key: cord-1049581-l5pi7ekx
authors: Friedrich, Lior; Levin, Gabriel; Maixner, Nitzan; Bart, Yossi; Tsur, Abraham; Yinon, Yoav; Meyer, Raanan
title: Hematologic adaptation to mask‐wearing among pregnant women and obstetrical outcome during the coronavirus disease 2019 pandemic
date: 2021-05-12
journal: Int J Gynaecol Obstet
DOI: 10.1002/ijgo.13715
sha: 171b5250ad75425a767cd46519e50a68f00a5130
doc_id: 1049581
cord_uid: l5pi7ekx

OBJECTIVE: To evaluate the effect of the coronavirus disease 2019 (COVID‐19) mask‐wearing on hematological laboratory components and obstetrical outcomes among women delivering during the COVID‐19 pandemic. METHODS: Laboratory results and obstetrical outcomes of women with singleton gestations, admitted for delivery during the COVID‐19 mask‐wearing period (April–June 2020) were compared with those of women delivering during the parallel period in 2019 and with a larger cohort derived from nine pre‐pandemic years (March 2011–April 2020). RESULTS: Overall, 1838 women delivered during the COVID‐19 pandemic. Compared with the pre‐pandemic period, mean hemoglobin and fibrinogen levels were significantly higher during the mask‐wearing period (12.15 ± 1.1 vs 11.96 ± 1.2, P < 0.001 and 472 ± 103.6 vs 448 ± 85.1 mg/dl, P < 0.001, respectively). Platelet levels were lower (200 ± 56.0 vs 206 ± 57.5 K/µl, P < 0.001). The rate of delivery at <34 weeks of gestation was lower during the mask‐wearing period (1.1% vs 2%, odds ratio [OR] 0.57, 95% confidence intervals [CI] 0.37–0.88, P = 0.01), whereas cesarean delivery and postpartum hemorrhage rates were higher (26.7% vs 24.4%, OR 1.13, 95% CI 1.02–1.25, P = 0.022 and 4.1% vs 2.8%, OR 1.5, 95% CI 1.2–1.8, P = 0.001, respectively). CONCLUSION: A hard‐to‐ventilate space created by wearing a mask during the COVID‐19 era may be the underlying cause of the observed higher hemoglobin level among pregnant women, possibly affecting obstetrical outcomes.

presence of postpartum hemorrhage or blood products transfusion.

The composite neonatal outcome included the presence of any of the neonatal outcomes studied.

Patient characteristics are described as proportions for categorical variables and as means and standard deviations for continuous variables. Significance between study groups was assessed by χ 2 test and Fisher's exact test for categorical variables, t test and Mann-Whitney U test were used as appropriate in relation to cohort distribution. We further divided the whole study cohort into two groups: hemoglobin <11 and 11 g/dl or more. A logistic regression analysis was performed to underline independent determinants associated with hemoglobin levels below 11 g/dl. The model included variables with a potential association with hemoglobin level, age, BMI, smoking status, parity, gestation at delivery, and the period evaluated with respect to the COVID-19 pandemic. A two-sided P value <0.05 indicated statistical significance. The data were analyzed using SPSS version 24 (IBM Corp., Armonk, NY, USA).

This article does not contain any studies with human participants or animals performed by any of the authors. Ethical approval was waived by the local ethics committee of Sheba Medical Center in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.

Institutional review board approval was obtained for this retrospective study on March 30, 2020 (# 7068-20-SMC).

From April 19 to June 27, 2020, 1838 women were referred to the delivery unit, compared with 88 973 women between March 21, 2011 and April 18, 2020. A comparison of clinical parameters, delivery data, and neonatal outcomes between the mask-wearing period and pre-pandemic periods is presented in Table 1 . Compared with the 2011-2020 pre-pandemic period, the mean hemoglobin levels and the proportion of women with hemoglobin above 13 g/dl were significantly higher during the mask-wearing period (12.15 ± 1.1 vs 11.96 ± 1.2 g/dl, P < 0.001; 21.5% vs 16%, OR 1.43, 95% CI 1.28-1.61, P < 0.001, respectively), whereas the proportion of women with hemoglobin below 11 g/dl was lower (13.5% vs 16.5%, OR 0.79, 95% CI 0.69-0.91, P = 0.01). Platelet levels were lower during the pandemic period compared with the pre-pandemic period (200 ± 56.0 vs 206 ± 57.5 K/µl, P < 0.001), whereas fibrinogen levels were higher (472 ± 103.6 vs 448 ± 85.1 mg/dl, P < 0.001). Cesarean delivery rates were higher during the mask-wearing period compared with the pre-pandemic period ( A comparison between the mask-wearing period and the parallel period in 2019 demonstrated the same hematologic findings, rates of preterm delivery before 34 weeks of pregnancy, and postpartum hemorrhage.

Neonatal outcomes are presented in Table 2 . Mean birth weights were higher during the mask-wearing period compared with the 2011-2020 pre-pandemic period (3232 vs 3200 g, P = 0.009).

Incidence of neonatal Apgar score <5 at 1 min after delivery was lower during the mask-wearing period, as were NICU admissions Further dividing the whole study cohort into two groups; a group with hemoglobin less than 11 g/dl and the other with hemoglobin of 11 g/dl or more, we performed a multivariate regression analysis, which identified that the pre-pandemic period was independently associated with hemoglobin level below 11.0 g/dl (Table 3 ).

This comparative study of the current COVID-19 pandemic versus the pre-pandemic period reported an increase in hemoglobin and fibrinogen levels and a decrease in platelets and white blood cell levels. The periods analyzed were independently associated with hemoglobin level after adjusting for confounders in a regression analysis. Additionally, we report an increase in postpartum hemorrhage and a decrease in preterm delivery, before 34 weeks of pregnancy, and in the occurrence of composite neonatal outcome during the mask-wearing period.

The impact of airflow-restricting-masks was previously shown to facilitate hemoglobin production. 2,5 Accordingly, we demonstrated increased hemoglobin levels during the COVID-19 pandemic, during which wearing of masks covering the mouth and nose was obligatory. Elevated hemoglobin levels can protect against anemia during pregnancy, which has been associated with adverse obstetrical outcomes, including preterm birth. 6, 7 The decrease in preterm birth at <34 weeks of gestation found in our study may result from the mildly elevated hemoglobin levels during the pandemic period. However, preterm birth rates during the COVID-19 pandemic are still disputed. 8, 9 During the pandemic period, during which the population was instructed to wear a face mask, we found increased fibrinogen levels and decreased platelet levels. These findings match the results of studies conducted to examine the impact of long-term hypoxic exposure. 10 Mild platelet decrease was previously associated with higher postpartum hemorrhage rates, 11 which corresponds with the present study's results. 11 Wearing face masks plays a substantial role in preventing the spread of COVID-19. 12 However, using face masks that restrict airflow was previously described as being associated with elevated hemoglobin levels. 2, 5 The micro-environment present within the mask's hard-to-ventilate space, consisting of low O 2 and high CO 2 concentrations, may result in decreased oxygen saturation (Sao 2 ) 3 and elevation in the partial pressure of carbon dioxide (Pco 2 ), 13 respectively.

The relative hypoxia induced by a low inhaled O 2 concentration may stimulate erythropoietin secretion, which in turn increases reticulocyte production, which eventually mature into red blood cells. 14 A previous study by Vij 10 investigated the effect of chronic hypoxia on hematologic parameters. The study followed hemoglobin, fibrinogen, platelets, and white blood cell concentrations of 40 healthy men at sea level and at the following 3-and 13-month sojourns at high altitude. The study's results suggest that a prolonged stay at high altitude leads to elevated hemoglobin and fibrinogen levels and lower platelet and white blood cell levels. 10 It is also possible that hemoglobin, which has a role as a Pco 2 buffer to prevent acidosis, may arise secondary to acidosis induced by mask-wearing. 2 It should be noted that the studies mentioned above evaluated the effect of face-mask-wearing on blood hemoglobin levels using different mask types, and neither the duration of mask-wearing nor the physical activity measured was accounted for. Furthermore, it is important to acknowledge that there is no consensus regarding the hypoxemic effect of mask-wearing, as different studies among different populations with various methodological approaches have been used, 15 reaching conflicting results.

There is a debate regarding the impact of hypoxia on other, nonhemoglobin, hematologic parameters. However, when examining long-term hypoxia exposure, previous research has found elevated fibrinogen levels and lower platelet levels, in accordance with our results. 10 As for the clinical aspects of the data collected in our study, we have found higher postpartum hemorrhage rates during the maskwearing period and a lower platelet count. The American College of Obstetricians and Gynecologists classifies platelet count less than 70 K/µl as a risk factor for postpartum hemorrhage. Nevertheless, it was previously reported that there is a two-fold greater likelihood of postpartum hemorrhage among women with mild thrombocytopenia (platelet count 100-149 K/µl). 11 Our results may reflect the same consequences of mild thrombocytopenia on postpartum hemorrhage rates.

