Lamazou et al. BMC Infectious Diseases (2020) 20:845 https://doi.org/10.1186/s12879-020-05551-0 CASE REPORT Open Access COVID-19 infection in first trimester of pregnancy marked by a liver cytolysis in a woman previously treated by hydroxychloroquine for repeated implantation failure: a case report F. Lamazou1* , P. Oger1, R. Dieli-crimi2,3, A. Guerin4, V. Letouzey5, S. Octernaud6, V. Place6, P. Calès7,8, P. Descamps9,10 and L. Delaroche1,11 Abstract Background: In December 2019, a new disease (COVID-19) caused by a novel coronavirus called SARS-CoV-2 emerged in China and spread to many other countries. There is only limited data about the clinical features of COVID-19 during pregnancy, especially in first trimester. Case presentation: We report a COVID-19 infection in a 35 years-old patient in first trimester of pregnancy and its consequent medical care. At 7 weeks of pregnancy, the patient, who did not have any pregestational comorbidities, complained of intense nausea and asthenia. An important liver cytolysis was discovered with biological perturbations of transaminases levels. No respiratory symptoms were recorded. Classical viral aetiologies and drug-related toxicity were discarded. Because of the aggravation of the symptoms and the occurrence of the breathlessness, the patient was tested for the COVID-19 in a nasopharyngeal swab. The RTq-PCR assay indicated the presence of SARS-CoV-2 RNA. In the absence of severe symptoms, the patient was monitored at home according to the French government guidelines. After a few days, the symptoms resolved without any complications. The pregnancy is still ongoing without any visible sequelae on the foetus so far. Conclusions: This first case illustrated the difficulty of COVID-19 diagnosis in patients with isolated digestive symptoms in first trimester of pregnancy that could be confused with gravida hyperemesis. Monitoring of pregnancy after an episode of COVID-19 should be strengthened with bimonthly foetal growth ultrasounds and doppler assessments because of the risks for intrauterine growth restriction. Comprehensive data on larger numbers of first trimester gravid women with COVID-19 are required to better understanding the overall impact of SARS- CoV-2 on maternal and birth outcomes. Keywords: COVID-19 , First trimester , Hepatic cytolysis , Liver , Case report , Hydroxychloroquine * Correspondence: dr.lamazou@gmail.com 1 Ramsay Générale de Santé, Hôpital Privé de Parly 2, Institut Fertilité Maternité Parly 2, 21 rue Moxouris, 78150 Le Chesnay, France Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lamazou et al. BMC Infectious Diseases (2020) 20:845 Page 2 of 5 Background This study was approved by the French Ethics Commit- In December 2019, a newly identified coronavirus tee (IRB 00010835). A copy of the written consent is named severe acute respiratory syndrome coronavirus 2 available for review by the Editor-in-Chief of this (SARS-CoV-2) emerged in Wuhan, Hubei Province, journal. China [1]. The coronavirus disease 2019 (COVID-19) is mainly transmitted by droplets emitted from the respira- Case presentation tory tract or by handling. The most frequent symptoms A 35-year-old Caucasian woman developed a COVID-19 are fever (98%), cough (76%), myalgia (44%), expectora- infection during the 7th week of pregnancy. tions (28%) and headache (8%) [2]. However, severe The pregnancy was achieved after a frozen-thawed forms have been described with a severe acute respira- embryo transfer performed on the 20 February 2020 in a tory syndrome particularly in older patients and those gametes donation programme after autologous repeated who have comorbidities such as diabetes or obesity. The implantation failure (RIF). The patient was monitored mortality rate of SARS-CoV-2 infection has been evalu- according to a substituted protocol with daily 6 mg of ated to 1·38% (1·23–1·53), with substantially higher ra- oral oestradiol (Provames®, SERB, France), 800 mg of tios in older age groups [3]. intravaginal progesterone (Utrogestan®, Besins, France). The virus enters cells after binding to membrane Because of the RIF history, an immunological treatment angiotensin-converting enzyme II (ACE2) receptor [4]. with 7·5 mg of prednisone (Cortancyl®, Sanofi Aventis, Therefore, organs with large proportion of cells with France), 400 mg of hydroxychloroquine (Plaquenil®, ACE2 receptors (lung, heart, esophagus, kidney, bladder, Sanofi Aventis, France), 100 mg of aspirin (Aspegic®, and ileummay) act as target and thus are susceptible to Sanofi Aventis, France), 0·4 mL of enoxaparin (Lovenox®, COVID-19 infection [5]. Gastrointestinal