Evaluation of the Relationship Between Hyperemesis Gravidarum With Hemoglobin to Red Cell Distribution Width Ratio and Eosinophil to Lymphocyte Ratio


 Introduction: This study, it was aimed to investigate the relationship between the severity of hyperemesis gravidarum (HEG) disease and subclinical inflammatory factors such as Hemoglobin to red cell distribution width ratio (HRR), platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), monocytes to lymphocyte ratio (MLR), eosinophil to lymphocyteratio (ELR), which are known to be closely associated with inflammation in patients with hyperemesis gravidarum.Material method: This retrospective case control study was conducted between December 2020 and December 2021. A total of 215 pregnant women, 121 with hyperemesis gravidarum and 94 healthy pregnant women, were included in the study. HEG patients were divided into three groups according to the modified PUQE classification as mild (n=38), moderate (n=41), and severe (n=42).Results: HRR, PLR, NLR, and MLR values were found to be statistically significantly higher in the HEG group compared to the control group, and ELR values were lower (p<0.05). MON, NEU, PCT, PLR, NLR, MLR values increase from mild to severe in HEG patients. EO, LYM, and ELR values decreased (p<0.05). There was a positive correlation between HEG and PCT (rho=0.45, p< 0.001), PLR (rho=0.76, p< 0.001), NLR (rho=0.79, p< 0.001), MLR (rho=0.81, p< 0.001) values. There was a significant negative correlation between ELR (rho= 0.72, p< 0.001) and HEG.Conclusion: NLR, PLR, and PCT are inflammatory markers that increase in patients with HEG and have predictive value for HEG development. In our study, we suggested the use of two new prognostic markers for patients with HEG. We think that our study will be a source for further studies on the subject.


Introduction
Nausea and vomiting are common during pregnancy. It is an uncomfortable condition that most pregnant women experience with varying severity. It is among the most common causes of hospitalization in the rst trimester of pregnancy [1]. Hyperemesis gravidarum (HEG), a severe form of nausea and vomiting in pregnancy, can cause a loss of more than 5% of body weight, electrolyte, uid, and acid base imbalances, and the nutritional de ciency [2]. Although the prevalence of HEG varies between societies, it affects approximately 0.5%-2% of all pregnancies. In addition, it is known that the risk of recurrence increases in pregnant women with a previous HEG history [3].
There are several possible mechanisms suggested being involved in the pathogenesis of HEG. Many different pathological conditions such as hormonal changes, immunological mechanisms, Helicobacter pylori infection, abnormal gastric motility, genetic predisposition, liver dysfunction have been counted [4].
The role of in ammation in the pathogenesis of HEG is not clear enough. In some studies, it is stated that there are important links between indicators of in ammation and HEG [5][6].
As a result of chronic in ammation, thrombocytosis and proliferation occur in the blood precursor series.
In addition to its role in coagulation and hemostasis, platelets also have a role in regulating in ammatory reactions [7].
Although complete blood count (CBC) is a simple and inexpensive method, it contains important parameters for the diagnosis of many diseases. While there are more expensive methods to evaluate the in ammatory process, white blood cell (WBC), platelet distribution width (PDW), mean platelet volume (MPV), red cell distribution width (RDW), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and platelet crit (PCT) have been shown to re ect disease activity [8][9].
Neutrophils are a type of white blood cell that plays an important role in the body's protection and defense. Lymphocytes are another type of white blood cell that is very important in the formation of the body's immune response. Red cell distribution width (RDW) is a blood parameter that is measured depending on the distribution of erythrocytes over diameter or volume and has a close relationship with in ammatory factors [10]. Hemoglobin (Hb) and RDW are markers derived from red blood cells. It has been reported that these two markers re ect in ammation and correlate with cancer prognosis [11][12]. In some cancers, Hb and RDW have each been shown to be prognostic on their own. There are limited studies on the HB/RDW (HRR) ratio, which is used as a very new marker. Studies on the HRR value were specially conducted on cancer patients [13]. The Pregnancy Unique Quanti cation of Emesis/Stomach (PUQE) scoring system was used to determine severity. The PUQE score was calculated by adding the scores of the answers to the three questions. In the original PUQE index, these questions ask how many times the patient has felt nauseous or nauseous, vomited, and retching or dry blistering in the past 12 hours. In a modi ed PUQE index, these symptoms were questioned for the past 24 hours. Scores from 1 to 5 were added for each question to determine the PUQE score. A patient's PUQE score can range from 4 to 15. A PUQE score of ≤ 6 is classi ed as a mild case of HEG, between 7 and 12 as moderate and ≥ 13 as severe HEG [14][15]. The same scoring system was applied for the modi ed PUQE used in our study. Body mass index (BMI) (kg/m2) was obtained by dividing body weight (kg) by height (m2) squared. Gestational age was determined using the rst day of the last month and con rmed by sonographic examination.

