Measuring Omega-3 Status in Pregnant Women – Australia’s Pilot Program
OmegaMatters: Episode 22
Hosts: Drs. Bill Harris & Kristina Harris Jackson
Guest: Dr. Robert Gibson
Background and Key Takeaways:
In this episode, Drs. Harris and Jackson speak with Dr. Robert Gibson, a senior research fellow and professor of food science and nutrition at the University of Adelaide in South Australia, among many other titles. At his core, he is a biochemist and a nutritionist who has published 260 peer reviewed papers in high impact journals like the New England Journal of Medicine. He has conducted many large scale trials in nutrition, particularly during the perinatal period, and he is currently spearheading a pilot project to measure omega-3 status in pregnant women as the standard of care in Australia. For more information on OmegaMatters, visit: https://omegaquant.com/omegamatters-broadcasts/
SHOW TRANSCRIPT:
Dr. Kristina Harris Jackson: Welcome to Omega Matters, where we talk all things Omegas. I’m Kristina Jackson, this is Bill Harris. And today we have the pleasure of speaking with a giant in this field, Dr. Robert Gibson. He is a senior research fellow and professor of food science and nutrition at the University of Adelaide in South Australia, among many other titles. At his core, he is a biochemist and a nutritionist. He has published 260 peer reviewed papers in high impact journals like the New England Journal of Medicine, and he’s conduct conducted many large scale trials in nutrition, particularly during the perinatal period. He is currently spearheading a pilot project to measure omega-3 status in pregnant women as the standard of care in Australia. So thank you so much for joining us today, Bob. We are excited to talk to you.
Dr. Robert Gibson: You’re very, very welcome. It’s lovely seeing you both and it’s nice to be able to reach out like this. We’re on different continents, but we’re both cold by the way. We’re having a very cold spring and you guys are in winter.
Dr. Kristina Harris Jackson: Oh, I’m sorry. I mean, we are having normal cold, but that’s too bad to have a cold spring. It’s supposed to be cold, though. So we could talk to you about many, many things, you have a long and illustrious career, but today we thought you could talk about a paper you just published in the New England Journal of Medicine. So basically, I would like you to set up the study for us. It was in premature infants, giving them DHA and then following up later on in life on their cognitive functions. So if you want to set the stage for the why you did the study in the first place and the follow up, all of that.
Dr. Robert Gibson: Thanks, Kristina. We should probably talk about the previous study, the one before that. Then I start thinking about the other studies and how far back it all went. And goes all the way back to Bill Connor and your work, Bill, and Martha Neuringer. I remember that it seemed like yesterday that the Martha Neuringer paper came out when she fed omega-3 deficient diets to monkeys and then looked at visual responses. It had a devastating effect [because first of all, it was the first time that any of us had really seen… Something that had been hypothesized as possible is a deficiency symptom of omega-3s.] Remember, the whole story had been, up until that point, it had all been about omega-6s and the omega-6 deficiency and the early work of Holman and others in both humans and in animals.
But suddenly here was this model which was the closest one to humans. We had this effect whereby visual responses were affected by this omega-3 deficient diet. Yet, when they gave the omega-3s back later, you couldn’t restore this visual response and that sent shockwaves through the industry, really.
Then Ricardo Uauy a few years later followed that up with a preterm study and he had a small group about 10 per group, I think it was, of infants who had been fed a standard preterm infant formula or formula with extra alpha linolenic acid (ALA), the precursor of DHA or a marine source of omega-3 fatty acids. Again, he found that the visual response was way better in those receiving the omega-3s, whether they’re a marine source or the vegetable source.
So those shock waves went through the formula industry and it reminded me that at that time, Bill, you may remember this, but the infant formulas at the time heavily favored omega-6. There were massive levels of linoleic acid in the formula. There was one formula that was commonly used at the time that had 70% of the fatty acids in the form of linoleic acid. So they were highly deficient in omega-3 fatty acids, in particular alpha linolenic acid.