symptoms Sanofi Aventis, France) and 0·2 mL of filgrastim (Growth such as diarrhea, vomiting, and abdominal pain have Hormon (GH)), (Neupogen®, Amgen, Holland) per day been reported in COVID-19 patients [6]. In addition, pa- was started 10 months before the embryo transfer. The tients with COVID-19 can have liver injury with raised patient did not have any pregestational comorbidities enzymes found in blood tests during disease progression such as hypertension, diabetes, or cardiovascular disease. [7]. The liver injury could be because of direct viral in- At 7 weeks of amenorrhea (WA), namely day zero (D0) fection of hepatocytes immune-related injury, or drug of the symptoms, the patient started to complain about hepatotoxicity [8, 9]. There is also suggestion that the nausea, asthenia, and symptoms of gastroesophageal re- virus may bind to cholangiocytes through the ACE2 re- flux. At day seven (D7), liver tests showed that aspartate ceptor to dysregulate the liver function [8, 9]. aminotransferase (AST), alanine aminotransferase (ALT) Furthermore, there is currently limited data about the and gamma-glutamyl transpeptidase (GGT) were 3, 5 and clinical features of COVID-19 during pregnancy [10]. 2 times the upper level of normal (ULN) respectively Pregnant women may be more susceptible to COVID-19 (Table 1). At day ten (D10), symptoms worsened (asthe- since pregnant women, in general, are vulnerable to re- nia, permanent nausea, mild and diffuse abdominal pain, spiratory infection due to their state of special immune shortness of breath when exercising), but the patient did tolerance. Reports suggest that pregnancy is associated not complain about fever (37·5 °C). The clinical exam was with increased risk for intensive care units and receipt of normal, and an ultrasound scan at 8WA + 2 days con- mechanical ventilation compared with non-pregnant firmed an evolutive intra uterine pregnancy without any women but their risk for death is similar [11]. Moreover, sign of molar pregnancy. The length of the embryo was severe acute respiratory syndrome during pregnancy is 20·9 mm corresponding to the gestational age with a per- not associated with an increased risk of spontaneous ceptible heartbeat. Treatment was changed: oral oestradiol abortion and spontaneous preterm birth [12]. To date, was switched to oestrogenic patches of 100 mg per 2 days the risk of vertical transmission of the SARS-CoV-2 to (Vivelledot®, Sandoz, France), and prednisone was in- the foetus is not well known even if few reports seems creased to 10 mg per day. Hydroxychloroquine was to be reassuring [12–15]. Some new-borns, whose stopped. Serology for viral hepatitis A, B, C, E, cyto- mothers were infected by the SARS-CoV-2 during late megalovirus (CMV), and Epstein Barr virus (EBV) pregnancy, seemed in good health [16, 17]. However, returned negative. The new blood tests showed white some perinatal COVID-19 infection with adverse effects blood cell count of 13·0 G/L with neutrophil count of on newborns such as fetal distress, premature labor, re- 10·88 G/L and lymphocyte count of 1·39 G/L. Transami- spiratory distress, thrombocytopenia accompanied by ab- nases AST and ALT increased to 4 and 8 ULN, respect- normal liver function have been reported [15, 18]. ively and, GGT to 4 ULN but alkaline phosphatases (PAL) We report a first case of COVID-19 infection in a 7 and lipase were still normal. Electrolytes and creatinine weeks pregnant woman suffering from isolated liver were also normal. D-dimers were slightly increased at damage with cytolysis and the subsequent medical care. 0·506 μg/mL. C-reactive protein (CRP) was 14 mg/L. Lamazou et al. BMC Infectious Diseases (2020) 20:845 Page 3 of 5 Table 1 Course of blood tests between day 7 and day 31 after the first symptoms Reference values Day 7 Day 10 Day 11 Day 13 Day 16 Day 18 Day 22 Day 31 White blood cell count (G/L) 4·0–11·0 6·6 13·0 14·2 17·0 15·4 10·0 9·3 7·9 Neutrophil count (G/L) 1·50–7·50 5·23 10·88 12·50 12·45 12·74 7·74 6·46 5·44 Lymphocyte count (G/L) 1·10–4·40 1·00 1·39 1·84 2·24 2·11 1·74 2·23 1·75 Platelets count (G/L) 150–400 179 188 211 237 238 265 291 233 CRP (mg/L) <5 4 14 18 8 1 1 2 4 Procalcitonine (ng/mL) ≤ 0·12 – < 0·12 – – – – – AST (IU/L) 5–34 96 137 130 94 41 26 19 17 ALT (IU/L) < 55 296 434 404 364 211 99 67 31 GGT (IU/L) 9–36 87 117 121 109 87 64 53 32 PAL (IU/L) 40–150 74 90 78 88 76 76 57 45 Total Bilirubin (mg/L) 3·0–10·0 3·4 4·7 4·9 5·7 5·1 5·3 5·4 3·6 Lipase (IU/L) 8–78 55 69 – – – – – Prothrombin index (%) 70–150 – 89 – 93 97 95 93 91 D-dimers (ng/mL) < 500 – 506 – – – – – Sodium (mmol/L) 136–145 – 137 – – – – – Potassium (mmol/L) 3·5–5·2 – 3·4 – – – – – Creatinine (μmol/L) 40–90 – 85 74 73 65 65 73 65 ALT Alanine aminotransferase, AST Aspartate aminotransferase, GGT Gamma-glutamyl transpeptidase, PAL Alkaline phosphatases, CRP C-reactive protein Biological results are resumed in Table 1. Liver ultrasound generally favourable for both mothers and foetuses. scan found sludge in the gallbladder which had a thin wall There seems to be no evidence of vertical transmission whereas the bile ducts and liver were normal. [12–16], but previous experience with infections caused In the COVID-19 epidemic context, it was decided to by similar virus such as SARS and MERS, indicates that screen the patient for COVID-19 infection. The RTq- intra-uterine transmission is not an exclusive cause of PCR assay indicated the presence of SARS-CoV-2 RNA foetal morbidity and mortality [14, 19]. There have been in the nasopharyngeal swab. In the absence of signs of adverse outcomes reported in the infants of women with severity, it was decided to monitor the patient at home COVID-19, although causality from the infection cannot according to the French government guidelines. No yet be determined [14, 18]. These include preterm labor symptomatic treatment was given to the patient for the and delivery, premature rupture of membranes, intra- COVID-19 infection. However, the luteal phase support uterine growth restriction, low birth weight, intrauterine treatment was maintained. Gradually, the severity of fetal distress, feeding intolerance, asphyxia, pneumonia nausea, asthenia and shortness breath diminished, and and respiratory distress, and stillbirth [14]. Moreover, the blood tests returned to normality. Ultrasound scans the available literature on possible placental changes and performed on the 11th week of amenorrhea confirmed consequences for the course of pregnancy during an in- the satisfactory evolution of the pregnancy: the foetus fection in gravidate is very limited, even if recent articles had followed a normal growth with a size of 51·0 mm reported no increased risk of spontaneous abortion [12]. and the morphological exam did not reveal any malfor- Samples from amniotic fluid, umbilical cord blood, mations and the nuchal translucency was normal at 1·3 breast milk and throat swabs of the new-borns after de- mm. livery were reported negative for the SARS-CoV-2 [12, 18]. As recommended by the guidelines for the manage- Discussion and conclusion ment of laboratory-confirmed SARS-CoV-2 pregnant To our knowledge, we report for the first time a women [15], this patient will be monitored with bi- COVID-19 infection marked by a cytolysis diagnosed in monthly foetal growth ultrasounds and doppler associ- first trimester of pregnancy (7th to 11th week of amen- ated to a morphological analysis of the foetus. We chose orrhea) with spontaneous resolution, and no visible se- to add to this monitoring a hepatic assessment also quelae on the foetus so far. bimonthly. Currently, there are limited data about COVID-19 in- This case illustrated the difficulty of the diagnosis of fections during pregnancy. Some authors reported cases the COVID-19 infection in a patient who suffered from from the 24th week of pregnancy with outcomes nausea and asthenia in the first trimester of pregnancy, Lamazou et al. BMC Infectious Diseases (2020) 20:845 Page 4 of 5 without any respiratory symptoms. The risk was to miss and GH during this period, that could explain the lack the COVID-19 diagnosis and consider it was a gravida of these abnormalities. In addition, the white blood cell hyperemesis which is classically observed in the first tri- count is often higher in the first trimester of pregnancy. mester of the pregnancy. The changes in liver enzymes Furthermore, hepatic dysfunction in severe COVID-19 is alerted us because transaminases levels are usually nor- often accompanied by greater activation of coagulative mal in the beginning of the pregnancy. Transaminases and fibrinolytic pathways, relatively depressed platelet perturbations can be observed as adverse side effects of counts, increased neutrophil counts and neutrophil to drugs, especially after oestrogen and hydroxychloroquine lymphocyte ratios, and high ferritin levels [18]. We did administration as described in rare cases [20]. In our not observe coagulative dysfunctions, probably because case, we cannot rule out drug-induced hepatitis. How- an antithrombotic therapy (0·4 mL of enoxaparin (Love- ever, hydroxychloroquine was stopped, and oestradiol nox®, Sanofi Aventis, France)) was administered consid- was reduced without any