key: cord-0842753-ri4zd1xl authors: Pereira, Augusto; Cruz‐Melguizo, Sara; Adrien, Maria; Fuentes, Lucia; Marin, Eugenia; Perez‐Medina, Tirso title: Clinical course of Coronavirus Disease‐2019 (COVID‐19) in pregnancy date: 2020-05-22 journal: Acta Obstet Gynecol Scand DOI: 10.1111/aogs.13921 sha: 664855cf39ac092d62f9182f3e3fe14cf0cf8abb doc_id: 842753 cord_uid: ri4zd1xl INTRODUCTION: The aim of this study is to report our clinical experience in the management of pregnant women infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) during the first thirty days of the Coronavirus disease (COVID‐19) pandemic. MATERIAL AND METHODS: We reviewed clinical data from the first 60 pregnant women with COVID‐19 whose care was managed at Puerta de Hierro University Hospital, Madrid, Spain from March 14(th) to April 14(th), 2020. Demographic data, clinical findings, laboratory test results, imaging findings, treatment received, and outcomes were collected. An analysis of variance (Kruskal‐Wallis test) was performed to compare the medians of laboratory parameters. Fisher's exact test was used to evaluate categorical variables. A correspondence analysis was used to explore associations between variables. RESULTS: A total of 60 pregnant women were diagnosed with COVID‐19. The most common symptoms were fever and cough (75.5%, each) followed by dyspnea (37.8%). Forty‐one patients (68.6%) required hospital admission (18 due to disease worsening and 23 for delivery) of whom 21 patients (35%) underwent pharmacological treatment, including hydroxychloroquine, antivirals, antibiotics and tocilizumab. No renal or cardiac failures or maternal deaths were reported. Lymphopenia (50%), thrombocytopenia (25%), and elevated C‐reactive protein (CRP) (59%) were observed in the early stages of the disease. Median CRP, D‐dimer and the neutrophil/lymphocyte ratio were elevated. High CRP and D‐dimer levels were the parameters most frequently associated with severe pneumonia. The Neutrophil/lymphocyte ratio was found to be the most sensitive marker for disease improvement (relative risk: 6.65; 95% CI: 4.1‐5.9). During the study period, 18 of the women (78%) delivered vaginally. All newborns tested negative for SARS‐CoV‐2 and none of them were infected during breastfeeding. No SARS‐CoV‐2 was detected in placental tissue. CONCLUSIONS: Most of the pregnant COVID‐19 positive patients had a favorable clinical course. However, one‐third of them developed pneumonia, of whom 5% presented a critical clinical status. CRP and D‐dimer levels positively correlated with severe pneumonia and the neutrophil/lymphocyte ratio decreased as the patients improved clinically. Seventy‐eight percent of patients had a vaginal delivery. No vertical or horizontal transmissions were diagnosed in the neonates during labor or breastfeeding. The Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus responsible for the 2019 coronavirus disease . 1 COVID-19 can present with common cold-like symptoms to a more severe disease, such as pneumonia and Severe Acute Respiratory Syndrome, and may cause multiple organ failure and death. In the three months since the World Health Organization's worldwide Public Health emergency declaration (first COVID-19 case was reported on Dec 31, 2019), 2,3 more than 3,207,543 confirmed cases and 227,379 deaths were reported globally, including 212,917 cases and 24,275 deaths in Spain (as of April 30, 2020) . 4 Progression of the COVID-19 disease has been exponential; the first Spanish case was confirmed on Feb 1, 2020 (Canary Islands), followed by a second case ten days later (on the peninsula). Since then, an exponential growth of cases has continued. The global management of more than 3 million COVID-19 patients within a relatively short period has provided important data on epidemiological characteristics, viral transmission mechanisms, clinical symptoms, diagnosis as well as prevention and treatment of the disease. 1,2-11 However, the knowledge regarding clinical course and management of pregnant women with COVID-19 is still limited. The published literature to date indicates that pregnant women may be more vulnerable to COVID-19. The disease may be associated an increased risk of premature rupture of membranes, preterm delivery, fetal tachycardia, and fetal distress. Lymphocytopenia and elevated C-reactive protein (CRP) levels were observed in the majority of the COVID-19 pregnant women. 12, 13 A recently published systematic review suggested that there is a higher risk of severe maternal morbidity and perinatal death associated with COVID-19 infection, although maternal-fetal transmission was not detected. 