Impact of COVID-19 during pregnancy on placental pathology, maternal and neonatal outcome - A cross-sectional study on anemic term pregnant women from a tertiary care hospital in southern India.

Background: SARS-CoV-2 infection during pregnancy may cause adverse maternal, neonatal and placental outcomes. While tissue hypoxia is often reported in COVID-19 patients, pregnant women with anemia are suspected to be more prone to placental hypoxia-related injuries. Methods: This hospital-based cross-sectional study was conducted between August-November 2021, during COVID-19 second wave in India. Term pregnant women (N=212) admitted to hospital for delivery were enrolled consecutively. Since hospital admission mandated negative RT-PCR test for SARS-CoV-2 virus, none had active infection. Data on socio-demography, COVID-19 history, maternal, obstetric, and neonatal outcomes were recorded. Pre-delivery maternal and post-delivery cord blood samples were tested for hematological parameters and SARS-CoV-2 IgG. Placentae were studied for histology. Results: Of 212 women, 122 (58%) were seropositive for SARS-CoV-2 IgG, but none reported COVID-19 history; 134 (63.2%) were anemic. In seropositive women, hemoglobin (p=0.04), total WBC (p=0.009), lymphocytes (p=0.005) and neutrophils (p=0.02) were significantly higher, while ferritin was high, but not significant and neutrophils to lymphocytes (p=0.12) and platelets to lymphocytes ratios (p=0.03) were lower. Neonatal outcomes were similar. All RBC parameters and serum ferritin were significantly lower in anemic mothers but not in cord blood, except RDW that was significantly higher in both, maternal (p=0.007) and cord (p=0.008) blood from seropositive anemic group compared to other groups. Placental histology showed significant increase in villous hypervascularity (p=0.000), dilated villous capillaries (p=0.000), and syncytiotrophoblasts (p=0.02) in seropositive group, typically suggesting placental hypoxia. Maternal anemia was not associated with any histological parameters. Univariate and multivariate logistic regression analyses of placental histopathological adverse outcomes showed strong association with SARS-CoV-2 seropositivity but not with maternal anemia. When adjusted for several covariates, including anemia, SARS-CoV-2 seropositivity emerged as independent risk factor for severe chorangiosis (AOR 8.74, 95% CI 3.51-21.76, p<0.000), dilated blood vessels (AOR 12.74, 95% CI 5.46-29.75, p<0.000), syncytiotrophoblasts (AOR 2.86, 95% CI 1.36-5.99, p=0.005) and villus agglutination (AOR 9.27, 95% CI 3.68-23.32, p<0.000). Conclusion: Asymptomatic COVID-19 during pregnancy seemed to be associated with various abnormal placental histopathologic changes related to placental hypoxia independent of maternal anemia status. Our data supports an independent role of SARS-CoV-2 in causing placental hypoxia in pregnant women.

Suspected twin anemia polycythemia sequence in a dichorionic, diamniotic twin pregnancy: a case report.

BACKGROUND: Twin anemia polycythemia sequence is a rare complication in monochorionic twin pregnancy. CASE PRESENTATION: We describe a case of dichorionic twin pregnancy presenting with suspected twin anemia polycythemia sequence. A 31-year-old White female, on her third pregnancy, had a routine ultrasound scan at 12 weeks gestation, which demonstrated a dichorionic twin pregnancy with one placenta located in the anterior wall and the other in the posterior wall of the uterus. At 21 weeks, a scan demonstrated a 24% growth discordance between the two fetuses with normal Doppler studies and amniotic fluid. At 27 weeks, one twin showed signs of anemia and the other polycythemia; the fetal middle cerebral artery peak systolic velocity was high in the anemic fetus and low in the polycythemic twin (1.8 and 0.5 multiples of the median). An intrauterine blood transfusion was carried out and this increased the fetal hemoglobin concentration in the anemic twin from 3.5 to 12.5 g/dL. At 29 weeks, delivery by cesarean section was carried out because of evidence from middle cerebral artery peak systolic velocity of recurrence of anemia in one twin and worsening polycythemia in the co-twin; at birth the hemoglobin concentrations were 5.6 and 24.9 g/dL, respectively. Histopathological examination confirmed dichorionicity with no communicating vessels between the two placentas. CONCLUSIONS: This is the first case of twin anemia polycythemia sequence in a dichorionic, diamniotic twin pregnancy where intrauterine blood transfusion was used to prolong the pregnancy by almost 2 weeks in a "twin anemia polycythemia sequence-like" setting.

Is biomass fuel smoke exposure associated with anemia in non-pregnant reproductive-aged women?

