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Pre-eclampsia and trisomy 13: A possible association
Abstract
Pregnancies of fourteen women who gave birth to babies with trisomy 13 were studied retrospectively for evidence of pre-eclampsia, with twenty-eight controls matched for age and parity. Of the five nulliparous women who subsequently gave birth to a baby with trisomy 13 all had had severe pre-eclampsia, compared with none of the control group. The records of eleven women whose first babies had had trisomy 18 (four) or trisomy 21 (seven) were also studied with appropriate controls and none of these pregnancies had been complicated by pre-eclampsia. Development of pre-eclampsia may be influenced by a gene or genes on fetal chromosome 13.
... Cohen et al [13] found oligohydramnios, intrauterine growth restriction, a cystic hygroma, congenital heart defects, and a normal postnatal maternal serum β-hCG level a few weeks after delivery in the case of trisomy 13. Müngen et al [17] reported a case of trisomy 13 with the karyotype 46,XY,der(13)t(13;13) (q11;q11) [20]/47,XY,+13 [11], normal levels of maternal serum α-fetoprotein, hCG and unconjugated estriol, multiple hypoechoic lesions throughout the entire placenta, and a malformed fetus with postaxial polydactyly of the hands and an atrial septal defect. The histopathologic finding of the placenta was consistent with placental mesenchymal dysplasia. ...
... reported severe toxemia and polyhydramnios in a case with possible trisomy 13. Since then, numerous case studies of preeclampsia with trisomy 13 have been reported [5,18,[20][21][22][23][24][25]. Boyd et al [20] studied 14 women who gave birth to trisomy 13 infants and matched them for age and parity to 28 normal controls, and found that there was a significant increase in the incidence of preeclampsia in the trisomy 13 group (5/14) compared with the controls (0/28). ...
... Since then, numerous case studies of preeclampsia with trisomy 13 have been reported [5,18,[20][21][22][23][24][25]. Boyd et al [20] studied 14 women who gave birth to trisomy 13 infants and matched them for age and parity to 28 normal controls, and found that there was a significant increase in the incidence of preeclampsia in the trisomy 13 group (5/14) compared with the controls (0/28). Thornton et al [21] reported that preeclampsia occurred in two out of five multiparous women who gave birth to trisomy 13 infants. ...
Women who are carrying a trisomy 13 fetus are prone to have an abnormal placenta as well as to develop preeclampsia in the second and third trimesters. This article provides a comprehensive review of placental abnormalities, such as small placental volume, reduced placental vascularization, a partial molar appearance of the placenta and placental mesenchymal dysplasia, and preeclampsia associated with trisomy 13 pregnancies. The candidate preeclampsia-causing genes on chromosome 13, such as sFlt1, COL4A2 and periostin, are discussed.
... Another fetal chromosomal association with changes in maternal blood pressure in pregnancy is the association between an increased risk of developing pre-eclampsia and fetal trisomy 13 which has been reported in both (modestly-sized) case-control [45][46][47] and case report form [48][49][50][51][52]. The emergence of pre-eclampsia in these pregnancies may relate to changes in placental development and function associated with the trisomy 13 [52,53] such as a small placental volume and reduced placental vascularisation. Candidate genes from chromosome 13 that may be involved in pre-eclampsia include FMS-related tyrosine kinase 1 (the vascular endothelial growth factor receptor), the alpha-2 chain of type IV collagen and periostin [53]. ...
... Similarly fetal trisomy 21, which causes Down's syndrome and is associated with a reduced risk of maternal pre-eclampsia [42,43], is associated with lower birth weight [97]. Fetal trisomy 13, which causes Patau syndrome and is also associated with risk of maternal pre-eclampsia [45][46][47], may cause fetal growth restriction early in pregnancy [98]. Even fetal trisomy 18 which causes Edward's syndrome and may be associated with maternal HELLP syndrome [54], is also associated with reduced birth weight [99]. ...
The heritability of pregnancy-induced hypertension (encompassing both gestational hypertension and preeclampsia) is around 0.47, suggesting that there is a genetic component to its development. However, the maternal genetic risk variants discovered so far only account for a small proportion of the heritability. Other genetic variants that may affect maternal blood pressure in pregnancy arise from the fetal genome, for example wild-type pregnant mice carrying offspring with Cdkn1c or Stox1 disrupted develop hypertension and proteinuria. In humans, there is a higher risk for preeclampsia in women carrying fetuses with Beckwith-Wiedemann syndrome (including those fetuses with CDKN1C mutations) and a lower risk for women carrying babies with trisomy 21. Other risk may be associated with imprinted fetal growth genes and genes that are highly expressed in the placenta such as GCM1. This article reviews the current state of knowledge linking the fetal genotype with maternal blood pressure in pregnancy.
... Some studies have reported that presence of a type III placental trisomy can cause IUGR [74,90] or preeclampsia [3,9,74]. Especially CPM of trisomy 13 has been reported as having an increased risk of preeclampsia [7,9,33,50]. ...
... Some studies have reported that presence of a type III placental trisomy can cause IUGR [74,90] or preeclampsia [3,9,74]. Especially CPM of trisomy 13 has been reported as having an increased risk of preeclampsia [7,9,33,50]. This might relate to the fact that the FLT1 gene is localized on 13q12.3. ...
Preeclampsia is characterised by new onset hypertension and proteinuria and is a major obstetrical problem for both mother and foetus. Haemolysis elevated liver enzymes and low platelets (HELLP) syndrome is an obstetrical emergency and most cases occur in the presence of preeclampsia. Preeclampsia and HELLP are complicated syndromes with a wide variety in severity of clinical symptoms and gestational age at onset. The pathophysiology depends not only on periconceptional conditions and the foetal and placental genotype, but also on the capability of the maternal system to deal with pregnancy. Genetically, preeclampsia is a complex disorder and despite numerous efforts no clear mode of inheritance has been established. A minor fraction of HELLP cases is caused by foetal homozygous LCHAD deficiency, but for most cases the genetic background has not been elucidated yet. At least 178 genes have been described in relation to preeclampsia or HELLP syndrome. Confined placental mosaicism (CPM) is documented to cause early onset preeclampsia in some cases; the overall contribution of CPM to the occurrence of preeclampsia has not been adequately investigated yet. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.
... The anti-angiogenic state induced by excess placental production of sFLT-1 can be 'rescued' by administering VEGF-A and PlGF (Maynard et al., 2003). The hypothesis that excess placental sFLT-1 may contribute to the pathogenesis of pre-eclampsia is further supported by the increased incidence of pre-eclampsia in mothers carrying trisomy 13 fetuses (Boyd et al., 1987). The genes for sFLT-1 and FLT-1 are localized to chromosome 13. ...
