Case Report Fetal Transient Skin Edema in Two Teaching Point Pregnant Women With 1. Maternal coronavirus disease 2019 (COVID-19) might have an effect on the fetus during pregnancy. Coronavirus Disease 2019 (COVID-19) globulin M antibodies have been detected in neonates Pablo Garcia-Manau, MD, born to mothers with infection. Itziar Garcia-Ruiz, MD, CASES: The first case is a woman at 22 3/7 weeks of Carlota Rodo, MD, PhD, gestation with coronavirus disease 2019 (COVID-19) who was admitted to the intensive care unit. In the Elena Sulleiro, MD, PhD, second case, the patient remained at home with mild Nerea Maiz, MD, PhD, symptoms, starting at 20 weeks of gestation. In both Marina Catalan, MD, cases, fetal skin edema was observed on ultrasound Nuria Fernández-Hidalgo, MD, PhD, examination while maternal SARS-COV-2 RT-PCR test Joan Balcells, MD, PhD, results were positive and resolved when maternal SARS-COV-2 RT-PCR test results became negative. Andrés Antón, MD, PhD, The RT-PCR test result for SARS-CoV-2 in amniotic fluid Elena Carreras, MD, PhD, was negative in both cases. The two pregnancies are and Anna Suy, MD, PhD ongoing and uneventful. CONCLUSION: Transient fetal skin edema noted in BACKGROUND: The risk of vertical transmission of these two patients with COVID-19 in the second tri- severe acute respiratory syndrome coronavirus 2 mester may represent results of fetal infection or altered (SARS-CoV-2) infection remains unknown. Positive fetal physiology due to maternal disease or may be reverse-transcription polymerase chain reaction (RT- unrelated to the maternal illness. PCR) test results for SARS-CoV-2 infection in neonates (Obstet Gynecol 2020;136:1016–20) and placental tissue have been reported, and immuno- DOI: 10.1097/AOG.0000000000004059 C From the Maternal Fetal Medicine Unit, Department of Obstetrics, the oronavirus disease 2019 (COVID-19) is a highly Microbiology Department, the Pediatric Critical Care Department, and the Department of Infectious Diseases, Vall d’Hebron Barcelona Hospital Campus, infectious disease caused by severe acute respira- Universitat Autònoma de Barcelona, Barcelona, and the Red Española de In- tory syndrome coronavirus 2 (SARS-CoV-2). Spain vestigación en Patología Infecciosa (REIPI), Instituto de Salud Carlos III, Ma- reported its first case on January 31, 2020, and more drid, Spain. than 241,000 confirmed cases and 27,100 deaths have Funding was provided for the Gesta-COVID19 Study by Instituto de Salud Carlos III (ISCIII) (PR(AMI)181/2020) (ISCIII’s reference: COV20/00188). been reported.1 Some maternal infections during pregnancy are The authors thank all the members of the Gesta-COVID19 Collaboration Group for their help in data collection for the Gesta-COVID19 Study, and Erika Bokor associated with poor perinatal outcomes and fetal for the English language correction of the manuscript. anomalies. In infections such as cytomegalovirus or Each author has confirmed compliance with the journal’s requirements for Zika virus, gestational age at the time of maternal authorship. infection plays a role in the risk of both intrauterine Published online ahead-of-print July 7, 2020. infection and severe sequelae.2,3 In SARS-CoV-2 infec- Corresponding author: Carlota Rodó, MD, PhD, Department of Obstetrics, Vall tion, there is a paucity of reports of pregnancy out- d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron, Barcelona, Spain; comes with infection before the third trimester. email: crodo@vhebron.net. The risk of maternal–fetal transmission of SARS- Financial Disclosure The authors did not report any potential conflicts of interest. CoV-2 infection remains controversial. Severe acute respiratory syndrome coronavirus 2 has been de- © The Author(s). Published by Wolters Kluwer Health, Inc. This is an open- access article distributed under the terms of the Creative Commons Attribution- tected in placental swabs or biopsies in five cases, Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is but not in amniotic fluid.4–7 However, it is unknown permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission whether the virus, the immune response it causes, or from the journal. the gestational age at which the infection occurs may ISSN: 0029-7844/20 have consequences for the fetus.8 1016 VOL. 136, NO. 5, NOVEMBER 2020 OBSTETRICS & GYNECOLOGY Herein, we present two cases of unexplained fetal amount of amniotic