Reduction in Preterm Preeclampsia after Contingent First-Trimester Screening and Aspirin Prophylaxis in a Routine Care Setting.

Objectives: Several multivariate algorithms for preeclampsia (PE) screening in the first trimester have been developed over the past few years. These models include maternal factors, mean arterial pressure (MAP), uterine artery Doppler (UtA-PI), and biochemical markers (pregnancy-associated plasma protein-A (PAPP-A) or placental growth factor (PlGF)). Treatment with low-dose aspirin (LDA) has shown a reduction in the incidence of preterm PE in women with a high-risk assessment in the first trimester. An important barrier to the implementation of first-trimester screening is the cost of performing tests for biochemical markers in the whole population. Theoretical contingent strategies suggest that two-stage screening models could also achieve high detection rates for preterm PE with lower costs. However, no data derived from routine care settings are currently available. This study was conducted to validate and assess the performance of a first-trimester contingent screening process using PlGF for PE, with prophylactic LDA, for decreasing the incidence of preterm PE. Methods: This was a two-phase study. In phase one, a contingent screening model for PE was developed using a multivariate validated model and a historical cohort participating in a non-interventional PE screening study (n = 525). First-stage risk assessment included maternal factors, MAP, UtA-PI, and PAPP-A. Several cut-off levels were tested to determine the best screening performance, and three groups were then defined (high-, medium-, and low-risk groups). PlGF was determined in the medium-risk group to calculate the final risk. Phase two included a validation cohort of 847 singleton pregnancies prospectively undergoing first-trimester PE screening using this approach. Women at high risk of PE received prophylactic treatment with 150 mg of LDA. The clinical impact of the model was evaluated by comparing the incidence of early-onset (<34 weeks) and preterm (<37 weeks) PE between groups. Results: Cut-off levels for the contingent screening model were chosen in the first and second stages of screening to achieve a performance with sensitivities of 100% and 80% for early-onset and preterm PE detection, respectively, with a 15% false positive rate. In the development phase, 21.5% (n = 113) of the women had a medium risk of PE and required second-stage screening. In the prospective validation phase, 15.3% (n = 130) of the women required second-stage screening for PlGF, yielding an overall screen-positive rate of 14.9% (n = 126). The incidence of preterm PE was reduced by 68.4% (1.9% vs. 0.6%, p = 0.031) after one year of screening implementation. Conclusions: Implementation of contingent screening for PE using PlGF in a routine care setting led to a significant reduction (68.4%) in preterm PE, suggesting that contingent screening can achieve similar results to protocols using PlGF in the whole population. This could have financial benefits, with a similar reduction in the rate of preterm PE.

Impact of the COVID-19 Pandemic on Maternal Well-Being during Pregnancy.

The outbreak of a pandemic has negative psychological effects. We aimed to determine the impact of the SARS-CoV-2 pandemic during pregnancy and identify the risk factors for maternal well-being. A multicenter, prospective, population-based study was carried out that included women (n = 1320) who were pregnant during the SARS-CoV-2 pandemic in Barcelona (Spain) compared against a pre-pandemic cohort (n = 345). Maternal well-being was assessed using the validated World Health Organization Well-Being Index Questionnaire (WHO-5 Index). Pregnant women attended during the COVID-19 pandemic showed worst WHO-5 well-being scores (median (IQR) of 56 (36-72) for the pandemic cohort vs. 64 (52-76) for the pre-pandemic cohort p < 0.001), with 42.8% of women presenting a poor well-being score vs. 28% for the pre-pandemic cohort (p < 0.001). Presence of a previous psychiatric disorder (OR 7.1; 95% CI 2.6-19, p < 0.001), being in the third trimester of pregnancy (OR 1.7; 95% CI 1.5-2, p < 0.001), or requiring hospital admission for COVID-19 (OR 4.7; 95% CI 1.4-16.7, p = 0.014), significantly contributed to low maternal well-being during the COVID-19 pandemic (multivariate analysis). Being infected by SARS-CoV-2 was not associated with a lower well-being score. We conclude that, during the COVID-19 pandemic, there were higher rates of poor maternal well-being; the infection of SARS-CoV-2 itself did not worsen maternal well-being, but other factors as psychiatric disorders, being in the third trimester of pregnancy or hospital admission for COVID-19 disease did.

First-Trimester SARS-CoV-2 Infection: Clinical Presentation, Inflammatory Markers, and Obstetric Outcomes.

