1. Introduction

Nausea and vomiting of pregnancy (NVP) affects more than half of pregnant women and typically develops during the first trimester [11]. While symptoms are mild in most cases, approximately 10–15% of women experience moderate or severe manifestations, with hyperemesis gravidarum representing the extreme form of the condition [5,6]. Despite extensive research, the underlying mechanisms of hyperemesis gravidarum remain incompletely understood [6]. Recent evidence suggests a central role of placental-derived factors influencing appetite regulation and emetic pathways [1,3]. Growth Differentiation Factor-15 (GDF-15) is a stress-responsive cytokine belonging to the transforming growth factor-β family and is actively secreted by trophoblastic tissue during early pregnancy [1]. Experimental and clinical studies have demonstrated that GDF-15 acts on the brainstem via the GFRAL receptor, leading to appetite suppression and induction of nausea and vomiting [2]. Elevated maternal circulating levels of GDF-15 have been associated with increased severity of NVP and hyperemesis gravidarum [3,10].

2. Materials and Methods

Serum GDF-15 levels were measured using enzyme-linked immunosorbent assay (ELISA), as described in previous studies evaluating GDF-15 in pregnancy-related nausea and vomiting [3,10].

Disease severity classification was based on commonly accepted clinical criteria, including frequency of vomiting, weight loss, and signs of dehydration [5,12].

This observational study included 120 pregnant women between 6 and 12 weeks of gestation.

• Study group: 80 women with clinical symptoms of nausea and vomiting

• Control group: 40 asymptomatic healthy pregnant women

The groups were comparable in terms of age, gestational age, parity, and pre-pregnancy body mass index.

Assessment of Disease Severity

Severity was classified as mild, moderate, or severe (hyperemesis gravidarum) based on:

• Frequency of vomiting episodes per day

• Percentage of weight loss

• Clinical signs of dehydration and ketonuria

Laboratory Analysis

Venous blood samples were collected after overnight fasting. Serum GDF-15 levels were measured using a commercially available ELISA kit. Results were expressed in pg/mL.

Statistical Analysis

Data were analyzed using SPSS software.

Quantitative variables were expressed as mean ± standard deviation. Group comparisons were performed using Student’s t-test. ROC curve analysis was used to determine predictive thresholds, sensitivity, specificity, and area under the curve (AUC). A p-value <0.05 was considered statistically significant.

3. Results

The observed progressive increase in serum GDF-15 levels with increasing disease severity is consistent with findings reported in previous cohort and case-control studies [3,10]. Women with hyperemesis gravidarum demonstrated significantly higher GDF-15 concentrations compared with asymptomatic pregnant controls (p < 0.001), which aligns with earlier reports [1]. Serum GDF-15 levels increased significantly with disease severity: 3180 ± 760 pg/mL in mild cases, 4620 ± 910 pg/mL in moderate cases, and 6720 ± 1250 pg/mL in hyperemesis gravidarum, compared to 2170 ± 640 pg/mL in controls (p < 0.001). ROC analysis demonstrated high predictive accuracy of GDF-15 for moderate-to-severe disease (AUC = 0.89). A threshold value >4000 pg/mL showed 82% sensitivity and 78% specificity for predicting severe clinical progression.

Mild symptoms were observed in 56.3% of women, moderate in 31.2%, and severe hyperemesis gravidarum in 12.5%.

A significant progressive increase in serum GDF-15 concentration was observed with increasing disease severity. Women with hyperemesis gravidarum exhibited more than a threefold elevation in GDF-15 levels compared with controls (p < 0.001).

ROC analysis demonstrated that serum GDF-15 effectively discriminated women with moderate-to-severe disease from those with mild or no symptoms. A cut-off value >4000 pg/mL showed optimal diagnostic performance (AUC = 0.89).

4. Discussion

Our findings support the hypothesis that excessive placental secretion of GDF-15 plays a key role in the pathogenesis of hyperemesis gravidarum [1,2]. Activation of appetite-regulating pathways in the brainstem by elevated GDF-15 may exacerbate nausea, vomiting, and weight loss during early pregnancy [2,3]. Early identification of women at high risk using biochemical markers such as GDF-15 may improve clinical management, reduce hospitalization rates, and prevent severe maternal complications [4,8,12]. Previous cohort and case-control studies have reported significantly higher circulating GDF-15 levels in women with HG compared with asymptomatic pregnant controls [3,10]. From a clinical perspective, identification of reliable biomarkers such as GDF-15 may improve early risk stratification and management of HG [4,12]. Psychological and quality-of-life impairment associated with severe HG further highlights the importance of early diagnosis and intervention [7].

5. Conclusions

Serum GDF-15 is a strong predictor of disease severity in nausea and vomiting of pregnancy, confirming its potential clinical utility as an early biomarker for hyperemesis gravidarum [1,3,10]. Measurement of serum GDF-15 in early pregnancy may assist in identifying women at increased risk of moderate-to-severe NVP and hyperemesis gravidarum.