Preventing Term Stillbirth: How Important is Fetal Size?

The presentation will seek to differentiate the nutritional (food) and respiratory (oxygen) functions of the placenta and discuss which assessments are more strongly associated and predictive of pregnancies at high risk of stillbirth.

Professor Basky Thilaganathan was appointed Director of Fetal Medicine at St George’s Hospital in 1999. His research interests are focused on Maternal-Fetal medicine, with a particular interest on placental dysfunction and preeclampsia (TED talk: http://bit.ly/2i1SqDk). He undertook his undergraduate training at King’s College London, where he obtained a BSc in Genetic Engineering (1985) and MBBS (1988). He completed his postgraduate training at King’s College London and St Bartholomew’s Hospitals, culminating in attainment of MRCOG (1995), MD in Fetal Medicine (1996) and Certificate of Completion of Training (1998). He was awarded the Fellowship of the Royal College of Obstetricians and Gynaecologists (FRCOG) and an Honorary Doctorate (PhD) from Uppsala University in 2007.

He has authored two undergraduate and six postgraduate text books in obstetrics and fetal medicine. He is the Clinical Director of the Tommy’s National Centre for Maternity Improvement located at the RCOG/RCM and is Editor Emeritus of Ultrasound in Obstetrics and Gynaecology, the medical journal affiliated to ISUOG. He is a Council Member on the Royal College of Obstetrics and Gynaecology (RCOG) and represents the RCOG on the UK National Screening Committee and the DH Saving Babies Lives Care Bundle oversight committee. He is also the Clinical Lead for the development of the first dedicated high-throughput cfDNA screening NHS lab to undertake cfDNA aneuploidy screening in pregnancy (www.theSAFEtest.co.uk).

He has authored over 300 peer-reviewed publications in indexed journals. His major research interest is placental dysfunction leading to pre-eclampsia, fetal growth restriction and stillbirth. He currently holds research and commercial grants to the value of £1.5m – including EU-funded research. He has led on the implementation of algorithm-based screening at St Georges which has led to a 80% reduction in preterm pre-eclampsia – the severest form of the disease  

Professor Thilaganathan has disclosed that he does not have any real or perceived conflicts of interest in making this presentation.

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Jen Chappell: Dr. Basky Thilaganathan was appointed Director of Fetal Medicine at St George’s Hospital in 1999. His research interests are focused on Maternal-Fetal medicine, with a particular interest on placental dysfunction and preeclampsia. He undertook his undergraduate training at King’s College London, where he obtained a BSc in Genetic Engineering and MBBS. He completed his postgraduate training at King’s College London and St Bartholomew’s Hospitals, culminating in attainment of MRCOG, MD in Fetal Medicine, and Certificate of Completion of Training. He was awarded the Fellowship of the Royal College of Obstetricians and Gynecologists, FRCOG, and an Honorary Doctorate, PhD, from Uppsala University in 2007.

He has authored two undergraduate and six postgraduate text books in obstetrics and fetal medicine. He is the Clinical Director of the Tommy’s National Centre for Maternity Improvement located at the RCOG/RCM and is Editor Emeritus of Ultrasound in Obstetrics and Gynecology, the medical journal affiliated to ISUOG. He is a Council Member on the Royal College of Obstetrics and Gynecology and represents the RCOG on the UK National Screening Committee and the DH Saving Babies Lives Care Bundle oversight committee. He is also the Clinical Lead for the development of the first dedicated high-throughput cfDNA screening NHS lab to undertake cfDNA aneuploidy screening in pregnancy.

He has authored over 300 peer-reviewed publications in indexed journals. His major research interest is placental dysfunction leading to preeclampsia, fetal growth restriction, and stillbirth. He currently holds research and commercial grants to the value of £1.5m, including EU-funded research. He has led on the implementation of algorithm-based screening at St Georges which has led to a 80% reduction in preterm preeclampsia, the severest form of the disease.

Dr. Thilaganathan’s presentation is titled, Preventing Term Stillbirth: How Important is Fetal Size?

