Abstract
Background
Despite the clinical importance of brain sparing in fetal growth restriction (FGR), current data on the specific patterns of brain growth trajectory in early-onset FGR (EO-FGR) remain sparse.
Methods
A multicenter prospective longitudinal study was conducted between November 2024 and February 2026. Three-dimensional tomographic ultrasound imaging was used to measure brain parameters in 36 pregnant women with EO-FGR and 36 with appropriate-for-gestational-age (AGA) fetuses at three time points: 26–28, 30–32, and 34–36 weeks of gestation.
Results
The EO-FGR group initially showed delayed growth in normalized cavum septi pellucidi length (CSPL′) at GA 30–32 weeks compared with the AGA group, with values of 0.03 ± 0.001 and 0.03 ± 0.01, respectively (P-value = 0.007). Further significant reductions were observed in the EO-FGR group at a GA of 34–36 weeks in the CSPL′ (0.03 ± 0.01 vs 0.04 ± 0.01, P-value < 0.001), normalized CSP width (0.03 ± 0.01 vs 0.03 ± 0.01, P-value < 0.001), and normalized occipitofrontal diameter (0.32 ± 0.09 vs 0.35 ± 0.01, P-value = 0.031).
Conclusion
The cavum septi pellucidi and occipitofrontal diameter may serve as early structural indicators of brain growth trajectory in EO-FGR. However, larger cohort studies are needed to validate these findings and correlate them with post-natal imaging and long-term outcomes.
Keywords: fetal growth restriction, brain fissure, brain parameters, brain growth
Introduction
According to ACOG, Fetal growth restriction (FGR) is defined as estimated fetal weight less than the 10th percentile or abdominal circumference (AC) less than the 3rd percentile of gestational age (GA).1,2 The global prevalence of FGR is estimated at 5–10%, though this figure rises disproportionately to 25% in low- and middle-income countries (LMIC).3,4 FGR disrupts normal organogenesis and physiological maturation, frequently resulting in deleterious short- and long-term health sequelae.5
A previous study on 10-year-old children born with growth restriction revealed an increased risk of diminished cognitive function and neurological disease.6 These findings are further supported by evidence of more severe neurodevelopmental outcomes in children with intrauterine growth restriction, born with evidence of circulatory redistribution.7 Chronic hypoxemia and nutrient deficiencies directly suppress fetal growth. While hypoxia triggers a redistribution of cardiac output to prioritize the cerebral circulation—known as the brain-sparing effect—this compensatory mechanism is insufficient to guarantee optimal neurodevelopmental outcomes.8
Magnetic resonance imaging (MRI) has been used to diagnose fetal brain pathology in developed countries.9 Fetal brain MRIs revealed that FGR fetuses had decreased brain volumes and gyrification relative to appropriate for gestational age (AGA) fetuses in the previous study.10 However, this is rarely used for the diagnosis or follow-up of fetal brain in LMICs due to a lack of availability, high cost, and limited expertise in fetal brain MRI.
Three-dimensional (3D) ultrasonography has increasingly emerged as a pivotal diagnostic adjunct in prenatal screening, offering enhanced precision in characterizing neurodevelopmental structures, particularly cortical fissures.11 A recent study showed that 3D ultrasound could detect delayed fetal gyrification in FGR.12 Tomographic ultrasound imaging (TUI) of 3D ultrasonography is a new modality that demonstrates a series of parallel cutting slices on a single screen, as in MRI.13 The advantages of TUI include offline measurement, adjustable slice width, image magnification, and rotation in any direction. This function is extremely useful for detailed CNS assessment.
While neurological changes in late-onset FGR are well established, data on specific areas of early brain changes in early-onset FGR (EO-FGR) remain sparse. Therefore, this study aims to evaluate brain growth trajectories in EO-FGR fetuses compared with AGA fetuses by using 3D ultrasound TUI.
