Release Date: November 2012

By Erika Barth Cottrell, PhD, MPP; Roger Chou, MD; Ngoc Wasson, MPH; Basmah Rahman, MPH; and Jeanne-Marie Guise, MD, MPH

The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in Annals of Internal Medicine on November 27, 2012 (Ann Intern Med 2012; http://www.annals.org).

Background: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States.

Purpose: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV.

Data Sources: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists.

Study Selection: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV.

Data Extraction: Investigators abstracted and reviewed study details and quality using predefined criteria.

Data Synthesis: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality, 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission.

Limitations: Only English-language articles were included. Studies were observational, and most had important methodologic shortcomings, including failure to adjust for potential confounders and small sample sizes.

Conclusion: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not appear indicated for reducing transmission risk.

Primary Funding Source: Agency for Healthcare Research and Quality.

An estimated 40,000 children are born to hepatitis C virus (HCV)–positive women each year¹. Mother-to-infant (vertical) transmission is the main route of childhood HCV infection². Estimates for the rate of vertical transmission range from 3% to 10%^2-5. Risk for transmission is highest among women with a high viral load at delivery^2-6 and those co-infected with HIV^5,7. Although antiviral therapies are contraindicated in pregnancy because of teratogenic risks, prenatal HCV screening to identify HCV-infected women unaware of their status might lead to other interventions during labor and delivery or in the perinatal period that reduce risk for mother-to-infant transmission⁸.

The purpose of this review was to synthesize the evidence on the effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission. This review was performed as part of a larger report on HCV screening⁹ and will be used by the U.S. Preventive Services Task Force (USPSTF) to inform its prenatal HCV screening recommendations.

Scope

We developed a review protocol by using a standardized process with input from experts and the public to address the following key question: “What is the effect of mode of delivery, labor management strategy, or breastfeeding on risk for mother-to-infant transmission of HCV?” Detailed methods and data for the review, including the full USPSTF analytic framework on screening, search strategies, detailed abstraction tables, and quality ratings of individual studies, are available in the full report⁹.

Data Sources

A research librarian searched Ovid MEDLINE (1947 to May 2012), EMBASE, the Cochrane Library Database, Scopus, PsycINFO, clinical trial registries (including clinicaltrials.gov), and grants databases. We supplemented electronic searches by reviewing reference lists of retrieved articles. Searches were peer reviewed by a second librarian.

Study Selection

At least 2 reviewers independently evaluated each study to determine inclusion eligibility. We selected for full review randomized trials, cohort studies, and case–control studies that evaluated the association between mode of delivery (cesarean versus vaginal delivery), labor management strategies (use of internal fetal monitoring or management of premature rupture of membranes), or breastfeeding on risk for mother-to-infant transmission. We restricted inclusion to English-language articles and excluded studies published only as abstracts. Women co-infected with HIV are advised to avoid breastfeeding and deliver by elective cesarean if they are viremic in order to reduce risk for HIV transmission¹⁰. Therefore, we excluded studies of HIV co-infected women, unless results for women not co-infected with HIV were reported separately or co-infected women made up less than 10% of the study sample.

Data Extraction and Quality Rating

One investigator abstracted details about the study design, patient population, setting, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied predefined criteria to assess the quality of each study as good, fair, or poor^11-13. Discrepancies were resolved through a consensus process.

Data Synthesis

We assessed the overall strength of each body of evidence as “high,” “moderate,” “low,” or “insufficient” in accordance with the AHRQ “Methods Guide for Comparative Effectiveness Reviews”¹⁴, based on the quality of studies, consistency between studies, precision of estimates, and directness of evidence.

Role of the Funding Source

This research was funded by AHRQ's Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the scope, analytic framework, and key questions. AHRQ staff had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ staff provided project oversight, distributed the draft report for peer review, and reviewed the draft report and manuscript. The investigators are solely responsible for the content of the manuscript and the decision to submit for publication.

The search and selection of articles are summarized in the study flow diagram (Appendix Figure). Of 2580 potentially relevant citations, 444 articles were selected for full-text review and 18 met inclusion criteria.