OBJECTIVES: Sri Lanka is a developing country where the majority of households still rely on firewood for cooking. Furthermore, the prevalence of anemia among reproductive-aged women is of moderate public health importance, according the classification of World Health Organization. Despite the researchers' ongoing efforts to investigate a link between solid fuel smoke exposure and anemia, the veracity of their findings remains uncertain. As a result, the purpose of this study was to examine the relationship between biomass fuel smoke exposure and anemia in non-pregnant reproductive-aged women in Sri Lanka. METHODS: A descriptive cross-sectional study was conducted among 382 non-pregnant reproductive-aged (15 to 49 years) women in Central Province, Sri Lanka. Data was collected using a standardized interviewer-administered questionnaire, and exposure was assessed using a breath carbon monoxide monitor. Drabkin's cynomethhemoglobin technique was used to determine blood hemoglobin concentration. RESULTS: The overall prevalence of anemia was 36.1%. The logistic regression model revealed no effect of cooking fuel type on anemic or non-anemic status after adjusting for potential confounding factors (p > 0.05). The multivariate regression analysis also discovered that cooking fuel type had no effect on women's blood hemoglobin concentration. CONCLUSIONS: The study results suggest no impact of solid fuel smoke exposure on anemia among non-pregnant, reproductive-aged women. Larger scale prospective cohort studies are recommended. The reasons behind the high prevalence of anemia among reproductive-aged women should be further investigated, and corrective measures should be implemented urgently.

Long-term efficacy, safety, and medication compliance of roxadustat on peritoneal dialysis patients with renal anemia affected by the COVID-19 pandemic: a retrospective study.

BACKGROUND: Current studies have limited data on long-term treatment safety and medication compliance of roxadustat for renal anemia in peritoneal dialysis (PD) patients. We aimed to analyze the long-term efficacy, safety, and medication compliance of roxadustat in the treatment of renal anemia in patients with PD who discontinued recombinant human erythropoietin (rhEPO) treatment due to the corona virus disease 2019 (COVID-19) outbreak. METHODS: We retrospectively collected patients who were switched from rhEPO to roxadustat in our hospital due to the pandemic. The criteria for subject inclusion: aged >18 years with a dialysis vintage >3 months, without malignant tumor, no severe cardiovascular and cerebrovascular diseases, and not combined hemodialysis. Patients were followed up until the end of December 2021. Hemoglobin (Hb), red blood cell (RBC) and hematocrit (Hct) were recorded at baseline, month 1-12 and month 20, and iron parameters at baseline, 3, 6, 9, 12, and 20 months were collected. The Morisky Medication Adherence Scale-8 (MMAS-8) was used to score medication compliance during rhEPO treatment and roxadustat treatment, and adverse reactions occurred during treatment were collected. The efficacy and medication compliance of roxadustat were analyzed using Wilcoxon rank sum test or t-test. RESULTS: The median follow-up time was 21.1 (20.6, 21.7) months. After 1 month of treatment, the Hb level was significantly increased by 9.4 g/L (95% CI: 6.0-12.8 g/L) compared with the baseline, follow up at 20 months showed the Hb level had remained stable, increased by 20.7 g/L (95% CI: 15.9-25.4 g/L) compared with before treatment. At the beginning of treatment, total iron binding capacity increased, transferrin saturation and serum ferritin decreased, serum iron remained stable during treatment. During roxadustat treatment, no patient discontinued treatment due to the pandemic, and the Morisky score was improved compared with that during rhEPO treatment [5.75 (4.25, 6.00) vs. 6.75 (5.75, 7.00), P=0.000]. There were no serious adverse events associated with roxadustat were observed. CONCLUSIONS: Roxadustat can effectively improve anemia and had good tolerance in patients undergoing PD who have difficult using rhEPO, and the medication compliance was better than rhEPO during the COVID-19.

Acute blood loss anemia after COVID-19 nasopharyngeal sampling.

ABSTRACT: Long-term care residents with novel coronavirus disease 2019 (COVID-19) experience high mortality rates and require frequent screening. Most resident testing occurs via nasopharyngeal swab that potentially causes epistaxis with rates of 5% to 8% in healthy populations. It is estimated that 48% of long-term care residents receive oral anticoagulation that increases risk of bleeding. A long-term care resident receiving oral anticoagulation experienced an episode of acute blood loss anemia after nasopharyngeal sampling. Current medications were not reviewed before testing, and oral anticoagulation was not held resulting in acute blood loss anemia. A medication review is indicated for skilled nursing and assisted living residents to identify oral anticoagulation before nasopharyngeal testing. Less invasive testing may be recommended or should bleeding occur, discontinuation of oral anticoagulation for a short term may be appropriate.

Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

High immature platelet fraction with reduced platelet count on hospital admission. Can it be useful for COVID-19 diagnosis?