Materials and Methods
This multicenter prospective longitudinal study was conducted at two participating tertiary hospitals in Thailand: Srinagarind Hospital and Khon Kaen Hospital, between November 2024 and February 2026. Participants were enrolled consecutively at both participating centers. The inclusion criteria included singleton pregnant women aged 18 years or older, with a gestational age (GA) of 26 weeks or more. The pregnant women were divided into two groups: the EO-FGR group and the AGA group. The exclusion criteria included fetal anomaly, abnormal chromosomes, fetal infection, a family history of a neurogenetic disorder, or active maternal obstetric conditions such as placental abruption or preterm pre-labor rupture of membranes. Pregnant women who had undergone fewer than two consecutive measurements or had fetal demise in utero were withdrawn.
After written informed consent was obtained, two-dimensional ultrasonography was performed to assess fetal biometric parameters, including biparietal diameter (BPD), head circumference (HC), AC, and femur length (FL). The estimated fetal weight was calculated using Hadlock’s formula.14
Three-dimensional ultrasound volume datasets of the fetal brain were acquired in the axial transthalamic plane (Figure 1A) and the cerebellar plane (Figure 1B) using tomographic ultrasound imaging (TUI), on Voluson E10 (GE Healthcare, Zipf, Austria) equipped with a RAB6-D volumetric convex transducer. Volume acquisition was performed while the fetus was quiescent, using an 85° sweep angle at the highest available image-quality setting. The slice thickness was set at 1.0 mm. The acquired volumes were reviewed sequentially to identify the optimal images. The reconstructed 3D intracranial brain images were properly adjusted in the sagittal, coronal, and axial planes, and offline measurements were performed.
Figure 1.
The 3D tomographic ultrasound images of the fetal brain in the axial plane (A) and the cerebellar plane (B). The Orange arrow indicates the reference line on the horizontal axis, and the white arrow represents the vertical axis.
The brain parameters, including BPD, HC, frontal antero-posterior diameter (FAPD), cavum septi pellucidi length (CSPL), cavum septi pellucidi width (CSPW), Sylvian fissure depth (SF), insular depth (IL), and occipitofrontal diameter (OFD), were measured in the axial plane. Additionally, a transverse cerebellar diameter (TCD) was identified in the transcerebellar plane. BPD was measured from the outer edge of the proximal parietal bone to the inner edge of the distal parietal bone. HC was measured as the circumference of the fetal skull. OFD was measured along the midline from the outer edges of the frontal bone to the outer edge of the occipital bone (Figure 2A). The FAPD was measured from the inner line of the frontal bone to the posterior edge of the CSP along the fetal brain midline. The CSPL was measured as the total length of CSP in an axial plane, whereas CSPW was measured perpendicular to CSPL at its midpoint (Figure 2B). Insular depth was measured by drawing a perpendicular line from the midline to the superior border of the insular cortex, at its most prominent point. The SF depth was assessed by drawing a line perpendicular to the midline, from the insular cortex to the inner layer of the parietal bone (Figure 2C). To minimize acoustic shadowing from the fetal calvarium, both SF and IL measurements were performed in the cerebral hemisphere contralateral to the ultrasound transducer.15 A TCD was measured at the widest portion of the cerebellum (Figure 2D). The brain parameters were measured at three time points: GA 26–28 weeks, 30–32 weeks, and 34–36 weeks. Each measurement was performed three times, and the mean value was used for analysis. To account for interindividual variation in cranial dimensions, brain parameters were normalized to the HC.16 These values were expressed as brain length-to-HC ratios, which have been reported to be independent of head shape.17 The normalized parameters were denoted as BPD′, FAPD′, CSPL′, CSPW′, TCD′, SF′, IL′, and OFD′.
Figure 2.
Sonographic measurements of the fetal brain in the transthalamic plane (A–C) and transcerebellar plane (D). (A) Head circumference (yellow line), biparietal diameter (red line), occipitofrontal diameter (light-blue line), and thalamus (Th). (B) Cavum septi pellucidi length (Orange line), width (green line), and frontal anteroposterior diameter (red stripe line). (C) Sylvian fissure depth (white line) and insular depth (white stripe line). (D) Transverse cerebellar diameter (orange stripe line).