14 The aim of our study was to describe our experience in the clinical management of 60 COVID-19 positive pregnant women who were attended to in our hospital during the first month of the epidemic in Spain. This article is protected by copyright. All rights reserved Data were collected from the first 60 pregnant women with COVID-19 who were treated at Puerta de Hierro University Hospital Madrid, Spain from March 14 th to April 14 th , 2020. Demographic variables collected were maternal age, type of exposure, gestational age, parity and information on the course of the pregnancy. In addition, the following clinical data were extracted from the medical records: symptoms, pneumonia diagnosis, CURB65 (Confusion, Urea, Respiratory rate, Blood pressure, 65 years) score for pneumonia severity (shown in figure 1 ), hospital admission, respiratory co-infections, type of delivery and treatment. All patients were seen in the Obstetrics Emergency Room either due to showing clinical symptoms (e.g., fever, cough and respiratory distress) or because they were in labor. COVID-19 diagnosis was confirmed by a quantitative reverse transcription PCR (RT-PCR) test for SARS-CoV-2 on nasopharyngeal swabs. All COVID-19 patients were classified as: a) Stage I, or early infection phase, if the patient was asymptomatic or if symptoms were fever, cough, diarrhea, or headache. B) Stage II, or lung disease phase, if patient presented dyspnea; c) Stage III, or hyperinflammatory phase, if sepsis, shock, or cardiac failure were diagnosed. Laboratory tests included a complete blood count, complete coagulation, renal and liver function tests, D-dimer, CRP, lactate dehydrogenase (LDH), creatine kinase, troponin I, ferritin and interleukin 6 levels. Moreover, patients with symptoms underwent chest radiography, obstetric ultrasound, fetal heart rate monitoring (if >23 weeks pregnant). For those prescribed hydroxychloroquine, an electrocardiogram (normal QTc interval=460) was also performed. Pregnant COVID-19 women were admitted to the hospital either because they were in labor or due to presenting symptoms or signs of disease complications (e.g., persistent fever, dyspnea, radiological diagnosis of pneumonia or oxygen saturations below 95%). The severity of pneumonia was classified following a radiography-based score in which each of the five lung lobes was assessed for degree of involvement and classified as normal: 0%, mild pneumonia: 1% to 25%, moderate pneumonia: 26% to 50%, or severe pneumonia: >50%. 15 The protocols implemented at our hospital were: a) Mainly symptomatic treatment for asymptomatic patients: rest at home and 1 gr. of Paracetamol every 8 hours, as needed, for fever or general discomfort; b) Protocol 1 for pregnant women with This article is protected by copyright. All rights reserved comorbidities and/or symptoms of upper respiratory tract infection; c) Protocol 2 for patients with mild pneumonia; d) Protocol 3 for patients with severe pneumonia and acute respiratory distress syndrome or for patients with poor clinical progression. The description of protocols 1, 2 and 3 are shown in figure 2. Protocols 2 and 3 required hospital admission and oxygen therapy. Vaginal delivery or cesarean section were indicated according to the protocols of the Spanish Society of Gynecology and Obstetrics. Additionally, caesarean sections were indicated for maternal benefit if a severe health disorder, such as Severe Acute Respiratory Syndrome, appeared. Delivery care was performed by obstetricians and all delivery staff followed the precautions and recommendations on infection prevention and control. All newborns were tested for SARS-CoV-2 in the first 2 hours after delivery by quantitative RT-PCR on samples from the respiratory tract (nasopharyngeal swab). In cases where the newborns had respiratory distress syndrome, the SARS-CoV-2 test was repeated 24 hours later. Samples of six placentas were also tested for SARS-CoV-2 by quantitative RT-PCR. Medians and ranges of all the variables were calculated and an analysis of variance (Kruskal-Wallis test) was performed to compare the medians of the laboratory parameters obtained on the first and last days of assessment. The Fisher´s exact test and the relative risk were used to evaluate associations between variables and the health status of pregnant COVID-19 patients; p-values less than 0.05 were considered significant. A correspondence analysis was used to explore associations between CRP, D-Dimer, and LDH levels, and lymphopenia and the progression of the disease in patients with mild, moderate and severe pneumonia. This analysis was also used to establish the value of the goodness-of-fit statistics and assign order to unordered variables. The statistical analysis was performed using R version 3.6.3 software (R Core Team, 2020). Approval was given by the hospital's Research Ethics Committee (reference number: PI 78/20; date of approval: April 14, 2020) and an Informed Consent was signed by all patients. A total of 60 pregnant women were confirmed to have COVID-19 by an RT-PCR test (cobas ® SARS-CoV-2 by Roche Diagnostics) for SARS-CoV-2 on nasopharyngeal swabs. The demographic