INTRODUCTION: Health professions are heavily engaged facing the current threat of SARS-CoV-2 (COVID-19). Although there are many diagnostic tools, an accurate and rapid laboratory procedure for diagnosing COVID-19 is recommended. We focused on platelet parameters as the additional biomarkers for clinical diagnosis in patients presenting to the emergency department (ED). MATERIALS AND METHODS: Five hundred and sixty-one patients from February to April 2020 have been recruited. Patients were divided into three groups: (N = 50) COVID-19 positive and (N = 21) COVID-19 negative with molecular testing, (N = 490) as reference population without molecular testing. A Multiplex rRT-PCR from samples collected by nasopharyngeal swabs was performed and the hematological data collected. RESULTS: We detected a mild anemia in COVID-19 group and lymphopenia against reference population: hemoglobin (g/dL) 13.0 (11.5-14.8) versus 13.9 (12.8-15.0) (P = .0135); lymphocytes (109 /L) 1.24 (0.94-1.73) versus 1.99 (1.49-2.64) (P < .0001). In addition, abnormal platelet parameters as follows (COVID group vs reference population): PLT (×109 /L) 209 (160-258) vs 236 (193-279) (P = .0239). IPF (%) 4.05 (2.5-5.9) versus 3.4 (2.2-4.9) (P = .0576); H-IPF (%) 1.25 (0.8-2.2) versus 0.95 (0.6-1.5) (P = .0171) were identified. In particular, COVID positive group had a high H-IPF/IPF Ratio compared to reference population [0.32 (0.29-0.36) versus 0.29 (0.26-0.32), respectively, (P = .0003)]. Finally, a PLT difference of nearly 50 × 109 /L between pre/postCOVID-19 sampling for each patient was found (N = 42) (P = .0194). CONCLUSIONS: COVID-19 group results highlighted higher IPF and H-IPF values, with increased H-IPF/IPF Ratio, associated to PLT count reduction. These findings shall be adopted for a timely diagnosis of patients upon hospital admission.

Peripheral granular lymphocytopenia and dysmorphic leukocytosis as simple prognostic markers in COVID-19.

INTRODUCTION: Developing prognostic markers can be useful for clinical decision-making. Peripheral blood (PB) examination is simple and basic that can be performed in any facility. We aimed to investigate whether PB examination can predict prognosis in coronavirus disease (COVID-19). METHODS: Complete blood count (CBC) and PB cell morphology were examined in 38 healthy controls (HCs) and 40 patients with COVID-19. Patients with COVID-19, including 26 mild and 14 severe cases, were hospitalized in Juntendo University Hospital (Tokyo, Japan) between April 1 and August 6, 2020. PB examinations were performed using Sysmex XN-3000 automated hematology analyzer and Sysmex DI-60 employing the convolutional neural network-based automatic image-recognition system. RESULTS: Compared with mild cases, severe cases showed a significantly higher incidence of anemia, lymphopenia, and leukocytosis (P < .001). Granular lymphocyte counts were normal or higher in mild cases and persistently decreased in fatal cases. Temporary increase in granular lymphocytes was associated with survival of patients with severe infection. Red cell distribution width was significantly higher in severe cases than in mild cases (P < .001). Neutrophil dysplasia was consistently observed in COVID-19 cases, but not in HCs. Levels of giant neutrophils and toxic granulation/Döhle bodies were increased in severe cases. CONCLUSION: Basic PB examination can be useful to predict the prognosis of COVID-19, by detecting SARS-CoV-2 infection-induced multi-lineage changes in blood cell counts and morphological anomalies. These changes were dynamically correlated with disease severity and may be associated with disruption of hematopoiesis and the immunological system due to bone marrow stress in severe infection.

COVID-19 induces proatherogenic alterations in moderate to severe non-comorbid patients: A single-center observational study.

Patients with COVID-19 can be asymptomatic or present mild to severe symptoms, leading to respiratory and cardiovascular complications and death. Type 2 diabetes mellitus (T2DM) and obesity are considered risk factors for COVID-19 poor prognosis. In parallel, COVID-19 severe patients exhibit dyslipidemia and alterations in neutrophil to lymphocyte ratio (NLR) associated with disease severity and mortality. To investigate whether such alterations are caused by the infection or results from preexisting comorbidities, this work analyzed dyslipidemia and the hemogram profile of COVID-19 patients according to the severity and compared with patients without T2DM or obesity comorbidities. Dyslipidemia, with a marked decrease in HDL levels, and increased NLR accompanied the disease severity, even in non-T2DM and non-obese patients, indicating that COVID-19 causes the observed alterations. Because decreased hemoglobin is involved in COVID-19 severity, and hemoglobin concentration is associated with metabolic diseases, the erythrogram of patients was also evaluated. We verified a drop in hemoglobin and erythrocyte number in severe patients, independently of T2DM and obesity, which may explain in part the need for artificial ventilation in severe cases. Thus, the control of such parameters (especially HDL levels, NLR, and hemoglobin concentration) could be a good strategy to prevent COVID-19 complications and death.