The measurements were independently performed by two experienced sonographers (SN and CD). Inter- and intraobserver reliability were assessed in a subset of 10 fetuses using intraclass correlation coefficients (ICCs). A two-way random-effects model for single measurements was used. The ICC values were interpreted as poor (<0.50), moderate (0.50–0.75), good (0.75–0.90), or excellent (>0.90).
Maternal characteristics, including maternal age, gravida and parity, underlying medical condition, GA at the first antenatal care visit, GA at enrollment, and Doppler indices, were recorded. Neonatal outcomes, including GA at delivery, birth weight, gender, route of delivery, APGAR score, neonatal intensive care unit admission, and neonatal seizures, were also recorded.
Operational Definition
In this study, EO-FGR was defined as an estimated fetal weight (EFW) below the 10th percentile for gestational age, in combination with an abnormal umbilical artery (UA) Doppler finding, defined as a UA pulsatility index above the 95th percentile, with diagnosis established before 32 weeks of gestation.1,2 This definition represents the contributory criterion for early-onset FGR in the Delphi consensus definition. Mild to moderate FGR was defined as FGR with antegrade flow in the UA, while severe FGR was defined as FGR with the presence of absent end-diastolic flow in the UA (UA-AEDF) or reverse end-diastolic flow in the UA (UA-REDF).18 Appropriate-for-gestational-age (AGA) was defined as an EFW and AC between the 10th and 90th percentiles for GA.2 Gestational age was established using the first-trimester crown–rump length measurement when available; otherwise, it was based on a reliable last menstrual period in women with regular menstrual cycles.
Sample Size Calculation
The sample size was calculated based on the difference in mean BPD between fetuses with growth restriction (6.5 ± 0.9 cm) and the normal group (7.1 ± 0.9 cm).11 With 80% power, a two-sided alpha level of 0.05, and a 5% dropout rate, the required sample size was estimated at 36 per group.
Statistical Analysis
Descriptive statistics were used for baseline characteristics. Continuous variables with a normal distribution were reported as the mean ± standard deviation, while those with a non-normal distribution were presented as the median (interquartile range; IQR 25th, 75th). Categorical variables were reported as number (percentage). Continuous variables were compared between the two groups using the independent t-test for normally distributed data and the Mann–Whitney U-test for non-normally distributed data. For normalized fetal brain length-to-HC, differences between the groups were further analyzed using linear mixed-effects regression models to adjust for neonatal male gender. Statistical significance was set at P < 0.05. All analyses were performed using STATA software version 18.0 (College Station, Texas, United States).
Results
A total of 134 pregnant women were enrolled. Of these, 62 were excluded, 61 declined to participate, and one had a fetal chromosome abnormality. Therefore, 72 pregnant women were analyzed. The participant flow is shown in Figure 3. Maternal characteristics and neonatal outcomes are presented in Table 1. The mean maternal ages in the EO-FGR and AGA groups were 30.4 ± 5.7 and 31.8 ± 4.5 years, respectively. One participant (2.8%) at 30–32 weeks of gestation and two participants (5.6%) at 34–36 weeks of gestation had UA-AEDF/REDF. The mean birth weight was 2180.0 ± 474.5 grams in the EO-FGR group and 2,962.8 ± 494.5 grams in the AGA group. Brain parameters in the EO-FGR and AGA groups at the three study time points are presented in Table 2. Table 3 compares normalized brain parameters between groups. At 30–32 weeks of gestation, the EO-FGR group exhibited a significantly lower CSPL′ compared to the AGA group (0.03 ± 0.001 vs 0.03 ± 0.01; P-value = 0.007). Similarly, at 34–36 weeks of gestation, the EO-FGR group also had significantly lower CSPL′ (0.03 ± 0.01 vs 0.04 ± 0.01; P-value < 0.001), CSPW′ (0.03 ± 0.01 vs 0.03 ± 0.01, P-value < 0.001), and OFD′ (0.32 ± 0.09 vs 0.35 ± 0.01, P-value = 0.031), respectively. No statistically significant differences were found in BPD′, TCD′, SF′, IL′, and FAPD′ between the two groups (P-value = 0.944, 0.473, 0.062, 0.803, 0.212, respectively). Table 4 presents the intra- and inter-rater reliability of brain parameters. All intraclass correlation coefficients exceeded 0.80, indicating good to excellent reliability.
