Determination of the Effects of Prenatal Remdesivir Exposure on Placenta Morphology, Placental IgG Transfer, and Fetal Growth in a Humanized Mouse Model

Remdesivir (RDV) is an antiviral medication used most recently for the treatment of COVID-19. Although no adverse effects were observed on perinatal parameters in reproductive and development toxicology studies at doses up to four-fold clinical area under the curve (AUC) exposures, some researchers have reported that therapeutic levels of RDV may impair early embryogenesis, as observed by in vitro studies. In addition, the influence of prenatal RDV exposure on maternal IgG transfer in the placenta is still unknown. Administration of RDV in pregnant humanized mouse model (Tg32), which expresses the human Fc gamma receptor and transporter (FCGRT) gene, was used to further evaluate potential effects on IgG transfer and concurrent perinatal endpoints. Animals were dosed daily from gestational days (GDs) 10- 14 with 25 mg/kg RDV (GS-5734) via intravenous injection (n=3-5 per group). Concurrent vehicle control animals were dosed intravenously with 12% sulfobutyl ether- beta-cyclodextrin in water (pH3.5;NaOH/HCl). All animals were administered 2 mg/kg human IgG via intravenous injection on GD 14. Placentae and fetuses were collected from dams on GD 14, 15, 16, and 18 and evaluated using histopathology and qPCR for inflammation markers. No abnormal morphologies (necrosis/apoptosis) of placentae were observed between the concurrent control and RDVdosed groups. Additionally, no differences in maternal body weights were observed. There were no statistically significant differences in placenta weights. There were no statistically significant changes in pregnancy parameters (implantation sites and dead fetuses/litter) and fetal weights between the RDV-dosed group and concurrent controls at GD 14, 15, 16, and 18. No changes were observed in transcript levels of inflammation markers in the RDV-dosed group when compared to the concurrent control group. There was a slightly lower ratio of fetal IgG level to maternal IgG levels in the RDV-dosed group;however, no statistically significant differences were observed between the RDV-dosed group and concurrent controls on GD 14, 15, 16, and 18. Our results suggest that a daily dose of 25 mg/kg RDV on GDs 10-14 in humanized mice did not cause adverse effects on placenta and fetal development. (Funded by the Perinatal Health Center of Excellence: E0300201.).

SARS-CoV-2 infection with mild symptoms during pregnancy and fetal outcome, experience of an Italian second level hospital

Objective. COVID-19 is a pandemic inflammatory disease where endothelial dysfunction, observed also in mildly symptomatic patients, could affect the placenta and compromise pregnancy outcome. Our aim was to study the pregnancy outcome of patients with previous SARS-CoV-2 infection contracted during gestation. Materials and Methods. This is a retrospective study and patients were enrolled with an anamnestic interview during the puerperium. We enrolled 41 women who contracted SARSCoV- 2 infection before twenty-four weeks of gestational age;87 who contracted the infection after twenty-four weeks of gestational age;and a control group of 159 women, who did not contract infection during pregnancy. Results. Maternal anthropometric, anamnestic and obstetric features were similar in the three groups. There is no relevant difference between the results of the three categories examined in terms of gestational age at delivery (273.54 days vs 273.73 days vs 274.39 days, p = 0.84), mode of delivery (vaginal delivery 53.66% vs 58.62 % vs 58.49 %;operative vaginal delivery 5.88% vs 9.19% vs 8.80%;cesarean section 41.46% vs 32.18 % vs 32.71 %;p = 0.49), fetal weight at birth (3224.02 g vs 3276.65 g vs 3235.57 g, p = 0.75) admission in neonatal intensive care (0 % vs 2.2 % vs 4.4%, p = 0.30). Conclusions. The SARS-CoV-2 disease with mild symptomatology, contracted during pregnancy, regardless of the gestational age at the time of infection, does not apparently impact on the fetal outcome in any significant way.

