Fetal Diagnosis and Therapy最新文献

Introduction: Dilated colon or rectum on fetal imaging raises concern for underlying anorectal malformation (ARM) or Hirschsprung's disease (HD).

Methods: We evaluated pregnant women referred to a dedicated fetal center between 2006-2024 for suspected fetal rectal/colonic dilation. Findings by US and MRI were compared to neonatal outcomes. Those with a statistically significant association with postnatal distal bowel abnormality were identified by univariate analysis and used to formulate a risk score.

Results: 18/47 (38.2%) patients had normal imaging. 29/47 (61.7%) demonstrated persistent "prominence" (15/29) or "dilation" (14/29) of the fetal colon/rectum. Seven male fetuses with large bowel dilation/prominence were diagnosed postnatally with an imperforate anus. None had HD. Compared to the no-ARM group, ARM patients were more likely to have earlier initial referral imaging; imaging noting persistent bowel dilation/prominence; imaging with an abnormal amniotic fluid level, meconium signal, bowel echogenicity, or anal sphincter; enterolithiasis; or concern for VACTERL (all p≤ 0.035). These 8 variables were used to create a risk score to diagnose ARM with 100% sensitivity and specificity in our cohort.

Conclusion: Fetal imaging showing a dilated colon/rectum is rarely pathologic. When targeted imaging does not reveal any features predictive of pathology, reassurance may be provided to families and providers.

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease asociated to low survival disease into adulthood. The appearance of the cystic fibrosis transmembrane conductance regulator (CFTR) therapy has revolutionized the management and the prognosis of this patients with an improvement in the pancreatic and lung function with a much better quality of life. More women with CF are considering being mothers. Other clinical scenario is the prenatal diagnosis of fetus with CF. Three cases reports have been published suggesting that CFTR therapy during pregnancy in fetuses affected by CF might prevent prenatal meconium ileous (MI), which are the one who have a higher risk of gastrointestinal morbidity and long-term complications.

Case presentation: We present two cases reports in which the diagnosis of CF occurred during intrauterine life and treatment with CFTR therapy was administered to healthy pregnant women in order to reduce the risk MI in their fetuses. In both cases the diagnosis suspicion was by ultrasound findings with a genetic confirmed diagnosis by amniocentesis. In the first case, the mother received the CTFR therapy during five weeks and MI was not developed by the newborn. In the second one, the mother received the treatment only for a week and MI could not be avoided.

Conclusion: This clinical situation has special ethical considerations, since a drug is being administered through compassionate use to a women who does not need it. The fundamental reason is the lack of authorization for the use of these drugs in newborns but in adults. We hope that these two clinical cases, together with those already published, will increase the knowledge and experience of using this drug in this context helping with the management of pregnant women with fetuses affected by CF in order to reduce associated complications.

Introduction: Currently, risk stratification criteria and indications for early postnatal resection of high-risk congenital lung malformations (CLM) are not universally accepted. In this study, we sought to characterize prenatal risk factors and outcomes associated with early postnatal resection in prenatally diagnosed CLMs.

Methods: Retrospective cohort study of patients seen at the Fetal Care Center from 01/2014 to 12/2023. Categorical data was analyzed with chi-square calculations. Receiver-operating characteristic (ROC) curves were generated for optimal CVR and imaging cutoff values associated with hydrops development and/or need for early resection.

Results: Of the 204 patients analyzed, 10.2% (21/204) patients underwent early postnatal resection. Hydropic fetuses required early resection significantly more than non-hydropic fetuses (33.3% vs. 5.0%, p < 0.001). A greater number of early resection patients had macrocystic lesions compared to non-early resection patients (76.2% vs. 12.3% p < 0.001). A maximum CVR ≥ 1.66 was highly predictive of early postnatal resection (AUC = 0.90; 95% CI = 0.84-0.96). An initial CVR < 0.88 indicated a low likelihood of developing hydrops (negative predictive value = 98.6%).

Conclusion: Prenatally, hydrops, macrocysts, and a maximum recorded CVR ≥ 1.66 are associated with early postnatal resection. Hydrops development is unlikely with an initial CVR < 0.88.