Figure 3.
Presents the participant flow diagram.
Table 1.
Maternal Characteristics and Neonatal Outcomes
| Maternal Characteristics | AGA (N = 36) | EO-FGR (N = 36) | P-Value |
|---|---|---|---|
| Age (years) | 31.8 ± 4.5 | 30.4 ± 5.7 | 0.284 |
| Primigravida | 20(55.6) | 22(61.1) | 0.642 |
| Underlying medical condition | 4(11.1) | 6(16.7) | 0.496 |
| GA at first ANC (weeks) | 8.3 ± 3.2 | 9.8 ± 4.4 | 0.110 |
| GA at enrollment (weeks) | 27.8 ± 1.9 | 28.1 ± 1.8 | 0.252 |
| Doppler velocimetry at GA 26–28 weeks | |||
| UA PI | NA | 1.5 ± 0.3 | NA |
| MCA PI | NA | 2.1 ± 0.4 | NA |
| CPR | NA | 1.4 ± 0.4 | NA |
| UA-AEDF/REDF | NA | 0(0) | NA |
| Doppler velocimetry at GA 30–32 weeks | |||
| UA PI | NA | 1.6 ± 0.3 | NA |
| MCA PI | NA | 1.9 ± 0.5 | NA |
| CPR | NA | 1.2 ± 0.5 | NA |
| UA-AEDF/REDF | NA | 1(2.8) | NA |
| Doppler velocimetry at GA 34–36 weeks | |||
| UA PI | NA | 1.6 ± 0.3 | NA |
| MCA PI | NA | 1.7 ± 0.4 | NA |
| CPR | NA | 1.1 ± 0.5 | NA |
| UA-AEDF/REDF | NA | 2(5.6) | NA |
| Neonatal Outcomes | |||
| GA at delivery (weeks) | 38.3 ± 0.9 | 36.3 ± 1.0 | <0.001 |
| Birth weight (g) | 2,962.8 ± 494.5 | 2,180 ± 474.5 | <0.001 |
| Male gender | 25(69.4) | 11(30.6) | 0.001 |
| Route of delivery | 0.230 | ||
| Vagina | 17(47.2) | 12(33.3) | |
| Cesarean section | 19(52.8) | 24(66.7) | |
| APGAR at 1 minute | 8(8, 8) | 8.0(8, 8) | 0.146 |
| APGAR at 5 minutes | 9(9, 9) | 9.0(9, 9) | 0.039 |
| NICU admission | 0(0) | 3(8.3) | 0.239 |
| Neonatal seizure | 0(0) | 0(0) | NA |
Notes: Data are presented as mean ± SD or median (interquartile range [IQR]) for continuous data, and as number and percentage for categorical data.
Abbreviations: AGA, appropriate for gestational age; ANC, antenatal care; CPR, cerebroplacental ratio; EO-FGR, early-onset fetal growth restriction; GA, gestational age; g, gram; MCA, middle cerebral artery; NA, not applicable; NICU, neonatal intensive care unit; PI, pulsatility index; UA, umbilical artery; UA-AEDF, umbilical artery absent end diastolic flow; UA-REDF, umbilical artery reverse end diastolic flow.
Table 2.
