Abstract

Objective

This study aimed to evaluate the predictive value of second-trimester maternal hemogram parameters in identifying small for gestational age (SGA) fetuses and assessing the severity of SGA based on umbilical artery Doppler (UAD) findings and birthweight percentiles.

Method

A total of 150 singleton pregnancies were retrospectively analyzed and divided into three groups: SGA with abnormal UAD, SGA with normal UAD, and non-SGA controls. Maternal white blood cell (WBC) count, neutrophil count, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were compared among groups. SGA cases were further stratified into ≤3^rd percentile (high risk) and 4^th-10^th percentile (lower risk) subgroups based on birthweight percentiles, categorizing them as high-risk and low-risk SGA.

Results

Maternal WBC and neutrophil counts were significantly higher in SGA pregnancies compared to non-SGA controls (p<0.05). The highest WBC and neutrophil levels were observed in the SGA group with abnormal UAD and in fetuses ≤3^rd percentile. No significant differences were found in lymphocyte count, platelet count, NLR, or PLR across groups. A strong association was noted between elevated maternal WBC and markers of SGA severity, including lower gestational age at delivery, reduced birthweight, and abnormal Doppler findings.

Conclusion

Second-trimester maternal WBC and neutrophil counts may serve as useful non-invasive markers for both identifying SGA and evaluating its severity. These routinely available parameters could support early risk stratification and management in clinical practice.

Introduction

Small for gestational age (SGA) refers to a condition in which a fetus fails to achieve its genetically expected growth by the time of birth. Together with intrauterine growth restriction (IUGR), SGA is associated with adverse perinatal outcomes affecting both the mother and the newborn (1, 2). By definition, SGA is characterized by a birth weight below the 10^th percentile for gestational age (1).

Fetal growth restriction (FGR) increases the risk of early neonatal complications such as low birth weight, the need for neonatal intensive care, and perinatal mortality. In addition, it has been linked to long-term health problems, including obesity, neurodevelopmental disorders, cardiovascular diseases, and type 2 diabetes later in life (3-5). These complications may emerge during the neonatal period and often persist into later stages of life (2). The severity of FGR has been shown to correlate inversely with estimated fetal weight; that is, lower fetal weight is typically associated with more profound placental dysfunction and a worse perinatal prognosis (6).

The development of SGA and IUGR is attributed to various maternal and fetal factors, including fetal chromosomal abnormalities, structural anomalies, and maternal infections (1). Notably, increased resistance and abnormal findings in the umbilical artery Doppler are indicative of more severe FGR and are associated with poorer perinatal outcomes. Such Doppler abnormalities reflect impaired placental perfusion, which further contributes to adverse neonatal prognosis (7).

Recent studies have increasingly emphasized a strong association between FGR and inflammation, indicating that inflammatory mechanisms may be central to the initiation and progression of FGR (8, 9). Inflammatory states may activate immune responses that impair placental function and hinder nutrient exchange, thereby contributing to FGR (10). Such impairment can result in compromised fetal development, posing serious risks to both immediate and long-term neonatal health.

Previous studies have indicated that elevated levels of first and second trimester maternal serum inflammatory markers—such as neutrophil count, white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR)—may serve as significant and predictive biomarkers of impaired intrauterine growth (11-15).

The primary objective of this study was to evaluate the predictive value of second trimester maternal serum inflammatory markers—including WBC count, neutrophil count, lymphocyte count, platelet count, NLR, and PLR—for identifying SGA fetuses; the secondary objective was to investigate the utility of these markers in predicting the severity of SGA based on umbilical artery Doppler findings and birthweight percentiles.

Materials and Methods

This retrospective observational case-control study included a total of 150 pregnant women who were followed at the Perinatology Outpatient Clinic of University of Health Sciences Turkey, Başakşehir Çam and Sakura City Hospital between January 2024 and December 2024.The participants were categorized into three groups based on fetal growth status and umbilical artery Doppler findings. Fetuses with an estimated fetal weight below the 10^th percentile on ultrasonographic evaluation were diagnosed with SGA.

Group 1 consisted of 50 pregnant women carrying fetuses diagnosed with SGA accompanied by abnormal umbilical artery Doppler findings, such as an increased resistance index. These cases were considered high-risk SGA pregnancies.

Group 2 included 50 pregnant women carrying fetuses diagnosed with SGA but with normal umbilical artery Doppler findings, and were therefore considered to have lower-risk SGA pregnancies.

Group 3 served as a control group and consisted of 50 randomly selected pregnant women with appropriately grown fetuses and normal Doppler findings, representing healthy pregnancies. In the control group, all patients delivered at ≥37 weeks of gestation without obstetric or neonatal complications.

