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Early pregnancy ultrasound and biochemical markers of pre-eclampsia and growth restriction

Final Activity Report Summary - PE-IUGR SCREENING (Early pregnancy ultrasound and biochemical markers of pre-eclampsia and growth restriction)

Pre-eclampsia (PE), a condition manifesting with high maternal blood pressure and proteinuria, complicates 8 to 10 % of pregnancies and represents one of the leading causes of maternal mortality and morbidity. PE is also a major cause of fetal mortality and morbidity, particularly as a result of placental abruption, Intra-uterine growth restriction (IUGR) and premature delivery.

Although the underlying mechanisms responsible for PE and IUGR are largely unknown, these conditions are characterised by placental abnormalities, consistent with inadequate development and dysfunction. In particular, a failure of placental cells, namely trophoblasts, to invade and remodel the maternal arteries bringing blood to the uterus is often observed. During the last years, a considerable amount of research concentrated on investigating biological markers potentially employable as PE screening tools. The most promising markers could be summarised under two main categories:
1. biochemical markers, which could be assessed on maternal blood or urine;
2. biophysical markers, namely Doppler ultrasound of the uterine arteries, a non-invasive technique which allowed to estimate how efficiently blood was brought to the placenta for the exchange of oxygen and nutrients.

However, none of the markers investigated so far represented a satisfactory screening test for PE and IUGR when used in isolation. The main objective of this project was to investigate the possibility of combining multiple early, i.e. before 20 weeks, pregnancy ultrasound and biochemical markers, in order to identify pregnancies at high risk of subsequently developing PE or IUGR, given that early identification might allow for preventive measures.

While the research was still ongoing by the time of the project completion, promising preliminary results had already been obtained. We measured a range of maternal serum markers, i.e. proteins that could be measured with a blood test, at 10 to 14 and 15 to 18 weeks of pregnancy, studying their association with fetus' growth and PE occurrence. We found that, at 10 to 14 weeks, levels of pregnancy-associated plasma protein A (PAPP-A) were positively associated with weight at birth, i.e. the higher the amount of PAPP-A, the bigger the baby at birth and vice versa. Moreover, PAPP-A seemed to be specifically involved in bone growth regulation, as levels in maternal serum were correlated with fetal bone length. At the same pregnancy period, levels of the free beta subunit of the human chorionic gonadotropin (free hCG) tended to be lower than normal and levels of inhibin A higher than normal in women who developed PE later in pregnancy. At 15 to 18 weeks, high Alfa-fetoprotein (AFP), hCG and inhibin A and low unconjugated estriol (uE3) levels were associated with pregnancy complications. During both pregnancy intervals, a higher resistance to flow in the uterine arteries, synonym to less blood flow towards the uterus, was associated with lower birth weight and pregnancy complications. Nevertheless, none of these markers alone performed well enough to be clinically used as a screening test for adverse pregnancy outcome in the general population.

It was hypothesised that the combination of multiple Doppler and maternal serum markers might allow for better prediction capabilities. However, a pre-requisite for the use of a combination of markers in a screening test was the lack of association between different markers, and this issue had to be verified. We could demonstrate that there was no significant correlation between first trimester uterine artery Doppler measurements and maternal serum marker levels. Both Doppler measurements and PAPP-A and hCG levels appeared to be independently associated with birth weight. These findings constituted the rational basis for a multiple marker evaluation of the risk of PE and IUGR, which was assessed in a larger number of pregnancies in our ongoing project.