Severity of COVID-19 Respiratory Complications during Pregnancy are Associated with Degree of Lymphopenia and Neutrophil to Lymphocyte Ratio on Presentation: A Multicenter Cohort Study

Abstract

Objective This study aimed to determine if laboratory inflammatory markers can predict critical disease in symptomatic COVID-19 pregnant women.

Study Design Multicenter, retrospective cohort study of all pregnant women presenting to New York City Health + Hospitals emergency departments from March 1 to May 30, 2020. We assessed all symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive pregnant women with room air oxygen saturation <95% on presentation. Logistic regression modeled the relationship of inflammatory markers to outcomes. Area under receiver operating characteristic (ROC) curve and maximum Youden index determined prognostic ability and optimal predictive cut-off values.

Results A total of 498 of 5,002 pregnant women were SARS-CoV-2 RT-PCR positive of which 77 presented with hypoxemia. The absolute lymphocyte count (ALC) and neutrophil to lymphocyte ratio (NLR) were highly sensitive for progression to severe illness. ROC curve analysis identified predictive cutoffs: ALC < 1.49 × 10⁹/L (96% sensitivity, 52% specificity, area under the receiver operating characteristic curve [AUC] = 0.80 (95% confidence interval [CI]: 0.70–0.90) and NLR >8.1 (100% sensitivity, 70% specificity, AUC = 0.86 (95% CI: [0.76–0.96]).

Conclusion ALC and NLR on presentation are sensitive markers of progression to critical COVID-19 disease in symptomatic pregnant women. This finding provides a practical, rapid method for assessment and can assist clinicians with decision-making regarding triage, level of care, and patient management.

Key Points

• Few tools exist to gauge risk of severe COVID-19 disease in pregnancy.

• ALC and NLR are sensitive predictive markers of disease progression in symptomatic women.

• Cut-off values for ALC and NLR will help direct patient triage and management.

Keywords

COVID-19 - pregnancy - lymphopenia - neutrophil-lymphocyte ratio - hypoxemia - inflammatory markers

• References

• 1 Allotey J, Stallings E, Bonet M. et al; for PregCOV-19 Living Systematic Review Consortium. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ 2020; 370: m3320
• 2 London V, McLaren Jr R, Atallah F. et al. The relationship between status at presentation and outcomes among pregnant women with COVID-19. Am J Perinatol 2020; 37 (10) 991-994
• 3 American College of Obstetricians and Gynecologists (ACOG) Practice Advisory. Novel coronavirus 2019 (COVID-19). Accessed November 8, 2020 at: https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/novel-coronavirus-2019
• 4 New York Department of Health. Task force on maternal mortality and disparate racial outcomes. (Published March 2019). Accessed December 9, 2020 at: http://www.health.ny.gov/community/adults/women/task_force_maternal_mortality/docs/maternal_mortality_report.pdf
• 5 Council on Patient Safety in Women's Health Care. Maternal early warning criteria - February 2015. Accessed December 9, 2020 at: https://safehealthcareforeverywoman.org/council/patient-safety-tools/maternal-early-warning-criteria/
• 6 Liu J, Liu Y, Xiang P. et al. Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J Transl Med 2020; 18 (01) 206
• 7 Liu Y, Du X, Chen J. et al. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect 2020; 81 (01) e6-e12
• 8 Liang W, Liang H, Ou L. et al; China Medical Treatment Expert Group for COVID-19. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. JAMA Intern Med 2020; 180 (08) 1081-1089
• 9 Li X, Liu C, Mao Z. et al. Predictive values of neutrophil-to-lymphocyte ratio on disease severity and mortality in COVID-19 patients: a systematic review and meta-analysis. Crit Care 2020; 24 (01) 647
• 10 Song M, Graubard BI, Rabkin CS, Engels EA. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci Rep 2021; 11 (01) 464
• 11 Świtońska M, Piekuś-Słomka N, Słomka A, Sokal P, Żekanowska E, Lattanzi S. Neutrophil-to-lymphocyte ratio and symptomatic hemorrhagic transformation in ischemic stroke patients undergoing revascularization. Brain Sci 2020; 10 (11) 771
• 12 Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. Neutrophil-to-lymphocyte ratio and neurological deterioration following acute cerebral hemorrhage. Oncotarget 2017; 8 (34) 57489-57494
• 13 Dong CH, Wang ZM, Chen SY. Neutrophil to lymphocyte ratio predict mortality and major adverse cardiac events in acute coronary syndrome: a systematic review and meta-analysis. Clin Biochem 2018; 52: 131-136
• 14 Ling H, Hu ZD. The clinical utility of neutrophil to lymphocyte ratio in pregnancy related complications: a mini-review. J Lab Precis Med 2020; 5: 1
• 15 Zambrano LD, Ellington S, Strid P. et al; CDC COVID-19 Response Pregnancy and Infant Linked Outcomes Team. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status - United States, January 22-October 3, 2020. MMWR Morb Mortal Wkly Rep 2020; 69 (44) 1641-1647
• 16 Ramsey PS, Ramin KD. Pneumonia in pregnancy. Obstet Gynecol Clin North Am 2001; 28 (03) 553-569
• 17 Heidemann BH, McClure JH. Changes in maternal physiology during pregnancy. Br J Anaesth 2003; 3 (03) 65-67
• 18 Pierce-Williams RAM, Burd J, Felder L. et al. Clinical course of severe and critical coronavirus disease 2019 in hospitalized pregnancies: a United States cohort study. Am J Obstet Gynecol MFM 2020; 2 (03) 100134
• 19 Huang I, Pranata R. Lymphopenia in severe coronavirus disease. (COVID-19): systematic review and meta-analysis. J Intensive Care 2020; 8: 36 Published 2019;2020:24
• 20 Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19) - October 27th, 2020. Accessed December 1, 2020 at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
• 21 Zaigham M, Andersson O. Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies. Acta Obstet Gynecol Scand 2020; 99 (07) 823-829
• 22 Taghavi-Farahabadi M, Mahmoudi M, Hashemi SM. et al. Neutrophils to lymphocytes ratio and the prognosis of the COVID-19 patients. Immunoregulation 2020; 3 (02) 89-96
• 23 Taghiloo S, Aliyali M, Abedi S. et al. Apoptosis and immunophenotyping of peripheral blood lymphocytes in Iranian COVID-19 patients: clinical and laboratory characteristics. J Med Virol 2021; 93 (03) 1589-1598
• 24 Cizmecioglu A, Cizmecioglu HA, Goktepe MH. et al. Apoptosis-induced T-cell lymphopenia is related to COVID-19 severity. J Med Virol 2021; 93 (05) 2867-2874
• 25 Meizlish ML, Pine AB, Bishai JD. et al. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv 2021; 5 (05) 1164-1177
• 26 Hassanipour S, Faradonbeh SB, Momeni K. et al. A systematic review and meta-analysis of pregnancy and COVID-19: Signs and symptoms, laboratory tests, and perinatal outcomes. Int J Reprod Biomed (Yazd) 2020; 18 (12) 1005-1018
• 27 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009; 114 (06) 1326-1331
• 28 Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med 2020; 173 (04) 262-267