Post-COVID-19 syndrome in early reproductive age women

Three years have passed since the World Health Organization (WHO) officially named the infection caused by the new coronavirus COVID-19 (coronavirus disease 2019) on February 11, 2020. On March 11, 2020, the WHO announced the beginning of a pandemic caused by SARS-CoV-2. According to WHO statistics, over the course of the three-year pandemic, there have been more than 758 million registered cases of COVID-19 and over 6.8 million deaths from the disease [1].

Another urgent medical and social problem associated with the pandemic is the emergence of new persistent symptoms after patients recover from the new coronavirus infection (NCI). Researchers worldwide have reported numerous cases showing that COVID-19 has various long-term effects on the respiratory, cardiovascular, nervous, endocrine, digestive systems, skin, and mental health [2–6].

International experts have proposed the term "post-COVID-19 syndrome" (PCS, post-COVID-19 syndrome, or long COVID) to describe persistent symptoms that arise or persist for more than 4 weeks from the initial clinical manifestations of COVID-19 [3, 7]. However, there is currently no globally recognized nomenclature for symptoms that persist after recovery from COVID-19, and there are no unified approaches to determining the duration of these symptoms [7–9].

In October 2021, WHO experts reached a consensus that PCS is a post-COVID-19 condition that occurs in individuals with probable or confirmed SARS-CoV-2 infection. It typically manifests approximately 3 months after the onset of COVID-19 symptoms, lasts for at least 2 months, and cannot be explained by an alternative diagnosis. PCS symptoms usually affect a person's daily activities, may appear immediately after the acute phase of COVID-19 or persist after recovery, and may be permanent or recurrent. Currently, there are no specific criteria for the minimum number of symptoms required for diagnosis [10]. However, PCS is included in the International Classification of Diseases, 10th revision, under the code U09.9, which refers to "Condition after COVID-19, unspecified."

Based on patient referrals and surveys of individuals who have recovered from COVID-19, it is estimated that 35% to 87.5% of people continue to experience various symptoms affecting multiple organs (such as headache, fatigue, sleep disturbances, memory issues, shortness of breath, cough, heart pain, palpitations/rhythm disturbances, myalgia, hair loss, skin rashes, etc.) [5–8, 11].

Recent research has revealed a complex multicomponent pathogenesis of PCS involving chronic immune inflammation, nervous system dysfunction, systemic endothelial damage, generalized microvascular thrombosis, and thrombovasculitis as the main pathogenetic mechanisms [2, 3, 5, 6, 12].

Despite the considerable number of publications on PCS, there are several contradictions. First, the severity of the initial NCI did not directly correlate with the incidence and severity of PCS symptoms. Even patients who experience asymptomatic or mild COVID-19 can subsequently experience PCS for an extended period [8, 13]. Second, PCS is believed to primarily develop in patients with comorbid conditions, such as arterial hypertension, diabetes mellitus, and obesity. [3, 12, 14]. Thirdly, some authors attribute the symptoms of PCS to stress-anxiety disorders caused by the high morbidity and mortality rates, a constant sense of health-related threat, social isolation, negative changes in employment status and financial well-being, and other factors [13, 15, 16].

Despite a substantial number of publications on the pathogenesis and clinical presentation of PCS in adults and children, we found no information on this COVID-19 complication in young women. It is crucial to study this group, as they form the reproductive foundation of the nation, and the physical and mental well-being of future generations depends on their health [17].

This study aimed to compare the frequency and severity of new persistent symptoms in young, physically healthy women who have experienced NCI and those who have remained uninfected during the pandemic.

Materials and methods

To assess the independent impact of COVID-19 and avoid the effect of possible co-factors in the development of post-COVID syndrome (PCS), such as obesity, arterial hypertension, diabetes mellitus, and advanced age [3, 13], clinical groups were formed. These groups consisted of non-pregnant women under the age of 35 years who did not have excess body weight/obesity, diabetes mellitus, chronic arterial hypertension, or other somatic or chronic infectious diseases. The study group included patients (n=181) who were diagnosed with COVID-19 between July and October 2021, with NCI confirmed by polymerase chain reaction in nasopharyngeal material [18]. The duration of illness was calculated from the first day of the onset of the clinical symptoms of COVID-19 to recovery, as confirmed by clinical, laboratory, and virological data. The severity of the acute period of NCI in patients was classified as mild, moderate, or severe (no critical cases were reported) following the criteria outlined in the clinical guidelines of the Russian Ministry of Health for COVID-19 [18]. Persistent symptoms of PCS were considered symptoms that were absent before COVID-19, appeared no earlier than 4 weeks from the onset of the disease, and lasted at least 2 months, without explanation by alternative diagnoses [3, 7, 10]. The control group consisted of women who had not contracted COVID-19 during the same period (n=71). The survey of the study participants was conducted in the 1st phase of the menstrual cycle to exclude symptoms of premenstrual syndrome, which may have a similar clinical presentation to PCS manifestations.

The severity of symptoms was assessed using the Yorkshire Rehabilitation Screen (COVID-19 Yorkshire Rehabilitation Screen, C19-YRS), where each symptom was scored from 0 (absent) to 10 (very disturbing) [19].

A specialized questionnaire was developed to gather data from the database. This questionnaire contained information on the social, biomedical, and clinical characteristics of the women. Primary medical documentation (outpatient medical care records, form 025/y; medical history, form 003/y) was used to complete the questionnaire. An additional survey of the patients was conducted to assess persistent symptoms.

Statistical analysis

When conducting statistical analysis, the authors followed the principles of the International Committee of Medical Journal Editors (ICMJE) and the recommendations of "Statistical Analysis and Methods in the Published Literature" (SAMPL) [20, 21]. The normality of the distribution of quantitative and ordinal variables, considering the number of studied groups to be more than 50 women, was evaluated using the Kolmogorov–Smirnov criterion. The Mann–Whitney (U) test was used to compare two independent groups. Categorical data are described as counts and percentages, and comparisons were performed using Pearson's χ² test. If the expected number of observations in at least one cell of the 2×2 table was less than 10, a chi-square test was used with Yates' correction for continuity. Fisher's exact test was employed if the expected number of observations in at least one cell of the 2×2 table was less than 5. Statistical significance was defined as p<0.05. Given the retrospective nature of the analysis, the significance of the differences in categorical data was assessed by determining the odds ratio (OR). Statistical significance (p) was estimated based on the 95% confidence interval (CI). Statistical analyses were performed using IBM SPSS Statistics Version 25.0 (International Business Machines Corporation, USA).

Results and discussion

The age of the patients was comparable, with a mean age of 25.0 (25.0; 26.6) years in the study group and 24.0 (24.0; 25.1) years in the control group. The difference in age between the two groups was not statistically significant (U=5606.0, p=0.12). This similarity in age, combined with the inclusion criteria for the study, allowed us to draw the following conclusions.

The incidence of new persistent symptoms during the pandemic was similar in young, initially somatically healthy women who had recovered from COVID-19 (96.1%, 174/181) and in the group without the disease (93.0%, 66/71). The odds ratio (OR) was 1.88 (95% CI 0.58; 6.14), and the p-value for the chi-square test was 0.327. We could not find any studies in the domestic or international literature that examined gender and age differences in the prevalence of post-COVID syndrome (PCS). Published data from different countries show a wide range of PCS prevalence, varying from 10.0% to 96.0%, with more than 50.0% in most cases [3, 11, 22]. In our study, we observed a relatively high incidence of persistent symptoms after recovery from NCI (96.1%), which is likely due to the young age of the patients (< 35 years) who were initially somatically healthy and thus more attentive to any previously absent clinical signs.

Regarding the severity of COVID-19, we found that 86.7% (157/181) of women in the early reproductive age group had mild disease, while 12.2% (22/181) had moderate disease. The odds ratio for moderate disease was 47.28 (95% CI 25.46; 87.81), and the chi-square test result was χ²=195.5, p<0.001. Only 1.1% (2/181) of patients had a severe disease (all p_χ2<0.001). Overall, the incidence of moderate and severe COVID-19 was approximately 6.5 times lower than that of the mild form (OR=42.8, 95% CI 23.3; 78.6; χ²=201.4; p<0.001).

Therefore, our findings confirm that young age, absence of pregnancy, and lack of comorbidities significantly reduce the risk of moderate and severe NCI [18, 23].

Table 1 presents the types and frequency of new persistent symptoms that occurred during the pandemic in women with and without COVID-19.

Tiredness and/or fatigue were the most common new persistent symptoms in young women during the pandemic, with the same frequency reported both after NCI and in those who were not ill: 71.8% (130/181) vs. 69.0 % (49/71, p_χ2=0.66). Our findings regarding the prevalence of this symptom are generally consistent with the conclusions of other authors reporting that this complication develops at the highest frequency of 46.8–84.5% [3, 24]. However, it should be noted that the severity of the disease was higher in the group of women who had COVID-19 (5.0 points vs. 2.0 points, p<0.001).

Of the neurological symptoms of a patient with PCS, memory impairment was more often noted in 49.2% (89/181) versus 12.7% (9/71) (OR=6.66 (95% CI 3.13; 14.21); p_χ2<0.001); headache – 43.1% (78/181) vs. 11.3% (8/71) (OR=5.96 (95% CI 2.7; 13.17); p_χ2<0.001), the intensity of which exceeded that in the group of women who did not fall ill during the pandemic:4.0 vs. 1.0 points (p<0.001) and 5.0 vs. 3.0 points (p=0.001). A similar incidence of memory impairment (50%) in PCS was reported by Shan et al. (2022) in a large cohort of patients. They attributed this to pronounced bilateral metabolic disorders in the parts of the central nervous system that regulate cognitive processes and short-term and long-term memorization of information [25].

Women with a history of COVID-19 were significantly more likely to complain of depression than those who did not experienced the disease: 19.9% (36/181) vs. 8.5% (6/71) (OR=2.69 (95% CI 1.08; 6.7); p_χ2=0.029). At the same time, the severity of symptoms was comparable:4.0 the 3.0 points (p=0.97). Domestic studies conducted on a population of women (78.9%) and men (21.1%) aged 18 and ≥ 55 years revealed a higher incidence of depression (68.6%) in the post-COVID period [3].

