Innovation for small-scale experiments: ReceptIVFity test.

Currently, approximately 35% of all IVF/IVF-ICSI treatments result in a
pregnancy and a subsequent live birth (1). Since an IVF/IVF-ICSI treatment is a
mentally as well as physically incriminating process, there is a great need for
accurate prediction of pregnancy success. The first step has recently been made
in a prospective cohort study in which the composition of the vaginal
microbiome two months prior to the embryo transfer was predictive for pregnancy
outcome in a specific defined set of patients. In patients harboring the most
favorable composition of the vaginal microbiome as determined by use of the
ReceptIVFity test, 53% became pregnant during that cycle. In contrast, in those
with an unfavorable ReceptIVFity test profile only 6% became pregnant (2).
Determination of the vaginal microbiome and its related predictive profile
prior to the start of IVF/IVF-ICSI is now possible by the use of the
ReceptIVFity test, which is now standard of care at the department of
Reproductive Endocrinology and Infertility at the Erasmus MC, Rotterdam.
Patients receive the test prior to start of hormonal treatment. Subsequently,
their attending physician will discuss the reported vaginal microbiome profile
and a decision regarding whether or not to continue with hormonal treatment is
made in a shared decision between the couple and their doctor (3).
In 2019 and 2020, the ReceptIVFity test was introduced to all IVF/IVF-ICSI
patients in both aforementioned hospitals, which was made possible by a grant
received from health insurance company *CZ-groep*. CZ-groep wanted to
investigate how introduction of the test would be received by clinicians and
their patients, as well as how different predictive vaginal microbiome profiles
might impact on the decision to continue with the IVF/IVF-ICSI treatment or
postpone it until a more favorable vaginal profile at a later stage.
Recent data shows that there is a new and better predictive algorithm that can
predict the chance of not conceiving and is independent of the obstetric
history. The prediction is thus predictive for both nulligravida and those who
have been pregnant before. In addition, the algorithm is based on data from a
larger patient cohort of n=527 patients. The new percentages for the
RecepIVFity profiles are: low 3.3%, medium 32.3% and high 66.7% chance of
pregnancy. Data is not published yet.

More recently (January 2023), analyses of the current data showed that the
predictive value of the algorithm for the RecepIVFity test seems to be optimal
for women of European origin, and not predictive for women of non-European
origin. This is in line with reported differences in vaginal microbiome
attributed to ethnicity (4, 5). Moreover, women suffering from severe
endometriosis (grade III or IV) are confronted with a significantly impact on
their fertility by affecting ovarian function, egg quality, and implantation
rates. Recent study shows that the composition of the vaginal microbiome is
significantly difference at genus level between women with stage 3-4
endometriosis and healthy controls. Analyzing the vaginal microbiome
composition of these women will provide valuable insights in the effects of
endometriosis on fertility and vaginal health. In order to develop a predictive
algorithm for women of non-European origin and women suffering from
endometriosis, collection of more data for input is essential. As part of an
observational sub-cohort, we intend to collect and analyse their vaginal
microbiome composition, to optimize their fertility treatment and improve their
chance of achieving a successful pregnancy.

