COVID-19 e pré-eclâmpsia: uma revisão sistemática de interações fisiopatológicas

Nascimento, Maria Isabel do; Cunha, Alfredo de Almeida; Falcão Rangel Netto, Nercélio; Santos, Raphael Alves dos; Barroso, Rodrigo Roberto; Alves, Thiago Rodrigues de Carvalho; Soares, Wender Emiliano

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Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

Review Article • Rev Bras Ginecol Obstet 45 (6) • 2023 • https://doi.org/10.1055/s-0043-1770091 copiar

COVID-19 e pré-eclâmpsia: uma revisão sistemática de interações fisiopatológicas

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Objetivo:

Revisar a literatura e sintetizar evidências sobre interações fisiopatológicas atribuídas à ocorrência simultânea de COVID-19 e pré-eclâmpsia.

Métodos:

Uma revisão sistemática foi conduzida entre novembro (2021) a janeiro (2022) para recuperar estudos observacionais publicados no PubMed, LILACS, SciELO Brasil e Google scholar. A busca foi baseada nos descritores [(eclâmpsia OR pré-eclâmpsia) AND (COVID-19)]. Estudos quantitativos que apontaram interações fisiopatológicas foram incluídos. Estudos de revisão, com participante HIV e apenas com enfoque clínico foram excluídos. A seleção dos estudos foi padronizada com avaliação por duplas de pesquisadores.

Resultados:

Nesta revisão, 155 publicações foram recuperadas; 16 preencheram os critérios de inclusão. Em síntese, a expressão fisiológica de receptores da enzima conversora da angiotensina-2 (ECA-2) é fisiologicamente potencializada em gestantes, especialmente no sítio placentário. Os estudos sugerem que o coronavírus se liga à ECA-2 para entrar na célula humana, ocasionando desregulação do sistema renina-angiotensina-aldosterona e da razão entre angiotensina-II e angiotensina-1-7, induzindo manifestações sugestivas de pré-eclâmpsia. Ademais, a tempestade de citocinas conduz à disfunção endotelial, vasculopatia e formação de trombos, também presentes na pré-eclâmpsia.

Conclusão:

Os estudos recuperados nesta revisão sugerem que a superposição de alterações fisiopatológicas entre a COVID-19 e a pré-eclâmpsia envolve, principalmente, a ECA-2 e disfunção endotelial. Tendo em vista que a pré-eclâmpsia cursa com alterações clínicas e laboratoriais progressivas, a atenção pré-natal de qualidade pode ser capaz de detectar parâmetros clínicos e laboratoriais importantes para diferenciar a pré-eclâmpsia verdadeira sobreposta por COVID-19, bem como os casos que mimetizam a doença hipertensiva consequente à infecção viral.