Professor Basky Thilaganathan: I’ve been asked to speak on fetal size and the relationship to stillbirth. There is no doubt that there is an association, which is why size is targeted as a key factor in preventing stillbirth. When it comes to assessment of size, universally, the symphysis fundal height measurements are undertaken. However, this must be questioned. In this prospective blinded study, Gordon Smith and colleagues looked at the relative value of symphysis fundal height measurements to ultrasound in the detection of small for gestational age babies.

What they demonstrated is that the use of symphysis fundal height detected 20% of SGA births. Whereas the use of universal ultrasound at 34 to 36 weeks gestation detected 57% of small for gestational age babies. Noting that not all SGA babies are pathologically small, they looked at a sub-group of severe SGA. Those are babies below the third centile. Here the detection rate of fundal height measurements was 32% for that. Whereas almost 80% of severe IUGR babies were detected by ultrasound measurements. There is no doubt in a head to head comparison that if we care about detection of small babies, the right tool and the right approach is the use of third trimester ultrasound.

Now, there is some debate about the timing of ultrasound. Many hospitals in many countries favor 32 to 34 weeks scan, as opposed to 36 to 37 weeks scan. In this randomized controlled trial called the ROUTE study conducted by Francesc Figueras et al, they compared scans done at 32 to 34 weeks versus studies done at 36 to 37 in the detection of SGA birth at term. What they showed is that for the same false positive rate of 10% false positive rate, they were able to double the detection of SGA at term from around 30% to just over 60%. If one is going to do an ultrasound, it has to be done at 36 or 37 weeks to prevent term stillbirth.

Now, there are two issues when one does an ultrasound. One is calculating how heavy the baby is, and the second is saying, is that weight too small or too big for gestational age? In terms of how do we use the ultrasound measurements to calculate the size of the baby? This was a large study conducted in several thousand babies where the baby was weighed a few days after ultrasound and across many gestational ages.

What they did was they compared over 70 different formulas for calculating fetal weight, and they demonstrated that the most accurate formula was the Hadlock formula from 1985, which uses head circumference, abdominal circumference, and femur length. Using this formula means that your ultrasound measurements are most approximate to the real baby size.

The first learning point is to go back, make sure that the ultrasound machines or the programs that you use to calculate fetal weight, not fetal center, fetal weight, use the Hadlock 1985 HC, AC, femur length formula. Interestingly, this 1985 formula perform better than the formula that the authors derived from their own work.

Now, the issue is now you have the baby size, how do we say whether the baby’s big or small for gestational age? The problem here is that there are many, many different charts. There are over 93 published charts by nationality. For all I know, Singapore has its own. Here in lies the problem, which is this, one can have a baby here, and on this chart, it looks small and we can go back and say, “Well, what I need to do is change the charts.” Here we go, we changed the chart and suddenly the baby becomes normal.

Let me do that again. It’s now small. You swap charts, it becomes normal. The issue is, can this be right? I’m going to argue with you that it cannot, because most of the charts that have been developed are done by nationality. I want to ask you this question. How does the baby know what passport the mother carries? That’s my wife on the right. My elder daughter is half Sri Lankan, half English, and my younger daughter who’s adopted from Sri Lanka and completely Sri Lankan. Now, they all own a British passport, but which chart should we use for plotting their baby’s growth? The baby cannot know nationality, and nationality cannot be a factor in determining fetal size.

What you’re going to say is that perhaps it is down to the ethnicity. There we bring in the issue of customization. The problem with customization is that customization doesn’t work. In this 11 million birth assessment done in Scotland, they showed that the implementation of the GAP and GROW program did not make a significant difference to the rates of stillbirth. They did a study comparing rates of stillbirth changes in Scotland versus those in England. This is the implementation of the GAP and GROW customization program in Scotland with little or no change in stillbirth rates throughout here.