Mode of Delivery

Fourteen observational studies reported in 16 publications (sample sizes of 56 to 1034 mother–infant pairs) evaluated the association between mode of delivery and vertical transmission of HCV (Appendix Table)^4,5,15-28. Nine studies were conducted in Europe^{4,15-17,19-21,23,25,27,28}, 2 in Australia^18,24, 2 in Japan^22,26, and 1 in the United States⁵. Two studies were rated as good quality^5,15,16, 4 fair quality^4,19,21,23, and the remainder poor quality. Two reports from the European Pediatric Hepatitis C Network evaluated overlapping populations^15,16, and 2 studies evaluated nonoverlapping (different time periods of enrollment) populations in Dublin, Ireland^19,21. Only 4 studies adjusted for potential confounders in analyses^4,5,15,16,19; no study reported baseline characteristics according to mode of delivery or matched women on key potential confounders.

Four studies^5,15,19,21 totaling 2080 mother–infant pairs (2 good-quality^5,15 and 2 fair-quality^19,21 studies) compared risk for transmission after elective cesarean delivery before the onset of labor versus vaginal or emergency (after onset of labor) cesarean delivery (Appendix Figure). Three of these studies^5,19,21 reported higher transmission risk after vaginal or emergent cesarean delivery, but the difference was statistically significant in only 1 fair-quality study¹⁹. That study (n = 424) reported no cases of transmission after elective cesarean delivery, compared with 7.4% after vaginal or emergency cesarean delivery (adjusted odds ratio, 0.0 [95% CI, 0.0 to 0.87])¹⁹. The 2 good-quality studies reported conflicting results. One (n = 181) reported a direction of effect that was not statistically significant but was similar to that of the fair-quality study, with a vertical transmission rate of 4.1% (7 of 169) after vaginal or emergent cesarean delivery compared with no cases after 12 elective cesarean births (relative risk, 1.1 [CI, 0.07 to 19])⁵. The other, larger (n = 1034) good-quality study found elective cesarean to be associated with increased risk for vertical transmission compared with vaginal or emergency cesarean delivery (adjusted odds ratio, 1.6 [CI, 0.88 to 2.9])¹⁵.

Eleven studies (total of 2308 mother–infant pairs) compared the risk for vertical transmission after vaginal versus cesarean delivery, without specifying whether the cesarean delivery was elective or emergent (Appendix Figure)^{4,16-18,20,22-28}. Ten of the 11 studies (1 good-quality¹⁶, 2 fair-quality^4,23, and 8 poor-quality^{17,18,20,22,24-28} studies) found no association between mode of delivery and risk for HCV transmission^{4,16-18,20,23-28}. The exception was 1 small (n = 59), poor-quality Japanese prospective cohort study that reported a statistically significant increase in risk with vaginal delivery in a subgroup of women with high viral load (≥2.5 x 10⁶ RNA copies/mL)²².

Labor Management

Internal Fetal Monitoring

Three studies (2 good-quality^5,16 studies and 1 fair-quality²¹ study) reported conflicting findings on the relationship between use of internal fetal monitoring and risk for vertical transmission (Appendix Figure). One good-quality study (n = 181)⁵ found internal fetal monitoring versus no monitoring was associated with increased risk (adjusted odds ratio, 6.7 [CI, 1.1 to 36]), but another, larger good-quality study (n = 724) found no association (relative risk, 1.2 [CI, 0.70 to 2.2])¹⁶.

Duration of Rupture of Membranes

One good-quality study⁵ and 1 poor-quality study²⁴ (total of 245 mother–infant pairs) found an association between longer duration of rupture of membranes and increased risk for transmission (Appendix Figure). The good-quality study reported greater risk for vertical transmission in women with membrane rupture longer than 6 hours (odds ratio, 9.3 [CI, 1.5 to 180]) ⁵. The poor-quality study reported longer average duration of membrane rupture in women who transmitted virus to their infant than in those who did not transmit virus (28 versus 16 hours; P = 0.03)²⁴.

Breastfeeding

Fourteen cohort studies (total of 2971 mother–infant pairs) found no association between breastfeeding by women infected with HCV and risk for transmission to infants (Appendix Figure)^{5,15,17,19,20,23-32}. Most studies prospectively followed infants for at least 1 year. Sample sizes ranged from fewer than 50^29,31,32 to more than 1000¹⁵. Two studies were rated good quality^5,15, 2 fair quality^19,23, and 10 poor quality^17,20,24-32. Methodologic shortcomings in the poor-quality studies included failure to perform statistical adjustment on potential confounders and insufficient information to determine comparability of groups at baseline stratified by breastfeeding status.

