Objective
The objective of the study was to evaluate the magnitude of normal fetal brain asymmetry.
Study Design
This was a prospective study. Normal fetuses between 19–28 weeks of gestation were studied. The cerebral atria, occipital cortex, and hemispheres in both sides were measured. The difference between each side was evaluated and was correlated with sex, head biometry, and estimated weight.
Results
Four hundred six fetuses were studied. Mean atrial width was larger in the males and on the left side (5.2% and 6.5%, respectively). Mean cortical width was 2.6% larger in males but 5.5% thinner on the left side. Mean hemisphere width was larger in males and on the left side (2.3% and 1.5%, respectively). The atria and the cortex presented an inverse relationship regarding fetal growth parameters.
Conclusion
Brain asymmetry represents normal fetal brain developmental phenomena. It is sex dependent and lateralized in most cases to the left. Lateralization was more accentuated in males.
Asymmetry of the human brain is a normal developmental phenomenon. It is a continuing biologic process that begins in fetal life, maturing and changing during neonatal and adult life. This asymmetry is the result of 2 biologic processes: lateral asymmetry and sexual dimorphism. Both have been shown to have a genetic and endocrinologic basis. The end result of this process is an anatomic and volumetric asymmetry, reflected in a functional difference between specific areas inside the 2 cerebral hemispheres, as well as behavioral differences between males and females.
The size and the shape of the lateral ventricles depend on the brain tissue development. Abnormal brain development will be associated in most of the cases with abnormal uni- or bilateral ventricular dilatation. In fact, fetal cerebral ventricle measurement is the most sensitive and most frequently used sonographic tool for the evaluation of brain development. Usually, only the distal cerebral atria width is measured during routine fetal anatomic examination, and data concerning its normal range of asymmetry are therefore limited.
Asymmetrical involvement of the normal fetal lateral cerebral ventricles in a low-risk population has been described, but it was limited to only cases in which the atrial width asymmetry was superior to 2.4 mm or 2 SD above the mean. Only 1 prenatal study has examined the normal asymmetry of the fetal cerebral hemispheres. Cerebral cortex thickness measurement was proposed as a diagnostic tool of fetal abnormalities by pathologic postmortem studies, but, to the best of our knowledge, no data exist regarding the normal values and asymmetry magnitude of the cerebral cortex width in normal fetuses during normal pregnancies.
The objective of this study was to evaluate the magnitude of cerebral atria, hemispheres, and cortex asymmetry in normal fetuses, in order to collect data that might serve as reference values while counseling couples with such findings observed during routine sonographic screening.
Materials and Methods
A cross-sectional, prospective study was carried out during routine second-trimester anatomic sonographic survey, between 19–28 weeks of gestation. This interval period was selected for 2 reasons: first, technical limitation to evaluate the proximal atria, cortex, and inner margin of the hemispheres, beyond this range, because of the common appearance of acoustic reverberations, and, second, it represents the most important period of fetal anatomic evaluation. The study group consisted of only low-risk pregnant woman, with normal pregnancy follow-up and perinatal outcome.
All measurements were done using the standard planes of fetal brain evaluation. The atrial ventricular width was measured on both sides in the same paraxial plane, perpendicular to the ventricle axis, at the level of the posterior edge of the choroid plexus and between its inner margins, as described in the literature ( Figure 1 , A and B). The occipital cortical gray and white matter were measured on the medial side of the hemisphere, at the same plane of the atrial measurement and in its widest diameter, as shown in Figure 2 , A and B.
The 2 hemispheres were measured at the biparietal diameter (BPD) plane, each between their inner margins, which included the third ventricle, and the inner margin of the cranial bone, as shown in Figure 3 . Fetal sex, head circumference (HC), BPD, estimated fetal weight (EFW), and estimated fetal weight percentile (EFWP) according to the built-in Hadlock 4 formula were recorded and statistically evaluated in relation to the aforementioned brains’ parameters.
Exclusion criteria included all fetuses with any abnormal sonographic findings, including soft markers for aneuploidy in which normal karyotype was not ascertained, pregnancies complicated by maternal diseases that could affect fetal growth, or abnormal amniotic fluid volume and/or abnormal intrauterine growth rhythm.