The elevated hemoglobin levels may be a plausible explanation for our reported lower rates of preterm birth and composite neonatal outcome. Hemoglobin concentrations greater than 14.6 g/dl at prenatal visits were previously associated with an increased risk of preterm birth, stillbirth, and growth restriction. 16 during pregnancy, which has been previously associated with adverse obstetrical outcomes, including preterm birth, low birth weight, stillbirth, and neonatal mortality. 6, 7 These results can potentially reflect the effect of anemia correction due to hemoglobin elevation. Additionally, a proposed underlying mechanism for the pregnancy outcomes is the induction of heme oxygenase-1 during hypoxia. 18 Heme oxygenase-1 induction has been shown to improve pregnancy outcomes, and to reduce the rate of placenta-mediated complications 19 and spontaneous preterm birth. 20 Reports of preterm birth rates during the COVID-19 pandemic are scarce and mainly include women infected with COVID-19. 21, 22 A previous report regarding preterm births during the pandemic among women who were mostly not infected with COVID-19 did not find a difference in preterm birth rates. 23 A possible explanation for the difference between the two studies is the different populations studied and different sample sizes.

Masks restricting the airflow may reduce ventilation and respiratory rate. 24 Alongside spirometric alterations, masks may lead to hematologic changes such as increased hemoglobin levels, CO 2 accumulation, and decreased oxygen saturation, as described above.

It is possible that populations suffering from impaired pulmonary or cardiac function, such as those with chronic obstructive pulmonary disease, heart failure, or asthma, may bear increased sensitivity to factors overloading these systems. 25, 26 The retrospective design of this study raises the possibility of the biases inherent to such investigations. As a result, we cannot exclude the possibility that additional unknown factors could explain the differences observed between the groups.

Moreover, although some women wear a surgical mask, others prefer to wear an N-95 mask, a variation not accounted for by our study. Additionally, although significant, we underline small hematologic variations observed between study groups, of which the clinical impact should be further studied. Nonetheless, these mild differences may have been disguised by patients who spent shorter time periods wearing a mask throughout the day, or by the short period of time evaluated after wearing a mask became obligatory.

Additionally, we did not analyze blood gases and Sao 2 , so we can only rely on the blood count data to determine whether patients were hypoxic or hypercapnic.

Finally, the conduct of the study in a single tertiary care center may limit the generalizability of the results. On the other hand, the main strengths of our study include its relatively large cohort of patients and the meticulous data collection on a broad set of variables.

The present study demonstrates significant hematologic changes among pregnant women admitted to the obstetrical emergency unit during the COVID-19 pandemic after the initiation of mask-wearing regulations. Our clinical results present a decrease in composite neonatal outcomes and lower preterm birth rates, possibly secondary to elevated hemoglobin levels measured during the COVID-19 pandemic. These hematologic changes may have a substantial impact on high-risk non-pregnant populations as well.

Further research is required to better understand the consequences of long-term mask-wearing among high-risk populations, including pregnant women.

The authors report no conflict of interest.

LF, NM, GL, YY, and RM contributed to the conception and design of the work. LF, GL, YB, AT, and RM contributed to the acquisition and interpretation of the data. LF, GL, and RM wrote the paper. All authors revised and approved the final manuscript.

Physiological impact of the N95 filtering facepiece respirator on healthcare workers

The effect of an airflow restriction mask (ARM) on metabolic, ventilatory, and electromyographic responses to continuous cycling exercise

Preliminary report on surgical mask induced deoxygenation during major surgery

Hypoxic regulation of erythropoiesis and iron metabolism

Effect of wearing the elevation training mask on aerobic capacity, lung function, and hematological variables

Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study

Significance of an abnormally low or high hemoglobin concentration during pregnancy: special consideration of iron nutrition

Clinical course of severe and critical coronavirus disease 2019 in hospitalized pregnancies: a United States cohort study

Decreased incidence of preterm birth during coronavirus disease 2019 pandemic

Effect of prolonged stay at high altitude on platelet aggregation and fibrinogen levels

Mild thrombocytopenia and postpartum hemorrhage in nulliparous women with term, singleton, vertex deliveries

Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis

Return to training in the COVID-19 era: the physiological effects of face masks during exercise

Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

COVID-19: electrophysiological mechanisms underlying sudden cardiac death during exercise with facemasks

Work-up of stillbirth: a review of the evidence

Maternal hemoglobin level and fetal outcome at low and high altitudes

Heme oxygenase-1 and chronic hypoxia

Pravastatin improves fetal survival in mice with a partial deficiency of heme oxygenase-1

Statins prevent cervical remodeling, myometrial contractions and preterm labor through a mechanism that involves hemoxygenase-1 and complement inhibition

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis

A marked decrease in preterm deliveries during the coronavirus disease 2019 pandemic

Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic

Functional" respiratory muscle training during endurance exercise causes modest hypoxemia but overall is well tolerated

Mortality and mortalityrelated factors after hospitalization for acute exacerbation of COPD

Evaluation of SaO 2 as a predictor of outcome in 280 children presenting with acute asthma