Use of hyperbaric oxygenation as an adjunctive treatment for severe pernicious anaemia in a bloodless medicine patient.

Severe anaemia in patients who cannot receive blood transfusion is an indication for the use of hyperbaric oxygen therapy (HBO). Most reports of the use of HBO for anaemia involve patients with acute blood loss. This report details a case of HBO used for a patient with severe pernicious anaemia. A 35-year-old Jehovah's Witnesses believer presented to a hospital with fatigue, dyspnoea and haemoglobin of 26 g/L. She was diagnosed with pernicious anaemia. As she could not receive blood transfusion due to her religious beliefs, vitamin B12 supplementation and HBO were administered and resulted in significant improvement in her condition. The mechanisms of action of HBO, including increased systemic plasma oxygenation, can alleviate signs and symptoms of anaemia regardless of its aetiology. HBO administration can greatly enhance the plasma arterial oxygen content, leading to clinical improvement in patients with anaemia who cannot receive blood transfusion.

Acquired factor V inhibitor in the setting of coronavirus disease 2019 infection.

Factor V inhibitors are a rare cause of life-threatening bleeding. We present a case of an acquired factor V inhibitor likely caused by coronavirus disease 2019 infection. Bleeding was manifested by severe anemia requiring frequent red-cell transfusion, left psoas muscle hematoma, and left retroperitoneal cavity hematoma. Factor V activity was less than 1% and the factor V inhibitor titer was 31.6 Bethesda units. Severe acute respiratory syndrome coronavirus 2 RNA testing of the nasopharynx was positive 2 weeks before presentation and continued to be positive for 30 days. The patient failed treatment with intravenous immunoglobulin and dexamethasone. Three cycles of plasmapheresis with fresh frozen plasma replacement resulted in correction of the bleeding and laboratory coagulopathy. This is the first reported case of a factor V inhibitor in a coronavirus disease 2019 patient and suggests that plasmapheresis may be a successful treatment strategy.

Iatrogenic anaemia and transfusion thresholds in ICU patients with COVID-19 disease at a tertiary care hospital.

BACKGROUND: Patients with severe COVID-19 disease frequently develop anaemia as the result of multiple mechanisms and often receive transfusions. The aims of this study were to assess the impact of repeated blood samplings on patients' anaemic state using standard-volume tubes, in comparison with the hypothetical use of low-volume tubes and to evaluate the transfusion policy adopted. STUDY DESIGN AND METHODS: Transfusion data of mechanically ventilated non-bleeding patients with COVID-19 disease hospitalized in ICU for a minimum of 20 days were recorded. The total volume of blood drawn for samplings with standard-volume tubes and the corresponding red blood cell mass (RBCM) removed during hospitalization for each patient were calculated and compared with the hypothetical use of low-volume tubes. RESULTS: Twenty-four patients fulfilled the inclusion criteria. Ten patients were anaemic at ICU admission (41.7 %). Overall, 6658 sampling tubes were employed, for a total of 16,786 mL of blood. The median RBCM subtracted by blood samplings per patient accounted for about one third of the total patients' RBCM decrease until discharge. The use of low-volume tubes would have led to a median saving of about one third of the drawn RBCM. Eleven patients were transfused (45.8 %) at a mean Hb value of 7.7 (± 0.5) g/dL. CONCLUSION: The amount of blood drawn for sampling has a significant role in the development of anaemia and the use of low-volume tubes could minimize the problem. Large high-powered studies are warranted to assess the more appropriate transfusion thresholds in non-bleeding critically ill patients with COVID-19 disease.

Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective observational cohort study.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology. METHODS: We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing. RESULTS: We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia. DISCUSSION: Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04416100.

A Case Report to Assess Passive Immunity in a COVID Positive Pregnant Patient.

INTRODUCTION: Data regarding transplacental passage of maternal coronavirus disease 2019 (COVID-19) antibodies and potential immunity in the newborn is limited. CASE REPORT: We present a 25-year-old multigravida with known red blood cell isoimmunization, who was found to be COVID-19 positive at 27 weeks of gestation while undergoing serial periumbilical blood sampling and intrauterine transfusions. Maternal COVID-19 antibody was detected 2 weeks after positive molecular testing. Antibodies were never detected on cord blood samples from two intrauterine fetal cord blood samples as well as neonatal cord blood at the time of delivery. CONCLUSION: This case demonstrates a lack of passive immunity of COVID-19 antibodies from a positive pregnant woman to her fetus, neither in utero nor at the time of birth. Further studies are needed to understand if passage of antibodies can occur and if that can confer passive immunity in the newborn. KEY POINTS: · Passive immunity should not be assumed in COVID-19 infection in pregnancy.. · Isoimmunization may impair passive immunity of certain antibodies.. · Vaccination to or maternal infection of COVID-19 may not be protective for the fetus..