Fetal growth restriction (FGR) signifies that the fetus has not achieved its growth potential and is associated with increased perinatal mortality and morbidity. The exact aetiology of FGR, in the absence of any identifiable fetal and maternal factors, remains unclear and is attributed to placental insufficiency. The FGR placenta has a characteristic phenotype including: increased resistance in the fetoplacental circulation, an alteration in trophoblast cell turnover and reduced activity of placental nutrient transport systems, the best characterised being the amino acid transporter, system A. The placenta strongly expresses the cortisol inactivating enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 11β-HSD2 activity was reduced in placentas from pregnancies complicated by FGR, suggesting increased exposure of the fetoplacental unit to maternal cortisol. In animal models, excessive exposure to glucocorticoids (GCs) is associated with a reduction in both fetal and placental weight. This reduction in placental weight was associated with abnormalities in placental function, consistent with those observed in the FGR placenta. This PhD investigated whether excess GC exposure during pregnancy is responsible placental insufficiency in human pregnancies and tested the hypotheses that excess GC exposure adversely affects placental vascular tone, trophoblast cell turnover and activity of the amino acid transporter, system A. Term placentas were collected from uncomplicated pregnancies and first trimester placental samples were obtained following elective surgical termination of pregnancy. Wire myography was used to explore the acute and chronic effects of GCs on term chorionic plate artery (CPA) function. The impact of GC treatment on trophoblast cell turnover in both first trimester and term placenta was investigated using the placental explant system. The effect of GCs on the activity of the system A transporter was also investigated in term explants and in isolated cytotrophoblasts where the expression of 11β-HSD2 was reduced using siRNA. Gene microarray studies on first trimester placental explants treated with GCs were utilised to identify genes regulated by GCs. Blunted constriction to thromboxane A2 was observed following acute GC treatment, whilst chronic exposure resulted in enhanced vasoconstriction, mimicking the altered reactivity of CPAs from pregnancies complicated by FGR. GC excess in first trimester placental explants increased apoptosis and decreased proliferation, thereby replicating the disordered turnover of the trophoblast observed in FGR placentas. No demonstrable effect was observed in cell turnover or system A activity in term placental explants treated with GCs, however, these experiments were hindered by the in-vitro regeneration of the syncytiotrophoblast in the model employed. The attenuation of 11β-HSD2 activity observed in FGR placentas was replicated in term primary cytotrophoblasts utilising siRNA to knock-down expression of 11β-HSD2. Preliminary results suggested an increase in system A activity in response to cortisol. Gene microarray studies identified a significant number of genes (~500) that were regulated by dexamethasone, confirming that GCs have an impact on many aspects of placental function. Potential mediators for the characteristic features of the FGR placenta replicated here in response to GC treatment were identified and validated at the mRNA level. The studies described in this thesis support the hypotheses that GC excess within the placenta contributes to the development of raised vascular resistance in the fetoplacental circulation and the disordered trophoblast turnover in placentas from pregnancies complicated by FGR. However, with the preliminary studies performed, the hypothesis that elevated levels of GCs contribute to the reduced placental amino acid transfer by the system A transporter in the FGR placenta can not be confidently disproven.

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Advanced maternal age (AMA) is defined as childbearing in mothers ≥35 years of age and is becoming increasingly prevalent in high income countries. AMA has been associated with increased risk of adverse pregnancy outcomes, particularly stillbirth. Although AMA mothers have higher rates of chromosomal abnormalities and maternal co-morbidities, AMA remains an independent risk factor for stillbirth. Despite these findings, the etiology behind this increased risk is unknown. We hypothesise that an altered maternal environment, including increased oxidative stress and inflammation, due to ageing causes placental dysfunction which increases AMA mothers’ vulnerability to stillbirth. A holistic approach was applied to investigate placental dysfunction in AMA. Firstly, a systematic review and meta-analysis comprehensively reviewed existing data on AMA and associated adverse pregnancy outcomes. Secondly, Manchester Advanced Maternal Age Study (MAMAS), a multi-centre prospective observational cohort study, was conducted to investigate risk factors for composite adverse pregnancy outcome (CAPO) in AMA. MAMAS utilised both uni- and multivariate analysis on demographic and clinical data, and measuring biomarkers of ageing and placental dysfunction by ELISA in maternal circulation during the third trimester of pregnancy. Utero-placental dysfunction was directly investigated in uncomplicated AMA pregnancies by quantifying placental morphology, placental nutrient transport capabilities and both placental and maternal uterine vascular responses. Finally, a C57BL/6J murine model of AMA was developed and characterised to further investigate maternal age on pregnancy outcome and the role of the placenta. In the meta-analysis, maternal age was linearly associated with increased risk of stillbirth and other adverse outcomes strongly associated with placental dysfunction (fetal growth restriction, preeclampsia and placental abruption). In MAMAS, smoking status and primiparity were predictive of CAPO. After adjustment, AMA mothers had an odd ratio of 2.05-3.43 of CAPO compared to 20-30 year old mothers. AMA mothers showed evidence of increased oxidative stress and pro-inflammatory bias. AMA mothers who suffered CAPO showed reduced placental endocrine capacity seen in placental dysfunction. Placentas from uneventful AMA pregnancies showed evidence of accelerated ageing and placental adaptation with increased nutrient transport, increased placental weight but reduced efficiency, and altered vascular function. AMA mice showed many similar aspects to human AMA with increased fetal loss, fetal growth restriction and increased placental size. These studies provide robust evidence for increased incidence of adverse pregnancy outcome due to placental dysfunction in pregnancies of women of AMA. This finding requires the appropriate recognition in a clinical context, with a greater focus on personalised obstetric care in an attempt to reduce stillbirth rates in this high risk population. By optimising antenatal and obstetric care for AMA mothers, we could reduce stillbirth rates by 4.7% - the population attributable risk due to AMA. These studies highlight key areas of future research that will further understanding into stillbirth risk in AMA pregnancy, test predictive models and test therapies and clinical care interventions an ultimately improve pregnancy outcome in mothers of AMA.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.