characteristics of the study population are shown in table 1. More than one-third of patients were infected at home or by relatives. The median maternal age was 34 years (range, 22-43 years). The median gestational age was 32 weeks (range, 5-41 weeks). During the first 5 days of illness, patients were asymptomatic but already contagious. Subsequently, 25% remained asymptomatic, 70% developed mild or moderate symptoms, and 5% severe to critical symptoms. The most common symptoms among our patients were fever and This article is protected by copyright. All rights reserved During the study period, twenty-three women with COVID-19 delivered in our Hospital; five of them had cesarean section (one due to maternal respiratory failure at 34 +2 weeks gestation with uterine activity and breech presentation, two for non-progression of labor, one for induction failure and one due to hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome) and 18 had vaginal deliveries. Placental tissue from 6 cases was sent to the Microbiology Unit; SARS-CoV-2 was not identified in any of the placental samples. Two of the 23 deliveries were preterm. The clinical course in the puerperium was uncomplicated for 22 patients; only one patient (a HELLP syndrome) required ICU admission. The twenty-three newborns tested negative for SARS-CoV-2 by RT-PCR nasopharyngeal swabs. Twenty-one of the 23 neonates were breastfed and two of them needed admission to the Neonatal Intensive Care Unit: one because of a respiratory distress syndrome and the other due to hemolytic anemia. The statistical analysis demonstrated that continuous decreases of NLR was shown to be the most sensitive marker for disease improvement (relative risk: 6.65; 95% CI: 4.1-5.9). Furthermore, a multivariate analysis with a correspondence analysis revealed an association between CRP and D-dimer levels with severe pneumonia (p<0.000). Likewise, elevated neutrophil counts are associated with severe pneumonia (p =0.024). According to the evolution of our patients, we describe COVID-19 as a three phase disease: The early infection phase is a viral response phase, where the most common symptoms are fever, cough, diarrhea, or headache. Seventy percent of our patients were asymptomatic or had mild symptoms at the time of diagnosis; they only received symptomatic treatment and the disease did not progress further in any of these cases. Lymphopenia (50%) and thrombocytopenia (25%) were observed in early stages of disease, and close to 60% of patients had an increased CRP (table 4 ). In the lung disease phase, SARS-CoV-2 can cause massive damage to the liver and renal tissues which results from an excessive release of cytokines that, in turn, induces a severe proinflammatory response in the lungs which frequently causes dyspnea and hypoxemia. In our study, 38% of our patients showed dyspnea and 40% of symptomatic patients presented with pneumonia. Moderate or severe pro-inflammatory response in the lung accounts for 15% of them (table 2) . Transitory hepatic disorder was present in 25-50% of pregnant women with pneumonia (table 3) . This article is protected by copyright. All rights reserved During the observation period, lymphopenia (40%), and increased NLR (85%), CRP (75%), and D-dimer (95%) levels were present in pregnant COVID-19 patients, which is consistent with the published medical data. [12] [13] [14] Moreover our study demonstrated NLR decrease as a potential marker of patient improvement. The hyperinflammatory phase occurs when an excessive immune and inflammatory response arises. As we previously stated above, critical status in pregnant COVID-19 women accounts for 5%. 14 interleukin 6 and ferritin levels, were significantly elevated during the critical infection phase. However, no patients developed hepatic, renal or cardiac failure in our cohort. In general terms, respiratory viral infections increase the risk of bacterial infections leading to a more severe respiratory disease. In our cohort, the most severe cases had neutrophilia and a concurrent bacterial sepsis (one with pneumococcus and one with methicillin-resistant staphylococcus aureus) or were associated with HELLP syndrome. For this reason, we believe that pregnant COVID-19 women with pneumonia should be investigated for the early diagnosis and treatment of possible bacterial respiratory co-infections. women is similar to that of the general population. [16] [17] [18] In our experience, the normal course of pregnancy was altered in 18% of COVID-19 positive women. In our cohort, 5% had preeclampsia, 5% fetal growth restriction, 5% preterm birth and 3% had coagulopathy. The incidence of preeclampsia in non-COVID-19 pregnant population is reported to be 3.4% to 4.6%. 19, 20 One of our patients developed a HELLP syndrome and two had preeclampsia. There could be an association between COVID-19 and preeclampsia as it has been described that SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor for cell entry. 