PCORIHSV: Comparative Effectiveness of Treatment Options for Genital Herpes Infection to Reduce Adverse Pregnancy Outcomes

• Sponsor: Kaiser Permanente (Other)
• Overall Status: Completed
• CT.gov ID: NCT02986802
• Collaborator: Patient-Centered Outcomes Research Institute (Other)
• Enrollment: 89,132
• Location: 1
• Actual Duration (Months): 47.5
• Patients Per Site Per Month: 1874.9

Study Details

Study Description

Brief Summary

Preterm delivery (PTD), together with low birthweight (LBW), is the leading cause of infant death and illness, affecting 500,000 births with annual medical costs of more than $26 billion in the U.S. each year. Identifying changeable risk factors to reduce PTD is considered a top research priority. Recent research has shown genital herpes infection (HSV) is associated with increased risks of PTD and LBW. More importantly, treating this infection, including infection with no symptoms, using readily available antiviral medications can be effective in removing the risk due to HSV. Thus, early identification and treatment of HSV in pregnant women could be an effective way to prevent PTD and LBW. Currently, many pregnant women with HSV infection, especially those with no symptoms, choose not to treat due to (a) a lack of demonstrated benefit of treatment and (b) general hesitance to use medications during pregnancy due to safety concerns for the fetus. Thus, emerging evidence of an increased risk of PTD/LBW associated with HSV infection, if untreated, and treatment effectiveness by anti-herpes medications has significantly changed current treatment paradigms among pregnant women. This evidence also provides new hope that effectively treating HSV infection among pregnant women, especially before the 3rd trimester, could lead to a new method to reduce PTD and LBW and reduce racial/ethnic disparities in these risks due to high rates of the infection in minority groups. To further examine the effectiveness of treating HSV in pregnant women to reduce adverse pregnancy outcomes, the investigators propose to conduct a prospective cohort study with a two-stage design combining the large pregnant women population (N=90,000) in Stage I identified through Kaiser Permanente Northern California (KPNC) electronic medical records (EMRs), with a Stage II sample to collect detailed information on additional factors that might muddle our understanding of this issue. This study will address the following: (1) Does treating HSV infection in pregnant women reduce the risk of PTD or LBW? (2) Does timing of the treatment during pregnancy influence treatment effectiveness? (3) Do other factors influence treatment effectiveness? and (4) Does HSV infection in pregnancy, if untreated, increase the risk of PTD and LBW, compared to no infection? Answers to these questions will be valuable to pregnant women and clinicians, and directly address their concerns when making treatment decisions

Condition or Disease	Intervention/Treatment	Phase
HSV-2 Infection; PreTerm Birth; Pregnancy Complications

Detailed Description

Preterm delivery (PTD), along with low birthweight (LBW), is the leading cause of perinatal mortality and morbidity. In the U.S., 12% of livebirths are PTDs, resulting in more than $26 billion in medical costs annually. The impact on infant health and staggering costs makes PTD one of the top research priorities of PCORI, AHRQ, the Institute of Medicine (IOM) and the World Health Organization (WHO), due to a lack of effective interventions to reduce PTD.

Genital herpes infection is prevalent, with a recent WHO estimation of 500 million people worldwide infected. Treating pregnant women with genital herpes infection, especially before the 3rd trimester, has been shown to reduce the risk of PTD and LBW, thus it can be an effective intervention to reduce PTD/LBW. However, the effectiveness and benefit of treating genital herpes to reduce PTD and LBW needs to be further demonstrated in order to be incorporated into the treatment decision making process. Currently, many pregnant women choose not to treat genital herpes due to a general aversion to taking medications during pregnancy for the safety of their fetuses, and a lack of demonstrated evidence of benefits. Paradoxically, the choice of no treatment for genital herpes may adversely impact fetal health, leading to PTD and LBW. Given that pregnant women frequently prefer no treatment, studies are urgently needed to establish the risk-benefit profile between treatment and no treatment for genital herpes infection in the context of improving fetal health, including the timing of treatment (before the 3rd trimester). This study is designed to provide clear evidence of treatment effectiveness in real-world clinical practice, and risk-benefit profiles to inform both treatment decisions by pregnant women and clinicians.

Study Aims:

This proposed comparative effectiveness study will address the following questions:

1. Does treating genital herpes infection in pregnant women reduce the risk of adverse pregnancy outcomes including PTD or LBW? (treated vs. untreated)

2. Does the timing of the treatment during pregnancy influence the treatment effectiveness on reducing adverse pregnancy outcomes (PTD and LBW)? (head-to-head comparison of treatment timing: before the 3rd trimester vs. during the 3rd trimester).

3. Do other treatment metrics, including treatment duration, dosage, and compliance, impact treatment effectiveness in reducing the risk of PTD and LBW?