Comparison of Brain Parameters Between Fetuses with Early-Onset Growth Restriction and Appropriate for Gestational Age Fetuses
| Brain Parameters (mm) | GA 26–28 Weeks | GA 30–32 Weeks | GA 34–36 Weeks | |||
|---|---|---|---|---|---|---|
| AGA (N = 36) |
EO-FGR (N = 36) |
AGA (N = 36) |
EO-FGR (N = 36) |
AGA (N = 36) |
EO-FGR (N = 36) |
|
| BPD | 69.5 ± 5.2 | 69.4 ± 5.5 | 78.6 ± 4.3 | 76.3 ± 5.2 | 83.0 ± 3.2 | 82.4 ± 4.6 |
| HC | 254.1 ± 33.7 | 252.9 ± 16.1 | 291.3 ± 13.4 | 280.1 ± 16.3 | 311.3 ± 15.2 | 300.1 ± 12.3 |
| TCD | 29.0 ± 2.9 | 28.5 ± 2.1 | 34.2 ± 4.3 | 32.0 ± 3.7 | 37.5 ± 5.2 | 35.5 ± 4.7 |
| SF | 11.3 ± 2.1 | 10.3 ± 2.4 | 12.4 ± 3.0 | 11.6 ± 2.7 | 14.5 ± 2.9 | 13.7 ± 2.5 |
| IL | 21.9 ± 3.6 | 21.8 ± 2.4 | 25.2 ± 3.8 | 23.9 ± 2.9 | 27.3 ± 4.4 | 26.1 ± 3.5 |
| FAPD | 44.9 ± 3.5 | 41.1 ± 4.4 | 49.9 ± 5.2 | 48.7 ± 3.5 | 54.0 ± 3.1 | 53.4 ± 1.4 |
| CSPL | 8.5 ± 1.7 | 8.2 ± 1.5 | 9.1 ± 1.5 | 9.0 ± 1.4 | 10.9 ± 1.8 | 9.3 ± 1.4 |
| CSPW | 7.3 ± 1.4 | 6.8 ± 1.2 | 7.9 ± 1.3 | 7.8 ± 1.2 | 8.4 ± 1.2 | 8.3 ± 1.6 |
| OFD | 90.1 ± 5.6 | 87.4 ± 10.3 | 101.5 ± 6.7 | 96.5 ± 10.1 | 104.7 ± 4.7 | 99.0 ± 7.8 |
Notes: Data presented as mean ± SD.
Abbreviations: AGA, appropriate for gestational age; BPD, biparietal diameter; CSPL, cavum septi pellucidi length; CSPW, cavum septi pellucidi width; FAPD, frontal antero-posterior diameter; EO-FGR, early-onset fetal growth restriction; HC, head circumference; IL, insular depth; OFD, occipitofrontal diameter; SF, Sylvian fissure; TCD, transverse cerebellar diameter.
Table 3.
Comparison of Normalized Brain Parameters Between Fetuses with Early-Onset Growth Restriction and Appropriate for Gestational Age Fetuses
| Normalized Brain Parameters |
GA 26–28 Weeks | GA 30–32 Weeks | GA 34–36 Weeks | ||||||
|---|---|---|---|---|---|---|---|---|---|
| AGA (N = 36) |
EO-FGR (N = 36) |
P-Value* | AGA (N = 36) |
EO-FGR (N = 36) |
P-Value* | AGA (N = 36) |
EO-FGR (N = 36) |
P-Value* | |
| BPD′ | 0.28 ± 0.08 | 0.27 ± 0.01 | 0.769 | 0.27 ± 0.01 | 0.27 ± 0.01 | 0.226 | 0.27 ± 0.01 | 0.27 ± 0.01 | 0.944 |
| TCD′ | 0.12 ± 0.03 | 0.11 ± 0.01 | 0.552 | 0.12 ± 0.01 | 0.11 ± 0.01 | 0.447 | 0.12 ± 0.02 | 0.12 ± 0.02 | 0.473 |
| SF′ | 0.04 ± 0.02 | 0.04 ± 0.02 | 0.583 | 0.04 ± 0.01 | 0.04 ± 0.01 | 0.070 | 0.05 ± 0.01 | 0.04 ± 0.01 | 0.062 |
| IL′ | 0.09 ± 0.01 | 0.09 ± 0.03 | 0.790 | 0.09 ± 0.01 | 0.09 ± 0.01 | 0.720 | 0.09 ± 0.01 | 0.09 ± 0.01 | 0.803 |
| FAPD′ | 0.18 ± 0.02 | 0.17 ± 0.07 | 0.640 | 0.17 ± 0.02 | 0.17 ± 0.01 | 0.512 | 0.18 ± 0.01 | 0.17 ± 0.04 | 0.212 |
