Prophylactic Antibiotics Prior to Embryo Transfer (PAPET): RCT (PAPET)

Prophylactic Antibiotics Prior to Embryo Transfer: a Randomized Controlled Trial

The objective of this study is to determine the impact on clinical pregnancy rate of withholding routine prophylactic antibiotic therapy during IVF. The hypothesis is that withholding antibiotic prophylaxis will be non-inferior to routine administration. To test this hypothesis, the investigators will conduct a randomized controlled non inferiority trial. Additionally an exploratory study will be conducted among the first 30 patients undergoing their first cycle enrolled to evaluate the microbiome across the IVF cycle, in addition to the human virome

Study Overview

• Status: Terminated
• Conditions: Embryo Transfer; Assisted Reproductive Technology; Antibiotic Prophylaxis
• Intervention / Treatment: Other: Withholding antibiotic prophylaxis

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63108
      • Washington University Reproductive Endocrinology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Prophylactic antibiotics; Current standard of care in our practice for a fresh in vitro fertilization cycle is to administer one dose of 1 gram oral azithromycin on day one of the IVF cycle start to both the male and female partner. In cases of same-sex couples, only the female undergoing the embryo transfer receives prophylaxis. This will serve as our control arm entitled: prophylactic antibiotics.
Experimental: No antibiotic prophylaxis.; Couples randomized to the no-antibiotic treatment group will not be prescribed oral antibiotic prophylaxis.	Other: Withholding antibiotic prophylaxis; Our intervention will be a deviation from our current standard of care which is universal antibiotic prophylaxis, even in low risk populations. Our intervention will be withholding antibiotic prophylaxis in low risk populations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy rate	Defined as a gestational sac, with fetal pole and cardiac activity, on ultrasound	Our primary outcome measure will be obtained at 5-8 weeks gestational age following embryo transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miscarriage rate	Pregnancy loss per clinical pregnancy before 20 weeks	Prior to 20 weeks gestation in a previously established clinical pregnancy
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).	Intraoperative (This outcome measure will be assessed from the time of egg retrieval to embryo transfer or embryo cryopreservation)
Live birth	Number of live births per embryo transfer	delivery
Reproductive Tract Microbiome	Swabs will be obtained across the IVF cycle to evaluate changes in the reproductive tract microbiome	Approximately 30 days from start of IVF cycle
Reproductive Tract Virome	Swabs will be obtained at the time of embryo transfer to evaluate the virome	Intraoperative (At the time of embryo transfer)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

General Publications

• Kroon B, Hart RJ, Wong BM, Ford E, Yazdani A. Antibiotics prior to embryo transfer in ART. Cochrane Database Syst Rev. 2012 Mar 14;(3):CD008995. doi: 10.1002/14651858.CD008995.pub2.
• Brook N, Khalaf Y, Coomarasamy A, Edgeworth J, Braude P. A randomized controlled trial of prophylactic antibiotics (co-amoxiclav) prior to embryo transfer. Hum Reprod. 2006 Nov;21(11):2911-5. doi: 10.1093/humrep/del263. Epub 2006 Jul 10.
• Kaye L, Bartels C, Bartolucci A, Engmann L, Nulsen J, Benadiva C. Old habits die hard: retrospective analysis of outcomes with use of corticosteroids and antibiotics before embryo transfer. Fertil Steril. 2017 Jun;107(6):1336-1340. doi: 10.1016/j.fertnstert.2017.04.003. Epub 2017 May 10.
• Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Performing the embryo transfer: a guideline. Fertil Steril. 2017 Apr;107(4):882-896. doi: 10.1016/j.fertnstert.2017.01.025.
• Franasiak JM, Scott RT Jr. Reproductive tract microbiome in assisted reproductive technologies. Fertil Steril. 2015 Dec;104(6):1364-71. doi: 10.1016/j.fertnstert.2015.10.012. Epub 2015 Oct 24.
• Fox C, Eichelberger K. Maternal microbiome and pregnancy outcomes. Fertil Steril. 2015 Dec;104(6):1358-63. doi: 10.1016/j.fertnstert.2015.09.037. Epub 2015 Oct 19.
• Ledger WJ, Blaser MJ. Are we using too many antibiotics during pregnancy? BJOG. 2013 Nov;120(12):1450-2. doi: 10.1111/1471-0528.12371. No abstract available.
• Wylie TN, Wylie KM, Herter BN, Storch GA. Enhanced virome sequencing using targeted sequence capture. Genome Res. 2015 Dec;25(12):1910-20. doi: 10.1101/gr.191049.115. Epub 2015 Sep 22.
• Eskew AM, Stout MJ, Bedrick BS, Riley JK, Herter BN, Gula H, Jungheim ES, Wylie KM. Association of vaginal bacterial communities and reproductive outcomes with prophylactic antibiotic exposure in a subfertile population undergoing in vitro fertilization: a prospective exploratory study. F S Sci. 2021 Feb;2(1):71-79. doi: 10.1016/j.xfss.2021.01.002. Epub 2021 Jan 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2018
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): July 31, 2019

Study Registration Dates

• First Submitted: December 21, 2017
• First Submitted That Met QC Criteria: December 28, 2017
• First Posted (Actual): December 29, 2017

Study Record Updates

• Last Update Posted (Actual): August 18, 2020
• Last Update Submitted That Met QC Criteria: August 14, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Microbiome; Assisted Reproductive Technology; Antibiotic Prophylaxis
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: WashingtonU_REI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes