Post-COVID syndrome in pregnant women with a history of mild and moderate COVID-19

The clinical impact of COVID-19 may extend beyond the acute infectious period, leading to long-term consequences of the novel coronavirus infection (NCVI), which significantly affects the health and quality of life of affected individuals. This presents a substantial global health concern, prompting a recent focus on the long-term effects of COVID-19.

In 2020, the International Classification of Diseases (ICD-10) introduced a new classification called "Post COVID-19 condition, unspecified." [1]. Additionally, the updated Clinical Guidelines for the treatment of patients with COVID-19, released at the beginning of 2021, included a chapter on "Care for patients with COVID-19 after acute illness." [2].

While the issue of post-COVID syndrome is actively being studied, there is a scarcity of data on its course in pregnant women in the available literature [3–5].

This study aimed to investigate the characteristic features of the course of post-COVID syndrome in women with a history of mild and moderate forms of novel coronavirus infection (NCVI) at different gestational ages.

Materials and methods

This was a single-center, prospective cohort study [6]. To assess the clinical manifestations of post-COVID syndrome, an online questionnaire was compiled and developed in the Google Forms Google application [7]. The questionnaire consisted of 40 questions of open, closed, semi-closed, evaluative, and control type.

The psycho-emotional state of the pregnant women was studied using the Hamilton test (HRDS, 1960) [8]. Patients were given sufficient time to answer the question in detail but were not allowed to deviate from the topic of the question. The results were interpreted by summing the scores of the first 17 items of the scale according to the following scheme: 0–7 – normal; 8–13 – mild depressive disorder; 14–18 – moderate depressive disorder; 19–22 – severe depressive disorder; and >23 – extremely severe depressive disorder.

The study group (n=200) included pregnant women who had NCVI at a mean gestational age at the time of the disease of 24.4 (9.3) weeks and a mean gestational age at the time of their examination of 38.3 [37.0–40.2] weeks.

The criteria for inclusion in the study group were mild to moderate NCVI at a gestation period of 6 or more weeks, signed informed consent to participate in the study, and clinical recovery at the time of the study. The exclusion criterion was the acute phase of COVID-19.

To assess the duration of symptoms of post-COVID syndrome in pregnant women, the study group was divided into the following subgroups:

Subgroup 1 (n=22) included patients who had NCVI within 6-12.6 weeks of gestation (first trimester). The mean gestational age at the time of infection was 6.8 (4.0) weeks, and the mean gestational age at the time of examination was 38.1 [37.1–40.2] weeks. The time between the onset of NCVI and the start of the study was > 20 weeks (mean 31.3 (1.1) weeks).

Subgroup 2 (n=76) included patients who had NCVI at 13.0-27.6 weeks of gestation (II trimester), mean gestational age at the time of NCVI was 20.6 (4.3) weeks, gestational age at study entry was 38.2 [37.0–40.1] weeks. The interval between the NCVI and study entry was 13–20 weeks (17.6 (1.1) weeks).

Subgroup 3 (n=102) included patients who had NCVI at 28 weeks or more (III trimester), mean gestational age at time of infection was 31.5 (3.3) weeks, gestational age at study entry was 38.4 [37.2–40.0] weeks. The interval between NCVI and study entry was 4–12 weeks (6.9 (1.0) weeks).

The control group comprised 99 full-term pregnant patients without signs of acute respiratory viral infection (ARVI) during pregnancy and at the time of the study. The control group sample size was calculated using a power calculator [9]. The gestational age at the time of the study of patients in the control group was 38.2 [37.1–40.2] weeks.

Evaluation of patients in the study and control groups was carried out at full-term pregnancy; no significant differences were found in gestational age at the time of the study (p=0.1).

Statistical analysis 

Statistical analysis was conducted using Microsoft Excel (2010) and SPSS Statistics version 22.0 (IBM Microsoft, USA). For comparison of the three independent subgroups by categorical variables, 2×2 contingency tables and χ² test were used. Categorical variables are reported as counts and proportions (%). The hypothesis about the normal distribution of the sample was tested using the Kolmogorov–Smirnov and Shapiro–Wilk tests. The equality of variances was tested using the F-test in the SPSS Statistics package version 22.0, which is directly included in the procedure for testing the hypothesis regarding the difference in means. Quantitative variables showing a normal distribution were expressed as mean (M) and standard deviation (SD) and presented as M (SD. Relative risk (RR) with a 95% confidence interval (CI) was calculated to estimate the likelihood of a particular event occurring in individuals in the study group exposed to the risk factor relative to the control group. Correlation analysis was conducted by calculating Spearman’s rank correlation coefficient for non-normally distributed quantitative variables (׀r׀≤0.25 – weak correlation; 0.25<׀r׀<0.75 – moderate correlation; ׀r׀ ≥0. 75; strong correlation). Statistical significance was assumed at p<0.05. When comparing more than two groups, the Bonferroni correction was used (p<0.017).

