First-trimester preterm preeclampsia prediction model for prevention with low-dose aspirin.

INTRODUCTION: Preeclampsia (PE) is a major maternal and fetal threat. Previous risk-scoring methods in guidelines lacked precision. The Fetal Medicine Foundation (FMF) proposed a first-trimester PE screening model using Bayes' theorem. PE PREDICTION MODEL: FMF prediction model combines maternal characteristics and medical/obstetrical history to determine prior risk and further incorporate maternal blood pressure, maternal serum biomarkers, and uterine Doppler pulsatility index expressed as multiples of the median (MoM) to estimate posterior risk. LOW-DOSE ASPIRIN PREVENTION: Low-dose aspirin is one of the potential PE prevention strategies. Initiating it before 16 weeks is crucial. Aspirin's antiplatelet and anti-inflammatory properties align with PE's pathophysiology. Dosing and resistance warrant further study, but a standard regimen of 150 mg nightly, starting before 16 weeks, is widely supported. PE PREVENTION IN PRACTICE: Clinical trials, including ASPRE, affirm aspirin's role in PE prevention. Starting aspirin based on FMF screening significantly reduces preterm PE and associated complications. ADVANCEMENTS AND PROSPECTS: Emerging research explores predictors like maternal ophthalmic arterial waveform. Regional variations, especially in Asian populations, are considered. Machine learning and AI show promise, but examiner expertise remains essential for accurate prediction. In conclusion, integrating FMF's first-trimester PE screening with low-dose aspirin offers a promising strategy. Further advancements may enhance precision and broaden prevention efforts.

Thyroid hypogenesis is associated with a novel AKT3 germline variant that causes megalencephaly and cortical malformation.

The molecular mechanisms involved in thyroid organogenesis have not been fully elucidated. We report a patient with a de novo germline AKT3 variant, NM_005465.7:c.233A > G, p.(Gln78Arg), who presented with congenital hypothyroidism in addition to typical AKT3-related brain disorders. The report of this patient contributes to delineating the associated yet uncertain endocrine complications of this AKT3 disease-causing variant.

Clinical Validation of Fetal cfDNA Analysis Using Rolling-Circle-Replication and Imaging Technology in Osaka (CRITO Study).

BACKGROUND: Noninvasive prenatal genetic testing (NIPT) has been adopted as the first choice for aneuploidy screening. The purposes of this study were to investigate the accuracy of Vanadis® NIPT (hereafter CRITO-NIPT) in order to gain a deeper insight into the reasons for discrepancies, as well as to discuss the role of fetal ultrasound. METHODS: Between 2019 and 2020, CRITO-NIPT was performed in 1218 cases of patients who underwent CVS or amniocentesis after a detailed fetal ultrasound exam and genetic counseling. The CRITO-NIPT results were compared with the genetic results. In cases of test discrepancies, the placentae were collected for detailed genetic research, and the pre-procedure fetal ultrasound findings were referred to. RESULTS: The positive predictive value of T21, T18, and T13 was 93.55%, 88.46%, and 100%, respectively. In 90% of the of false positive (FP) cases, the placentae were examined. In 75% of the CRITO FP-T21 cases, placental mosaicism, or a demised twin's T21, were confirmed. There were complicated mosaic cases, including tetrasomy 21/trisomy7 and monosomy 21/trisomy21 cases. In one of three no-call cases, an intermediate deletion of chromosome 13 was detected. CONCLUSIONS: The CRITO study investigated the mechanism of false positives, and the detailed mechanisms in mosaic and no-call cases. There have hitherto been no reports that have provided insight by partitioning the placenta to compare the NIPT and invasive test results, nor that have provided detailed ultrasound findings in the cases of discordant results, revealing the demonstrated importance of, and necessity for, detailed ultrasonography. This article describes the potential of rolling-circle replication as a powerful biosensing platform, as well as the importance of examining the fetus in detail with ultrasound. However, we should remember that the potential applications raise ethical and social concerns that go beyond aneuploidy and its methodology.

Fetal Megalencephaly with Cortical Dysplasia at 18 Gestational Weeks Related to Paternal UPD Mosaicism with PTEN Mutation.

The phosphatase and tensin homolog (PTEN) gene is a tumor-suppressor gene located on 10q22-23. Since the introduction of molecular genetics in prenatal diagnostics, various birth defects associated with gene mutations have been diagnosed. However, no reports on fetal cases related to PTEN mutation have been found, so far. We encountered a rare case of fetal PTEN mutation. Fetal macrocephaly was noted at 16 weeks. At 18 and 20 weeks, neurosonography revealed megalencephaly with an asymmetrical structure and multifocal polygyria. The head circumference (HC) was +6.2 SD at 18 weeks and +8.1 SD at 20 weeks. The parents opted for pregnancy termination, and the male fetus was delivered at 21 weeks, with HC +9.3 SD. Single-nucleotide polymorphism (SNP) array for amniotic cells showed paternal uniparental disomy (UPD) 10q mosaicism, and the mosaic ratio was calculated as 56% from B-allele frequency. Exome sequencing revealed the pathogenic PTEN mutation with mosaicism. The heterozygous PTEN mutation may not cause early manifestations from the fetal period, and an abnormal phenotype may appear after birth. This may be the reason why fetal defects associated with PTEN mutation are not detected. Since this case had homozygous and heterozygous mutations, survival was possible, exhibiting an incredibly huge head with cortical dysplasia from early pregnancy.

