Inflammation-driven pathogenesis of hyperemesis gravidarum: assessing the role of pan-immune-inflammation value and hematologic parameters

Abstract

Objective

Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting during pregnancy that frequently leads to hospitalization and significant maternal morbidity. Despite its clinical significance, the pathogenesis of HG remains poorly understood, with systemic inflammation emerging as a possible contributing factor. The aim of this study was to investigate the role of novel inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV), in the pathophysiology of HG and their association with disease severity.

Materials and methods

This retrospective case–control study included 259 pregnant women (159 with HG and 100 healthy controls) enrolled in Inonu University School of Medicine between January 2020 and August 2023. Hematologic parameters, including leukocyte, neutrophil, lymphocyte, and platelet counts and ketonuria levels, were collected from electronic medical records. Inflammatory indices (NLR, PLR, SII, and PIV) were calculated and their diagnostic performance was evaluated using receiver-operating characteristic (ROC) curve analysis. Logistic regression was used to assess the risk factors for HG. Statistical analyses were performed using SPSS version 22, with p < 0.05 considered significant.

Results

The HG group had significantly higher NLR (p = 0.004), PLR (p = 0.003), SII (p < 0.001), and PIV (p < 0.001) compared to controls. ROC analysis revealed that NLR [cut-off: 5.67, area under the curve (AUC) 0.608, 95% confidence interval (CI) 0.545–0.668, p = 0.002], PLR (cut-off: 154.5, AUC 0.610, 95% CI 0.547–0.669, p = 0.002), SII (cut-off: 948.4, AUC: 0.636, 95% CI 0.575–0.695, p < 0.001), and PIV (cut-off: 866.51, AUC 0.637, 95% CI 0.575–0.696, p < 0.001) showed moderate diagnostic performance with high specificity (70–94%) but variable sensitivity (25.8–55.3%). Logistic regression identified low gestational age and increased platelet distribution width (PDW) as significant risk factors for HG (p < 0.05), while PIV and other inflammatory markers did not emerge as independent predictors.

Conclusion

This study emphasizes the role of systemic inflammation in HG as evidenced by increased inflammatory indices in HG patients. NLR, PLR, SII, and PIV prove to be promising diagnostic markers for HG and offer high specificity and sensitivity. However, their lack of correlation with ketonuria suggests that inflammation alone cannot fully explain the severity of the disease. These findings highlight the need for further research to validate these markers and explore their potential for the development of personalized treatment strategies for HG.

What does this study add to the clinical work

This study demonstrates that inflammatory indices (NLR, PLR, SII, PIV) are significantly elevated in hyperemesis gravidarum. These easily accessible and cost-effective blood parameters may assist clinicians in the diagnosis and follow-up of the disease.

Introduction

Nausea and vomiting are among the most common symptoms of pregnancy and occur in about 80% of all pregnancies, especially in the first trimester. While these symptoms are often mild and self-limiting, in about 3% of pregnancies, they can escalate to a severe condition known as hyperemesis gravidarum (HG) [1]. HG is characterized by persistent nausea, vomiting, weight loss (> 5% of pre-pregnancy body weight), dehydration, and the presence of ketonuria and/or ketonemia. Despite its clinical significance, there are no universally accepted diagnostic criteria for HG, and it is primarily defined by the severity of symptoms along the spectrum of nausea and vomiting in pregnancy [2]. HG is the most common cause of hospitalization in the first half of pregnancy and places a significant physical, emotional, and economic burden on those affected and on healthcare systems [3].

The etiology of HG remains poorly understood, although several potential contributing factors have been proposed. Hormonal fluctuations, particularly in relation to sex hormones [e.g., human chorionic gonadotropin (hCG)] and thyroid hormones, have been implicated in the pathogenesis of HG. In addition, Helicobacter pylori infections, paternal genetic contributions, and placental factors are thought to play a causal role, although a definitive consensus has not yet been reached [4]. Known risk factors for HG include young maternal age, being underweight or overweight before pregnancy, multiple pregnancies, molar pregnancies, having a female fetus, and the use of assisted reproductive technology [5]. New evidence also suggests that psychological factors, such as stress and anxiety, may contribute to the development or exacerbation of HG [6].