COVID-19 in pregnancy may significantly affect fetal growth

Objective. Whilst most cases of COVID-19 in pregnancy evolve uneventfully, some others have a poor outcome, such as preterm birth and HDP. The effect of COVID-19 on fetal growth still has to be addressed and appears controversial. Our study aims to focus on fetal growth velocity across the trimesters in pregnancy affected with COVID-19. Materials and Methods. This is a multicentric prospective observational study on data from COVID-19 pregnancies referred to the centers of Careggi University Hospital and S. Stefano Hospital in Prato from 2020 to 2022, included in the local branch of ItOSS surveillance. Fetal growth was evaluated across the three trimesters of pregnancy by abdominal circumference (AC) and expected fetal weight (EFW). Both AC, and EFW plus birthweight were used to calculate growth velocity (Vannuccini et al., 2017). Results. Data from a cohort of 211 cases was collected. The majority (80%) of COVID-19 cases occurred in the third trimester. Of note, the percentage of gestational diabetes (12.3%) and preterm births (7.1%) was comparable to the general population. Mean birthweight was 3259 +/- 509 g. The percentage of cesarean sections was acceptable (13.7%). Concerning the velocity of growth, AC decreased from the second to third trimester to reach values < 10th centile in 24% of cases and < 5th percentile in 17% of cases, even in presence of 2% of hypertensive disorders (HDP). Fetal growth restriction according to Gordjin et al. (2015) was antenatally identified in 4.7% of cases. Fetal growth > 95th centile occurred in 5.7% of cases. At birth, the cumulative percentage of small for gestational age newborns defined as birth weight < 2500 g resulted 5.2%. A significant percentage of newborns required NICU assistance (7.8%). Conclusions. Regardless of the association and prevalence of preterm birth, SGA and HDP in pregnant women, fetal growth appears to be affected by COVID-19 with a higher incidence of impaired growth velocity compared to the general population.

Features and outcomes of adolescent deliveries during COVID-19 pandemic - a bicentric study

Introduction: adolescent pregnancies represent a global public health problem associated with multiple consequences on the well-being of young mothers, their babies and general population. The biggest prevalence of adolescent pregnancies in Europe can be found in southeastern countries. Objective(s): to analyze the features and outcomes of adolescent deliveries during the COVID-19 pandemic. Material(s) and Method(s): retrospective, descriptive study of adolescent mothers delivered in the period 01.01.2020-31.12.2021 in two university medical centers: the Emergency Clinical County Hospital of Arad (Romania), and Clinic of Gynecology and Obstetrics of University Clinical Center of Vojvodina (Serbia). Demographic and anthropometric parameters of adolescent mothers, number and way of delivery, birth weight and Apgar score of neonate, COVID-19 status and data about pathologies and complications associated with pregnancy and delivery were collected from medical records and analyzed statistically using IBM SPSS. Result(s): there were total of 458 adolescent mothers, aged between 12 and 17 (average 16.07+/-1.07 year). From urban environment there were 182 (60.3%) cases and from rural 276 (39.7%) cases. Number of previous pregnancies and births ranged from 0-3, with majority of mothers being primiparas (76.2%). Cesarean section was performed in 40.8%, vaginal birth in 59.2%. The most common indications for cesarean section were maternal-pelvic disproportion, transverse lie or deflected cephalic presentation, twin pregnancies, severe fetal distress, preeclampsia, scarred uterus with risk of rupture and premature placental abruption. The average fetal weight at birth was 3010.22g ranging from 860 to 4500 g. The average Apgar score was 8.73. There were 9.66% of premature labors. There were 9 (2%) positive COVID-19 cases at birth and additional 4 (0.9%) cases who had COVID-19 during pregnancy. We observed a very high percentage (73.86%) of pregnancies without adequate prenatal care. Conclusion(s): Adolescent mothers are prone to develop complications compared to general population. The COVID-19 pandemic might have additional negative influence on the addressability of underage mothers to medical care, this phenomenon being the basis of most complications during pregnancy. Effective interventions, better sexual education and social programs are needed to reduce the number of adolescent mothers and to help them get a much better social reinsertion and an increase in the general quality of life.Copyright © 2023