... The genes for sFLT-1 and FLT-1 are localized to chromosome 13. Therefore, fetuses with an extra copy of this chromosome are likely to produce more of the gene products compared with their normal counterparts (Boyd et al., 1987). It has been shown that the ratio of circulating sFLT-1 to PlGF is significantly increased in women carrying trisomy 13 fetuses, possibly contributing to the increased risk of preeclampsia seen in these women . ...
Pre-eclampsia, small-for-gestational-age infants, preterm birth and recurrent miscarriage complicate a significant number of pregnancies. The vascular endothelial growth factor (VEGF) family of angiogenic growth factors is implicated in the pathophysiology of these complications. We aimed to elucidate the role of these angiogenic factors in placentation and to evaluate the predictive value of their protein concentrations and genetic variations in pregnancy complications.
We performed a systematic search of PubMed, and retrieved original articles. The search included a combination of terms such as VEGF-A, placental growth factor (PlGF), kinase insert domain receptor, fms-like-tyrosine-kinase receptor 1, soluble fms-like-tyrosine-kinase receptor 1, pre-eclampsia, small-for-gestational-age infants, preterm birth, recurrent miscarriage, placenta, prediction and polymorphisms.
This review summarizes the current knowledge of the roles of the VEGF family in early placentation and of the abnormalities in maternal plasma and placental expression of angiogenic proteins in adverse pregnancy outcomes compared with normal pregnancy. PlGF and sFLT-1 in combination with other clinical and biochemical markers in late first or second trimester appear to predict early-onset pre-eclampsia with a high sensitivity and specificity. However, VEGF family proteins do not have sufficient power to accurately predict late-onset pre-eclampsia, small-for-gestational age pregnancies or preterm birth. Functional polymorphisms in these angiogenic genes are implicated in pregnancy complications, but their contribution appears to be minor.
Although the VEGF family has important roles in normal and complicated pregnancy, the current predictive value of the VEGF family as biomarkers appears to be limited to early-onset pre-eclampsia.
... Preeclampsia is thought to be more likely among those with a history of obesity or being overweight, hypertension (high blood pressure), antiphospholipid disorder, and diabetes before pregnancy [61]. There are some other factors that lead to preeclampsia; these include null parity or first pregnancy, mother's age greater than 35, chronic kidney disorders, and ART (assisted reproductive technologies) [62]. EVs have a key connection to the pathologic process of preeclampsia. ...
Extracellular vehicles (EVs) have been involved in several aspects of pregnancy, including endometrial receptivity, embryo implantation, and embryo-maternal communication showing them associated with pregnancy disorders, such as preeclampsia, gestational diabetes mellitus, and preterm birth. Further research is warranted to fully comprehend the exact pathophysiological roles of EVs and to develop new therapies targeting EVs thereby improving pregnancy outcomes. Herein, we review the recent knowledge on the multifaceted roles of EVs during pregnancy and address the majority of the molecular interactions between EVs, maternal, and fetal cells with an emphasis on disorders of pregnancy under the influence of EVs. Moreover, we also discuss its applications in clinical trials followed by prospects.
... Preeclampsia risk factors include prior preeclampsia, pregestational diabetes mellitus, obesity, chronic hypertension, antiphospholipid antibody syndrome, nulliparity, autoimmune diseases, maternal age of >35 years, and use of assisted reproductive technologies (Bartsch et al., 2016) and also women who have trisomy13 fetuses are at risk of preeclampsia (Boyd et al., 1987). It seems that removal of the placenta is an effective cure for the disease but there are some treatments for the management of the disease before labor. ...
Preeclampsia (PE) is a pregnancy-related multisystem disorder that is characterized by hypertension and proteinuria after the 20th week of gestation. Although multiple factors are found to be associated with the risk of preeclampsia, the exact pathogenic reason remained unclear. Accumulated data revealed that lncRNAs are dysregulated in the placenta of preeclampsia patients and they alter trophoblast cellular features including
apoptosis, migration, proliferation, and invasion. The current review deals with the recently published data about lncRNAs involved in the pathogenesis of preeclampsia. It provides detailed information on three different sections. First, function and regulation of cancer-related lncRNAs associated with PE, second, lncRNAs discovered by transcriptome analysis and third part will discuss lncRNAs acting through miRNA-lncRNA interaction.
lncRNAs could exert an impact on the pathogenesis of PE through the change in biological functions, epigenetic regulation, miRNA-related gene regulation and signaling pathways (including Notch1, HIF1α, PI3K/AKT). Therefore, based on these important roles, some lncRNAs can act as a biomarker of PE.
... 7,8,13 Especially confined placental mosaicism of trisomy 13 has been reported as having an increased risk of preeclampsia. [14][15][16][17] This is assumed to be due to the localisation of FLT1 gene on 13q12.3. 18 sFLT1 protein levels in maternal serum of pregnancies with a trisomy 13 confined to the placenta, were 35% higher compared to normal pregnancies. ...
Background: Preeclampsia is a pregnancy-related complication characterized by increased blood pressure
without any history of hypertension. Confined placental mosaicism is the presence of chromosomal
abnormalities in the extra-embryonic tissue such as placenta. The association between confined placental
mosaicism of chromosomal aneuploidy and preeclampsia in the Indian population is unknown.
Objective: To determine the association of confined placental mosaicism of chromosomal aneuploidy with
preeclampsia.
Methods: Cross-sectional study was designed to find the association of confined placental mosaicism and
preeclampsia. Placenta (trophoblasts) (n=17), cord blood (n=8), and both placenta (trophoblasts) and cord
blood (n=8) samples were collected from preeclamptic women after delivery. The samples were then
processed and analyzed to find the mosaicism in trisomy 13 (13q14) and 16 (D16Z2) using FISH and
karyotyping.
Results: Both FISH and karyotyping analysis showed that there was no chromosome 13 (13q14) and 16
(D16Z2) mosaicism in both placenta (trophoblasts) and cord blood samples, collected from preeclamptic
women after delivery. The results suggest that confined placental mosaicism was not observed in preeclamptic
women.
Conclusion: The results showed that the confined placental mosaicism of chromosome 13 (13q14) and 16
(D16Z2) aneuploidy is not associated with preeclampsia.
... Both PE and IUGR are heterogeneous in etiology, with many different factors contributing to these phenotypes (6,7,8). Risk factors for PE include genetic abnormalities, such as triploidy, some trisomies, and point mutations, as well as maternal health factors, such as obesity, preexisting hypertension, and diabetes (9,10,11,12). Normotensive IUGR (nIUGR) can arise due to confined placental mosaicism, placental dysfunction, chronic inflammation of the placenta, poor maternal nutrition, smoking, stress, and other causes (12,13,14). Due to the heterogeneity in etiology of PE and IUGR, the ability to sub-classify placentas into more homogeneous groups can aid in our understanding of disease pathogenesis and prediction. ...
