Abstract
Objectives
To evaluate the value of the thickness of the frontal lobe (TFL) and foramen magnum‐to‐cranium distance (FCD) for predicting poor neurodevelopmental outcomes in fetuses with a small head circumference (HC).
Methods
This retrospective observational study included 39 fetuses with HC < −2 standard deviations (SD) and 592 prospectively collected controls with normal growth. TFL was defined as the shortest distance between the upper outer border of the corpus callosum and the upper inner cranial border parallel to the FCD. Reference ranges for FCD and TFL were established in 592 healthy fetuses between 21 and 38 weeks of gestation and applied to fetuses with suspected microcephaly. Diagnostic performance was assessed using sensitivity, specificity, and SD‐based thresholds.
Results
Normal reference ranges for FCD and TFL across gestation were established. All fetuses with normal postnatal outcomes had TFL values within the normal range, whereas reduced TFL was observed only in fetuses with poor neurodevelopmental outcomes. For predicting adverse outcomes, TFL <−2 SD showed a specificity of 100%, compared with 88% for FCD <−2 SD. Combining HC <−2 SD with TFL <−2 SD improved identification of fetuses with poor outcomes, including cases with borderline HC measurements (−2 to −3 SD).
Conclusions
When combined with HC, reduced TFL may serve as a highly specific prenatal marker for identifying fetuses at risk for adverse neurodevelopmental outcomes in suspected microcephaly.
Keywords: fetal microcephaly, head circumference, neurosonography, prenatal diagnosis
Abbreviations
- ASQ‐3
Ages and Stages Questionnaires, Third Edition
- FCD
foramen magnum‐to‐cranium distance
- GA
gestational age
- HC
head circumference
- ICC
intraclass correlation coefficient
- MCD
malformation of cortical development
- MRI
magnetic resonance imaging
- NSG
neurosonography
- SD
standard deviation
- TFL
thickness of the frontal lobe
- WES
whole‐exome sequencing
Prenatal evaluation of fetal microcephaly primarily relies on ultrasonographic measurement of head circumference (HC). 1 Microcephaly reflects impaired brain development and may be associated with structural abnormalities and long‐term neurodevelopmental impairment. 2 , 3 , 4 , 5 It is commonly defined as an HC below −3 standard deviations (SD) from the mean for gestational age (GA) and sex, with a reported incidence of 1.5–7.4 per 10,000 births. 5
Importantly, prenatal microcephaly represents a clinical finding rather than a definitive diagnosis. 6 , 7 Neurodevelopmental outcomes vary widely according to the degree of HC reduction, with reported risks of intellectual disability ranging from approximately 10% for HC between −2 and −3 SD to nearly 100% for HC below −4 SD. 6 Reliance on a single HC threshold may therefore lead to both false‐positive diagnoses and failure to identify fetuses with borderline HC measurements (−2 to −3 SD) who subsequently develop neurodevelopmental impairment.
Early prenatal identification of fetuses at risk for poor outcomes is essential for appropriate counseling and pregnancy management. However, the positive predictive value of HC‐based criteria for postnatal microcephaly remains limited, reported at approximately 25–57%. 8 To improve diagnostic accuracy, vertical intracranial measurements such as the foramen magnum‐to‐cranium distance (FCD) have been introduced. Combining HC with FCD has been shown to reduce false‐positive diagnoses related to cranial shape deformation and improve predictive performance. 9 Nevertheless, FCD alone may not fully capture abnormalities in anterior brain development.
Given the critical role of the frontal lobe in neurodevelopment and its vulnerability in microcephaly, assessment of a more anterior intracranial parameter may further enhance prenatal risk stratification. Children with microcephaly may experience severe frontal lobe dysplasia, 10 suggesting that frontal lobe involvement may precede global cranial size reduction. We therefore hypothesized that measuring frontal lobe thickness (TFL) in the mid‐sagittal plane could improve prediction of adverse neurodevelopmental outcomes, particularly in fetuses with borderline HC measurements. Accordingly, this study aimed to evaluate the value of TFL, in combination with HC and FCD, for identifying fetuses at risk for poor outcomes in suspected microcephaly.