MATERNAL SARS-COV-2 INFECTION IN THE SECOND TRIMESTER AND VENTRICULOMEGALY AND DEVELOPMENTAL DELAY IN AN INFANT

Case Report History: Mother is a 23 year old gravida 4 para 1021, with a history of type 1 diabetes since 12 years of age. Prenatal sonogram at 20 weeks of gestation showed normal fetal anatomy with an EFW 21st percentile & 2-vessel cord. She was admitted at 23 weeks of gestation for acute hypoxic respiratory failure secondary to SARS-CoV-2 pneumonia, diabetic ketoacidosis & acute kidney failure. She refused intubation in spite of saturations in low 80s & was treated with high flow nasal cannula, non-rebreather mask, & nasal CPAP. She received convalescent plasma, Remdesivir, Tocilizumab, steroids, hydroxychloroquine, ceftriaxone & azithromycin, and was discharged home on oxygen after 29 days. Prenatal sonogram at 29 weeks of gestation demonstrated severe IUGR (abdominal & head circumference, fetal weight and femur length all < 3rd percentile), ventriculomegaly & a 2-vessel cord. Fetal MRI showed severe lateral ventriculomegaly of the brain, diffuse white matter parenchymal edema, bilateral germinal matrix & intraventricular hemorrhage & severe parenchymal volume loss. Mother was lost to follow up until time of delivery. Physical examination An infant female was born at 39 weeks of gestation via repeat cesarean-section. She was admitted to NICU for severe IUGR. The newborn's birth weight was 2126 g, head circumference 30 cm, length 43.5 cm (all <3rd percentile). Baby had mild hypertonia and tremors, rest of the exam was normal. The newborn was treated for TTN with NCPAP, hypoglycemia requiring IVF and hyperbilirubinemia requiring phototherapy and was extremely slow to feed. Diagnostic work-up CBC, BMP, LFT & CSF microscopy were normal, SARS-CoV-2 PCR was negative. SARS-CoV-2 IgM was negative in serum & CSF, but IgG was positive in serum & CSF. Baby's titers were slightly higher than mother's. US & MRI confirmed ventriculomegaly due to volume loss, a component of hydrocephalus was suspected due to presence of intraventricular hemorrhage, however there was no evidence of raised ICP. Retinal exam, hearing and BAER were normal. Chromosome analysis was normal & Zika titers were negative. The newborn was discharged home after 20 days with weighing 2580 g and head circumference of 32 cm. Placental was 222 g with <10% infarction and moderate acute chorioamnionitis. Infant has significant developmental delay at 1 year of age. Discussion There is definitive evidence of adverse neonatal outcomes in third trimester maternal SARS-CoV-2 infection, effects of earlier infections are not well reported. In our case the neurological injury can't be attributed definitively to fetal SARS-CoV-2 infection as IgM was negative, but the interval of 16 weeks between maternal infection and delivery need to be taken into account. Maternal illness likely contributed to severe acute on chronic fetal hypoxia which resulted in IUGR and in utero IVH with resultant CNS tissue loss and ventriculomegaly. (Figure Presented).

Association between maternal Sars-Co-V2 infection and fetal growth restriction (FGR) at a single county hospital

Objective: Prior studies have shown maternal viral infections are associated with fetal growth restriction (FGR);however, the relationship between FGR and Sars-CoV-2 (SCOV2) infection during pregnancy remains unclear. In this study, we investigate the association between FGR & parental SCOV2 infection at a county hospital in Atlanta, Georgia. Study Design: A prospective cohort study was created by matching patients who had positive SCOV2 (PSCOV2) and negative SCOV2 (NSCOV2) PCR tests between 1/2020-4/2021 utilizing an institutional database. Cohorts were drawn from patients who received a 3rd trimester ultrasound (3TUS) & were matched by gestational age & month SCVO2 testing was performed. FGR was present when estimated fetal weight (EFW) was ≤10% or abdominal circumference (AC) ≤10% at time of either late 2nd or 3rd trimester ultrasound. Sample size calculations were performed to investigate a 15% difference in FGR rate requiring 74 subjects per group. Univariate analyses, chi-square tests and logistic regression were performed. Regression models were adjusted for comorbidities including preeclampsia, gestational diabetes, chronic hypertension, gestational hypertension, and maternal race. Results: 157 subjects were in the analyses (n=78 PSCOV2 and n=79 NSCVO2). 83.4% (n =131) self-identified as African American. FGR rates were 15.3% and 16.4% among PSCOV2 and NSCOV2 respectively. After adjusting for confounders, no difference in FGR was observed between the groups (adjusted OR: 1.12, 95% CI 0.46-2.73). Absolute EFW at time of FGR diagnosis was lower in PSCOV2 vs NSCOV2 (1,250 grams vs.1,337 grams, p= 0.015), a relationship that remained after adjusting for confounders (p=0.015). Conclusion: Our data suggest that despite a high background FGR rate (15.2%), there was no significant association between FGR and SCOV2. Also, EFW was lower in PSCOV2 cohort vs NSCOV2 cohort. Therefore, unlike other viral illnesses, while SCOV2 may not clinically drive FGR, further studies are necessary to investigate the effects of maternal SCVO2 on fetal growth & examine whether growth exams improve outcomes in this setting.