The Role of Systemic Immune-inammation Index in the Severity of Hyperemesis Gravidarum

Purpose Hyperemesis gravidarum (HEG) is one of the most common causes of hospitalization in early pregnancy. Complete blood count parameters can be used as inammatory markers in patients with HEG. We aimed to investigate the Systemic Immune-Inammation Index (SII) in predicting the severity of HEG. Methods This cross-sectional study was performed with pregnant women who were hospitalized in the Perinatology Department, Ankara City Hospital, with the diagnosis of HEG. The study data were obtained from the electronic database of Ankara City Hospital. The study parameters were calculated from complete blood count tests and urine analysis. A total of 469 pregnant women diagnosed with HEG were included in this study. There was a positive correlation between the increased degree of ketonuria and SII. The cut-off value of SII for predicting the severity of HEG was 1071.8, sensitivity and specicity were 59% and 59%, respectively. The cutoff value of SII to predict the length of hospitalization was 1073.6, p= 0.039; sensitivity and specicity were 56.3% and 55.5%, respectively. Considering the positive relationship between ketonuria and inammation markers, the evaluation of SII in pregnant women with HEG may facilitate the clinical management of these patients.


Introduction
Hyperemesis gravidarum (HEG) is a condition with severe nausea and vomiting during pregnancy. It is estimated to occur in 0.3-3.6% of all pregnancies worldwide [1]. Persistent vomiting resulting in weight loss, nutritional de ciencies, ketonuria, electrolyte imbalance, and dehydration is one of the most common reasons for hospital admission in early pregnancy [2]. Many studies have been conducted to understand the etiology and pathogenesis of HEG, but no consensus has been reached on its cause and mechanism [3]. Psychological and hormonal changes during pregnancy, thyrotoxicosis, upper gastrointestinal dysmotility, hepatic abnormalities, autonomic nerve dysfunction, nutritional de ciencies, and Helicobacter pylori infection were considered involved in the etiology [4].
For the assessment of complete blood count (CBC), parameters including white blood cell (WBC) count, neutrophil count, lymphocyte count, hemoglobin (Hb), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT) and red cell distribution width (RDW), were all collected from patients' les. Only pretreatment laboratory results were used.
The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated by obtaining the ratios of absolute neutrophil count to absolute lymphocyte count and absolute platelet count to absolute lymphocyte count, respectively. Lymphocyte-to-monocyte ratio (LMR) was calculated from the differential count by dividing the absolute lymphocyte count by the absolute monocyte count.
The SII was calculated using P x N/L, where P, N, and L were the peripheral platelet, neutrophil, and lymphocyte counts, respectively. The ketonuria was graded as 1+, 2+, 3+ and 4+. The decision to discharge patients was based on the improvement of hydration and nutritional intake.
The patients were divided into two groups based on their degree of ketonuria at the time of hospital admission as Group A and Group B. Patients with +1 and +2 degrees of ketonuria were included in Group A, those with +3 and +4 were in Group B.
Statistical analyses were performed using SPSS 17 software (SPSS, Inc., Chicago, IL, United States). Statistical methods such as descriptive frequency, percentage, mean, standard deviation, median, and interquartile range(IQR) were used to express the quantitative data. The groups with different degrees of ketonuria were compared using Mann-Whitney U test according to non-normal distribution. The Jonckheere-Terpstra test was used to determine the trend of each variable according to the degree of ketonuria. Spearman's correlation coe cient was used to estimate the relationship between the degree of ketonuria and other variables. Receiver operating characteristic (ROC) curve analysis was used to assess the optimal cut-off values of NLR, PLR, and SII for predicting the severity of HEG with sensitivity and speci city. Also, this analysis was used to identify the cut-off value of SII to predict the length of hospital stay. The Pvalues < 0.05 were regarded as statistically signi cant.

Results
A total of 469 pregnant women with HEG were included in this study. The demographic and clinical characteristics of patients are demonstrated in Table 1. The laboratory test results, in ammation markers, and SII were analyzed and summarized in Table 2. The comparison of Group A and Group B classi ed according to the degree of ketonuria is shown in Table 3. The trend of each laboratory parameter according to the degree of ketonuria is shown in Table 4.
RBC, PLT, PDW, NLR, PLR, and SII signi cantly increased with the advancing degree of ketonuria, but lymphocytes, eosinophils, and LMR decreased. Table 5 provides the correlation between ketonuria and hemogram parameters, in ammation markers, and length of hospitalization. There was a positive correlation between increased ketonuria and length of hospitalization, PCT, PDW, NLR, PLR, and SII. However, there was a negative correlation between the increase in the degree of ketonuria, the counts of lymphocytes and eosinophils, and LMR.     Spearman Correlation's Test ROC curve analysis for assessing the cut-off value of SII to predict the severity of HEG was shown in Figure 1. The severity was de ned as +4 degrees of ketonuria. The cut-off value of SII was 1071.8 x 10 9 ; sensitivity and speci city were 59% and 59%, respectively (AUC: 0.637, 95% CI [ 0.582-0.693], p<.001).
The cut-off value of SII to predict the length of hospitalization was shown in Figure 2. The hospitalization over two days was de ned as the top quartile for the length of hospital stay. The cut-off value of SII was 1073.6 x 10 9 for > 2 days hospitalization ( AUC: 0.565, 95% CI: (0.501-0.628), p= 0.039); sensitivity and speci city were 56.3% and 55.5% , respectively.