Materials and Methods
This retrospective case–control study included fetuses with suspected microcephaly and prospectively collected normal controls. Controls were recruited prospectively by convenience sampling from low‐risk pregnancies, while all fetuses with HC <−2 SD identified between June 2018 and October 2023 were retrospectively reviewed.
Establishment of Normal Reference Ranges
The normal growth of the fetal brain and frontal lobe in the mid‐sagittal plane was assessed for 592 singleton pregnancies with low obstetric risk that were evaluated by routine fetal ultrasound scanning in the second and third trimesters between July 2021 and June 2024 at our hospital. Inclusion criteria were confirmed GA in first‐trimester ultrasound, normal fetal anatomy and growth on second‐ and third‐trimester ultrasound scans, and fetal HC within the normal range according to National Institute of Child Health and Human Development for Asians reference values. 11
Inclusion and Exclusion Criteria
Fetuses whose HC was measured as <–2 SD at our hospital between June 2018 and October 2023 were retrospectively selected. The microcephaly workup protocol was initiated when the HC was 2 SD below the mean for the GA. 12 The inclusion criteria for these cases were HC <–2 SD of the mean for GA according to NICHD reference values for Asians 11 ; singleton pregnancy with GA confirmed in first‐trimester ultrasound; and available medical and imaging records. The initial screening, exclusion criteria, and final inclusion process are summarized in Figure 1. Cases that were lost to prenatal or postnatal follow‐up and those without complete medical records or appropriate images for FCD and TFL measurements were excluded. Clinical information, including genetic abnormalities identified by karyotyping, chromosomal microarray, or whole‐exome sequencing (WES), virology test results, and development after birth, was collected from all patients.
Figure 1.
Subject enrollment flowchart. Flowchart illustrating the inclusion and exclusion of fetuses with suspected microcephaly. All cases with a head circumference (HC) below −2 SD were reviewed. A total of 102 fetuses were initially identified; 63 were excluded due to loss to follow‐up (n = 21), incomplete imaging studies (n = 35), or pregnancy termination with incomplete medical records (n = 7), resulting in 39 cases included in the final analysis.
Classification of the Included Cases
The included cases were divided into 2 groups based on the combined malformations, genetic results, and development after birth: Group 1, normal development after birth, and Group 2, confirmed adverse neurodevelopmental outcome. The fetuses in Group 1 met all of the following criteria: no other intracranial and extracranial malformations detected by neurosonography (NSG) or magnetic resonance imaging (MRI); no family history of microcephaly; and normal neurodevelopment observed at the time of follow‐up (ranging from 6 months to 4 years of age), with Ages and Stages Questionnaires scores within the normal range. 13 The fetuses in Group 2 met at least one of the following criteria: presence of intracranial malformations associated with a poor prognosis, detection of genetic variants of pathogenetic or likely pathogenic significance that may be associated with neurodevelopmental disorders, postnatal or infant death.
Ultrasound Diagnostic Procedures
All ultrasound examinations were performed using a Voluson E10 ultrasound system (General Electric Healthcare Ultrasound, Milwaukee, WI, USA). Transabdominal and transvaginal ultrasonography were performed using 3–5‐, 4–6‐, and 5–9‐MHz probes, with transvaginal NSG being preferred. The mid‐sagittal plane was obtained through the anterior fontanelle or sagittal suture in every fetus. Two parameters were measured in the mid‐sagittal plane, as explained below:
Novel Intracranial Biometric Measurements
The FCD was measured as the distance between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem, as defined by Leibovitz et al 9 (Figure 2).
Figure 2.
Measurement of brain parameters on prenatal ultrasound. A, 1D measurement of the FCD was measured in the mid‐sagittal plane as the distance from the level of the foramen magnum to the inner upper border of the cranium along the posterior margins of the brainstem. B, 2D measurement of the TFL, the shortest distance between the upper outer border of the corpus callosum and the upper inner cranial border parallel to the FCD on the same plane (displaying a 36‐week fetus). FCD, the foramen magnum‐to‐cranium distance; TFL, the thickness of the frontal lobe.
