Prenatal chromosomal microarray analysis in 2466 fetuses with ultrasonographic soft markers: a prospective cohort study.

BACKGROUND: Soft markers are nonspecific findings detected by ultrasonography during the second trimester that are often transient and nonpathologic but may imply an increased risk of underlying fetal aneuploidy. However, large-scale prospectively stratified studies focusing on the prevalence of chromosomal aberrations, including copy number variants, in fetuses with different types of isolated soft markers have rarely been published in the literature. OBJECTIVE: This study aimed to investigate clinical outcomes in fetuses with isolated soft markers by single nucleotide polymorphism array with long-term follow-up and to propose a diagnostic algorithm based on specific types of soft markers. STUDY DESIGN: The prevalence of fetal isolated soft markers was 13.2% (7869 of 59,503). A total of 2466 fetuses with ultrasonographic soft markers during the second trimester, which were subjected to single nucleotide polymorphism array with long-term follow-up, were selected in this prospective study over a 5-year period. Soft markers were categorized into 12 groups. The demographic profile and chromosomal microarray analysis detection results were analyzed and compared among different groups. RESULTS: The overall prevalence of chromosomal aberrations in fetuses with soft markers was 4.3% (107 of 2466), which comprised 40.2% with numeric chromosomal abnormalities, 48.6% with pathogenic copy number variants, and 11.2% with likely pathogenic copy number variants. The incidence of numeric chromosomal abnormalities was significantly higher in multiple soft markers (5.5% vs 1.5%; P=.001) and the thickened nuchal fold group (8.3% vs 1.7%; P=.024). Meanwhile, the incidence of pathogenic copy number variants was significantly higher in multiple soft markers (5.5% vs 2.4%; P=.046) and the short femur length group (6.6% vs 2.2%; P<.0001). The incidences of pathogenic copy number variants in fetuses with isolated echogenic intracardiac focus, enlarged cisterna magna, choroid plexus cysts, echogenic bowel, or single umbilical artery were lower than 1.5%. The normal infant rate in fetuses without chromosomal aberrations was 91.7%; however, it was significantly lower in the mild ventriculomegaly (86.2% vs 93.0%; P<.0001) and short femur length groups (71.4% vs 93.6%; P<.0001). CONCLUSION: The potential chromosomal aberrations and clinical prognoses varied widely among different types of isolated soft markers. Pathogenic copy number variants are more often present in specific soft markers, especially when multiple soft markers are found. Thus, a specific soft marker type-based prenatal genetic testing algorithm was proposed.

Short Femur in the Second Trimester Scan Is Related to Maternal Preeclampsia and Small for Gestational Age Newborns.

OBJECTIVE: To determine the contribution of short femur diaphysis length (FDL) at 19-22 weeks of gestation in the prediction of adverse pregnancy outcomes. METHODS: The study included singleton pregnant women who underwent a routine anomaly scan at 19-22 weeks of gestation at the Virgen de la Arrixaca University Clinical Hospital (Murcia, Spain) between August 2011 and August 2012. Fetal biometry and Doppler ultrasound of uterine arteries were assessed as part of the anomaly scan, and the mean pulsatility index of both uterine arteries was recorded. Maternal obstetric characteristics, such as ethnicity, age, weight, parity, cigarette smoking, and medical history including hypertension and diabetes mellitus were collected from our database system. RESULTS: A total of 6,366 women were included in the study after excluding cases with abnormal karyotype, major fetal abnormalities, or termination of pregnancy. There were 88 cases of preeclampsia (PE) (1.4%). Logistic regression was performed including maternal and fetal characteristics. Short FDL at 19-22 weeks was significantly associated with subsequent development of PE (OR = 0.89, 95% CI: 0.80-0.99, p = 0.025). The best model to predict PE from our sample included gestational age at scan, parity, maternal weight, chronic hypertension, mean pulsatility index in the uterine arteries, and FDL (AUC = 0.78, 95% CI: 0.71-0.84). Regarding small for gestational age (SGA) neonates, there were also significant differences in FDL and FDL <5th centile between the control group and SGA newborns below the 3rd, 5th, and 10th centile. In the groups of preterm births (delivery before 32, 34, and 37 weeks), there were no differences in FDL compared with the control group (term births). DISCUSSION: Our results suggest that FDL at 19-22 weeks of gestation is an independent predictor of PE and SGA newborns.

Identification of Novel Compound Heterozygous Variants of MMP9 in Fetus With Metaphyseal Anadysplasia Type 2.

Matrix metalloproteinase 9 (MMP9) is an important member of the matrix metalloproteinase family and plays a key role in balancing extracellular matrix proteins. Studies have shown that the homozygous mutations in MMP9 can lead to metaphyseal anadysplasia type 2 (MANDP2, OMIM#613073). The clinical phenotype of this disease is limited and there were only five reported cases of MANDP2 associated with homozygous MMP9 mutations from three families. In this study, we described a case of a fetus with skeletal system malformation. The main clinical manifestations include the short bilateral femur, absence of right fibula, and curved ipsilateral tibia with short length. Importantly, two novel compound heterozygous variants of the MMP9 gene (NM_004,994.3: c.151C > T and c.929del) were found through the trio whole exome sequencing and Sanger sequencing. This is the first report that identified the compound heterozygous variants of the MMP9 gene associated with metaphyseal dysplasia type 2.

Obstetrical and perinatal outcomes in fetuses with early versus late sonographic diagnosis of short femur length: A single-center, prospective, cohort study.

OBJECTIVES: The aim of this study was to evaluate obstetrical and perinatal outcomes in fetuses with short femur length diagnosed before or after 24 weeks of gestation. STUDY DESIGN: This was a prospective cohort study on singleton pregnancies with a diagnosis of fetal femur < 5 centile. Included patients were divided into two groups: patients with a first diagnosis of femur length < 5th percentile at 14-24 weeks (group A) and those with the first diagnosis made at > 24 weeks (group B). RESULTS: 147 patients were included for the analysis. Group A and group B included 66 (44.9%) and 81 (55.1%) cases. Abnormal fetal karyotype and skeletal dysplasia rates were significantly higher (27.3% vs 3.7%,P < 0.001 and 19.7% vs 3.7%, P = 0.002) in group A. Women in group B had a higher incidence of small for gestational age and intrauterine growth restriction (7.6% vs 24.7%, P = 0.007 and 19.7% vs 44.4%, P = 0.002). There was a significant higher incidence of live births in group B (34.9% vs 97.5%, P < 0.001), while the rate of termination of pregnancy was increased in group A (56.1% vs 1.2%, P < 0.001). No significant difference was found in perinatal outcomes of live births, when comparing group A and B. CONCLUSIONS: The incidence of abnormal karyotype and skeletal dysplasia is higher when short femur length diagnosed earlier in gestation, while the incidence of small for gestational age, intrauterine growth restriction and the rate of live births are significantly increased when short femur length is diagnosed later during pregnancy.