| CSPL′ | 0.03 ± 0.01 | 0.03 ± 0.01 | 0.879 | 0.03 ± 0.01 | 0.03 ± 0.001 | 0.007 | 0.04 ± 0.01 | 0.03 ± 0.01 | <0.001 |
| CSPW′ | 0.03 ± 0.01 | 0.03 ± 0.01 | 0.302 | 0.03 ± 0.002 | 0.03 ± 0.003 | 0.210 | 0.03 ± 0.01 | 0.03 ± 0.01 | <0.001 |
| OFD′ | 0.36 ± 0.02 | 0.35 ± 0.07 | 0.981 | 0.35 ± 0.01 | 0.34 ± 0.03 | 0.657 | 0.35 ± 0.01 | 0.32 ± 0.09 | 0.031 |
Notes: Data presented as Mean ± SD. P-value* adjusted for neonatal male gender.
Abbreviations: AGA, appropriate gestational age; BPD′, normalized biparietal diameter; CSPL′, normalized cavum septi pellucidi length; CSPW′, normalized cavum septi pellucidi width; EO-FGR, early-onset fetal growth restriction; FAPD′, normalized frontal antero-posterior diameter; IL′, normalized insular depth; OFD′, normalized occipitofrontal diameter; SF′, normalized Sylvian fissure; TCD′, normalized transverse cerebellar diameter.
Table 4.
Intra- and Inter-Rater Reliability for Measuring Brain Parameters
| Brain Parameters | Intra-Rater Reliability (95% Confidence Interval) |
Inter-Rater Reliability 95% Confidence Interval) |
|---|---|---|
| BPD | 0.96 (0.95, 0.99) | 0.91 (0.79, 0.98) |
| HC | 0.92 (0.69, 0.97) | 0.91 (0.86, 0.99) |
| TCD | 0.99 (0.99, 1.00) | 0.98 (0.98, 0.99) |
| SF | 0.90 (0.72, 0.97) | 0.82 (0.65, 0.91) |
| IL | 0.96 (0.93, 0.99) | 0.89 (0.56, 0.97) |
| FAPD | 0.94 (0.88, 0.99) | 0.90 (0.78, 0.99) |
| CSPL | 0.95 (0.87, 0.98) | 0.91 (0.64, 0.97) |
| CSPW | 0.98 (0.94, 0.99) | 0.96 (0.84, 0.99) |
| OFD | 0.93 (0.92, 0.99) | 0.91 (0.78, 0.97) |
Abbreviations: BPD, biparietal diameter; CSPL, cavum septi pellucidi length; CSPW, cavum septi pellucidi width; FAPD, frontal antero-posterior diameter; HC, head circumference; IL, insular depth; TCD, transverse cerebellar diameter; OFD, occipitofrontal diameter; SF, Sylvian fissure.
Discussion
The study demonstrates that early-onset mild-to-moderate FGR may be associated with altered prenatal brain growth, particularly the cavum septi pellucidi and the occipitofrontal diameter. Notable morphological differences emerged during the early third trimester (30–32 weeks’ gestation) and profound distinctions in the late third trimester (34–36 weeks’ gestation). However, no differences in BPD, TCD, SF, IL, or FAPD were observed between the two groups. These findings suggest that three-dimensional (3D) ultrasound with tomographic ultrasound imaging (TUI) may be a feasible tool for longitudinal assessment of selected fetal brain structures in EO-FGR. Although these results are encouraging, validation across larger, multi-center cohorts is necessary before these findings can be generalized.
