Late‐onset intrauterine growth restriction and HHV‐6 infection: A pilot study

Abstract

Late-onset Intrauterine growth restriction (IUGR) refers to impaired growth and development of the fetus, characterized by placental morphological abnormalities that affect the fetus's supply of nutrients. Human leukocyte antigen-G (HLA-G) is physiologically expressed during pregnancy, but decreased in normal placenta during the last weeks of gestation possibly inducing childbirth. Several viruses involved in congenital infection, such as herpesviruses, exploit HLA-G expression as an immune-escape mechanism. To date, despite different congenital herpetic infections having been associated with late IUGR, no direct implication of Human herpesvirus 6 (HHV-6) infection has been reported. We evaluated HLA-G expression and HHV-6 infection in 11 placentas from late-onset IUGR newborns and 11 placentas from uncomplicated pregnancies by histopathological and immunohistochemistry analysis. We found higher levels of HLA-G expression and HHV-6 presence in IUGR placenta samples compared with control placenta samples.We report HHV-6 staining in IUGR placenta samples, characterized by high HLA-G expression. These preliminary data suggest a possible involvement of HHV-6 infection in HLA-G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in the IUGR condition.

Pityriasis rosea, human herpesvirus 6 infection and pregnancy

“…[6][7][8][9] The high percentage of newborns (42%) with low weight in relation to their gestational age from women suffering from PR in the early weeks of gestation, should confirm indirectly the finding of Bortolotti et al 1,2 It is plausible that HHV-6 infection of the placental endothelial cells may block different angiogenetic properties by inducing HLA-G molecules expression in endothelial cells and make the endothelial cells themselves insensitive to different vasculogenetic factors. [1][2][3] The final outcome would be endothelial cell dysfunction, inhibition of angiogenesis and inadequate remodeling of the spiral arteries with a reduced flow of maternal blood to the fetoplacental unit resulting in placental insufficiency, IUGR, and pre-eclampsia. 11 Overall, HHV-6 transplacental infection occurs in 1%-2% of pregnancies and may play a role in 43% of cases of primary unexplained infertility.…”

Effect of SARS-CoV-2 infection in pregnancy on CD147, ACE2 and HLA-G expression

“…Since we have previously shown that HLA-G molecules are modulated during SARS-CoV-2 infection in the intestinal villi during thromboembolic events [ [19] , [20] , [21] ], we evaluated HLA-G expression in placenta samples taking into consideration the implication of HLA-G molecules during viral infection in pregnancy [ 18 ].…”

“…HLA-G placenta expression during pregnancy is characterized by peculiar changes, with high levels of the molecules in the first trimester, which are reducing as they approach the birth, in order to promote the typical inflammatory environment needed to induce the delivery [ 17 ]. The presence of placental infections might affect HLA-G expression, leading to placental and fetal disorders, as recently reported for HHV-6 infection in association with IUGR condition [ 18 ].…”

“…The placenta samples were collected after delivery and sent to the Pathology Lab for examination as previously described [ 18 ]. They were initially examined in the unfixed state then the membranes were removed by trimming them along the placental margin and the umbilical cord was removed after recording the length and site of insertion.…”

Gestational exposure to unmethylated CpG oligonucleotides dysregulates placental molecular clock network and fetoplacental growth dynamics, and disrupts maternal blood pressure circadian rhythms in rats

“…As a result, pregnant women show greater susceptibility and worse clinical outcomes in response to bacterial and viral infections, such as Listeria monocytogenes and COVID19, compared to age-matched non-pregnant women (2)(3)(4)(5). Moreover, infections and dysregulation of the immune system during pregnancy are associated with adverse cardioobstetric outcomes such as gestational hypertension and preeclampsia, as well as other obstetric complications including preterm birth, intrauterine growth restriction, and stillbirth (2,(6)(7)(8)(9). Unmethylated cytosine-phosphodiester-guanine (CpG) motifs are potent triggers of host immune responses via stimulation of toll-like receptor 9 (TLR9), which is a pattern recognition receptor of the innate immune system (10)(11)(12)(13).…”