Post-viral fatigue following SARS-CoV-2 infection during pregnancy: a longitudinal comparative study

doi:10.21203/rs.3.rs-1629974/v1

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Research Article

Post-viral fatigue following SARS-CoV-2 infection during pregnancy: a longitudinal comparative study

https://doi.org/10.21203/rs.3.rs-1629974/v1

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Background: Several studies have reported post-COVID-19 fatigue in the general population, but none explored post-COVID-19 fatigue among pregnant women. The objectives of this study were to determine the prevalence over time, duration and risk factors of post-viral fatigue among pregnant women infected with SARS-CoV-2.

Methods: Longitudinal comparative study involving 588 pregnant women with SARS-CoV-2 investigation during pregnancy or at delivery in Sao Paulo, Brazil. Three groups were investigated: G1 (N=259) women with COVID-19 (symptomatic SARS-CoV-2 infection) identified during pregnancy; G2 (N=131) women with positive SARS-CoV-2 serology determined at delivery; G3 (N=198) women with negative SARS-CoV-2 serology at delivery. Questionnaires investigating fatigue were applied at 6 weeks, 3 and 6 months after SARS-CoV-2 identification for G1; and at delivery, 6 weeks, 3 and 6 months after delivery for all groups. The prevalence of fatigue, fatigue most of the time, and significant fatigue were determined at all timepoints. Cox regression analysis was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the risk of remaining with fatigue over time in G1 women.

Results: Prevalence of overall fatigue in G1 women at 6 weeks, 3 and 6 months were 40.6%, 33.6% and 27.8%, respectively. The cumulative risk of remaining with fatigue increased over time according to the severity of disease, with HR of 1.69 (95%CI: 0.89-3.20) and 2.43 (95%CI: 1.49-3.95) for women with moderate and severe symptoms, respectively. In multivariate analysis, the independent risk factors of fatigue in G1 women were cough and myalgia. At and after delivery the prevalence of fatigue was significantly higher in G1 women compared to G2 and G3 women at all time points.

Conclusions: The prevalence of post-viral fatigue is higher in pregnant women acquiring SARS-CoV-2 during pregnancy, and the risk and duration of fatigue increase with severity of infection.

SARS CoV-2

COVID-19

post-viral fatigue

pregnancy

The severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) emerged in Eastern Asia in late 2019 causing the worldwide pandemic of COVID-19 (coronavirus-associated disease 2019) [1]. Initial manifestations of the disease, when symptomatic, were flu-like symptoms, such as fever, cough, fatigue and shortness of breath. Typically, affected individuals have displayed a variable extent of dyspnea, hypoxia and radiological signs [2]. Patients who have recovered from COVID-19 can develop a post-viral syndrome referred to as “post‐COVID‐19 Syndrome”, which presents with profound and persistent fatigue, intolerance to exertion and post-exertional malaise, disturbed sleep/wake cycle and neuro‐cognitive symptoms [3].

Recent studies have shown that, following COVID-19, patients can present persistent physical symptoms such as fatigue (15 to 87%), dyspnea (10 to 71%), chest pain or tightness (12 to 44%), cough (17 to 34%), which lead to a reported worsened quality of life in 44.1% of the cases [4, 5]. Although fatigue appears to resolve spontaneously for most patients, it can be profound and may last for three months or longer, especially among intensive care unit survivors [6, 7].

Fatigue can be defined as an overwhelming and sustained feeling of exhaustion, a diminished ability to perform physical and mental work at the usual level and feelings of tiredness to exhaustion, creating a general condition of lack of relief, which interferes with the individual's ability to perform normal activities [8].

