Fetal cardiac defects and third-trimester maternal serum placental growth factor

Fetal echocardiography is considered the best screening tool for congenital heart defects (CHDs). However, the use of ultrasound is limited to a few specialized and experienced centers, in which it is offered to high-risk mothers1. Other strategies for screening have been proposed, including the use of biomarkers. In an observational study by Llurba et al., maternal placental growth factor (PlGF) was proposed as a first-trimester marker for the detection of conotruncal and valvular defects2. We performed a case–control study in the third trimester of pregnancy, involving 10 pregnant patients carrying a fetus affected by a CHD and 50 unaffected control pregnancies, matched for gestational age, at a 1:5 ratio. Maternal serum PlGF quantification was performed using the Alere PlGF Test, using Triage® MeterPro instrument (Alere Srl, Milan, Italy), a test based on a fluorescence immunoassay technique that allows measurement of PlGF over a range from 12 to 3000 pg/mL. The mean rank of PlGF concentration obtained from each case sample was significantly lower than that of the controls (2.00 vs 3.80; P = 0.003). Seven cases of valvular and conotruncal defects had very low rank values (Figure 1). Figure 2 reports the multiples of the median (MoM) stratified according to each set of data. As shown for each data set, one of the five controls had a PlGF-MoM value of 1, which represents the median (1 MoM) for that specific data set. The median MoM for CHD cases was 0.26, compared with the expected MoM of 1 for the 50 controls (P = 0.028). Speculation about levels of PlGF and other angiogenic factors such as vascular endothelial growth factor in the presence of CHD has been reported previously3. Intrinsically altered angiogenesis is thought not only to cause abnormal formation of the heart but also to result in abnormal placentation. We have reported previously that the placental tissue of fetuses affected with CHD shows dysregulated expression of several genes that regulate the extracellular matrix (ECM) of both endocardial cushions and valvular components4. We therefore speculate that such genes are somehow associated with the malformed features of CHD, and that extra-embryonic mesoderm (from which the mesenchymal axis of the villus arises) and intra-embryonic mesoderm (from which the heart, dermis and many other organs arise) have a similar origin. In support of this hypothesis, our previous data identified dysregulation in the expression pattern of selected genes implicated in the control of heart development and markers of functional abnormalities, such as contractile dysfunction and congestive heart failure, which may result from the presence of CHD. These results are consistent with a common mesodermal origin (intra- and extra-embryonic, respectively) of the heart and of the central core of the chorionic villi. In further support of this hypothesis, it has previously been shown that chorionic villus samples from euploid fetuses with isolated enlarged nuchal translucency display an aberrant profile in genes that control ECM biosynthesis5. Thus, it is likely that mesenchymal villus tissue is characterized by a similar genetic pattern that is present in pathological conditions that affect mesodermally-derived organs. In summary, the occurrence of fetal CHD and possibly fetal heart failure may be associated with aberrant levels of PlGF. Prospective studies are therefore required to understand better if PlGF can be used as a potential marker for fetal CHD. A. Curti†, C. Zucchini‡, I. De Maggio†, Y. S. Ismail†, D. Morano§, V. Falcone†, M. C. Meriggiola† and A. Farina*† †Department of Medical Surgical Sciences, Division of Obstetrics and Prenatal Medicine, St Orsola Malpighi Hospital, University of Bologna, 13 Via Massarenti, 40138 Bologna, Italy; ‡Department of Specialist, Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy; §Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy *Correspondence. (e-mail: antonio.farina@unibo.it)