4. Does treatment effectiveness vary depending on the type (or severity) of underlying genital herpes infection? (e.g., treating symptomatic genital herpes infection vs. treating latent/asymptomatic genital herpes)

5. Does genital herpes infection in pregnancy, if untreated, increase the risk of PTD and LBW, compared to no genital herpes infection? (untreated vs. controls without genital herpes) In addition, this study is especially relevant in addressing racial disparities, given that minority pregnant women have higher rates of both genital herpes infection and PTD: 3 times the infection rate and 150% higher PTD rate among African-Americans compared to Whites. Thus, demonstrating the effectiveness of treating genital herpes in reducing PTD could lead to a reduction in the existing racial disparity in PTD rates.

Study Description Overall study design: The investigators will conduct a prospective cohort study with a two-stage design based on more than 90,000 pregnant KPNC members in real-world clinical practice. Due to the increased fetal risk of untreated genital herpes infection, randomizing pregnant women with the infection into treated and untreated groups presents ethical problems, thus is not feasible. Our innovative two-stage prospective cohort design, leveraging our large membership and comprehensive electronic medical record (EMR) data, is a robust alternative option for examining the comparative effectiveness of treating genital herpes infection in pregnant women to reduce PTD and LBW.

Comparators: Three comparisons will be made:

1. When assessing treatment effectiveness, women with the infection who choose not to receive treatment will serve as the comparator (untreated). This comparator is a frequently preferred treatment option chosen by pregnant women due to their reluctance to use medications during pregnancy, based on their predominant concerns for the safety of their developing fetus as well as a lack of evidence that treating genital herpes infection is beneficial to their fetus. This comparator will also make the comparison groups more comparable by controlling for confounding by indication.

2. When assessing the timing of treatment effectiveness (before vs. after the start of the 3rd trimester), those who receive treatment during the 3rd trimester will be used as the comparator. Using this comparator will allow a head-to-head comparison between the timing of the treatment.

3. When assessing the effect of choosing not to treat during pregnancy, women without an underlying genital herpes infection or receipt of any treatment will serve as the comparator (normal controls). This comparison will provide evidence of the increased risk of PTD and LBW if genital herpes infection is not treated during pregnancy.

Our comparators will allow us to control for confounding by indication (genital herpes, its type and severity). Our EMR contains extensive questions on risk factors, including lifestyle factors, for all 90,000 mother-infant dyads. Through the unique two-stage study design, investigators will collect additional information, through interviews, on a subsample of women that will further allow controlling for additional confounders. Multiple statistical methodologies, in accordance with PCORI's methodology standards, will be employed in the analytic plan (e.g., propensity scores, instrumental variable methods) to ensure compatibility between comparison groups.

Study Design

• Study Type: Observational
• Actual Enrollment: 89132 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Comparative Effectiveness of Treatment Options for Genital Herpes Infection in Pregnant Women to Reduce Adverse Pregnancy Outcomes
• Actual Study Start Date: Mar 14, 2017
• Actual Primary Completion Date: Oct 15, 2019
• Actual Study Completion Date: Feb 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
Genital herpes treated before third trimester Women with genital herpes receiving treatment before the 3rd trimester
Genital herpes treated only during third trimester Women with genital herpes receiving treatment during the 3rd trimester
Genital herpes untreated Women with untreated genital herpes
Control group Women (controls) with neither genital herpes nor treatment

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Preterm Delivery [Up to 37 weeks]

   Participants who gave birth before 37 completed weeks of gestation

2. Number of Participants With a Low Birthweight Child [Through the end of pregnancy, an average of 40 weeks]

   Women having a child born with birthweight <2500 grams

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Kaiser Permanente Northern California members

• Pregnant women

Exclusion Criteria:

• Non Kaiser Permanente Northern California members

• Non pregnant women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Division of Research	Oakland	California	United States	94612

Sponsors and Collaborators

• Kaiser Permanente
• Patient-Centered Outcomes Research Institute

Investigators

• Principal Investigator: De-Kun Li, MD, Kaiser Permanente

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 30, 2016

More Information

Publications

None provided.

• Responsible Party: Kaiser Permanente
• ClinicalTrials.gov Identifier: NCT02986802
• Other Study ID Numbers: CN-16-2669
• First Posted: Dec 8, 2016
• Last Update Posted: Sep 17, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Infections; Communicable Diseases; Herpes Genitalis; Herpesviridae Infections; Premature Birth; Pregnancy Complications