The fatigue symptoms following COVID-19 may be multi-factorial or be caused by any of prolonged illness, organ damage or dysfunction or psychological factors, triggered or enhanced by the wide consequences of the pandemic or the fears that getting COVID-19 brings to those affected [9, 10, 11]. However, prolonged and chronic fatigue following infectious diseases, and particularly acute viral diseases, have commonly been described, in some cases leading to the development of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) [12, 13]. Fatigue is commonly reported as a COVID-19 symptom per se and may present after recovery from acute infection [14]. However, fatigue is also a common complaint in the general population, with 21 to 33% of patients seeking attention in primary care settings, describing it as an important symptom [15, 16], and more frequently reported by women [17].

While several studies have described post-COVID-19 fatigue in the general population, we are not aware of studies reporting post-COVID-19 fatigue experienced by women during or after a pregnancy, a population group that could be assumed to experience more frequent effects of fatigue. In this study, we sought to determine the prevalence over time duration and factors associated with fatigue following a diagnosis of COVID-19 (symptomatic SARS-CoV-2 infection) during pregnancy, positive serology at delivery (asymptomatic SARS-CoV-2 infection) compared to women with SARS-CoV-2 negative serology in Sao Paulo, Brazil.

Study design, settings and populations

We conducted a longitudinal comparative study within a cohort of pregnant women attending antenatal care, maternity and post-natal clinics or the delivery unit of one of the two public hospitals belonging to the University of Sao Paulo (USP) medical complex, specifically the Hospital das Clinicas and the Hospital Universitario, between May 1st 2020 and May 31st 2021.

Study participants included two groups of women identified with SARS-CoV-2 infection: i) women who had been diagnosed with COVID-19 (symptomatic SARS-CoV-2) during pregnancy (G1; n = 259); ii) women with no investigation for SARS-CoV-2 infection during pregnancy and a positive SARS-CoV-2 serology at delivery (G2; n = 131); and iii) a comparison group of pregnant women (G3; n = 198) with no investigation for SARS-CoV-2 during pregnancy and negative SARS-CoV-2 serology at delivery. G3 women were enrolled consecutively, following identification of G2 women, from the same delivery unit and within the same day of delivery, if they consented. During the study period, SARS-CoV-2 serology was offered systematically to all women delivering at the USP delivery suites. Pregnant women who had been vaccinated for SARS-CoV-2 during the study period were not included in this study.

The study was conducted with the approval of the Ethics Committee of Hospital das Clinicas – FMUSP, Sao Paulo, Brazil and the Ethics Committee of Hospital Universitario, Sao Paulo, Brazil (CAAE: 30270820.3.0000.0068). The study protocol was registered at ClinicalTrials.gov on 01/12/2020 (NCT04647994). All methods were carried out in accordance with relevant guidelines and regulations. All participants provided signed informed consent.

Data collection

Questionnaires for fatigue evaluation were applied face-to-face by trained research assistants following a specific schedule for each group: G1 participants were interviewed at 6 weeks, 3 months and 6 months after their COVID-19 diagnosis, then again at delivery, and at 6 weeks, 3 months and 6 months after delivery, whichever follow-up visit came first. Participants from G2 and G3 were interviewed at delivery and at 6 weeks, 3 months and 6 months after delivery.

Four types of questionnaires were used to ascertain fatigue and related symptoms: (i) a screening questionnaire was applied at recruitment and at each follow-up visit, if the previous screening was negative for ‘significant’ fatigue; the questionnaire determined the presence or absence of fatigue, including duration and any loss of activity, and measured mental and physical fatigue and pain on 10-point scales; (ii) a follow-up fatigue screening questionnaire, with similar structure to the first one but with modifications to account for any changes in fatigue since last assessment, was applied at follow-up visits; (iii) an additional in-depth complementary fatigue questionnaire was administered to women screened positive for ‘significant fatigue’ at any visit using (i) or (ii), to identify presence and severity of symptoms associated with fatigue, possible comorbidities or other possible causes of fatigue; and (iv) a follow-up for the additional ‘significant fatigue’ questionnaire at subsequent visits, which however omitted questions about comorbidities or other possible causes of fatigue already probed [18, 19, 20]. ‘Fatigue’ was identified when the pregnant women reported persistent or recurrent profound tiredness, weariness or fatigue. ‘Fatigue most of the time’ was considered when the patient indicated feeling fatigue more than 50% of the time and when they needed to substantially reduce some activities or could no longer do some routine activities. ‘Significant fatigue’ included the same requirements for ‘fatigue most of the time’ with the addition of a positive answer to the statement “the patient could do half or less than half, as much as she could”, the fatigue would not be due to a long-standing disease or illness, and fatigue would not disappear with rest. The questionnaire also included self-scoring items (from 0 as absent, to 10 for worst) relating to how the participant felt over the previous seven days regarding fatigue, physical fatigue, mental fatigue and pain.