Really that carried on for some years afterwards. Much of the work that then became controversial about whether omega-3s were needed in infants or not were a bit muddy, particularly in the term infant area by the fact that some infant formula companies moved and got their alpha linolenic acid levels up to above 2% of the total fatty acids and others were kind of a bit slower. So if you look back at the literature now, it all seems so obvious to us that if you got a beneficial effect of fish oil in a term infant study, it was because probably the base formula was deficient in alpha linoleic acid and omega-3s.
So you had this crazy thing going on whereby you really had infant formulas that were kind of low in omega-3s, that they were the poor cousin of the fatty acid world. Then the industry caught up and they worked out ways of putting DHA into infant formulas. Whether it had been proven or not, whether the infant formulas needed DHA, they went ahead and put them in.
So it pretty much became a situation where you almost could not do a study anymore without DHA. So that’s really where we’re at with the term infants really. But the level of DHA they put in was about the same level, it’s common say, in the breast milk of American moms. So it was a relatively low level and we did calculations that estimated that the level of DHA that was needed in the diet of a preterm infant was much higher, for example, estimated that they needed 60 milligrams per kilogram per day and that’s not what they’re going to get from infant formulas or from human breast milk.
So we decided that we really needed to address this head on in these preterm infants, since it was impossible to really do meaningful studies in the term infants anymore. And the greatest need was hypothesized to be in those infants that were born less than 37 weeks gestation. So the first study we did, we called DINO and it was about 600 infants that were born less than 31 weeks gestation. We tried to give them a diet that was enriched in DHA and we did that by intervening through the mother. So we gave the mother fish oil capsules or soybean capsules and basically then that would enrich the breast milk because all infants in Australia at that time were getting expressed breast milk. So it seemed like that was a great idea to see if we could test the hypothesis that omega-3s were really essential and needed to be at a certain level for preterm infants.
Well, the results were kind of mixed, actually. Like so many of our studies, we do these really well designed studies with huge numbers and in the end you end up with an equivocal result. It’s so frustrating but it does highlight the enormous variation there is in humans. Really, I think if I could get amnesia and go back to the old days when we did studies with 20 infants and you got an effect and you can talk about it forever.
Dr. Kristina Harris Jackson: Yeah.
Dr. Robert Gibson: Those were the good old days, but sadly it wasn’t the truth. Really, when you do the power calculations, you need big numbers. But in the DINO study that we published we got some short-term benefits in measuring neurodevelopment and visual development, mainly in girls, but also in the infants that were born less than 1,250 grams. But when we followed those infants up, when they became children at seven years of age, there was no difference and we couldn’t see any beneficial effects whatsoever.
I have to say that it was a really great learning experience, one, how to do really big trials in preterm infants. Number two, the things that we needed to have at hand. And we realized two things, is that, number one, the studies needed to be bigger. Secondly, we needed to make sure that the supplement got to the infants sooner, right from the very beginning. So we decided to abandon the idea of trying to intervene through the mother. Rather, we developed an emulsion, which we gave intravenously into the infant because they’ve already got lines inserted in them to deliver nutrients to them. So it was a way of getting a high dose from day one.
Also, we realized that we had to monitor what was going on in the blood of these babies. So we had to develop a dry blood spot test, as much as the same way that you’ve done Bill, and so that we could afford to measure the babies both at the start and at the intervention. Interestingly, the intervention was such that we wanted to make sure that we got enough. So we estimated that the amount they needed was around about 60 milligrams per kilogram per day, and we went ahead and did the study. As you know, it was a big study. There was 1,273 infants in that study. We enrolled from a large number of neonatal units across Australia, New Zealand and Singapore. So we had a really diverse population so we could be representative of the neonatal population of the world. It wasn’t just some little center in Adelaide or Akron, Ohio or something like that. It was broad based.
All along we needed two outcomes. One was a short-term outcome that was clinically meaningful and the second was one that was neurologically meaningful and we could test. The one that we decide to test for the clinical one in the short term was bronchopulmonary dysplasia because it’s something that all preterm infants get and it’s a chronic lung condition and it has sequela here, it’s got long-term negative effects in terms of respiratory outcomes. But also it has got this small but significant downside on mental development probably because they’re not getting enough oxygen.
