Maternal serum markers, placental pathophysiology and Down's syndrome pregnancies

Dalgliesh, Gillian Louise (2001) Maternal serum markers, placental pathophysiology and Down's syndrome pregnancies. PhD thesis, University of Glasgow.

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Abstract

Down's syndrome (DS) is the most common congenital cause of mental retardation and is caused by trisomy of chromosome 21. Initially prenatal diagnosis of chromosome abnormalities was offered only to pregnant women aged 35 years or over. In the last decade, maternal serum screening programmes have been introduced across the UK to give a risk of a pregnancy being affected of DS. These screening programmes are largely based on measurement of maternal serum concentrations of alpha-fetoprotein, human chorionic gonadotrophin (hCG) and also, in some cases, unconjugated estriol and inhibin-A, combined with maternal age. Despite being routinely used to screen for DS pregnancies, little is understood about the mechanisms that underlie the alterations in maternal serum levels of these markers. It was the aim of this study to examine maternal serum markers of DS synthesised by the placenta. This mainly focused on the elevation in hCG and inhibin-A in DS pregnancies. Placental levels and localisation of inhibin-A and activin-A were studied in control and DS pregnancies, as well as the maternal serum concentrations of both markers. Levels of inhibin-A and activin-A were significantly elevated in DS placental extracts (1.46MoM and 1.62MoM respectively) and staining intensity of the inhibin/activin PA and a subunits tended to be stronger in DS placentae. This suggested that elevated maternal serum levels of both markers in DS had their origin in increased placental synthesis, similar to previous observations on elevated placental production of hCG in DS. Dimeric inhibin-A has recently been introduced as a screening marker of DS in some programmes and the elevation in maternal serum inhibin-A to 2.06MoM reported in the current study is similar to previous reports. The use of activin-A as a screening marker for DS was investigated by other groups during the course of the current study and it was noted that the small degree of elevation and the overlap in levels between control and DS makes it of little use as a screening marker. This was independently confirmed by the current study which noted an elevation in maternal serum level of activin-A in DS pregnancies to 1.26MoM. Growth factors laiown to have opposing effects on hCG secretion from placental trophoblast cells (epidermal growth factor (EGF) and transforming growth factor (3i (TGpPi)) were studied in maternal serum, placentae, maternal urine and amniotic fluid from control and DS pregnancies. It was discovered that amniotic fluid levels of EGF and TGpPi were significantly reduced in DS pregnancies to 0.5MoM and 0.685MoM respectively. Maternal urine levels of EGF were significantly reduced (0.726MoM), as were placental levels of TGF(3i (0.675MoM) in DS pregnancies. It was postulated that reduced TGPPi levels in DS placentae could have a bearing on placental hCG secretion since TGpPi has an inhibitory effect on hCG secretion from and differentiation of cytotrophoblast cells. Reduced TGpPi could result in a diminished inhibitory effect of this growth factor on hCG secretion. A reduction in amniotic fluid EGF and TGPPi was an interesting finding, particularly in the case of EGP. EGP is not produced by the placenta suggesting that amniotic fluid EGP is likely to be of fetal origin, with reduced levels of EGF indicating abnormal fetal synthesis of this factor. Reduced urinary EGF but normal maternal serum levels of EGF was a surprising finding since maternal urine is a filtrate of maternal blood. It was postulated that this could be due to rapid maternal clearance of EGF secreted by the fetus resulting in the reduction in EGF secretion by the fetus being detectable only in amniotic fluid and maternal urine. This is the first study to analyse EGP and TGP(3i in control and DS pregnancies and the results suggest that fetal and placental growth may be affected by altered levels of these growth factors. However, it was also recognised that altered levels of EGP and TGpPi may be a result of abnormal placental or fetal function in DS. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: David Aitken
Keywords: Pathology, Obstetrics, Genetics
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-72648
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06
URI: http://theses.gla.ac.uk/id/eprint/72648

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