G3 participants were serologically tested at each visit to confirm that they had remained seronegative.

Information regarding participant’s demographics, medical and obstetrical history was obtained directly from their antenatal and postnatal clinic notes or obstetrical charts. Data regarding SARS-CoV-2 investigations or COVID-19 diagnosis during pregnancy were obtained from the REDCap database specifically developed for a cohort study of the incidence of SARS-CoV-2/COVID-19 during pregnancy developed by the research team at the same maternal units [21].

Laboratory methods

SARS-CoV-2 diagnosis was based on serological and molecular assays performed at our hospital during the aforementioned cohort study [21]. In brief, pregnant women with suspected COVID-19 symptoms had samples from the nasopharynx and/or back of throat tested by real-time polymerase chain reaction (RT-PCR, RealStar SARS‐CoV‐2 RT‐PCR kit 1.0 RUO, Altona Diagnostics, Germany) using the LightCycler 96 Instrument (Roche, Mannheim, Germany). In addition, a serological assay was systematically performed for all women presenting at the USP delivery units during the study period using the Roche Elecsys anti-SARS-CoV-2 E2G300 assay (Roche Diagnostics, Mannheim, Germany), a chemiluminescence assay detecting IgG antibodies against SARS-CoV-2 nucleocapsid protein.

Statistical analysis

Participants with identified COVID-19 by molecular and/or serological methods (G1) were further classified in three sub-groups according to the severity of their acute infection: 1) women with mild symptoms not needing hospital admission; 2) women with moderate symptoms (oxygen saturation rate SpO₂ < 94% and/or respiratory rate > 24 breaths per minute) who needed hospital admission for supplemental catheter-administered oxygen; and 3) women with severe COVID-19 who needed hospital admission in intensive care units for mechanical ventilation, or because of multi-organ involvement.

Categorical variables were presented as absolute frequencies and percentages, and continuous variables as medians with interquartile range (IQR). The Chi-squared and Fisher´s exact tests were applied to assess association between categorical variables. The Kruskal-Wallis test was used to test for differences between groups for quantitative variables.

Cox proportional risk model for Group 1 was applied to estimate the risk of remaining with fatigue (HR) and its 95% confidence intervals (CI). The outcome variable was made using the time from the first day with fatigue to the date of the last event without fatigue or loss to follow-up. For the multivariate model, independent covariates such as maternal age, number of comorbidities, pregnancy trimester and severity of COVID-19 during pregnancy were applied. To test the proportional hazards assumptions, we employed the method based on scaled Schoenfield residuals. Differences were considered significant when the p-value was less than 0.05.

The data were analyzed using Statistical Package for the Social Sciences (SPSS version 20 IBM, Armonk, NY, USA). STATA Intercooled version 15 was used for survival analysis.