Objectives: This study evaluated fetal MRI lung measurements with ECMO use and survival of prenatally diagnosed CDH.

Methods: Retrospective chart review of 113 patients from 01/2012-12/2023 with prenatally diagnosed congenital diaphragmatic hernias. Lung measurements from prenatal MRIs, infant ECMO use, and survival were analyzed to determine optimal cut-off value for outcome prediction.

Results: Patients were categorized as mild (10.1%, n = 11), moderate (34.3%, n = 37), and severe (55.6%, n = 60). Mortality was 29.2% (n = 33), and 52.2% (n = 59) required ECMO. Patients undergoing FETO (n = 11) were excluded from statistical analysis. Median change in total lung volume, ipsilateral lung, and contralateral lung from early to late gestation MRI was 15.1 mL (IQR: 9.3-21.7), 1.5 mL (IQR: 0.1-3.1), and 13.4 mL (IQR: 8.1-18.34), respectively. Optimal cut-off values, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each volume parameter in terms of predicting ECMO use and mortality. Ipsilateral and contralateral lung growth below the cut-off significantly predicted ECMO use (p < 0.05). There was no significance for any cut-offs predicting mortality.

Conclusion: Lung volume growth measured by MRI in prenatally diagnosed CDH may be a useful predictor of ECMO use and mortality.

Introduction: The aim of this study was to assess the clinical utility of low-set ears (LSE) as a novel 2D-ultrasound marker for the prenatal detection of chromosomal anomalies.

Methods: A multicenter cohort study including 1,331 singleton pregnancies between 11+2 and 34+6 weeks of gestation was conducted in the two participating centers to determine the performance of LSE as an aneuploidy marker. LSE was defined as a dichotomous marker using a newly defined axial plane of the fetal head in 2D ultrasound. Intra- and interobserver variability were assessed to ensure marker reliability. Efficacy in predicting chromosomal anomalies was assessed using LSE alone or in combination with aneuploidy screening.

Results: A new axial plane of the fetal head, defined by both lenses and the cerebellum, was adopted for LSE detection. Intra-observer concordance Kappa index for LSE measurement was 1.0, and 0.82 for interobserver reliability. LSE could be assessed in 99% of the studied fetuses and was detected in 30 (2.3%) fetuses: in 19 (86%) of the 22 fetuses with chromosomal anomalies, in all cases (5/5, 100%) with other genetic anomalies, and in six (18%) of the 34 malformed fetuses without a genetic disorder. In one (3.3%) of the fetuses, LSE was not confirmed postnatally while the remaining 29 fetuses had an adverse outcome. When LSE was combined with aneuploidy screening, the detection rate of chromosomal anomalies remained the same and specificity increased from 89% to 100%.

Conclusions: Our study supports using LSE as a potential 2D-ultrasound marker for chromosomal anomaly detection. Studies with a larger sample size and in high-risk populations are warranted to prove its clinical utility before this marker can be included in prenatal screening protocols.

Introduction: The clinical phenotypes associated with 1q21.1 deletion or duplication syndromes vary considerably among individuals, and the underlying mechanisms remain poorly elucidated. Moreover, data on prenatal ultrasound findings in fetuses carrying these copy number variants are still limited. This study aimed to preliminarily evaluate the association between prenatal phenotypic features and 1q21.1 deletion/duplication syndromes.

Methods: A retrospective analysis was performed on 16 cases diagnosed with 1q21.1 deletions and 13 cases with 1q21.1 duplications, employing single nucleotide polymorphism arrays (SNP-arrays).

