key: cord-0741615-05vwtxix
authors: Mendoza, Manel; Garcia‐Ruiz, Itziar; Maiz, Nerea; Rodo, Carlota; Garcia‐Manau, Pablo; Serrano, Berta; Lopez‐Martinez, Rosa Maria; Balcells, Joan; Fernandez‐Hidalgo, Nuria; Carreras, Elena; Suy, Anna
title: Preeclampsia‐like syndrome induced by severe COVID‐19: a prospective observational study
date: 2020-06-01
journal: BJOG
DOI: 10.1111/1471-0528.16339
sha: 9443d6ba68f3e88779c6d555d235e7daa89ec131
doc_id: 741615
cord_uid: 05vwtxix

OBJECTIVES: To investigate the incidence of clinical, ultrasonographic and biochemical findings related to preeclampsia (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: 42 consecutive pregnancies were recruited and classified into two groups: severe and nonsevere 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: 34 cases were classified as nonsevere and 8 as severe COVID‐19. Six (14.3%) women presented signs and symptoms of PE, all six being among the severe COVID‐19 cases (75.0%). However, abnormal sFlt‐1/PlGF and UtAPI could only be demonstrated in one case. Two cases 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. Health care providers should be aware of its existence and monitor pregnancies with suspected preeclampsia with caution.

On March 11, 2020 , the World Health Organization (WHO) declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak a pandemic disease, given its increasing number of cases worldwide. 1 Studies have shown that the disease caused by SARS-CoV-2, named as COVID-19 (coronavirus disease 2019) typically presents with fever, dry cough, and fatigue; nevertheless, up to 14% of the cases can evolve to severe pneumonia and 5% to severe acute respiratory syndrome (SARS) both requiring admission to intensive care for intensive respiratory support. 2 Whereas COVID-19 is primarily a respiratory infection, it has important systemic effects including hypertension, kidney disease, thrombocytopenia, and liver injury. [3] [4] [5] [6] Since SARS-CoV-2 is believed to invade the host through the cell entry receptor angiotensin-converting enzyme 2 (ACE2), these signs and symptoms in SARS-CoV-2 infection are thought to be due to the vasoconstriction resulting from the dysfunction of the renin-angiotensin system. 7, 8 By contrast, clinical features of preeclampsia (PE) are mainly consequence of the endothelial damage originated by placental oxidative stress and antiangiogenic status, which leads to the appearance of hypertension and proteinuria, elevated liver enzymes, renal failure, or thrombocytopenia among others. 9,10 An increased incidence of PE has been reported among mothers infected with SARS-CoV-2 compared to general population. 11 Misdiagnosis, however, might have occurred in some of these cases since COVID-19 and PE have overlapping clinical features. Therefore, differential diagnosis might be challenging in COVID-19 pregnant women presenting with hypertension and proteinuria, thrombocytopenia, or elevated liver enzymes. 10 Thus, the aim of this study was to investigate the prevalence of clinical, ultrasonographic, and biochemical findings related to PE in women with SARS-CoV-2 infection and to assess their accuracy to differentiate between actual PE and PE-like features associated with COVID-19.

We carried out a prospective cohort study of all consecutive pregnant women at >20 weeks of gestation that presented to the emergency department of our tertiary care center for suspicion of COVID-19 (dry cough and fever) and had laboratory-confirmed SARS-CoV-2 infection, between March 13, and April 10, 2020. Patients were not actively involved in the research.

Patients were classified in two groups: severe and non-severe COVID-19, according to the occurrence of severe pneumonia. The laboratory and clinical data were prospectively recorded in a Accepted Article database. The recorded data included the following: platelet count (per microliter), D-dimer (µg/L), lactate dehydrogenase (U/L), aspartate aminotransferase (U/L), alanine amninotransferase (U/L), urine protein to creatinine ratio (mg/g), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), mean arterial pressure (mmHg), creatinine (mg/dL), and gestational age (GA) in weeks. GA to describe particular cases was expressed in weeks + days. Mean arterial pressure was calculated as: 1/3*(systolic blood pressure) + 2/3*(diastolic blood pressure). Maternal baseline characteristics were compared between groups. In severe cases, data was analyzed at three different moments during COVID-19: before, during, and after intensive care unit (ICU) admission for severe pneumonia.