Three-dimensional neurosonography - a novel field in fetal medicine.

Neurosonography is a promising technique for prenatal diagnosis, combining features of ultrasound imaging with fetal neurology. The brain is a three-dimensional structure, therefore observing brain structure in the three basic planes (sagittal, coronal and axial) is mandatory. The anterior fontanelle and sagittal suture may serve as acoustic ultrasound windows in the transvaginal brain scan, allowing to obtain high-resolution neuroimages of the intracranial structures. Furthermore, three-dimensional (3D) ultrasound combined with the transvaginal brain approach provides detailed and sophisticated neuroimages. Three orthogonal planes of the brain, tomographic ultrasound imaging (TUI) and other off-line approaches (e.g. volume contrast imaging (VCI) or HDlive silhouette imaging) may be obtained from a single 3D dataset. 3D Doppler ultrasound enables visualization of the intracerebral vascularity, allowing to obtain more precise information on cerebral perfusion. Various abnormal brain conditions, including ventriculomegaly, agenesis of the corpus callosum, posterior fossa abnormalities and others, can be well-demonstrated. Due to high rates of the associated anomalies and uncertain prognosis, any suspicion of CNS abnormalities shall imply detailed ultrasonographic evaluation of the fetal anatomy to exclude the associated anomalies. Despite a growing number of neuroimaging modalities, prenatal counselling remains a challenge as prediction of brain functionality and the neurological prognosis often remain uncertain. New investigations on the relations between various migration disorders and gene mutations, as well as recent clinical research on the relations between neuroimaging detection of local migration disorders using sophisticated imaging technologies and the postnatal neurological prognosis will contribute to the development of maternal-fetal medicine as well as pediatric neurology.

Novel application of three-dimensional HDlive imaging in prenatal diagnosis from the first trimester.

Recent development of three-dimensional (3D) high definition (HD) ultrasound has resulted in remarkable progress in visualization of early embryos and fetuses in sonoembryology. The new technology of HDlive assesses both structural and functional developments in the first trimester with greater reliably than two-dimensional (2D) ultrasound. The ability to visualize not only fetal face, hands, fingers, feet, and toes, but also amniotic membranes, is better with volumetric ultrasound than 2D ultrasound. In this article, detailed and comprehensive structures of normal and abnormal fetuses depicted by 3D HDlive are presented, including various faces of Down's syndrome and holoprosencephaly, as well as low-set ear and finger/toe abnormalities from the first trimester. Three-dimensional HDlive further "humanizes" the fetus, enables detailed observation of the fetal face in the first trimester as shown in this article, and reveals that a small fetus is not more a fetus but a "person" from the first trimester. There has been an immense acceleration in understanding of early human development. The anatomy and physiology of embryonic development is a field where medicine exerts greatest impact on early pregnancy at present, and it opens fascinating aspects of embryonic differentiation. Clinical assessment of those stages of growth relies heavily on 3D/four-dimensional (4D) HDlive, one of the most promising forms of noninvasive diagnostics and embryological phenomena, once matters for textbooks are now routinely recorded with outstanding clarity. New advances deserve the adjective "breathtaking", including 4D parallel study of the structural and functional early human development.

First trimester serum markers stability during sample transportation from the obstetrical site to the screening laboratory.

OBJECTIVE: To investigate the effect of temperature on first trimester free ß-hCG and PAPP-A in serum during transportation. METHODS: Maternal blood was collected from 30 East Asian women attending for Down syndrome screening at the primary obstetrical site. The extracted serum was split into two equal aliquots, placed in identical thermally insulated pouches with a temperature data logger and shipped to the screening laboratory. An 800 g frozen ice pack was placed in one of the pouches. Free ß-hCG and PAPP-A levels were determined in the 'Cooled' and 'Uncooled' serum samples using a DELFIA(®) Xpress analyzer. The proportion of 'Uncooled' samples not within 5% of the 'Cooled' sample marker level was assessed. RESULTS: The median age of subjects was 36 years, half were nulliparous and all were non-smokers. The assay stability ranged from 2.38% to 4.41%. The median total transport time from the obstetrical site to the laboratory was 17.37 h. Median recorded temperatures within the 'Cooled' pouch were significantly lower throughout the transportation of the samples (p < 0.0001). The median percentage change of free ß-hCG and PAPP-A concentrations in 'Uncooled' samples relative to 'Cooled' samples were 2.72% (range 0.27-7.64%) and 1.10% (range 0.03%-4.29%), respectively. Free ß-hCG concentrations differed by greater than 5% in eleven (37%) subjects. CONCLUSIONS: Insulated packaging, cooling media and temperature monitoring devices may be needed as additional measures to determine, minimize and exclude effects of ambient temperature on serum marker levels especially when travelling times are long or ambient temperatures are high.