key: cord-0841119-oxjzdngx authors: Jiménez‐Lozano, Inés; Caro‐Teller, José Manuel; Fernández‐Hidalgo, Nuria; Miarons, Marta; Frick, Marie Antoinette; Batllori Badia, Emma; Serrano, Berta; Parramon‐Teixidó, Carlos Javier; Camba‐Longueira, Fátima; Moral‐Pumarega, Maria Teresa; San Juan‐Garrido, Rafael; Cabañas Poy, Maria Josep; Suy, Anna; Gorgas Torner, Maria Queralt title: Safety of tocilizumab in COVID‐19 pregnant women and their newborn: A retrospective study date: 2021-02-26 journal: J Clin Pharm Ther DOI: 10.1111/jcpt.13394 sha: 7cf07e366989a9fe7750f24eaec06d3d06fb83cf doc_id: 841119 cord_uid: oxjzdngx 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. We conducted a retrospective study of pregnant woman treated with tocilizumab for COVID-19 between March 1 to April 31 2020, at two tertiary Spanish hospitals, the Vall d'Hebron University Hospital, Barcelona and the 12 de Octubre University Hospital, Madrid. A laboratory-confirmed case was defined as a patient with a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) SARS-CoV-2-positive result in any respiratory sample. The date of onset of disease was defined as the day when the symptoms were first noticed. The main outcome was adverse drug events (ADEs) related to tocilizumab administration in pregnant women and their offspring. Secondary outcomes were maternal and perinatal outcomes. Treatment with oral lopinavir/ritonavir, azithromycin and hydroxychloroquine was initiated following clinical practice guidelines for COVID-19 proposed by the Spanish Ministry of Health 10 and local protocols adapted to each centre. After subsequent protocols' amendment, lopinavir/ritonavir was removed in 12 de Octubre Hospital from mid-April onwards, and azithromycin was removed from the last week of April onwards in Vall d'Hebron Hospital. Subcutaneous interferon beta 1B (IFN β-1B) was used at the beginning of the pandemic if unfavourable evolution because of a potential role in reducing SARS complications. Intravenous tocilizumab was considered in patients that fulfilled the following criteria in both hospitals: (1) bilateral pulmonary infiltrates or radiological and/or gasometric worsening in 24 h in hospitalized patients; (2) respiratory failure; (3) IL-6 levels ≥40 ng/L (or PCR ≥ 100 mg/L) and/or D-dimer levels ≥1000 ng/ml and/or ferritin ≥700 ng/ml. When IL-6 levels were not available, the clinic criterion was used to start tocilizumab. Initially, a 600 mg dose of tocilizumab followed by a second infusion of 600 mg (in patients weighing ≥80 kg) or 400 mg (in patients weighting <80 kg) with an interval of 12 h between both doses was considered. After Spanish protocol amendment in mid-March, a 600 mg dose was established to patients weighing >75 kg, otherwise 400 mg. A second equal dose was considered in patients with a poor early response. We retrospectively collected sociodemographic characteristics, past medical and obstetric history, usual medication, gestational age and current obstetric pathology. Laboratory and radiologic findings, vital signs and symptoms, microbiological tests others than SARS-CoV-2 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. adverse events, COVID-19, maternal safety, newborn safety, tocilizumab RT-PCR on respiratory samples, clinical signs or symptoms, treatment and supportive measures needed and ADEs were evaluated at admission, at 48 h and weekly during hospital admission. Maternal and foetal outcomes were obtained from patients' medical records. Gestational age at pregnancy termination and type of labour were also collected. Neonatal SARS-CoV-2 nasopharyngeal aspirate samples, somatometric evaluation including weight, length and head circumference, neonatal ICU admission and follow-up at 14 and 28 days were also collected. Data were recorded in the Research Electronic Data Capture software (REDCap, Vanderbilt University). The date of data cut-off for outcomes was 30 September 2020, to allow 28 days follow-up for all newborns. ADEs cause-effect relationship was evaluated using the Naranjo's algorithm. 11 Briefly, this questionnaire is one of the more commonly used algorithms for determining the likelihood of whether an adverse drug reaction is actually due to the drug rather than the result of other factors. Probability is assigned via a score termed definite, probable, possible or doubtful, avoiding data omissions or inaccuracy among evaluators. 