From our DINO study, it seemed like there was less lung disease in those infants. So we thought “This is going to be the ideal great outcome for us to follow.” So after five years of incredibly hard work, I can’t tell you how difficult that study was to do, but we finally broke the code after all the analysis. I can still remember the day when the statistician came in and he was shaking and I knew we were in trouble then. Then he announced that we broke the code. There was dead silence in the room. We could not believe that we had a negative effect after all of that background work, the DINO study showed so much promise and then we did the big powered study, we found that there was a slight negative effect of on bronchopulmonary dysplasia at that time.
Dr. Bill Harris: Oh, you don’t mean just neutral, you mean negative.
Dr. Robert Gibson: It was negative. It was minus about 13%, 13% worse. So the scores were for the BPD incidence was 49% in the DHA group and about 44% in the control group. I mean, this is not what you want as a scientist and as a clinician scientist, you are working with great team and you only can, of course, get permission to do studies when you’re trying to do good. You’re not trying to do harm.
Dr. Bill Harris: Exactly.
Dr. Robert Gibson: It probably took us about a year to recover from that. It really shook us to the core and we had to think very carefully through what we were going to do about that. But fortunately we had pre-organized right from the very, very beginning.
The second outcome was always going to be neurodevelopment at five years. That was always there, that’s what it was designed to do, that’s what the numbers were there for. Obviously we didn’t need to be able to measure the IQ in all of the infants.
Then another wonderful thing happened to us when we decided to get together and we started to round up the children to look at the neural development where we had this thing called COVID and suddenly we couldn’t bring kids into the hospital. There was a complete ban on bringing children into the hospital unless they had a clinical condition that needed treatment.
So all clinical trials were stopped from that point of view. So we had to work out ways of being able to reach out and do tests in community centers, in homes, in all sorts of conditions. But we managed to get over, I think it was about 480 of those children, which was more than enough to be able to assess the neurodevelopment. I have to say that going back just one little bit is that remember all of the early studies we’re using the Bayley’s score of neurodevelopment, that was the only thing we had and probably still have.
We’re assessing neurodevelopment in infants at an early age. But it turns out it’s a great test for determining whether a child has got a severe mental delay that it is not very sensitive but it’s absolutely non-predictive of later neurodevelopment about what your IQ is going to be. So a lot of that early work that we did, we sent so much to hundreds and hundreds of children that we tested Bayleys on. Really it was not very useful. So we had to wait for these children to get to be five, so that they could do full scale tests, proper IQ tests that meant something and had 100% or close to that predictive nature for mature IQ.
Of course that’s the paper we reported in the New England Journal of Medicine and we found a clear 3.5 Point IQ advantage for those infants who received the DHA compared with the control group. Remember the control group was also getting DHA, they’re getting the standard treatment of the day. It’s not like DHA versus nothing, like it was in the old days, it’s DHA at this new high level, 60 milligrams per kilogram per day versus about the 20 milligrams per kilogram per day they get from breast milk and standard preterm formulas.
Dr. Bill Harris: Okay, yeah.
Dr. Robert Gibson: After too many years of doing these studies, we think that we really do have an answer that early preterm babies, those less than 29 weeks gestation, particularly, they’re the ones with the greatest need. We always thought that because that’s the longest time that they’re out of the womb and they’re likely to get the greatest benefit, and clearly there is a benefit and we need to get more into them.
The big problem the clinicians are facing now is this cost-benefit ratio, is, “Is there a benefit in neurodevelopment?” And remember that there’s no other treatment to enhance neurodevelopment in children other than the DHA. There’s no magic pill somewhere that the pharmaceutical industry’s developed. The only thing we’ve got is DHA.
Dr. Bill Harris: What about arachidonic acid? Where does this play a role?
Dr. Robert Gibson: Well, I must admit that even from the earliest days, I’ve never been a fan of arachidonic acid in any of its forms. We’ve never been able to see any benefit of it whatsoever. Certainly in all of our analyses and sub-analyses, when we’ve looked at the relationship between neurodevelopment and any other fatty acid in the blood, arachidonic acid had never entered into it.
