Strategies for investigating the maternal-fetal interface in the first trimester of pregnancy: What can we learn about pathology?

Abstract

The pathologies of the pregnancy complications pre-eclampsia (PE) and fetal growth restriction (FGR) are established in the first trimester of human pregnancy. In a normal pregnancy, decidual spiral arteries are transformed into wide diameter, non-vasoactive vessels capable of meeting the increased demands of the developing fetus for nutrients and oxygen. Disruption of this transformation is associated with PE and FGR. Very little is known of how these first trimester changes are regulated normally and even less is known about how they are compromised in complicated pregnancies. Interactions between maternal and placental cells are essential for pregnancy to progress and this review will summarise the challenges in investigating this area. We will discuss how first trimester studies of pregnancies with an increased risk of developing PE/FGR have started to provide valuable information about pregnancy at this most dynamic and crucial time. We will discuss where there is scope to progress these studies further by refining the ability to identify compromised pregnancies at an early stage, by integrating information from many cell types from the same pregnancy, and by improving our methods for modelling the maternal-fetal interface in vitro.

Keywords: Decidua; First trimester; Placenta; Pre-eclampsia; Uterine artery doppler screening.

Fig. 1

Tissue accessibility at different stages of pregnancy. The tissue available at termination of pregnancy (TOP), chorionic villous sampling (CVS) or at parturition (birth) are shown (grey boxes). The limitations and advantages of what can be studied from tissue obtained at these times is summarised (white boxes). Pre-eclampsia is shown as being detected clinically after approximately 20 weeks gestation.

Fig. 2

Scope for further refinement of the uterine artery Doppler screened first trimester patient groups. Women with a first trimester uterine artery Doppler resistance index (RI) > 95th percentile (high RI) had a 5-fold increased risk of that pregnancy developing placental complications of pregnancy compared to those with a normal RI (<95th percentile). We have used this as a proxy measure of poor remodelling in the first trimester to separate tissue from first trimester terminations of pregnancy into normal RI (normal remodelling) and high RI groups (poor remodelling). However even in the high RI group the majority of these women would not develop pregnancy complications had the pregnancy progressed. With the addition of other markers to further define the high RI group we will be able to investigate how an initial impairment in remodelling can be compensated for. In addition we can start to define the relative contribution of placental/decidual differences and how much of the endpoint is determined by the maternal response to a stressed placenta. The arrows with queries represent areas for possible therapeutic strategies to reverse the pathology once more is understood regarding the cellular and molecular events.