Prophylactic Antibiotics Prior to Embryo Transfer (PAPET): RCT

NCT ID: NCT03386227

Last Updated: 2020-08-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-21
• Study Completion Date: 2019-07-31

Brief Summary

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

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.

Conditions

Assisted Reproductive Technology; Antibiotic Prophylaxis; Embryo Transfer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

No antibiotic prophylaxis.

Couples randomized to the no-antibiotic treatment group will not be prescribed oral antibiotic prophylaxis.

Group Type: EXPERIMENTAL

Withholding antibiotic prophylaxis

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: OTHER

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 43 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Washington University Reproductive Endocrinology

St Louis, Missouri, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 22419341 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16832124 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28501367 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28366416 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26597628 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26493119 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24118809 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26395152 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34632426 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form: Informed Consent Female Subjects

View Document

Document Type: Informed Consent Form: Informed Consent Male Subjects

View Document

Other Identifiers

WashingtonU_REI

Identifier Type: -

Identifier Source: org_study_id