Efficacy Study of Preconception Treatment of an Asymptomatic Bacterial Infection in an Infertility Population

• Sponsor: Stanford University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01322971
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arms: 2
• Duration (Months): 16
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Bacterial vaginosis (BV) is a common vaginal infection characterized by a pathologic shift in the normal vaginal flora. BV has been associated with a number of poor reproductive outcomes, including infertility, preterm labor and premature rupture of membranes. If BV does disrupt normal embryologic development, then the treatment of BV prior to conception may improve implantation rates and other pregnancy outcomes in the infertile population.

This is a prospective, randomized, double-blind, placebo-controlled trial in which infertile women undergoing intrauterine insemination or embryo transfer are screened for BV prior to treatment. Those patients who screen positive for BV will then be randomized into the treatment arm(metronidazole 500mg by mouth twice daily for 7 days) or the control arm (placebo by mouth twice daily for 7 days). The primary outcome, positive pregnancy test rate (i.e. biochemical pregnancy rate), will then be assessed. Secondary outcomes, such as clinical pregnancy rate, miscarriage rate, and live birth rate will also be examined.

Condition or Disease	Intervention/Treatment	Phase
Vaginosis, Bacterial; Infertility; Miscarriage	Drug: Metronidazole; Drug: Placebo	N/A

Detailed Description

The purpose of this study is to determine if preconception treatment of asymptomatic bacterial vaginosis improves pregnancy outcomes (i.e. biochemical pregnancy rate). Study protocol as follows:

1. Patients will be notified of study via face-to-face contact at the initial clinic visit (baseline ultrasound visit, menstrual cycle day 2-5), by physician referral or the Stanford website. Patients expressing interest will be screened in person to confirm that they meet all enrollment criteria. The participant will be asked to sign informed consent documents and a brief intake questionnaire with then be administered.

2. Enrolled patients will then be screened for bacterial vaginosis at their next visit (typically on menstrual cycle day 12), prior to transvaginal ultrasound. The screening will require that a speculum be inserted into the vagina and a vaginal smear be collected with a swab from the posterior fornix. A microscopic slide will be prepared by rolling the swab on the surface of a glass slide. The diagnosis of bacterial vaginosis will be established clinically using the Amsel criteria to confirm 3 of the following 4 signs: clue cells; vaginal pH ≥4.5; fishy odor before or after the addition of 10% potassium hydroxide solution to a wet-mount side; and a homogeneous, off-white, discharge. For validation of clinical diagnosis, 100% of screen positive slides, and 10% of screen negative slides, will be sent for to the Department of Pathology for Gram staining.

3. The patients with a positive screen for bacterial vaginosis will then be randomized to receive metronidazole 500mg orally twice daily for seven days (treatment arm) or placebo orally twice daily for seven days(control arm). Randomization will be performed using a computer-generated code. Those patients whose screen is negative will also be followed for outcomes, but no randomization will be performed.

4. All randomized patients will continue with routine monitoring and insemination as planned by their treating physician.

5. If pregnancy is confirmed at least 12 weeks after intrauterine insemination by ultrasound evidence of a fetus with heartbeat, information will then be collected regarding the pregnancy and its outcome.

6. Primary and secondary outcomes will be followed for 2 years after date of enrollment for all patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pregnancy Outcomes Following Preconception Treatment of Asymptomatic Bacterial Vaginosis in an Infertility Population: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial.
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Metronidazole Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days.	Drug: Metronidazole; Metronidazole 500mg orally twice daily for seven days
Placebo Comparator: Placebo Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm	Drug: Placebo; Placebo will be administered orally twice daily for seven days

Outcome Measures

Primary Outcome Measures

1. Biochemical Pregnancy Rate (Positive Pregnancy Test) [up to 2 years]

   Biochemical pregnancy rate was defined as number of participants who had a positive pregnancy test

Secondary Outcome Measures

1. Pregnancy Rate (Pregnancy Visible on Ultrasound) [up to 2 years]

2. Miscarriage Rate (Loss of a Clinically Recognized Pregnancy) [up to 2 years]

3. Infectious Morbidity (i.e. Chorioamnionitis, Neonatal Sepsis) [up to 2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Women who are actively trying to conceive via intrauterine insemination or in vitro fertilization

Exclusion Criteria:

• Current use of an oral or vaginal antibiotic.

• History of allergy or adverse reaction to metronidazole.

• Prior enrollment in study (patients returning for repeat cycle may not be re-enrolled).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ruth Lathi	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Ruth Bunker Lathi, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

