点击显示 收起
School of Public Health, University of Texas, Houston
This issue of the Journal treats us to articles from 2 large multicenter studies of vertical transmission of hepatitis C virus (HCV). The studies are complementary and have largely similar findings, although the European study [1], with 1787 mother-infant pairs of HCV-positive mothers from 33 centers in 7 countries, dwarfs the American one [2], which included 244 mother-infant pairs from 2 centers. Overall, the estimated frequencies of HCV transmission were 6.2% (95% confidence interval [CI], 5.0%7.5%) in the European study and 3.6% (95% CI, 1.3%6.0%) in the American study. Both studies found an increased risk of transmission from mothers with higher viral loads, earlier rupture of membranes, and coinfection with HIV. Neither study found a correlation between transmission and either breast-feeding or cesarean-section delivery. Also of interest is that both studies found that a small proportion of apparently infected infants subsequently lost all HCV markers on longer follow-up.
The most interesting observation from the European study is that HCV infection was twice as frequent among female than male infants (unadjusted odds ratio, 2.03 [95% CI, 1.303.15]; P = .001). The difference was similar in the American study (6 girls and 3 boys) but was not statistically significant, because of the much smaller sample sizes. The European investigators indicate that these are probably the first data suggesting a differential response to HCV between males and females. Sex differences are found in responses to most infectious agents, but these findings are interesting because there are more HCV infections among the female than the male infants. This is quite remarkable, since a male excess is found for most infectious agents, and, in general, males respond more poorly than females to most external challenges. Males have a shorter life expectancy, and males of all age groups have higher overall mortality than females. Except for female end-organ disease and those illnesses explained by exposure differentials (e.g., skin cancer), there are relatively few conditions in which the incidence in females exceeds that in males. There are autoimmune diseases and a few cancers (e.g., of the thyroid and gall bladder) that are more common in females, but far and away most diseases, including infectious diseases, have a male excess. The extra X chromosome appears to be protective.
It is perplexing that the European investigators provide little information to help interpret the sex differences they observe and emphasize in the title of their article. They suggest that it "reflects hormonal or genetic differences in susceptibility or response to infection between males and females" (p. 1877), but they have not provided enough information to give reasonable assurance that these differences are not due to bias or confounding. However, if bias and confounding can be eliminated, then I believe that the most likely possibility is excess male mortality in utero rather than increased infections among females. The authors can help us interpret their findings by providing the complete sex distribution at birth of the infants in their study. Also absent is information about abortion rates, infection, and follow-up rates by sex at different ages, which must be available, since their protocol called for testing of infants at birth, age 6 weeks, and ages 3, 6, 9, 12, 18, and 24 months, as well as some beyond that. These deficiencies make it unnecessarily difficult to analyze the various possible interpretations.
If the sex ratio at birth in this study were decreased from the 1.05 (male : female) ratio found in the general populations of most Western countries, it would strongly suggest an adverse in utero effect on males. A decreased ratio was observed in the American study in Houston (the Hawaii component data were not available), where the birth sex ratio was 99 : 113, or 0.876. The sex ratio at enrollment in the European study was 668 : 802, or 0.833, which is probably the birth ratio, but the authors, unfortunately, do not define enrollment, so we cannot be certain what biases were introduced if the data were censored. In view of these numbers showing a low male : female ratio, I am unable to interpret the following statement by the European authors, which seems at odds with these data of theirs: "Because the male : female ratio in our study population was higher than that observed in the general population, this finding is unlikely to be due to excessive deaths of infected males in utero" (p. 1877).
For hepatitis B virus (HBV), males of all ages have slightly higher infection rates than females and slightly poorer responses (titers and conversion rates) to HBV vaccination, and there appears to be no distortion of the sex ratio at birth of infants born to carrier mothers. The incidence of chronic liver manifestations of the HBV carrier state (chronic hepatitis, cirrhosis, and hepatocellular carcinoma) are much more common in males than females, at ratios of 2.53.5, depending on the population. Intrauterine infections make up a small proportion of perinatal HBV infections, so it is conceivable that a differential adverse sex effect in that small proportion could have been missed by such relatively crude measures as sex ratios at birth.
The authors of the European study reference 3 HIV perinatal transmission studies, which found higher frequencies of HIV infection in female infants and lower male : female birth ratios. Taha et al. [3] reported data from a large vertical transmission study in Malawi, which showed HIV positivity of 12.6% among 998 girls, compared with 6.3% among 966 boys, a male : female ratio at birth of 0.968 for enrolled infants. A final observation from the Malawi study deserves comment. Female infants had a smaller average birth weight than male infants, as would be expected if there were more in utero fetal deaths among males, if the infections were more common in the smaller and/or weaker ones.
In conclusion, the observation of higher HCV infection rates in female infants of HCV-infected mothers is interesting, provocative, and worth further investigation. It is in accord with recent observations of similar excesses of HIV infections in female infants of HIV-infected mothers. Future studies investigating infant sex differences in relation to perinatal infections need to plan carefully to collect and present sex data in a fashion that minimizes potential bias, such as skewed abortions and stillbirths, if sex is known before birth, and distorted follow-up by sex.
Reference
1. European Paediatric Hepatitis C Virus Network. A significant sexbut not elective cesarean sectioneffect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005; 192:18729 (in this issue). First citation in article
2. Mast EE, Huang L-Y, Seto DSY, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis 2005; 192:18809 (in this issue). First citation in article
3. Taha TE, Nour S, Kumwenda NI, et al. Gender differences in perinatal HIV acquisition among African infants. Pediatrics 2005; 115:e16772. First citation in article