Effects of maternal characteristics and medical history on first trimester biomarkers for preeclampsia.

Objective: To identify and quantify the effects of maternal characteristics and medical history on the distribution of Placental Growth Factor (PlGF), mean arterial pressure (MAP), and Uterine Artery Mean Pulsatility Index (UtA-PI); and to standardize the expected values for these biomarkers in the first trimester to create unique multiples of the median (MoMs) for Latin-American population. Methods: This is a prospective cohort built exclusively for research purposes of consecutive pregnant women attending their first-trimester screening ultrasound at a primary care center for the general population in Mexico City between April 2019 and October 2021. We excluded fetuses with chromosomal abnormalities, major fetal malformations, and women delivering in another care center. Linear regression was used on log-transformed biomarkers to assess the influence of maternal characteristics on non-preeclamptic women to create MoM. Results: Of a total of 2,820 pregnant women included in the final analysis, 118 (4.18%) developed PE, of which 22 (0.78%) delivered before 34 weeks of gestation, 74 (2.62%) before 37 weeks, and 44 (1.56%) from 37 weeks gestation. Characteristics that significantly influenced PLGF were fetal crown rump length (CRL), maternal age, nulliparity, body mass index (BMI), chronic hypertension, Lupus, spontaneous pregnancy, polycystic ovary syndrome (PCOS), hypothyroidism, preeclampsia (PE) in a previous pregnancy, and mother with PE. MAP had significant influence from CRL, maternal age, PE in a previous pregnancy, induction of ovulation, a mother with PE, chronic hypertension, BMI, and hypothyroidism. UtA-PI was influenced by CRL, maternal age, a mother with PE, chronic hypertension, and gestational diabetes mellitus (GDM) in a previous pregnancy. Conclusion: Population-specific multiples of the median (MoMs) for PlGF, MAP, and UtA-PI in the first trimester adequately discriminate among women developing preeclampsia later in pregnancy.

sFlt-1 Is an Independent Predictor of Adverse Maternal Outcomes in Women With SARS-CoV-2 Infection and Hypertensive Disorders of Pregnancy.

Background: Preeclampsia (PE) and COVID-19 share a common vascular-endothelial physiopathological pathway that may aggravate or worsen women's outcomes when both coexist. This study aims to evaluate the association of sFlt-1 levels and adverse maternal outcomes among positive SARS-CoV-2 pregnant women with and without hypertensive disorders of pregnancy (HDP). Methods: We performed a multicenter retrospective cohort study of pregnant women with confirmed SARS-CoV-2 infection that required hospital admission. The exposed cohort comprised women with a diagnosis of an HDP. The primary outcome was a composite definition of adverse maternal outcome. The association between predictors and the main and secondary outcomes was assessed using an elastic-net regression which comprised a Lasso and Ridge regression method for automatic variable selection and penalization of non-statistically significant coefficients using a 10-fold cross-validation where the best model if automatically chosen by the lowest Akaike information criterion (AIC) and Bayesian information criteria (BIC). Results: Among 148 pregnant women with COVID-19, the best predictive model comprised sFlt-1 MoMs [odds ratio (OR): 5.13; 95% CI: 2.19-12.05], and HDP (OR: 32.76; 95% CI: 5.24-205). sFlt-1 MoMs were independently associated with an increased probability of an adverse maternal outcome despite adjusting for HDP. Conclusions: Our study shows that sFlt-1 is an independent predictor of adverse outcomes in women with SARS-CoV-2 despite hypertension status.

Plasma Total Antioxidant Capacity and Carbonylated Proteins Are Increased in Pregnant Women with Severe COVID-19.

Oxidative stress (OS) induced by SARS-CoV-2 infection may play an important role in COVID-19 complications. However, information on oxidative damage in pregnant women with COVID-19 is limited. Objective: We aimed to compare lipid and protein oxidative damage and total antioxidant capacity (TAC) between pregnant women with severe and non-severe COVID-19. Methods: We studied a consecutive prospective cohort of patients admitted to the obstetrics emergency department. All women positive for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-qPCR) were included. Clinical data were collected and blood samples were obtained at hospital admission. Plasma OS markers, malondialdehyde (MDA), carbonylated proteins (CP), and TAC; angiogenic markers, fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF); and renin-angiotensin system (RAS) markers, angiotensin-converting enzyme 2 (ACE-2) and angiotensin-II (ANG-II) were measured. Correlation between OS, angiogenic, and RAS was evaluated. Results: In total, 57 pregnant women with COVID-19 were included, 17 (28.9%) of which had severe COVID-19; there were 3 (5.30%) maternal deaths. Pregnant women with severe COVID-19 had higher levels of carbonylated proteins (5782 pmol vs. 6651 pmol; p = 0.024) and total antioxidant capacity (40.1 pmol vs. 56.1 pmol; p = 0.001) than women with non-severe COVID-19. TAC was negatively correlated with ANG-II (p < 0.0001) and MDA levels (p < 0.0001) and positively with the sFlt-1/PlGF ratio (p = 0.027). Conclusions: In pregnant women, severe COVID-19 is associated with an increase in protein oxidative damage and total antioxidant capacity as a possible counterregulatory mechanism.

