidelines by fertility clinics
Authors: Dongah Kim, Tim Child, Cynthia Farquhar
Department of Obstetrics and Gynaecology, University of Auckland, Auckland
1142, New Zealand Dongah Kim House Officer Oxford Fertility Unit,
Oxfordshire OX4 2HW, United Kingdom Tim Child Senior Fellow Department
of Obstetrics and Gynaecology, University of Auckland, Auckland 1142, New
Zealand Cynthia Farquhar Professor
Correspondence to: Dongah Kim [email protected]
Word count for text only (excluding Abstract, Article summary, References
and tables): 2882
Keywords: Intrauterine insemination, infertility, guideline.
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Abstract
Objective
To evaluate the awareness and response of fertility clinics in the United
Kingdom to the NICE guideline recommendation that intrauterine insemination
(IUI) should not be offered routinely, in order to report on current practice in
the United Kingdom.
Design
Online questionnaire survey of fertility clinics in the United Kingdom regarding
their current clinical practice of IUI, formal discussion of the guideline
recommendations and any alterations made since the recommendations.
Setting
Sixty-six United Kingdom fertility clinics licensed to provide IUI.
Participants
Forty-six fertility clinics, including six clinic groups which represent seventy
percent of all clinics and clinic groups licensed to provide IUI in April 2014 when
the survey email was sent.
Results
Of the forty-six clinics who responded, ninety-six percent (44/46) of clinics
continue to offer IUI. Ninety-eight percent (43/44) of those offering IUI also use
ovarian stimulation. The most commonly used medications for ovarian
stimulation are gonadotrophins (96%), followed by clomiphene citrate (49%)
and letrozole (19%). Seventy-eight percent (36/46) of clinics had formally
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discussed the NICE guideline recommendations. Seventeen clinics (37%) had
made some changes to their practices; as a result four clinics reported a
reduction in the number of IUI cycles, six clinics had restricted the indications
for IUI and five clinics had begun informing patients of the guideline
recommendations and two did not specify.
Conclusion
The majority of clinics were aware of the guideline recommendations. However,
only a small proportion of clinics had made significant changes to their practice
by reducing the number of IUI cycles or restricting the clinical indications for IUI.
The availability of further evidence will assist NICE and clinicians in making
recommendations on the use of IUI. There is a need to further explore the
reasons for the lack of adherence to the recommendations.
WORD COUNT (ABSTRACT): 292
ARTICLE SUMMARY
Strengths and Limitations
• The survey was emailed to all but three of the eighty five UK fertility
clinics licensed to carry out intrauterine insemination.
• A response rate of 70% was achieved with the use of an electronic
response system and direct communication with the lead clinician or
quality manager of each clinic.
• A comparison of some important characteristics showed no major
differences between the survey participants and non-responding clinics.
• The timing of the survey was one year after the recommendations were
published in February 2013. Some of the survey data related in the
2013 year may not have left sufficient time for the changes in practice to
impact on the data.
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Introduction
Intrauterine insemination (IUI) is a procedure typically used in the treatment of
couples with unexplained infertility. It involves the placement of sperm directly
into the uterus at the time of ovulation, either in a natural menstrual cycle or
following ovarian stimulation. IUI has the advantages of being less invasive and
more affordable than other assisted reproduction techniques such as in- vitro
fertilisation (IVF). However, randomised controlled trials of IUI with and without
stimulation compared with no treatment have not provided convincing
evidence of effectiveness of the procedure.1, 2
Pregnancy rates have been
observed to be higher when IUI is combined with ovarian stimulation however
this has to be weighed up against the risks of ovarian hyper-stimulation and
multiple pregnancies.3
The latest National Institute for Health and Care Excellence (NICE) guideline on
fertility (2013) recommends that intrauterine insemination should not be
routinely offered for people with unexplained infertility, mild endometriosis or
‘mild male factor infertility’ who are having regular unprotected sexual
intercourse.4 This is referring to the treatment either with or without ovarian
stimulation and acknowledges that exceptional circumstances include, for
example, when people have social, cultural or religious objections to IVF.