The TFL was measured in the median sagittal section as the shortest distance between the upper outer border of the corpus callosum and the upper inner cranial border parallel to the FCD. This parameter was assumed to represent frontal lobe development in the vertical sagittal section (Figure 2).
To evaluate the repeatability and reproducibility of the measurements, 2 clinicians obtained each numerical measurement (clinician A measured twice and clinician B measured once), and the average value was calculated. One mid‐sagittal plane was stored for each case, and each measurement was performed independently.
Follow‐Up Protocol
All infants were followed up postnatally to evaluate neurodevelopmental outcomes. The follow‐up duration ranged from 6 months to 4 years, depending on the family's compliance and the availability of clinical records. Neurodevelopmental assessment was performed using the Ages and Stages Questionnaires, Third Edition (ASQ‐3) at the time of follow‐up. The ASQ‐3 was completed by parents and reviewed by pediatric neurologists to determine whether the child's developmental milestones were within the normal range for age.
Postnatal neuroimaging (cranial ultrasound or MRI) was not performed routinely for all infants but was conducted when clinically indicated—such as in cases with abnormal prenatal findings, developmental delay, or neurological symptoms. Follow‐up information was collected through medical record reviews and telephone interviews.
Statistical Methods
We established optimal FCD and TFL cutoff values to identify suspected cases with poor outcomes while minimizing false‐positive results by excluding fetuses with normal postnatal neurodevelopment. For this purpose, the sensitivity and specificity were calculated for a range of SD thresholds, and the cutoff values with the best balance between sensitivity and specificity were selected.
The repeatability and reproducibility of FCD and TFL measurements were evaluated using the intraclass correlation coefficient (ICC). Data normality was assessed using the Shapiro–Wilk test. Quadratic regression analyses were performed to establish growth equations for FCD and TFL across GAs, and the model fit was evaluated using the coefficient of determination (R 2). The ICC (2,1) was calculated to assess intra‐ and interobserver reliability.
Sensitivity and specificity were calculated to assess the diagnostic performance. Statistical analyses were performed using IBM SPSS Statistics software (version 25.0; IBM Corporation, Armonk, NY, USA), and p‐values <.05 were considered statistically significant.
Ethics Statement
The study protocol was approved by the Institutional Review Board of Peking University First Hospital (approval number: 2021‐083). For the prospectively recruited control participants, written informed consent was obtained. For the retrospective case cohort, the ethics committee waived the requirement for written informed consent due to the minimal‐risk nature of the study; however, verbal consent was obtained from available parents/guardians after explaining the study procedures.
Results
Baseline Characteristics
Healthy Fetuses
Baseline maternal and pregnancy characteristics of both the control cohort (n = 592) and the case cohort (n = 39) are summarized in Table 1. The control cohort consisted of 592 low‐risk singleton pregnancies and was used to establish normal reference ranges for vertical cranial biometry between 21 and 38 weeks of gestation. The mean maternal age was 32.6 ± 4.1 years (range: 20–46 years). Other maternal and fetal characteristics, including GA at examination, parity, and fetal sex, are presented in Table 1. Data were normally distributed, allowing for parametric analysis.
Table 1.
Baseline Maternal and Pregnancy Characteristics of the Study Cohort
| Characteristic | Controls (n = 592) | Cases (n = 39) |
|---|---|---|
| Maternal age (years), mean ± SD (range) | 32.6 ± 4.1 (20–46) | 31.72 ± 3.4 (26–39) |
| Parity, n (%) | ||
| Nulliparous | 350 (59.1%) | 36 (92.3%) |
| Multiparous | 242 (40.9%) | 3 (7.7%) |
| Gestational age at examination (weeks), mean ± SD (range) | 29.3 ± 4.96 (21–38) | 33.3 ± 4.96 (26–38) |
| Fetal sex, n (%) |
Male: 306 (51.6%) Female: 286 (48.4%) |
Male: 26 (66.6%) Female: 13 (33.4%) |
Data are presented as the mean ± standard deviation (SD) with range in parentheses or as number (percentage).