Recent research has emphasized the role of systemic inflammation in the pathophysiology of HG [7]. Inflammation is increasingly recognized as a major cause of the disease. Studies have demonstrated elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with HG. These cytokines play a central role in the early inflammatory response and may contribute to the systemic manifestations of the disease [8]. In addition, chronic inflammation has been associated with changes in hematologic parameters, including relative thrombocytosis and megakaryocyte proliferation, which may exacerbate the inflammatory cascade. Platelets, traditionally known for their role in blood coagulation and hemostasis, are now recognized as active modulators of inflammation, further highlighting the interplay between hematologic and immunologic pathways in HG [9].

In recent years, there has been increasing interest in the use of hematologic biomarkers to assess inflammation and predict clinical outcome in various diseases. Parameters, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have been extensively studied in various diseases ranging from cardiovascular diseases to cancer and metabolic disorders. These indices, derived from routine peripheral blood counts, provide an inexpensive and easily accessible means of assessing systemic inflammation and immune activation [10]. More recently, a new biomarker known as the Pan-Immune Inflammation Score (PIV) has been introduced. PIV integrates four key immune cell types (neutrophils, platelets, monocytes, and lymphocytes), potentially offering a more holistic assessment of systemic inflammation than NLR or PLR, which rely on fewer parameters. In oncology, PIV has demonstrated superior prognostic value over SII and NLR in predicting disease progression and survival, suggesting its broader applicability in inflammatory conditions like HG. However, its comparative utility in HG remains to be validated. PIV was first validated in metastatic colorectal cancer, where it outperformed NLR and PLR in predicting survival and treatment response [11]. Subsequent studies confirmed its prognostic value in breast cancer and COVID-19, demonstrating its broad applicability as a measure of systemic inflammation [12, 13]. While NLR, PLR, and SII are well studied, PIV remains underexplored in HG, offering potential for a more integrated assessment of inflammation. Given its robust predictive capabilities in these contexts, PIV may also be a promising biomarker for the assessment of disease severity and prognosis in HG.

Despite these advances, there is a notable gap in the literature regarding the use of PIV in hyperemesis gravidarum. In particular, no studies have yet investigated the potential of PIV to predict disease prognosis or its relationship to ketonuria levels, an important clinical marker of HG severity. Understanding the immune- and inflammation-related pathogenesis of HG is crucial for developing targeted therapeutic strategies and improving treatment outcomes. This study aims to fill this gap by investigating the role of PIV and other hematologic parameters in the pathophysiology of HG, focusing on their potential as prognostic indicators and their association with ketonuria levels.

Materials and methods

Study design and setting

This retrospective case–control study included a convenience sample of 259 pregnant women (159 with HG and 100 healthy controls) enrolled in Inonu University School of Medicine between January 2020 and August 2023. While no formal sample size calculation was performed, the cohort size was determined by the availability of complete electronic medical records during the study period. Post hoc power analysis confirmed adequate power (β > 0.80) to detect significant differences in inflammatory indices (e.g., NLR and PIV) between groups at α = 0.05. Ethical approval for the study was obtained from the Institutional Ethical Committee of Inonu University (approval number: 2024/5511; date: 23.01.2024). All data were anonymized to ensure patient confidentiality. All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Study population and inclusion/exclusion criteria

The study population consisted of pregnant women diagnosed with HG during the specified period. Since there is no generally standardized diagnostic criterion for HG, we defined HG if the patient met all of the following clinical parameters: frequency of vomiting: at least three episodes per day; ketonuria: a result of + 1 or higher on the dipstick urine test. HG was defined by persistent vomiting (≥ 3 episodes/day), ketonuria (≥ + 1), and weight loss (≥ 5% of pre-pregnancy body weight), confirmed via medical records. Patients with the following conditions were excluded from the study to minimize confounding factors:

• Pre-existing medical conditions or inflammatory diseases (e.g., urinary tract infections, coronary artery disease, unstable angina, and myocardial infarction).