fluid. The day after admission (day 1), skin edema in two pregnant women diagnosed with the patient’s condition worsened and she was transferred to COVID-19 during the second trimester of pregnancy. the intensive care unit (ICU), where she underwent intuba- tion for mechanical ventilation on day 2 (23 1/7 weeks of gestation). Fetal prognosis was estimated to be poor owing CASE 1 to gestational age. After discussion with the mother, expec- A 50-year-old primigravid woman at 22 6/7 weeks of tant management of the pregnancy was decided on by gestation presented to the emergency department at Vall a multidisciplinary team (obstetricians and critical care d’Hebron University Hospital (Barcelona, Spain) with a 7- and infectious disease specialists). Elective delivery was day history of dry cough and fever. She was living with her accorded with the patient before intubation if deterioration mother, who had tested positive for SARS-CoV-2 infection persisted. Blood tests were performed daily, and pro- on reverse-transcription polymerase chain reaction (RT- inflammatory markers related to COVID-19 severity (IL-6 PCR) testing. The patient was a former smoker, had no and D-dimer) were also monitored (Fig. 1).9 The result of relevant medical history, and was receiving 150 mg of the SARS-CoV-2 RT-PCR test in peripheral blood was acetylsalicylic acid owing to a high risk of early-onset negative. preeclampsia. Her gestation was conceived by in vitro Fetal well-being scans (Siemens Acuson NX2) were fertilization with egg donation and had had an uneventful conducted daily by the ICU team to check fetal heart rate course. No genetic tests had been performed during the and weekly by a fetal medicine specialist to assess fetal pregnancy. Physical examination revealed a body mass growth, Doppler parameters, and the amount of amniotic index (BMI, calculated as weight in kilograms divided fluid and to detect any potential abnormalities. Fetal heart by height in meters squared) of 25.4, blood pressure rate was always within the normal range, without episodes 125/64 mm Hg, temperature 37˚C, and respiratory rate of tachycardia or bradycardia. of 30 breaths per minute, with a hemoglobin saturation On day 6 (23 5/7 weeks of gestation), fetal skin edema by pulse oximetry of 93% on room air. Blood tests per- was observed with no ascites, hydrothorax, thickened formed at admission showed lymphopenia and placenta, or other signs of hydrops fetalis. Edema was interleukin-6 (IL-6) and D-dimer levels above the normal generalized, but it was more evident in the scalp and range (Table 1). trunk. A detailed survey for anomalies and fetal echocar- A chest radiograph showed conspicuous bilateral diography were performed, showing no abnormal results. ground glass opacities, and the patient tested positive for The same findings persisted on day 10 (24 2/7 weeks), and SARS-CoV-2 infection on RT-PCR testing of oropharyngeal no structural anomalies were found (Fig. 2). Doppler ex- and nasopharyngeal swabs (Allplex 2019-nCoV assay). A aminations of the umbilical artery, middle cerebral artery, COVID-19 bilateral pneumonia was diagnosed, and the ductus venosus, and uterine arteries were also within nor- patient was admitted and put on azithromycin, lopinavir- mal limits. Maternal indirect antiglobulin and serologic ritonavir, and hydroxychloroquine medications (day 0). tests were obtained, being negative for cytomegalovirus, Obstetric ultrasound examination at admission showed no varicella zoster virus, parvovirus B19, Toxoplasma gondii, fetal anomalies, normal Doppler parameters, and a normal herpes virus, and rubella. An amniocentesis was Table 1. Patients’ Relevant Clinical Findings Clinical Characteristics Patient 1 Patient 2 Age (y) 50 30 Ethnicity White Latin American Nuchal translucency in 1st trimester (mm) 1.28 2.3 Gestational age at COVID-19 diagnosis (wk) 22.6 20.1 Time from symptom onset to fetal edema (d) 13 10 Maternal serum IL-6* level at COVID-19 diagnosis (pg/mL) 76.47 16.22 Maternal serum D-dimer* level at COVID-19 diagnosis (ng/mL) 576 953 Gestational age at fetal edema diagnosis (wk) 23.5 21.2 Maternal serum IL-6 level at fetal edema diagnosis (pg/mL) 409.5 3.59 Maternal serum D-dimer level at fetal edema diagnosis (ng/mL) 2,190 373 Time RT-PCR remained positive for SARS-CoV-2 infection (d) 17 22 Fetal edema duration (d) 11 14 RT-PCR test result for SARS-CoV-2 in maternal serum