Fetuses with Suspected Microcephaly
Of the 102 fetuses initially identified, 63 were excluded due to loss to follow‐up (n = 21), incomplete imaging (n = 35), or termination of pregnancy without complete medical records (n = 7), resulting in 39 cases for the final analysis (Figure 1). All underwent detailed ultrasound examinations to evaluate the overall development of the body and NSG to evaluate the intracranial development. Virologic screening results were negative in all cases. Based on neurodevelopmental outcomes and genetic findings, the cohort was divided into 2 groups (Table 2): Group 1 (normal outcome, n = 25) and Group 2 (poor outcome, n = 14). The maternal and fetal characteristics are summarized in Table 3.
Table 2.
Fetal Head Circumference (HC) and Neurodevelopmental Outcomes
| Group | HC Range (n) | GA at Diagnosis a (weeks) | Associated Abnormalities | Outcome |
|---|---|---|---|---|
| 1 | −2 to −3 SD (24) | 31.4 ± 4.0 | None | Normal |
| <−3 SD (1) | None | Normal | ||
| 2 | −2 to −3 SD (4) | 33.9 ± 2.7 b |
MCD: 2 None: 2 |
|
| <−3 SD (10) |
MCD: 9 None: 1 |
|
GA, gestational age; MCD, malformations of cortical development; TOP, termination of pregnancy; MMA, methylmalonic acidemia; CdLS, Cornelia de Lange syndrome; MIC, microcephaly.
Data are presented as the mean ± SD.
Significantly different from Group 1 (p = .013).
Table 3.
Etiological Analysis of Group 2 Fetuses
| Etiological Category | n | Genetic Testing | Outcome | Remarks |
|---|---|---|---|---|
| Malformation of cortical development (MCD) | 11 |
|
|
Primary etiology (78.6%) |
| Isolated microcephaly + family history | 1 | Not tested | Diagnosed at 1 year | Affected sibling; no pathogenetic or likely pathogenetic variants identified |
| Isolated microcephaly + syndromic microcephaly | 1 | Cornelia de Lange syndrome (WES) | Cornelia de Lange syndrome | Postnatal diagnosis |
| Isolated microcephaly + metabolic disorder | 1 | Methylmalonic acidemia (WES) | Methylmalonic acidemia | Postnatal diagnosis |
Microcephaly diagnosis criteria: HC <–2 SD below mean for gestational age; Cases with normal WES showed no clinically significant variants.
WES, whole exome sequencing; TOP, termination of pregnancy; VUS, variant of uncertain significance.
Associations Between Cranial Measurements and Gestational Age in Healthy Fetuses
Both the FCD and TFL were strongly correlated with GA, with Pearson correlation coefficients of 0.920 and 0.900, respectively (p < .01 for both; Figure 3).
Figure 3.
Relationships between gestational age and fetal head measurements. A, Relationship between gestational age (GW) and head circumference (HC). B, Relationship between gestational age and frontal cortical distance (FCD). C, Relationship between gestational age and temporal frontal length (TFL). Scatter plots show the distribution of normal fetuses (gray dots) and abnormal cases (orange for Group 1 and red for Group 2). Solid lines represent quadratic regression curves with the corresponding coefficients of determination (R 2), and dotted lines indicate the 99% confidence intervals. GW, gestational week; HC, head circumference; FCD, foramen magnum‐to‐cranium distance; TFL, thickness of the frontal lobe.
The TFL showed a strong positive correlation with FCD (r = 0.859, p < .01; Figure 4). Linear regression analysis confirmed this relationship, described by the equation Y = 0.3899X − 5.911 (R 2 = 0.810), indicating that FCD strongly predicts TFL.
Figure 4.
Correlation between the FCD and TFL. Scatter plot showing a significant linear correlation between FCD and TFL in fetuses. Each dot represents 1 fetus. The regression line and corresponding equation (Y = 0.3899 × X – 5.911; R 2 = 0.810) are shown, indicating a strong positive association between the 2 parameters. FCD, the foramen magnum‐to‐cranium distance; TFL, the thickness of the frontal lobe.