• Any major surgery or cardiovascular intervention within the last three months.

• Hypertension, proven peptic ulcer disease, or oral steroid use.

• Eating disorders, smoking, or psychiatric diseases.

• Multiple or molar pregnancies.

• Ovulation-induced pregnancies (e.g., through assisted reproductive technologies).

• Thyroid disorders (e.g., hyperthyroidism or hypothyroidism).

Data collection

Data were retrospectively collected from the electronic medical records of eligible patients. The following parameters were extracted:

• Hematologic parameters: white blood cell (WBC) count, neutrophil (NEU) count, lymphocyte (LYM) count, hemoglobin (Hb), monocyte count, platelet (PLT) count, mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), and red cell distribution width (RDW).

• Ketonuria levels: categorized as + 1, + 2, + 3, or + 4 based on urinalysis results.

Calculation of inflammatory ındices

The following inflammatory indices were calculated using the collected hematologic parameters:

• Neutrophil-to-lymphocyte ratio (NLR): calculated as NEU/LYM.

• Platelet-to-lymphocyte ratio (PLR): calculated as PLT/LYM.

• Systemic immune-inflammation index (SII): calculated as (PLT × NEU)/LYM.

• Pan-immune-inflammation value (PIV): calculated as (NEU × PLT × MON)/LYM.

Monocytes were included in the PIV calculation as they play a key role in systemic inflammation and immune response, providing a more comprehensive assessment of inflammatory status.

Statistical analysis

The analyses were evaluated in SPSS (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL) 22 package program. Descriptive data were presented as n, % values for categorical data and median interquartile range (25–75 percentile values) for continuous data. Chi-square analysis (Pearson chi-square) was used to compare categorical variables between groups. Compliance of continuous variables with normal distribution was evaluated by Kolmogorov–Smirnov test. Mann–Whitney U test was used to compare paired groups and Kruskal–Wallis analysis was used to compare more than two groups. Receiver-operating characteristic (ROC) curves were drawn to measure the value of NLR, PLR, SII, and PIV in the diagnosis of hyperemesis gravidarum. Logistic regression analysis was performed to calculate the risk of hyperemesis gravidarum. Those that were significant in pairwise comparisons were included in the multivariate model. Statistical significance level was accepted as p < 0.05 in the analyses.

Results

A total of 259 pregnant women were included in the study, comprising 159 women diagnosed with HG and 100 healthy pregnant women as controls. Comparative analysis revealed that women in the HG group were at a significantly earlier gestational week compared to the control group (p < 0.001)). The HG group also had significantly lower percentages of lymphocytes (p = 0.001) and eosinophils (p < 0.001), alongside significantly higher WBC counts (p = 0.044), percentages of neutrophils (p = 0.002), PCT (p = 0.032), and PDW (p = 0.003). In addition, the HG group had increased neutrophil counts (p = 0.033) and significantly higher values for all calculated inflammatory indices, including the NLR (p = 0.004), PLR (p = 0.003), SII (p < 0.001), and PIV (p < 0.001). These findings emphasize the presence of systemic inflammation and immune dysregulation in HG, as shown in Table 1.

Table 1.

Comparison of demographic, hematological, and inflammatory parameters between hyperemesis gravidarum (HG) patients and healthy controls

