Acceptability, feasibility, equity and resource use for prenatal screening for chlamydia and gonorrhea: A systematic review

Background A systematic review on acceptability, feasibility, equity and resource use was conducted as part of updating recommendations from the Public Health Agency of Canada on prenatal screening for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). Methods Information sources, including MEDLINE® All, Embase and Cochrane CENTRAL (January 2003–January 2021) electronic databases were searched for studies that assessed acceptability, feasibility, equity and resource use of screening for CT or NG in pregnant persons aged ≥12 years. The Risk of Bias Assessment Tool for Non-Randomized Studies was used for quality assessment and a narrative synthesis was prepared. Results Of the 1,386 records identified, nine observational studies (approximately 5,000 participants) and three economic evaluations met the inclusion criteria. In general, pregnant persons and healthcare providers accepted screening. Most pregnant persons and partners supported universal testing for CT. Pregnant persons preferred non-invasive sampling methods. Inequities in feasibility (accessibility to screening) exist in certain populations. Studies have shown that targeted screening can miss cases. Screening all pregnant persons for CT has net cost savings compared to no screening. Limitations include not identifying eligible literature on acceptability of prenatal screening for NG among partners of pregnant persons and some studies with increased risk populations that restrict the generalizability of the findings highlighting areas for future research. Conclusion Prenatal screening for CT and NG is generally acceptable among pregnant persons and healthcare providers. Evidence has shown that targeted screening can miss cases. The findings were included when updating PHAC’s recommendations on prenatal screening for CT and NG. This work was presented at the Society of Obstetricians and Gynaecologists of Canada’s 2024 Annual Clinical and Scientific Conference in Edmonton, Alberta.


Introduction
In Canada, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the most common reported sexually transmitted infections (STIs), with rates markedly increasing between 2010 and 2019 (CT, 33.1% and NG, 181.7%) (1).In 2010, 94,716 cases of CT and 11,381 cases of NG were reported in Canada, corresponding to rates of 278.5 and 33.5 per 100,000 population, respectively (1,2).In 2019, 139,386 cases of CT and 35,443 cases of NG were reported in Canada, corresponding to rates of 370.8 and 94.3 per 100,000 population, respectively (1,2).

SYSTEMATIC REVIEW
Chlamydia trachomatis and NG infections are often asymptomatic in females and can go undetected.In pregnant women/pregnant individuals (PWPI), this can lead to adverse outcomes.If the birthing parent has not received an effective treatment during the perinatal period, infection can potentially be transmitted to the neonate during delivery and lead to adverse neonatal health outcomes.If left untreated, CT in the birthing parent carries a 30%-50% risk of the neonate developing ophthalmia neonatorum and 10%-20% risk of developing CT pneumonia (3).Neisseria gonorrhoeae infection in the birthing parent carries a 30% risk of the neonate developing gonococcal ophthalmia neonatorum (4,5).Potential consequences of ophthalmia neonatorum include permanent visual impairment.There is lack of national surveillance information on gonococcal ophthalmia neonatorum, chlamydial ophthalmia neonatorum and neonatal pneumonia cases.
In 2010, the Public Health Agency of Canada (PHAC) recommended that all pregnant women should be evaluated for STI risk factors prior to and during pregnancy.Any woman with ongoing risk factors for STI acquisition during pregnancy should be considered for rescreening each trimester (6).In 2010, PHAC also recommended screening for CT early in pregnancy.Repeat screening should be performed in the third trimester for women at continuing risk for STI acquisition (6).In 2016 (reaffirmed in 2021), the Canadian Paediatric Society stated, "Neonatal ocular prophylaxis with erythromycin, the only agent currently available in Canada for this purpose, may no longer be useful and, therefore, should not be routinely recommended" (7).Variation in practice exists with regard to offering neonatal ocular prophylaxis to prevent ophthalmia neonatorum.Evidence shows that approximately 15%-22% of PWPI are not being screened for CT and NG (8)(9)(10).Screening and testing for these infections could help prevent adverse pregnancy and neonatal outcomes.Given the increasing rates of reported cases of CT and NG in the general population and suboptimal rates of prenatal screening for CT and NG in Canada (8)(9)(10), the National Advisory Committee on Sexually Transmitted and Blood-Borne Infections (NAC-STBBI) reviewed and updated PHAC's recommendations on prenatal screening for CT and NG.Canada's Drug Agency (CDA-AMC), formerly Canadian Agency for Drugs and Technologies in Health (CADTH) conducted a health technology assessment (HTA) (11).The main objective of PHAC's systematic review was to search, identify and synthesize relevant literature on acceptability, feasibility, equity and resource use on prenatal screening for CT and NG to support updating of the PHAC recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (12)(13)(14)

Methods
According to the GRADE approach, the determinants of the strength and direction of guideline recommendations include acceptability among stakeholders, feasibility of the intervention, equity (the likelihood to reduce inequities or increase equity) and resource implications (resource intensity) of the intervention (12,13).In alignment with the GRADE approach, this systematic review aimed to assess the domains of acceptability, feasibility, equity and resource use for prenatal screening for CT and NG.Table 1 shows the eligibility criteria for study selection.