Negative Negative IL-6 level in amniotic fluid* (pg/mL) 345.18 109.4 COVID-19, coronavirus disease 2019; IL-6, interleukin-6; RT-PCR, reverse-transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. * Reference ranges: serum IL-6: 0–4.3 pg/mL; D-dimer: 0–243 ng/mL; IL-6 in amniotic fluid: median values ranging from 150.5 to 339 pg/ mL.10 VOL. 136, NO. 5, NOVEMBER 2020 Garcia-Manau et al Fetal Skin Edema in Pregnant Women With COVID-19 1017 Fig. 1. Proinflammatory marker evolution during admission in case 1. Fetal skin edema was observed between days 6 and 17 and is de- limited by a grey area. Intensive care unit (ICU) admission and amniocentesis were on days 2 and 12, respectively. Garcia-Manau. Fetal Skin Edema in Pregnant Women With COVID-19. Obstet Gynecol 2020. performed on day 12. The results of the genetic test CASE 2 (Quantitative Genomic Hybridization Array, 8 60K Agilent G4827A CGH (ISCA v2 array) were normal. The RT-PCR A 30-year-old primigravid woman at 20 1/7 weeks of gestation test result for SARS-CoV-2 in amniotic fluid was negative, with no relevant medical history presented to the emergency and the IL-6 level in amniotic fluid was within the normal department (day 0) with cough and fever in the previous 48 range.10 Tests in amniotic fluid were negative for cytomeg- hours. She was living with her husband and her parents, and alovirus, varicella zoster virus, parvovirus B19, T gondii, all three had tested positive for SARS-CoV-2 infection. Her and sexually transmitted infectious agents (Chlamydia tra- gestation had had an uneventful course. Physical examination chomatis, Neisseria gonorrhoeae, Mycoplasma hominis, revealed a BMI of 32, blood pressure 130/71 mm Hg, Ureaplasma parvum, Mycoplasma genitalium, Ureaplas- temperature of 37.5˚C, respiratory rate 16 breaths ma urealyticum, and Trichomonas vaginalis). per minute, and a hemoglobin saturation of 99% on room One week later (day 17, 25 2/7 weeks of gestation), the air. The results of blood tests performed at admission are maternal condition improved: PaO2 progressively increased, shown in Table 1. Chest radiography showed no anomalies, and oxygen supplementation requirements lowered. Pro- and the patient tested positive for SARS-CoV-2 infection on inflammatory markers decreased, and the result of the RT-PCR of oropharyngeal and nasopharyngeal swabs. She was SARS-CoV-2 RT-PCR test on oropharyngeal and nasopharyn- diagnosed with mild COVID-19, and she was discharged with geal swabs was negative. Simultaneously, the fetal edema no medication to home isolation. Maternal well-being was had almost disappeared on ultrasound examination (Fig. 2). assessed daily by phone calls, and no deterioration requiring Fig. 2. Fetal skin edemas. Fetal ultrasound examinations. Case 1: skin edema in transcerebellar (A) and transthoracic (B) planes and its resolution (C). Case 2: skin edema in transthoracic (D) and midsagittal face (E) planes and its resolution (F). Garcia-Manau. Fetal Skin Edema in Pregnant Women With COVID-19. Obstet Gynecol 2020. 1018 Garcia-Manau et al Fetal Skin Edema in Pregnant Women With COVID-19 OBSTETRICS & GYNECOLOGY hospital admission was observed. On day 8 (21 2/7 weeks of cental or membrane samples are also described; gestation), an ultrasound examination was performed, detect- although none of the neonates tested positive.4 ing an isolated mild fetal skin edema with no other abnormal- Recently, the first two cases of positive RT-PCR test ities (Fig. 2). Fetal echocardiography and Doppler parameters results for SARS-CoV-2 infection in mother, neonate, were also within normal limits. Fetal heart rate was within the and placental tissues have been reported.5 However, normal range, and no episodes of tachycardia or bradycardia none of these studies demonstrate fetal abnormalities were recorded. Middle cerebral artery velocity was within the normal range. Maternal indirect antiglobulin and serologic or the presence of the virus in amniotic fluid or in tests were obtained, with negative results. Nasopharyngeal cord blood. RT-PCR test results remained positive, and RT-PCR test results Current protocols recommend, for safety reasons, in peripheral blood were negative. The IL-6 level in maternal delaying ultrasound scans while pregnant women are serum was within the normal range, and D-dimer levels were positive for SARS-CoV-2 infection, which may result slightly elevated (Table 