This study was reviewed and approved by the Research Ethics Committee of the Ural Research Institute of Maternity and Child Care (Ref. No. 12 dated 21.09.2021).

Results and discussion

Long COVID-19 is a multisystem disease [10–16]. To date, several hypotheses have been proposed for its pathogenesis, including the persistence of the SARS-CoV-2 virus in tissues [10], immune dysregulation [11] due to molecular mimicry [12], effects on the microbiota [13], virome [14], microvascular coagulation in endothelial dysfunction [15], and dysfunctional signaling in the nervous system [16].

Long COVID-19 is associated with all ages and acute illness severity, with the highest percentage of diagnoses occurring between the ages of 36 and 50. The majority of long COVID-19 cases occur in non-hospitalized patients with mild acute illness [17].

In our study, the mean age of the patients in the study group at the time of the study was 30.8 (5.9) years: in subgroup 1 – 31.8 (4.0) years; in subgroup 2 – 31.3 (5.9) years; and in subgroup 3 – 30.2 (6.5) years. The age of the patients in the control group was 30.9 (6.8) years.

At the time of the study, the study and control groups were comparable in age, obstetric-gynecological, and somatic history (p>0.05) (Tables 1 and 2).

According to an Office for National Statistics (ONS) survey, 2 million people in the UK had long COVID-19, of whom 72% reported long COVID-19 for 12 weeks, 42% for 1 year, and 19% for 2 years [18]. A prospective cohort study of 4182 COVID-19 cases found that 13.3, 4.5, and 2.5% of patients had symptoms of long COVID-19 for ≥28 days, ≥8 weeks, and ≥12 weeks, respectively [19].

The incidence of long COVID-19 is estimated to be 10–30% of non-hospitalized, 50–70% of hospitalized patients [20, 21], and 10–12% of vaccinated cases [22, 23]. We did not find any information in the international literature on the incidence of post-COVID syndrome among pregnant women.

We conducted a survey of pregnant women in the study and control groups during full-term pregnancy to identify symptoms that could not be explained by alternative diagnoses. The presence of at least one symptom was considered a manifestation of the post-COVID syndrome.

Clinical manifestations of post-COVID syndrome were observed in 186/200 (93.0%) pregnant women in the study group; the majority of them, 148/186 (79.6%) had 1–5 symptoms, and 38/186 (20.4%) had 6–10 symptoms; only 14/200 (7.0%) patients had no post-COVID symptoms. Pregnant women in the control group were 2.4 times less likely to experience such symptoms (38/99 (38.4%, p<0.001)).

Our results are consistent with those reported by Belokrinitskaya T.E. et al. (2023). According to their opinion, the prevalence of post-COVID syndrome in pregnant women was 93.7%, which did not differ significantly from non-pregnant patients (97.2%) [5].

Currently, there are no clear symptoms characteristic of COVID-19. When analyzing the literature, we identified the most common symptoms of post-COVID syndrome in the general population: general, respiratory, neuropsychological, cardiovascular, and gastrointestinal.

Common symptoms include fatigue (23–53%), arthralgia (10–26%), weight change (10.6–20.0%), myalgia (6–27%), and diaphoresis (6–10%) [24, 25]. Manifestations of dysfunction of the respiratory system include shortness of breath (14–35%), cough (5–40%), chest pain (5–29%), pulmonary fibrosis (0.6–1.0%) [26, 27]. Neurological disorders such as cognitive impairment (9–50%), anosmia (6–36%), headache (5–33%), dizziness (4–29%), ageusia (4–7%), stroke (0.1%) are the next most common [28, 29]. Cardiovascular disorders include a feeling of pressure in the chest (48%), rapid heartbeat at rest (5–44%), cardiac arrhythmia (11.2%), acute coronary syndrome (4.0%), and new-onset hypertension (1%) [28, 29]. Gastrointestinal manifestations close to the list of post-COVID problems include loss of appetite (6–14%), abdominal pain (4–10%), stool disturbances (3–21%), and nausea and vomiting (0.3–2%) [28, 29].

In our study, the most common manifestations of post-COVID syndrome in pregnant women in the study group were cognitive impairment (156/200 (78.0%)), disturbances in sleep, memory, and concentration, distortion of smell and taste (95/200 (47.5%)), dry mouth (55/200 (27.5%)), fatigue when performing household chores (54/200 (27.0%)), and weakness (52/200 (26.0%)). Similar symptoms occurred significantly less frequently in the control group: cognitive impairment (19/90 (19.2%)), dry mouth (9/99 (9.1%)), fatigue when performing household chores (9/99 (9.1%)), and weakness (8/99 (8.1%)) (Table 3). In a study by domestic authors, fatigue and memory impairment were common symptoms (71.2 %, 71.8 %, and 54.1 %, respectively) [5].

