Results from two demographically diverse samples of mostly unvaccinated pregnant women seeking antenatal care at publicly funded clinics demonstrate that self-reported history of varicella continues to be a strong predictor of serological evidence of varicella immunity, whereas a negative or uncertain history is a poor predictor of negative serology. These results are largely consistent with those of previous studies and suggest that reliance on self-reported positive disease history is still a good strategy for predicting varicella immunity among women of reproductive age, despite the changing epidemiology of the disease following vaccine introduction in 1995. An examination of 1,799 pregnant women in Los Angeles between April of 1998 and March of 1999 found serological evidence of varicella immunity among 96.1% of women who self-reported having had chickenpox.16
More recently, Plourd and Austin reported a PPV of 96.2% of 1,085 patients registering for prenatal care during the first half of 2002.17
PPV will decline if varicella susceptibility in the population increases. While the level at which PPV rates of self-reported disease history are deemed to be too low to justify using self-reported history for initial screening purposes is debatable, we note that PPV drops below 95% at a susceptibility rate of 15%, assuming sensitivity of 80% and specificity of either 70% or 60%. When vaccine-derived VZV immunity predominates among cohorts in their child-bearing years, screening methods based on varicella disease history alone will no longer be appropriate, and evaluations will need to include a history of varicella vaccination.
Follow-up gp-ELISA testing of specimens that tested negative or equivocal by wc-ELISA revealed that 19% did in fact have VZV-IgG antibodies. Thus, had these women been evaluated for postdelivery vaccination under typical clinic conditions (wc-ELISA only), they would have been unnecessarily vaccinated. However, the vaccination of some people who are mistakenly identified as susceptible should not result in untoward effects, considering the excellent safety profile of varicella vaccination.18
Of greater public health importance is the possibility of false-positive test results by wc-ELISA, which would lead to women being erroneously informed that they are not susceptible to varicella. While we did not evaluate the rate of false-positives among wc-ELISA seropositive specimens, prior research indicates that false positive results are rare using this assay (<0.01% of specimens, unpublished study comparing wc-ELISA, gp-ELISA, latex bead agglutination, and commercial ELISAs, Scott Schmid, PhD, Chief of the Herpes Viral Laboratory, CDC, Atlanta).
Despite extensive training of residents and attending nursing staff in Philadelphia, health-care providers did not provide the necessary postpartum vaccination to their patients who were determined to be susceptible to varicella; the study staff administered 81% of the postpartum vaccinations. It is possible that health-care providers will be less motivated to carry through on postpartum vaccination if the need for vaccination is based on self-reported disease history of untested validity as opposed to the actual serological evidence of lack of immunity. Regardless, instituting a method for postpartum vaccination of women deemed to be susceptible (e.g., standing orders for vaccination of women with negative/uncertain histories or with negative VZV serology) will be a key component to the ultimate success of any screening program.
Both the PPV and NPV of self-reported varicella disease history are impacted by the prevalence of varicella in the population, which is associated with age, race, and geography/climate of birth, among other factors. Prior to the introduction of the varicella vaccine in the U.S., increasing age was found consistently to be the most important factor determining infection with VZV. Nationally representative data from the National Health and Nutrition Examination Surveys (NHANES) administered from 1988–1994 showed varicella seroprevalence rates steadily increasing from 86% among 6- to 11-year-olds to 99.6% among adults aged 40 to 49 years.19
In AV, the median age of the seropositive subjects was 24 years compared to 21 years among those who were seronegative; in Philadelphia, the median age was 23 years for the seropositive subjects and 24.5 years for the seronegative subjects (data not shown).
NHANES data also demonstrated that race was associated with naturally acquired varicella infection independent of age, with non-Hispanic black women aged 20 to 39 years being 60% less likely to be varicella seropositive compared to their non-Hispanic white counterparts. Several studies have documented lower seropositive rates among adults born in tropical and semitropical environments compared with temperate zones.16,20–22
The current study did not have sufficient sample size or variability with respect to these three variables to consider their independent impact on PPV or NPV. Our study had higher proportions of women who traditionally have lower seropositive rates, including non-Hispanic black women (Philadelphia), women born outside the U.S., and women born in countries having subtropical/tropical climates (). Therefore, our results are likely to underestimate PPV of self-reported history compared to all women of child-bearing age in the U.S. Moreover, our findings may only be applicable to similar populations of women seeking prenatal care at publicly funded clinics.
Due to the possibility of selection bias in our samples, seroprevalence rates were not calculated independent of self-reported disease history. Study recruitment materials advertised that participants needing varicella vaccination would receive it for free as compensation for study participation. This incentive may have resulted in the disproportionate enrollment of women with no or uncertain history of varicella disease relative to women with a positive disease history, which would result in an inflated seronegative rate in this sample. As a clinical educational measure taken in light of the potentially serious ramifications of varicella disease in pregnancy, the study consent form framed the purpose of the study as identifying women who have never had chickenpox. This also may have resulted in biased recruitment toward women with no or uncertain history of varicella. Additionally, the sensitivity of reported varicella history would have been underestimated, while specificity would have been overestimated as a result of this bias.
When examining estimated PPVs at varying susceptibility levels, we selected a sensitivity and range of specificity values that would account for the potential bias instead of using values directly from the study. Although the potential for this kind of selection bias precludes the use of the study data for estimating overall seroprevalence rates as well as the sensitivity and specificity of varicella history in this sample, it did not result in biased estimations of seroprevalence rates within self-reported disease history groups.
A crude estimate of the number of women giving birth each year who are susceptible to varicella infection can be calculated by applying age-specific varicella susceptibility rates for women obtained from NHANES data to the estimated number of women who gave birth to a live-born infant annually from the Vital Statistics Natality Report. This calculation (data not shown) suggests that approximately 94,000 women aged 15 to 44 years in the U.S. who delivered a live-born infant in 2004 may have been susceptible to varicella disease during their pregnancy.
From a prevention standpoint, it is of course preferable to identify and vaccinate all susceptible women prior to their becoming pregnant. In the absence of a mechanism for doing so, the prenatal screening for varicella susceptibility, as provisionally recommended by ACIP, is a feasible next-best alternative that will likely prove to be efficacious in preventing the morbidity and mortality associated with maternal, fetal, and perinatal chickenpox. However, whether this strategy will remain efficacious and cost-effective until vaccine-derived immunity predominates among the cohort of women of reproductive age will in part depend on changes in population susceptibility and in the PPV of self-reported disease history. Both of these should continue to be monitored periodically.
A formal economic analysis of prevaccination serotesting compared with presumptive immunization of those self-reporting a negative or equivocal history of disease that considers a range of seroprevalence rates in sensitivity analyses would help determine the levels of population susceptibility and PPV of self-reported disease history at which this provisional policy is cost-effective. In situations in which serological testing followed by vaccination of susceptible women at subsequent visits is not feasible due to limited availability of laboratory services, poor rates of return for additional visits, or other constraints, presumptive varicella vaccination for women who lack a positive history of disease and are not pregnant or planning to become pregnant within the next month should be considered.