Human Herpesviruses-6A/6B linked to important reproductive diseases

A review from the Departments of Medicine and Obstetrics/Gynecology at Harvard Medical School and the University of Ferrara, Italy, summarizes evidence linking HHV6-A/B to several important reproductive diseases: primary unexplained infertility, preeclampsia, congenital infection and, possibly, spontaneous abortion and intrauterine growth restriction. 

Primary Unexplained Infertility

HHV-6A (not -6B) DNA was found in endometrial epithelial cells of 43% of women with primary unexplained infertility (n=30) and none of the fertile controls (n=36) (p=0.00001) (Marci 2016).

The mechanisms by which HHV-6A infection may cause some cases of primary unexplained infertility involve impairment of implantation of the placenta into the wall of the uterus during pregnancy. Successful implantation requires minimizing maternal immune responses against paternal antigens in the fetus, and the establishment of successful connections between the maternal circulation and the placental circulation. There are several established biomarkers of successful implantation.

HHV-6A infects and activates endometrial NK cells (Rizzo 2017), which generates a group of pro-inflammatory miRNAs (Pegoraro 2020). The virus also infects trophoblast cells—placental cells that implant into the endometrium (Bortolotti 2020)—as well as endometrial epithelial cells. Finally, the virus also can infect endothelial cells, thereby potentially affecting angiogenesis and implantation.

 Preeclampsia (PE)

A non-targeted study looking for viral RNA/DNA content in placental samples from 99 positive cases of PE found evidence of only two viruses: HHV-6A/B (Gacciolio 2020). 70% of positive cases involved inherited (iciHHV-6A/6B), and in 70% of these cases of iciHHV-6A/B the source was the father.

The investigators then compared iciHHV-6B/6A content in cord blood DNA of 368 pregnancies complicated by PE and 3,674 pregnancies without PE. iciHHV-6A/B was found in 2.1% of PE cases vs 0.8% of controls (OR 2.8, p=0.008), a significant difference (Gacciolio 2020). A similar comparison done on 743 new cases of PE vs. a large scale population study (n=61,549) also reveal incidence iciHHV-6A/6B to be 1.6% and 0.7% in PE cases and controls, respectively (OR 2.5, P=0.001) (Gacciolio 2020). This study assessed tissue obtained at term, and not earlier in the pregnancy (when infection may be more active). Thus, the study may have underestimated the fraction of cases of PE that is associated with iciHHV6A/6B.

Congenital Infection

Congenital HHV-6A/B infection can occur in 3 ways:

  1. iciHHV-6A/B integration into infant genome because of inheritance (~86% of cases)
  2. iciHHV-6A/B produce virions that are passed through the placenta (~10% of cases
  3. Acquired HHV-6A/B (not inherited) passed through the placenta (~4% of cases) (Hall 2010, Hall 2008)

 While 1-2% of neonates has congenital HHV-6A/B, it is unclear whether infection affects the health of the baby or mother. One study found that children with infection passed through the placenta have low scores on the Bayley Scale of Infant Development MDI instrument (Caserta 2014). However, more studies on development and health outcomes for this population are warranted.

Spontaneous Abortion

A meta-analysis concluded that, when compared to a control group (n=285), women with ici-HHV-6A/B (n=23) were nearly 6.5x more likely to undergo a spontaneous abortion (OR 6.41, 95% CI 1.10-37.4) (Miura 2021). It is logical to conclude that iciHHV-6A/B may increase the probability of intrauterine growth retardation, another mechanism worth investigating. Since the mechanisms of spontaneous abortion are thought to be similar to (just more severe than) the mechanisms of intrauterine growth restriction, it is possible that HHV-6A/B are linked to some cases of these reproductive illnesses, as well.

Read the full article: Komaroff 2021