Vertical transmission of SARS-CoV-2 - data from the German COVID-19 related obstetric and neonatal outcome study (CRONOS).

OBJECTIVES: We aimed to determine the frequency of SARS-CoV-2 positivity in newborns born to mothers with peripartum SARS-CoV-2 infection in a German cohort, to identify potential risk factors associated with neonatal SARS-CoV-2 infection, and to present short-term outcomes of newborns with vertical transmission of SARS-CoV-2. METHODS: Data on women with SARS-CoV-2 infection occurring anytime during their pregnancy was gathered prospectively within the CRONOS registry. From April 2020 to February 2023 a total of 8,540 women had been registered. The timing and the probability of mother-to-child transmission in neonates born to women with perinatal SARS-CoV-2 infection were classified using the WHO classification system. The severity of maternal infection, maternal vaccination status, type of dominant virus, and perinatal outcome parameters were analyzed as potential risk factors for neonatal SARS-CoV-2 infection. RESULTS: 6.3 % resp. 42.9 % of tested newborns and stillbirths were SARS-CoV-2 positive. 2.1 % of newborns with confirmed and possible SARS-CoV-2 infection were identified. Severe maternal COVID-19 (odds ratio 4.4, 95 % confidence interval 1.8-11.1) and maternal infection with the Delta virus (OR 3.2, 1.4-7.7) were associated with neonatal SARS-CoV-2 infection. Newborns with a confirmed or possible infection were significantly more often admitted to the NICU (65.2 % neonatal infection vs. 27.5 % non, p<0.001). CONCLUSIONS: The rate of neonatal SARS-CoV-2 positivity was higher in our cohort than previously reported, neonatal SARS-CoV-2 infections were rare. Our data emphasizes confirmative testing should be performed in newborns of SARS-CoV-2 infected mothers to identify neonatal SARS-CoV-2 infection as an underlying pathology leading to NICU admission.

Antenatal Ureaplasma Infection Causes Colonic Mucus Barrier Defects: Implications for Intestinal Pathologies.

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development.

Long-Term Outcome of Neonates and Infants whose Mothers Tested Positive for SARS-CoV-2 during Pregnancy - a Pilot of the Post-CRONOS Project.

OBJECTIVE: Long-term effects on infants of mothers with SARS-CoV-2 infection during pregnancy are increasingly discussed in the literature. Besides potential neurodevelopment impairments after intrauterine SARS-CoV-2 exposure, there might be differences in the postnatal pediatric care of those children, like the timing of preventive medical examinations (PME) or vaccinations. In this first national long-term follow-up study of women included in the CRONOS registry, we describe maternal impressions of their child´s development and the prevalence of regulatory disorders, and we analyze the timing of PMEs and vaccinations. METHODS: 773 women who were enrolled between April 3, 2020, and August 24, 2021, in the CRONOS registry were eligible to be contacted by the study coordinators and asked to fill out a web-based questionnaire. RESULTS: 110/773 (14%) women completed the questionnaire. Their children were between the ages of 12 and 31 months (median 20 months). All mothers were satisfied with their child´s development, milestones were achieved in a timely fashion. The reported prevalence for excessive crying, sleeping, and feeding disorders was 11%, 18-32%, and 7%, respectively. PMEs were mostly not delayed, but only 54% of infants received their first vaccination within their first 60 days of life. DISCUSSION: In summary, our exploratory findings suggest that developmental milestones in infancy are reached in time after maternal SARS-CoV-2 infection during pregnancy. However, there are effects on the implementation of PMEs and vaccinations. EINFüHRUNG: In der Literatur werden zunehmend potenzielle Langzeitfolgen für Säuglinge nach intrauteriner SARS-CoV-2-Exposition diskutiert. Neben möglichen Beeinträchtigungen der neurologischen Entwicklung können Unterschiede in der pädiatrischen postnatalen Betreuung bei diesen Kindern z. B. bei der Durchführung von Vorsorgeuntersuchungen (sog. U´s) oder Impfungen bestehen. In dieser ersten nationalen Langzeit-Follow-up-Studie aus dem CRONOS-Register beschreiben wir mütterliche Eindrücke zur Entwicklung ihres Kindes, sowie die Prävalenz von Regulationsstörungen. Wir analysieren den Zeitpunkt von U´s und Impfungen. METHODEN: 773 Frauen, die zwischen dem 03.04.2020 und dem 24.08.2021 in CRONOS aufgenommen wurden, wurden von den Studienkoordinatoren kontaktiert und gebeten, einen webbasierten Fragebogen auszufüllen. ERGEBNISSE: 110/773 (14%) Frauen füllten den Fragebogen aus, ihre Kinder waren zwischen 12 und 31 Monate alt (Median 20 Monate). Alle Mütter waren mit der Entwicklung ihres Kindes zufrieden, Meilensteine der Entwicklung wurden zeitgerecht erreicht. Die berichtete Prävalenz für exzessives Schreien, Schlaf- und Fütterstörungen betrug 11%, 18-32% bzw. 7%. U´s wurden meist zeitgerecht durchgeführt, aber nur 54% der Säuglinge erhielten ihre erste Impfung innerhalb der ersten 60 Lebenstage. DISKUSSION: Zusammenfassend deuten unsere explorativen Ergebnisse darauf hin, dass Entwicklungsmeilensteine im Säuglingsalter nach mütterlicher SARS-CoV-2-Infektion in der Schwangerschaft rechtzeitig erreicht werden. Es zeigen sich jedoch Auswirkungen auf die Durchführung von Vorsorgen und Impfungen.