Instead the guidelines recommend considering IVF as first line treatment after
two years of expectant management. The recommendation was informed by
two randomised controlled trials of IUI that did not find evidence of benefit
when compared with expectant management. 1, 2
A recent survey of fertility
doctors in the UK with a response rate of 33% found that 39% of respondents
agreed with the recommendation that all patients with unexplained subfertility
should be offered IVF directly and 27% reported that they would change their
treatment strategy.5
This study hypothesized that the adherence to the recent NICE guideline
recommendations would reflect the ongoing controversy surrounding the use
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of intrauterine insemination as a treatment for infertility. The objective of this
questionnaire survey was to evaluate the awareness and response of fertility
clinics to the recommendation regarding IUI, in order to report on current
practice in the United Kingdom.
Method
An online questionnaire survey was used as it was simple and easy to distribute
and complete. The questionnaire was designed using an online survey software
tool, Survey Monkey. All clinics licensed to carry out intrauterine insemination
were identified using an advanced clinic search with the keyword ‘insemination’
on the Human Fertilisation and Embryology Authority (HFEA) website. The clinic
email address was obtained from either the HFEA website, the clinic’s website
or the clinic was directly rung when no email address was acquired from these
two locations. Of the 85 clinics identified, 82 clinics were contacted by email
(three clinics had no email addresses available and were not contactable by
phone on numerous occasions). Some of these clinics were noted to be of the
same clinic group. Eight such clinic groups were identified through clinic website
searches. Although an email was sent to each of the clinics, the answers were
analysed for consistency prior to a clinic group being collated as one for the
purposes of this study. At the end of the study period, a total of 66 clinics/ clinic
groups were approached by email.
A link to the survey was emailed with an explanatory cover letter. The clinics
were requested to identify themselves solely for the purpose of knowing which
clinics had not completed the survey although it was emphasized that all
findings would be anonymized. The questionnaire comprised of seven short
multiple choice questions with a section for additional comments. The
questionnaire was revised by three fertility consultants and focused on whether
the clinics were offering intrauterine insemination, with or without ovarian
stimulation, whether the guidelines have been discussed at a clinic meeting and
if any changes had been made to clinical practice. Ethical consent was not
required for this survey as the findings were kept anonymous and there was a
link to opt out of the survey. The survey was conducted from the 8th
April 2014,
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with an email reminder sent out a week later and further links sent to
alternative emails in the remaining non-responders. The last of the completed
surveys were received on the 2nd
June 2014. The clinic data available on the
HFEA website was used to assess for potential differences between the
participants and non-responding clinics (Table 2).
The data was anonymised and analysed on Excel. Descriptive statistics were
calculated only. A search was carried out on the HFEA website for the success
rate of IUI with partner sperm for each clinic to obtain the figures for the IUI
cycles in 2013. The data was obtained for 61 clinics, including the three clinics
not contactable for the survey. The data was not available for 8 clinics. Eight
clinics had data available for 2013 but are no longer licensed to provide IUI.
Results
Forty-six of sixty-six (70%) clinics or clinic groups responded to the survey.
There were a total of 58 responses. Seven clinics provided more than one
response and there were five responses from within the same clinic groups.
Four of the six clinic group participants had more than one clinic respond to the
survey. These responses were found to have generally consistent answers prior
to being collated into clinic groups. Two clinic groups (one group consisting of
two clinics and the other of three clinics) had only one clinic respond, in which
case their answers were taken as representative of the clinic group. Responses
were received from fertility clinics in England, Scotland, Northern Ireland and
Wales. Of the 82 individual clinics contacted by email, responses were received
from all the three clinics in Wales, one of the three clinics in Northern Ireland,
three of the five clinics in Scotland and forty-four of the seventy-one clinics in
England. Three clinic groups comprise of clinics in more than one country.
The key findings are shown in Table 1. The survey findings indicate that ninety-
six percent (44/46) of clinics are continuing to offer IUI. Ninety-eight percent
(43/44) of those offering IUI use ovarian stimulation. The most commonly used
medications for ovarian stimulation are gonadotrophins (96%), followed by
clomiphene citrate (49%) and letrozole (19%).