Placental health is a key component to healthy pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analyzed these separately. This study aims to identify altered DNAm in EOPE, LOPE, and normotensive IUGR, validate these alterations, and use them to better understand the relationships between these related disorders.
Placental samples from a discovery cohort (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To minimize gestational age (GA) effects, EOPE samples were compared to pre-term controls (GA <37 weeks), while LOPE and IUGR were compared to term controls (GA >37 weeks). There were 1703 differentially methylated (DM) sites (FDR<0.05, Δβ>0.1) in EOPE, 5 in LOPE, and 0 in IUGR. Of the 1703 EOPE sites, 599 were validated in the second cohort. These sites cluster samples from both cohorts into 3 distinct methylation clusters. Interestingly, LOPE samples diagnosed between 34-36 weeks with co-occurring IUGR clustered with the EOPE methylation cluster. DNAm profiling may provide an independent tool to refine clinical diagnoses into subgroups with more uniform pathology. The challenges in reproducing genome-wide DNAm studies are also discussed.
... Relatively rare risk factors are a family history of preeclampsia and mother carrying a trisomy 13 fetus. 10,11 Genetic susceptibility to preeclampsia has been extensively studied. 12,13 A 2017 genome-wide association study analysis of neonates from 4380 cases of preeclampsia and 310 238 controls found a genome-wide susceptibility locus (rs4769613; P=5.4×10 −11 ) near the FLT1 (FMS-like tyrosine kinase 1) gene, the protein ...
Hypertensive disorders of pregnancy-chronic hypertension, gestational hypertension, and preeclampsia-are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus. While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular disease in women.
... Both PE and IUGR are heterogeneous in etiology, with many different factors contributing to these phenotypes (6)(7)(8). Risk factors for PE include genetic abnormalities, such as triploidy, trisomy 13 or 16, and point mutations, as well as maternal health factors, such as obesity, pre-existing hypertension, and diabetes (9)(10)(11)(12). Normotensive IUGR (nIUGR, i.e no co-occurring PE) can arise due to similar factors as PE as well as poor maternal nutrition, smoking, stress, and other causes (12)(13)(14). ...
Placental health is a key component to a successful pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analyzed them separately. This study aims to utilize DNAm profiling to better understand the underlying placental variation associated with PE and IUGR.Placental samples from a discovery (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To account for gestational age (GA) effects, EOPE samples were compared to pre-term births of varying etiologies (GA < 37 weeks). LOPE and IUGR were compared to term controls (GA > 37 weeks). While 1703 sites were differentially methylated (DM) (FDR<0.05, Δβ>0.1) in EOPE, few changes were associated with LOPE (N = 5), or IUGR (N = 0). Of the 1703 EOPE sites, 599 validated in the second cohort. Using these 599 sites, both cohorts clustered into 3 distinct groups. Interestingly, LOPE samples diagnosed between 34-36 weeks with co-occurring IUGR clustered with the EOPE. DNAm profiling may provide an independent tool to refine clinical/pathological diagnoses into subgroups with more uniform pathology. Despite large changes observed in EOPE, there were challenges in reproducing genome-wide DNAm hits that are discussed.
... Complement regulation at the placental interface becomes impaired in preeclampsia [46,47]. Over the course of pregnancy, placental strain increases due to a variety of factors such as aberrant placental blood flow and oxygenation [48,49], maternal conditions such as obesity or hypertension [50,51], or unusual conditions such as fetal hydrops [52] or aneuploidy [53]. Regardless of etiology, the net result is placental strain, excess complement activation, and systemic inflammation. ...
Preeclampsia continues to contribute to major maternal and neonatal morbidity and mortality worldwide. In this article, we review the pathophysiological mechanisms, screening strategies, and novel therapeutic options for preeclampsia.
... In terms of the obstetric clinical course, trisomic cases often have poor outcomes, for example, preeclampsia and intrauterine growth restriction 8,20,31,[46][47][48][49][50][51][52]61 . These conditions, which can be associated with all the aneuploidies that we studied, are most common in T13 and T18 pregnancies 8,48,49,62,63 . In contrast, T21-affected pregnancies have a more favorable outcome, not only over the course of pregnancy, but also during the postnatal period 64 . ...
Objective:
Chromosomal aberrations are frequently associated with birth defects and pregnancy losses. Trisomy13, Trisomy 18 and Trisomy 21 are the most common, clinically relevant fetal aneusomies. This study used a transcriptomics approach to identify the molecular signatures at the maternal-fetal interface in each aneuploidy.
Methods:
We profiled placental gene expression (13-22 wks) in T13 (n = 4), T18 (n = 4), and T21 (n = 8), and in euploid pregnancies (n = 4).
Results:
We found differentially expressed (DE) transcripts (≥2-fold) in T21 (n = 160), T18 (n = 80), and T13 (n = 125). The majority were upregulated and most of the misexpressed genes were not located on the relevant trisomic chromosome, suggesting genome-wide dysregulation. A smaller number of the DE transcripts were encoded on the trisomic chromosome, suggesting gene dosage. In T21, <10% of the genes were transcribed from the Down syndrome critical region (21q21-22), which contributes to the clinical phenotype. In T13, 15% of the upregulated genes were on the affected chromosome (13q11-14) and in T18 the percentage increased to 24% (18q11-22 region).
Conclusion:
The trisomic placental (and possibly fetal) phenotypes are driven by the combined effects of genome-wide phenomena and increased gene dosage from the trisomic chromosome.
... An association between trisomy 13 and pre-eclampsia but not the other more common aneuploidies (trisomy 21 and 18) has been reported (324,325). A difference in angiogenic factors may explain this increased risk with a significant decrease in PlGF in trisomy 13 ...
... Those who survive have serious intellectual and physical disabilities. Along with the maternal health risks associated with carrying any pregnancy, one small study specifically identified pre-eclampsia in mothers carrying trisomy 13 fetuses, but not in mothers carrying fetuses with other aneuploidies [17]. Early prenatal detection of trisomy 13 would allow parents time to come to terms with the diagnosis, receive counseling and prepare for the possible outcomes, and facilitate earlier decision-making. ...
To determine how a single nucleotide polymorphism (SNP)- and informatics-based non-invasive prenatal aneuploidy test performs in detecting trisomy 13.
Seventeen trisomy 13 and 51 age-matched euploid samples, randomly selected from a larger cohort, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex polymerase chain reaction assay that interrogated 19,488 SNPs covering chromosomes 13, 18, 21, X, and Y, and sequenced. Analysis and copy number identification involved a Bayesian-based maximum likelihood statistical method that generated chromosome- and sample-specific calculated accuracies.
Of the samples that passed a stringent DNA quality threshold (94.1%), the algorithm correctly identified 15/15 trisomy 13 and 49/49 euploid samples, for 320/320 correct copy number calls.
This informatics- and SNP-based method accurately detects trisomy 13-affected fetuses non-invasively and with high calculated accuracy.