Palavras-chave
COVID-19; SARS-CoV-2; Pré-eclâmpsia; Eclâmpsia; Patogênese

Author/Year	Country	Study design	Type of participant	Participant (n)	Other assessments
Naeh et al. (2022)¹¹11 Naeh A, Berezowsky A, Yudin MH, Dhalla IA, Berger H. Preeclampsia-Like Syndrome in a pregnant patient with coronavirus disease 2019 (COVID-19). J Obstet Gynaecol Can. 2022;44(02):193-195. Doi: 10.1016/j.jogc.2021.09.015 https://doi.org/10.1016/j.jogc.2021.09.0...	Canada	Case Report	Pregnant Women	1	^X X no additional evaluation was performed.
Aydin et al. (2021)¹²12 Aydın GA, Ünal S, Özsoy HGT. The effect of gestational age at the time of diagnosis on adverse pregnancy outcomes in women with COVID-19. J Obstet Gynaecol Res. 2021;47(12):4232-4240. Doi: 10.1111/jog.15051 https://doi.org/10.1111/jog.15051...	Turkey	Retrospective Study	Pregnant Women	167	^X X no additional evaluation was performed.
Laresgoiti-Servitje et al. (2021)¹³13 Laresgoiti-Servitje E, Cardona-Pérez JA, Hernández-Cruz RG, et al. COVID-19 infection in pregnancy: pcr cycle thresholds, placental pathology, and perinatal outcomes. Viruses. 2021;13(09):1884. Doi: 10.3390/v13091884 https://doi.org/10.3390/v13091884...	Mexico	Case-Control	Pregnant Women	298 ⁺ + number of positive COVID-19 cases. /828^- - number of negative COVID-19 cases.	^X X no additional evaluation was performed.
Osaikhuwuomwan et al. (2021)¹⁴14 Osaikhuwuomwan J, Ezeanochie M, Uwagboe C, Ndukwu K, Yusuf S, Ande A. Clinical characteristics and outcomes for pregnant women diagnosed with COVID-19 disease at the University of Benin Teaching Hospital, Benin City, Nigeria. Pan Afr Med J. 2021; 39:134. Doi: 10.11604/pamj.2021.39.134.27627 https://doi.org/10.11604/pamj.2021.39.13...	Nigeria	Descriptive	Pregnant Women	19 ⁺ + number of positive COVID-19 cases. /48^- - number of negative COVID-19 cases.	^X X no additional evaluation was performed.
Verma et al. (2021)¹⁵15 Verma S, Joshi CS, Silverstein RB, He M, Carter EB, Mysorekar IU. SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system. Med (N Y). 2021;2(05):575-590.e5. Doi: 10.1016/j.medj.2021. 04.009 https://doi.org/10.1016/j.medj.2021.04.0...	USA	Descriptive Translational	Pregnant Women	5 ⁺ + number of positive COVID-19 cases. /5^- - number of negative COVID-19 cases.	Placenta
Federici et al. (2020)¹⁶16 Federici L, Picone O, Dreyfuss D, Sibiude J. Successful continuation of pregnancy in a patient with COVID-19-related ARDS. BMJ Case Rep. 2020;13(08):e237511. Doi: 10.1136/bcr-2020-237511 https://doi.org/10.1136/bcr-2020-237511...	France	Case Report	Pregnant Women	1⁺ + number of positive COVID-19 cases.	^X X no additional evaluation was performed.
Ahmed et al. (2020)¹⁷17 Ahmed I, Eltaweel N, Antoun L, Rehal A. Severe pre-eclampsia complicated by acute fatty liver disease of pregnancy, HELLP syndrome and acute kidney injury following SARS-CoV-2 infection. BMJ Case Rep. 2020;13(08):e237521. Doi: 10.1136/bcr-2020-237521 https://doi.org/10.1136/bcr-2020-237521...	UK	Case Report	Pregnant Women	1⁺ + number of positive COVID-19 cases.	^X X no additional evaluation was performed.
Baracy et al. (2021)¹⁸18 Baracy M Jr, Afzal F, Szpunar SM, et al. Coronavirus disease 2019 (COVID-19) and the risk of hypertensive disorders of pregnancy: a retrospective cohort study. Hypertens Pregnancy. 2021;40(03): 226-235. Doi: 10.1080/10641955.2021.1965621 https://doi.org/10.1080/10641955.2021.19...	USA	Historical Cohort	Pregnant Women	70 ⁺ + number of positive COVID-19 cases. /210^- - number of negative COVID-19 cases.	^X X no additional evaluation was performed.
