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Trial registered on ANZCTR

Registration number

ACTRN12620000738921

Ethics application status

Approved

Date submitted

3/06/2020

Date registered

14/07/2020

Date last updated

6/10/2022

Date data sharing statement initially provided

14/07/2020

Date results provided

6/10/2022

Type of registration

Retrospectively registered

Titles & IDs

Public title

The effect of iodine excess on thyroid function of women undergoing infertility assessment (Hysterosalpingram) using Lipiodol dye and the potential impact on their babies

Scientific title

The effect of acute and chronic iodine excess on thyroid profile and reproductive function of women using lipiodol during hysterosalpingography and the potential impact on thyroid function of their offspring

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1227-4450

Trial acronym

SELFI trial (Safety and Efficacy of Lipiodol in Fertility Investigations)

Linked study record

nil

Health condition

Health condition(s) or problem(s) studied:

Infertility

Hashimotos thyroiditis

Subclinical hypothyroidism

Condition category

Condition code

Reproductive Health and Childbirth

Fertility including in vitro fertilisation

Reproductive Health and Childbirth

Complications of newborn

Metabolic and Endocrine

Thyroid disease

Reproductive Health and Childbirth

Fetal medicine and complications of pregnancy

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

We recruit women who undergo hysterosalpingogram(HSG) using Lipiodol dye as part of their infertility work up . Lipiodol is an oil soluble dye rich in iodine and had been in use for a century with increased use in last 20 years due to additional therapeutic benefit of increased pregnancy rates.

After screening, eligible participants are recruited for SELFI trial after informed consent.They undergo blood and urine test in the community lab before the HSG and serially for 6 months after the procedure. The investigations are done by the phlebotomist in the local community labs. This involves 8 lab visits over a period of 6 months.The thyroid results are chased by the research team and informed to the fertility doctor and participant. A record is made if thyroid replacement is initiated by the primary fertility doctor. A documentation is made if the participant gets pregnant during the study period. No additional blood or urine tests will be performed on these women beyond the study duration by the research team. However, relevant investigations (eg.thyroid function test) will be passed on to the treating doctor for ongoing care.

If the woman conceives during the study period of 6 months, the newborn's thyroid test is done on seventh day of life. This is by a heel prick test at the community lab or by a home visit by the phlebotomist as per parent's preference. Results are chased by the research team. If any thyroid hormone replacement necessary and started by the paediaric team, a record is kept.

In addition, the radiologist who does the Lipiodol HSG keeps a record of Lipiodol volume used. The Xray films are independently read by reaserch team radiologist to assesss peritoneal spill and they are blinded to the urine iodine levels. These data are used at the analysis to correlate if increased peritoneal retention of Lipiodol correlates with iodine excess and thyroid dysfunction.

Intervention code [1]

Early Detection / Screening

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Incidence of thyroid function abnormalities in offspring conceived within 6 months of Lipiodol HSG. This will be assessed by a serum assay of thyroid function from a heel prick sample

Timepoint [1]

on the seventh day of life.

Primary outcome [2]

Incidence of thyroid function abnormalities in women undergoing Lipiodol HSG. This will be assessed by serum assays of thyroid function

Timepoint [2]

at baseline, 7 days after HSG, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks and 24 weeks after the HSG.

Primary outcome [3]

Incidene of iodine excess in women undergoing Lipiodol HSG. This will be assessed by urinary iodine/ creatinine ratio

Timepoint [3]

at baseline, 7 days after the HSG , 4 weeks, 12 weeks and 24 weeks after the HSG.

Secondary outcome [1]

Peritoneal retention of Lipiodol assessed by radiologist

Timepoint [1]

on the pelvic X-ray 45 minutes after HSG

Eligibility

Key inclusion criteria

Any woman of the reproductive age group who is going for a Lipiodol HSG if they have

1. Normal thyroid function demonstrated by normal free T4

2. Subjects with subclinical hypothyroidism (defined as a TSH >97th percentile or 2.5 IU/L and normal Free T4 levels) are included.

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

1. Subject taking medication known to affect thyroid function or iodine metabolism (e.g. Lithium, amiodarone etc.)
2. Active thyroid disease including hyperthyroidism, hypothyroidism, thyroid cancer and benign goitre.
3. A previous radiological dye study within the last 3months for aqueous dyes and6months for fat soluble dyes as this will affect urine iodine interpretation.