... They reported maternal diseases in 15.4% of our cases. Despite the association described in the literature between fetuses with PS and preeclampsia (20)(21)(22) , there was no difference between the frequency noted in cases described here (7.7%) and in pregnant women in general (2.3%) (23) (p=0.12) ( Table 1). Perhaps this is related to the low frequency (7.4%) of primiparous mothers (a risk factor well associated with preeclampsia) in this study in comparison to pregnant women in general (43.8%) (18) (p=0.0001) or the actual sample size. ...
To describe gestational, perinatal and family findings of patients with Patau syndrome (PS).
The study enrolled patients with PS consecutively evaluated during 38 years in a Clinical Genetics Service of a pediatric referral hospital in Southern Brazil. The clinical data and the results of cytogenetic analysis were collected from the medical records. For statistical analysis, the two-tailed Fisher's exact test and the chi-square test with Yates' correction were used, being significant p<0.05.
The sample was composed of 27 patients, 63% were male, with a median age of nine days at the first evaluation. Full trisomy of chromosome 13 was the main cytogenetic finding (74%). Only six patients were submitted to obstetric ultrasound and none had prenatal diagnosis of PS. The patients' demographic characteristics, compared to born alive infants in the same Brazilian state showed a higher frequency of: mothers with 35 years old or more (37.5%); multiparous mothers (92.6%); vaginal delivery (77%); preterm birth (34.6%); birth weight <2500g (33.3%), and Apgar scores <7 in the 1st (75%) and in the 5th minute (42.9%). About half of them (53%) died during the first month of life.
The understanding of the PS patients' gestational, perinatal and family findings has important implications, especially on the decision about the actions to be taken in relation to the management of these patients.
... While the underlying cause of preeclampsia is unknown, an effect of fetal/placental genotype on preeclampsia risk has been demonstrated by the high risk associated with select human trisomies. Increased risk for preeclampsia is associated with trisomy 13 and 16 [7,31,32], but not trisomy 18 or 21 [33]. In fact, risk for preeclampsia is reduced in trisomy 21 pregnancies [34]. ...
... Most infants with a trisomy 18 or 13 die in utero and the others within the fi rst year of life. Especially in case of trisomy 13, there is an increased risk of severe and early onset pre-eclampsia 198 . ...
Down syndrome (DS) is the most common chromosomal abnormality, with an incidence of approximately 1 per 500 to 800 live births. The first-trimester combined test is mostly used for the prenatal prediction of carrying a child with DS. The test is composed of the maternal serum parameters pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (f?-hCG), and an ultrasound measurement of the foetal nuchal translucency (NT), combined with maternal age. The detection rate (DR) of DS screening in the Netherlands is currently 70-75%, which is rather low as compared to other countries. The aim of this research was to investigate ways to improve the performance of the current DS screening programme. The extra chromosome in DS not only leads to anomalies of the foetus, but also of the placenta. The inability of placental cells to develop properly is associated with a decrease of trophoblastic products. If this differential expression is traceable in maternal blood these products could have potential as new screening markers. Several markers have been investigated and found to be potentially useful as predictors of DS. One of those markers is placental protein 13 (PP13) which was found to be decreased in DS pregnancies. Moreover, serum concentrations of a disintegrin and metalloprotease 12 (ADAM12) and placental growth factor (PlGF) are decreased, while total hCG (thCG) is increased in first-trimester DS pregnancies. However, the addition of these markers to the current first-trimester combined test only slightly increases the DR. Therefore, a dedicated search for more markers was set up. An extensive review of the literature was carried out to study normal placental development and function during early pregnancy. Furthermore, a bioinformatics approach was developed using data from the literature on genes and protein expression. This way, a list of potential DS screening markers was generated. The list included three biomarkers that are already used for DS screening and several others, among which PP13 and PlGF. A more experimental approach was carried out by analyzing 90 different proteins from a pre-existing immunoassay. By comparing the protein concentrations in a small cohort of DS and control sera, seven potential screening markers were identified. To confirm the predictive value of these seven markers a subsequent validation study was carried out. Epidermal growth factor (EGF) and EN-RAGE were confirmed to be potential screening markers for DS and improved the DR of the current first-trimester combined test with approximately 6%. In addition, Cancer Antigen 19-9 (CA19-9), was found to be strongly predictive for DS and even further increased the DR. It turned out that the predictive power of serum markers differs within the first trimester. Therefore, it would be useful to draw two separate blood samples and analyze several markers to increase the DR of first-trimester screening to almost 90%. If such a screening test is to be developed, simultaneous assessment of markers is crucial and demands innovation of the test, i.e. by using Antibody microarrays.
... Most infants with a trisomy 18 or 13 die in utero and the others within the first year of life. Especially, in case of trisomy 13, there is an increased risk of severe and early onset pre-eclampsia (Boyd et al., 1987). To enable an early termination of trisomy 18 and 13 pregnancies, and to avoid maternal complications, screening for trisomy 18 and 13 seems a sensible option, especially since modelling has shown that current first trimester screening can detect both chromosomal anomalies with a high detection rate (DR) and low false positive rate (FPR) (Tul et al., 1999;Spencer et al., 2000). ...
Aims: Uteroplacental (uterine artery systolic/diastolic (S/D) ratio) and fetal circulation changes (umbilical artery pulsatility Index (PI) value) can be evaluated non-invasively by using Doppler ultrasonography spectral analysis. The present study aimed to demonstrate how Doppler ultrasonography should be combined with classical well-being tests to detect perinatal morbidity and mortality in hypertensive pregnancy. Methods: This prospective research was carried out with 88 pregnant women diagnosed with high-risk pregnancy and hypertension between April 1992 and May 1994. A non-stress test (NST) was performed in all cases, and fetal distress was evaluated by a biophysical profile (BP) and/or a contraction stress test (CST) subsequent to a non-reactive NST. Following the diagnosis of hypertension, longitudinal maternal (uterine artery) and fetal (umbilical artery) Doppler analyses were initiated at 7–10-day intervals. In the study, the Acuson 128 XP 10 device (Research project No. 515/080555592 was funded by the İstanbul University Research Fund) and a 3.5-5 MHz curvilinear probe were used. No Doppler pathology was considered solely in the timing of delivery. Results: There was no case of perinatal loss, antepartum and intrapartum fetal distress, neonatal asphyxia, and oligohydramnios in the group with normal uterine and umbilical artery Doppler analyses. There was one case with umbilical artery Doppler flow pathology only, which was delivered by preterm cesarean section with the diagnosis of antepartum fetal distress. Fetus diagnosed to have a fetal growth restriction (FGR) and the findings of fetal distress, FGR, and cesarean delivery were concordant with the literature. There was also increased perinatal mortality (9.1%) among patients with pathological uterine artery Doppler and normal umbilical artery Doppler group, but there was no case of oligohydramnios in this group and the rate of neonatal asphyxia (5.min Apgar score <7) was 21.7%. The antepartum loss was 27%, the neonatal loss was 23.8%, and perinatal mortality was 44.8% in the group with pathological uterine and umbilical artery Doppler findings, and this group had all cases of oligohydramnios. Conclusion: Overall, it seems reasonable to identify any pathologies with Doppler ultrasonography in hypertensive pregnant women in the early pregnancy and to follow them up with classical fetal antepartum surveillance tests at appropriate intervals related to their umbilical artery Doppler pathologies.