clinical improvement. Hydro- ering the RIF history. To prevent thrombotic and xychloroquine was administrated during 1 year because thromboembolic complications, an antithrombotic ther- of the RIF history in order to improve the implantation apy is recommended in COVID-19 patients [29, 30]. process as previously described [21]. In the recent emer- In conclusion, we report for the first time a case of gence of the COVID-19, hydroxychloroquine has been COVID-19 in the first trimester with spontaneous reso- proposed as an optional therapy [22]. It has been de- lution and no sequalae on the foetus so far. We believe scribed that hydroxychloroquine could reduce the that these findings will contribute to better understand- SARS-CoV-2 cell invasion and control of viral replica- ing the overall impact of SARS-CoV-2 on maternal and tion [23, 24]. It could also inhibit the toll-like receptors birth outcomes in order to establish guidelines for the activation and control the cytokine storm due to second- management of laboratory-confirmed SARS-CoV-2 ary hemophagocytic lympho-histiocytosis observed in se- pregnant women. vere cases. But hydroxychloroquine efficacy remains Abbreviations controversial. We questioned whether hydroxychloro- ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; quine administered during 1 year in our patient could CMV: Cytomegalovirus; CRP: C-reactive protein; D: Day; EBV: Epstein Barr virus; have partially reduced the progression of the SARS- GGT: Gamma-glutamyl transpeptidase; GH: Growth hormone; MERS: Middle East Respiratory Syndrome; PCR: Polymerase chain reaction; RIF: Repeated CoV-2 and decreased the risk of severe form [11]. implantation failure; SARS: Severe Acute Respiratory Syndrome; ULN: Upper Isolated digestive symptoms have already been re- level of normal; WA: Weeks of amenorrhea ported in COVID-19 patients [25]. As reported by Luo Acknowledgments and colleagues, among 1141 patients infected by the The authors thank Dr. Etienne Ruppé, David Abbott and Charlotte Dupont SARS-CoV-2, 16% presented digestive symptoms with for their careful reviewing of the manuscript. appetite loss, 66% nausea and vomiting, 37% diarrhoea and 25% abdominal pain without any other symptoms. Authors’ contributions FL, RDC, AG, VP, SO, PC, were in charge of the medical care of this patient. The review by Bangash et al. [26] on seven studies re- FL deigned the case report. FL and LD wrote the article. VL, PO and PD ported elevated aminotransferases and bilirubin, with a revised the article and approved the final draft. All of the authors higher prevalence of abnormal aminotransferases levels contributed to the scientific discussions and reviewed the article. The authors read and approved the final manuscript. in severe COVID-19 infections. Although abnormal liver function tests seem common in COVID-19 patients, the Funding impairment of liver function does not seem a prominent No funding was obtained for this article. feature of COVID-19 and may not have serious clinical Availability of data and materials consequences [9, 10, 27]. It has been proposed that All the data’s (biology, ultrasound scan) are available. COVID-19 can cause direct hepatocyte damage, but Ethics approval and consent to participate other authors believe that liver damage is due to virally This study was approved by the French Ethics Committee (IRB 00010835). induced cytotoxic T cells and the induction of dysregu- lated innate immune response or drug toxicity. The Consent for publication pregnancy bias towards T-helper 2 (Th2) system domin- Written informed consent was obtained from the patient for publication of this case report. A copy is available for review by the Editor-in-Chief of this ance which protects the foetus, leaves the mother vul- journal. nerable to viral infections, which are more effectively contained by the Th1 system [26]. In our case, the pa- Competing interests DL declared a competing interest with Patrick Choay SAS. tient did not present any lymphopenia and the CRP level FL, PO, PC, PD, RDC, AG, VP, VL declared non competiting interest. was only slightly elevated. Lymphopenia and elevated markers of inflammation have been reported as current Author details 1 Ramsay Générale de Santé, Hôpital Privé de Parly 2, Institut Fertilité biological signs of COVID-19 infection, even in pregnan- Maternité Parly 2, 21 rue Moxouris, 78150 Le Chesnay, France. 2Immunology cies [28]. However, our patient was treated by corticoids Division, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Research Lamazou et al. 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