Dr. Bill Harris: Okay.
Dr. Robert Gibson: In the earliest days when we looked at the brains of children who had unfortunately died of sudden infant death and other tragic circumstances, we looked at breastfed babies versus those who had had been fed infant formula of the day. Remember again, they were low omega-3 formulas of those days. When you look at the brain fatty acid patterns there’s this really large increase in arachidonic acid in the brain, it happens. But it’s quite independent of diet, whether you’re breast fed or formula fed made no difference. But with DHA, there was a huge difference between the levels of DHA in the brain of breastfed versus the formula-fed infants at that time. We’ve never been able to see any relationship between arachidonic acid in the formulas, in the diet, in the breast milk, whatsoever.
Dr. Bill Harris: Yeah. We think of before 34 as sort of early preterm birth. Has it been tested that age too?
Dr. Robert Gibson: Well, that’s essentially what we did in the previous study, in the DINO study, there were less than 31 weeks. You’re quite right, Bill. I mean 34 weeks is our early preterm cutoff. It’s really interesting that if you look at the more serious of all the things and that is mortality. Mortality for a preterm infant, born 34 weeks or above is absolutely what it is for on term infants, there’s no difference. But every week you go below 34 weeks, you increase your morbidity and your mortality and by 22 weeks it’s close to 100%.
Dr. Bill Harris: Oh, wow.
Dr. Robert Gibson: These babies are on a knife edge. There’s no question about it.
Dr. Bill Harris: Is BPD a problem in the under 34?
Dr. Robert Gibson: Sorry?
Dr. Bill Harris: Is the bronchopulmonary dysplasia a problem in the early preterm birth? I mean…
Dr. Robert Gibson: Oh, absolutely.
Dr. Bill Harris: … or under 34.
Dr. Robert Gibson: Even at that age, there is, most infants get it. We’re not entirely sure about BPD, about what causes it. Whether it’s about the massive intervention that you have to do to keep these kids alive, they’re all intubated. They can’t suckle.
Dr. Bill Harris: Yeah.
Dr. Robert Gibson: They’ve got many things going wrong with them and… Excuse me. My apologies. But BPD is really a chronic lung condition and the causes are multifactoral and there’s no single cause, but many of them are to do with the intubation and the whole fact of that the interventions we have to initiate to keep them alive. Sepsis is another common thing. I mean, you’re putting lines into these babies and you’re doing things. All of these things just keep them alive. But they’ve all got a risk factor. The result of our work is what are they going to do about it? You’ve got this tiny risk of increased risk of BPD as a result of giving DHA, but on the other hand you’ve got this really positive beneficial effect of neurodevelopment.
Some of the neonatologists say to us, “Ah, BPD, we’re handling it all the time. We’ve been handling it for 30 years. We know what to do.” They don’t see it as a problem. But others are worried very much, they say, “Well, the neurodevelopment is not their concern for the pediatricians. As we say in Australia, “… we’re going to pass that on and they can look after it.”
We presented at neonatal conferences in Europe earlier this year and there was a lot of debate about it and that’s not our role now. It’s in the world of the clinicians and they have to decide, and the various governing bodies of neonatologists need to decide what is the best way forward. So the colleges will all get involved, American College of Pediatrics and so forth, they will all get involved now and say, “What are we going to do about? What is the recommendation?”
Dr. Bill Harris: Yeah.
Dr. Robert Gibson: It’s certainly not clear in Australia anyway. Yeah, that is not been done. But it’s on the cards and there’s active debate I’d say.
Dr. Bill Harris: Yeah. If you looked at the kids at seven or 10 years old, would you still see something?
Dr. Robert Gibson: We figured that we’re going to be doing them again at 10. We’ve already started the whole process of keeping in touch with all of those children and giving the mother’s feedback. Of course, we’re fortunate in Adelaide. It’s not exactly the thriving capital of the world. But on the other hand, we’ve got a population of people in this town, particularly the women who volunteer and they see it’s okay to volunteer for these terribly invasive things that we do. Not so much at the clinical end because all that’s out of our hands, but we are following them up and prodding them and weighing them and measuring them, their growth and development and so forth. It’s a big time commitment.
