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Comment & Response
August 16, 2021

Further Observations on Pregnancy Complications and COVID-19 Infection

Author Affiliations
  • 1THAI StemLife, Bangkok, Thailand
  • 2Jetanin Institute for Assisted Reproduction, Bangkok, Thailand
  • 3Department of Laboratory Medicine, Changi General Hospital, Singapore
JAMA Pediatr. 2021;175(11):1185. doi:10.1001/jamapediatrics.2021.2613

To the Editor We read with interest the article by Villar and colleagues1 and wish to comment on the potential association between COVID-19 infection and higher rates of preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count syndrome. SARS-CoV-2 infection induces a state of renin-angiotensin system hyperactivity with elevated levels of angiotensin II (Ang II), interleukin 6 (IL-6), and plasminogen activator inhibitor 1.2,3 This proinflammatory state can potentially lead to acute respiratory distress syndrome, cytokine storm, and autoimmunity.2 Elevated Ang II levels in COVID-19 have been reported to induce pyroptosis, an inflammasome-initiated lytic form of programmed cell death that may further contribute to the COVID-19 cytokine storm. Via the exposure of autoantigens, pyroptosis may also lead to the development of multiple autoantibodies.4 Numerous studies have shown that preeclampsia is a pregnancy-induced autoimmune disease in which key features of the disease result from a pyroptosis-induced Ang II type 1 receptor autoantibodies (AT1-AA) correlating significantly with IL-6 and systolic blood pressure.4 This condition could be aggravated in the presence of the Ang II-augmenting ACE D allele,2 which has been reported to be associated with increased mortality in COVID-19.2 We believe that the possibility of Ang II-induced pyroptosis in pregnant women with COVID-19 infection could mediate persistent proinflammatory Ang II effects and induce preeclampsia via AT1-AA. It would be desirable to evaluate the presence of AT1-AA in pregnant women with COVID-19 infection as lipoxin A4 (LXA4), deficient in individuals with preeclampsia, has been shown to modulate caspase-1 and inhibit AT1-AA.4 Low-dose acetylsalicylic acid5 and increasing bioactive lipid intake (arachidonic acid, 20:4 n-6; eicosapentaenoic acid, 20:5 n-3; and docosahexaenoic acid, 22:6 n-3) may result in the formation of increased amounts of endogenous LXA4, thus offering a treatment option for a potentially lethal complication. Drug design research using LXA4 as a lead compound might result in novel treatment modalities in preeclampsia and other autoimmune diseases.

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Article Information

Corresponding Author: Konstantinos I. Papadopoulos, MD, PhD, THAI StemLife, 566/3 THAI StemLife Building, Soi Ramkhamhaeng 39 (Thepleela 1), Prachauthit Road, Wangthonglang, Bangkok 10310, Thailand (kostas@thaistemlife.co.th).

Published Online: August 16, 2021. doi:10.1001/jamapediatrics.2021.2613

Conflict of Interest Disclosures: None reported.

References
1.
Villar  J, Ariff  S, Gunier  RB,  et al.  Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID Multinational Cohort Study.   JAMA Pediatr. Published online April 22, 2021. doi:10.1001/jamapediatrics.2021.1050PubMedGoogle Scholar
2.
Pabalan  N, Tharabenjasin  P, Suntornsaratoon  P, Jarjanazi  H, Muanprasat  C.  Ethnic and age-specific acute lung injury/acute respiratory distress syndrome risk associated with angiotensin-converting enzyme insertion/deletion polymorphisms, implications for COVID-19: a meta-analysis.   Infect Genet Evol. 2021;88:104682. doi:10.1016/j.meegid.2020.104682PubMedGoogle Scholar
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Kang  S, Tanaka  T, Inoue  H,  et al.  IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.   Proc Natl Acad Sci U S A. 2020;117(36):22351-22356. doi:10.1073/pnas.2010229117Google ScholarCrossref
4.
Liu  H, Cheng  F, Xu  Q,  et al.  Lipoxin A4 suppresses angiotensin II type 1 receptor autoantibody in preeclampsia via modulating caspase-1.   Cell Death Dis. 2020;11(1):78. doi:10.1038/s41419-020-2281-yPubMedGoogle ScholarCrossref
5.
Shanmugalingam  R, Wang  X, Motum  P  et al.  The 15-epilipoxin-A4 pathway with prophylactic aspirin in preventing preeclampsia: a longitudinal cohort study.   J Clin Endocrinol Metab. 2020;105(12):e4811–e4822. doi:10.1210/clinem/dgaa642Google ScholarCrossref
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