The FCD/HC ratio was relatively stable (Figure S1, range: 0.21–0.29) and consistent with that in a previous report, 9 confirming the reliability of our data, and the TFL/HC ratio ranged from 0.05 to 0.10. Second‐order polynomial regression analyses revealed the following curvilinear relationships: FCD = −174.2 + 2.04 × GA − 0.2298 × GA2 (R 2 = 0.96) and TFL = −35.2 + 5.14 × GA − 0.0532 × GA2 (R 2 = 0.82). The FCD/TFL ratio showed a mild negative correlation with GA (R 2 = 0.27), described by Y = −0.038 × GA + 4.47, indicating a gradual acceleration of frontal lobe growth relative to that of the posterior structures during gestation (Figure 5).
Figure 5.
Relationship between gestational age and the ratio of the FCD and TFL (FCD/TFL). Scatter plot demonstrating a weak but significant negative linear correlation between gestational age (weeks) and the FCD/TFL ratio. The regression equation (Y = −0.03817 × X + 4.468; p < .0001; R 2 = 0.27) indicates a gradual decrease in the FCD/TFL ratio with advancing gestational age. FCD, the foramen magnum‐to‐cranium distance; TFL, the thickness of the frontal lobe.
The ICCs for FCD measurements were 0.901 (95% confidence interval [CI]: 0.885–0.915, p < .001) for intraobserver variability and 0.868 (95% CI: 0.847–0.887, p < .001) for interobserver variability. The ICCs for TFL measurements were 0.953 (95% CI: 0.945–0.960, p < .001) for intraobserver variability and 0.941 (95% CI: 0.931–0.949, p < .001) for interobserver variability (Table 4), indicating good repeatability and reproducibility. The average of 3 measurements was used for subsequent analyses to ensure accuracy.
Table 4.
Intra‐ and Interobserver Reliability Analysis of FCD and TFL Measurements
| Parameter | Intraobserver Variability | Interobserver Variability | ||
|---|---|---|---|---|
| ICC (95% CI) | p | ICC (95% CI) | p | |
| FCD | 0.901 (0.885–0.915) | <.001 | 0.868 (0.847–0.887) | <.001 |
| TFL | 0.953 (0.945–0.960) | <.001 | 0.941 (0.931–0.949) | <.001 |
ICC reliability thresholds: >0.90 excellent, 0.75–0.90 good, <0.75 moderate/poor.
CI, confidence interval; FCD, Foramen magnum‐to‐cranium distance; TFL, frontal lobe thickness.
Case Group Classification and Diagnostic Performance
Distribution of FCD and TFL Values in the Case Groups
We calculated ±1, ±2, and ±3 SD from the mean FCD and TFL values at different weeks. Reference ranges for the 2 parameters were applied to the 2 case groups. Both FCD and TFL values followed normal distributions (Shapiro–Wilk test, p > .05). Reference ranges derived from the control population were applied to the case cohort.
In Group 1, all fetuses showed TFL values within the normal range (>−2 SD), whereas 3/25 (12%) had a FCD <−2 SD. In Group 2, 5 fetuses (36%) had TFL <−2 SD, similar to FCD. Eleven of the 14 (78.6%) fetuses in Group 2 had combined malformation of cortical development (MCD), while 3 (21.4%) showed isolated microcephaly with no combined malformations on imaging (Table 5). One fetus with HC of −2.21 SD was diagnosed with microcephaly at 1 year of age. This case had a family history without pathogenic genetic variants. WES confirmed methylmalonic acidemia in an infant with HC of −2.41 SD at 36 weeks of gestation and Cornelia de Lange Syndrome in an infant with HC of −3.14 SD at 33 weeks of gestation after birth.
Table 5.
