Foetal growth restriction

Monday 30 September 2013 5:40PM (view full episode)

Researchers at University College London are developing a therapy for foetal growth restriction. This problem is affecting up to 8% of all pregnancies and affected foetuses are extremely small. Babies born from growth restricted pregnancies are at increased risk of perinatal death and complications such as cerebral palsy. They also suffer other long term health problems, including diabetes and cardiovascular disease.

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Norman Swan: One of the common problems in rural and remote Australia, especially amongst Indigenous communities, is babies who haven't grown well in the womb. It's also a significant issue in non-Indigenous Australia and not necessarily in rural and remote areas, and it's not always confined to women who are disadvantaged. It's called foetal growth restriction and a research group in London are developing a high-tech solution; gene therapy.

Anna David is an obstetrician and reader in Obstetrics and Foetal-Maternal Medicine at University College London.

Anna David: Foetal growth restriction is relatively common. It affects probably about one in ten pregnancies overall. We really don't have any effective treatment. We have no way of improving the growth of these babies in the womb.

Norman Swan: So this is what used to be called small-for-dates?

Anna David: Well, you can be small but appropriately grown, whereas the main issue is that you were meant to be bigger, you stopped growing, you didn't reach your growth potential, and that has big consequences on your later life.

Norman Swan: How do you know if a child is foetally growth restricted? Is it simply low-birth-weight?

Anna David: No, that's one of the big problems, it's not simply low-birth-weight. It depends on the mother's size, for instance. If the mother is five-foot and the baby is a girl then the baby is going to be smaller than a mother who is six-foot and the baby is a boy. So it depends on what you were meant to achieve in the womb.

Norman Swan: And is this routinely assessed? In Australia there is a huge issue about foetal growth restriction in Aboriginal children which then restricts their lives because they've got smaller kidneys, smaller lungs, and it's one of the factors that predicts poorer outcomes in adult life, they start off badly.

Anna David: It is routinely assessed in that we scan the babies through the middle of the pregnancy to have a look at them in detail, and we can tell if a baby is very small at that point. You have to see what the baby's size is at 20 weeks, and there are tests that are being developed to try to predict whether the baby is going to grow small. The babies that we are hoping to treat are those that are at the very, very smallest end of the spectrum that we can detect very easily at the 20-week scan. These babies are absolutely tiny, and some of them actually stop growing in the womb.

Norman Swan: And there's a list as long as your arm in terms of causes.

Anna David: Well, the main cause is really that there is abnormal development of the placenta. The placenta just doesn't develop properly. When you first get pregnant you alter the blood flow to your womb so it increases hugely from about 50 mls per minute up to about 500 mls per minute, and you divert your blood supply to your uterus. In foetal growth restriction we know that that actually doesn't happen, and so babies that are growth restricted, the mothers, if you have a look at their blood supply to their uterus, it's far lower, it's about two-thirds to half of what it should be.

Norman Swan: And the causes of placental insufficiency are things like smoking, high blood pressure…that's what I meant by a list as long as your arm.

Anna David: That's right, smoking does reduce the growth of the baby by a proportion. There are other causes. So, for instance, if you have a chromosomal problem like Down's syndrome.

Norman Swan: And I didn't really explore fully the outcomes as adults when you track this forwards. What's the adult life of a baby who is born with foetal growth restriction?

Anna David: There are quite definite short and long term outcomes. So short term you have a higher chance of dying immediately after birth or dying in the first few days after you are born. If you are born at term however, that risk is quite low, but later on in life you have a six-fold higher chance of diabetes, more than a 1.5-fold higher chance of a heart attack, your IQ points are lower, adults who were growth restricted are less attentive, they can't concentrate as much in school. So it has profound effects for the whole of the rest of the person's life.

Norman Swan: And you've been trying to find a way of treating this when you have detected it?

Anna David: Well, we've been working on a hypothesis that if we could increase the blood supply to the uterus, to the placenta, we could actually increase the amount of nutrients and oxygen that's going across the placenta to the baby.

Norman Swan: And how do you do that?

Anna David: We've been using a growth factor called vascular endothelial growth factor, or VEGF. We know this factor is very important for placental development, it's vital for the way the placenta invades the uterus and makes a good circulation for the uterus.

Norman Swan: And blockers of that messenger are being used for treating macular degeneration and indeed some cancers.

Anna David: That's right, so it's a very powerful growth factor, and it improves blood supply, it causes new vessel growth. So what we thought was we could express this VEGF protein, increase the availability of this VEGF protein in the uterine circulation and then that would vasodilate, that would dilate the circulation, that would cause new vessel growth, and that would overall increase the amount of blood flowing to the uterus.

Norman Swan: And has it worked in animals?

Anna David: It does. So first of all we showed that you could increase blood flow in the uterus in normal animals, in normal pregnancy. And then we've gone on to demonstrate in two different models of foetal growth restriction that this actually increases the foetal growth. And more importantly, it doesn't just increase foetal growth but it also alters some of the changes that we see in the different way that babies grow when they are growth restricted.

So babies that have growth restriction tend to shift their blood up to their brain. They preserve their brain growth, whereas to the rest of the body, the liver and their kidneys don't grow as well. What happens when we treat these growth restricted animal models is that the brain growth is preserved but the abdomen catches up. In other words, we are having an effect not just on the brain but also on the rest of the body.

Norman Swan: This is actually gene therapy where they use a virus to carry in the growth factor gene so it's turned on for a few weeks in the mother only. That's the theory.

This obviously has huge safety concerns, not to mention cost. But the researchers reckon that in severely growth restricted babies there are major gains to be made which could save vast amounts of money and disability throughout life.

But they still have many hoops to jump through before it's able to be tested on pregnant women. They have to be sure the gene isn't turned on in the baby and it's only temporary in the mother.

Anna David again:

Anna David: We have to do some reproductive toxicology to show that it is safe and to work out whether there is a toxic dose. Part of this work is being done actually in human placentas, which is work being done in Manchester where we apply the vector to the maternal side of the placenta after it has been delivered after a pregnancy and we have a look to see whether it crosses over the placenta.

But we are also talking to women, parents, healthcare workers, about what is effectively maternal gene therapy, to see would they in this situation where the baby is very unlikely to have a good outcome, would they consider having this therapy.

The babies that we hope to treat are those where the baby simply stops growing in mid-pregnancy, around 25 weeks, they don't get more than 500 grams, and these babies have a very high chance of dying, but more importantly they have a very high chance, if they are born alive, of having long-term problems like cerebral palsy and oxygen deprivation.

So we are hoping to improve the growth of these babies over about four weeks, and then we will deliver them and very much transform their outcome, and we hope to do the first in woman trial at UCL and across at three other centres in Europe in the next three and a half years

Norman Swan: Anna David is an obstetrician and reader in Obstetrics and Foetal-Maternal Medicine at University College London.


Dr Anna David
Honorary Consultant and Reader in Obstetrics and Maternal Fetal Medicine
Institute for Women's Health
University College London


Dr Norman Swan
Brigitte Seega

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