Post-COVID in women after SARS-CoV-2 infection during pregnancy - a pilot study with follow-up data from the COVID-19-related Obstetric and Neonatal Outcome Study (CRONOS).

BACKGROUND: Pregnant women are at an increased risk of severe COVID-19 and adverse pregnancy outcomes; data on maternal long-term outcome is scarce. We analyzed long-term follow-ups on women who experienced a SARS-CoV-2 infection during pregnancy to evaluate post-COVID symptoms, particularly fatigue, and their association with quality of life (QoL). METHODS: 773 women who enrolled in the CRONOS registry between April 2020 and August 2021 were contacted for follow-up from December 2022 to April 2023. Data was gathered through a web-based questionnaire. Subsequently, study coordinators matched the follow-up data with the existing CRONOS data. RESULTS: 110/773 (14%) women provided data. 20.9% experienced only acute symptoms during their SARS-CoV-2 infection in pregnancy, while 2.7% women experienced symptoms lasting longer than 4 weeks (long COVID). Symptoms lasting longer than 12 weeks (post-COVID) were reported by 63.6% women and occurred more often after severe COVID-19. Fatigue was the most frequently reported symptom (88%), with 55% of women still experiencing it more than one year after initial infection. 76% of women rated their QoL as "good" or "very good". Women experiencing post-COVID reported a significantly lower QoL. CONCLUSION: This is the first German long-term data on women after SARS-CoV-2 infection during pregnancy, showing a high rate of post-COVID, a persistence of fatigue, and the impact on QoL. Continuous monitoring of pregnant women with COVID-19 is needed to develop comprehensive management strategies.

Optimized lung expansion ventilation modulates ventilation-induced lung injury in preterm lambs.

INTRODUCTION: Preterm infants close to viability commonly require mechanical ventilation (MV) for respiratory distress syndrome. Despite commonly used lung-sparing ventilation techniques, rapid lung expansion during MV induces lung injury, a risk factor for bronchopulmonary dysplasia. This study investigates whether ventilation with optimized lung expansion is feasible and whether it can further minimize lung injury. Therefore, optimized lung expansion ventilation (OLEV) was compared to conventional volume targeted ventilation. METHODS: Twenty preterm lambs were surgically delivered after 132 days of gestation. Nine animals were randomized to receive OLEV for 24 h, and seven received standard MV. Four unventilated animals served as controls (NV). Lungs were sampled for histological analysis at the end of the experimental period. RESULTS: Ventilation with OLEV was feasible, resulting in a significantly higher mean ventilation pressure (0.7-1.3 mbar). Temporary differences in oxygenation between OLEV and MV did not reach clinically relevant levels. Ventilation in general tended to result in higher lung injury scores compared to NV, without differences between OLEV and MV. While pro-inflammatory tumor necrosis factor-α messenger RNA (mRNA) levels increased in both ventilation groups compared to NV, only animals in the MV group showed a higher number of CD45-positive cells in the lung. In contrast, mean (standard deviations) surfactant protein-B mRNA levels were significantly lower in OLEV, 0.63 (0.38) compared to NV 1.03 (0.32) (p = .023, one-way analysis of variance). CONCLUSION: In conclusion, a small reduction in pulmonary inflammation after 24 h of support with OLEV suggests potential to reduce preterm lung injury.

Multipotent adult progenitor cells prevent functional impairment and improve development in inflammation driven detriment of preterm ovine lungs.

Background: Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcomes following perinatal inflammation and pulmonary benefits of MAPC treatment at the interface of prenatal inflammatory and postnatal ventilation exposures were elucidated. Methods: Instrumented ovine fetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation to induce adverse systemic and peripheral organ outcomes. MAPC (10 × 106 cells) or saline were administered intravenously two days post LPS exposure. Fetuses were delivered preterm five days post MAPC treatment and either killed humanely immediately or mechanically ventilated for 72 h. Results: Antenatal LPS exposure resulted in inflammation and decreased alveolar maturation in the preterm lung. Additionally, LPS-exposed ventilated lambs showed continued pulmonary inflammation and cell junction loss accompanied by pulmonary edema, ultimately resulting in higher oxygen demand. MAPC therapy modulated lung inflammation, prevented loss of epithelial and endothelial barriers and improved lung maturation in utero. These MAPC-driven improvements remained evident postnatally, and prevented concomitant pulmonary edema and functional loss. Conclusion: In conclusion, prenatal inflammation sensitizes the underdeveloped preterm lung to subsequent postnatal inflammation, resulting in injury, disturbed development and functional impairment. MAPC therapy partially prevents these changes and is therefore a promising approach for preterm infants to prevent adverse pulmonary outcomes.