	HG (n = 159)	Control (n = 100)	p value
	Median (IQR)	Median (IQR)
Age (year)	29.00 (25.00–32.00)	30.00 (26.00–34.00)	0.319
Gravida	2.00 (1.00–3.00)	2.00 (1.00–3.00)	0.693
Parity	1.00 (0.00–2.00)	1.00 (0.00–1.50)	0.476
Gestational age (weeks)	10.00 (8.00–12.00)	12.00 (10.00–14.00)	< 0.001
Consanguineous marriage, n (%)	13 (8.2)	5 (5.0)	0.328**
Hb (g/dl)	12.90 (12.00–13.70)	12.65 (11.95–13.30)	0.063
NEU %	73.50 (66.60–79.20)	70.00 (65.55–74.20)	0.002
LYM %	18.80 (13.70–24.40)	22.15 (17.00–25.85)	0.001
PLT (× 103/μl)	255.00 (216.00–304.00)	242.00 (215.00–291.50)	0.172
PCT	0.27 (0.22–0.31)	0.25 (0.22–0.28)	0.032
PDW	12.40 (10.90–14.50)	11.75 (10.35–13.00)	0.003
MPV	10.50 (9.70–11.30)	10.00 (9.70–11.00)	0.161
RDW	13.30 (12.70–14.40)	13.35 (12.90–14.60)	0.129
Ketonuria, n (%)	105 (66.0)	0 (0)	< 0.001**
Monocyte count (103/μl)	0.59 (0.49–0.77)	0.56 (0.50–0.70)	0.352
Eozinofil	0.05 (0.02–0.10)	0.09 (0.05–0.15)	< 0.001
Bazofil	0.03 (0.02–0.05)	0.03 (0.02–0.04)	0.891
Lymphocyte count (103/μl)	1.87 (1.46–2.24)	2.00 (1.70–2.40)	0.084
Neutrophil count (103/μl)	7.25 (5.48–8.68)	6.60 (5.31–7.79)	0.033
ß-HCG (mIU/ml)	80,556.00 (18,981.00–150647.40)	–	–
NLR	3.83 (2.66–5.81)	3.15 (2.59–4.23)	0.004
PLR	142.16 (108.45–190.00)	128.16 (103.49–148.51)	0.003
SII	1027.55 (690.96–1519.00)	808.88 (601.54–1054.89)	< 0.001
PIV	633.74 (394.53–1020.71)	466.98 (320.21–703.03)	< 0.001

HG hyperemesis gravidarum, Hb hemoglobin, NEU neutrophil count, LYM lymphocyte count, PLT platelet count, PCT plateletcrit, PDW platelet distribution width, MPV mean platelet volume, RDW red cell distribution width, HCG human chorionic gonadotropin, NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio, PIV pan-immune-inflammation score, SII systemic immune-inflammation index

*p values in bold are statistically significant

The predictive ability of various hematologic and inflammatory indices for HG was evaluated using ROC curve analysis, and optimal cut-off values were determined for each parameter. For the NLR, a cut-off value of 5.67 demonstrated 25.8% sensitivity and 94% specificity, indicating its utility as a good predictor of HG. Similarly, a cut-off value of 154.5 for the PLR yielded 44% sensitivity and 81% specificity, further supporting its predictive value. The SII showed a cut-off value of 948.41, with 55.3% sensitivity and 70% specificity, reinforcing its role as a reliable predictor. Finally, a cut-off value of 866.51 for the PIV achieved 35.2% sensitivity and 88% specificity, confirming its potential as a good predictor of HG. These findings, summarized in Table 2 and illustrated in Fig. 1, highlight the diagnostic utility of these indices in identifying HG, with NLR and PIV demonstrating particularly high specificity, while SII and PLR offered balanced sensitivity and specificity. These indices showed moderate diagnostic performance, with NLR and PIV demonstrating high specificity but variable sensitivity.

Table 2.

Specificity and sensitivity of the measured hematologic and inflammatory indices in the determination of hyperemesis gravidarum

	AUC	p value	95% CI		Sensitivity	Specificity	PPV	NPV
			Lower bound	Upper bound
NLR > 5.67	0.608	0.002	0.545	0.668	25.8	94	87.2	44.3
PLR > 154.5	0.610	0.002	0.547	0.669	44.0	81	78.7	47.6
SII > 948.41	0.636	< 0.001	0.575	0.695	55.3	70	74.6	49.6
PIV > 866.51	0.637	< 0.001	0.575	0.696	35.2	88	82.4	46.1

AUC area under the curve, CI confidence interval, PPV positive predictive value, NPV negative predictive value, NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio, SII systemic immune-inflammation index, PIV pan-immune-inflammation score

*p values in bold are statistically significant

Fig. 1.

