Identifying symptom clusters among pregnant women during early and late pregnancy

To investigate the status of multiple psychosomatic symptoms among women and identify symptom clusters at different gestational stages.

28 weeks, the functional load on the maternal organs gradually approaches its maximum, subsequently producing symptoms such as difficulty in breathing and sleep disorders. 11 In addition, as the due date approaches, women become concerned about the outcomes of the delivery and the baby's health. 12 Faced with various problems, mothers-to-be are more prone to suffer from health impairment. Therefore, there is an urgent need to pay attention to the psychosomatic symptoms of women during early and late pregnancy and to emphasize early recognition and intervention.
Multiple symptoms of pregnancy commonly occur simultaneously and have complicated interactive relationships. For example, Andersson et al. 13 found that pregnant women with anxiety or depressive symptoms experienced more frequent nausea and vomiting. Considering the co-occurrence and interaction of symptoms, it may be feasible to manage the symptoms by grouping them, allowing the identification of symptom clusters. Symptom clusters, by definition, are two or more symptoms that interrelate and occur together, and the association between symptoms of one symptom cluster is usually stronger than symptoms of distinct symptom clusters and/or independent symptoms. 14 Current evidence has demonstrated that the treatments for one symptom may "cross over" the others within a cluster. 15 This complex interrelationship may potentially offer the possibility of targeting a single intervention to diminish the adverse effects of multiple co-occurring symptoms on individual outcomes. 14 At present, the majority of research on symptom clusters has focused on the areas of cancer and other chronic diseases. Given the distinctiveness of pregnancy and the concurrence and interaction of symptoms, it is reasonable to deduce that specific symptom clusters may also exist in pregnant women. However, existing studies on symptom clusters in pregnant women are insufficient, warranting further investigation.
To sum up, consideration is required for the assessment and management of multiple, co-occurring symptoms during early and late pregnancy, to improve outcomes in pregnant women. Strategies to promote the development of symptom science through symptom cluster research could potentially contribute to a relevant body of empirical knowledge, enabling innovative interventions for symptom management in this population. Therefore, the objectives of this research were to understand the occurrence of multiple symptoms in pregnant women during early and late pregnancy, and to identify symptom clusters, so as to diversify the research in this field. The optimal number of symptom clusters was investigated in all three steps: Spearman correlation analysis, partial correlation networks, and hierarchical cluster analysis. First, Spearman correlation analyses were performed to determine the interrelationships between the symptoms. Second, associations between symptoms were represented in a Gaussian graphical model based on the partial correlation matrix, which was applied to examine whether the associations between symptoms existed after controlling for other symptoms. We used the graphical least absolute shrinkage and selection operator to lower the probability of spurious edges and obtain a parsimonious network. Finally, hierarchical cluster analysis was used to cluster the symptoms, and the similarity between different clusters was assessed using Wald method with the Euclidean distance; a dendrogram was drawn up to provide visualization of the results of cluster analysis.

| RE SULTS
A total of 557 pregnant women were investigated, of which 249 were in the early pregnancy stage, with an average gestational week of 9.00 ± 2.71 SD, and 308 were in late pregnancy, with an average gestational week of 34.07 ± 3.26 SD. The sociodemographic characteristics and differences in the different stages of the participants are shown in Table 1.
The prevalence, intensity, and distress of symptoms in early and late pregnancy are reported in Figures 1 and 2, respectively. In terms of prevalence, the five most common symptoms experienced during early pregnancy were nausea, drowsiness, lack of energy, lack of appetite, and difficulty in concentrating. During late pregnancy, weight gain, lack of energy, drowsiness, sweating, and difficulty in sleeping were more common. Regarding the intensity of symptoms, the most severe symptoms reported during early pregnancy were nausea, lack of appetite, drowsiness, lack of energy, and vomiting, whereas those reported during late pregnancy were weight gain, difficulty in sleeping, lack of energy, sweating, and dry mouth. In addition, the most distressing symptoms during early pregnancy were nausea, loss of appetite, drowsiness, lack of energy, and vomiting, whereas weight gain, difficulty in sleeping, sweating, lack of energy, and dry mouth were highly distressing in late pregnancy.
We evaluated and ranked the scores for symptoms in different stages and found that the first five symptoms during early pregnancy were nausea, lack of appetite, drowsiness, lack of energy, and vomiting. In late pregnancy, weight gain, difficulty in sleeping, sweating, lack of energy, and dry mouth scored highly. The majority of scores for symptoms differed in these two periods ( Table 2).
To ensure the clinical implications of the investigation and have a manageable number of symptoms for cluster analysis, symptom clusters were identified by selecting more than 50% occurrence.
Therefore, 12 symptoms were eventually incorporated in early pregnancy, and 11 symptoms were included in late pregnancy. The results of the Spearman correlations between the symptoms above were presented, with the strongest correlations found in early pregnancy between nausea with vomiting (0.730) and lack of appetite  (Table S2).
Association networks based on partial correlation matrices in early pregnancy (Table S3) and late pregnancy (Table S4) were conducted to present description of the relationships among the symptoms, and hierarchical cluster analyses were performed in different stages, as illustrated by the dendrograms. Taking the above three methods into consideration, we finally described four symptom clusters in early pregnancy ( Figure 3) Three symptom clusters and two single symptoms were identified in late pregnancy, as shown in Figure 4. The three symptom clusters were mood-fatigue symptom cluster (feeling nervous, feeling irritable, lack of energy, difficulty in concentrating, and feeling drowsy), sleep-bloating symptom cluster (difficulty in sleeping and feeling bloated), and fluid deficiency symptom cluster (dry mouth and sweating), while pain and weight gain were recognized as independent symptoms.