Based on our data, we compiled a risk rating for the presence of post-COVID symptoms in pregnant women after mild and moderate NCVI (Fig. 1). Persistent cough after acute COVID-19 was ranked first (RR=15.7; 95% CI 3.7–66.2, p=0.001), followed by the development of cognitive impairment (RR=14.9; 95% CI 8.2–27.2, p=0.001) and headache (RR=7.6; 95% CI 1.8–32.5, p=0.002), which were not explained by an alternative diagnosis. Other symptoms: shortness of breath when walking on level ground (RR=4.9; 95% CI 1.5–16.9, p=0.005), palpitations at rest (RR=4.6; 95% CI 1.3–15 .5, p=0.008), changes in the condition of nails (RR=4.2; 95% CI 1.2–14.2, p=0.014) and hair (RR=2.8; 95% CI 1.1–7.1, p=0.02), rapid fatigue when performing household chores (OR=3.7; 95% CI 1.7–7.9, p=0.001), and distortions of smell and taste (OR=1.9; 95% 1.7–2.2, p=0.001). On psychological examination, there was an increased risk of moderate (RR=2.4; 95% CI 1.3–4.5, p=0.005) and mild depressive disorder (RR=1.9; 95% CI 1.2–3.1, p=0.001).

A detailed analysis of the results by subgroups of the study group revealed that pregnant women who had NCVI in the first trimester (subgroup 1) were significantly more likely to have clinical manifestations of post-COVID syndrome compared to those who had NCVI in the second and third trimesters. It is noteworthy that according to the survey data, their post-COVID symptoms persisted until full-term pregnancy. Patients who had NCVI in the first trimester (subgroup 1) significantly more often complained of visual impairment (5/22 (22.7%) versus 10/76 (10.5%) (subgroup 2) and 5/ 102 (4.9%) (subgroup 3), p=0.005), brittle nails (6/22 (27.3%) vs. 10/76 (9.2%) and 7/102 (6.9 %), p=0.005), change in hair condition (8/22 (36.4%) vs. 13/76 (15.8%) and 10/102 (9.8%), p=0.001), odor and taste distortion (17/22 (77.3%) vs. 39/76 (51.3%) and 39/102 (38.2%), p=0.001), and dizziness (5/22 (22.7%) vs. 4 /76 (5.3%) and 4/102 (3.9%), p=0.002) (Table 3).

Even before the COVID-19 pandemic, 22% of women experienced high levels of anxiety during pregnancy [30]. NCVI has caused an increase in the proportion of pregnant women with psychoemotional disorders, manifested by depressive disorders and anxiety (26.0–34.2%) [31]. A study by Wang С. et al. (2020) [32] reported that women's anxiety levels were 3.01 times higher than those of men during the COVID-19 pandemic. According to a study by Geren A. et al. (2021), 30.7% of pregnant women had depression: 12.4% – mild, 12.4% – moderate, 5.9% – severe [33].

In our study, psychological disorders in the study group occurred in 180/200 (90.0%) pregnant women (mild depression in 120/200 (60.0%), moderate depression in 60/200 (30. 0%) patients), and 20/200 (10.0%) had a normal psychological state. In the control group, mild depression was found in 44/99 (44.4%), moderate depression in 15/99 (15.2%) (p<0.001), and normal psychological health in 40/99 (40.4 %) pregnant women (p<0.001).

We did not identify severe depression but established a positive correlation (׀r׀>0.75) between the number of symptoms of post-COVID syndrome and the degree of depression in pregnant women after mild to moderate NCVI (Spearman correlation coefficient r_s=0.58; 95% CI 0 .81–0.89, p<0.001) (Fig. 2). We did not find this information in the literature.

Conclusion

The results of this study demonstrate the development of post-COVID syndrome in pregnant women with mild to moderate forms of NCVI. The proportion of pregnant women with clinical manifestations of post-COVID syndrome was 93.0%, of which most women have from 1 to five symptoms (79.6%), every fifth pregnant woman (20.4%) had 6 to 10 symptoms, and 90.0% of patients had psychological disorders. Pregnant women who experienced the disease in the first trimester were significantly more likely to be at risk of developing post-COVID disorders that persisted until full-term pregnancy. A correlation has been established between the number of symptoms of post-COVID syndrome and the Hamilton Scale score in pregnant women with mild to moderate NCVI.

The results of the study allowed us to substantiate the need for rehabilitation in pregnant women after NCVI, depending on the severity and duration of post-COVID symptoms.