Over the 13-month study period (May 1st 2020 to May 31st 2021), 1170 pregnant women were recruited to the main cohort study of SARS-CoV-2 incidence, and 627 were eligible to participate in this sub-study investigating post-viral fatigue; 31 women declined participation, and 8 were excluded because they were asymptomatic positive SARS-CoV-2 during antenatal care, leaving 588 (94%) for inclusion in the analysis. Of these, 259 were women with COVID-19 (symptomatic SARS-CoV-2 infection) during antenatal care (G1), 131 had positive SARS-CoV-2 serology at delivery, with no direct evidence of SARS-CoV-2 infection during pregnancy (G2) and 198 were the seronegative control groups for G2 women (G3). Detailed characteristics of the three groups are shown in Table 1. The median gestational age at SARS-CoV-2 diagnosis in G1 was 27.4 weeks (IQR, 21.9–32.9).

Table 1

Population characteristics (N = 588)
Maternal Characteristics	n (%) or median (IQR)
	Group 1 (N = 259)	Group 2 (N = 131)	Group 3 (N = 198)
Age, years, median	31.0 (26–36)	27.0 (23–75)	30.5 (24–36)
Parity
Nulliparous	78/256 (30.1)	59/131 (44.7)	75/198 (37.9)
Multiparous	178/256 (68.7)	73/131 (55.3)	123/198 (62.1)
Ethnicity
White	124/257 (48.2)	44/131 (33.6)	74/196 (37.8)
Other	133/257 (51.8)	87/131 (66.4)	122/196 (62.2)
Current smoking	19/248 (7.7)	9/131 (6.9)	19/197 (9.6)
Comorbidities
Diabetes mellitus	10/258 (3.9)	5/131 (3.8)	5/197 (2.5)
Hypertension	40/258 (15.5)	5/131 (3.8)	18/197 (9.1)
Heart disease	13/258 (5.0)	2/131 (1.5)	6/197 (3.0)
Lung disease	29/258 (11.2)	3/131 (2.3)	12/197 (6.1)
Mental health condition	24/257 (9.3)	6/131 (4.6)	19/197 (9.6)
Number of comorbidities
0	158/258 (61.8)	110/131 (84.0)	142/197 (72.1)
1	80/258 (28.1)	17/131 (13.0)	44/197 (22.3)
≥ 2	20/258 (7.8)	4/131 (3.1)	12/197 (6.1)
Obstetrical outcomes
Vaginal delivery	79/217 (36.4)	49/129 (37.5)	81/194 (41.7)
Cesarean delivery	138/217 (63.6)	79/129 (61.2)	107/194 (55.2)
Curettage	0/217	2/129 (1.5)	6/194 (3.1)
Group 1 = pregnant women with COVID-19 diagnosed during antenatal care; Group 2 = pregnant women with positive SARS-CoV-2 serology at delivery; Group 3 = pregnant women with negative SARS-CoV-2 serology at delivery.

(Table 1 here)

Prevalence over time of post-viral fatigue

The overall number of fatigue-assessment visits per participant ranged from 1 to 7 and 30.1% (177/588) participants attended at least three visits. Supplementary Table 1 shows frequency of visits by study group.

Table 2 displays the frequency of fatigue related outcomes after COVID-19 diagnosed during pregnancy (G1). The prevalence of fatigue at 6 weeks, 3 months and 6 months post diagnosis was 40.6% (95%CI: 33.3–47.9), 33.1% (95%CI: 25.3–41.9) and 27.5% (95%CI: 19.9–35.7), respectively.

Table 2

Prevalence over time of fatigue after COVID-19 diagnosed during pregnancy at each time point after infection (G1, N = 259).

Fatigue related outcomes	6 Weeks (N = 175) n (%)	3 Months (N = 125) n (%)	6 Months (N = 79) n (%)
Fatigue	71 (40.6)	42 (33.6)	22 (27.8)
Fatigue most of the time^#	6 (3.4)	5 (3.9)	5 (6.3)
Significant fatigue^##	2 (1.1)	3 (2.4)	1(1.3)
^#Fatigue most of the time: fatigue more than 50% of the time. ^##Significant fatigue: fatigue most of the time in addition to that “the patient could do half or less than half, as much as she could”, and the fatigue would not be due to a long-standing disease or illness and would not disappear with rest.