According to the WHO guidance, laboratory confirmation for SARS-CoV-2 was defined as a positive result of real-time reverse transcriptase-polymerase chain reaction (RTPCR) assay of nasal and pharyngeal swabs. 12 PE was defined as new onset of high blood pressure (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) or worsening of previous high blood pressure added to new onset proteinuria (protein to creatinine ratio >300) or worsening of previous proteinuria, or to at least one of the following signs and symptoms of severe PE: cerebral or visual symptoms, elevation of liver enzymes to twice normal concentration, platelet count less than 100,000/µL, serum creatinine concentrations greater than 1.1 mg/dL, or pulmonary edema. 10 The HELLP syndrome is frequently considered a variant of PE. Diagnostic criteria for HELLP syndrome are haemolysis with increased LDH (> 600 U/L) and AST (≥ 70 U/L), and platelets < 100,000/µL. 13 In women with new-onset hypertension, uterine artery pulsatility index (UtAPI) was assessed by transabdominal Doppler ultrasound and maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in pg/mL were determined by means of the fully automated Elecsys assays for sFlt-1 and PlGF on an electrochemiluminescenceimmunoassay platform (cobas e analyzers; Roche® Diagnostics, Rotkreuz, Switzerland). 14, 15 The sFlt-1/PlGF was then calculated. UtAPI above the 95 th centile for gestational age, and sFlt-1/PlGF values ≥85 (at <34 weeks) or ≥110 (at ≥34 weeks) were considered highly suggestive of underlying placental disease. [16] [17] [18] [19] Statistical analysis

This article is protected by copyright. All rights reserved R Commander, R package version 2.3-1 software was used for statistical analysis. Categorical data were reported as frequency and percentage and comparisons between severity groups were estimated by chi-square or Fisher tests, as appropriate. Continuous variables were described as median and interquartile (IQR) range and Mann-Whitney U test was used to assess differences between severity groups. Statistical significance level was set at p<0.05. (Table 1) .

Before severe pneumonia, all eight women were normotensive, had normal platelet count, liver enzymes, LDH, and proteinuria and only one case with UtAPI above the 95 th centile was identified. During severe pneumonia, the most frequent findings were: elevated liver enzymes to twice normal concentrations (87.5%), proteinuria >300mg/g (75.0%), and hypertension (62.5%) ( Figure 1 ). No cases with creatinine >1.1mg/dL or platelet count <100,000/µL were found; nevertheless, one case presented mild thrombocytopenia (platelet count <150,000/µL). sFlt-1/PlGF ≥85/110 and UtAPI >95 th centile were present only in one woman. Only one case with LDH >600 UI/L was identified. As a result of these findings, six (75.0%) had diagnostic criteria of PE and/or HELLP syndrome. Cesarean delivery was performed during ICU stay in four cases.

HELLP syndrome was the indication for delivery in case 1 (at a GA of 30+1) and SARS worsening in cases 3, 4, and 7 (at a GA of 37+6, 36+6, and 28+3, respectively). After recovery from severe pneumonia, hypertensive therapy was no longer required in all cases and only the woman that had presented the sFlt-1/PlGF >110, LDH>600 and UtAPI above the 95 th centile,

This article is protected by copyright. All rights reserved remained with PE diagnostic criteria (more details on clinical and laboratory findings and their evolution in severe cases can be seen in Table 2 and Figure 1 ).

This study shows that 14.3% of COVID-19 pregnant women develop PE features; however, they only appeared in COVID-19 cases complicated by severe pneumonia. In this situation, PE/HELLP diagnostic criteria were found in 6 (75.0%) of the cases; nevertheless, abnormal angiogenic status, increased LDH and placental underperfusion could only be confirmed in one of them, which indicates that this case was probably an actual PE. These findings suggest that the signs and symptoms compatible with PE/HELLP present in five out of these six cases, could be derived from the complex polypharmacy administrated or from the renal and cardiovascular dysfunction for severe SARS-CoV-2 infection. In our cohort, only two of these six cases remained pregnant after severe pneumonia recovery, and then, all PE/HELLP features recovered spontaneously. PE and HELLP syndrome do not resolve spontaneously and delivery is the only definitive cure. For these reasons, we believe that the five women with PE/HELLP signs and symptoms, and normal sFlt-1/PlGF, UtAPI and LDH<600, had developed a PE-like syndrome.

To our knowledge this is the first study to describe the incidence of signs and symptoms of PE in a relatively large cohort of pregnancies with COVID-19 and to show that a PE-like syndrome could be induced by severe COVID-19. Furthermore, our findings are of great value to improve maternal care of pregnancies with severe pneumonia due to COVID-19.

This study has several limitations. First, this is a small series and the results should be considered with caution. Further research is needed to better understand the systemic consequences of COVID-19 in pregnant women.. Second, only five women with PE-like syndrome are reported, which could make our findings not applicable to all pregnancies with severe pneumonia due to COVID-19. Third, only two of the five women that developed a PE-like syndrome remained pregnant after severe pneumonia and despite the PE-like syndrome recovered spontaneously in both, we cannot affirm that the three other cases did not improve due to delivery. Nevertheless, we believe that the PE-like syndrome alone may not be an obstetric indication for delivery, since it

This article is protected by copyright. All rights reserved seems that it might not be a placental complication itself, but one of the clinical manifestations of severe COVID-19. Finally, although UtAPI and sFlt-1/PlGF ratio have a high negative predictive value to predict the short-term absence of PE, they are not diagnostic criteria of PE; 27,28 thus, we cannot categorically state that the case with PE features and elevated UtAPI and sFlt-1/PlGF was an actual PE and not a PE-like syndrome.