Inflammatory-Metal Profile as a Hallmark for COVID-19 Severity During Pregnancy.

Pregnancy makes women more susceptible to infectious agents; however, available data on the effect of SARS-CoV-2 on pregnant women are limited. To date, inflammatory responses and changes in serum metal concentration have been reported in COVID-19 patients, but few associations between metal ions and cytokines have been described. The aim of this study was to evaluate correlations between inflammatory markers and serum metal ions in third-trimester pregnant women with varying COVID-19 disease severity. Patients with severe symptoms had increased concentrations of serum magnesium, copper, and calcium ions and decreased concentrations of iron, zinc, and sodium ions. Potassium ions were unaffected. Pro-inflammatory cytokines IL-6, TNF-α, IL-8, IL-1α, anti-inflammatory cytokine IL-4, and the IP-10 chemokine were induced in the severe presentation of COVID-19 during pregnancy. Robust negative correlations between iron/magnesium and zinc/IL-6, and a positive correlation between copper/IP-10 were observed in pregnant women with the severe form of the disease. Thus, coordinated alterations of serum metal ions and inflammatory markers - suggestive of underlying pathophysiological interactions-occur during SARS-CoV-2 infection in pregnancy.

Clinical characteristics and risk factors for SARS-CoV-2 infection in pregnant women attending a third level reference center in Mexico City.

BACKGROUND: COVID-19 symptoms vary widely among pregnant women. We aimed to assess the most frequent symptoms amongst pregnant women with SARS-CoV-2 infection in a tertiary hospital in Mexico City. METHODS: A cross-sectional study of pregnant women attending the National Institute of Perinatology in Mexico City was performed. All women who attended the hospital, despite their symptoms, were tested for SARS-CoV-2. A multivariate-age-adjusted logistic regression was used to assess the association between the main outcome and each characteristic of the clinical history. RESULTS: A total of 1880 women were included in the data analysis. Among all women, 30.74% (n = 578) had a positive PCR for SARS-CoV-2 from which 2.7 (n = 50) were symptomatic. Symptoms associated with a positive PCR result were headache (p=.01), dyspnea (p=.043), and myalgia (p=.043). CONCLUSIONS: At universal screening for SARS-CoV-2, one-third of the population had a positive result, while those symptoms associated with a positive PCR were headache, dyspnea, and myalgia.

Maternal Death by COVID-19 Associated with Elevated Troponin T Levels.

Cardiomyocyte injury and troponin T elevation has been reported within COVID-19 patients and are associated with a worse prognosis. Limited data report this association among COVID-19 pregnant patients. OBJECTIVE: We aimed to analyze the association between troponin T levels in severe COVID-19 pregnant women and risk of viral sepsis, intensive care unit (ICU) admission, or maternal death. METHODS: We performed a prospective cohort of all obstetrics emergency admissions from a Mexican National Institute. All pregnant women diagnosed by reverse transcription-polymerase chain reaction (RT-qPCR) for SARS-CoV-2 infection between October 2020 and May 2021 were included. Clinical data were collected, and routine blood samples were obtained at hospital admission. Seric troponin T was measured at admission. RESULTS: From 87 included patients, 31 (35.63%) had severe COVID-19 pneumonia, and 6 (6.89%) maternal deaths. ROC showed a significant relationship between troponin T and maternal death (AUC 0.979, CI 0.500-1.000). At a cutoff point of 7 ng/mL the detection rate for severe pneumonia was 83.3% (95%CI: 0.500-0.100) at 10% false-positive rate. CONCLUSION: COVID-19 pregnant women with elevated levels of troponin T present a higher risk of death and severe pneumonia.

Cord Blood SARS-CoV-2 IgG Antibodies and Their Association With Maternal Immunity and Neonatal Outcomes.