In symptomatic women infected during pregnancy (G1), the cumulative risk of remaining with fatigue increases over time according to the severity of the disease (Fig. 1). The group of patients with mild disease had a longer time of follow-up which may be because the disease did not influence in the time of delivery. Cases with severe COVID-19 had a significantly higher risk (HR = 2.43, 95%CI: 1.49–3.95) of remaining with fatigue compared with those with mild disease (Table 3). In addition, among G1 women there was no difference in duration of post-viral fatigue in relation to presence and number of comorbidities or trimester of pregnancy (Table 3). There was a tendency for fatigue to last longer with greater age, but this was not statistically significant. In addition, none of the investigated maternal comorbidities independently influenced the risk of fatigue in the multivariate analysis, with the following HR for hypertension, cardiac disease, lung disease, respectively: HR = 1.15 (95%CI: 0.72–1.85), HR = 0.89 (95%CI: 0.33–2.42), HR = 1.13 (95%CI: 0.65–1.95). Regarding diabetes mellitus and mental disease in G1, none of the patients with fatigue had these comorbidities.

Table 3

Risk of remaining with fatigue according to maternal COVID-19 severity. This is on G1 only, N = 259, of whom 178 had fatigue at any point and are included here.
Variables	Hazard ratio (HR)	95% CI	p
		Lower - Upper
SARS-CoV-2 infection
Positive with mild disease	Reference
Positive with moderate disease	1.69	0.89–3.20	0.107
Positive with severe disease	2.43	1.49–3.95	< 0.001
Age, years
≤ 25	Reference
25 to 34	1.43	0.64–3.23	0.383
≥ 35	2.08	0.95–4.80	0.084
Pregnancy trimester
1st	Reference
2nd	1.09	0.31–3.79	0.890
3rd	0.96	0.29–3.18	0.943
Comorbidities*
0	Reference
1	0.83	0.51–1.35	0.460
≥ 2	0.67	0.28–1.60	0.372
*Comorbidities include any of: diabetes mellitus, hypertension, heart disease, lung disease, rheumatologic disease and mental disease

In addition, symptoms at the time of infection (cough, myalgia, dyspnea, fever, fatigue, asthenia, headache, diarrhea, runny nose, anosmia, sore throat and dysgeusia) were significantly associated with risk of remaining with fatigue in univariate analysis (Table 4). In the multivariable analysis, the following were retained due to statistical significance: cough (HR = 1.76; 95%CI: 1.07–2.96), myalgia (HR = 1.57; 95%CI: 1.01–2.44) and anosmia (HR = 0.60; 95%CI: 0.40–0.88). Anosmia was a protective factor in the risk of remaining with fatigue.

Table 4

Univariate analysis of the risk of remaining with fatigue according to COVID-19 symptoms in G1 (N = 259).
Variables	Hazard ratio (HR)	95% CI	p
		Lower - Upper
Cough	1.80	1.08–2.99	0.024
Myalgia	1.51	0.98–2.33	0.060
Dyspnea	1.43	0.93–2.18	0.100
Fever	1.54	1.04–2.28	0.032
Fatigue	1.32	0.90–1.94	0.162
Asthenia	1.20	0.82–1.76	0.345
Headache	1.01	0.68–1.49	0.968
Diarrhea	1.33	0.82–2.15	0.245
Runny nose	0.72	0.49–1.06	0.092
Anosmia	0.66	0.45–0.97	0.033
Sore throat	0.76	0.49–1.18	0.218
Dysgeusia	0.67	0.46–0.99	0.042

Table 5 displays the frequencies and comparisons of fatigue-related outcomes in the three study groups, by follow-up visit from delivery onwards. There were significant differences in the frequency of overall fatigue between the three groups (G1 versus G2; G1 versus G3) at all four time points. Prevalence of fatigue was significantly higher at delivery, 6 weeks, 3 months and 6 months after delivery in G1 compared to respective visits in G2 and G3. For example, at 6 months after delivery, fatigue was reported by 9 (16.4%) women in G1 compared to none in G2 and 1 (0.3%) in G3 (p = 0.021). Regarding ‘fatigue most of the time’ and ‘significant fatigue’ outcomes no statistical test were applied for comparisons due to the very low frequencies of events in all groups (Table 5). In addition, no difference was observed in the scores of fatigue and pain between the groups at these time points (Supplementary Table 2).