• American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Assessment of risk factors for preterm birth. Clinical management guidelines for obstetrician-gynecologists. Number 31, October 2001. (Replaces Technical Bulletin number 206, June 1995; Committee Opinion number 172, May 1996; Committee Opinion number 187, September 1997; Committee Opinion number 198, February 1998; and Committee Opinion number 251, January 2001). Obstet Gynecol. 2001 Oct;98(4):709-16.
• Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, Heine RP, Nugent RP, Fischer ML, Leveno KJ, Wapner R, Varner M. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 2000 Feb 24;342(8):534-40.
• Donders GG, Van Bulck B, Caudron J, Londers L, Vereecken A, Spitz B. Relationship of bacterial vaginosis and mycoplasmas to the risk of spontaneous abortion. Am J Obstet Gynecol. 2000 Aug;183(2):431-7.
• Hay PE, Lamont RF, Taylor-Robinson D, Morgan DJ, Ison C, Pearson J. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ. 1994 Jan 29;308(6924):295-8.
• Hay PE. Bacterial vaginosis and miscarriage. Curr Opin Infect Dis. 2004 Feb;17(1):41-4. Review.
• Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, Cotch MF, Edelman R, Pastorek JG 2nd, Rao AV, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N Engl J Med. 1995 Dec 28;333(26):1737-42.
• Korn AP, Bolan G, Padian N, Ohm-Smith M, Schachter J, Landers DV. Plasma cell endometritis in women with symptomatic bacterial vaginosis. Obstet Gynecol. 1995 Mar;85(3):387-90.
• Liversedge NH, Turner A, Horner PJ, Keay SD, Jenkins JM, Hull MG. The influence of bacterial vaginosis on in-vitro fertilization and embryo implantation during assisted reproduction treatment. Hum Reprod. 1999 Sep;14(9):2411-5.
• McDonald HM, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD000262. Review. Update in: Cochrane Database Syst Rev. 2013;1:CD000262.
• Nelson DB, Bellamy S, Nachamkin I, Ness RB, Macones GA, Allen-Taylor L. First trimester bacterial vaginosis, individual microorganism levels, and risk of second trimester pregnancy loss among urban women. Fertil Steril. 2007 Nov;88(5):1396-403. Epub 2007 Apr 16.
• Platz-Christensen JJ, Brandberg A, Wiqvist N. Increased prostaglandin concentrations in the cervical mucus of pregnant women with bacterial vaginosis. Prostaglandins. 1992 Feb;43(2):133-4.
• Platz-Christensen JJ, Mattsby-Baltzer I, Thomsen P, Wiqvist N. Endotoxin and interleukin-1 alpha in the cervical mucus and vaginal fluid of pregnant women with bacterial vaginosis. Am J Obstet Gynecol. 1993 Nov;169(5):1161-6.
• Wilson JD, Ralph SG, Rutherford AJ. Rates of bacterial vaginosis in women undergoing in vitro fertilisation for different types of infertility. BJOG. 2002 Jun;109(6):714-7.

• Responsible Party: Ruth Bunker Lathi, Principal Investigator, Stanford University
• ClinicalTrials.gov Identifier: NCT01322971
• Other Study ID Numbers: SU-03212011-7604; IRB Protocol Number 20103
• First Posted: Mar 25, 2011
• Last Update Posted: Dec 20, 2021
• Last Verified: Dec 1, 2021

• Keywords provided by Ruth Bunker Lathi, Principal Investigator, Stanford University: Bacterial Vaginosis; Infertility; Miscarriage; Metronidazole
• Additional relevant MeSH terms: Vaginosis, Bacterial; Infertility; Vaginal Diseases; Abortion, Spontaneous; Metronidazole

Study Results

Participant Flow

Pre-assignment Detail	151 participants were screened ; 2 were randomized

Arm/Group Title	Metronidazole	Placebo
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days	Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days
Period Title: Overall Study
STARTED	1	1
COMPLETED	0	0
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Metronidazole	Placebo	Total
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days	Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days	Total of all reporting groups
Overall Participants	1	1	2
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 100%	1 100%	2 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	37 (0)	37 (0)	37 (0)
Sex: Female, Male (Count of Participants)
Female	1 100%	1 100%	2 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%	1 100%	2 100%

Outcome Measures

1. Primary Outcome

Title	Biochemical Pregnancy Rate (Positive Pregnancy Test)
Description	Biochemical pregnancy rate was defined as number of participants who had a positive pregnancy test
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

No data were collected for this outcome

Arm/Group Title	Metronidazole	Placebo
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days	Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days
Measure Participants	0	0

2. Secondary Outcome

Title	Pregnancy Rate (Pregnancy Visible on Ultrasound)
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

No data were collected for this outcome

Arm/Group Title	Metronidazole	Placebo
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days	Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days
Measure Participants	0	0

3. Secondary Outcome

Title	Miscarriage Rate (Loss of a Clinically Recognized Pregnancy)
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

No data were collected for this outcome

Arm/Group Title	Metronidazole	Placebo
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days	Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days
Measure Participants	0	0

4. Secondary Outcome

Title	Infectious Morbidity (i.e. Chorioamnionitis, Neonatal Sepsis)
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

No data were collected for this outcome

Arm/Group Title	Metronidazole	Placebo
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days	Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	All participants withdrew prior to entering any protocol specified adverse event collection period.
Arm/Group Title	Metronidazole		Placebo
Arm/Group Description	Patients randomized to the metronidazole arm will receive metronidazole 500mg orally twice daily for seven days. Metronidazole: Metronidazole 500mg orally twice daily for seven days		Patients randomized to the placebo arm will receive placebo orally twice daily for seven days(control arm Placebo: Placebo will be administered orally twice daily for seven days
All Cause Mortality
	Metronidazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Metronidazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Metronidazole		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

151 screened 2 were randomized both refused to take medication not knowing if it were placebo or drug

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.