Receiver-operating characteristic (ROC) curves of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV) in the prediction of hyperemesis gravidarum

When comparing the areas under the curve (AUC) for the diagnostic performance of the four inflammatory indices—NLR, PLR, SII, and PIV—no significant differences were observed among them (p > 0.05), as detailed in Table 3. Logistic regression analysis was performed to assess the risk factors associated with HG, revealing that low gestational age and elevated PDW levels were significant risk factors for HG, as shown in Table 4. Furthermore, when evaluating the relationship between ketonuria levels and inflammatory indices, no significant differences were observed for NLR (p = 0.453), PLR (p = 0.801), SII (p = 0.881), or PIV (p = 0.697), as summarized in Table 5. Additionally, no significant correlation was found between ketone levels and any of the inflammatory indices (NLR, PLR, SII, or PIV) in the HG group, as presented in Table 6. These findings suggest that while inflammatory indices are useful for distinguishing HG from healthy controls, they do not correlate with the severity of ketonuria, and their diagnostic performance is comparable across all four parameters.

Table 3.

Pairwise statistical comparison of the predictive performance (AUC values) of NLR, PLR, SII, and PIV based on ROC curve analysis for diagnosing hyperemesis gravidarum

	NLR (AUC = 0.608)	PLR (AUC = 0.610)	SII (AUC = 0.636)	PIV (AUC = 0.637)
NLR	–	P = 0.955	P = 0.111	P = 0.344
PLR	–	–	P = 0.321	P = 0.463
SII	–	–	–	P = 0.979
PIV	–	–	–	–

AUC area under the curve, CI confidence interval, NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio, SII systemic immune-inflammation index, PIV pan-immune-inflammation value

p values are from DeLong’s test for comparison of ROC curves

Table 4.

Multivariate logistic regression analysis of hematological and inflammatory parameters associated with hyperemesis gravidarum

	B	SE	p value	OR (CI 95%)
Gestational age	− 0.238	0.049	< 0.001	0.788 (0.716–0.867)
WBC	0.117	0.138	0.393	1.125 (0.859–1.473)
PCT	− 0.562	4.105	0.891	0.570 (0.000–1778.216)
PDW	0.163	0.071	0.022	1.177 (1.024–1.352)
Eosinophil	− 0.654	0.805	0.416	0.520 (0.107–2.518)
NLR	− 0.094	0.230	0.684	0.911 (0.580–1.430)
PLR	0.011	0.008	0.187	1.011 (0.995–1.028)
SII	0.000	0.001	0.706	1.000 (0.998–1.003)
PIV	0.000	0.000	0.160	1.000 (1.000–1.001)

*P values in bold are statistically significant

SE standard error, OR odds ratio, CI confidence interval, PCT plateletcrit, PDW platelet distribution width, NLR neutrophil-to-lymphocyte ratio; PLR: platelet-to-lymphocyte ratio; SII: systemic immune-inflammation index; PIV: pan-immune-inflammation score

Table 5.

Comparison of inflammatory markers (NLR, PLR, SII, and PIV) across different degrees of ketonuria in patients with hyperemesis gravidarum

	NLR	PLR	SII	PIV
Ketonuria + 1 (n = 29)	4.1 (2.7–6.1)	137.9 (126.2–166.3)	1035.6 (731.9–1570.6)	650.5 (499.5–1068.0)
Ketonuria + 2 (n = 34)	4.3 (3.3–6.3)	159.4 (110.1–201.0)	1112.2 (841.5–1464.7)	616.0 (416.6–893.5)
Ketonuria + 3 (n = 20)	3.8 (2.3–6.0)	131.5 (106.5–189.2)	1001.9 (615.1–1544.3)	842.8 (308.4–1032.0)
Ketonuria + 4 (n = 22)	4.2 (2.7–5.6)	147.9 (117.1–238.9)	1129.6 (696.9–1940.2)	667.9 (394.5–1134.9)
p*	0.453	0.801	0.881	0.697

*p: Kruskal–Wallis test for non-parametric comparison among groups

NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio, SII systemic immune-inflammation index, PIV pan-immune-inflammation value

Table 6.

