Oxidative stress contributes to hypermethylation of Histone H3 lysine 9 in placental trophoblasts from preeclamptic pregnancies.

Background and objective: Aberrant epigenetic regulation and increased oxidative stress in the placenta play a significant role in placental pathophysiology and fetal programming in preeclampsia, a hypertensive disorder in human pregnancy. The purpose of the study is to investigate if hypermethylation of histone H3K9 occurs in placental trophoblasts from preeclampsia. Methods: Trophoblasts were isolated and cultured from 14 placentas, 7 from normotensive pregnant women and 7 from preeclamptic pregnancies. Methylated H3K9 expression and antioxidant superoxide dismutase expression were determined by Western blot. We also examined consequences of oxidative stress and the downstream effects of histone methyltransferase inhibition on H3K9 expression associated with antioxidant CuZn-SOD and Mn-SOD expression in placental trophoblasts. Results: We found that expression of mono-, di-, and tri-methylation of histone H3 lysine 9 (H3K9me1, H3K9me2 and H3K9me3) was significantly increased, p<0.01, which correlated with downregulation of antioxidant superoxide dismutase CuZn-SOD and Mn-SOD expression, in trophoblasts from preeclamptic placentas compared to those from uncomplicated control placentas. We further demonstrated hypoxia could promote histone H3K9 methylation in placental trophoblasts, and hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression was reversible when hypoxic condition was removed. In addition, we also uncovered that inhibition of methyltransferase not only prevented hypoxia-induced upregulation of H3K9me1, H3K9me2 and H3K9me3 expression, but also abolished hypoxia-induced downregulation of CuZn-SOD and Mn-SOD expression in placental trophoblasts. Conclusions: These findings are noteworthy and provide further evidence that increased oxidative stress in the intrauterine environment is likely a mechanism to induce aberrant histone modification in placental trophoblasts in preeclampsia. Moreover, CuZn-SOD and Mn-SOD expression/activity are possibly H3K9 methylation-dependent in placental trophoblasts, which further suggest that oxidative stress and aberrant histone modification have significant impact on placental trophoblasts/fetal programming in preeclampsia.

Eclampsia, HELLP and PRES in a 16-week partial molar pregnancy.

Eclampsia spectrum disorders are a set of serious complications of pregnancy that commonly present after 20 weeks of gestation. There is an association between molar pregnancy, a gestational trophoblastic disease resulting from abnormal fertilisation and gametogenesis, and eclampsia spectrum disorders which can result in manifestation of pre-eclamptic symptomatology earlier than 20 weeks of gestation. We report a case of a gravida 1 para 0 in her mid 20s at 16-weeks gestation presenting with partial hydatidiform mole who developed eclampsia, haemolysis, elevated liver enzymes and low platelets syndrome and posterior reversible encephalopathy syndrome. Ultrasound findings were consistent with molar pregnancy and pathology confirmed partial molar pregnancy with triploid 69, XYY karyotype. This case highlights the early onset potential of eclampsia spectrum disorders in molar pregnancies while suggesting screening such patients for hypertensive disorders.

Safety of Ancestral Monovalent BNT162b2, mRNA-1273, and NVX-CoV2373 COVID-19 Vaccines in US Children Aged 6 Months to 17 Years.

Importance: Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials. Objective: To conduct near-real-time monitoring of health outcomes after COVID-19 vaccination in the US pediatric population. Design, Setting, and Participants: This cohort study evaluated 21 prespecified health outcomes after exposure before early 2023 to BNT162b2, mRNA-1273, or NVX-CoV2373 ancestral monovalent COVID-19 vaccines in children aged 6 months to 17 years by applying a near-real-time monitoring framework using health care data from 3 commercial claims databases in the US (Optum [through April 2023], Carelon Research [through March 2023], and CVS Health [through February 2023]). Increased rates of each outcome after vaccination were compared with annual historical rates from January 1 to December 31, 2019, and January 1 to December 31, 2020, as well as between April 1 and December 31, 2020. Exposure: Receipt of an ancestral monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose identified through administrative claims data linked with Immunization Information Systems data. Main Outcomes and Measures: Twenty-one prespecified health outcomes, of which 15 underwent sequential testing and 6 were only monitored descriptively due to lack of historical rates. Results: Among 4 102 016 vaccinated enrollees aged 6 months to 17 years, 2 058 142 (50.2%) were male and 3 901 370 (95.1%) lived in an urban area. Thirteen of 15 sequentially tested outcomes did not meet the threshold for a statistical signal. Statistical signals were detected for myocarditis or pericarditis after BNT162b2 vaccination in children aged 12 to 17 years and seizure after vaccination with BNT162b2 and mRNA-1273 in children aged 2 to 4 or 5 years. However, in post hoc sensitivity analyses, a statistical signal for seizure was observed only after mRNA-1273 when 2019 background rates were selected; no statistical signal was observed when 2022 rates were selected. Conclusions and Relevance: In this cohort study of pediatric enrollees across 3 commercial health insurance databases, statistical signals detected for myocarditis or pericarditis after BNT162b2 (ages 12-17 years) were consistent with previous reports, and seizures after BNT162b2 (ages 2-4 years) and mRNA-1273 vaccinations (ages 2-5 years) should be further investigated in a robust epidemiologic study with confounding adjustment. The US Food and Drug Administration concludes that the known and potential benefits of COVID-19 vaccination outweigh the known and potential risks of COVID-19 infection.