All participants had hemogram parameters measured during the second trimester (between 14-28 weeks of gestation). The maternal complete blood count (CBC) values analyzed included WBC count, neutrophil count, lymphocyte count, platelet count, NLR, and PLR. CBC analyses were performed using the Sysmex XN-1000 automated hematology analyzer (Sysmex Corporation, Kobe, Japan). These parameters were assessed to investigate their potential predictive value in identifying IUGR fetuses.

Additionally, within the SGA group (Groups 1 and 2), further stratification was performed based on birth weight percentiles. Fetuses born below the 3^rd percentile were defined as higher-risk SGA, whereas those between the 3^rd and 10^th percentiles were considered lower-risk SGA. The predictive performance of the hemogram parameters for both the identification and risk stratification of SGA was statistically analyzed.

Pregnancies complicated by multiple gestations, congenital anomalies, pre-existing maternal chronic illnesses (e.g., diabetes mellitus, hypertension, autoimmune diseases), or incomplete medical records were excluded from the study.

The study protocol, procedures, and ethical conduct were reviewed and approved by the Local Ethics Committee of the University of Health Sciences Turkey, Başakşehir Çam and Sakura City Hospital (approval number: KAEK/12.02.2025.41, date: 04.03.2025). All procedures were performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Because of the retrospective nature of the study, written informed consent was not required from participants.

Selection and Description of the Participants

This study included 150 pregnant women followed at our tertiary care center. Inclusion criteria were singleton pregnancies between 14-28 weeks of gestation with complete medical and ultrasonographic data, including second trimester hemogram results and umbilical artery Doppler findings. Participants were selected to reflect a spectrum of fetal growth status: High-risk SGA, low-risk SGA, and normal fetal growth.

Exclusion criteria were as follows: Multiple gestations, fetal congenital or chromosomal anomalies, known maternal infections, use of medications influencing hematological parameters, maternal hematologic disorders, and chronic maternal conditions such as diabetes mellitus, hypertension, or autoimmune diseases. Cases with incomplete or missing medical records were also excluded.

The study population was not restricted by maternal age, ethnicity, or parity; however, all participants were selected from the same geographical region and healthcare facility to ensure consistency in clinical protocols and data acquisition. The rationale for this selection was to minimize confounding factors related to clinical variability and to reflect a representative sample of patients typically seen in tertiary obstetric care.

Statistical Analysis

All statistical analyses were conducted using R software (version 4.4.2). The Shapiro-Wilk test was used to assess the normality of continuous variables. Normally distributed variables are presented as mean ± standard deviation, and non-normally distributed variables as median and interquartile range (IQR). Categorical variables are expressed as counts and percentages.

Group comparisons for categorical variables were performed using Fisher’s exact test or the chi-square test, as appropriate. For continuous variables, the Wilcoxon Rank-Sum test was used for two-group comparisons, and the Kruskal-Wallis test was applied for comparisons across more than two groups. A p-value of <0.05 was considered statistically significant.

Results

A total of 150 pregnant women were included and categorized into three groups based on fetal growth and umbilical artery Doppler findings. Hematologic and perinatal outcomes were compared between groups to assess the predictive value of maternal second-trimester hemogram parameters for SGA fetuses and SGA severity.

Comparison of SGA and Non-SGA Groups

Patients with SGA fetuses (Groups 1 and 2) demonstrated significantly higher maternal neutrophil counts [7,970.00/µL (IQR: 6,380.00-10,390.00)] compared to the non-SGA control group [6,970.00/µL (IQR: 6,230.00-8,440.00]; p=0.021)]. Similarly, WBC counts were significantly elevated in the SGA group [11,765.00/µL (IQR: 9,500.00-13,240.00)] compared to controls [9,965.00/µL (IQR: 8,740.00-11,540.00); p=0.004]. There were no statistically significant differences in lymphocyte count, platelet count, NLR, or PLR between groups (p>0.05 for all) (Table 1).

Comparison of Non-SGA, SGA with Abnormal UAD and SGA with Normal UAD Groups

A significant difference in gestational age at delivery was observed across the three groups (p<0.001). Pregnancies complicated by SGA with abnormal UAD had the earliest deliveries [29.71 weeks (IQR: 27.93-32.29)] compared to SGA with normal UAD [37.00 weeks (IQR: 36.00-37.14)] and non-SGA pregnancies [39.00 weeks (IQR: 38.57-40.00)]. Birthweights were lowest in the abnormal UAD group [855.00 g (IQR: 635.00-1,190.00)] compared to the normal UAD group [2,330.00 g (IQR: 1,965.00-2,450.00)] and the non-SGA group [3,425.00 g (IQR: 3,140.00-3,630.00); p<0.001].

