Out of 1,276 pregnancies all three iciHHV-6 cases involved preeclampsia or growth restriction.
Preeclampsia (PE) is a major cause of maternal morbidity and mortality in pregnant women. In 2020, a large study (437 cases of PE and 3854 non-PE controls) reported a strong association between PE and fetal inherited chromosomally-integrated HHV-6 (iciHHV-6) (Gaccioli 2020).
A collaboration of several institutions in Finland reports failing to confirm this prior report, in large part because they failed to find iciHHV6 – only three out of 1,276 pregnancies. To examine the issue of prevalence more closely, the investigators looked for evidence of iciHHV-6 in the white cells of 3421 subjects in the Finnish biobank data and found none. This is puzzling since prevalence of iciHHV-6 has been measured at 0.5 to 3% in every other country where it has assessed.
The research team analyzed cord plasma samples from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort: 539 of the samples were from a pregnancy with preeclampsia (PE) and 737 were from pregnancies not complicated by PE. The team also studied placentas from 30 patients with PE.
To assess the presence of herpesvirus DNA in the cord blood plasma and placental samples, the team used a multiplex qPCR to detect the DNAs of all nine human herpesviruses. While “positive controls” were used in each run, it is unclear what the sensitivity of the assay was for detecting each of the herpesviruses, in each of the two different tissues (cord plasma and placenta).
The team also analyzed whole-genome sequencing data from blood-derived DNA of 3421 biobank subjects in Finland, in order to assess the population prevalence of iciHHV-6. It is not stated whether the telomeric regions necessary to identify iciHHV-6 were regularly sequenced.
The investigators were able to detect herpesvirus DNA in only two (0.37%) cases of PE and only one (0.14%) control sample (OR 2.74, 95% CI 0.25–30.4). Thus, while the risk of PE appeared elevated in people with detectable herpesvirus DNA, the increased risk was not statistically significant. At the same time, this study was grossly underpowered to recognize a significant difference, given the relatively small sample size.
One PE sample contained iciHHV-6B (based on a high viral load, rather than sequencing the integration site) and another contained HHV-7 DNA. In the one case with HHV-7 DNA, no viral load measurement is reported even though cases of iciHHV-7 have been reported. The one control (non-PE) sample that contained herpesvirus DNA was determined to be iciHHV-6B (based on a high viral load). However, this “control”—while not being diagnosed as having PE—did have growth restriction and preterm birth, conditions related to preeclampsia: i.e., the “control” might really have been a case.
None of the 30 placentas from mothers with PE were reported to have detectable herpesvirus DNA, in contrast to the previous study in which HHV-6 DNA was detected in 6% of placentas of women with PE.
It is surprising that this study of the Finnish population found so few instances of iciHHV6. It is doubtful that the Finnish population has had so little contact with Northern European populations over the past several hundred thousand years. Indeed, this finding—along with the finding of no herpesvirus DNA in any placenta—raises the question of whether the multiplex herpesvirus assay used was sensitive enough even to detect endogenous virus, let alone exogenous herpesvirus.
While this report concludes that it cannot confirm the findings of the prior report (Gaccioli 2020) it must be pointed out that the prior report, in contrast to this new one:
- Was much larger—large enough to have sufficient power to recognize real differences as being statistically significant;
- Documented the sensitivity of its assay;
- Studied two different large population samples, and found comparable results in both populations;
- Studied offspring and spouses of cases of PE linked to iciHHV-6, including sequencing the chromosomally-integrated virus, and demonstrated that the putative iciHHV-6 in a woman was inherited from a parent and passed on to the child in a Mendelian manner;
- Studied HHV-6 gene expression (using various techniques including RNA-seq), and demonstrated that the integrated virus was transcriptionally active.
In short, this report does not persuasively challenge the conclusions of the previous report.
Read the full text: Häkkinen 2024