Discussion
Although the role of in ammation in the pathophysiology of HEG is not clear, subclinical in ammation associated with oxidative stress might play an important role [8,9]. Maternal in ammation causes an increase in cytokine and chemokine levels in the fetal/placental compartments. Uncontrolled in ammation may cause ischemia and destruction in the growing fetal tissues and adverse perinatal outcomes [10]. Many studies on in ammation markers in HEG patients proposed strong associations between HEG development and in ammation. The increase in some cytokines and mediators such as TNF-alpha, IL-6, CRP, vaspin in HEG patients has indicated the in ammation in HEG [11,12]. Also, increased Sirtuin-1 and CRP levels in the HEG patients supported this in ammatory response [13]. Therefore, it is important to assess the degree of maternal in ammation to predict perinatal outcomes.
Complete blood count parameters have been investigated in many studies to predict adverse pregnancy outcomes such as preeclampsia, preterm birth, placental invasion anomalies, and preterm premature rupture of membranes (PPROM) [14][15][16], but there are not enough studies in which SII is used in obstetrics. However, Tanacan et al. showed that SII and platelet counts may be useful in the prediction of adverse outcomes in pregnancies complicated by PPROM. This study emphasized that the in ammation in PPROM and thus higher value of SII could be used as an additional parameter to predict adverse outcomes in these patients [17]. In our study, we suggested that SII might be useful in demonstrating in ammation-related outcomes in HEG patients.
In recent studies, hematological parameters such as NLR, PLR, RDW, MPV, and PCT obtained from peripheral blood complete blood count have been shown to have prognostic and predictive value in various diseases such as in ammatory, autoimmune diseases, gynecological or gastrointestinal malignancies [18,19].
In a study in which hematological parameters were evaluated as a marker of subclinical in ammation in HEG, NLR and PLR were found signi cantly higher in HEG patients than control groups. Also, in the same study, PDW and MPV, which are also used for platelet activation and diagnosis of many in ammatory diseases, did not differ signi cantly between HEG patients and the controls [20]. However, Tayfur et al. showed the PCT value to be signi cantly higher in HEG patients [21]. Studies on the relationship with systemic in ammatory markers obtained from complete blood count and ketonuria showed that these markers can be used in clinical practice. Our study found that NLR, PLR, PCT, and PDW increased as the degree of ketonuria increased. We also showed that SII signi cantly increased with the advancing degree of ketonuria, but lymphocytes, eosinophils, and LMR decreased. Increased levels of these parameters might be the consequences of an altered immune response of blood cells to physical stress in HEG.
Dehydration caused by vomiting can cause increased hemoconcentration, so hematocrit levels may raise in pregnant women with HEG. However, a previous study showed no signi cant changes in Hb and Hct values in patients with HEG (7). Although it was not statistically signi cant, our study found Hb and Hct values higher in patients with +3 and +4 ketonuria compared to those with +1 and +2 ketonuria. Hemoconcentration caused by dehydration can trigger systemic consequences such as oxidative stress and in ammation.
The relationship between the severity of disease and the degree of ketonuria is uncertain. Severe nausea and vomiting lead to ketonuria, which plays an important role in hospitalization. Some studies investigate whether HEG severity is associated with length of hospitalization, readmission, metabolic, biochemical, hematological, and clinical parameters, and in ammatory markers [22,23]. The relationship between the degree of ketonuria and length of hospitalization was evaluated, and they found that ketonuria was not associated with the prolonged hospital stay. However, a previous study showed that women with a higher degree of ketonuria at hospital admission had a longer hospital stay [24]. In our study, we examined the relationship between ketonuria and length of stay and we found a positive correlation between increased ketonuria and length of hospitalization.
Lymphocytes, neutrophils, and platelets, which are components of the SII formula, play a role in in ammation. Neutrophils are one of the major effectors of acute in ammation. They also contribute to chronic in ammatory circumstances and adaptive immune responses. While neutrophils have a destructive effect on the immune system, lymphocyte count decreases due to increased apoptosis in chronic in ammatory processes [25]. Platelets enable to initiate and modulate immune functions by expressing several pro-and anti-in ammatory molecules [26]. Considering the role of these blood cells in in ammation separately, we thought that their inclusion as a formula might be a better indicator of in ammation, so we evaluated SII as a study parameter.
As well as the role of NLR and PLR was described in HEG patients, there is not enough data on the use of SII in obstetrics in the literature. This is the rst study in which SII has been used to predict the severity of HEG to date. Considering the positive relationship between ketonuria and length of hospitalization, the evaluation of SII in pregnant women with HEG may facilitate the clinical management of these patients. So it may differentiate the patients who need longer hospitalization, especially in this pandemic period. The fact that this parameter is cost-effective, practical, and noninvasive may expand its use in obstetrics.
The strength of the study was a large number of patients and study parameters. The limitations of this study were that it did not include long-term pregnancy outcomes.

Conclusion
HEG is one of the severe health problems in early pregnancy. SII is a cheap and easily available method, and it might be used as a parameter in patient selection for hospitalization and management. The use of SII should be supported by future studies in obstetrics.

Declarations
Funding search and the project development. Dilek Sahin was responsible for conceptualization, methodology, visualization, and reviewing and editing. All authors read and approved the nal manuscript.

Ethics approval
The study protocol was approved by the ethics committee of Ankara City Hospital and was conducted following the guidelines of the Helsinki Declaration(E2-

Con ict of Interest
The authors declare that they have no con ict of interest.