The newborn immune system is characterized by an impaired Th1-associated immune response. Hepatitis B virus (HBV) transmitted from infected mothers to newborns is thought to exploit the newborns’ immune system immaturity by inducing a state of immune tolerance that facilitates HBV persistence. Contrary to this hypothesis, we demonstrate here that HBV exposure in utero triggers a state of trained immunity, characterized by innate immune cell maturation and Th1 development, which in turn enhances the ability of cord blood immune cells to respond to bacterial infection in vitro. These training effects are associated with an alteration of the cytokine environment characterized by low IL-10 and, in most cases, high IL-12p40 and IFN-α2. Our data uncover a potentially symbiotic relationship between HBV and its natural host, and highlight the plasticity of the fetal immune system following viral exposure in utero.

Objectives: The IGF system is central to fetal growth. Recently, the relationships between cytokines and the IGF system have been shown in specific tissues. It is unknown whether these occur in the placenta. The aim of this study was to assess whether interleukin-6 (IL-6) modulated the IGF system. Methods: Whole villous tissue and cord serum were collected from fetal growth restriction (FGR) neonates diagnosed before birth with altered Doppler velocimetry and controls. Sixteen FGR and 20 controls, born after week 32 of gestation from elective Caesarean sections, were compared. Total RNA was extracted from the placenta samples, reverse transcribed, and real-time quantitative reverse transcriptase (RT)-PCR was performed to quantify cDNA for IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-2, and IL-6. The same proteins were assayed in placenta lysates and cord serum using specific commercial kits and western immunoblotting. Results: FGR subjects had significantly more IGFBPs-1 and -2, and IL-6 mRNA and corresponding proteins in the placenta. In particular, the less phosphorylated isoforms of IGFBP-1 were highly increased. IL-6 and IGFBPs-2 mRNA, and IL-6 and IGFBP-1 peptides were positively and significantly correlated in the placenta. The IGF-II peptide was also significantly increased in FGR placentas. In cord serum, IGFBPs-1 and -2 were significantly more elevated in the FGR neonates. Serum IL-6 was significantly and positively correlated with both IGFBP-1 and IGFBP-2. Conclusions: The placenta of FGR neonates has higher IGF-II, IGFBP-1, IGFBP-2, and IL-6 contents compared with controls. At birth, IGFBPs-1 and -2 are increased in the cord blood of FGR neonates. IL-6 and IGFBP-2 gene expressions are closely related in the placenta. We suggest that the increase in IL-6 and IGFBP-2 could be subsequent to hypoxia and nutrient deficiency. As IGFBP-2 has a strong affinity for IGF-II, which is crucial for fetal growth, it could be an important bioregulator of IGF-II in the placenta.European Journal of Endocrinology 155 567-574

ObjectivesTo evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19.MethodsSecondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI).ResultsMean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8–0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09–1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3–7.9; p=0.001) were independently associated with composite adverse fetal outcome.ConclusionsEarly gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

Despite the increasing number of published studies, objective evidence is still needed to draw any conclusion on the course of SARS-COV-2 infection acquired during pregnancy. What are the clinical implications of this work? The study showed that in pregnancies complicated by SARS-COV-2, the risk of maternal mortality was 0.8%, but about 11% of women required admission to ICU. Pregnancies affected by SARS-COV-2 were also complicated by 23% rate preterm birth, and 4.1% rate of perinatal death. The risk of vertical transmission was negligible.

Our study shows that cervical length is comparable in nulliparous and multiparous women throughout pregnancy. In both groups, it actually shows a progressive, linear reduction between the 10th and 40th weeks. Reference ranges constructed for the whole gestational period might be more useful than a single cut-off value for more efficient prevention and management of preterm birth.