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Genetic Disorders and the Fetus


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These appear to be distinct entities with placental pathology playing a greater role in EOPE.96 Gene expression changes have also been used to demonstrate heterogeneity among PE‐associated placentas, with only a subset showing alterations in classical markers of angiogenesis, such as sFLT‐1 and sENG.97100

      Preeclamptic placentas exhibit areas of syncytial knots (clusters of pre‐apoptotic/apoptotic nuclei) and areas of necrosis associated with loss of the syncytial trophoblast microvillous membranes (STMBs).101 These STMB fragments are released into the mother's blood and have disrupting effects on the maternal endothelium.102 Correspondingly, increased maternal serum levels of cell‐free fetal (i.e. placental) DNA have been reported in PE; however, this may not be predictive after accounting for associated maternal characteristics.103 Furthermore, measuring the ratio of fetal/placental to maternal cell‐free DNA may have limited predictive power for PE as the maternal cell‐free DNA may also increase in these pregnancies.104

      Early diagnosis of preeclampsia

      Early identification of at‐risk pregnancies can improve outcomes through more careful monitoring and early intervention, and thus there is great interest in determining whether there are clinically relevant and assessable markers of this risk to aid early intervention. Administration of low‐dose aspirin prior to 16 weeks of gestation has been linked to reduced risk for PE.105, 106 Once symptoms occur, antihypertensive and/or anticonvulsant medication may be prescribed, although ultimately only delivery of the baby can cure the disease.

      A number of biomarkers quantifiable in maternal blood have been investigated for utility in prediction of PE. An increase in sFLT‐1 and decrease of free vascular endothelial growth factor (VEGF) and PlGF are found in the blood of some women in the first trimester prior to the onset of PE.107, 108 Abnormal levels of endoglin (involved in vascular remodeling) have also been observed, and it has been suggested that PE may be the result of an imbalance between pro‐ and antiangiogenic factors.109 Other factors that have been reported as altered in the serum of pregnant women with or at risk of PE include leptin, ADAM12, PP13, PlGF, PAPP‐A, and inhibin‐A. A screening approach using maternal risk factors (e.g. advanced maternal age, increased weight, previous pregnancy with PE), combined with the uterine artery pulsatility index, mean arterial pressure, and maternal serum markers (PlGF and PAPP‐A), has been reported to detect 95 percent of EOPE with a 5 percent false‐positive rate.110 As all associated biophysical and serum markers are correlated with each other in PE, this needs to be accounted for in the models. It is important to appreciate that the factors contributing to PE may vary by population, and this model needs to be validated in other populations. Furthermore, the predictive value for LOPE is much lower than for the more severe early‐onset form. These factors may explain why other studies suggest less clear predictive benefits of individual serum markers, although combinations of markers may prove useful for early screening.111, 112

      Genetics of preeclampsia

      An effect of fetal genotype on PE risk is demonstrated by the high risk associated with some human trisomies and mutations in rare cases of familial PE. PE is associated with trisomy 13 and 16 but not trisomy 18 or 21.113116 In fact, a reduction in the risk of PE was observed in a large study of trisomy 21 (relative risk of 0.19).115 One in four pregnancies surviving past 20 weeks with trisomy 16 confined to the placental tissues is associated with PE (mostly EOPE).69, 70 The varying risk for PE with different trisomies likely reflects distinct effects on placental development. In trisomy 21, both placenta and fetus are normally sized and show normal78 blood flow by Doppler ultrasound.117119 However, trisomy 21 has a deficiency in formation of the syncytiotrophoblast,117, 118 which could lower the risk of PE because of a reduction in syncytiotrophoblast apoptosis.

      Genetic linkage in large pedigrees segregating for PE has identified mutations in ACVR2A120, 121 and STOX1.122, 123 These mutations appear though to be rare and found in only isolated pedigrees. BWS due to mutations in CDKN1C has also been linked with increased risk for PE.124 In addition, there is some evidence for contribution of genetic variants in several genes, including HLA genotypes and variants in FLT1, to risk of PE.125, 126

Defect Mechanism Placenta/fetus
Digynic triploidy Majority the result of errors in maternal second meiotic division (MII) Very small placenta; no cystic change. Lacy trophoblastic with irregular villus contours. Asymmetric intrauterine growth restriction (IUGR) with associated adrenal hypoplasia. Fetal anomalies attributable to triploidy
Diandric triploidy Fertilization of normal egg by two sperm (dispermy) Large placenta with cystic villi. Cystic chorionic villi, focal trophoblastic hyperplasia – findings of partial hydatidiform mole. Fetal vasculature present, p57 staining positive (normal). May have symmetric IUGR. Fetal anomalies attributable to triploidy
Complete hydatidiform mole (CHM) Fertilization of egg by two sperm with no contribution from the maternal pronucleus Grossly evident cystic villi. Cystic chorionic villi, diffuse circumferential trophoblastic hyperplasia, ± cytologic atypia, stromal karyorrhexis. p57 staining negative (abnormal)
Androgenetic chimerism/mosaicism Two cell populations: one normal, one androgenetic (paternal genome only) Grossly, large placenta, large fetal vessels and associated Wharton's jelly extending into placental disc. Abnormal vessels extend into enlarged and myxomatous appearing stem villi. No trophoblastic hyperplasia. Beckwith–Wiedemann syndrome. Skin and hepatic hemangiomas. Hepatic mesenchymal hamartomas
Trisomy 13 Generally maternal meiotic error Small placental volume. Reduced fetal growth. Abnormal fetus. Increased risk of maternal preeclampsia
Trisomy 18 Generally maternal meiotic error Small placenta leading to reduced fetal growth. Fetal anomalies
Trisomy 21 Generally maternal meiotic error Normal size. Placenta shows deficiencies in the process of cytotrophoblast fusion leading to syncytiotrophoblast formation. Decreased risk of maternal preeclampsia
Confined placental mosaicism: trisomy 16 Almost always