This chapter reviews the causes of placental disease and the role of the placenta in diagnosis of fetal health with a focus on genetic associations. Evaluating the placenta requires an understanding of its unique structure and development. Placental insufficiency is the situation whereby the placenta does not deliver an adequate supply of nutrients and oxygen to the growing fetus. Although the mechanisms linking prenatal events to childhood health are largely unknown, it seems plausible that examining molecular profiles and pathogenic markers in the placenta at delivery may be useful in predicting future risks for childhood and adult disease. Distinguishing fetal growth restriction (FGR) from a constitutionally small baby prenatally is important, as it is specifically the FGR baby that is at risk of adverse perinatal outcomes, including intrauterine death, premature birth, neonatal sepsis, and neurological impairment. Maternal preeclampsia frequently occurs with FGR and shares many similar pathologic features.
Este é um sumário de informações acerca da Síndrome de Patau que tem como público-alvo mães, pais e familiares. Sumarizamos e traduzimos parte do conhecimento disponibilizado em artigos e outras fontes de informação, com a intenção de apoiar o processo de acolhimento, cuidado e tomada de decisão após o diagnóstico. Este sumário não substitui a orientação de pediatras, geneticistas ou de outros profissionais de saúde.
What's already known about this topic? Trisomy 13 (T13) pregnancies are associated with increased risk of gestational hypertensive disorders (GHDs).
It is unclear if false positive cell‐free DNA results for T13, which may be caused by confined placental mosaicism, are associated with increased risk for GHD.
What does this study add? Among six women with false positive cell‐free DNA for T13, four developed GHD, raising the possibility that there may be an increased risk for GHD in women with false positive cell‐free DNA results for T13.
© 2017 John Wiley & Sons, Ltd.
Introduction The last decade has seen increasing evidence of the power of molecular genetics to generate novel hypotheses of disease etiology. Clinical observation suggests that there is a familial predisposition to a number of disorders associated with impaired placentation, including preeclampsia, fetal growth restriction, recurrent miscarriage, and preterm labor [1, 2, 3]. From this spectrum of disorders, preeclampsia is the condition which has attracted most attention from geneticists, and will be the focus of this chapter. The identification of susceptibility genes offers unique insights into the pathophysiology of disease. In many patients, perhaps the majority, preeclampsia has its origins in the early stages of pregnancy prior to the onset of symptoms, at a time when basic research into its etiology is impossible for practical and ethical reasons. Once the disease is established, pathophysiological research is hampered by the transient phenotype of the condition, and confounded by secondary responses to the widespread maternal endothelial damage. Genetic research is an attractive option, as the patient’s genotype is unaffected by time or disease severity. The evidence for inheritance First-degree relatives of women affected by preeclampsia have a two- to three-fold increase in risk of the disorder compared with the rest of the pregnant population [4, 5, 6]. In genetic terminology, this is known as the relative risk ratio, λR, and is calculated as the ratio of the incidence of disease in first-degree relatives to its incidence in the population.
Purpose of investigation:
To detect the candidate genes for preeclampsia (PE).
Materials and methods:
The gene expression profiles in preeclamptic and normal placental tissues were analyzed using cDNA microarray approach and the altered expression of important genes were further confirmed by real-time RT-PCR (reverse transcription polymerase chain reaction) technique. Total RNA was extracted from placental tissues of three cases with severe PE and from three cases with normal pregnancy. After scanning, differentially expressed genes were detected by software.
Results:
In two experiments (the fluorescent labels were exchanged), a total of 111 differentially expressed genes were detected. In placental tissue ofpreeclamptic pregnancy, 68 differentially expressed genes were up-regulated, and 44 differentially expressed genes were down-regulated. Of these genes, 16 highly differentially expressed genes were confirmed by real-time fluorescent quantitative RT-PCR, and the result showed that the ratio of gene expression differences was comparable to that detected by cDNA microarray.
Conclusion:
The results of bioinformatic analysis showed that encoding products of differentially expressed genes were correlated to infiltration of placenta trophoblastic cells, immunomodulatory factors, pregnancy-associated plasma protein, signal transduction pathway, and cell adhesion. Further studies on the biological function and regulating mechanism of these genes will provide new clues for better understanding of etiology and pathogenesis of PE.
Preeclampsia and eclampsia are familial, as genetic research on these conditions over the last century has shown. Preeclampsia occurs when placental ischemia or inflammation causes various mediators to be released directly into the maternal circulation. The maternal endothelium and arterioles respond initially in an adaptive manner, but ultimately cause profound dysfunction of various major organs. Any number of disorders with a genetic component might interfere with maternal vascular responses, affect trophoblast function, or increase the placental mass, causing fetal demands to outpace the supply. Every ligand, every receptor, every amplification cascade, every aspect of the programmed responses that orchestrate the pathophysiological response is under the control of either the mother's or the fetus' genes. Preeclampsia is a difficult phenotype to study using genetic methodologies. A major lesson of modern genetics is that syndromes defined on the basis of clustering of clinical symptoms often reveal marked heterogeneity once they are understood at a molecular level. In this respect, the boundaries around preeclampsia, gestational hypertension, and HELLP syndrome are likely to be redrawn when genetic determinants can be examined directly. Candidate gene studies require the prioritization of specific genes-and only genes-for investigation into links with identifiable biological functions that are consistent with the pathogenesis of the studied disease.
Key content
Congenital anomalies are the number one cause of infant mortality in the developed world. Antenatal diagnosis of lethal fetal abnormality is likely to have a profound psychological impact.
The multidisciplinary team should aim to meet the medical, emotional and spiritual needs of the family, through appropriate referral in the latter aspect.
Learning objectives
To consider the psychological impact of an antenatal diagnosis of lethal fetal abnormality.
To review the principles of informing parents about the diagnosis.
To provide a framework for the management of a pregnancy involving a lethal fetal anomaly.
To increase the awareness of the emotional and spiritual needs of the family.
Ethical issues
The dilemma of psychological impact of carrying a pregnancy with a lethal fetal anomaly for a mother and a family.
The issues around care including feeding the liveborn baby with an anomaly.