OBJECTIVE: Second- and third-trimester SARS-CoV-2 infections may have an increased risk of obstetric complications. However, data on first-trimester infections are scarce. We sought to characterize the clinical and inflammatory presentations and pregnancy outcomes of first-trimester infections. METHODS: A population-based multicenter study including 817 singleton pregnancies with SARS-CoV-2 serologic testing at 8-14 weeks between March and May 2020. Blood count, uterine artery Doppler, and pregnancy-associated plasma protein A (PAPP-A) were performed in all women. Placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), IL-6, and ferritin were determined in positive women. Obstetric outcomes were evaluated. RESULTS: The prevalence of first-trimester infection was 15.2% (n = 124). 72.6% of positive women were asymptomatic. Symptomatic women had higher rates of lymphopenia (1.91 × 109/L vs. 2.16 × 109/L, p = 0.017) and increased levels of IL-6 (9.1% vs. 1.2%, p = 0.051), but lower rates of decreased ferritin (6.3% vs. 19.8%, p = 0.015). PAPP-A was higher in symptomatic women compared with asymptomatic and negative women (1.44 [IQR 0.90-1.82] vs. 1.08 [IQR 0.66-1.61] p = 0.014, vs. 1.08 [IQR 0.77-1.55] p = 0.019, respectively). Obstetric outcomes were not increased. CONCLUSIONS: First-trimester SARS-CoV-2 infections are mostly asymptomatic, with a mild increase of inflammatory markers in symptomatic women. Obstetric complications were not increased, but PAPP-A levels were higher in symptomatic women.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Infection on Pregnancy Outcomes: A Population-based Study.

BACKGROUND: We performed a population-based study to describe the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pregnancy outcomes. METHODS: This prospective, population-based study included pregnant women who consecutively presented at first/second trimester visits or at delivery at 3 hospitals in Barcelona, Spain. SARS-CoV-2 antibodies (immunoglobulin [Ig] G and IgM/IgA) were measured in all participants, and nasopharyngeal real-time polymerase chain reaction (RT-PCR) was performed at delivery. The primary outcome was a composite of pregnancy complications in SARS-CoV-2-positive vs negative women that included miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational-age newborn, or neonatal admission. Secondary outcomes were components of the primary outcome plus abnormal fetal growth, malformation, or intrapartum fetal distress. Outcomes were also compared between positive symptomatic and positive asymptomatic SARS-CoV-2 women. RESULTS: Of 2225 pregnant women, 317 (14.2%) were positive for SARS-CoV-2 antibodies (n = 314, 99.1%) and/or RT-PCR (n = 36, 11.4%). Among positive women, 217 (68.5%) were asymptomatic, 93 (29.3%) had mild coronavirus disease 2019 (COVID-19), and 7 (2.2%) had pneumonia, of whom 3 required intensive care unit admission. In women with and without SARS-CoV-2 infection, the primary outcome occurred in 43 (13.6%) and 268 (14%), respectively (risk difference, -0.4%; 95% confidence interval, -4.1% to 4.1). Compared with noninfected women, those with symptomatic COVID-19 had increased rates of preterm delivery (7.2% vs 16.9%, P = .003) and intrapartum fetal distress (9.1% vs 19.2%, P = .004), while asymptomatic women had rates that were similar to those of noninfected cases. Among 143 fetuses from infected mothers, none had anti-SARS-CoV-2 IgM/IgA in cord blood. CONCLUSIONS: The overall rate of pregnancy complications in women with SARS-CoV-2 infection was similar to that of noninfected women. However, symptomatic COVID-19 was associated with modest increases in preterm delivery and intrapartum fetal distress.

Fetal heart rate changes on the cardiotocograph trace secondary to maternal COVID-19 infection.