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Seventy-eight percent (36/46) of clinics had discussed the NICE guideline
recommendations. The remaining clinics had either not considered the
recommendations (4), did not respond (2), did not know (2) or did not offer IUI
(2). Seventeen clinics (37%) had made changes to their practices; four clinics
reported a reduction in the number of IUI cycles, six clinics had restricted the
indications for IUI and five clinics had begun informing patients of the guideline
recommendations and two did not specify. Of the twenty-five clinics that had
not made any changes, two were offering the treatment before and had since
stopped and four had already made restrictions on the indications for IUI.
The clinical indications for IUI cycles in 2013 were unexplained infertility at 26
clinics, endometriosis at ten clinics and male factor infertility at 13 clinics and all
three indications at nine clinics. Ten clinics did not answer the question. Two
clinics noted that the IUI cycles in 2013 were only offered for religious, social or
cultural reasons and two clinics offered IUI only for donor insemination and in
the treatment of cancer patients. A range of other indications for IUI were
noted by the respondents and included couples with psycho-sexual dysfunction,
women with polycystic ovarian syndrome, couples who required donor sperm,
women with immunological factors and cervical factors, and couples who
wished to avoid IVF.
Table 2 reports on differences between the responding clinics and the non-
responding clinics and there were no significant differences detected.
Table 3 reports on the categories for the number of IUI cycles in each clinic. The
majority of clinics were doing less than 100 cycles of IUI a year and only 34% of
clinics (of those where the data was available) were doing more than 100 IUI
cycles per year.
Table 4 shows the figures for the number of IUI cycles with partner sperm
undertaken in 2013 and compares the data available on the HFEA website with
the data available from clinics who answered the specific question. The HFEA
data shows that of the 5934 cycles of IUI undertaken in 2013, 4970 cycles (84%)
were stimulated. With the inclusion of the eight clinics that are no longer
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licensed to carry out IUI, of the 6944 cycles of IUI undertaken in 2013, 5950
cycles (86%) were stimulated.
Discussion
The key finding of this survey is that while the majority of clinics were aware of
the recent guideline recommendations, only a small proportion of clinics had
made significant changes to their practice by reducing the number of IUI cycles
or restricting the clinical indications for IUI. Several reasons as to why some
clinics have not made changes were given. Several clinics commented that
there is continued funding for IUI by local Clinical Commissioning Groups
(CCGs). Interestingly, one respondent commented that their own audit findings
showed a success rate of up to 28% with IUI in couples where the clinical
indications included unexplained infertility, male factor infertility and
endometriosis. Another respondent commented that they disagreed with the
guidelines, questioning the evidence behind the recommendations. It was also
noted that some clinics were still offering IUI if it was preferred by patients,
particularly for self-funded patients or for patients who have only one cycle of
IVF funded by NHS. The majority of responding clinics treat both NHS and
private patients and only three of the forty-six respondents treat only NHS
patients. Private patients may be discouraged from paying for the more
expensive IVF treatment, yet on the other hand it may be more financially
desirable for clinicians to offer IVF. Guideline adherence may also be affected
by whether clinics offer only IUI or both IUI and IVF. Six of the forty-six
responding clinics offer only IUI, two clinics were previously licensed to carry
out IUI but now only offer IVF and the remaining thirty-eight clinics offer both
IUI and IVF, hence this is unlikely to be of significance.
Strengths and Limitations of the survey
The survey was emailed to all but three of the fertility clinics licensed to carry
out intrauterine insemination in the United Kingdom. The response rate was
70%, which is better than other similar surveys exploring guideline awareness
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and adherence to recommendations. A similar recently published survey
focused on the management of women with unexplained subfertility and also
included whether doctors would change practice according to the NICE
guidelines.5 A total of 420 members of the British Fertility Society were
contacted by email and a disappointing response rate of 33% was reported.