Case Information in Group 2 with Malformation of Cortical Development (MCD)
| Case | GA | HC (mm) | SD | Imaging Diagnosis | Gene Mutation | Outcome | Variant Type |
|---|---|---|---|---|---|---|---|
| 1 | 26 | 213.4 | –3 | MCD | SHMT2 | Termination | VUS |
| 2 | 28 | 218.3 | −5 | MCD | LMNB1 | Termination | VUS |
| 3 | 28 | 228.2 | −4 | MCD | — | Termination | — |
| 4 | 28 | 218.5 | −5 | MCD | ASPM | Termination | P |
| 5 | 28 | 213.3 | −5 | MCD | RNU4ATAC | Termination | P |
| 6 | 29 | 220.1 | −6 | MCD | MCPH1 | Termination | LP |
| 7 | 29 | 194.2 | −9 | MCD | — | Termination | — |
| 8 | 30 | 257.7 | −2 | MCD | — | Termination | — |
| 9 | 32 | 253.7 | −5 | MCD | — | Termination | — |
| 10 | 36 | 288.7 | −2 | MCD | — | Termination | — |
| 11 | 38 | 283.3 | −3 | MCD |
Chr5:24261‐29782846, seq[GRCH37]del(5) (p15.33p13.3) |
Died | LP |
GA, gestational age; HC, head circumference; SD, standard deviations; MCD, malformation of cortical development; P, pathogenic; LP, likely pathogenic; VUS, variants of uncertain significance.
Diagnostic Performance
The diagnostic performance of the 2 parameters for predicting poor neurodevelopmental outcome is summarized in Table 6. For FCD <−2 SD, sensitivity and specificity were 35.7 and 88.0%, respectively. For TFL <−2 SD, sensitivity and specificity were 35.7 and 100%, respectively. Combining HC <−2 SD with TFL <−2 SD improved specificity to 100% and identified 2 fetuses with HC between −2 and −3 SD who had adverse neurodevelopmental outcomes after birth.
Table 6.
Diagnostic Performance of FCD and TFL at Different Standard Deviation Thresholds
| Diagnosis | Number of Cases | Sensitivity (%) | Specificity (%) |
|---|---|---|---|
| HC <–3 SD | Group 1 (n = 1) | 71.4 | 96.0 |
| Group 2 (n = 10) | |||
| FCD <–1 SD | Group 1 (n = 6) | 78.6 | 76.0 |
| Group 2 (n = 11) | |||
| FCD <–2 SD | Group 1 (n = 3) | 35.7 | 88.0 |
| Group 2 (n = 5) | |||
| FCD <–3 SD | Group 1 (n = 2) | 7.1 | 92.0 |
| Group 2 (n = 1) | |||
| TFL <–1 SD | Group 1 (n = 8) | 57.1 | 68.0 |
| Group 2 (n = 8) | |||
| TFL <–2 SD | Group 1 (n = 0) | 35.7 | 100.0 |
| Group 2 (n = 5) | |||
| TFL <–3 SD | Group 1 (n = 0) | 14.3 | 100.0 |
| Group 2 (n = 2) |
FCD, measurement of foramen magnum‐to‐cranium distance; TFL, frontal lobe thickness; SD, standard deviations.
Summary of Regression and Measurement Reproducibility
Regression equations and derived reference ranges for both parameters are shown in Figure 3, enabling external validation. The linear relationship between FCD and TFL (r = 0.859, p < .01) confirmed the parallel growth of the posterior and anterior brain structures, whereas the decreasing FCD/TFL ratio with advancing gestation suggested relatively accelerated frontal lobe maturation. These findings support the use of TFL as an early indicator of frontal lobe developmental disturbance in fetuses at risk for microcephaly.
Discussion
In this study, we established normative reference ranges for 2 vertical intracranial parameters—FCD and TFL—in a large cohort of healthy fetuses and evaluated their diagnostic value for predicting poor neurodevelopmental outcomes in suspected microcephaly. Our main finding is that TFL <−2 SD, when combined with HC <−2 SD, achieved 100% specificity and identified additional fetuses with adverse outcomes whose HC ranged between −2 and −3 SD. This suggests that measuring the frontal lobe in the mid‐sagittal plane can complement conventional HC assessment, thereby improving risk stratification in the prenatal evaluation of fetal microcephaly.