Discussion
HEG has a pathophysiological mechanism that depends on many causes. In ammation has a critical role in HEG [16]. HEG may be severe enough to require hospitalization. It may even progress to central pontine myelinolysis and Wernicke's encephalopathy. Therefore, early diagnosis and treatment of HEG are very important for maternal and child health [17].
Although the link between HEG and in ammation is not fully understood, studies on in ammation markers in HEG patients suggest that there is a strong relationship between them [6,18]. The role of in ammatory processes in the development of HEG has been studied from various aspects. WBC, neutrophil, monocytes, lymphocyte, basophil, and eosinophil counts, which are among the hematological parameters, are important determinants of the in ammatory process. While neutrophils are common in active in ammation, lymphocyte counts re ect the regulatory pathway of the same process [19].
Caglayan et al.'s studies, no signi cant difference was found between the HEG and control groups in terms of lymphocyte and neutrophil counts [6]. Differently, in another study, neutrophil and monocyte counts were higher in the HEG group, while lymphocyte counts were higher in the control group [20]. In another clinical study, neutrophil levels were found to be higher in the HEG group, while the lymphocyte count was found to be lower [21]. In our study, monocyte and neutrophil counts were found to be signi cantly higher in the HEG group compared to the control group. Eosinophil and lymphocyte levels were found to be lower. In addition, when the HEG subgroups are compared, monocyte and neutrophil counts increase, and eosinophils and lymphocyte counts decrease from mild to severe groups.
Mean platelet volume (MPV) is a machine calculated measurement of the average size of platelets present in the blood and is typically included in blood tests as part of the CBC. MPV is an indicator of in ammation due to increased destruction of platelets [22]. There are studies showing that there is no difference between the HEG group and control groups in terms of MPV values [23][24]. Differently, MPV values were found to be higher in the HEG group in our study. In addition, a signi cant difference was found between the mild to the moderate group and the moderate to severe group according to MPV value (p<0.05).
Recently, it has been stated that in ammatory markers such as PCT, RDW, and MPV obtained from complete blood count have prognostic and predictive properties in various diseases such as gynecological and gastrointestinal malignancies, autoimmune diseases, and coronary artery diseases [25][26]. There are not many studies on the relationship between PCT and HEG. Tayfur et al.'s PCT values were found to be higher in women with HEG in their study. In the same study, mild, moderate, and severe HEG cases were compared and it was stated that PCT values were higher in severe HEG cases [21]. In our study, PCT values were found to be signi cantly higher in the HEG group than in the control group. In addition, mild, moderate, and severe HEG cases were compared, and PCT values increase as one goes from the mild group to the severe group. A positive and signi cant relationship was found between PCT values and HEG..
RDW, another parameter in the complete blood count, shows the distribution of red blood cell sizes. RDW tends to increase hemolysis and red blood cell production disorders. RDW is mainly used for diagnosing anemia. It has been shown that RDW is increased in acute and chronic conditions such as pulmonary embolism, acute renal failure, and skin disease [27].
It is reported that HRR alone is a stronger prognostic indicator than Hb or RDW. As the reason for this, it is thought that combining the prognostic information from Hemoglobin and RDW by HRR will provide more information than a single variable [13]. HRR is a recently used in ammatory marker derived from Hb and RDW, which are complete blood count parameters used in routine practice. In addition, it has been shown to be a bad prognostic factor alone in many cancers such as stomach cancer and lung cancer [28][29]. Cintesun et al.'s found no signi cant difference in RDW between the HEG and control groups in their study. In the same study, only a relationship was found between RDW and ketonuria among the available parameters. Contrary to this study, RDW was found to be higher in the control group compared to the HEG group in our study. However, no signi cant difference was observed between mild, moderate, and severe groups [30].
HEG patients are expected to develop hemoconcentration due to vomiting and dehydration. Bulanik et al.'s Hemoglobin and white blood count (WBC) values were not different from the control group in their study [31]. Unlike this study, in our study, WBC values were found to be higher in the HEG group than in the control group.