This study also shows that the normalized CSP and OFD are smaller in EO-FGR than in AGA fetuses. This may be due to FGR-related delays in cerebral maturation prenatally, likely stemming from hemodynamic adaptations to chronic hypoxia, acidemia, and malnutrition.11,18–20 This indicates that development in an adverse prenatal environment affects the FGR-impaired cortical folding.21 Consequently, neonates affected by growth restriction exhibit diminished maturity in the attention-interaction subsystem, as well as in motor and cognitive outcomes and academic achievement at school age.5,22
While previous automated 3D ultrasound studies of FGR have primarily evaluated cortical maturation using whole-brain gyrification and surface fissures.12 Our study demonstrates that structural delays in EO-FGR were initially region-specific. Specifically, we identified distinct growth alterations in deep axial parameters (CSP and OFD), whereas conventional biometry (BPD, TCD) and the sulci (SF, IL) remained comparable to controls.
A normal, properly sized CSP suggests normal midline brain development.23 In this study, a smaller normalized CSP in EO-FGR may represent a potential early marker of altered brain growth. Its detection should prompt a review of fetal brain growth trajectories. The observed structural differences in CSP and OFD may have potential implications for the antenatal assessment of EO-FGR. Quantitative evaluation of these parameters could provide additional imaging information to identify fetuses at risk of subclinical central nervous system compromise. However, a small CSP should not be regarded as an established diagnostic marker of impaired neurodevelopment or used alone for clinical risk stratification, decisions regarding antenatal corticosteroid administration, or timing of delivery. Further studies are needed to establish HC-adjusted normative values for CSP and OFD, assess reproducibility across operators and ultrasound systems, and evaluate associations with neonatal and long-term neurodevelopmental outcomes.
This study shows a good-to-excellent agreement when using 3D TUI to evaluate the fetal brain. High inter- and intra-rater reliability supported the internal consistency of these findings. Future validation across larger, expanded multicenter cohorts will help establish their broader generalizability.
Strengths and Limitations
This prospective longitudinal study maintained high adherence to participant protocols. All neurosonographic evaluations were performed by two sonographers using a standardized protocol consistent with ISUOG recommendations.2 However, there were several limitations. TUI diagnostic accuracy depends heavily on the quality of 3D volume acquisition and the quantity of amniotic fluid. Suboptimal image resolution may reduce its clinical utility. In addition, fetal movement during volume acquisition can compromise image quality and impair visualization. Accurate slice selection and image interpretation also require adequate operator training and the expertise of experienced professionals. Since most instances of FGR in this cohort were mild to moderate, these findings may not fully reflect brain growth in cases of severe FGR. Consequently, the brain trajectories in severe FGR warrant further prospective, larger-scale studies, and the assessment of long-term postnatal neurodevelopmental outcomes will be essential to fully establish their prognostic utility.
Conclusions
The cavum septi pellucidi and occipitofrontal diameter may serve as early structural indicators of brain growth trajectory in EO-FGR. However, larger cohort studies are needed to validate these findings and correlate them with post-natal imaging and long-term outcomes.
Acknowledgments
We gratefully acknowledge the nurses at the ANC clinic, the Srinagarind Hospital, and Khon Kaen Hospital for their valuable assistance and logistical support throughout the study.
Funding Statement
The authors have received no specific funding for this study.
Data Sharing Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations, Ethics Approval, and Consent to Participate
The study was conducted in accordance with the Declaration of Helsinki. This study was approved by two ethics committees: Khon Kaen University (HE671530) and Khon Kaen Hospital (KEF68028). This trial was registered at the Thai Clinical Trials Registry with the number TCTR20260213003. https://www.thaiclinicaltrials.org/show/TCTR20260213003. The study adhered to the STROBE guidelines.24
Author Contributions
SN, CD conceptualization; SN and CD data curation; SN and CD data analysis; SN, CD, RK, and JK writing– original draft; CD writing– review and editing. All authors read and approved the final manuscript. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare no competing interests.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.