Pre-eclampsia is a serious complication of the second half of human pregnancy which occurs at frequencies of 1 % to 5% in most parts of the world. It is characterized clinically by high blood pressure, proteinuria, and generalized edema in association with a wide range of pathophysiological organ and system disturbances. Untreated, it can lead to the occurrence of epileptic-like grand-mal convulsions (eclampsia), which is a source of considerable maternal and fetal morbidity. The disease is unusual in having no known cause, although an immunological impairment is suspected. Here we review the evidence that the condition is genetic in origin. Several genetic models are discussed. Markedly raised incidences are seen in blood relatives (mothers, daughters, sisters, and granddaughters) but not in relatives by marriage (daughters-in-law, mothers-in-law). This suggests that the condition is caused by maternal genes. Other evidence, however, implicates the fetal genotype. The most decisive data supporting this show a lack of concordance in monozygous twins. Thus the condition may be the result of a maternal-fetal genotype by genotype interaction, broadly analogous to Rhesus disease. To date, most attempts to find the genes involved have focused on the human leucocyte antigen (HLA) system. It is clear that the maternal genes are not in the HLA system, but the possibility that the postulated fetal genes are located there remains open. Current work concentrates on linkage studies aimed at finding the responsible genes. There is still a need for more pedigree and twin data, especially from non-European ethnic groups.
The incidence of pre-eclampsia is significantly higher in trisomy 13 pregnancies than in normal pregnancies. Soluble fms-like tyrosine kinase-1 (sFlt-1), located on chromosome 13, is an anti-angiogenic molecule derived from the placenta and contributes to the pathogenesis of pre-eclampsia. Elevated sFlt-1 and reduced placental growth factor (PlGF) are associated with trisomy 13 pregnancies and may play a pathogenic role in the subsequent development of pre-eclampsia. Here we present a case of a trisomy 13 pregnancy without any signs of pre-eclampsia that showed alterations in circulating angiogenic factors and abnormal placental appearance. The placenta developed edematous changes and contained multiple small cysts. Histology of the placenta confirmed avascular edematous cystic villi and did not show the typical appearance of a partial mole or mesenchymal dysplasia. The sFlt-1/PlGF ratio in maternal serum (134) was much higher than that in gestational age-matched women who were normotensive (2.9-7.2; mean, 5.0). Immunostaining for Flt-1 and endoglin was more intense in our case compared with gestational age-matched controls, and at a similar level to a case of pre-eclampsia. Placental findings that showed avascular edematous cystic villi in our case may be associated with angiogenic imbalance involved in the pathogenesis of pre-eclampsia in trisomy 13 pregnancies.
Objective: To investigate how well various inheritance models would explain the familial tendency of the preeclampsia/eclampsia syndrome. Methods: The prevalence among seven groups of women with definite probabilities of exhibiting the disorder from six different family studies was used to obtain maximum likelihood estimates of the contributions to disease liability from major genes and multifactorial transmission. Results: Models involving a single major gene with incomplete penetrance or multifactorial inheritance offered considerably better fit to the observed data than no familial transmission at all or autosomal dominant and recessive inheritance models with complete penetrance. Of the major gene models, a dominant mode of transmission was preferred. From the extremes of the joint 95% confidence region for the gene frequency (p) and penetrance (f), the corresponding confidence limits for the best estimates were 0.06 < p < 0.16 and 0.38 > f > 0.23, respectively. Conclusions: These results indicate that the prevalence of the disease is not best explained by simple Mendelian inheritance as previously suggested. A major dominant gene model with reduced penetrance or multifactorial inheritance should be considered the best working hypotheses at present.
Objective To assess the reported association between field trisomy 13 and maternal pre-eclampsia.
Design A retrospective case-control study.
Subjects Twenty-five women who gave birth to trisomy 13 infants in southwest England between 1971 and 1989; 38 women who gave birth to trisomy 18 infants in the same region over the same time and 50 women with normal karyotype infants matched for age, parity, and date of delivery with the trisomy 13 group.
Main outcome measures The medical records of all the women in the three groups were analysed for evidence of pre-eclampsia. Four different thresholds of pre-eclampsia were used. The incidence of pre-eclampsia was compared between the three study groups and analysed separately for primigravid and multigravid women.
Results The incidence of pre-eclampsia in pregnancies complicated by trisomy 13 was significantly higher than the incidence in the trisomy 18 and the normal karyotype control groups. This association was more pronounced in primigravid pregnancies.
Conclusions This, the largest survey of trisomy 13 and pre-eclampsia to date, suggests an association between the two conditions. It also supports the argument for a fetal factor in the pathogenesis of pre-eclampsia. We speculate on how genes encoded on chromosome 13 may be responsible.
Increased levels of soluble fms-like tyrosine kinase (sFlt-1) in Trisomy 13 pregnancies are thought to be mediated by the placenta. This study aimed to compare sFlt-1 expression in Trisomy 13 (n = 7) placentas with that in control placentas (Trisomy 21, n = 11, and euploid, n = 6).
This was a retrospective case-control study analyzing paraffin-embedded placental blocks that were stained with hematoxylin and eosin and antibodies to sFlt-1. Their staining intensity was compared using a semiquantitative technique. The Kruskal-Wallis test and Wilcox rank sum test were used for statistical analysis.
The median staining was significantly higher in Trisomy 13 compared with control specimens (P = .008) (for Trisomy 13 vs Trisomy 21, P = .003, and Trisomy 13 vs euploid, P = .004).
Our study demonstrates that Trisomy 13 placentas express more sFlt-1 than control placentas. These results strengthen the hypothesis that the increased incidence of preeclampsia in Trisomy 13 pregnancies is secondary to placental up-regulation of sFlt-1.
Normal pregnancy is associated with significant vascular remodeling in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. The pregnancy-associated vascular changes are largely due to alterations in the amount/activity of vascular mediators released from the endothelium, vascular smooth muscle and extracellular matrix. The endothelium releases vasodilator substances such as nitric oxide, prostacyclin and hyperpolarizing factor as well as vasoconstrictor factors such as endothelin, angiotensin II and thromboxane A(2). Vascular smooth muscle contraction is mediated by intracellular free Ca(2+) concentration ([Ca(2+)](i)), and [Ca(2+)](i) sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Extracellular matrix and vascular remodeling are regulated by matrix metalloproteases. Hypertension in pregnancy and preeclampsia are major complications and life threatening conditions to both the mother and fetus, precipitated by various genetic, dietary and environmental factors. The initiating mechanism of preeclampsia and hypertension in pregnancy is unclear; however, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduction in the uteroplacental perfusion pressure and placental ischemia/hypoxia. This placental hypoxic state is thought to induce the release of several circulating bioactive factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and vascular receptor antibodies. Increases in the plasma levels and vascular content of these factors during pregnancy could cause an imbalance in the vascular mediators released from the endothelium, smooth muscle and extracellular matrix, and lead to severe vasoconstriction and hypertension. This review will discuss the interactions between the various circulating bioactive factors and the vascular mediators released during hypertension in pregnancy, and provide an insight into the current and future approaches in the management of preeclampsia.