PLR and NLR are used as important markers in many diseases such as Diabetes Mellitus, kidney failure, heart diseases, in ammatory diseases, autoimmune diseases, and hypertensive disorders [32]. It is stated that these two special indicators increase gastrointestinal diseases, gynecological diseases, malignancies, cardiac diseases, and in ammation [33][34]. Looking at the literature, there are a few studies on the severity of MLR, PLR, NLR, and HEG. Soysal et al.'s In the study conducted by MLR, PLR, and NLR levels were reported to be higher in the patient group. In the same study, a signi cant correlation was found between increasing ketonuria levels and MLR, PLR, and NLR [20]. In another study, PLR and NLR levels were found to be high in HEG patients. However, no correlation was found between PLR and NLR values and the degree of ketonuria [30]. Kan et al.'s In their study, PLR, and NLR levels were found to be higher in the HEG group. However, no correlation was found between the severity of the disease and PLR and NLR values [35]. In another similar study, a signi cant relationship was found between NLR levels and HEG groups [5]. In our study, PLR, NLR, and MLR values were found to be higher in the HEG group. PLR, NLR, MLR values increase as one goes from the mild group to the severe group. A signi cant positive correlation was found between HEG group and PLR, NLR, and MLR values (p<0.05). NLR> 3.06, PLR> 155.4, and MLR> 0.22 rates were determined statistically and these parameters were signi cantly associated with increased risk of HEG disease.
There is no study in the literature regarding HRR in patients with hyperemesis gravidarum. We believe that the data we obtained in this study will lay the groundwork for future studies. In our study, HRR levels were found to be signi cantly higher in the HEG group than in the control group. When the HEG subgroups were examined, no signi cant difference was observed between mild, moderate and severe groups. There was no signi cant correlation between HRR and HEG (p>0.05). However, in our ROC analysis, the rate of HRR>0.97 was detected and it was found to be signi cantly associated with increased risk of HEG.
Eosinophil lymphocyte ratio (ELR) is a new marker evaluated in in ammation and malignancies. In one study, high ELR levels were associated with smoking. It has been said that it may be a useful indicator of systemic disease [36]. It has been reported that ELR helps in distinguishing those with and without hypersensitivity to non steroidal anti in ammatory drugs in patients with bronchial asthma [37]. In addition, it has been reported that increased ELR level worsens the survival of endometrial cancer and is associated with the high risk group [38]. There are not many studies on ELR in the obstetric eld in the literature. It is seen that some studies have been done in other medical elds. Our study is the rst in the literature investigating the relationship between ELR and HEG patients. In our study, ELR levels were found to be signi cantly higher in the healthy control group. However, in HEG subgroups, the level of ELR decreases from mild to severe. In addition, a negative correlation was found between ELR value and HEG in the correlation study. However, according to the data we obtained, ELR levels were not associated with an increased risk of HEG disease.
Limitations of this study: First, the patient data was single center, the number of patients was not very large, and it was a retrospective study. Second, only HRR, PLR, NLR, ELR, MLR, and other hematological parameters are used as in ammatory markers. The strength of our study is that it is the rst study that will lead to the demonstration of the relationship of MLR, PLR, and NLR as well as the new parameters ELR and HRR with HEG.
Conclusion NLR, PLR, and PCT are in ammatory markers that increase in patients with HEG and have predictive value for HEG development. In our study, we suggested the use of two new prognostic markers for patients with HEG. These are the Hb/RDW ratio and the eosinophil to lymphocyte ratio (ELR), which are viably operated at no additional cost. Since the relationship of HRR, ELR markers with HEG has not been de nitively investigated, we cannot make a de nitive statement about their clinical use yet. ELR and HRR may prove to be markers of HEG as more data are collected on HRR and ELR levels to demonstrate the relationship between HEG and in ammation. We think that our study will be a source for further studies on the subject.

Declarations Con ict of interest
The author disclosed no con ict of interest during the preparation or publication of this manuscript.

Financing
The author disclosed that they did not receive any grant during conduction or writing of this study.