Study Results

Participant Flow

Arm/Group Title	Genital Herpes Treated Before Third Trimester	Genital Herpes Treated Only During Third Trimester	Genital Herpes Untreated	Control Group
Arm/Group Description	Women with genital herpes receiving treatment before the 3rd trimester	Women with genital herpes receiving treatment during the 3rd trimester	Women with untreated genital herpes	Women (controls) with neither genital herpes nor treatment
Period Title: Overall Study
STARTED	1360	2839	1873	83060
COMPLETED	1360	2839	1873	83060
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Genital Herpes Treated Before Third Trimester	Genital Herpes Treated Only During Third Trimester	Genital Herpes Untreated	Control Group	Total
Arm/Group Description	Women with genital herpes receiving treatment before the 3rd trimester	Women with genital herpes receiving treatment during the 3rd trimester	Women with untreated genital herpes	Women (controls) with neither genital herpes nor treatment	Total of all reporting groups
Overall Participants	1360	2839	1873	83060	89132
Age, Customized (Count of Participants)
18-24	149 11%	250 8.8%	152 8.1%	9170 11%	9721 10.9%
25-29	278 20.4%	625 22%	399 21.3%	21155 25.5%	22457 25.2%
30-34	431 31.7%	986 34.7%	595 31.8%	30900 37.2%	32912 36.9%
≥35	502 36.9%	978 34.4%	727 38.8%	21835 26.3%	24042 27%
Sex: Female, Male (Count of Participants)
Female	1360 100%	2839 100%	1873 100%	83060 100%	89132 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	633 46.5%	1338 47.1%	758 40.5%	28887 34.8%	31616 35.5%
Asian	116 8.5%	331 11.7%	232 12.4%	22591 27.2%	23270 26.1%
African American	217 16%	381 13.4%	299 16%	4660 5.6%	5557 6.2%
Hispanic	302 22.2%	615 21.7%	460 24.6%	22026 26.5%	23403 26.3%
Other/multiple/unknown	92 6.8%	174 6.1%	124 6.6%	4896 5.9%	5286 5.9%
Region of Enrollment (participants) [Number]
United States	1360 100%	2839 100%	1873 100%	83060 100%	89132 100%
Parity (Count of Participants)
0	639 47%	1249 44%	664 35.5%	38369 46.2%	40921 45.9%
1	428 31.5%	954 33.6%	659 35.2%	27965 33.7%	30006 33.7%
2 or more	278 20.4%	595 21%	485 25.9%	15923 19.2%	17281 19.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Preterm Delivery
Description	Participants who gave birth before 37 completed weeks of gestation
Time Frame	Up to 37 weeks

Outcome Measure Data

Analysis Population Description

Women who could not be classified into any of the designed Arms/Groups as listed due to their starting treatment too late for examining preterm delivery (< 37 weeks of gestation) were considered as ineligible and therefore excluded from the analyses related to preterm delivery. They did not contribute to the results or conclusions related to preterm delivery.

Arm/Group Title	Genital Herpes Treated Before Third Trimester	Genital Herpes Treated Only During Third Trimester	Genital Herpes Untreated	Control Group
Arm/Group Description	Women with genital herpes receiving treatment before the 3rd trimester	Women with genital herpes receiving treatment during the 3rd trimester	Women with untreated genital herpes	Women (controls) with neither genital herpes nor treatment
Measure Participants	1360	1411	1873	83060
Preterm	100 7.4%	83 2.9%	247 13.2%	5407 6.5%
Not Preterm	1260 92.6%	1328 46.8%	1626 86.8%	77653 93.5%

2. Primary Outcome

Title	Number of Participants With a Low Birthweight Child
Description	Women having a child born with birthweight <2500 grams
Time Frame	Through the end of pregnancy, an average of 40 weeks

Outcome Measure Data

Analysis Population Description

Participants with birth weight data were included.

Arm/Group Title	Genital Herpes Treated Before Third Trimester	Genital Herpes Treated Only During Third Trimester	Genital Herpes Untreated	Control Group
Arm/Group Description	Women with genital herpes receiving treatment before the 3rd trimester	Women with genital herpes receiving treatment during the 3rd trimester	Women with untreated genital herpes	Women (controls) with neither genital herpes nor treatment
Measure Participants	1353	2829	1845	83052
Low Birth Weight	66 4.9%	59 2.1%	153 8.2%	4068 4.9%
Not Low Birth Weight	1287 94.6%	2770 97.6%	1692 90.3%	78984 95.1%

Adverse Events

Time Frame	Through the end of pregnancy, an average of 40 weeks.
Arm/Group Title	Genital Herpes Treated Before Third Trimester		Genital Herpes Treated Only During Third Trimester		Genital Herpes Untreated		Control Group
Arm/Group Description	Women with genital herpes receiving treatment before the 3rd trimester		Women with genital herpes receiving treatment during the 3rd trimester		Women with untreated genital herpes		Women (controls) with neither genital herpes nor treatment
All Cause Mortality
	Genital Herpes Treated Before Third Trimester		Genital Herpes Treated Only During Third Trimester		Genital Herpes Untreated		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1360 (0%)		0/2839 (0%)		0/1873 (0%)		0/83060 (0%)
Serious Adverse Events
	Genital Herpes Treated Before Third Trimester		Genital Herpes Treated Only During Third Trimester		Genital Herpes Untreated		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1360 (0%)		0/2839 (0%)		0/1873 (0%)		0/83060 (0%)
Other (Not Including Serious) Adverse Events
	Genital Herpes Treated Before Third Trimester		Genital Herpes Treated Only During Third Trimester		Genital Herpes Untreated		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1360 (0%)		0/2839 (0%)		0/1873 (0%)		0/83060 (0%)

Limitations/Caveats

[Not Specified]

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.