Results: The deletion fragment sizes of the 16 deletion cases ranged from 1.30 Mb to 2.18 Mb, with the overlapping region located at 146.5 Mb to 147.5 Mb, encompassing nine OMIM genes such as ACP6, BCL9, and CHD1L. The fragment sizes of the 13 duplication cases ranged from 0.87 Mb to 3.87 Mb, with the overlapping region located at 146.5 Mb to 147.0 Mb, encompassing a total of 4 OMIM genes, namely, BCL9, CHD1L, FMO5, and PRKAB2. Among the 16 fetuses with deletions, eight exhibited ultrasound-detected abnormalities. Specifically, three fetuses had urinary tract malformations, four were diagnosed with fetal growth retardation, three displayed lateral ventricle enlargement, and one had aortic stenosis. Of the 13 fetuses with duplication, six were found to have ultrasound abnormalities, including four fetuses with cardiovascular malformations, one fetus with fetal growth retardation, one fetus with widened posterior fossa, and one fetus with widened lateral ventricle. Among the 16 fetuses identified with deletions, nine pregnancies were electively terminated, while seven pregnancies were carried to term, resulting in normal births. During follow-up, one child was diagnosed with epilepsy, and another exhibited delays in language and motor development. In the cohort of 13 fetuses with duplications, four pregnancies were terminated, and nine proceeded to term, yielding normal births. However, follow-up assessments revealed that one child experienced hearing impairment and another demonstrated speech delays.

Conclusion: This study suggests that fetuses with prenatal 1q21.1 deletions may be associated with malformations of the urinary system, whereas those with 1q21.1 duplications are likely associated with cardiac malformations. For fetuses diagnosed with 1q21.1 deletions or duplications who present with a normal phenotype prenatally, it is essential to conduct close monitoring of their neurodevelopmental trajectory postnatally.

Introduction: Tubulinopathies are a heterogeneous group of rare disorders which are primarily characterized by brain malformations caused by pathogenic variants in the genes that encode tubulin. Although scarce, prenatal diagnosis has been recently reported through expert neurosonography and magnetic resonance imaging, most commonly at 28-34 weeks' gestation, followed by identification of pathogenic variant in TUBA1A, TUBB, TUBB2A, TUBB2B, TUBB3, or TUBG1 using gene sequencing.

Case presentation: We present detailed ultrasound findings of 21-week fetus with brain abnormalities including low normal head circumference, cerebellar hypoplasia, dysmorphic cavum vellum pellucidum, partial agenesis and dysgenesis of the corpus callosum, distortion with interdigitation of the interhemispheric fissure, ventricular asymmetry with dysmorphic, and/or dilated frontal horns, as well as asymmetry in the basal ganglia. Amniocentesis with trio genome sequencing detected a novel, de novo heterozygous c.799T>C variant in TUBA1A that has not been previously reported.

Conclusions: This case offers a detailed characterization of the subtle neurosonographic phenotype in this fetus with early manifestation of malformations of cortical development related to tubulinopathy and provides information regarding the novel variant in the TUBA1A gene. It further underscores the importance of neurosonography and genetic analysis in identifying tubulinopathies and informing clinical decision-making during pregnancy.

Objective: Invasive prenatal diagnostic tests have higher detection rates (DR) than screening tests. Cell-free (cf)DNA screening has higher detection than Combined testing (CT). We estimated cost per cytogenetic abnormality diagnosed for prenatal testing and screening methods (USA data).

Methods: We compared seven strategies: universal diagnosis with microarray; with karyotype; cfDNA screening with four methodologies (DANSR, MPSS, SNPs and RCA); and CT. Five abnormality groupings were considered: common autosomal trisomies (21,18,13); sex chromosome aneusomies; triploidy; clinically significant sub-chromosome changes; and CNVs. Prevalence, detection, false-positive rates, and unit costs (literature) were obtained. DR was aggregated across groups as were costs, including diagnostic tests following positive screening results.

Results: All six high detection strategies had greater cost per abnormality diagnosed than CT ($19,600). Costliest was cfDNA using MPSS ($96,100), followed by universal karyotyping ($95,900), cfDNA using SNPs, DANSR ($94,800 - $92,800), universal microarray ($56,600) and cfDNA with RCA ($32,200). The additional cost per extra abnormality diagnosed compared to CT ('marginal' cost) was lowest for universal microarray ($62,100); others were considerably higher ($170,900-$238,300).

Conclusions: Preferred prenatal strategies vary among stakeholders. As monopolies (large systems and Accountable Care Organizations) now control many American healthcare decisions, lowest cost cfDNA screening will likely prevail in decision making.