Normal pregnancy is associated with significant hemodynamic changes and vasodilation in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Hypertension in pregnancy (HTN-Preg) and preeclampsia (PE) are major complications and life-threatening conditions to both the mother and fetus. PE is precipitated by various genetic, dietary and environmental factors. Although the initiating events of PE are unclear, inadequate invasion of cytotrophoblasts into the uterine artery is thought to reduce uteroplacental perfusion pressure and lead to placental ischemia/hypoxia. Placental hypoxia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II receptor. These bioactive factors affect the production/activity of various vascular mediators in the endothelium, smooth muscle and extracellular matrix, leading to severe vasoconstriction and HTN. As an endothelial cell disorder, PE is associated with decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin, angiotensin II and thromboxane A(2). PE also involves enhanced mechanisms of vascular smooth muscle contraction including intracellular free Ca(2+) concentration ([Ca(2+)](i)), and [Ca(2+)](i) sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Changes in extracellular matrix composition and matrix metalloproteases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Characterization of the predisposing risk factors, the biologically active factors, and the vascular mediators associated with PE holds the promise for early detection, and should help design specific genetic and pharmacological tools for the management of the vascular dysfunction associated with HTN-Preg.
We examined the potential value of the uterine artery pulsatility index (PI) in pregnancies with fetal aneuploidies and in those that developed preeclampsia (PE) with the aim of distinguishing between these complications in pregnancies with low pregnancy-associated plasma protein-A (PAPP-A).
Uterine artery PI and serum PAPP-A at 11-13 weeks were measured in 165 cases of PE, including 33 that required delivery before 34 weeks (early PE) and 132 with late PE, and in 301 cases with aneuploidies, including 200 with trisomy 21. Each case of aneuploidy and PE was matched with 4 unaffected controls.
Serum PAPP-A was lower in early PE (0.58 multiples of the normal median, MoM) and in trisomy 21 (0.54 MoM), trisomy 18 (0.22 MoM) and Turner syndrome (0.51 MoM) - but not in late PE (0.90 MoM) - than in controls (1.01 MoM). Uterine artery PI was higher in early PE (1.52 MoM), late PE (1.20 MoM), trisomy 18 (1.20 MoM) and Turner syndrome (1.29 MoM) - but not in trisomy 21 (1.02 MoM) - than in controls (1.0 MoM).
The uterine artery PI at 11-13 weeks may be useful in distinguishing between low PAPP-A due to trisomy 21 and early PE.
Pre‑eclampsia is a major cause of maternal and perinatal mortality and morbidity worldwide, but remains unclear about the underlying disease mechanisms. Pre‑eclampsia is currently believed to be a two‑ stage disease. The first stage involves shallow cytotrophoblast invasion of maternal spiral arteriole, resulting in placental insufficiency. The hypoxic placenta release soluble factors, cytokines, and tropho-blastic debris into maternal circulation, which induce systemic endothelial damage and dysfunction. This cause the second stage of the disease: maternal syndrome. Epidemiological research has consistently demonstrated a familial predisposition to pre‑eclampsia. Intensive research efforts have been made to discover susceptibility genes that will inform our understanding of the pathophysiology of pre‑ eclampsia and that may provide direction for therapeutic or preventative strategies. In this review, we summarize the current understanding of the role of genetic factors in the pathophysiology of pre‑eclampsia and explain the molecular approach to search for genetic clues in pre‑eclampsia.
A 41 year old multiparous woman with an uncomplicated obstetric history was referred because of pre-eclampsia. As ultrasonic examination revealed severe IUGR and multiple congenital anomalies, trisomy 13 was suspected and confirmed by amniocentesis. This chromosomal anomaly should be suspected in cases where pre-eclampsia is associated with abnormal fetal morphology.
A previously healthy young primigravida suffered very severe pre-eclampsia and was delivered at 32 weeks gestation. The baby was growth retarded with dysmorphic features, and died aged 4 days. Chromosome analysis of the baby revealed partial trisomy 13 resulting from recombination within a maternal insertion of part of 13q into 3p. To date, the maternal insertion has been identified in a further three members of the family and may have contributed to a number of spontaneous abortions, stillbirths and neonatal deaths in other family members. The various possibilities for recombination and malsegregation are discussed. An association between pre-eclampsia and trisomy 13 has been reported previously. To our knowledge this present paper constitutes the first report of partial trisomy for 13q occurring with pre-eclampsia.
Trisomy 13 is very rare in live-born children. Only a small number of these children survive the first year and very few cases are reported to live longer. Survival time depends partly on the cytogenetic findings--full trisomy 13 or trisomy 13 mosaicism--and partly on the existence of serious somatic malformations. We report on a 11-year-old girl with full trisomy 13. In this case, missing cerebral and cardiovascular malformations probably allowed the long survival.
We report the case of a 39-year-old para-4 gravida-4 who received polychemotherapy 5-fluorouracil 600 mg/m2, cyclophosphamide 600 mg/m2 and epirubicin 50 mg/m2 for invasive breast cancer (pT2N2Mo) with extensive metastatic involvement of all 23 axillary lymph nodes removed at 29 gestational weeks. Soon after the second course of chemotherapy at 35 weeks, she developed two eclamptic tonic-clonic seizures which were treated by antihypertensive and anticonvulsive drugs and delivery of a healthy infant, 1650 g (< 10th percentile) by cesarean section. That this patient indeed suffered from eclampsia was supported by the findings of transient postpartum severe hypertension (peak 170/110 mmHg), proteinuria (peak 3.2 g/24 h), incomplete features of the HELLP syndrome (thrombocytopenia 81,000/mm3, haptoglobin < 10 mg/dl) and of DIC, and by the results of cerebral CT scanning showing two 1-cm ischemic lesions. Since the detrimental effect of antineoplastic agents on the rapidly proliferating trophoblast is well known and as abnormal placental function, such as in triploidy, trisomy or hydatiform mole, has been associated with an increased risk for preeclampsia/eclampsia, a possible causal relationship between polychemotherapy and the subsequent development of this rare disorder is suggested.
The etiology of preeclampsia is unknown. At present, 4 hypotheses are the subject of extensive investigation, as follows: (1) Placental ischemia-Increased trophoblast deportation, as a consequence of ischemia, may inflict endothelial cell dysfunction. (2) Very low-density lipoprotein versus toxicity-preventing activity-In compensation for increased energy demand during pregnancy, nonesterified fatty acids are mobilized. In women with low albumin concentrations, transporting extra nonesterified fatty acids from adipose tissues to the liver is likely to reduce albumin's antitoxic activity to a point at which very-low density lipoprotein toxicity is expressed. (3) Immune maladaptation-Interaction between decidual leukocytes and invading cytotrophoblast cells is essential for normal trophoblast invasion and development. Immune maladaptation may cause shallow invasion of spiral arteries by endovascular cytotrophoblast cells and endothelial cell dysfunction mediated by an increased decidual release of cytokines, proteolytic enzymes, and free radical species. (4) Genetic imprinting-Development of preeclampsia-eclampsia may be based on a single recessive gene or a dominant gene with incomplete penetrance. Penetrance may be dependent on fetal genotype. The possibility of genetic imprinting should be considered in future genetic investigations of preeclampsia.
