Fetal iciHHV-6 associated with a 3-fold increased risk of preeclampsia

A large UK study utilizing RNA sequencing metagenomics of placental tissue samples identified HHV-6 RNA in 6.1% of pre-eclampsia cases and 2.2% of healthy pregnancies, with iciHHV-6 representing the majority of these positive cases.

Upon analyzing umbilical cord DNA samples from over 1,000 pre-eclampsia cases and several thousand controls, iciHHV-6 was also found to be significantly more prevalent in newborns of mothers who experienced pre-eclampsia. Together, these results suggest that regardless of a mother’s iciHHV-6 status, iciHHV-6 positivity in her fetus might put her at risk for pre-eclampsia.

In analyzing RNA sequencing datasets of placental samples from 99 cases of pre-eclampsia, 48 cases of fetal growth restriction, and 132 controls, HHV-6, detected in 10 cases, emerged as the only clear viral signal. Of the 10 positive placental samples, 6 were from pre-eclampsia cases, 1 was from a case of fetal growth restriction, and 3 were from healthy pregnancies.

Once the 10 cases had been identified, the investigators utilized qPCR to detect viral DNA in both the placental samples as well as in parental DNA samples isolated from whole blood or saliva. Of these, 7 placentas and a corresponding parental DNA sample were strongly positive for HHV-6 DNA, which was indicative of chromosomal integration in each child/parent pair. Integration was confirmed by analyzing informative single nucleotide polymorphisms, and in one parent/offspring pair, by identifying the iciHHV-6B integration site at 4p16.3. In total, 2 cases of iciHHV-6A were identified, and the majority of the positive samples, 5 in all, were iciHHV-6B. Chromosomally integrated virus was transmitted by the father in 4/10 cases (2 healthy pregnancies, 2 pre-eclampsia cases).

Next, the team analyzed umbilical cord DNA samples that had not been included in the initial RNA-seq and found an iciHHV-6 prevalence of 2.1% (10/467) among children with mothers who had pre-eclampsia and 0.8% (30/3,854) among those without the condition (p=0.008). Fetal inheritance of iciHHV-6 was associated with a threefold increased risk of pre-eclampsia (OR 2.8, CI 1.4-5.6, p=0.008). Genotyping of cord blood DNA samples was also performed with a separate group of 740 cases of pre-eclampsia, and in this cohort, 1.6% of children were iciHHV-6. Compared to a control prevalence of 0.7%, which was determined based on meta-analysis of other large-scale population-based studies of iciHHV-6, this represented a 2-3 fold higher risk of pre-eclampsia associated with iciHHV-6.

The authors note that the association between HHV-6 and pre-eclampsia risk found in three study groups makes a strong case for a link between viral integration in a fetus and the risk of developing pre-eclampsia in a mother, while also providing evidence against an association between the condition and any other viral agents.

Notably, of the 10 RNA-positive placental samples, 3 were not found to be associated with chromosomal integration of the virus, but rather with community strains. This may indicate viral reactivation in the mother affecting the placenta. All three of these samples were from women with pre-eclampsia.

Moreover, all cases of iciHHV-6A (2) and HHV-6A (2) placental positivity were associated with pregnancies characterized either by fetal growth restriction or pre-eclampsia- no (ici)HHV-6A RNA was detected in placentas from healthy pregnancies. Continued typing of HHV-6 species in studies such as this is integral to understanding the differences in pathogenicity between the species as well as providing a clearer perspective on the epidemiology of HHV-6A. HHV-6A has previously been implicated in idiopathic female infertility, having been found in the endometrial tissue of about 40% of women with the condition (Coulam 2018).

Inherited chromosomally integrated HHV-6 has also been associated with increased risk of angina (Gravel 2015), and women with preeclampsia are also pre-disposed to the development of heart disease. Reactivation of HHV-6 & 7 during pityriasis rosea also has an unfavorable impact on the fetus, if it occurs during the first 15 weeks (Drago 2018).

The results of the present study lend further support to the potential for HHV-6 to trigger dysfunction in the female reproductive system. The timing of active HHV-6 infections across the course of a pregnancy, as well as the location and extent of viral activity, may lead to different outcomes. For instance, a 2016 case report documented reactivation of iciHHV-6B, presumed to be a result of progesterone administration during pregnancy, in a newborn with dilated cardiomyopathy who died shortly after birth (Das 2016). As the placenta is not a barrier to drugs, knowing the iciHHV-6 status of a fetus, even in mothers without iciHHV-6, may be a relevant factor in choosing whether to administer certain drugs that can reactivate the virus during pregnancy.

Find the full paper here: Gaccioli 2020.