1). An amniocentesis was performed, in lack of observation of transient fetal abnormali- and the RT-PCR assay of the amniotic fluid was negative for ties.12,13 However, at our center we are scanning preg- SARS-CoV-2 infection. Result s of genetic tests (Quantitative nant women weekly in the framework of an Genomic Hybridization Array) and tests for congenital infec- Institutional Review Board–approved observational tions (cytomegalovirus, varicella zoster virus, parvovirus B19, study (PR(AMI)181/2020), which includes microbio- T gondii, Chlamydia trachomatis, N gonorrhoeae, M hominis, logical sampling and ultrasound examinations in U parvum, M genitalium, U urealyticum, and T vaginalis) in amniotic fluid were negative. The IL-6 level in amniotic fluid pregnant women with COVID-19. During the pan- was normal.10 On day 22 (23 2/7 weeks of gestation), fetal demic, we performed 31 ultrasound examinations edema had disappeared after the SARS-CoV-2 RT-PCR test on pregnant women with COVID-19, and fetal skin result was negative. edema was seen in two cases (6.5%; 95% CI 1.8– At the time of submission, both women are still 20.7%). pregnant. Their gestations are being closely followed-up, Some patients with COVID-19 develop a rapid with a complete resolution of the fetal edema, and no other deterioration related to a cytokine storm syndrome fetal anomalies have been reported. due to a massive, virally driven hyperinflamma- tion.14,15 It has been demonstrated that maternal cy- DISCUSSION tokines during pregnancy can lead to a failure in Two cases of fetal transient skin edema in pregnant multiple fetal organ systems.16 The fetal edema women with COVID-19 in their second trimester of described in case 1 appeared when the highest mater- pregnancy are described. In case 1, the patient was nal serum IL-6 concentrations were noted and while admitted to the ICU and fetal edema followed a time D-dimer was rapidly increasing. By contrast, its res- course parallel to the maternal respiratory condition olution was preceded by a progressive decrease in and the pro-inflammatory markers; the edema dis- both serum IL-6 and D-dimer values; the lowest con- appeared with maternal recovery. Patient 2 remained centrations were noted when the edema had disap- at home with mild symptoms and did not require peared on day 17, coinciding with a negative SARS- hospital admission. Pro-inflammatory markers were CoV-2 RT-PCR test result (Fig. 1). In case 2, edema lower, and the edema was milder and it also dis- was observed with a low pro-inflammatory status, as appeared with maternal improvement. In both cases, IL-6 levels were within the normal range. The IL-6 viremia and amniotic fluid RT-PCR test results were levels in amniotic fluid were normal in both cases. negative for SARS-CoV-2 infection. For this reason, we believe that SARS-CoV-2 might There is still inconclusive evidence of transpla- have an effect on the fetus, regardless of the pro- centally acquired fetal infection reported in the inflammatory maternal profile. literature. A study investigated the expression of Despite the overwhelming amount of data gener- SARS-CoV-2 receptors, identified as angiotensin- ated since the beginning of the COVID-19 outbreak, converting enzyme 2, in human maternal–fetal inter- many questions about the virus–host interactions face and the main fetal organs. The authors conclude remain unanswered. Pregnant women represent that angiotensin-converting enzyme 2 is widely pres- a small subgroup of patients with COVID-19, and ent in the human placenta and in the main fetal or- there is a dearth of data about the potential effects gans.11 Another article describes a second-trimester of the virus on the fetus. miscarriage in a woman diagnosed with COVID-19 This report has several limitations. Firstly, two in which placental and amniotic membranes tested cases are insufficient to draw out significant conclu- positive for SARS-CoV-2 infection.6 In another study, sions. Fetal edema is a nonspecific finding and often three cases of detection of SARS-CoV-2 RNA in pla- idiopathic. Considering other congenital infections, the VOL. 136, NO. 5, NOVEMBER 2020 Garcia-Manau et al Fetal Skin Edema in Pregnant Women With COVID-19 1019 time interval from infection to fetal edema was shorter 7. Yu N, Li W, Kang Q, Zeng W, Feng L, Wu J. No SARS-CoV-2 detected in amniotic fluid in mid-pregnancy. Lancet Infect Dis than expected, and fetal edema is not a common 2020 [Epub ahead of print]. finding in cases of intraamniotic inflammation or 8. Lamouroux A, Attie-Bitach T, Martinovic J, Leruez-Ville M, chorioamnionitis. We, therefore, cannot state that fetal Ville Y. Evidence for and against vertical transmission for skin edema was caused by SARS-CoV-2 infection, severe acute respiratory syndrome coronavirus 2. Am J Obstet despite the correlation between the disappearance of Gynecol 2020;223:91.e1–4. the edema and the negative test results for the virus. 9. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Ser- gentanis TN, Politou M, et al. Hematological findings and com- Secondly, the interpretation of a negative result on RT- plications of COVID-19. Am J Hematol 2020;95:834–7. PCR test for detection of SARS-CoV-2 infection in 10. Bamberg C, Fotopoulou C, Linder M, Roehr CC, Dudenhau- amniotic fluid is unknown, and the possibility of the sen JW, Henrich W, et al. Mid-trimester amniotic fluid concen- virus testing negative in utero cannot be excluded, trations of the proinflammatory cytokines IL-6, IL-8, TNF-a, and lipopolysaccharide binding protein in normal pregnancies: because this has been demonstrated for other a prospective evaluation according to parity, gestational age, viruses.7,17 and fetal gender. J Perinat Med 2011;39:403–9. To conclude, we report a fetal complication 11. Li M, Chen L, Zhang J, Xiong C, Li X. The SARS-CoV-2 potentially related to COVID-19 in pregnant women. receptor ACE2 expression of maternal-fetal interface and fetal Given these findings and the lack of reports of organs by single-cell transcriptome study. PLoS One 2020;15: e0230295. COVID-19 in the first and second trimesters, a close 12. Abu-Rustum RS, Akolekar R, Sotiriadis A, Salomon LJ, Da follow-up of these pregnancies may help to under- Silva Costa F, Wu Q, et al. ISUOG consensus statement on stand the effect on the fetus. organization of routine and specialist obstetric ultrasound serv- ices in context of COVID-19. Ultrasound Obstet Gynecol 2020;55:863–70. REFERENCES 13. Bourne T, Kyriacou C, Coomarasamy A, Al-Memar M, Leo- 1. World Health Organization. Coronavirus disease (COVID-19) nardi M, Kirk E, et al. ISUOG Consensus Statement on ration- situation reports. Available at: https://www.who.int/emergen- alization of early-pregnancy care and provision of cies/diseases/novel-coronavirus-2019/situation-reports. ultrasonography in context of SARS-CoV-2. Ultrasound Obstet Retrieved April 18, 2020. Gynecol 2020;55:871–8. 2. Rodó C, Suy A, Sulleiro E, Soriano-Arandes A, Maiz N, Gar- 14. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, cía-Ruiz I, et al. Pregnancy outcomes after maternal Zika virus Manson JJ, et al. COVID-19: consider cytokine storm syn- infection in a non-endemic region: prospective cohort study. dromes and immunosuppression. Lancet 2020;395:1033–4. Clin Microbiol Infect 2019;25:633.e5–9. 15. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 3. Neu N, Duchon J, Zachariah P. TORCH infections. Clin Peri- cytokine storm in COVID-19. J Infect 2020;80:607–13. natol 2015;42:77–103, viii. 16. Yockey LJ, Iwasaki A. Interferons and proinflammatory cyto- 4. Penfield CA, Brubaker SG, Limaye MA, Lighter J, Ratner AJ, kines in pregnancy and fetal development. Immunity 2018;49: Thomas KM, et al. Detection of SARS-COV-2 in placental and 397–412. fetal membrane samples. Am J Obstet Gynecol MFM 2020. 17. Rodó C, Suy A, Sulleiro E, Soriano-Arandes A, Antón A, Gar- [Epub ahead of print]. cía-Ruiz I, et al. In utero negativization of Zika virus in a foetus 5. Patanè L, Morotti D, Giunta MR, Sigismondi C, Piccoli MG, with serious central nervous system abnormalities. Clin Micro- Frigerio L, et al. Vertical transmission of COVID-19: SARS- biol Infect 2018;24:549.e1–3. CoV-2 RNA on the fetal side of the placenta in pregnancies with COVID-19 positive mothers and neonates at birth. Am J Obstet Gynecol MFM 2020. [Epub ahead of print]. PEER REVIEW HISTORY 6. Baud D, Greub G, Favre G, Gengler C, Jaton K, Dubruc E, Received May 26, 2020. Received in revised form June 11, 2020. et al. Second-trimester miscarriage in a pregnant woman with Accepted June 23, 2020. Peer reviews and author correspondence SARS-CoV-2 infection. JAMA 2020;323:2198–200. are available at http://links.lww.com/AOG/B990. 1020 Garcia-Manau et al Fetal Skin Edema in Pregnant Women With COVID-19 OBSTETRICS & GYNECOLOGY