Correlation analysis between the degree of ketonuria and inflammatory markers (NLR, PLR, SII, and PIV) in patients with hyperemesis gravidarum

	Ketone
	r	p
NLR	− 0.041	0.676
PLR	0.001	0.996
SII	− 0.004	0.969
PID	− 0.014	0.885

r: Spearman’s correlation coefficient; p: significance level

NLR neutrophil-to-lymphocyte ratio, PLR platelet-to-lymphocyte ratio, SII systemic immune-inflammation index, PIV pan-immune-inflammation value

Discussion

Hyperemesis gravidarum (HG) is one of the most serious health complications in early pregnancy, the pathogenesis of which is still poorly understood and probably multifactorial [14]. Hyperemesis gravidarum usually occurs in the first trimester and can lead to serious complications that require hospitalization. In extreme cases, it can lead to life-threatening conditions, such as central pontine myelinolysis and Wernicke’s encephalopathy [15]. Early diagnosis and prompt treatment are therefore crucial for improving maternal and fetal outcomes. Despite its clinical significance, the role of inflammation in the pathogenesis of HG remains unclear, as current evidence is insufficient to establish a definitive link [16]. While several theories have been proposed, none have consistently shown strong predictive value for HG. However, emerging evidence suggests that subclinical inflammation, possibly triggered by oxidative stress, may play an important role in the disease process [8]. This is supported by studies highlighting the utility of simple hematologic markers, such as MPV, PDW, NLR, RDW, PCT, and PLR, in reflecting inflammatory burden and disease activity in a variety of diseases [17–19].

In our study, we observed significant changes in these markers, including increased PDW and inflammatory indices, such as NLR, PLR, SII, and PIV, further emphasizing the potential role of systemic inflammation in HG. These findings are consistent with the growing body of evidence suggesting that inflammatory processes may contribute to the pathophysiology of HG. However, further research is needed to elucidate the exact mechanisms and to establish these markers as reliable diagnostic or prognostic tools. Notably, our results also showed that the HG group had a significantly lower gestational age, which may act as a confounding factor influencing inflammatory marker levels. Future studies should account for gestational age as a covariate to better isolate the specific impact of HG on inflammatory responses.

Recent research has highlighted the prognostic and predictive value of systemic inflammatory markers derived from the complete peripheral blood count, such as NLR, PLR, RDW, MPV, and PCT, in a variety of diseases, including coronary artery disease, inflammatory and autoimmune diseases, preeclampsia, and gynecologic or gastrointestinal malignancies [10, 11]. Notably, Dal et al. similarly reported elevated delta neutrophil index (DNI) and other inflammatory markers in HG patients, supporting the role of neutrophil activation in HG pathogenesis. However, their findings contrast with ours regarding lymphocyte counts, possibly due to differences in disease severity or timing of blood sampling [20]. Additionally, Doğru Şükran et al. demonstrated that systemic inflammatory index (SII) values correlated with longer hospital stays in HG patients, suggesting that inflammatory markers may have prognostic value for clinical outcomes beyond diagnosis [21]. Among these markers, NLR has emerged as a simple, cost-effective and easily accessible indicator of systemic inflammatory response, which has been shown to be useful for predicting outcomes in various diseases, including cardiovascular, neoplastic, and inflammatory diseases [22, 23]. In the context of HG, increased hemoconcentration due to dehydration and fluid loss could theoretically be expected. However, studies such as that by Sari et al. have shown that hemoglobin and hematocrit levels remain unchanged in HG patients, a finding that is consistent with our own results [24]. The lack of significant changes in Hb and hematocrit levels could be due to the physiologic hemodilution that occurs during pregnancy, which could mask the expected hemoconcentration in HG. These observations underscore the complexity of interpreting hematologic parameters in pregnancy-related disorders and highlight the need for further research to clarify the role of systemic inflammation and hemoconcentration in the pathophysiology of HG.