Again, this is the issue here. These are the stillbirth rates per thousand and really parallel changes with no difference here in England’s GAP adoption, and here in England, Scotland GAP adoption. Despite massive differences in the adoption of customization, really no differences in the incidence of stillbirth. That’s because ethnicity is complex. Because ethnicity is not a biological construct, it’s a human construct. In Asia, most people define the ethnicity according to the language they use. In China, most people define their ethnicity according to their physical appearance. In Caucasian or white populations, the country of citizenship is commonly used to represent ethnicity.

Ethnicity is not biology, and in fact, it is incongruence or wrong to believe that the 1% of the human genome that determines skin color also determines fetal science, it cannot be that those genes are coincidental. There are other factors and possibly confounding factors that determine that.

The best way to understand our need as obstetricians for customization or some sort of defined cut off is that we want wherever we are in the world for only 10% of our babies to be small when we’re scanning as ultrasound specialists. That’s why in Singapore or Asia or India, or even Sri Lanka, there are nationality-based charts because there are lots of small babies and we want only 10% of our babies at birth to be small. It can’t be that 20 or 30% are small.

This is a chart showing malnutrition at birth. Malnutrition at birth. You can see that as soon as the baby’s born, the rates of malnutrition in central and Sub-Saharan Africa is 33%. In South Africa, 34%. In the Asian sub-continent 35% of babies are small or malnourished at birth. Whereas in Northern Europe, that finger is about 8%.

It’s only obstetricians who believe that 10% of babies are allowed to be small before birth. But in reality, when babies are born, we understand that the rates of malnutrition and the rates of undergrowth throughout the world vary dramatically. If you use the same cut off and the same standards, there is a huge variation. We have to acknowledge that either we are wrong in insisting and imposing a 10% rate of SGA before birth, or we are right that only 10% of babies can be small before birth. During the course of labor babies suddenly shrink so that when they are born, you’re allowed to have a 35% malnutrition rates in Asia. I leave you with that question to consider what the right answer is.

In recognition of the fact that the babies do not know what nationality their mothers are, and that the skin color of the woman cannot also determine the baby size, the international INTERGROWTH-21 Project was undertaken. Where they looked at women from five different subcontinents. What they did was they took women of average height with normal nutrition and lack of comorbidity. They took healthy women who were comparable in size, and they demonstrated very elegantly that skin color and nationality did not affect fetal science. If you had healthy women who were five and a half feet tall in Africa, Asia, or Europe, if they were healthy and they were fed normally, and didn’t have any diseases, that babies were equivalent in size.

This implies that the variation we see throughout the world is not due to skin color, but it is due to confounding effects such as malnutrition, comorbidities and socioeconomic differences, and not really down to the individual biology of the woman. Therefore I leave it with you that the right thing to do is to use an international growth standard. Personally, it doesn’t matter to me whether you use the WHO or the IG-21 charts, my belief is that the IG-21 charts are slightly better constructed, but it doesn’t matter. An international growth standard should be adopted.

Now, the real question and the one that I was asked to talk on is does size really matter? Here I have to argue that it probably does not for term stillbirth. Here is a demonstration of something like 110,000 pregnancies with 400 stillbirths. You can see the majority of stillbirths in preterm are very small. Here you can see that 70% of the stillbirths that occur at term are appropriate for size. They are normal in size, and a lot of the LGA ones were intrapartum stillbirth. If you consider the majority of antepartum stillbirths, they were normal in size.

What this means is that a strategy targeted at looking for SGA births will automatically miss 70% of stillbirths at term just in the way that a strategy targeted at maternal age for the prediction of Down syndrome will miss 80% of Down syndrome if you use the age 37. Although the risks for Down syndrome may be higher as one gets older, the majority of Downs syndrome babies are born to younger women by virtue of the fact that there’s so many of them. This is true here too. That the risk of stillbirth may be higher if one is smaller, but the majority of stillbirths occur in the AGA group by virtue of the fact that 90% of the population is contained in this cohort.

Now the second portion is about if we can use growth velocity. Unfortunately, that has not been substantiated in all of the studies. This is a Kypros Nicolaides study of about 40,000 babies where they looked at changes in growth velocity between 22 and 36 weeks and looked at adverse outcome and SGA birth. They demonstrated that the use of growth velocity was no better than the use of the last scan in assessing the adverse outcome of pregnancy. Therefore there is no added value to making complex measurements and assessments of the change in growth velocity. I know that it’s clinically used commonly to look at science changes and say, “That’s important,” but we don’t know by how much the growth velocity must change over how many weeks, at which gestation to determine the right time to clinically intervene.

Let alone Kypros Nicolaides, Gordon Smith’s work from the POP study showed exactly the same thing. This graph is commonly misinterpreted to say that AC growth velocity and umbilical artery Dopplers are useful. What happens here is the fact that this graph represents the value of predicting adverse neonatal composite outcomes, only in babies that were already SGA. AC growth velocity and umbilical doppler in isolation were not useful in AGA. This is only of value to look at growth velocity, once the baby’s already small. The use of growth velocity in AGA infants has not been shown. In fact, has been shown not to be of value.

Here’s the problem. We’re missing most of the stillbirths when we talk of SGA. Why is that? Why is it that the majority of babies that die are normal in size? That’s because we have mixed up symptoms with disease and disease with symptoms. Now, I’m going to argue with you that the disorder we are looking at is placental dysfunction.

The problem, the disease is that the placenta doesn’t work properly. The symptom can be slow fetal growth because of a lack of food, a lack of nutrition. Another symptom can be disability and death due to a lack of oxygen delivery. Stillbirth and neurodevelopmental handicap are related to hypoxemia, but not related to malnutrition. You and I can go without food for two weeks. We will not become neurodevelopmentally handicap, neither will we die if you don’t have food for two weeks. We go without oxygen for two minutes, for sure, we will become neurodevelopmentally damaged and die a minute later. I’m going to argue with you that placental dysfunction can cause changes in size for sure, but these changes in size do not determine handicap and death. It’s the inability of the placenta to deliver oxygen that determines damage to the brain and death.

I’m going to explain to you now why early and late fetal growth restriction are not different disorders. They are the same disorder, but the symptoms they present with will be different depending on the timing of onset. The graph in green here represents what you see all the time, which is your fetal growth chart. Your AC chart looks like that. That represents the nutritional demands of the baby with advancing gestation from 20 to 40 weeks, that is nutritional demands. In red are the metabolic demands of the baby. That is the oxygen requirements of the baby, and they have different curves. You can look at this paper here, or this opinion I’ve published to tell you about them.

If the placenta starts to go wrong in early gestation, placental dysfunction onset is at 25 weeks gestation. At this gestation, the nutritional needs are rising exponentially. Placental dysfunction early will have a disproportionate effect on fetal size. At this gestation, the baby is still only 300, 400 grams. The oxygen demands are very low and therefore the baby can survive for a long time with a dysfunctional placenta. During this time, the baby has time to become small. If placental dysfunction onset is at 36 weeks gestation when the baby has already reached 3.2 kilos, let’s say, at this stage, nutritional demands are pretty static and plateaued off. There will not be much change in size, but the metabolic oxygen demands are increasing exponentially. Placental dysfunction that occurs late in pregnancy will act on baby’s oxygen demands very quickly and the baby may only survive for a few days or a week during which time it doesn’t have the availability to become smaller. It can’t shrink within a few days. That’s why the majority of babies at term that die are normal in size.

This is the same thing expressed in a different way. Early onset placental dysfunction, when the oxygen demands are low, means that the baby can survive for several weeks during which time it can shrink because nutritional demands are increasing rapidly. It will shrink over the three to four weeks before it becomes neurodevelopmentally handicap and dies. If the baby has grown normally to 35 weeks, and then the placenta starts to fail, what happens here is that oxygen demands are so high that it’ll only survive for a week or so, during which time it doesn’t really have the time to shrink. Therefore late onset placental dysfunction has a short latency between onset and demise and babies don’t have to become small.

It remains for me to say, well, what are the options here for monitoring the babies and finding out how we can improve outcomes? I’m going to argue with you that the most important thing is cerebral redistribution, CPR, cerebroplacental ratio, you can use umbilical cerebroplacental ratio. It doesn’t really matter. You’re looking at the relative assessment of redistribution.