At the out-patient clinic, non-naïve patients also request and want to benefit
from the RecepIVFity-test to enhance their chance of achieving a successful
pregnancy. Not only do non-naïve patients request inclusion in the study, from
an ethical point of view we want to respect the principles of autonomy,
beneficence and justice: excluding them would not be fair. Recent data
indicates that hormonal changes during IVF/IVF-ICSI treatment do not
significantly affect the vaginal microbiome of infertile women. By also
offering non-naïve patients the effectiveness of the shared decision and
physician decision-making can be investigated to ensure the broad applicability
of this test when implemented as standard care. The CZ-trial has shown that
couples with a low ReceptIVFity test profile often decide to temporarily
refrain from starting an IVF/IVF-ICSI cycle. In 2019, an interim analysis
showed that 63.9% of the couples decided to temporarily postpone continuation
of treatment in case of a low ReceptIVFity test profile. Moreover, couples who
have a previous failed attempt seem more inclined to postpone treatment: in the
first IVF/IVF-ICSI cycle 57.8%, which increased to 75% in the second cycle, and
till 100% in the third cycle (which is also generally the last treatment to be
reimbursed by the health insurance companies).
The ReceptIVFity acts as a timing-tool for prediction of optimal pregnancy
chances and provides insight in the patient*s current (two months after
sampling) success rate of an IVF/IVF-ICSI treatment. Benefits of postponing
treatment in case of an unfavourable vaginal profile and a low chance of
achieving a pregnancy include reducing unnecessary morbidity and treatment
burden, stress and disappointment, while increasing efficiency of actual
treatment. In order to be able to offer this innovative standard of care
without additional costs for the patient for the coming three years, the Dutch
Healthcare Authority (NZa) has authorized funding within the context of
"Innovation for small-scale experiments".

1. Evaluation of the efficiency of Shared Decision Making compared to Physician
Decision in terms of
a) the success probability of an IVF cycle,
b) the proportion of women with a successful pregnancy
c) the number of unsuccessful IVF cycles.
2. Determine the accuracy (positive and negative predictive value) of the
ReceptIVFity test to predict success of an IVF/IVF-ICSI treatment cycle.
3. Evaluation of patient satisfaction and cost effectiveness for SDM and
physician decision
4. Gain experience with the use of the ReceptIVFity test for all IVF/IVF-ICSI
indications and patients to facilitate the embedding of the test in the
reimbursement system of health care.
5. Observational cohort: Develop and evaluate a success-rate stratification
based on the ReceptIVFity test for 1. women of non-European origin and
2. Women with 3rd and 4th grade of endometriosis.
6. Evaluation of the effectiveness of Shared Decision Making compared to
Physician Decision in non-naïve women.

A prospective, clinical non-invasive randomized controlled study with an
additional observational study arm (for women of non-European origin), will be
performed in women visiting the outpatient clinic of the Department of
Reproductive Endocrinology and Infertility (and collaborating
intake-/transport-clinics) and eligible for IVF/IVF-ICSI who use the standard
of care vaginal swab (ReceptIVFity test) for determination of the vaginal
microbiome.

Randomization component (for naïve and non-naïve patients):
Women of European origin will be randomized 1:1 to either the shared decision
group or the physician decision group. All women of European origin may undergo
one to three cycles of IVF/IVF-ICSI reimbursed by the health insurance. The
follow-up ends after the outcome of the last of these cycles has been
determined. The desired outcome of the IVF or IVF/ICSI treatment is a
successful pregnancy, i.e., a pregnancy with a heart-beat at 12 weeks of
gestation.

Observational component:
Women of non-European origin are invited to take part in an observational
component of this study. Without further evaluation of the results of their
vaginal microbiome, they will continue with the IVF/IVF-ICSI cycle. Women
eligible for participation are naïve and non-naïve patients and the follow-up
ends after the outcome of the IVF/IVF-ICSI cycle has been determined. Women
diagnosed with stage III and IV of endometriosis are also invited to take part
in an observational component of this study.

A vaginal self-swab is performed by the patient.

For women of European origin randomization in one of the following groups:
SDM group: Using Shared-Decision-Making according to the ReceptIVFity
microbiome profile with its predicted chance of achieving a pregnancy in the
current cycle.
Physician decision group: Postponing treatment until a switch to a favorable
ReceptIVFity microbiome profile.

For women of non-European origin and for women with endometriosis grade 3-4:
A vaginal self-swab is performed by the patient. The results of the vaginal
microbiome composition will be used for the development of an algorithm with a
predictive value of the ReceptIVFity test in women of non-European origin and
for women with endometriosis grade 3-4.

The risk associated with this study is minimal. The use of the commercially
available ReceptIVFity test is safe. No adverse events have been reported since
the introduction of the ReceptIVFity test in 2015 (4).