While c-reactive protein (CRP) is an established marker of inflammation, NLR and PLR have emerged in recent years as important indicators of both acute and chronic inflammatory processes. Dehydration, electrolyte disturbances, and metabolic changes are known to occur in association with HG, potentially contributing to systemic inflammation. Studies investigating the role of inflammation in HG have yielded mixed results. For example, Engin-Ustun et al. reported elevated CRP levels in women with HG compared to controls, suggesting that inflammation may play a role in the pathophysiology of HG. They suggested that elevated CRP levels could serve as a marker for the inflammatory process in HG [25]. However, S. Y. Tunc et al. reported contradictory results as they found no significant differences in CRP levels between HG patients and control subjects [26]. In addition, immunologic factors, such as immunoglobulin levels, complement activity, and lymphocyte count, have been associated with HG, with some studies reporting higher levels of these markers in HG patients, indicating a possible immunologic involvement in the disease process [27]. In our study, we found that the percentage of lymphocytes was significantly lower in the HG group compared to the control group (p = 0.001), supporting the hypothesis that immune system dysregulation and inflammation may contribute to the pathogenesis of HG. These findings highlight the complex interplay between inflammatory and immunological factors in HG and emphasize the need for further research to clarify their role in the disease.

In this study, we aimed to investigate the relationship between the presence and severity of HG and systemic inflammatory indices, hypothesizing that patients with HG would have elevated levels of inflammatory markers. Our results confirmed this hypothesis and showed that NLR, PLR, and combined systemic inflammatory indices, such as the SII and PIV, were significantly higher in the HG group compared to the control group. Notably, these indices showed strong diagnostic performance with high sensitivity and specificity rates, suggesting their potential utility in identifying HG. Among these markers, SII and PIV showed particularly high odds ratios, further supporting their importance in the inflammatory pathogenesis of HG. In addition, our results revealed a positive association between SII and PIV levels and the presence of HG, emphasizing the role of systemic inflammation in the disease. While SII and PIV showed elevated levels in HG patients, they did not emerge as independent predictors in the multivariate regression, suggesting that their role may be adjunctive rather than definitive. The moderate AUC values (0.60–0.63) indicate diagnostic utility, but the low sensitivity of some markers (e.g., NLR at 25.8%) limits their standalone clinical application. While PIV’s multi-parametric design may theoretically capture inflammatory complexity better than NLR or PLR, our study found no significant difference in AUC values among indices. This underscores the need for larger studies to evaluate whether PIV’s integrative approach translates to clinical superiority in HG diagnosis or monitoring. The results of this study are consistent with the growing body of evidence suggesting inflammation in the pathophysiology of HG and highlight the potential of these novel markers as diagnostic tools. However, further research is needed to validate their clinical utility and investigate their relationship to symptom severity and disease progression.

Ketonuria is a widely used parameter in the diagnosis of severe HG; however, its relationship with disease severity remains unclear. While some studies have investigated possible associations between the degree of ketonuria and the severity of HG, others have found no significant correlation, especially with regard to outcomes such as rehospitalization rate [28, 29]. In our study, we found no significant correlation between inflammatory markers—such as NLR, PLR, SII, and PIV—and ketonuria levels. This result is in line with several previous studies that also failed to show a relationship between ketonuria and inflammatory markers [16]. However, there are also contradictory results in the literature. For example, Soysal et al. reported that NLR, PLR, and monocyte-to-lymphocyte ratio (MLR) increased with higher ketonuria levels, suggesting a possible link between inflammation and ketonuria in HG [30]. These discrepancies may be due to differences in study populations, methods, or the multifactorial nature of HG itself. Our findings and those of other studies highlight the complexity of using ketonuria as a sole indicator of disease severity and emphasize the need for further research to clarify the role of ketonuria in the context of systemic inflammation and the pathophysiology of HG. Also, the lack of correlation between PIV/SII and ketonuria may reflect that systemic inflammation in HG is independent of metabolic disturbances like ketosis, highlighting the multifactorial nature of the disease.