OBJECTIVE: To determine the cardiotocograph (CTG) changes in women with symptomatic COVID-19 infection. STUDY DESIGN: 12 anonymised CTG traces from 2 hospitals in Spain were retrospectively analysed by 2 independent assessors. CTG parameters were studied based on fetal pathophysiological responses to inflammation and hypoxia that would be expected based on the pathogenesis of COVID-19 patients. Correlation was made with perinatal outcomes (Apgar score at 5 min and umbilical cord pH). RESULTS: All fetuses showed an increased baseline FHR > 10 percent compared to the initial recording, in addition to absence of accelerations. 10 out of 12 CTG traces (83.3 percent) demonstrated late or prolonged decelerations and 7 out of 12 fetuses (58.3 percent) showed absence of cycling. Not a single case of sinusoidal pattern was observed. ZigZag pattern was found in 4 CTG traces (33 percent). Excessive uterine activity was observed in all CTG traces where uterine activity was monitored (10 out of 12). Apgar scores at 5 min were normal (>7) and absence of metabolic acidosis was found in the umbilical cord arterial pH (pH > 7.0) in the cases that were available (11 and 9, respectively). CONCLUSION: Fetuses of COVID-19 patients showed a raised baseline FHR (>10 percent), loss of accelerations, late decelerations, ZigZag pattern and absence of cycling probably due to the effects of maternal pyrexia, maternal inflammatory response and the "cytokine storm". However, the perinatal outcomes appear to be favourable. Therefore, healthcare providers should optimise the maternal environment first to rectify the reactive CTG changes instead of performing an urgent operative intervention.

Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial.

OBJECTIVES: The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group. 6. To determine the risk of vertical transmission (intra-utero and intra-partum) of SARS-CoV-2. TRIAL DESIGN: Randomized double-blind placebo-controlled two-arm multicentre clinical trial to evaluate the safety and efficacy of HCQ to prevent and/or minimize SARS-CoV-2 infection during pregnancy. Participants will be randomized to receive a 14-day oral treatment course of HCQ or placebo, ratio 1:1. PARTICIPANTS: Study population: pregnant women undergoing routine prenatal follow up or attending emergency units at the participating hospitals who report either symptoms/signs suggestive of COVID-19 disease or close contact with a suspected or confirmed COVID-19 case. Inclusion criteria Women will be invited to participate in the trial and sign an informed consent if they meet the following inclusion criteria. • Presenting with fever (≥37.5°C) and/or one mild symptom suggestive of COVID-19 disease (cough, dyspnoea, chills, odynophagia, diarrhoea, muscle pain, anosmia, dysgeusia, headache) OR being contact* of a SARS-CoV-2 confirmed or suspected case in the past 14 days • More than 12 weeks of gestation (dated by ultrasonography) • Agreement to deliver in the study hospitals Exclusion criteria • Known hypersensitivity to HCQ or other 4-amonoquinoline compounds • History of retinopathy of any aetiology • Concomitant use of digoxin, cyclosporine, cimetidine • Known liver disease • Clinical history of cardiac pathology including known long QT syndrome • Unable to cooperate with the requirements of the study • Participating in other intervention studies • Delivery onset (characterized by painful uterine contractions and variable changes of the cervix, including some degree of effacement and slower progression of dilatation up to 5 cm for first and subsequent labours) The study participants will be stratified by clinical presentation and SARS-CoV-2 PCR results. Assignment of participants to study groups will be as follows: • SARS-CoV-2-PCR confirmed, infected pregnant women: a. symptomatic (n=100) b. asymptomatic (n=100) • SARS-CoV-2 PCR negative pregnant women in contact* with a SARS-CoV-2-infected confirmed or suspected case (n=514). *The ECDC definition of close contact will be followed. The trial will be conducted in five hospitals in Spain: Hospital Clínic of Barcelona, Hospital Sant Joan de Déu and Hospital de la Santa Creu i Sant Pau, in Barcelona, and HM Puerta del Sur and Hospital Universitario de Torrejón, in Madrid. INTERVENTION AND COMPARATOR: Participants will be randomized to HCQ (400 mg/day for three days, followed by 200 mg/day for 11 days) or placebo (2 tablets for three days, followed by one tablet for 11 days). MAIN OUTCOMES: The primary outcome is the number of PCR-confirmed infected pregnant women assessed from collected nasopharyngeal and oropharyngeal swabs at day 21 after treatment start (one week after treatment is completed). RANDOMISATION: Allocation of participants to study arms will be done centrally by the trial's Sponsor (the Barcelona Institute for Global Health, ISGlobal) by block randomization. This method will ensure balanced allocation to both arms. The electronic CRF will automatically assign a study number to each participant, depending on her study group and recruitment site. Each number will be related to a treatment number, which assigns them to one of the study arms. BLINDING (MASKING): Participants, caregivers, investigators and those assessing the outcomes will be blinded to group assignment. Study tablets (HCQ and placebo) will be identically packaged in small opaque bottles. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. TRIAL STATUS: Protocol version 1.0, from May 8th, 2020. Recruitment is ongoing (first patient recruited the 19th May 2020 and recruitment end anticipated by December 2020). TRIAL REGISTRATION: EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562 , retrospectively registered 1 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.