21 Coronavirus infection is often complicated by coagulopathy, which is associated with a high mortality rate. Additionally, high D-dimer levels is a sign of coagulopathy and indicates poor prognosis. [22] [23] [24] As in non-pregnant women, D-dimer may be increased in pregnant and puerperal women with coronavirus infection. In fact, our study showed that D-dimer increases in those patients with severe clinical features. Given the increased thromboembolic risk during pregnancy and puerperium, consideration should be given to prescribing thromboprophylaxis to these patients. Based on our experience and several observations, 25 we have developed a protocol to initiate low molecular weight heparin at prophylactic dose for at least 10 days after delivery. We recommend increasing low molecular weight heparin to therapeutic dose for 6 weeks after delivery, in those patients with higher thromboembolic risk. This article is protected by copyright. All rights reserved Finally, the scarce evidence published until now suggests the lack of vertical transmission, as SARS-CoV-2 was not detected in the placental, amniotic fluid or neonate samples immediately after birth. 26-28 However, caesarean sections were performed in almost all previously published cases. 14 At our hospital, 18 of 23 COVID-19 positive women had a vaginal delivery and the delivery care followed the World Health Organization recommendations. In all of our 60 cases, neonates tested negative, irrespective of the mode of delivery. Therefore, we hypothesize that there is no vertical transmission through the birth canal. The Breastfeeding Committee at Puerta de Hierro University Hospital approved breastfeeding of newborns by mothers with COVID-19, provided that adequate protection measures were taken and World Health Organization and United Nations International Children's Emergency Fund recommendations were followed. 29, 30 We did not diagnose COVID-19 any of the breast-fed infants. The present study has several limitations resulting from its retrospective design and small sample size. This study was carried out in the first 4 weeks of an epidemic that has caused devastating consequences in our country. The scarcity of diagnostic tests, limited knowledge about the disease, the limited access to antiretroviral drugs, restricted hospital capacity for admission and intensive care could have affected the clinical outcomes. Therefore, our results should be interpreted with caution and their generalizability may be limited. In 70% of our cases, the clinical course of COVID-19 in pregnant women was mild. Only 30% of patients had pneumonia, 5% of which developed a critical condition. High CRP and D-dimer levels correlated with severe pneumonia, while an NLR decrease suggested a favorable outcome for pregnant women. Vaginal delivery appears to be safe, as 78% of our patients had vaginal delivery and none of the newborns were infected. 1. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270-273. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV) Report on current pneumonia epidemic situation in the city Emerging coronaviruses: genome structure, re-plication, and pathogenesis A novel coronavirus from patients with pneumonia in China Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia A new coronavirus associated with human respiratory disease in China Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan Real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in Wuhan, China, as at 22 Drug treatment options for the 2019-new coronavirus (2019-nCoV) Novel corona virus disease (COVID-19) in pregnancy: what clinical recommendations to follow? Global interim guidance on coronavirus disease COVID-19) during pregnancy and puerperium from FIGO and allied partners: Information for healthcare professionals All rights reserved 14. Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study Pregnancy and Perinatal Outcomes of Women With Coronavirus Disease (COVID-19) Pneumonia: A Preliminary Analysis Global and regional estimates of preeclampsia and eclampsia: a systematic review Pre-eclampsia rates in the United States, 1980-2010: ageperiod-cohort analysis The species Severe acute respiratory syndromerelated coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical features of patients infected with 2019 novel coronavirus in Wuhan The versatile heparin in COVID-19 Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Lack of Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2, China. Emerg Infect Dis An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes Protecting, promoting, and supporting breastfeeding in facilities providing maternity and newborn services: the revised Baby-friendly Hospital Department of Nutrition for Health and Development World Health Organization. World Health Organization Accepted Article