Similarly, WBC counts were highest among patients with SGA and abnormal UAD [12,430.00/µL (IQR: 10,750.00-14,835.00)], followed by those with normal UAD [10,075.00/µL (IQR: 9,030.00-12,625.00)] and non-SGA pregnancies [9,965.00/µL (IQR: 8,740.00-11,540.00); p<0.001]. Neutrophil counts were also significantly different among groups (p=0.012), while lymphocyte counts, platelet counts, NLR, and PLR did not show significant differences (p>0.05) (Table 2).

Comparison Based on Birthweight Percentiles Among SGA Fetuses

Further stratification of SGA fetuses by birthweight percentiles revealed that those born at ≤3^rd percentile had significantly lower gestational age at birth [32.36 weeks (IQR: 29.29-35.29)] compared to those between the 4^th-10^th percentile [37.00 weeks (IQR: 36.86-37.14); p<0.001]. Birthweights were also significantly lower in the ≤3^rd percentile group [1,095.00 g (IQR: 715.00-1,630.00)] compared to the 4^th-10^th percentile group [2,390.00 g (IQR: 2,340.00–2,470.00); p<0.001]. Maternal WBC counts were significantly higher in the ≤3^rd percentile group [12,110.00/µL (IQR: 9,720.00-13,390.00)] compared to the 4^th-10^th percentile group [9,760.00/µL (IQR: 8,800.00-12,500.00); p=0.021]. No significant differences were observed in other hematological parameters (Table 3).

Discussion

The pathophysiological basis of SGA is multifactorial, with increasing attention directed toward the potential role of inflammation in placental dysfunction and suboptimal fetal growth. Although the association between inflammation and FGR has been hypothesized—particularly due to impaired placental function and nutrient exchange—this mechanism has yet to be fully substantiated with definitive causal evidence.

Previous studies have highlighted the association between systemic inflammation and FGR. Elevated maternal inflammatory markers have been implicated in placental dysfunction, which is a key pathophysiological mechanism underlying SGA (14, 15). Consistent with these findings, our study showed significantly higher maternal WBC and neutrophil counts in the SGA group compared to controls. These results align with the findings of Kırmızı et al. (11), who also reported higher WBC counts in pregnancies complicated by FGR.

When SGA pregnancies were further stratified by UAD results, our study revealed that those with abnormal UAD—representing higher-risk SGA—had the earliest gestational age at delivery and the lowest birthweights. This group (Group 1) also exhibited the highest WBC and neutrophil levels, supporting the hypothesis that inflammation may be more pronounced in severe cases of SGA. These findings are in agreement with prior research indicating that elevated WBC levels are linked not only to the presence of SGA but also to the extent of placental insufficiency (16).

Additionally, subgroup analysis based on birthweight percentiles revealed that fetuses below the 3^rd percentile had significantly earlier gestational ages at delivery and lower birthweights compared to those between the 4^th and 10^th percentiles. Notably, WBC counts were significantly higher in the ≤3^rd percentile group. The high rate of abnormal UAD findings (59%) in this subgroup, compared to only 3.7% in the 4^th-10^th percentile group, further emphasizes the clinical value of WBC as a potential marker for severe SGA.

Importantly, in contrast to several previous studies in the literature (13-15), this study did not find a significant association between other hematologic parameters—such as lymphocyte count, platelet count, NLR, and PLR—and the presence or severity of SGA. These findings suggest that while WBC and neutrophil counts may have predictive value, the broader range of hemogram parameters may have limited diagnostic utility in this context. Further large-scale studies are warranted to determine whether these markers could contribute meaningfully to SGA prediction.

As in the present study, various previous investigations have assessed the predictive ability of different maternal serum hemogram parameters for identifying SGA (17, 18). However, to the best of our knowledge, this is the first study to comprehensively evaluate multiple second-trimester hemogram parameters specifically for predicting the severity of SGA. Taken together, these findings suggest that routine, non-invasive parameters such as CBC-derived inflammatory markers may hold clinical promise in the early identification of high-risk SGA cases. This could be particularly beneficial in settings with limited access to advanced diagnostic tools. However, prospective, large-scale studies are warranted to validate their utility in broader clinical practice.

Study Limitations

Limitations of our study include its retrospective design and single-center setting, which may limit the generalizability of the findings. Future prospective studies with larger cohorts are warranted to validate our findings and to explore the potential integration of these biomarkers into SGA screening protocols.

Conclusion

In conclusion, maternal WBC and neutrophil counts in the second trimester appear to be promising non-invasive markers for predicting SGA and identifying its severity. These parameters, readily available through routine antenatal care, may enhance current screening strategies when combined with fetal biometric and Doppler assessments.