Information sources
Studies were identified by searching electronic databases, scanning reference lists of included articles and consulting subject matter experts from the NAC-STBBI.The CDA-AMC HTA report on screening for CT and NG during pregnancy, consisting of a review of the clinical literature, an economic analysis and a review of qualitative studies on patients' preferences and experiences (11), was also reviewed to identify relevant studies. In

Study selection and data extraction
For the original search, the number of retrieved records was split among three individuals and screened by title and abstract based on inclusion criteria.For the update search, the retrieved records were independently screened by two individuals.For both searches, any differences were resolved through discussion between the reviewers or in consultation with another individual.Any uncertainty in the inclusion of titles and abstracts led to the retrieval of the full text article.
Any full text articles that were not available online were retrieved via the PHAC library.For the original search, the number of selected full text articles was split among three individuals and assessed based on inclusion criteria, which were then verified by another individual.For the update search, one individual assessed the selected full text articles based on inclusion criteria, which were then verified by two individuals.For both searches, any differences were resolved through discussion between the reviewers and in consultation with another individual.
A data extraction form was developed, pilot-tested on two randomly selected included studies and revised accordingly.
Reviewers were trained on extracting data using the form by the primary author.For the original search, the number of articles that met the inclusion criteria was split among three individuals who then extracted data and another individual verified the extracted data.For the update search, an individual extracted data from the articles that met the inclusion criteria and two individuals verified the extracted data.

Quality assessment
The Risk of Bias Assessment Tool for Non-Randomized Studies (RoBANS) was used for quality assessment of the included observational studies (17).The RoBANS tool consists of six domains and a judgment of "high", "low" or "unclear" can be assigned to each domain.Each included study was assessed for risk of bias by a reviewer and another reviewer verified the assessments.

Synthesis of evidence
A narrative synthesis of the included studies was performed for this review.Findings were presented by acceptability, feasibility, equity, resource use or combination thereof.

Results
Supplemental material, Figure S1 shows the flow diagram of study selection.Of the 1,386 records (original search=1,226 and update search=160) identified through searching electronic databases and reviewing the CDA-AMC HTA report (11), 12 articles (original search=9 and update search=3) met the inclusion criteria and were included in this systematic review.The combined results from the original search and the update search are presented herein.
Supplemental material, Table S1 displays the characteristics and findings of the included studies on acceptability, feasibility, equity and resource use.The study designs were cross-sectional, retrospective chart reviews and economic evaluations.The studies were conducted in Australia, Canada, the Netherlands, the United Kingdom and the United States.Supplemental material, Table S2 shows the risk of bias assessment findings for each included observational study.The quality of the included articles was generally strong.Selection bias was "high" for eight studies.Four studies did not report on sources of funding and three studies did not report on competing interests.

Acceptability
Four studies reported on acceptability of prenatal screening for CT or NG.Logan et al. compared screening approaches to identify CT in a sample of 209 miscarriage individuals at a hospital in Scotland, United Kingdom (18).Among participants, a urine sample was significantly preferred over vulval swab (p<0.0001) or endocervical swab (p<0.0001).A vulval swab was significantly preferred compared to an endocervical swab (p<0.0001).However, there was reduced test performance with urine sample.The reasons for declining the endocervical method were categorized into the following themes: physically negative aspects, positive aspects of non-invasive testing, not wishing to repeat an internal exam, feeling psychologically unable to cope with the procedure and the impact of the screening procedure on the pregnancy.
As part of a larger study assessing the prevalence and factors associated with CT in pregnancy ( 19), Bilardi et al. examined the acceptability of screening for CT in 100 pregnant persons aged 16-25 years at four major antenatal services across Melbourne, Australia (20).The researchers found that all participants supported testing for CT as part of their routine antenatal care and nearly all strongly preferred urine testing compared to the other methods, as it was quick, easy and non-invasive.The main motivating factor in the acceptability of screening was concern for the health of the baby and the main concern expressed was whether testing and treatment could potentially harm the baby.

Feasibility and equity
Four articles reported on feasibility and equity for prenatal screening for CT or NG.

Feasibility and resource use
One observational study and three economic evaluations reported on feasibility and resource use of prenatal screening for CT or NG.Tyker et al. examined screening for CT and NG in 102 pregnant persons aged 13-19 years at an adolescent obstetrics practice in Ontario, Canada (25).Urine Nucleic Acid Amplification Test (NAAT) was used for 88 of 89 (98.9%) patients screened in the third trimester.The researchers noted that the decision to use urine samples was based on feasibility and ease SYSTEMATIC REVIEW of collecting samples, whereas using an endocervical swab in the third trimester is more resource intensive and invasive.