If you and I were to hold our breath for a few minutes, one or two minutes, we would redistribute. Our blood flow would go into our brains in preference to the rest of the body. The baby’s no different, and that’s been demonstrated from early fetal life. Here in a cohort of about 10,000 babies, we looked at and demonstrated that smaller babies had increased levels of redistribution. This is a seminal paper which is highly cited. Demonstrating that the smaller you are, the higher the probability that there will be oxygen deprivation and forcing the baby to redistribute.

In this smaller study of 3,000 babies with 18 perinatal deaths, we showed that birth weight centile, uterine artery PI, and redistribution CPR MoM were all related to death, but in a logistic regression, we showed that the only one that continued to be significant was the degree of redistribution. Therefore redistribution is a better marker of damage and death than fetal size at term.

Now this is often argued. There are many publications that say, “Well, CPR is not of value.” I would say two things. One is what’s called intervention bias. In a lot of the studies they did, they looked at clinically the CPR value, and they wouldn’t let the baby die. CPR is a bit low, they deliver the baby. It can’t die. In our studies, we did MCA Doppler, but we did not calculate CPR because we did not understand the value of CPR. Our study was a retrospective study where CPR was not calculated and then this was revealed when we did so. That’s the first thing.

Secondly, even in those studies where there was some degree of intervention bias, they demonstrated that CPR was two to three times more predictive of fetal demise than AC. They said, “Well, it wasn’t good enough to use, but it’s two to three times better.” They said, “Well, we mustn’t use it because it’s not good enough to use.” Well, the reality is where here we’re letting perfection be the enemy of the good. I would argue that what we’re using now is not working and hasn’t worked for 20 years and having something better, even when it’s not good enough to meet the standards of screening tools, we must try and do better and only if we do better, can we start to change stillbirth rates significantly.

Now there are systematic reviews and this systematic review showed actually, 128 studies, 50,000 pregnancies in terms of perinatal deaths, CPR was better than using umbilical artery lining. Here with a 10% false positive rate, there was about a 60% prediction for perinatal death. I would argue that’s better than what we’re doing now.

One of my colleagues said, “Well, this is not a good study.” He has a vested interest in fetal science, and you will understand why when you see that his name was Aris Papageorghiou, fundamental to the IG-21. He said, “Well, I’m going to do a better study. I’m going to look at really high-quality study.” He reduced the number of studies involved and ran only 4,000 women. Said, “Look, I’m going to show that Doppler doesn’t work.” He showed the same thing, unfortunately. Well, fortunately for me. Again, with a 10% false positive rate there was about a 60% prediction of perinatal death.

CPR in systematic reviews is a good tool and is better than fetal size in the prediction of adverse outcomes. We simply yet don’t understand how to use it in the clinical context. I know data is being gathered now, and I hope in two to three years’ time when I come to see you in Singapore personally, I’ll be able to tell you how to use it properly.

This, however, is an interim measure used by the Saving Babies’ Lives Care Bundle in the UK. That if we do a scan from 36 weeks gestation, if the findings are normal, you deliver at 41 weeks and that’s standard routine care. If the baby is less than the third centile, because there’s a 70 to 80% chance that it already has fetal growth restriction, you should deliver from 37 weeks. If the Dopplers are normal and the baby’s between the 3rd to 10th cent of time, then we can deliver from 39 weeks. But remember the Dopplers must be normal. This indicates a baby that is probably physiologically small, but physiologically small babies also have an increased rate of adverse outcome later on, so you should deliver from 39 weeks.

Then there should be bespoke measurement and assessment and management of babies where their umbilical artery Dopplers and the middle cerebral artery Dopplers indicate that there are redistribution at hand and those babies should be managed by a team. At the moment we don’t know. My feeling is that CPR is not an acute and immediate phenomenon, but CPR needs to be taken seriously to increase the levels of monitoring these women to decide when they might deliver, not to leave them to go to 41 weeks gestation. Thank you very much. I’m going to leave you with the summary.