BMJ Open › content › bmjopen › 5 › 5 › e007588.draft-revisions.pdfAn online questionnaire survey was used as it was simple and easy to distribute and complete. The questionnaire

For peer review only

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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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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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.

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%)


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 8.5%, range (0-100%)

Median 10.6%, range (0-24.2%)


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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BMJ Open › content › bmjopen › 5 › 5 › e007588.draft-revisions.pdfAn online questionnaire survey was used as it was simple and easy to distribute and complete. The questionnaire