Objectives To investigate the incidence of clinical, ultrasonographic and biochemical findings related to pre‐eclampsia (PE) in pregnancies with COVID‐19, and to assess their accuracy to differentiate between PE and the PE‐like features associated with COVID‐19. Design A prospective, observational study. Setting Tertiary referral hospital. Participants Singleton pregnancies with COVID‐19 at >20+0 weeks. Methods Forty‐two consecutive pregnancies were recruited and classified into two groups: severe and non‐severe COVID‐19, according to the occurrence of severe pneumonia. Uterine artery pulsatility index (UtAPI) and angiogenic factors (soluble fms‐like tyrosine kinase‐1/placental growth factor [sFlt‐1/PlGF]) were assessed in women with suspected PE. Main outcome measures Incidence of signs and symptoms related to PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, abnormal UtAPI and increased sFlt‐1/PlGF. Results Thirty‐four cases were classified as non‐severe and 8 as severe COVID‐19. Five (11.9%) women presented signs and symptoms of PE, all five being among the severe COVID‐19 cases (62.5%). However, abnormal sFlt‐1/PlGF and UtAPI could only be demonstrated in one case. One case remained pregnant after recovery from severe pneumonia and had a spontaneous resolution of the PE‐like syndrome. Conclusions Pregnant women with severe COVID‐19 can develop a PE‐like syndrome that might be distinguished from actual PE by sFlt‐1/PlGF, LDH and UtAPI assessment. Healthcare providers should be aware of its existence and monitor pregnancies with suspected pre‐eclampsia with caution. Tweetable abstract This study shows that a pre‐eclampsia‐like syndrome could be present in some pregnancies with severe COVID‐19.

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

SARS-CoV-2 has been associated with an increased rate of venous thromboembolism in critically ill patients. Since surgical patients are already at higher risk of venous thromboembolism than general populations, this study aimed to determine if patients with peri-operative or prior SARS-CoV-2 were at further increased risk of venous thromboembolism. We conducted a planned sub-study and analysis from an international, multicentre, prospective cohort study of elective and emergency patients undergoing surgery during October 2020. Patients from all surgical specialties were included. The primary outcome measure was venous thromboembolism (pulmonary embolism or deep vein thrombosis) within 30 days of surgery. SARS-CoV-2 diagnosis was defined as peri-operative (7 days before to 30 days after surgery); recent (1-6 weeks before surgery); previous (≥7 weeks before surgery); or none. Information on prophylaxis regimens or pre-operative anti-coagulation for baseline comorbidities was not available. Postoperative venous thromboembolism rate was 0.5% (666/123,591) in patients without SARS-CoV-2; 2.2% (50/2317) in patients with peri-operative SARS-CoV-2; 1.6% (15/953) in patients with recent SARS-CoV-2; and 1.0% (11/1148) in patients with previous SARS-CoV-2. After adjustment for confounding factors, patients with peri-operative (adjusted odds ratio 1.5 (95%CI 1.1-2.0)) and recent SARS-CoV-2 (1.9 (95%CI 1.2-3.3)) remained at higher risk of venous thromboembolism, with a borderline finding in previous SARS-CoV-2 (1.7 (95%CI 0.9-3.0)). Overall, venous thromboembolism was independently associated with 30-day mortality ). In patients with SARS-CoV-2, mortality without venous thromboembolism was 7.4% (319/4342) and with venous thromboembolism was 40.8% (31/76). Patients undergoing surgery with peri-operative or recent SARS-CoV-2 appear to be at increased risk of postoperative venous thromboembolism compared with patients with no history of SARS-CoV-2 infection. Optimal venous thromboembolism prophylaxis and treatment are unknown in this cohort of patients, and these data should be interpreted accordingly.

Background Among non-pregnant individuals, diabetes mellitus (DM) and high body mass index (BMI) increase the risk of Covid-19 and its severity. Objective To determine whether DM and high BMI are risk factors for Covid-19 in pregnancy and whether gestational diabetes mellitus (GDM) is also associated with covid-19 diagnosis. Study Design INTERCOVID was a multinational study, conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women ≥18 years; 2071 were included in these analyses. For each woman diagnosed with Covid-19, two non-diagnosed women delivering or initiating antenatal care at the same institution were also enrolled. Main exposures were pre-existing DM or high BMI (overweight/obesity defined as ≥25 kg/m 2 ), and GDM in pregnancy. Main outcome was a confirmed diagnosis of Covid-19 based on an RT-PCR test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined Covid-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and Covid-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. We also conducted sensitivity analyses: 1) restricted to those with an RT-PCR or antigen test in the last week of pregnancy; 2) restricted to those with an RT-PCR or antigen test during the entire pregnancy; 3) generating values for missing data using multiple imputation; and 4) analyses controlling for month of enrollment. In addition, among those who were diagnosed with Covid-19, we examined whether having GDM, DM, or high BMI, increased risk for having symptomatic vs. asymptomatic Covid-19. Results Covid-19 was associated with preexisting DM (RR=1.94, 95% CI=1.55, 2.42), overweight/obesity (RR=1.20; 95% CI=1.06, 1.37), and GDM (RR=1.21; 95% CI=0.99, 1.46). The GDM association was specifically among women requiring insulin, whether they were of normal-weight (RR=1.79, 95% CI=1.06, 3.01) or overweight/obese (RR=1.77, 95% CI=1.28, 2.45). A somewhat stronger association with Covid-19 diagnosis was observed among women with pre-existing DM, whether they were of normal weight (RR=1.93, 95% CI=1.18, 3.17) or overweight/obese (RR=2.32, 95% CI=1.82, 2.97). When the sample was restricted to those with a RT-PCR or antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation, or controlling for month of enrollment, the observed associations were comparable. Conclusion DM and overweight/obesity are risk factors for Covid-19 diagnosis in pregnancy, and insulin-dependent GDM is also associated with the disease. It is therefore essential that those women with these co-morbidities are vaccinated.

Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.

What is known and objective Tocilizumab is an IL‐6 receptor inhibitor agent which has been proposed as a candidate to stop the inflammatory phase of infection by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). However, safety data of tocilizumab in pregnant women and their newborn are scarce. We aimed to describe maternal and neonatal safety outcomes associated with tocilizumab treatment in pregnant women with severe COVID‐19. Methods This is a retrospective study of severe COVID‐19 pregnant women, treated with tocilizumab in two Spanish hospitals between 1 March and 31 April 2020. Demographics, medical history, clinical and radiologic findings, treatment information and laboratory data of mothers and their newborns were collected from electronic medical records. Results and discussion A total of 12 pregnant women were identified to have received tocilizumab during pregnancy in the two hospitals. Median gestational age at admission was 27.7 weeks (interquartile range, 18.0–36.4). Most of them received lopinavir/ritonavir, azithromycin and hydroxychloroquine, two patients received corticosteroids and one received interferon beta 1B. All 12 pregnancies resulted in live births. Somatometric values were normal for all newborns, and evolution at 14 and 28 days was favourable for all of them. Hepatotoxicity was observed in 2 patients, which improved or resolved at discharge. Cytomegalovirus reactivation was detected in another patient who had also received corticosteroids for 15 days, causing a congenital infection in her newborn. Both hepatotoxicity and viral reactivation adverse events were classified as possibly related to tocilizumab administration according to Naranjo's causality algorithm. What is new and conclusions It does not appear that tocilizumab has detrimental effects for the mother and newborn. Close monitoring of infections should be considered, especially if other immunosuppressive agents are used.

What are the novel findings of this work? The performance of combined first-trimester screening in predicting early-onset and preterm pre-eclampsia (PE) is similar when serum levels of pregnancy-associated plasma protein-A and placental growth factor are measured before or after 11 weeks' gestation. What are the clinical implications of this work? Measurement of serum biomarkers for both PE and aneuploidy screening before the first-trimester scan permits risk calculation for both screening tests at the time of the scan without compromising PE screening performance.

Introduction Increased soluble fms‐like tyrosine kinase to placental growth factor ratio (sFlt‐1/PlGF) has been demonstrated in early‐onset fetal growth restriction (FGR) and small for gestational age (SGA). sFlt‐1/PlGF cut‐offs have been described to assess preeclampsia severity; however, sFlt‐1/PlGF values present in early‐onset SGA and different FGR severity stages remain unknown. Hence, the objective of this study was to describe and compare the sFlt‐1/PlGF values and pregnancy outcomes among early‐onset SGA/FGR stages. Material and methods This is a prospective case‐control study conducted at Vall d’Hebron University Hospital. Singleton pregnancies with estimated fetal weight <10th centile and a control group of uncomplicated pregnancies between 20+0 and 31+6 weeks of gestation were enrolled. Study women were classified at diagnosis into different stages, according to estimated fetal weight centile and Doppler ultrasound. sFlt‐1/PlGF serum concentrations were measured at diagnosis and, together with pregnancy outcomes, were compared among FGR severity stages, SGA, and controls. Finally, correlations between sFlt‐1/PlGF values and time to delivery, gestational age at delivery, days of neonatal admission, and birthweight z‐scores were investigated. Results Among the 207 women enrolled, 32 (15.4%) had uncomplicated pregnancies, 49 (23.7%) pregnancies showed SGA, and 126 (60.9%) involved FGR (92 being stage I, 17 stage II, and 17 stage III). SGA and controls had similar median sFlt‐1/PlGF values (25.7 vs 27.1, P > .05) and pregnancy outcomes. However, all FGR stages had significantly poorer outcomes and greater sFlt‐1/PlGF values than those of SGA and controls. Furthermore, median values differed significantly among all FGR severity stages (9.76 for stage I; 284.3 for stage II, and 625.02 for stage III, P < .05) increasing with FGR severity as well as the frequency of adverse pregnancy outcomes. Additionally, a significant correlation was found between greater sFlt‐1/PlGF ratio values and gestational age at delivery, time from diagnosis to delivery, birthweight z‐scores, and time in neonatal intensive care unit (r = −.637, r = −.576, r = −.161, and r = .311, respectively). Conclusions Values of sFlt‐1/PlGF at diagnosis permit early‐onset FGR/SGA severity classification with good correlation with Doppler ultrasound findings and the occurrence of adverse outcomes. Thus, sFlt‐1/PlGF could aid in early‐onset FGR/SGA severity classification and clinical management when Doppler assessment is not feasible.