Prophylactic Antibiotics Prior to Embryo Transfer (PAPET): RCT

Over 200,000 in vitro fertilization (IVF) cycles were initiated in the United States in
2015,1 allowing thousands of infertile couples to start families. Although most of the steps
in IVF protocols are based on strong evidence, one, prophylactic antibiotic administration,
is commonplace but not proven to produce benefit. This practice began in 1978 as a means to
prevent bacterial contamination of the tip of the catheter used to transfer embryos into the
uterus.2 Although subsequent studies showed that bacterial contamination of the transfer
catheters had a negative impact on IVF cycle outcomes,3,4 a more recent, robust randomized
controlled trial powered to detect catheter tip contamination rates noted a decrease in
contamination with routine administration of amoxicillin-clavulanate but no difference in
clinical pregnancy rate.5 Given the limited evidence for benefit and the true risk for
subjecting patients to unnecessary treatments, one must determine whether prophylactic
antibiotics actually improve the IVF outcome that matters most to couples: pregnancy.

The objective of this study is to determine the impact on clinical pregnancy rate of
withholding routine prophylactic antibiotic therapy during IVF. The investigators hypothesis
is that withholding antibiotic prophylaxis will be non-inferior to routine administration.

Additionally the investigators propose to conduct a smaller exploratory study in this
population of the first 30 women enrolled (15 in each arm) to assess the vaginal microbiome
and human virome as obtained by vaginal swab. Existing studies are limited and conflicting
regarding influence of the microbiome on IVF cycle outcomes. This would be the first study to
evaluate alterations in the vaginal microbiome across the IVF cycle in response to
medications and supraphysiologic hormone levels, and the first to evaluate the human virome
in this patient population.8 The investigators would examine differences within and between
groups and assess for the potential impact and association clinical outcomes of those
patients exposed to prophylactic azithromycin, and those who are not. Optimizing the vaginal
microbiome could serve as a potential target for therapy to help increase IVF success rates
in the future with the goal of a full term, live birth. Samples for male partners will be
evaluated as well.

To test the hypothesis, the investigators will conduct a randomized controlled noninferiority
trial and pursue the following specific aims:

Specific Aim 1: Determine the effect of withholding prophylactic antibiotic administration on
clinical pregnancy rate (defined as a gestational sac, with fetal pole and cardiac activity,
on ultrasound).

The investigators hypothesize that withholding prophylactic antibiotics before embryo
transfer will be non-inferior (absolute difference ≤15%) to routine prophylaxis in terms of
clinical pregnancy rates.

Specific Aim 2: Evaluate the impact of prophylactic antibiotic administration on miscarriage
rate (pregnancy loss per clinical pregnancy) before 20 weeks.

The working hypothesis is that miscarriage rates will be equivalent between the two groups.

Specific Aim 3: Determine the effect of no prophylactic antibiotic administration on embryo
development.

The investigators hypothesize that embryo development, as evaluated by fertilization rate
(number of two-pronuclei embryos per mature oocyte), blastocyst conversion rate (number of
day 5 embryos from two-pronuclei embryos), and blastocyst utilization rate (number of day 5
embryos transferred or frozen per two-pronuclei embryos) will be equivalent between the two
groups.

Specific Aim 4: Determine the impact of prophylactic antibiotics or withholding prophylaxis
on the vaginal and endometrial microbiome.

The investigators hypothesis is that azithromycin will impact the vaginal microbiome.
Additionally, it is expected to see changes across the IVF cycle that may be associated with
cycle outcome endpoints.

Specific Aim 5: Evaluate the clinical implications of the human virome on IVF outcomes.

The investigators hypothesize that existence of subclinical eukaryotic viruses will be
associated with negative IVF cycle outcomes.

Impact: The investigators expect to define the clinical impact of withholding antibiotic
prophylaxis before embryo transfer as measured by markers of a successful IVF cycle. As the
hypothesis is that withholding prophylaxis will be non-inferior to routine antibiotic
administration, these results are expected have a positive clinical impact by decreasing
unnecessary broad-spectrum antibiotic exposure and potentially creating a paradigm shift in
IVF protocols.

Approach:

This will be a prospective randomized controlled non-inferiority trial in which 178 couples
will receive the standard of care prophylactic antibiotics (control) and 178 will not receive
prophylactic antibiotics (experimental). The primary outcome is clinical pregnancy rate. The
first 50 women enrolled undergoing their first cycle will also be enrolled in the micro biome
and virome pilot study as described above. The expected primary outcome is that withholding
prophylactic antibiotics will be non-inferior to antibiotic prophylaxis in terms of clinical
pregnancy rate with an acceptable non inferiority margin of 15%. Secondary outcomes include
spontaneous miscarriage rate and embryo development as measured by fertilization rate,
blastocyst conversion rate, blastocyst utilization rate, and live birth rate.Couples with a
female partner aged 18-43 years going through a fresh IVF cycle will be recruited. Couples
will be excluded from enrollment if they have any contraindication to antibiotic treatment,
are not intending to undergo embryo transfer (fertility preservation patients and oocyte
donors), require use of extended antibiotic coverage at time of egg retrieval, are already on
antibiotics for any reason (ie: upper respiratory infection etc), have a recent history of
pelvic infection, or are planning on limited insemination (inseminating a limited number of
the eggs retrieved). Couples will only be included in the study once. The primary outcome is
clinical pregnancy rate. Secondary outcomes include spontaneous miscarriage rate and embryo
development as measured by fertilization rate, blastocyst conversion rate and blastocyst
utilization rate and live birth rate.

Couples going through fresh IVF cycles will be identified and their charts reviewed to assess
eligibility for inclusion. Couples who meet inclusion criteria will then be contacted via
phone by a trained study coordinator and offered enrollment. Those who express interest will
have a time arranged for their consent to be signed for both partners. Couples will be
randomized after the receipt of signed consent. Randomization to prophylactic antibiotics or
no antibiotics will be performed in a block-randomized fashion per cycle number via computer
random number generator in a 1:1 ratio. Couples randomized to the antibiotic group will
receive the above stated current regimen the day of gonadotropin start. Couples randomized to
the no antibiotic treatment group will not be prescribed oral antibiotic prophylaxis. Couples
who agree to participate will have their charts marked indicating participation in the study.
The couple's respective nurse will receive a message that will remain part of the electronic
medical record regarding patient treatment group allocation so they can prescribe antibiotics
appropriately. Embryologists will be blinded to patient treatment group allocation.

The expected outcome is that clinical pregnancy rate will be non-inferior without the use of
routine antibiotic prophylaxis.

Inclusion Criteria:

- The female partner must be aged 18-43 years and going through a fresh IVF cycle

Exclusion Criteria:

- Couples will be excluded from enrollment if they have any contraindication to
antibiotic treatment, are not intending to undergo embryo transfer (fertility
preservation patients and oocyte donors), require use of extended antibiotic coverage
at time of egg retrieval, are already on antibiotics for any reason (e.g., upper
respiratory infection), have a recent history of pelvic infection, or are planning on
limited insemination (inseminating a limited number of the eggs retrieved) or are
using donor sperm.