According to literature, pain in the muscles and joints is a fairly common symptom of PCS, with a frequency of 63.9% in the Russian population [3]. In our study, myalgia was registered in the post-COVID period in 31.5% (57/181) of cases and many times less often in those who did not have COVID-19 – 8.5% (6/71) (OR=4.98 (95% CI 2.04; 12.17); p_χ2<0.001). The intensity of the symptom was more pronounced in those who had recovered from NCI:5.0 vs. 1.0 points (p<0.001).

Based on the pathogenesis and clinical manifestations of COVID-19, our findings regarding the presence of cough in recovered patients in the post-COVID period look logical and explainable (43.6% (79/181) vs. 0.0% (0/71), p_χ2<0.001), shortness of breath (26.5% (48/181) vs. 0.0% (0/71), p_χ2<0.001), chest pain 18.2% (33/181) vs. 0.0% (0/71 ), p_χ2< 0.001), weight loss (18.8% (34/181) vs. 0.0% (0/71), p_χ2< 0.001), and hair loss (60.8% (110/181) vs 0, 0% (0/71), p_χ2<0.001). In the current NICE (2020), CDC (2020), and WHO (2021) guidelines and available domestic and international sources, these symptoms are noted as characteristic of patients with PCS [3, 7–10, 19]. Experts believe that multiple organ disorders associated with PCS are caused by virus-induced inflammation. After the patient has recovered from COVID-19, the inflammation becomes immunological and chronic and is accompanied by hyperproduction of cytokines, damage to the vascular endothelium, hemocoagulation, autoimmune disorders, and oxidative stress [3, 4, 6, 12, 14, 25].

According to the information presented in Table 1, patients who did not have COVID-19 during the study period also reported numerous new persistent symptoms that had not been previously reported. Tiredness/fatigue (69.0% (49/71) versus 71.8% (130/181), p_χ2=0.66), drowsiness (54.9% (39/71)), sleepiness (54.9% (39/71) 71) vs. 43.6% (79/181), p_χ2=0.11), heartbeat (19.7% (14/71) vs. 29.8% (54/181), p_χ2=0.1), change the menstrual cycle (22.5% (16/71) vs. 21.0% (38/181), p_χ2=0.865), skin manifestations (2.8% (2/71) vs. 6.6% (12/181), p_χ2=0.24). Insomnia occurred significantly more often (32.4% (23/71) vs. 26.0% (47/181), p_χ2=0.012), although it was less severe (3, 0 vs 5.0, p=0.004).

Our findings regarding the occurrence of new persistent symptoms in patients who did not fall ill during the pandemic are explained in the studies by Shepeleva et al. (2020) [26], Abritalina E.Yu. (2021) [13] and Kotova et al. (2020) [15], who showed that COVID-19 has not only a direct (neurotoxic) but also an indirect effect on the human nervous system and psyche, due to the fear of infection and loss of loved ones in conditions of mass morbidity, difficult access to medical care, and lack of effective treatments. The psychological state of the population was significantly affected by negative emotional reactions to self-isolation, social distancing, panic demand for a number of goods, the difficulty of planning one's life in the future, changes in labor status and material well-being, and systematic information about the human victims of the pandemic.

Our study was conducted in the second year of the pandemic, in 2021, when the SARS-CoV-2 Delta variant dominated, resulting from a natural mutation and characterized by greater pathogenicity, an increase in the incidence of severe pneumonia and adverse outcomes [27, 28]. Psychiatrists and psychologists noted that during the COVID-19 pandemic, a specific syndrome was observed, called “headline stress disorder”: a high emotional response in the form of stress and anxiety. According to researchers, this syndrome can lead to physical symptoms, including palpitations, insomnia, menstrual irregularities, and other psychosomatic disorders. The symptoms and early warning signs of post-traumatic stress disorder may be chronic or episodic in nature [13, 15].

Thus, the formation of PCS is undoubtedly influenced by the biological properties of SARS-CoV-2 and its ability to cause a number of multiple organ pathological processes caused by chronic immune inflammation, generalized endotheliopathy, microthrombosis, and vasculitis. [2, 3, 5, 6, 12]. The emergence of new persistent symptoms similar to the clinical manifestations of PCS in young somatically healthy women who have not contracted COVID-19 may be caused by a high emotional response to changes in living conditions during the pandemic, followed by post-traumatic stress-anxiety disorders in the form of a whole spectrum of psychosomatic disorders [13, 15, 26].

Conclusion

Our study demonstrated that PCS is highly prevalent among initially somatically healthy women of an early reproductive age. The occurrence of several similar symptoms of similar frequency in women who did not become ill during the pandemic may be associated with post-traumatic stress-anxiety disorder. Further in-depth interdisciplinary studies are required to elucidate the pathophysiological mechanisms underlying the development of new persistent symptoms associated with the COVID-19 pandemic.