Prenatal diagnosis of microcephaly remains challenging because HC represents only a single horizontal dimension of a 3‐dimensional cranial structure and demonstrates limited predictive accuracy for postnatal outcomes. Previous studies have shown that incorporating vertical intracranial parameters, such as the FCD, can improve diagnostic performance by accounting for variations in cranial shape. 9 However, FCD primarily reflects posterior cranial development and may not sufficiently capture abnormalities in anterior brain regions.
Microcephaly encompasses a heterogeneous group of disorders characterized by impaired neuronal proliferation and migration, frequently resulting in reduced cerebral cortex volume and frontal lobe dysplasia. 14 , 15 , 16 Severe microcephaly has been associated with a small frontal fossa, flattening of the frontal bone, and preferential involvement of the frontal lobes. 10 , 17 Pilu et al previously suggested that frontal lobe assessment and recognition of a sloping forehead may aid in the prenatal identification of microcephaly. 18 , 19 These observations provide the biological and imaging rationale for evaluating frontal lobe development as part of prenatal assessment.
Alternative approaches, such as measuring the distance between the posterior margin of the cavum septum pellucidum and the inner calvarium in the transthalamic axial plane, have also been proposed. 20 However, the thinnest portion of the frontal lobe is not consistently visualized in the axial plane. In contrast, the mid‐sagittal plane allows visualization of the entire frontal lobe, enabling measurement of its minimal thickness and potentially providing a more accurate representation of frontal lobe involvement.
Goldstein et al demonstrated that frontal lobe growth correlates closely with GA and biparietal diameter in normal fetuses. 18 Consistent with these findings, we observed strong correlations between TFL, FCD, and GA in healthy fetuses, supporting coordinated anterior–posterior brain growth. The association between reduced TFL and adverse neurodevelopmental outcomes suggests that frontal lobe growth restriction may precede global cranial size reduction in certain cases, particularly among fetuses with borderline HC measurements.
Clinical Implications
Our findings highlight TFL as a simple, reproducible parameter that can be obtained in the same mid‐sagittal plane used for routine fetal NSG. Incorporation of TFL may improve prenatal risk stratification, particularly in fetuses with isolated or borderline microcephaly (HC −2 to −3 SD), where prognostic uncertainty is greatest. Combining TFL with HC may assist clinicians in differentiating fetuses at risk for adverse neurodevelopmental outcomes from those with isolated small head size and normal postnatal development.
Strengths and Limitations
The strengths of this study include the establishment of normative reference ranges across a wide GA range, the use of a standardized imaging protocol, and high inter‐ and intraobserver reliability. We specifically focused on isolated microcephaly and the diagnostically challenging subgroup with HC between −2 and −3 SD.
Limitations include the retrospective design, the relatively small number of poor‐outcome cases, and heterogeneous follow‐up durations, which may underestimate late‐onset developmental abnormalities. In addition, genetic testing was not uniformly available, and the heterogeneity of underlying etiologies limits broad generalization of diagnostic thresholds. Prospective multicenter studies with standardized neurodevelopmental follow‐up and genetic correlation are therefore warranted.
Conclusions
Measurement of TFL and FCD in the mid‐sagittal plane provides reliable vertical intracranial parameters during routine prenatal ultrasonography. A TFL below −2 SD, particularly when combined with an HC below −2 SD, demonstrates excellent specificity for predicting adverse neurodevelopmental outcomes and identifies high‐risk fetuses within the borderline HC range. Incorporation of TFL into prenatal NSG may improve risk assessment and counseling in suspected fetal microcephaly.
Supporting information
Figure S1. FCD/HC was relatively stable.
The authors are especially grateful to the Peking University First Hospital who helped with data acquisition for this study. This study was supported by Capital's Funds for Health Improvement and Research (CFH 2020‐2‐4074) and the National Nature Science Foundation of China (82371965). All authors have stated that they have no conflicts of interest.
Data Availability Statement
Research data are not shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. FCD/HC was relatively stable.
Data Availability Statement
Research data are not shared.