Pre-eclampsia is a syndrome with a strong familial component. Autosomal recessive inheritance acting only in the mother is not consistent with the epidemiological data, and a more complex genetic susceptibility, involving interactions between maternal and fetal genomes, seems likely. The human leukocyte antigen (HLA) system has been implicated, but many of the findings reported have been inconsistent or contradictory. Pre-eclampsia is unlikely to be the simple result of excessive HLA-class II antigen sharing between mother and fetus, as was first thought, but a more complex mechanism involving feto-maternal compatibility cannot be excluded. The reported increase in HLA-DR4 in mothers and babies from pre-eclamptic pregnancies has not been independently confirmed for mothers, and no further studies have been conducted with babies. Consequently, the allegedly stronger relationship with HLA-DR4 sharing between mother and fetus has neither been confirmed nor refuted. Certain (B44-DR7)-containing haplotypes appear to confer increased risk for pre-eclampsia on the basis of independent analyses of American and Scottish populations. HLA-DR53 may be associated with the antiphospholipid antibody syndrome, which is itself a strong risk factor for pre-eclampsia. The tumour necrosis factor (TNF)-alpha allele, TNF1, may be associated with pre-eclampsia and certainly elevated concentrations of the cytokine appear to be a feature of the disease. The inducibility of TNF-alpha is HLA-class II-dependent, and the relevance of HLA-class II genes might be entirely in relation to TNF-alpha synthesis and secretion.
To estimate the maternal genetic contribution to the hypertensive diseases of pregnancy.
A cohort study of female twins with information on hypertensive diseases of pregnancy obtained by questionnaire screening, and verification of diagnosis from hospital or general practitioner records.
A volunteer twin registry in the UK with recruitment through the media without reference to pregnancies or disease status.
Adult female, same-sex twin pairs who completed a pregnancy history questionnaire and consented to record inspection.
Self-reported and hospital-validated diagnosis of non-proteinuric pregnancy hypertension and of pregnancy hypertension with proteinuria (pre-eclampsia).
Self-reported pre-eclampsia had a heritability of 0.221 and non-proteinuric hypertension of 0. 198. However, none of the pairs who were self-reported as concordant for pre-eclampsia were confirmed from hospital records. Using hospital records, the heritability of pre-eclampsia was 0 and 0.375 for non-proteinuric hypertension. Using a model treating pre-eclampsia as a separate disease from non-proteinuric hypertension, and assuming that the next pair identified was both monozygotic and concordant for pre-eclampsia, the estimated heritability of pre-eclampsia remained 0 (95% CI 0-0.49). Using a threshold model in which non-proteinuric hypertension is treated as a mild form of pre-eclampsia, heritability is estimated at 0.247 (95% CI 0.23-0.454).
Neither non-proteinuric hypertension nor pre-eclampsia are inherited in simple Mendelian fashion. The genetic contribution to multi-factorial inheritance is smaller than hitherto believed.
Pre-eclampsia, a human disease of pregnancy, is the leading cause of maternal morbidity in the western world. Despite the ubiquity of the disease and the plethora of studies concerning its aetiology and pathogenesis no comprehensive theory concerning its aetiology and pathogenesis have been put forward until now and so far there are no adequate therapies other than bed rest and, if necessary, early delivery. We recently developed an animal model for preeclampsia [1,2], whereby activation of the inflammatory response by low dose endotoxin resulted in pregnant rats, and not in non-pregnant rats, in a pre-eclampsia-like syndrome. Analysis of the inflammatory reaction induced by low dose endotoxin in pregnant — and non-pregnant rats revealed that this reaction was much more persistent and intense in pregnant rats as compared with non-pregnant rats; this is in line with the vast literature showing that pregnant individuals are much more sensitive to endotoxin than nonpregnant individuals [3‐5]. Based on the animal model, we have thus put forward the hypothesis that also human preeclampsia results from activation of the inflammatory system [6,7]. Here, we raise and try to answer, from a biological point of view, various questions such as ‘‘why is pregnancy a pro-inflammatory condition?’’, ‘‘what triggers the inflammatory response leading to human pre-eclampsia?’’ and ‘‘why is pre-eclampsia so relatively common in humans?’’.
Two cases of trisomy 13 are reported. One case presented heart and kidney anomalies not yet described in Patau's syndrome. The second case was specially striking by the chromosomal findings: there was a trisomy 13 by centric fusion between two chromosomes No. 13 [46,XY,-13,+t(13q13q)]. The authors discuss the genetic counselling in cases of trisomy 13, either of the free type or by translocation, in relation to the karyotypes of the parents and the age of the mother.
The articles published by the Annals of Eugenics (1925–1954) have been made available online as an historical archive intended for scholarly use. The work of eugenicists was often pervaded by prejudice against racial, ethnic and disabled groups. The online publication of this material for scholarly research purposes is not an endorsement of those views nor a promotion of eugenics in any way.
A genetic analysis has been made of published and new data on the familial occurrence of severe pre-eclampsia in primigravid women. This has shown that the condition may be largely a Mendelian recessive one. Bcause the condition occurs only in pregnancy, and because susceptible women cannot otherwise be identified, it is difficult to decide whether the genotype of the parent or of the offspring carried in utero leads to the condition. Data on the incidence of severe pre-eclampsia in the relatives of women who have suffered eclampsia support the maternal genotype hypothesis, while similar data, in which the index cases were women who had had severe pre-eclampsia, are more compatible with the fetal genotype hypothesis. Data on the incidence of the condition in blood relatives of index cases compared to the incidence in their corresponding in-laws are now required. Such a comparison would allow a choice to be made between the two hypotheses if one or the other were correct, or would assess the contribution of each if a genotype X genotype interaction were involved. Recurrent severe pre-eclampsia seems to have the same genetic basis as the more common primigravid type. However, mild, that is non-proteinuric, pre-eclampsia usually seems to be inherited independently of the severe form.
Two infants with cyclops malformation were born at the University of Southern California Medical Center during the past three years. The karyotypes of both infants demonstrated an extra chromosome No. 13: one with 47,XX,+13 and one with 46,XX,-14,+t(13q14q). The physical findings, karyotypes with trypsin-Giemsa banding, and association of trisomy 13 syndrome with cyclops malformation are presented.