This study has several notable strengths that contribute to the growing body of knowledge on HG and its association with systemic inflammation. First, the use of readily available and cost-effective hematologic parameters, such as NLR, PLR, SII, and PIV, provides a practical approach to the assessment of inflammation in the clinical setting. These markers are derived from routine complete blood count (CBC) studies, making them accessible for broad application in the diagnosis and monitoring of HG. Second, the inclusion of a control group allowed a direct comparison of inflammatory markers between HG patients and healthy pregnant women, which increases the validity of the results. Third, the study’s focus on novel inflammatory indices such as SII and PIV adds to the limited literature on their potential role in HG and provides new insights into the pathophysiology of the disease. Finally, the retrospective design of the study enabled the analysis of a relatively large sample, which increases the statistical power of the results.

However, this study is not without limitations. First, there may be selection bias due to the retrospective nature of the study, and there is limited ability to account for confounding factors such as differences in clinical treatment or underlying comorbidities. Second, the study relied on a single measurement of hematologic parameters and ketonuria levels at the time of hospitalization, which may not fully capture the dynamic nature of inflammation and disease progression in HG. Longitudinal studies with repeated measurements would provide a more comprehensive understanding of these relationships. Third, the study population was from a single center, which may limit the generalizability of the results to other populations or healthcare settings. Fourth, the use of a convenience sample may introduce selection bias, though the sample size was sufficient to detect clinically relevant differences. Future prospective studies should include formal power calculations to optimize cohort sizes. Fifth gestational age was significantly lower in the HG group compared to controls, which may influence inflammatory marker levels as a confounding factor. Due to the retrospective design, statistical adjustment for gestational age could not be conducted. Future prospective studies should control for gestational age to better elucidate its effect on systemic inflammation in HG. Finally, the lack of correlation between inflammatory markers and ketonuria, despite both being HG hallmarks, suggests that these may represent distinct pathological pathways. While inflammation could drive symptoms (e.g., nausea), ketonuria may reflect metabolic derangements from prolonged vomiting. This dissociation aligns with Soysal et al.’s null findings [30] but contrasts with Çintesun et al. [16], underscoring the need for standardized protocols to assess these markers concurrently. In addition, while the study examined the relationship between inflammatory markers and HG, it did not investigate the causal mechanisms underlying these relationships. Future research should include prospective, multicenter studies with larger and more diverse cohorts to validate these findings and investigate the potential role of inflammatory markers in predicting disease severity, response to treatment, and long-term outcomes. Despite these limitations, this study provides valuable insights into the role of systemic inflammation in HG and highlights the potential utility of novel inflammatory indices for the diagnosis and treatment of the disease.

Conclusion

In conclusion, this study highlights the important role of systemic inflammation in the pathophysiology of HG, as shown by the elevated levels of inflammatory markers, such as NLR, PLR, SII, and PIV in HG patients compared to healthy controls. These results suggest that these readily available and cost-effective hematologic indices may serve as valuable tools for the diagnosis and monitoring of HG, especially in resource-limited settings. The strong diagnostic performance of these markers, as evidenced by their high sensitivity and specificity, supports their potential utility in clinical practice. However, the lack of a significant association between inflammatory markers and ketonuria levels emphasizes the complexity of HG and the need for a multi-faceted approach to assess disease severity.

While this study provides important insights into the underlying inflammatory mechanisms of HG, further research is needed to validate these findings in larger, more diverse populations and to investigate the causal links between inflammation and HG. Prospective, multicenter studies with longitudinal follow-up are essential to better understand the dynamic nature of inflammation in HG and its impact on maternal and fetal outcomes. In addition, future studies should investigate the potential role of these inflammatory markers in predicting treatment response and developing personalized therapeutic strategies. Overall, this study contributes to the growing body of knowledge on the role of inflammation in HG and points the way for further research aimed at improving the diagnosis, management, and outcomes of this debilitating disease.

Author contributions

S.C. and E.I.C. designed the project, made data analysis, and wrote the main manuscript. N.A. and E.Y. made the data collection and edited the manuscript.

Funding

The authors declare that no funds, grants, or other supports were received during the preparation of this manuscript.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Inonu University (January 23, 2024; Approval No. 2024–5511).