12,13 Descriptive characteristics were calculated for the variables of interest. Continuous variables were expressed median and range. Categorical variables were summarized as absolute number and relative frequencies. The study included 12 COVID-19 pregnant women, 6 from of Vall d'Hebron University Hospital (of 49 admitted) and 6 from of 12 de Octubre Hospital (of 38 admitted). Median (range) age and gestational age at admission were 37 (23-50) years and 27.7 (18.0-36.4) weeks, respectively. One patient had an increased uterine artery resistance index, and two patients had gestational diabetes. Baseline analytical characteristics at admission are shown in Table 1 . Median hospital length of stay was 11.5 (7-42) days. Oxygen support was required in all 12 patients; seven (58%) of them required high flow oxygen, two (17%) required noninvasive ventilation and 3 (25%) required invasive mechanical ventilation (these last 3 patients for 2, 8 and 21 days, respectively). Five patients were admitted to ICU due to acute respiratory failure, with a median stay of 6 days (2-27 days). Eight of 12 patients (66.7%) received lopinavir/ritonavir, azithromycin and hydroxychloroquine. Azithromycin was omitted in the other 4 patients and lopinavir-ritonavir in 3 of these 4 patients, as per protocol's amendments during the study period. Lopinavir/ritonavir was discontinued early in 3 patients due to diarrhoea and in 1 patient due to vomiting. Empiric antibiotic therapy was initially added to 10 patients (ceftriaxone in 7; cefuroxime in 1; amoxicillin-clavulanate in 1; levofloxacin in 1) due to bacterial superinfection suspicion. One patient received IFN β-1B. All patients received thromboprophylaxis with low-molecular-weight heparin at standard (n = 11) or high prophylaxis doses (n = 1). Two patients received methylprednisolone, for 3 and 15 days, respectively. Tocilizumab dosing, and respiratory and analytical data immediately before tocilizumab administration are shown in Table 2 . Eight patients (67%) received a single dose of tocilizumab and 4 (33%) received two doses. Dosing followed current protocol in all patients but 1, which was above 75 kg and received 400 mg of tocilizumab (no specified reasons). Analytical data before and after tocilizumab dosing are shown in Figure 1 . All 12 pregnancies resulted in live births. Median gestational age at delivery was 38.9 weeks (27.7-40.6). Ten patients (83.3%) were discharged before delivery due to COVID-19 improvement and were admitted subsequently for pregnancy termination. Caesarean section was performed in 7 patients due to urgent maternal conditions (2), prolonged labour (1) Cytolytic hepatotoxicity was observed in 2 patients. Evolution of hepatic parameters is shown in Figure 3 . Follow-up allowed confirming levels' normalization in one patient before discharge, and the other had a downward trend at discharge. According to Naranjo's causality algorithm, both CMV reactivation and hepatotoxicity adverse events were classified as possibly related to tocilizumab administration. To our knowledge, this is the first report that specifically as- involving 100 patients treated with tocilizumab, two patients died due to septic shock and 1 patient had gastrointestinal perforation requiring urgent surgery. However, other authors did not find this increased risk of infection. 18 Nevertheless, there is no conclusive evidence explaining which of these adverse effects were directly related to tocilizumab therapy. Since IL-6 plays a crucial role in B-cell proliferation, antibody production and T-cell differentiation and cytotoxicity, the inhibition of the complex formation with its receptor may trigger the dysfunction of antigen-specific CD8-positive T cells, which is associated with CMV reactivation. 16 In fact, CMV reactivation has been reported previously in a few publications, basically in immunosuppressed patients who were also treated with other immunosuppressive agents, as is the case of our patient, and in some occasions shortly after tocilizumab initiation. [16] [17] [18] [19] [20] [21] [22] Noteworthy, our patient was also treated with methylprednisolone during 15 days, which might add immunosuppressive effects and contribute to viral reactivation. Evidence supports corticosteroids association with viral infections, including CMV, either in immunocompetent or immunocompromised patients. 9, 23, 24 The incidence of mild liver injury in hospitalized patients with COVID-19 ranges from 14% to 53%, which is higher in more se- shortly before conception or early in the first trimester. 