Shchegolev et al. (2021)¹⁹19 Shchegolev AI, Kulikova GV, Lyapin VM, Shmakov RG, Sukhikh GT. The number of syncytial knots and vegf expression in placental villi in parturient woman with covid-19 depends on the disease severity. Bull Exp Biol Med. 2021;171(03):399-403. Doi: 10.1007/s10517-021-05236-x https://doi.org/10.1007/s10517-021-05236...	Russia	Comparative Morphological Study	x	23 ⁺ + number of positive COVID-19 cases. /7^- - number of negative COVID-19 cases.	Placenta
Papageorghiou et al. (2021)²⁰20 Papageorghiou AT, Deruelle P, Gunier RB, et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am J Obstet Gynecol. 2021;225(03):289.e1-289.e17. Doi: 10.1016/j.ajog.2021.05.014 https://doi.org/10.1016/j.ajog.2021.05.0...	Multinational	Prospective Observational	Pregnant Women	725 ⁺ + number of positive COVID-19 cases. /1459^- - number of negative COVID-19 cases.	^X X no additional evaluation was performed.
Lu-Culligan et al. (2021)²¹21 Lu-Culligan A, Chavan AR, Vijayakumar P, et al. SARS-CoV-2 infection in pregnancy is associated with robust inflammatory response at the maternal-fetal interface. medRxiv [Preprint]. 2021 Jan 26:2021.01.25.21250452. doi: Doi: 10.1101/2021.01.25.21250452 https://doi.org/10.1101/2021.01.25.21250...	USA	Obervational	Pregnant Women	15⁺ + number of positive COVID-19 cases.	Placenta
Braga and Sass (2020)²²22 Braga LFB, Sass N. Coronavirus 2019, thrombocytopenia and HELLP syndrome: association or coincidence? Rev Bras Ginecol Obstet. 2020;42(10):669-671. Doi: 10.1055/s-0040-1718437 https://doi.org/10.1055/s-0040-1718437...	Brazil	Case Report	Pregnant Women	1⁺ + number of positive COVID-19 cases.	^X X no additional evaluation was performed.
Bloise et al. (2021)²³23 Bloise E, Zhang J, Nakpu J, et al. Expression of severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across gestation and at the maternal-fetal interface in pregnancies complicated by preterm birth or preeclampsia. Am J Obstet Gynecol. 2021;224(03):298.e1-298.e8. Doi: 10.1016/j.ajog.2020.08.055 https://doi.org/10.1016/j.ajog.2020.08.0...	Canada	Cross-Sectional Study	Pregnant Women	87⁺ + number of positive COVID-19 cases.	Placenta
Shanes et al. (2020)²⁴24 Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA. Placental pathology in COVID-19. medRxiv [Preprint]. 2020 May 12:2020.05.08.20093229. doi: Doi: 10.1101/2020.05.08. 20093229 https://doi.org/10.1101/2020.05.08.20093...	USA	Comparative	Pregnant Women	16⁺ + number of positive COVID-19 cases.	Placenta
Garcia Rodriguez et al. (2020)²⁵25 Garcia Rodriguez A, Marcos Contreras S, Fernandez Manovel SM, et al. SARS-COV-2 infection during pregnancy, a risk factor for eclampsia or neurological manifestations of COVID-19? Case report. BMC Pregnancy Childbirth. 2020;20(01):587. Doi: 10.1186/s12884-020-03275-2 https://doi.org/10.1186/s12884-020-03275...	Spain	Case Report	Pregnant Women	1⁺ + number of positive COVID-19 cases.	^X X no additional evaluation was performed.
Mendoza et al. (2020)²⁶26 Mendoza M, Garcia-Ruiz I, Maiz N, et al. Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study. BJOG. 2020;127(11):1374-1380. Doi: 10.1111/1471-0528.16339 https://doi.org/10.1111/1471-0528.16339...	Spain	Observational	Pregnant Women	42⁺ + number of positive COVID-19 cases.	^X X no additional evaluation was performed.