The ultrasound examinations were performed using Voluson 730 Expert (Kretz Ultrasound; GE Medical Systems, Zipf, Austria), with abdominal probe 4–8 MHz or transvaginal 5–9 MHz probe, set at a high-pass filter of 70 Hz. No color or power Doppler imaging was applied. All measurements were done by 1 examiner (Z.K.).
All women provided oral informed consent prior to the ultrasound examination, as routinely done in our department. The study protocol was approved by the institutional review board of Sheba Medical Center.
Statistical evaluation was done using SPSS statistical package version 15 for Windows (SPSS, Inc, Chicago, IL) and Microsoft Excel 2007 software (Microsoft Corp, Richmond, CA). The normal distribution of the parameters was assessed by the 1-sample Kolmogorov-Smirnov test.
The intraobserver variability was assessed in the first 40 cases. Each parameter was measured twice using the same technique in the same patient, and the difference was transformed to an equivalent percentage scale according to the following formula: 100 – (a-b)/[(a+b)/2] in which a and b represent the first and the second measurements, respectively. In addition, Bland and Altman plots were used to evaluate the 2 SD limits of agreement. An unpaired Student t test was used to evaluate the statistical significance between the means’ parameters of the males and the females and the paired Student t test between the left and right side of the same fetus. A P value less than .05 was considered significant.
The bivariate Pearson’s 2-tailed correlation coefficient was used to evaluate the correlation between the various brain parameters and the EFW, EFWP, HC, and BPD. The asymmetric index was calculated according to the formula used by postnatal studies to evaluate brain asymmetry: 100 × (left/male – right/female)/0.5 × (left/male + right/female). A positive value indicates a larger left side or male parameter, and a negative value means that the right or female parameter is larger. The values below or above 10 were considered significant.
Results
During 6 months of the study, 406 fetuses, were included in the study. One hundred ninety-nine were females, 207 were males. The mean gestational age at examination was 22.2 weeks (±1.7 SD) and the median 22.0 weeks. The distribution according to week of gestation is shown in Figure 4 . Normal distribution was not ascertained, because 74% of the examinations were performed between 21–23 weeks of gestation ( P < .05).
The mean intraobserver variability was 0.6 mm (±0.4) and 10.8% (95% confidence interval [CI], 8.7–12.8) for the atria, 0.4 mm (±0.4) and 10.0% (95% CI, 7.4–12.5) for the cortex, and 0.6 mm (±0.4) and 2.4% (95% CI, 1.9–2.8) for the hemispheres.
Bland and Altman plots indicated an acceptable degree of agreement for all 3 parameters ( Figure 5 , A–C).
The atrial width: sex and laterality
The overall mean atrial diameter was 5.5 mm (±1.18 SD; range, 1.9–11 mm) ( Table 1 ).
| Variable | Mean | SD | Median | Range | Difference | |||
|---|---|---|---|---|---|---|---|---|
| Millimeters (95% CI) | Ratio | % | P | |||||
| Males | 5.64 | 1.24 | 5.50 | 1.9–11.0 | 0.28 (0.12–0.45) | 1.1 | 5.2 | .001 |
| Females | 5.36 | 1.09 | 5.30 | 2.0–10.1 | ||||
| Left | 5.68 | 1.18 | 5.6 | 2.0–10.6 | 0.27 (0.14–0.39) | 1.06 | 6.5 | .000 |
| Right | 5.33 | 1.18 | 5.2 | 1.9–11.0 | ||||
| Males left | 5.81 | 1.23 | 5.7 | 2.0–10.5 | 0.36 (0.19–0.53) | 1.06 | 6.6 | .000 |
| Males right | 5.45 | 1.20 | 5.3 | 1.9–11.0 | ||||
| Females left | 5.50 | 1.17 | 5.4 | 2.5–9.3 | 0.22 (0.02–0.42) | 1.04 | 4.3 | .024 |
| Females right | 5.27 | 1.18 | 5.2 | 2.0–10.1 | ||||
| Left males | 5.81 | 1.23 | 5.7 | 2.0–10.5 | 0.31 (0.07–0.54) | 1.05 | 6.0 | .009 |
| Left females | 5.50 | 1.17 | 5.4 | 2.5–9.3 | ||||
| Right males | 5.45 | 1.20 | 5.3 | 1.9–11.0 | 0.17 (0.06–0.40) | 1.03 | 3.4 | .147 |
| Right females | 5.27 | 1.18 | 5.2 | 2.0–10.1 | ||||
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