| DISCUSS ION
By employing the MSAS to assess the status of multiple psychosomatic symptoms among women at different gestational stages, we investigated the multidimensional nature of symptoms (e.g., frequency, severity, and distress) and identified four symptom clusters in early pregnancy, along with three symptom clusters and two independent symptoms in late pregnancy. In this study, the symptoms with higher symptom scores, frequency, severity, and distress in early pregnancy were nausea, lack of appetite, drowsiness, lack of energy, and vomiting. This result is consistent with previous studies, indicating that these symptoms are commonly experienced during early pregnancy. 11,17 This may be related to an increase in the levels of human chorionic gonadotropin, a decrease in gastric acid secretion, and prolonged gastric emptying time, which occur during early pregnancy. 18 Whereas the symptoms with higher symptom scores, frequency, severity, and distress in late pregnancy were weight gain, difficulty in sleeping, sweating, lack of energy, and dry mouth. Among them, lack of energy was a common symptom experienced in both stages, which is similar to the findings of Beebe et al. 7 In addition, consistent with previous studies, weight gain and difficulty in falling asleep were common during late pregnancy. 7 Pregnant women tend to gain weight due to local changes (e.g., fetal growth and development, uterine enlargement, and the formation of placenta and amniotic fluid) and metabolic changes (e.g., water retention, fat deposition, and protein storage). 19,20 In addition, as the pregnancy progresses, the uterus enlarges and gradually presses upward on the diaphragm, causing mechanical changes in the respiratory system, thereby increasing susceptibility to difficulty in breathing and affecting sleep patterns. 6,19 Difficulty in falling asleep may be related to fetal movement and specific types of pain commonly experienced during late pregnancy (e.g., leg cramps, lumbopelvic pain or pressure, F I G U R E 4 Symptom clusters in late pregnancy (n = 308). Thicker and darker lines suggest stronger partial correlations. Solid lines represent positive partial correlations; there were no negative partial correlations. BLO, feeling bloated; DC, difficulty concentrating; DM, dry mouth; DR, feeling drowsy; DS, difficulty sleeping; IRR, feeling irritable; LEN, lack of energy; NER, feeling nervous; PA, pain; SW, sweats; WG, weight gain. and restless legs syndrome). 6,11 Moreover, during the gestational period, women's basal metabolic rate increases, 20 which accounts for dry mouth and sweating in late pregnancy.
To the best of our knowledge, this study is the first to identify symptom clusters in pregnant women. In early pregnancy, nausea, vomiting, and lack of appetite formed a cluster called the pregnancy reaction symptom cluster. These three symptoms are typically noted during early pregnancy, and the underlying mechanism might be related to the elevation of progesterone during pregnancy, i.e., progesterone can inhibit the smooth muscles of both the pylorus and the small intestine, resulting in reduced contractility of the gastrointestinal tract and decreased intestinal motility. 21  The first cluster determined during late pregnancy was the mood-fatigue symptom cluster, which was also one of the clusters detected in early pregnancy. This indicated that the mood-fatigue cluster persisted during the two periods and that there was an interaction among these symptoms. This finding implies the need to pay special attention to these interrelated symptoms related to mood and fatigue in symptom management during both early and late pregnancy, which would help pregnant women and their families to adjust psychologically and physically until the birth. The second symptom cluster included difficulty in sleeping and feeling bloated.
This gathering phenomenon might be attributed to a shared biologic mechanism underlying these symptoms. Specifically, in late pregnancy, due to the fluctuations in estrogen and progesterone and the mechanical effects of uterine enlargement, the transit rate of the small intestine and colon decreases, which results in symptoms of abdominal distension. Simultaneously, owing to the combined effects of these factors, pregnant women often have difficulty in falling asleep. 6,25 We also identified another symptom cluster consisting of dry mouth and sweating. One assumption was that the two symptoms are due to increased basal metabolic rate. 20 Besides, two independent symptoms, pain and weight gain, were also observed.
As these two symptoms were not incorporated into a specific cluster, this may, to some extent, account for their prominence and independence in late pregnancy, without being greatly associated with symptoms in other clusters, which needs to be explored in future investigations.
There are some limitations to the present study. First, the participants were enrolled from only two tertiary hospitals, and the representability and generalization of the results are somewhat restricted.
Second, the available data were self-reported rather than being clin- In conclusion, pregnant women experience multiple psychosomatic symptoms during pregnancy, and the manifestation of symptoms varies at different gestational stages. The present study has provided new insights into the symptom clusters of pregnant women, with four clusters identified in early pregnancy, along with three clusters and two independent symptoms in late pregnancy.
In particular, the mood-fatigue cluster was a persistent and stable symptom cluster in both phases. The awareness of existence of symptom clusters during the progression of pregnancy would enable clinical staff to promptly identify some potentially neglected symptoms and facilitate the design of comprehensive and appropriate healthcare programs to manage symptoms for multiple potential conditions.

AUTH O R CO NTR I B UTI O N S
Yunxue Zhang participated in participant recruitment and interpretation of data and prepared the draft manuscript. Xiaofang Xu participated in the study design and recruitment of participants and prepared the draft manuscript. Zihui Xie, Yuanyuan Li, Di Zhao, and Gaorong Lv joined the study design and provided critical revisions for this manuscript. Ping Li designed the study, coordinated the data collection and analyses, and contributed to critical revisions for this manuscript. All authors approved the final version.

ACK N OWLED G M ENTS
The present study was supported by the National Natural Science Foundation of China (81773296). The authors are grateful to all the participants who were recruited in this study.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors have no conflicts of interest to disclose.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author.