Discussion
This is the first systematic review on acceptability, feasibility, equity and resource use for prenatal screening for CT and NG.Nine observational studies reporting on approximately 5,000 participants and three economic evaluations were included in this review.Individuals who were pregnant in the past 12 months and living outside of the principal city of metropolitan statistical areas (e.g., suburban area) were less likely to receive CT testing compared to those living in other areas.This finding is in slight contrast to evidence showing that pregnant individuals living in rural or remote areas may not always have access to trained prenatal healthcare providers in Canada (33).Evidence on pregnant persons with high risk for and a high prevalence of CT and NG from an underserved area in the United States showed that, if repeat screening was limited to individuals aged ≤19 years, eight cases could have been missed among those aged ≥20 years.This finding highlights how targeted screening could miss cases in those who do not meet the screening criteria and that limiting screening to earlier in pregnancy could potentially miss detecting new infections and reinfections (11).

SYSTEMATIC REVIEW
With regard to resource use, screening all pregnant persons compared to no screening has cost savings.In general, the studies showed that an increase in the prevalence of CT and NG infections contributes to better cost-effectiveness.

Limitations
The included studies have several limitations to consider when interpreting the findings.Firstly, some of the observational studies were conducted in a miscarriage sample, younger age groups or those with a high risk for and a high prevalence of CT and NG that could contribute to selection bias.The findings from these studies may not be generalizable to the larger population of pregnant persons and those with lower prevalence of CT or NG.Secondly, some of the observational studies used self-report questionnaires (e.g., self-reported CT testing) that could potentially introduce recall bias.Thirdly, the economic evaluations focused on CT only.In addition, two of these studies were limited to younger age groups, a 12-month time horizon and a third-party payer perspective (26,28).One study was conducted in a higher burden setting and the researchers noted possible uncertainty in the estimated rates of CT-related sequelae that could contribute to overestimating the cost savings of CT screening (28).The strengths of the studies included in this review were the use of semi-structured interviews and the inclusion of a variety of healthcare settings.
This systematic review did not identify eligible literature on acceptability, feasibility, equity and resource use of timing of repeating universal screening (e.g., third trimester or at delivery).It also did not identify eligible literature on acceptability of prenatal screening for NG among partners of pregnant persons.These gaps in the literature highlight areas for future research.
The strengths of this review include the incorporation of the GRADE search strategies on acceptability, feasibility, equity and resource use and inclusion of different types of studies.

Implications
The evidence from this systematic review supported the development of the updated NAC-STBBI recommendations on prenatal screening for NG and CT in Canada (34).Screening all PWPI at first and third trimesters is likely more acceptable than targeting high-risk PWPI because it may reduce the stigma associated with screening for an STI.A recommendation about the sampling method for screening was not made since the preference and capacity may vary according to the individual, healthcare provider and the healthcare system.The updated NAC-STBBI recommendations are as follows (34): • We suggest screening all PWPI for NG and CT during the first trimester or at the first antenatal visit and again in the third trimester (conditional recommendation; low certainty evidence)

Table 1 :
Eligibility criteria consultation with an external methodology expert, the GRADE search strategy tool (not yet validated) for identifying published literature on acceptability, feasibility, equity and resource use was modified to avoid limiting the search by country.During screening, studies conducted in countries comparable to Canada's healthcare context were included in the review.
(16)alth Canada librarian incorporated the modified GRADE search strategies within the original CDA-AMC HTA clinical review search strategy.The MEDLINE search strategy was reviewed by the evidence review team.MEDLINE® All, Embase and the Cochrane Central Register of Controlled Trials (Cochrane CENTRAL) were searched on the Ovid platform from 2003 to present (January 14, 2021).The search start year of 2003 was informed by PHAC's laboratory diagnosis recommendations of STIs(16).No study design limit was applied and language was limited to English or French.The search strategies for the three databases are presented in Appendix, Supplemental material, Appendices A to F. Results from the original search were exported on September 19, 2019, and results from the update search were exported on January 14, 2021 (to identify any relevant new studies published since June 1, 2019).RefWorks was used to remove duplicates and store the citations.Microsoft Excel databases were used to record the process.
In general, pregnant persons and healthcare providers accepted prenatal screening for CT and NG.Most pregnant persons and partners supported testing of all pregnant individuals for CT as part of routine antenatal care.Some pregnant persons and partners reported feelings of stigma and shame when offered testing for CT.Similarly, Pavlin et al.
• We suggest screening PWPI at the time of labour for NG and CT in any of the following situations (conditional recommendation; low certainty evidence): • No prenatal screening has occurred (no valid results available at the time of labour) • Third trimester screening has not occurred • A positive test result was obtained for NG or CT during pregnancy without appropriate follow-up, including treatment and a test-of-cure Conclusion In general, prenatal screening for CT and NG is acceptable among pregnant persons and healthcare providers.Most pregnant persons and partners supported testing of all pregnant individuals for CT as part of routine antenatal care.Inequities in feasibility (accessibility to screening) exist in certain populations.Studies have shown that targeted screening can miss cases.Screening all pregnant persons for CT has net cost savings compared to no screening in the included studies.More comparative research is needed on acceptability, feasibility, equity and resource use for prenatal screening for CT and NG in the Canadian context.These findings were used to support the updated NAC-STBBI recommendations on prenatal screening for CT and NG.