Several disorders have previously proved to imitate PE since they share some of the clinical and laboratory findings of patients with PE. The pathophysiologic causes of these conditions include vasospasm, platelet activation or destruction, microvascular thrombosis, endothelial cell dysfunction, and reduced tissue perfusion. Some of these disorders include gestational hypertension, chronic kidney disease, acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura, haemolytic uremic syndrome, acute exacerbation of systemic lupus erythematosus, severe hypothyroidism, and sepsis. 17, 20, 21 Differential diagnosis may be a challenge to caregivers due to the overlap of diagnostic criteria among them. Additionally, some of them are potentially lifethreatening for both the mother and the fetus; thus, accurate diagnosis is important since the management and prognosis of these conditions differ widely. Recent studies have shown that angiogenic factors support the differential diagnosis between PE and some of its imitators. 17, 22, 23 PlGF and sFlt-1 are placenta-related angiogenic factors that are highly specific of placental insufficiency. 24 In PE, the placenta fails to properly invade and remodel maternal uterine spiral arteries, leading to impaired perfusion and placental oxidative stress. 25, 26 This condition leads to increased UtAPI and to an antiangiogenic status with increased s-Flt-1/PlGF ratio due to upregulation of sFlt-1 and down-regulation of PlGF. 9, 27 The identification of an sFlt-1/PlGF imbalance is detectable in the maternal circulation at least five weeks before the onset of clinical PE. 24 

This article is protected by copyright. All rights reserved pregnancies with severe COVID-19. In our cohort, the case 1 was probably misdiagnosed as HELLP syndrome which in addition to the concurrence of SARS, influenced the indication of delivery. The fact that the sFlt-1/PlGF results were not available at the time of maternal condition worsening, and the scarce evidence available at that time of the consequences of COVID-19 during pregnancy, prompted the delivery indication at 30+1 weeks. After the experience with this first case, a more conservative management was adopted in the following cases that developed PElike syndrome. Fortunately, they completely recovered after severe pneumonia and became normotensive again with no antihypertensive drugs and without being delivered.

Pregnant women with severe COVID-19 could develop a PE-like syndrome, which might be distinguished from actual PE by sFlt-1/PlGF, LDH and UtAPI assessment. Therefore, health care providers should be aware of its existence and monitor pregnancies with suspected PE with caution. PE-like syndrome might not be an indication for earlier delivery in itself since it might not be a placental complication and could resolve spontaneously after recovery from severe pneumonia.

Manel Mendoza and Itziar Garcia received lecture fees by Roche diagnostics. The other authors have no conflicts of interest to declare. Completed disclosure of interest forms are available to view online as supporting information.

AS and EC had full access to all of the data in the study and take responsibility for the integrity of 

This study was approved by the Vall d'Hebron University Hospital Ethics Committee (PR(AMI)181/2020) on March 13, 2020. Written informed consent was waived due to the rapid emergence of this infectous disease. However, verbal informed consent was obtained in all patients, which was included in the patient's medical record.

None. 

WHO Director-General's opening remarks at the media briefing on COVID-19 -11

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Kidney disease is associated with inhospital death of patients with COVID-19

Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis

Angiotensin Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

The Science Underlying COVID-19: Implications for the Cardiovascular System

Association between adverse pregnancy outcome and imbalance in angiogenic regulators and oxidative stress biomarkers in gestational hypertension and preeclampsia

Accepted Article This article is protected by copyright. All rights reserved

American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy

Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy

Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and metaanalysis

Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance

The HELLP syndrome: clinical issues and management. A Review

Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11-14 weeks of gestation

Multicenter evaluation of the first automated Elecsys sFlt-1 and PlGF assays in normal pregnancies and preeclampsia

Reference ranges for uterine artery mean pulsatility index at 11-41 weeks of gestation

The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients

Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice

Accepted Article This article is protected by copyright. All rights reserved

Distinctive patterns of placental lesions in pre-eclampsia vs small-for-gestational age and their association with fetoplacental Doppler

Imitators of severe pre-eclampsia

Severe hypothyroidism causing pre-eclampsia-like syndrome

Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers

Clinical usefulness of serum levels of soluble fms-like tyrosine kinase 1/placental growth factor ratio to rule out preeclampsia in women with new-onset lupus nephritis during pregnancy

Circulating angiogenic factors and the risk of preeclampsia

In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies

Interaction of interstitial trophoblast with placental bed capillaries and venules of normotensive and pre-eclamptic pregnancies

Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia

Recommendations | PlGF-based testing to help diagnose suspected pre-eclampsia (Triage PlGF test, Elecsys immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1-2-3 test

PlGF plus Kryptor PE ratio). NICE Guidance

We thank all the physicians who facilitated the recruitment of individuals at the Hospital Universitari Vall d'Hebron and the participants who agreed to take part in the study.

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