Maternal infection of SARS-CoV-2 during the first and second trimesters leads to newborn telomere shortening

Abstract

Background: Initial telomere length (TL) in newborns is the major determinant for TL in later life while TL in newborn/early-life predicts long-term health and lifespan. It is important to identify key factors that affect telomere homeostasis throughout embryonic development for precision interventions to maintain optimal TL in fetus/prenatal infants. SARS-CoV-2 has caused a widespread global pandemic of COVID-19, but it remains unclear whether maternal SARS-CoV-2 infection impairs prenatal telomere homeostasis.

Methods: We recruited 413 normally delivered newborns whose mothers were either non-infected or infected with SARS-CoV-2 during different trimesters of pregnancy (otherwise healthy). Telomere length (TL) in cord blood (CB) was assessed using qPCR. CB and maternal blood were analyzed for cytokine levels. Placental senescence was determined using senescence-associated β-galactosidase staining.

Results: Control (non-infected maternal) newborn TL was significantly longer than that from maternal infection (1.568 ± 0.340 vs 1.390 ± 0.350, P = 0.005). Such shorter TL was observed only if maternal infection of SARS-CoV-2 occurred in the first and second trimesters of pregnancy (1.261 ± 0.340 and 1.346 ± 0.353, P < 0.0001 and 0.001, respectively). There were no differences in TL between controls and infection at the third trimester (1.568 ± 0.340 vs 1.565 ± 0.329, P > 0.05). Across the first trimester, there was a positive correlation between newborn TL and gestational weeks with maternal infection, suggesting that the earlier maternal infection occurs, the worse effect is taken on fetal telomere homeostasis. Placental senescence coupled with the downregulated expression of telomerase reverse transcriptase was significantly more frequent from the maternal infection at the first trimester. There were no differences in IL-6, C reactive protein and other cytokine levels in CB and maternal serum or placentas.

Conclusions: Maternal SARS-CoV-2 infection at the first and second trimesters leads to significantly shorter TL and earlier infection causes much more severe TL damage. The infection-mediated cell senescence and other histopathological abnormalities result in defective placental function through which fetal telomere homeostasis is impaired. Thus, vaccination against COVID-19 should be done in advance for women who plan pregnancy.

Keywords: Maternal infection; Newborns; Placental senescence; SARS-CoV-2; Telomere length.

Fig. 1

Maternal SARS-CoV-2 infection in the first and second trimester causes telomere length (TL) shortening in newborns. Newborn TL in cord blood cells were assessed using qPCR. A Significantly shorter TL in newborns from maternal SARS-CoV-2 infection. B TL shortening in newborns from maternal infection in the first and second but not third trimester. C A positive correlation between newborn TL and gestational age of infection in the first trimester. Gestational age^a, gestational age when maternal infection occurs. D An inverse correlation between newborn TL and time interval from infection in the first trimester to delivery. Time interval^b, time interval from infection to delivery. E, F No association between newborn TL shortening and COVID-19 severity in all newborns (E) or infection in the first trimester (F). NS, not significant. *, **, *** and ****, P < 0.05, 0.01, 0.001 and 0.0001, respectively

Fig. 2

Differences or correlation of newborn TL with neonate sex, weight, gestational age and maternal BMI. A Significantly longer TL in female newborns than male ones. B Lack of correlation between newborn TL and weight. C No correlation between newborn TL and gestational age. D No correlation between newborn TL and maternal age. E, F No correlation between newborn TL and pre-pregnant or pre-delivery BMI. **, P < 0.01

Fig. 3

Expression of inflammatory factors and cytokines in serum from maternal blood and cord blood, or placentas. CRP and IL-6 protein levels in serum were assessed using ELISA. A No differences in serum CRP and IL-6 levels among groups without and with maternal SARS-CoV-2 infection in different trimesters. NS, not significant. B No differences in cord blood CRP and IL-6 levels among newborn groups without and with maternal SARS-CoV-2 infection in different trimesters. For CRP and IL-6, detectable threshold levels were 0.5 mg/L and 7 pg/L, respectively. C No differences in IFNA, IFNB, MXA, IFIT, IL-6 and IL-1B expression between placentas without and with maternal SARS-CoV-2 infection. The assessment was done using qPCR. IFNA and IFNB, Interferon A and B; MXA, Myxovirus-resistant protein 1; Interferon induced protein with tetratricopeptide repeats, IFIT; Interleukin 1 beta (IL-1B)

Fig. 4

Placental senescence and TERT downregulation mediated by maternal SARS-CoV-2 infection in the first trimester. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to assess placental senescence from different groups. TERT and TERC expressions were determined using qRT-PCR. A Representative images from the non-infected (Top) and infected (Bottom) placentas. B Quantification of positive SA-β-Gal staining cells. C TERT mRNA levels in the placentas from non-infected women and those infected at different trimesters, as determined using qRT-PCR. D TERC RNA levels in the placentas from non-infected women and those infected at different trimesters, as determined using qRT-PCR. *, ** and ***, P < 0.05, 0.01 and 0.001, respectively. ns, not significant