Passive transplacental immunity is crucial for neonatal protection from infections. Data on the correlation between neonatal immunity to SARS-CoV-2 and protection from adverse outcomes is scarce. This work aimed to describe neonatal seropositivity in the context of maternal SARS-CoV-2 infection, seropositivity, and neonatal outcomes. This retrospective nested case-control study enrolled high-risk pregnant women with a SARS-CoV-2 RT-PCR positive test who gave birth at the Instituto Nacional de Perinatología in Mexico City and their term neonates. Anti-SARS-CoV-2 IgG antibodies in maternal and cord blood samples were detected using a chemiluminescent assay. In total, 63 mother-neonate dyads (mean gestational age 38.4 weeks) were included. Transplacental transfer of SARS-CoV-2 IgG occurred in 76% of neonates from seropositive mothers. A positive association between maternal IgG levels and Cycle threshold (Ct) values of RT-qPCR test for SARS-CoV-2 with neonatal IgG levels was observed. Regarding neonatal outcomes, most seropositive neonates did not require any mechanical ventilation, and none developed any respiratory morbidity (either in the COVID-19 positive or negative groups) compared to 7 seronegative neonates. Furthermore, the odds of neonatal respiratory morbidity exhibited a tendency to decrease when neonatal IgG levels increase. These results add further evidence suggesting passive IgG transfer importance.

Novel Ratio Soluble Fms-like Tyrosine Kinase-1/Angiotensin-II (sFlt-1/ANG-II) in Pregnant Women Is Associated with Critical Illness in COVID-19.

BACKGROUND: In healthy pregnancies, components of the Renin-Angiotensin system (RAS) are present in the placental villi and contribute to invasion, migration, and angiogenesis. At the same time, soluble fms-like tyrosine kinase 1 (sFlt-1) production is induced after binding of ANG-II to its receptor (AT-1R) in response to hypoxia. As RAS plays an essential role in the pathogenesis of COVID-19, we hypothesized that angiogenic marker (sFlt-1) and RAS components (ANG-II and ACE-2) may be related to adverse outcomes in pregnant women with COVID-19; Methods: Prospective cohort study. Primary outcome was severe pneumonia. Secondary outcomes were ICU admission, intubation, sepsis, and death. Spearman's Rho test was used to analyze the correlation between sFlt-1 and ANG-II levels. The sFlt-1/ANG-II ratio was determined and the association with each adverse outcome was explored by logistic regression analysis and the prediction was assessed using receiver-operating-curve (ROC); Results: Among 80 pregnant women with COVID-19, the sFlt-1/ANG-II ratio was associated with an increased probability of severe pneumonia (odds ratio [OR]: 1.31; p = 0.003), ICU admission (OR: 1.05; p = 0.007); intubation (OR: 1.09; p = 0.008); sepsis (OR: 1.04; p = 0.008); and death (OR: 1.04; p = 0.018); Conclusion: sFlt-1/ANG-II ratio is a good predictor of adverse events such as pneumonia, ICU admission, intubation, sepsis, and death in pregnant women with COVID-19.

Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19.

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.

Características poblacionales y placentarias asociadas a óbito en infección asintomática por SARS-CoV-2 / Population characteristics and placental findings associated with stillbirth in asymptomatic SARS-CoV-2 infection

Resumen Objetivo: Comparar características poblacionales y hallazgos placentarios asociados a óbito, en mujeres con infección asintomática por coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2) al momento de la resolución del embarazo. Material y métodos: Estudio transversal analítico, mujeres con diagnóstico de óbito e infección asintomática por SARS-CoV-2. Se excluyeron pacientes con patología ginecológica y aquellas con más de una prueba RT-PCR. Resultados: No hay diferencia estadísticamente significativa entre las pacientes con infección asintomática por SARS-CoV-2 comparadas con pacientes sin infección para las características poblacionales como edad materna, antecedentes obstétricos, edad gestacional, escolaridad, estado civil, hábito tabáquico y enfermedades crónico-degenerativas. Tampoco hubo diferencia en los hallazgos placentarios de corioamnionitis, vasculitis, deciduitis, trombosis, aterosis aguda y necrosis fibrinoide. Conclusiones: No hay diferencia estadísticamente significativa en las características poblacionales y placentarias en embarazadas con diagnóstico de óbito, con y sin infección asintomática por SARS-CoV-2. Tenemos datos insuficientes para afirmar alguna característica asociada a óbito en pacientes con infección por SARS-CoV-2 asintomática.

Abstract Objective: To compare population characteristics and placental findings associated with stillbirth, in women with asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at the time of delivery. Materials and methods: Analytical cross-sectional study women with a diagnosis of stillbirth and with asymptomatic SARS-CoV-2 infection. Patients with gynecological pathology and those with more than one RT-PCR test were excluded. Results: There is no statistically significant difference between patients with asymptomatic SARS-CoV-2 infection compared to patients without infection for population characteristics such as maternal age, obstetric history, gestational age, education, marital status, smoking habit, chronic-degenerative diseases. There was no difference in placental findings of chorioamnionitis, vasculitis, deciduitis, thrombosis, acute atherosis, and fibrinoid necrosis. Conclusions: There is no statistically significant difference in the population and placental characteristics, in pregnant women diagnosed with stillbirth with and without confirmed asymptomatic SARS-CoV-2 infection. For the moment, we have insufficient data to affirm any population characteristic associated with stillbirth in patients with asymptomatic SARS-CoV-2 infection.