Table 5

Comparison of fatigue related outcomes after delivery between the groups (N = 588).
Outcome at each time point		Group 1 (N = 259) n (%)	Group 2 (N = 131) n (%)	Group 3 (N = 198) n (%)	P-value
Fatigue	Delivery	28/145 (19.3)	1/125 (0.8)	4/181 (2.2)	< 0.001*
	6 weeks	34/134 (25.4)	2/56 (3.6)	3/69 (4.3)	< 0.001*
	3 months	18/78 (23.1)	3/34 (8.8)	2/44 (4.5)	0.011**
	6 months	9/55 (16.4)	0/28	1/34 (2.9)	0.011**
Fatigue most of the time	Delivery	2/145 (1.4)	0/125	2/181 (1.0)	NA
	6 weeks	2/134 (1.5)	1/56 (5.3)	0/69	NA
	3 months	2/78 (2.6)	0/34	0/44	NA
	6 months	1/55 (1.8)	NA	0/34	NA
Significant fatigue	Delivery	2/145 (1.4)	0/125	1/181 (0.6)	NA
	6 weeks	0/134	0/56	0/69	NA
	3 months	1/78 (1.3)	0/34	0/44	NA
	6 months	0/55	NA	0/34	NA
Chi-squared test; *Fisher exact test; ^#Fatigue most of the time: fatigue more than 50% of the time. NA = not applicable. ^##Significant fatigue: fatigue most of the time in addition to that “the patient could do half or less than half, as much as she could”, and the fatigue would not be due to a long-standing disease or illness and would not disappear with rest.
Group 1 = pregnant women with COVID-19 diagnosed during antenatal care; Group 2 = pregnant women with positive SARS-CoV-2 serology at delivery; Group 3 = pregnant women with negative SARS-CoV-2 serology at delivery

This study investigating the prevalence and persistence of post-viral fatigue after a diagnosis of SARS-CoV-2 infection during pregnancy or at delivery among nearly 600 women had a number of important findings. First, the prevalence of overall fatigue following COVID-19 was significantly higher compared to groups that had positive serology at delivery, but no evidence of infection during pregnancy (G2) or negative serology at delivery and in subsequent follow-ups. Second, approximately a quarter of pregnant women with COVID-19 during pregnancy presented fatigue 6 months after infection. Third, the risk of fatigue increased with the severity of the acute infection during pregnancy with 2.4-fold increased risk in women with severe disease compared to mild disease. On the other hand, there was no increase in risk of presenting fatigue according to trimester of infection or background comorbidity. Fourth, the presence of classic COVID-19 symptoms such as cough and myalgia were significantly associated with the risk of fatigue. Conversely, anosmia was a protective factor for fatigue.

The observed occurrence of overall fatigue in our population 6 weeks, 3 months and 6 months after initial diagnosis of COVID-19 during antenatal care were 40.6%, 33.6% and 27.8%, respectively. Other studies have reported an even higher occurrence of post-viral fatigue following a COVID-19 diagnosis in other population than pregnant women, however rates vary between studies. Goertz et al. in The Netherlands described extremely high rates of fatigue (87%) 79 days after infection in general population (85.3% of non pregnant women), although that study may have suffered from selection and reporting biases as only patients with persistent COVID-19 symptoms were recruited through an internet survey and filled an online self-administered questionnaire [5]. Another study conducted in Mexico [22] reported a 53% (69/119) fatigue prevalence among patients 3 months after discharge from hospital, of whom about 40% were women. However, we did not find any previous study investigating post-viral fatigue after a diagnosis of SARS-CoV-2 infection in the specific group of pregnant women to compare with our data.