Another UK survey conducted in 2012 assessed the management of infertility in
women aged 40 and over.6 Sixty-nine fertility clinics offering IVF and IUI were
contacted by email and better response rate of 64% was achieved.6 A postal
survey evaluated clinician attitudes to IUI and was sent to 150 fertility clinics in
the UK.7A response was received from 101 practitioners; the survey did not
specify whether the responses were from different clinics. The better response
rate in our own survey may have been due to the use of an electronic response
system and because we communicated directly with the lead clinician or quality
manager of each clinic.
It is expected that there would be non-responders to the survey, however the
response rate of 46 of the 66 clinics emailed (70%) was sufficient to draw
conclusions. It is possible that those who responded were the motivated clinics,
in which case the findings would be an overestimation of the actual awareness
and adherence to the guidelines. However, a comparison of some important
characteristics showing no major differences between the survey participants
and non-responding clinics is reassuring that the clinics who responded are
representative. (Table 2)
Another potential form of response bias is that the responders may have
selected what they believed to be ‘right’ answers, which would also lead to an
overestimation. The anonymity of the findings was emphasized in the cover
letter and survey in an attempt to minimise this. The cover letter specifically
requested for the email to be forwarded to the most appropriate person,
however it can only be inferred that the personnel from each clinic who
completed the survey were knowledgeable about the actual practice in their
clinic, aware of whether discussions took place and of any changes made. It is
assumed that the practice protocols and any changes are generally followed
through by the consultants within each clinic. In the two clinic groups where
there was only one response, it is assumed that the answers are representative
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of the practice within the clinic groups. A comparison between answers within
the other clinic groups (the largest consisting of six clinics where three clinics
responded) showed general consistency, however it is still possible that they
are not reflective of practice in all the clinics within a group. If this assumption is
inaccurate it would have a relatively minor effect on the findings considering
the small total number of clinic groups.
The timing of the survey was one year after the recommendations were
published in February 2013. Some of the survey data related in the 2013 year
may not have left sufficient time for the changes in practice to impact on the
data. However, the majority of the survey questions were not related to the
2013 year but more focused on the practice changes made. Furthermore, the
survey was conducted between April and June 2014 and adherence to the
guidelines since then may have improved due to reduced funding for IUI by
Clinical Commissioning Groups. The survey findings are generalizable to fertility
clinics throughout the UK. The NICE guidelines recommend the level of funding
for fertility treatment in England and Wales.
Relationship between evidence and recommendations
The NICE guideline recommendations were based on studies that showed no
evidence of a benefit in terms of live birth rates with IUI compared to expectant
management. 1, 2
However the Steures et al study (2006) involved couples with
mild unexplained infertility with a probability of pregnancy greater than 30%.1
The Bhattacharya et al study (2008) showed no improvement in live birth rates
with unstimulated IUI in couples with unexplained infertility.2 It has been
previously suggested that the success rate of IUI remains controversial due to
the influence of multiple factors.7 These include the timing, localization,
preparation of sperm, use of ovarian stimulation, the number and size of the
follicles and techniques used when carrying out the procedure. Considering the
lack of robust evidence to support the guidelines and the range of factors that
influence the efficacy of IUI, it is not surprising that the survey findings indicate
a variety of different attitudes towards the use of IUI.
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Some clinics noted that they are still discussing and offering IUI due to patient
preference over IVF. The European Society of Human Reproduction and
Embryology Capri Workshop in December 2009 suggested that for couples with
a better chance of conception, it is more likely that ovulation induction is
equally effective to IUI. For couples with lower chances of conception, IVF
would more likely be effective over IUI. They concluded that although IUI may
be more affordable and less demanding, IVF is more effective in the treatment
of infertility.8 This is supported by the findings of the recent FORT-T trial
(the Forty and Over Treatment Trial), which compared two cycles of IUI with
controlled ovarian stimulation using clomiphene citrate or FSH versus
immediate IVF (2014).9 This randomised controlled trial involved 154 older
couples (females aged between 38 and 42 years) with unexplained infertility
and a reasonable chance of conception. In these couples, immediate treatment
with IVF was the most efficient option with higher live birth rates and fewer
treatment cycles. The previous Fast Track and Standard Treatment (FAST-T) trial
had suggested that for young couples with unexplained infertility, proceeding to
IVF after three cycles of IUI with clomiphene citrate was more cost effective
than continuing with further three cycles of IUI with FSH (2010).10
However,
these findings do not agree with a recently published RCT (INeS) comparing 3
cycles of IVF with single embryo transfer and with 6 cycles of IUI with
stimulation which did not report a difference in live birth rate between the two
arms of the study.11
In addition to the issue of efficacy, the survey respondents highlighted
affordability and funding for IVF as influencing clinical practice and guideline
adherence. IUI is considerably cheaper that IVF and if it has similar outcomes
then it may be difficult to convince couples to have IVF.
