Abstract-Maternal predisposition to vascular and metabolic disease may underlie both vascular-related pregnancy complications, such as preeclampsia and intrauterine growth restriction, as well as future maternal cardiovascular disease. We aimed to substantiate this hypothesis with biochemical and anthropometric evidence by conducting an intergenerational case-control study in a Dutch isolated population including 106 women after preeclampsia or intrauterine growth restriction (median follow-up: 7.1 years) and their fathers (nϭ43) and mothers (nϭ64), as well as 106 control subjects after uncomplicated pregnancies with their fathers (nϭ51) and mothers (nϭ68). Cardiovascular risk profiles were assessed, including fasting glucose, lipids, anthropometrics, blood pressure, intima-media thickness, and metabolic syndrome. We found significantly higher fasting glucose levels, larger waist circumferences, and a 5-fold increased prevalence of hypertension in women with a history of preeclampsia as compared with control subjects (PϽ0.001). Likewise, their parents had higher glucose levels than control parents (PϽ0.05). Their mothers had larger waist circumferences and higher blood pressures (PϽ0.05). Also, women after pregnancies complicated by intrauterine growth restriction had higher glucose levels and increased prevalence of hypertension (PϽ0.01). Their fathers showed higher glucose levels as well (PϽ0.05). Mean carotid intima-media thickness was increased in a subset of women after preeclampsia diagnosed with chronic hypertension as compared with those without hypertension (PϽ0.01). Metabolic syndrome was more prevalent both in women with a history of preeclampsia and their mothers (PϽ0.05). We demonstrated intergenerational similarities in cardiovascular risk profiles between women after preeclampsia or intrauterine growth restriction and their parents. These findings suggest shared constitutional risks for vascular-related pregnancy complications and future cardiovascular disease. (Hypertension. 2008;51:1034-1041.)

It is hypothesized that this novel and de novo polyalanine expansion in ZIC3 contributes to the VACTERL association in this patient. A newborn male is described with features of the VACTERL association, including anal atresia, laryngeal and oesophageal atresia with tracheo-oesophageal fistula, dextroposition of the heart with persistent left superior vena cava, and unilateral multicystic kidney. As the clinical picture of the VACTERL association overlaps with X-linked heterotaxy caused by ZIC3 mutations, the ZIC3 coding region was sequenced, and a 6-nucleotide insertion was found that is predicted to expand the amino-terminal polyalanine repeat from 10 to 12 polyalanines. This novel mutation was not present in the mother, nor in 336 chromosomes from 192 ethnically matched controls. It is hypothesised that this novel and de novo polyalanine expansion in the ZIC3 gene contributes to the VACTERL association in this patient.

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Prenatal diagnostics has been impacted by technological changes in the past decade, which have affected the diagnostic yield. The aim of this study was to evaluate the impact of SNP array and noninvasive prenatal testing (NIPT) on the diagnostic yield and the number of invasive tests in our center. The frequency of pathogenic fetal unbalanced chromosome aberrations was studied in 10,005 cases referred for prenatal testing in 2009-2015. Chromosomal SNP microarray analysis replaced karyotyping in all invasively tested pregnancies and since 2014 a choice between NIPT and diagnostic testing with microarray was offered to women with an increased risk for common aneuploidy. The introduction of microarray led to an additional yield of submicroscopic pathogenic chromosome aberrations: 3.6% in fetuses with ultrasound anomalies and 1.9% in fetuses without ultrasound anomalies. The introduction of NIPT led to a decrease of invasive tests and of diagnostic yield. Moreover, a diagnostic delay in about 1:350 cases was observed. Since 20%-33% of pathogenic fetal chromosome aberrations are different from the common aneuploidies and triploidy, whole-genome analysis should be offered after invasive sampling. Because NIPT (as a second screening) has led to a decreased diagnostic yield, it should be accompanied by an appropriate pretest counseling.

Data from 23 twin pregnancies with one structurally affected fetus were compared with data from 23 twin pregnancies with proven absence of structural fetal anomalies and matched for maternal age, parity, and year of delivery. The preterm delivery rate (< 37 weeks) was high in both groups but not significantly different (57 vs. 48 per cent). Perinatal mortality was significantly higher in the structurally affected twin pregnancies (65 vs. 9 per cent). In the affected twins, birth weight of the anomalous fetus was significantly lower than that of the normal co-twin. Since there was no difference in the incidence of maternal disease (hypertensive disorders, diabetes), it was concluded that the higher perinatal mortality was determined mainly by the nature of the anomaly and not by the preterm delivery rate.