Importantly, our study also measured various standard outcomes of fatigue, with overall fatigue, fatigue most of the time and significant fatigue in the three different groups after delivery (Table 5). In G1, 6 months after delivery, 16.4% women reported overall fatigue, 1.8% women with fatigue most of the time, but none reported significant fatigue. Overall, ‘significant fatigue’ was an uncommon event in our cohort (4 of 588 individuals), a finding that differs from other studies reporting higher rates in the context of post-COVID-19 [23, 24]. This could be explained, as most of the studies did not differentiate between significant fatigue and overall fatigue, and by the fact that our population was an unselected cohort at various stages of SARS-CoV-2 infection severity. Moreover, the rates of fatigue most of the time and significant fatigue were similar with prevalence of ME/CFS, associated with chronic diseases which vary between 0.1% and 0.7%, at a median 0.4% [25].

On the other hand, the frequency of the outcome “fatigue” as a symptom is more directly comparable with rates measured in studies investigating post-COVID-19 fatigue. A meta-analysis of post-COVID-19 fatigue based on 25.000 cases found a prevalence of 32% (95%CI: 27–37) at 12 weeks or more following diagnosis in the general population, although most patients had been hospitalized and children were also included [26]. Our results indicated that one third (33.6%) of women were still having fatigue 3 months after contracting SARS-CoV-2 infection during pregnancy. However, small numbers at follow-up and potential selection of returnees may have biased these results.

The reasons of fatigue occurrence during or after SARS-CoV-2 infection or COVID-19 remain poorly elucidated. Until COVID-19, most studies had focused on ME/CFS and measuring fatigue incidence in chronic illnesses, and some mechanisms have been described such as inflammation, dysregulation of the hypothalamic–pituitary–adrenal axis and the autonomic nervous system [27]. Fatigue following acute infection has been studied following a number of agents such as dengue, Chikungunya, Ebola virus, mononucleosis, Rock River fever, Lyme and others [28, 29, 30]. The mechanisms of post-infectious fatigue related to COVID-19 likely overlap with those originated following other infections, except for the operation of agent-specific factors (e.g. chronic lung disease following COVID-19), and seem to suggest primarily immuno-neurological mechanisms, leading to a range downstream of abnormalities such as micro-circulatory dysregulation and intra and extracellular mitochondrial dysfunction [31]. However, none of these have yet been implicated in the occurrence of long COVID-19 or SARS-CoV-2 post viral fatigue [32].

In this study, we have investigated factors that may influence the risk of having post-viral fatigue when SARS-CoV-2 is acquired during pregnancy. The most significant factor was the severity of initial disease, with patients admitted to ICU having the highest risk, while no risk was observed for infected women without symptoms. Other factors such as maternal age and comorbidities did not influence the risk of fatigue, although our sample size may have been limited to investigate these effects.

This study had several strengths, including a relatively large number of COVID-19 cases recruited from a single centre, the inclusion of comparative SARS-CoV-2 seropositive and seronegative groups, its longitudinal design with several follow-up visits at predefined timepoints to determine fatigue outcomes; the application of detailed and validated fatigue outcome measurement tools; and the opportunity to estimate risks according to the severity of COVID-19. The originality of the study derives from its population of pregnant women, a group that may conceivably be at higher risk of fatigue. However, as fatigue is not an unusual symptom in pregnancy and post-partum, many women may not have reported it, leading to some underestimates.