Conclusion
The purpose of the NICE guidelines is to optimise the quality of care by assisting
clinicians and patients in making appropriate and safe decisions. This survey
reflects the continued variation in the practice of IUI in the UK and a general
poor response to the guidelines. There is a need for more high quality trials
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such as the FORT-T trial, INeS trial11
and the ongoing TUI study12
. The availability
of further evidence will aid NICE and clinicians in making recommendations on
the use of IUI as a treatment for infertility. Adherence to the guidelines will also
improve when there is a reflection of the recommendations in the funding by
the local CCGs. Further studies that evaluate the specific reasons and barriers to
adherence to the guideline will also help.
Acknowledgments
We would like to thank all the individuals who took the time to complete the
survey. Other individuals who provided invaluable assistance are Ursula Foley,
University of Auckland, Karen Kumar, Oxford Fertility Unit, Mr Andrew Bond,
Oxford Fertility Unit and Clare Lewis-Jones, Infertility Network UK.
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Contributorship statement: Cynthia Farquhar and Tim Child were involved in
the conception and design of the study. Dongah Kim and Tim Child were
involved in data acquisition. Dongah Kim and Cynthia Farquhar carried out data
analysis and interpretation. All three authors revised the work.
Competing interests: All authors have completed the ICMJE uniform disclosure
form and declare: no support from any organisation for the submitted work, Mr
Tim Child is a member of the NICE Guideline Development Group and the
Medical Director of Oxford Fertility Unit, a UK fertility clinic offering both IUI
and IVF.
Funding: 'This research received no specific grant from any funding agency in
the public, commercial or not-for-profit sectors'
Data sharing statement: Clinic responses are available on the electronic
response system, Survey Monkey. Raw data on Excel spreadsheets are kept by
Dongah Kim and will be stored on Dryad data repository for open access.
"the Corresponding Author has the right to grant on behalf of all authors and
does grant on behalf of all authors, an exclusive licence on a worldwide basis to
the BMJ Publishing Group Ltd to permit this article (if accepted) to be published
in BMJ editions and any other BMJPGL products and sublicences such use and
exploit all subsidiary rights, as set out in our licence."
Dongah Kim affirms that this manuscript is an honest, accurate, and transparent
account of the study being reported; that no important aspects of the study
have been omitted; and that any discrepancies from the study as planned (and,
if relevant, registered) have been explained.
“The Corresponding Author has the right to grant on behalf of all authors and
does grant on behalf of all authors, a worldwide licence to the Publishers and its
licensees in perpetuity, in all forms, formats and media (whether known now or
created in the future), to i) publish, reproduce, distribute, display and store the
Contribution, ii) translate the Contribution into other languages, create
adaptations, reprints, include within collections and create summaries, extracts
and/or, abstracts of the Contribution, iii) create any other derivative work(s)
based on the Contribution, iv) to exploit all subsidiary rights in the Contribution,
v) the inclusion of electronic links from the Contribution to third party material
where-ever it may be located; and, vi) licence any third party to do any or all of
the above.”
Ethical consent was not required for this survey. There was no direct patient
involvement, the findings were kept anonymous and there was a link to opt out
of the survey
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References
1. Steures P, Van der Steeg JW, Hompes PG, Habbema JD, Eijkemans MJ,
Broekmans FJ, et al. Intrauterine insemination with controlled ovarian
hyperstimulation versus expectant management for couples with
unexplained subfertility and an intermediate prognosis: a randomised
clinical trial. Lancet 2006;368:216-21.
2. Bhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, et
al. Clomifene citrate or unstimulated intrauterine insemination
compared with expectant management for unexplained subfertility:
pragmatic randomised controlled trial. BMJ 2008;337:a716.
3. Veltman-Verhulst SM, Cohlen BJ, Hughes E, Heineman MJ. Intra-uterine
insemination for unexplained subfertility. Cochrane Database Syst Rev
2012;(4) CD001838 doi:10.1002/14651858.CD001838.
4. NICE. (2013). Nice guideline: Fertility: for people with fertility problems.
NICE clinical guideline 156 February 2013, 1.8.1.3–4.
5. Nandi A, Gudi A, Shah A, Homburg R. An online survey of specialists’
opinion on first line management options for unexplained subfertility.
Hum Fertil 2014;Aug 27:1-6.
6. Marinakis G, Nikolaou D. National survey of the current management of
infertility in women aged 40 and over in the UK. J Obstet Gynaecol
2012;32(4):375-8.
7. Rawal N, Drakeley A, Haddad N. Intrauterine insemination practice in the
UK. J Obstet Gynaecol 2008;28(7):738–741.
8. ESHRE Capri Workshop Group. Intrauterine insemination discussed by
the ESHRE Capri Workshop Group 2009. http://www.eshre.eu/
(accessed August 30 2014).
9. Goldman MB, Thornton KL, Ryley D, Alper MM, Fung JL, Hornstein MD,
et al. A randomised clinical trial to determine optimal infertility
treatment in older couples: the Forty and Over Treatment Trial (FORT-
T). Fert Steril 2014;101:1574-81.
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10. Reindollar RH, Regan MM, Neumann PJ, et al. A randomized clinical trial
to evaluate optimal treatment for unexplained subfertility: the fast track
and standard treatment (FASTT) trial. Fert Steril 2010;94:888-899.
11. Bensdorp AJ, Tjon-Kon-Fat RI, Bossuyt PMM, Koks C, Oosterhuis J, Hoek
A, et al. Prevention of multiple pregnancies in couples with unexplained
or mild male subfertility: randomised controlled trial of in vitro
fertilisation with single embryo transfer or in vitro fertilisation in
modified natural cycle compared with intrauterine insemination with
controlled ovarian hyperstimulation. BMJ 2015;350:g7771.
12. Liu E, Armstrong S, Farquhar C. The intrauterine insemination with
stimulation in women with unexplained infertility study.
ACTRN12612001025820. Date registered 24/09/2012.
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Table 1: Survey responses from fertility clinics in the United Kingdom
Question Total (%) Yes (%) No (%) Don’t know (%) Did not answer (%)
1) Is your clinic offering intrauterine insemination? 46 44/46 (96) 2/46 (4)* 0 (0) 0 (0)
2) If yes, are you offering intrauterine insemination with
ovarian stimulation?
44 43/44 (98) 0 (0) 0 (0) 1/44 (2)
3) If yes, which of the following medications are used? **
Gonadotropins
Clomiphene citrate
Letrozole
43
43
43
41/43
21/43
8/43
1/43
21/43
34/43
0
0
0
1/43
1/43
1/43
4) Has the 2013 NICE clinical guideline 156 been discussed at
a clinic meeting? ***
46 36/46 (78) 6/46 (13) 2/46 (4) 2/46 (4)
5) Have any alterations in your clinic practice been made
since this recommendation? ****
46 17/46 (37) 25/46 (54) 2/46 (4) 2/46 (4)
6) What were the clinical indications for the IUI cycles in
2013? *****
Unexplained infertility
Endometriosis
Male factor infertility
Cervical factor infertility
Immunological factor infertility
Only for religious, social, cultural reasons
Only for donor insemination and cancer patients
Question not answered
26/44
10/44
13/44
6/44
1/44
2/44
2/44
10/44
7) Table 4
* Note: Two clinics are licensed to carry out IUI and were offering the treatment before and have since stopped.