Author	Main pathophysiological findings or conclusions
Naeh et al.¹¹11 Naeh A, Berezowsky A, Yudin MH, Dhalla IA, Berger H. Preeclampsia-Like Syndrome in a pregnant patient with coronavirus disease 2019 (COVID-19). J Obstet Gynaecol Can. 2022;44(02):193-195. Doi: 10.1016/j.jogc.2021.09.015 https://doi.org/10.1016/j.jogc.2021.09.0...	“Endothelial dysfunction has been suggested as the mechanism for both manifestations; [...] hypertension and kidney injury ...”
Aydin et al.¹²12 Aydın GA, Ünal S, Özsoy HGT. The effect of gestational age at the time of diagnosis on adverse pregnancy outcomes in women with COVID-19. J Obstet Gynaecol Res. 2021;47(12):4232-4240. Doi: 10.1111/jog.15051 https://doi.org/10.1111/jog.15051...	“Upon entry into the human body, SARS-CoV-2 spike binds to ACE2 receptor through its receptor-binding domain. ... we found a significant difference in the laboratory parameters among the groups. D-dimer is an indicator of fibrinolysis and plays a key role in the diagnosis of thromboembolism.”
Laresgoiti-Servitje et al.¹³13 Laresgoiti-Servitje E, Cardona-Pérez JA, Hernández-Cruz RG, et al. COVID-19 infection in pregnancy: pcr cycle thresholds, placental pathology, and perinatal outcomes. Viruses. 2021;13(09):1884. Doi: 10.3390/v13091884 https://doi.org/10.3390/v13091884...	“…we further explored the placentas of a group of pregnant women regarding the presence of placental dysmaturity, vasculopathy, fibrinoid, chorangiosis, chorioamnionitis, hemorrhage, or infarction. The placentas of women infected with SARS-CoV-2 had a higher rate of fibrinoid deposition, a clinical feature of maternal vascular malperfusion, than controls”.
Osaikhuwuomwan et al.¹⁴14 Osaikhuwuomwan J, Ezeanochie M, Uwagboe C, Ndukwu K, Yusuf S, Ande A. Clinical characteristics and outcomes for pregnant women diagnosed with COVID-19 disease at the University of Benin Teaching Hospital, Benin City, Nigeria. Pan Afr Med J. 2021; 39:134. Doi: 10.11604/pamj.2021.39.134.27627 https://doi.org/10.11604/pamj.2021.39.13...	“…adverse pregnancy outcomes were high, especially among those with other co-morbidities such as pre-eclampsia or other complications because respiratory syndromes may aggravate pulmonary oedema and decrease oxygen saturation. The endothelial dysfunction associated with pre-eclampsia predisposes patients to respiratory failure from pulmonary oedema.”
Verma et al.¹⁵15 Verma S, Joshi CS, Silverstein RB, He M, Carter EB, Mysorekar IU. SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system. Med (N Y). 2021;2(05):575-590.e5. Doi: 10.1016/j.medj.2021. 04.009 https://doi.org/10.1016/j.medj.2021.04.0...	“In sum, we demonstrate that SARS-CoV-2 colonizes fetal trophoblasts, stromal cells, and macrophages in the placenta, which express the ACE2 receptor. S binding to ACE2 leads to reduction of the receptor expression and results in alterations of the RAS pathway—changes that are similar to those typically noted in pre-eclampsia.”
Federici et al.¹⁶16 Federici L, Picone O, Dreyfuss D, Sibiude J. Successful continuation of pregnancy in a patient with COVID-19-related ARDS. BMJ Case Rep. 2020;13(08):e237511. Doi: 10.1136/bcr-2020-237511 https://doi.org/10.1136/bcr-2020-237511...	“HELLP is an acronym which refers to the triad of microangiopathic haemolysis with elevated liver enzymes and a low platelet count. HELLP syndrome is a serious complication of pre-eclampsia [...]. Some biological disorders linked to SARS-CoV-2 infection associated with hypertension may mimic a pre-eclampsia or a HELLP syndrome.”
Ahmed et al.¹⁷17 Ahmed I, Eltaweel N, Antoun L, Rehal A. Severe pre-eclampsia complicated by acute fatty liver disease of pregnancy, HELLP syndrome and acute kidney injury following SARS-CoV-2 infection. BMJ Case Rep. 2020;13(08):e237521. Doi: 10.1136/bcr-2020-237521 https://doi.org/10.1136/bcr-2020-237521...	“Both pre-eclampsia and COVID-19 infection are examples of microvascular disease causing endothelial injury. They both cause a high prothrombotic tendency leading to multiorgan failure. The presence of both diseases likely had either a synergistic or an opportunistic effect, which may have led to severe clinical manifestations via the interplay of the renin-angiotensinogen-aldosterone system in their pathogenesis.”
Baracy et al.¹⁸18 Baracy M Jr, Afzal F, Szpunar SM, et al. Coronavirus disease 2019 (COVID-19) and the risk of hypertensive disorders of pregnancy: a retrospective cohort study. Hypertens Pregnancy. 2021;40(03): 226-235. Doi: 10.1080/10641955.2021.1965621 https://doi.org/10.1080/10641955.2021.19...	“When comparing only COVID-19 positive pregnancies, early infection conferred a significantly higher risk for HDP than late infection. This observation is consistent with the inflammatory explanation of increased HDP risk in COVID-19. Through modulation of angiogenic factors and inflammatory cytokines, it is likely that COVID-19 exerts maximal impact on placental physiology at earlier gestations, enabling these physiologic changes to manifest as HDP over time.”