The study also had a number of limitations. Firstly, we had a low visit completion rate, which can be explained by the low socio-economic status of the group of women coming to the USP maternity (ie, users of the Brazilian public health system) who may have incurred significant difficulties in using public transportation system during the COVID-19 pandemic from their distant suburban dwellings, and who may have perceived the potentially high risk of travel with little incentive or benefit from attendance. This low attendance rate may have led to an overestimation of risk, if originally sicker patients were more inclined to attend, or an underestimation of risk if, conversely, they had decided to stay home plagued with fatigue or for other reasons, e.g. to avoid further exposure to infection. A low number of visits will have led to more limited power to find significant associations. A more convenient means of follow up using phones and internet could have been used but this may have excluded participants with low access to modern communication technology. Secondly, we cannot entirely pinpoint when infection occurred in women only found seropositive at delivery, hence the estimation of incidence or duration of fatigue cannot be precise.

In conclusion, SARS-CoV-2 during pregnancy was associated with higher prevalence of post-viral fatigue. Moreover, the risk and duration of fatigue increased with severity of infection.

CAAE – Certificate of Presentation of Ethical Appreciation

COVID-19 - CoronaVirus-associated Disease 2019

IQR - Interquartile Range

ME/CFS – Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

RT‐PCR –Real time polymerase chain reaction

SARS-CoV-2 - Respiratory Syndrome Coronavirus type-2

SpO_{2 -}Oxygen Saturation

SPSS - Statistical Package for the Social Sciences

USP - University of Sao Paulo

Ethics approval and consent to participate

The study was conducted with the approval of the Ethics Committee of Hospital das Clinicas – FMUSP, Sao Paulo, Brazil and the Ethics Committee of Hospital Universitario, Sao Paulo, Brazil (CAAE: 30270820.3.0000.0068). The study protocol was registered at ClinicalTrials.gov (NCT04647994). All methods were carried out in accordance with relevant guidelines and regulations. All participants provided signed informed consent.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

HCCOMVIDA- Chamada 01/2020 (CPq N 02.25) and by the European Union’s Horizon 2020 Research and Innovation Programme under ZIKAlliance Grant Agreement No 734548. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by Ana Maria da Silva Sousa Oliveira, Amanda Wictky Fabri, Nilton Hideto Takiuti, Shennae O'Boyle, Maria de Lourdes Brizot, Mariana Azevedo Carvalho and HC-FMUSP-Obstetric COVID-19 Study Group. The first draft of the manuscript was written by Mariana Azevedo Carvalho, Philippe Mayaud, Maria de Lourdes Brizot and Fábio Roberto Cabar. Stela Verzinhasse Peres and Neal Alexander performed statistical analysis. Rossana Pulcineli Vieira Francisco, Luis Nacul, and Philippe Mayaud commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We acknowledge all members of the HC-FMUSP-Obstetric COVID-19 Study Group: Adriana Lippi Waissman; Aline Scalisse Bassi, Ana Claudia Rodrigues Lopes Amaral de Souza; Ana Claudia Silva Farche; Ana Maria Kondo Igai; Carlos Eduardo do Nascimento Martins; Cristiane de Freitas Paganoti; Danielle Rodrigues Domingues; Fernanda Cristina Ferreira Mikami; Fernanda Spadotto Baptista; Jacqueline Kobayashi Cippiciani; Jéssica Gorrão Lopes Albertini; Joelma Queiroz de Andrade; Juliana Ikeda Niigaki, Lucinda Cristina Pereira; Marco Aurélio Knippel Galletta; Mariana Yumi Miyadahira, Mariana Vieira Barbosa; Monica Fairbanks de Barros; Sckarlet Ernandes Biancolin Garavazzo; Silvio Martinelli; Tiago Pedromonico Arrym; Ursula Trovato Gomez; Veridiana Freire Franco.

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No competing interests reported.

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Post-viral fatigue following SARS-CoV-2 infection during pregnancy: a longitudinal comparative study

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Abstract

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Background

Methods

Study design, settings and populations

Data collection

Laboratory methods

Statistical analysis

Results

(Table 1 here)

Prevalence over time of post-viral fatigue

Discussion

Abbreviations

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