Study design

Purpose

Screening

Duration

Longitudinal

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

Sample Size Calculation:
The primary outcome is altered TSH levels. However, this will be examined in the context of iodine exposure and in particular the group of women with the highest and most prolonged iodine excess. Although other studies have investigated the association of thyroid function and iodine excess after Lipiodol, the numbers were small, sample heterogeneous and the subjects with higher iodine levels not specifically identified and assessed.

Conservatively assuming 50% of the subjects develop iodine excess (Kaneshige etal, J Clin Endocrinol Metab, 2015. 100(3): p. E469-72) and that 15-20% of adult women of reproductive age will have Hashimoto’s thyroiditis and sub clinical hypothyroidism predisposing to greater thyroid dysfunction, a minimum sample size of 200 subjects will be required. This would identify a group of approximately 100 women with markedly elevated iodine levels (>2SD) of which we can expect approximately 20 to have pre-existing evidence of autoimmune thyroiditis.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

28/06/2019

Date of last participant enrolment

Anticipated

30/06/2021

Actual

30/08/2021

Date of last data collection

Anticipated

30/09/2022

Actual

14/02/2022

Sample size

Target

200

Accrual to date

Final

196

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Guerbet

Address [1]

PO Box
BP 57400
95943 Roissy CdG Cedex
France

Country [1]

France

Primary sponsor type

University

Name

Liggins Institute,University of Auckland

Address

Liggins Institute
The University of Auckland
Private Bag 92019
Victoria Street West
Auckland 1142
New Zealand

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

none

Address [1]

none

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern B Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

14/05/2019

Approval date [1]

22/05/2019

Ethics approval number [1]

Ethics ref:19/NTB/52

Summary

Brief summary

This is primarily a safety study of an infertility investigation that has been performed since the 1920s. This infertility investigation called hysterosalpingogram (HSG) is a radiology study where radio-opaque dye is injected into the uterus to establish anatomy and the patency of both fallopian tubes. Recently it has been shown that using a fat soluble dye (lipiodol) as the contrast agent in  HSG increases the pregnancy rates in unexplained infertility up to 40% in the following 6 months. Though Lipiodol had been in use for a century,  the recent confirmation that fertility is substantially increased after these procedures has increased interest in performing these procedures as an intervention for infertility.

However, Lipiodol dye contains very large amounts of iodine and if the dye spills into the abdomen it can be released over several months, potentially causing toxicity for the mother and fetus. This is primarily due to the effect of iodine excess on thyroid function and small studies have suggested that there are changes in thyroid function, both in the women and neonates conceived within a few cycles following a Lipiodol HSG.

This project aims to
 1) Investigate the effects of thyroid function in the women and establish protocols to ensure normal thyroid function in those having thyroid function abnormalities.

2) Establish which women are most at risk of these problems.

3)Investigate the effect on thyroid function in the offspring conceived within the six months following the HSG.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Paul Hofman

Address

Private Bag 92019
Liggins Institute
University of Auckland
Auckland 1142

Country

New Zealand

Phone

+64 21938897

Fax

p.hofman@auckland.ac.nz

Contact person for public queries

Name

Paul Hofman

Address

Private Bag 92019
Liggins Institute
University of Auckland
Auckland 1142

Country

New Zealand

Phone

+64 21938897

Fax

p.hofman@auckland.ac.nz

Contact person for scientific queries

Name

Paul Hofman

Address

Private Bag 92019
Liggins Institute
University of Auckland
Auckland 1142

Country

New Zealand

Phone

+64 21938897

Fax

p.hofman@auckland.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Email	Other Details
8153	Study protocol	d.mathews@auckland.ac.nz	alternate email-p.hofman@auckland.ac.nz
8154	Informed consent form	d.mathews@auckland.ac.nz	alternate email-p.hofman@auckland.ac.nz
8155	Ethical approval	d.mathews@auckland.ac.nz	alternate email-p.hofman@auckland.ac.nz

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The SELFI Study: Iodine Excess and Thyroid Dysfunction in Women Undergoing Oil-Soluble Contrast Hysterosalpingography.	2022	https://dx.doi.org/10.1210/clinem/dgac546
Embase	The impact of prolonged, maternal iodine exposure in early gestation on neonatal thyroid function.	2023	https://dx.doi.org/10.3389/fendo.2023.1080330

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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Documents added manually

Documents added automatically