Dr. Bill Harris: That’s great. Yeah.
Dr. Robert Gibson: So it’s an ideal city for doing that.
Dr. Bill Harris: Tina, do you have a question?
Dr. Kristina Harris Jackson: I mean, that was really fascinating. I’m glad you just took us through the whole trajectory of how we got to where we are and how science is usually, doesn’t give us a clear answer, gives us more questions. I guess, we are getting into this implementation piece where maybe, in the preterm birth area, we feel like there’s maybe a clearer way to go with implementation on that when you’re talking about with this premature infant treatment, it’s a lot more high stakes it feels like.
Dr. Robert Gibson: Yeah.
Dr. Kristina Harris Jackson: So those clinical decisions… I mean it’s hard because you have this huge study and it’d be like, “Well, what if it was 40 milligrams per kilogram instead of 60, would that be better?” But rerunning that whole study is just… It’s really hard to do. But, so I guess, in both ways, you are interacting with implementation with clinicians, with the state, with giving recommendations. What have you learned through that process?
Dr. Robert Gibson: That’s a really interesting question, Kristina. I think five years ago I couldn’t have answered that question, but we’ve been involved in a big implementation study here in South Australia where we are monitoring the omega-3 status of all pregnant women in the state as a means of determining if they’re low in omega-3s. And if so, whether the supplementation helps to reduce the incidence of early preterm birth.
It struck me at the time that when we first started, I used to hear these stories about the length of time it took from between discovery and implementation of a treatment. I think it was then about 17 years. I thought, “How can it take 17 years? You cannot conceive of such a number. But having walked the walk through, particularly the infancy which has been going so for so long, and then now the pregnancy situation, it’s all very well to do the very big trial and come up with what you say is or you feel is the answer to a problem. You’ve done the systematic reviews and meta-analysis, you’ve done the largest clinical trial, you’ve published in New England Journal of Medicine, and it gets you nowhere.
It might get you another grant maybe, but not necessarily. Because the real thing is how are you going to help people? I mean, I’m in this racket not to make money. We never made a cent. It’s because you want to do good and you’re trying to improve the life of people, and if there’s something I can do within the nutritional realm, that’s what I’ve dedicated my life to. Sounds very grandiose, but it’s been a driving passion.
I got really shocked when we finished the big trial in the pregnancy trial and we got this clear answer about the need for the omega-3s to prevent early preterm birth that confirmed the work of Susan and others. But we found that there was… Because we’d monitored the levels of omega-3s in the women, there were this population of women who were at risk. They were the ones that had the lowest level of omega-3s in their blood.
We published the paper and then we thought, well what are we going to do about it? You just cannot just sit on your hands. We are morally obligated to do something about it. We had limited resources. So we had to try to hassle around and try to find out ways of, “Well, how can we make our few research dollars stretch to do something in this state?”
We’ve got a state pathology service which collects the serum of all pregnant women to screen for what may be inborn errors or genetic errors of metabolism. So they collect at least 85% of all the pregnant women. So when we had to develop, we thought, “Okay, we can get into partnership with them.” Well, that took 18 months of negotiations. Why? Because they’ve got this smooth running machine, the blood gets taken, it gets subdivided, it goes to this great big room where there’s this big computer thing goes and there’s all sub sampling going and thousands of different tests are done and it’s all logged on computer.
You can’t just go and grab a sample. It’s like… You’ve got to fit in with that sort of system and you’ve got to work out a way of doing it. It took 18 months to get that. Then it took us a while to demonstrate that if we could get a system of measuring the serum fatty acids in a single vial so that we could do the whole thing in one shot, put all the reagents in, shake it up, wave your hands about, stick it on the machine and measure it. So that took a while to validate that.