30 However, an increased rate of preterm birth and low birth weight children was observed in pregnant patients with rheumatoid arthritis. Of the patients exposed in the second and third trimesters, an incidence of premature birth was observed in 6 of 17 neonates and a low birth weight (<2500 g) in 4 of 17 neonates. Although it cannot be ruled out that tocilizumab exposure contributes to this risk, the poor control of the disease (measured by the increase in IL-6 and IL-18) has also been associated with worse results in terms of foetal abnormalities, preterm birth and low birth weight. Retrospective data from another report showed no increased rates of spontaneous abortion or congenital abnormalities in 61 patients with rheumatic disease exposed to tocilizumab. 31 F I G U R E 2 Cytomegalovirus evolution. Evolution of cytomegalovirus viral load and serology tests in patient 2. CMV, Cytomegalovirus; IgM, Immunoglobulin M; IgG, Immunoglobulin G; PCR, polymerasechain-reaction F I G U R E 3 Evolution of hepatic parameters. Evolution of hepatic parameters in the two patients in whom hepatic involvement was possibly associated with tocilizumab administration. AST, aspartate aminotransferase; ALT, aspartate aminotransferase; AP, Alkaline phosphatase; GGT, Gamma-glutamyltransferase We did not observe any congenital malformation, apart of the cleft lip and palate in one foetus, which was diagnosed before COVID-19 and tocilizumab treatment in the mother. CMV congenital infection in the newborn whose mother had CMV reactivation reveals the risk of vertical transmission in previously CMV immune pregnant women, although the severity of the infection tends to be less and is usually asymptomatic for both mother and newborn. 32 The potential role of tocilizumab in COVID-19 patients is still un- Although no routine use of tocilizumab for COVID-19 is recommended at this moment, upcoming clinical trials' results might add evidence to ascertain tocilizumab benefits. 9 This study has some limitations. Methodology sample size of the study was small, which precludes definitive conclusions to be reached, but gives preliminary results of ADE related to the use of tocilizumab in pregnant women. Also, co-medication could be a potential confounding factor that might contribute to ADE development. Finally, data inaccuracy inherent to the retrospective use of databases may occur, but careful review of computerized medical records allowed us to accurately evaluate drug exposure and ADE. Tocilizumab has shown no detrimental effects in COVID-19 pregnant women and their newborns in our setting. Although there was a low risk of secondary infections observed, close monitoring of infections should be considered especially if other immunosuppressive agents are used. All authors report no conflict of interest and are alone responsible for the content and the writing of the article. The institutional review board of both centres provided ethical clearance (reference number: VHI-TOC-2020-01), on 19 June 2020 at Vall d'Hebron Hospital and on 6 July 2020 at 12 de Octubre Hospital, and granted a waiver of informed consent due to retrospective data collection. The institutional review board of both centres granted a waiver of informed consent due to retrospective data collection. Does not apply. This manuscript has not been published previously, neither is not under consideration for publication elsewhere. Its publication is approved by all authors and also by the responsible authorities where the work was carried out, specifically, by Ethics' Committees of both hospitals and Spanish Agency of Medicines and Medical Devices. If the manuscript is accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder. The data that support the findings of this study are available within the article. Inés Jiménez-Lozano https://orcid.org/0000-0003-4473-6768 Marta Miarons https://orcid.org/0000-0001-7847-1580 Carlos Javier Parramon-Teixidó https://orcid. org/0000-0001-8023-3979 Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know Update: characteristics of symptomatic women of reproductive age with laboratoryconfirmed SARS-CoV-2 infection by pregnancy status -United States Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome Maternal and perinatal outcomes and pharmacological management of Covid-19 infection in pregnancy: a systematic review protocol COVID-19) Treatment Guidelines. Bethesda, MD: National Institutes of Health Why are pregnant women susceptible to COVID-19? 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