Shchegolev et al.¹⁹19 Shchegolev AI, Kulikova GV, Lyapin VM, Shmakov RG, Sukhikh GT. The number of syncytial knots and vegf expression in placental villi in parturient woman with covid-19 depends on the disease severity. Bull Exp Biol Med. 2021;171(03):399-403. Doi: 10.1007/s10517-021-05236-x https://doi.org/10.1007/s10517-021-05236...	“...study demonstrated increased level of VEGF expression mainly in syncytiotrophoblast of the terminal villi in parturient women with moderate COVID-19 to a greater extent than in women with mild disease severity. These changes, along with increased number of syncytial knots, also indicate the development of placental hypoxia in parturient women with COVID-19. hypoxia promotes increased production of pro-angiogenic factors by placental cells, in particular, VEGF, which not only regulates proliferation and migration of endotheliocytes, but also contributes to BP elevation in pregnant women.”
Papageorghiou et al.²⁰20 Papageorghiou AT, Deruelle P, Gunier RB, et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am J Obstet Gynecol. 2021;225(03):289.e1-289.e17. Doi: 10.1016/j.ajog.2021.05.014 https://doi.org/10.1016/j.ajog.2021.05.0...	“…pre-eclampsia and GH are vascular conditions, preceding infection with SARS-CoV-2, which increase the risk for COVID-19 in the same way essential hypertension does.”
Lu-Culligan et al.²¹21 Lu-Culligan A, Chavan AR, Vijayakumar P, et al. SARS-CoV-2 infection in pregnancy is associated with robust inflammatory response at the maternal-fetal interface. medRxiv [Preprint]. 2021 Jan 26:2021.01.25.21250452. doi: Doi: 10.1101/2021.01.25.21250452 https://doi.org/10.1101/2021.01.25.21250...	“…we found that ACE2 protein was present at significantly higher levels in term placentas collected from COVID-19 cases. These findings suggest that detection of ACE2 mRNA expression is not a reliable surrogate for ACE2 protein expression in the placenta and, importantly, that ACE2-mediated risk for placental infection by SARS-CoV-2 may vary over the course of pregnancy, with our detection of higher ACE2 levels in the first and second trimesters suggesting that the most vulnerability may exist prior to term.”
Braga and Sass²²22 Braga LFB, Sass N. Coronavirus 2019, thrombocytopenia and HELLP syndrome: association or coincidence? Rev Bras Ginecol Obstet. 2020;42(10):669-671. Doi: 10.1055/s-0040-1718437 https://doi.org/10.1055/s-0040-1718437...	“Thrombocytopenia in patients with COVID-19 appears to be multifactorial, including endothelial damage, platelet activation with aggregation and thrombosis, impairment of bone marrow and megakaryocyte activity. [...] synergism of these pathophysiological mechanisms could accelerate the compromise of maternal conditions”
Bloise et al.²³23 Bloise E, Zhang J, Nakpu J, et al. Expression of severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across gestation and at the maternal-fetal interface in pregnancies complicated by preterm birth or preeclampsia. Am J Obstet Gynecol. 2021;224(03):298.e1-298.e8. Doi: 10.1016/j.ajog.2020.08.055 https://doi.org/10.1016/j.ajog.2020.08.0...	“...SARS-CoV-2 present in the maternal circulation has the potential to enter the maternal blood bathed syncytiotrophoblast and infect the placenta via ACE2 binding.”
Shanes et al.²⁴24 Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA. Placental pathology in COVID-19. medRxiv [Preprint]. 2020 May 12:2020.05.08.20093229. doi: Doi: 10.1101/2020.05.08. 20093229 https://doi.org/10.1101/2020.05.08.20093...	“The histologic changes of MVM are thought to represent some chronicity, though exact timing is unknown, and these features can be seen in women who develop pre-eclampsia only during or after childbirth. Whether systemic vascular changes due to maternal COVID-19 are responsible for the histologic changes of MVM cannot be determined. [...] there are increased rates of maternal vascular malperfusion features and intervillous thrombi, suggesting a common theme of abnormal maternal circulation, as well as an increased incidence of chorangiosis”
Garcia Rodriguez et al.²⁵25 Garcia Rodriguez A, Marcos Contreras S, Fernandez Manovel SM, et al. SARS-COV-2 infection during pregnancy, a risk factor for eclampsia or neurological manifestations of COVID-19? Case report. BMC Pregnancy Childbirth. 2020;20(01):587. Doi: 10.1186/s12884-020-03275-2 https://doi.org/10.1186/s12884-020-03275...	“…we believe SARS-COV-2 infection could promote brain endothelial damage, triggering the cited neurological complications in our patient.”
Mendoza et al.²⁶26 Mendoza M, Garcia-Ruiz I, Maiz N, et al. Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study. BJOG. 2020;127(11):1374-1380. Doi: 10.1111/1471-0528.16339 https://doi.org/10.1111/1471-0528.16339...	“…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. [...] 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”.

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