But the great thing then is the communication, and Bill and Kristina, this is something you know about and we are so lost in, but is, “How do you get out there? How do you get the message out there? How can you tell the moms?” You’re competing with the manufacturers of diapers, you’re competing with the nutraceuticals, it’s vitamin D, it’s this, it’s that. It’s inositol, it’s folate. “You must take this, you must take that.” “You must do these exercises.” “You got to eat fish.”
It just… There’s this massive information flooding them. So how does your little voice get heard? Then you need to reach the key opinion leaders and that’s always been difficult. So currently I’m spending my life going around this state and knocking on the door of every clinical practice in this state. Maria is part of the team. We’ve got a team of other young women as well and we’re all going on knocking on the doors and talking to the general practitioners and saying, “Do you know about the omega-3 test?” Now, we’ve had stuff online for weeks, months, years now, two years now. Most of them haven’t heard of it.
Dr. Bill Harris: Right. Sure.
Dr. Robert Gibson: They’re too busy. They got a backlog of patients, they’re overwhelmed. So we are in this translation, implementation side of things and currently we’ve done about six and a half thousand pregnant women in this state. It’s only represents about 35% of the live births. We want to get it up to 80% so that we get meaningful numbers so that we can do two things. Number one is show definitely that such a program of screen and treat is actually going to be beneficial in terms of reduced numbers of infants in the neonatal unit, and that’s reduced cost to the hospital system as a whole, and that there are benefits and that it’s cost-efficient.
Dr. Bill Harris: Right.
Dr. Robert Gibson: So when you talk to me about implementation and I start looking at this paper that I published in New England Journal of Medicine and you asked me, “What are you planning about implementation?” I go quite weak at the knees because I’m thinking, “Oh, no. Not again.” But we have to. So we are meeting and we first of all need guidance from the clinicians to say, “Well, is this something you’re going to endorse? Is this something that you’ve made the decision that yes, we have to increase the level of DHA?” Fortunately we don’t have that answer. We’ve only got perhaps two groups that we need to really focus on. One’s going to be the infant formula manufacturers and the other is the neonatologist. We won’t have to reach the moms and or the general practitioners because all the treatment of neonates happens in the neonatal unit, in the NICUs.
Dr. Bill Harris: Yeah. At least more focused group then…
Dr. Robert Gibson: But as you can see from the beard, Kristina, I’m an old man and I just want to go fishing.
Dr. Kristina Harris Jackson: Yeah.
Dr. Bill Harris: When are you going fishing, Bob? When are you going to wrap it up?
Dr. Robert Gibson: Well, I’m not going. I’m just going to keep on going until they put me in the box. I think. I’m having too much fun, Bill. Really.
Dr. Kristina Harris Jackson: Yeah. Your team in Australia has been pushing the whole world. You guys are ahead of everybody, so we’re cheering you on. We see the same issues implementation-wise and where it needs to go, but it is kind of that slow burn I feel like. It’ll be fun to see where it goes in the next 20 or so years.
Dr. Bill Harris: You’re going to have to carry it, Tina.
Dr. Robert Gibson: Absolutely. I mean that’s why I married young because Maria can carry it on.
Dr. Kristina Harris Jackson: That’s right. We keep passing it. Exactly.
Dr. Bill Harris: Great. Good plan.
Dr. Kristina Harris Jackson: Oh. This was wonderful.
Dr. Bill Harris: I’m sure that was the plan all along. Right, Bob?
Dr. Robert Gibson: That’s right.
Dr. Kristina Harris Jackson: That’s good. Well, thank you so much for giving us your time and this great story and we will be watching what you guys do and cheering you on and hopefully getting to collaborate here in the US doing our own.
Dr. Robert Gibson: Thanks guys. It’s nice chatting to you. It’s been nice actually interacting a bit too on the academic side. I’m sure we’ve got some really good active discussions, disagreements.
Dr. Kristina Harris Jackson: Oh, yeah.
Dr. Bill Harris: Right.
Dr. Kristina Harris Jackson: Absolutely.
Dr. Robert Gibson: Nice to come and I’m looking forward to it. I love it. Take care. See you guys.
Dr. Bill Harris: Bye-Bye.
Dr. Kristina Harris Jackson: Bye.