**: More than one option possible. One clinic uses Tamoxifen.
*** 2/6 clinics that did not discuss the guideline were not offering intrauterine insemination.
**** 2/25 clinics that had not made alterations were not offering intrauterine insemination.
*****More than one clinical indication for the IUI cycles possible.
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Table 2: Comparison of characteristics of responding and non-responding clinics
*Note: (%) is the percentage of the total number of responding clinics, non-responding clinics or total. Percentages do not
necessarily sum up to 100% due to rounding.
Characteristic Responding clinics Non-responding clinics Total
Type of patients, n (%)
Private patients only
NHS and private
NHS patients only
Total
6 (13)
37 (80)
3 (7)
46
4 (20)
11 (55)
5 (25)
20
10 (15)
48 (73)
8 (12)
66
Clinic groups 6 (13) 2 (10) 8
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Table 3: The total number of IUI cycles in each clinic in 2013.
* Note: The figures for the ‘Number of women who began IUI cycles in 2013’ indicate the number of clinics that began
IUI cycles for the number of women shown. Source: HFEA Website 2013.
Total number of IUI cycles in each clinic in 2013 Number of responding clinics Number of non-responding clinics
0 1 0
1-50 17 8
51-100 6 6
101-150 4 1
151-200 3 1
201-250 5 1
251-300 3 1
≥ 301 1 0
Only DI data or no data available 6 2
Total 46 20
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Table 4: The number of IUI cycles with partner sperm in the UK during 2013.
2013 IUI figures Clinics who answered Question 7 HFEA data
Total number of cycles 2146 (24 clinics) 5934 (61 clinics)
Total number of stimulated cycles 1830 (24 clinics) 4970 (61 clinics)
Total number of unstimulated cycles 316 (23 clinics) 964 (61 clinics)
Clinical pregnancy rate
- Per stimulated cycle of IUI
- Per natural cycle of IUI
Median 12%, range (0-28%)
Median 8.5%, range (0-100%)
Median 10.6%, range (0-24.2%)
Median 0%, range (0-100%)
Question 7: Finally, if you have access to the following statistics please answer the following:
a) How many women at your clinic underwent intrauterine insemination in 2013?
b) What was the number of stimulated IUI cycles in 2013?
c) What was the number of natural IUI cycles in 2013?
d) What was the clinical pregnancy rate per stimulated cycle of IUI in 2013?
What was the clinical pregnancy rate per natural cycle of IUI in 2013?
HFEA data source: HFEA website 2013.
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STROBE 2007 (v4) Statement—Checklist of items that should be included in reports of cross-sectional studies
Section/Topic Item
# Recommendation Reported on page #
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1, 2
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 2, 3
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4, 5
Objectives 3 State specific objectives, including any prespecified hypotheses 4
Methods
Study design 4 Present key elements of study design early in the paper 2
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
collection
2, 5, 6
Participants
6
(a) Give the eligibility criteria, and the sources and methods of selection of participants 2, 5
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if
applicable
6, 7 tables 1, 2, 3, 4
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group
5, 6
Bias 9 Describe any efforts to address potential sources of bias 8, 9, tables 2, 3.
Study size 10 Explain how the study size was arrived at 5
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and
why
6
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 6
(b) Describe any methods used to examine subgroups and interactions
(c) Explain how missing data were addressed
(d) If applicable, describe analytical methods taking account of sampling strategy
(e) Describe any sensitivity analyses
Results
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Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow-up, and analysed
5, 6
(b) Give reasons for non-participation at each stage
(c) Consider use of a flow diagram
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential
confounders
6, 7, 8, tables 2, 3
(b) Indicate number of participants with missing data for each variable of interest Table 1
Outcome data 15* Report numbers of outcome events or summary measures 7, 8, tables 1, 4
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence
interval). Make clear which confounders were adjusted for and why they were included
6, 7, 8, tables 1, 4
(b) Report category boundaries when continuous variables were categorized
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses
Discussion
Key results 18 Summarise key results with reference to study objectives 8
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and
magnitude of any potential bias
8, 9, 10
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from
similar studies, and other relevant evidence
11
Generalisability 21 Discuss the generalisability (external validity) of the study results 10
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based
13
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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