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Placenta pivotal in influencing pregnancy outcome

New research provides the first clear evidence that the amount of nutrients transported to the fetus by the placenta is adjusted according to both the fetal need to grow, and the mother's physical ability to provide food.


For the first time, research has shown how the placenta "umpires" a fight for nutrients between a pregnant mother and her unborn baby. The study suggests that the placenta will adjust the amount of nutrients transported to the fetus for growth in line with the mother's physical ability to supply them.

Published in the journal PNAS, the findings suggest that if the environment a mother provides for her baby is unfavourable, the placenta will change the flow of nutrients to the fetus relative to her state, affecting fetal development, and can result in complications at birth.


This is the first time scientists have been able to provide clear evidence the placenta plays the decisive role in a delicate balancing act, rather than merely acting as a passive interface enabling transfer of nutrients from mother to fetus.


The study, by researchers at the University of Cambridge, involved making a precise genetic change in mice, which caused poor growth and changed the mother's bodily environment. They then observed how the placenta developed and acted in response, finding that in mothers in which this alteration had been made, the structure of the placenta was different, and fewer nutrients reached the fetus.

A better understanding of how the placenta manages the trade-off will eventually enable researchers to reduce pregnancy complications in both humans and other mammals.

The study is part of a five-year project in the Department of Physiology, Development and Neuroscience examining the relationship between the placenta and pregnancy complications. It was led by Dr Amanda Sferruzzi-Perri, a Research Associate at St John's College, University of Cambridge, in the United Kingdom.

"During pregnancy there is a kind of 'tug-of-war' going on between the mother and the fetus over who gets the nutrients that the mother ingests," adds Sferruzzi-Perri. "This work shows for the first time that the placenta is the umpire which controls that fight. Understanding more about the placenta's role is extremely important. If nutrients cannot be divided correctly during pregnancy, it can lead to life-threatening complications for expectant mothers, and long-term health consequences for both mother and child."


In the UK, at least one in every eight pregnancies is affected by placental impairment. In the developing world the rate is higher with at least one in every five pregnant women affected. Potential consequences include abnormal birth weight, premature delivery, pre-eclampsia, and maternal diabetes.

Unfavourable biological changes in the mother appear to be a major cause of poor placental performance. For example, poor nutrition, high stress levels, metabolic dysfunction, or maternal obesity.


But how the placenta allocates nutrients in these situations, and hormonal signals that the placenta may be releasing, are not yet fully understood. Better understanding these processes, researchers hope to identify early biological warnings that a problem has arisen, these warnings as they relate to specific causes, and enable medical therapeutic interventions to reduce complications.

The new study represents a step towards these aims as researchers were able to directly influence the balancing act the placenta performs, and observe it relative to both the physiology of the mother, and the actual growth and nutrient supply to the fetus.

Working with mice as their model system, researchers genetically modified an enzyme called p110 alpha in pregnant mice. In a healthy mouse, this enzyme is activated by hormones such as insulin and insulin-growth factors (IGFs), to kick-start a relay race inside cells stimulating nutrient uptake, resulting in normal growth and metabolic function. By altering p110 alpha enzyme, researchers reduced the mouse mother's overall responsiveness to such hormones, creating an unfavourable placental environment.


Mice with the altered form of p110 alpha showed placental growth and structure were impaired. As well as being physically altered, the placenta transported fewer nutrients to the unborn pups.


The research also reflected what would happen to the placenta if the fetus carried the altered form of p110 alpha, while the mother was normal. In those cases the placenta also showed defects, but was able to compensate by transporting more nutrients to the fetus, thus optimising pup nutrition.

This was the first demonstration that the placenta will fine-tune distribution of nutrients between mother and fetus in response to its own altered circumstances. It also indicates that the placenta will optimise fetal nutrition, so that the mother's health is not compromised — as a mother needs to support her baby both during pregnancy and after birth.


"The placenta is taking in signals all the time from the mother and the fetus. If the mother has some sort of defect in her ability to grow, the placenta will limit the amount of nutrients it allocates to the fetus to preserve her health."

"What this tells us is that the mother's environment is a very strong, modifiable characteristic to which we should be paying more attention. In particular, to see if there are specific factors we can change to improve the outcome of pregnancies.

"Being able to influence the mother's environment through changes in p110 alpha gives us a means to study, in a controlled way, and work out what those critical factors are."


Amanda Sferruzzi-Perri PhD, Department of Physiology, Development and Neuroscience, Developmental biology and reproduction, University of Cambridge, Cambridge, UK


The next phase of research will examine signals sent by the placenta to the mother regarding the nutrients she ingests, potentially illuminating important biomarkers providing an early warning of pregnancy complications.

Significance
During pregnancy, nutrients are required for fetal growth and for the mother to maintain the pregnancy. The placenta is central to this tug-of-war over nutrients, as it is responsible for materno-fetal resource allocation. Failure to allocate resources appropriately can lead to pregnancy complications and abnormal fetal development, with long-term health consequences for both mother and baby. Here we use manipulation of a growth-regulatory protein, p110α, in mice to compare the importance of the maternal environment and genotype with fetal genotype in determining placental resource allocation. This study shows that the placenta fine-tunes the supply of maternal resources to the fetus via p110α in accordance with both the fetal drive for growth and the maternal ability to supply the required nutrients.

Abstract
Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, Pik3ca (encoding PIK3CA also known as p110α, α/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and α/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of α/+ fetuses. Despite its defective development, the α/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was α/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110α deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation.

Key Words
resource allocation fetus placenta PI3K nutrient transport

Dr Sferruzzi-Perri's research is supported by a Dorothy Hodgkin Fellowship from the Royal Society. Her paper, "Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signalling to modify placental resource allocation," is published in PNAS.


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Sep 13, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Research suggests if the environment a mother provides her babies is unfavourable,
the placenta will change the flow of nutrients in favor of the fetus. But can complicate birth.
Image Credit:
Public domain.


 


 

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