Vertical transmission is the leading cause of childhood HCV infection, and identification of effective management strategies to reduce risk for transmission is an important clinical and public health concern. However, the primary finding of this review as summarized in the Table is that no perinatal management strategy has clearly been shown to reduce risk for HCV transmission. Observational studies consistently found no evidence of an association between breastfeeding and risk for vertical transmission, consistent with data suggesting that transmission typically occurs in utero^23,33. Evidence on the effects of labor management strategies and mode of delivery on risk for transmission was somewhat conflicting. Two studies^5,24 reported increased risk for HCV transmission with more prolonged duration of ruptured membranes, similar to findings for other infectious agents transmitted vertically (such as group B streptococcus and HIV). However, other studies did not find vaginal delivery associated with increased risk for vertical transmission versus cesarean delivery, and the largest single study¹⁵ reported a non–statistically significant trend toward decreased risk, even though vaginal delivery is associated with longer duration of ruptured membranes. Possible explanations for the failure to find an association between vaginal delivery and increased risk for transmission could include threshold or modifying effects related to the duration of rupture, viral load, or other factors. Cohort studies that focus on women with longer rupture of membranes or high viral load and perform statistical adjustment on other potential confounding factors could help clarify the effects of mode of delivery on transmission risk. Randomized trials are less susceptible to confounding but would involve potential challenges related to the acceptability of randomly assigning HCV-infected women to elective cesarean delivery versus planned vaginal birth.

Other reviews and reports were consistent with our findings. A review of cesarean delivery versus vaginal delivery for preventing mother-to-infant HCV transmission found no randomized trials and concluded that a systematic review of observational studies is needed³⁴. A 2007 American College of Obstetricians and Gynecologists report identified a possible association between prolonged rupture of membranes after labor and increased risk for vertical transmission but concluded that no preventive measures have been proven effective for reducing the risk for mother-to-infant transmission³⁵.

Our review has limitations. Evidence on the effects of interventions to prevent mother-to-infant transmission was restricted to observational studies, most with methodologic shortcomings (including failure to adjust for confounders) and small sample sizes. If practices that are more effective at reducing transmission are preferentially used in women at higher risk, this could have biased results toward null findings. We excluded non–English-language articles, which could result in language bias. We were also unable to formally assess publication bias due to small numbers of studies and methodologic shortcomings in the studies.

This review was conducted as part of a larger review on HCV screening⁹. For prenatal screening to be effective, there must be an effective intervention. Our findings indicate that avoidance of breastfeeding is not warranted to reduce risk for vertical transmission. Given limited evidence of an association between prolonged rupture of membranes and increased transmission risk, clinicians may consider avoiding prolonged rupture of membranes in HCV-infected women until more definitive data are available.

Source: Agency for Healthcare Research and Quality.

Acknowledgment: The authors thank Robin Paynter, MLIS; Rose Campbell, MLIS; Christina Bougatsos, MPH; Ian Blazina, MPH; Tracy Dana, MLS; Jessica Griffin, MS; AHRQ Task Order Officer Christine Chang, MD, MPH; and USPSTF Medical Officer Iris Mabry-Hernandez, MD, MPH.

Grant Support: From the Agency for Healthcare Research and Quality (Contract Number 290-2007-10057-I, Task Order 8), Rockville, Maryland.

Potential Conflicts of Interest: Dr. Cottrell: Other: unpaid board member of AHRQ. Dr. Chou: Grant: AHRQ. Dr. Wasson: Grant: AHRQ. Dr. Guise: Grant (money to institution):AHRQ (5. HHSA 290-2007-10057, task order no. 6); Support for travel to meetings for the study and other purposes: AHRQ; Provision of writing assistance, medicines, equipment, or administrative support (money to institution): AHRQ. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1085.

Requests for Single Reprints: Roger Chou, MD, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current author addresses and author contributions are available at http://www.annals.org.

HCV = hepatitis C virus; OR = odds ratio.
* The full report is available on the Agency for Healthcare Research and Quality Web site at www.effectivehealthcare.ahrq.gov⁹.

EPHN = European Paediatric Hepatitis C Virus Network; HCV = hepatitis C virus; NR = not reported; OR = odds ratio; RR = relative risk; SD = standard deviation.
* Unadjusted unless otherwise indicated.

† One study resulting in 2 publications.
* Includes hand searches and gray literature searches.