​Guest lecture: Dr Emily R Smith of George Washington University 

​Addressing hidden hunger in pregnancy: Current controversies and new evidence on micronutrient supplementation 

Dr Emily Smith delivered this lecture at AKU on April 18, 2024. Below is a lightly edited AI-generated transcript.

I'll say just a few words about the case for maternal nutrition recommendations and what the current recommendations are. I thought we'll spend most of our time on what is the new evidence out there. Then the latter half about kind of this current controversies around maternal multiple micronutrients and some of the new studies that are being planned, including some work here at AKU. So this is a framework I like to think about why we care.

Why do we care about maternal nutrition? We care about maternal nutrition both for mom's health and for baby's health. So a lot of the causes of a baby being born too soon or too small are related to maternal nutrition. So we see that short maternal stature, which reflects kind of a lifetime of undernutrition, starting pregnancy with a low BMI or being too thin, not gaining enough weight in pregnancy, and then micronutrient deficiencies and anemia are all important risk factors for a baby being born too soon and too small. And the thing is, starting off life too soon or too small is related to even survival.

Babies who are born early are more likely to die in the first month of life, in the first year of life. But newer work, and some of the work you all have done as well, shows that this is also a risk for getting sick in childhood, but also not reaching optimal cognitive development in early childhood development.

When we think about it from the life course perspective, we argue that maternal nutrition deserves attention here. Maternal nutritional status increases the risk for mom's morbidities herself. Here I'm just showing a bit from our COVID work showing that underweight pregnant women or women with anemia at the time they get COVID are more likely to end up in the ICU, more likely to experience critical care, and more likely to experience pregnancy-related death. This is based on an update to some of our previous published work that includes, including from some of some colleagues at AKU, almost 200,000 cases of COVID in pregnancy.

That said, this is an area I think we should really, the epi evidence should be strengthened here. There's a lot less about mom's health. So I think this is a good opportunity in these pregnancy cohorts to strengthen the epi evidence here.

How can we preserve maternal, support maternal nutrition?

The first is iron and folic acid, or IFA. Daily IFA with 30 to 60 milligrams of iron is recommended to prevent anemia, sepsis, low birth weight, and preterm birth. A pretty good intervention here.

Multiple micronutrients or MMS, or in the U.S. we'll call them prenatal vitamins, but this is like a comprehensive multivitamin that includes iron and folic acid. Right now WHO actually doesn't recommend this for everyone. It's still recommended in the context of research. That said, MMS is part of UNICEF. A lot of people are scaling up MMS, but it's currently not recommended for everyone.

Then we have balanced energy protein supplements, or BEP, which is a food supplement during pregnancy. And that's recommended to prevent preeclampsia. This is recommended in contexts where people don't get enough calcium, although that's hard to measure exactly, but nonetheless, it's recommended. And then lastly, recommended is counseling on healthy eating and activities. the kind of five things key in current WHO, ANC guidelines.

What evidence is this based on? If you take MMS, the multivitamins, you can see there's a ton of data here. There's been 20 trials, mostly in low and middle income countries, 141,000 women and most of that data is quite old, 60s, 70s, 80s. The calcium data, 23 trials, 18,000 women, kind of mixed global evidence.

Sometimes I hear from people, we should just do counseling and ignore the other things. I would say the counseling is recommended to prevent overweight. It's not recommended for undernutrition outcomes. It's also mostly high-income country data, and it's about 11,000 women. And then BEP, 12 studies, mostly high-income, only 6,000 people. I always find it interesting how much data are we talking about, what's good evidence.

There are five interventions here for nutritional support of pregnancy, which are good, they're well supported, they can and should be scaled up now. In parallel, I think we should do research for the next generation of interventions, but I don't want the two things to be mixed up because it's not we have research questions, but those research questions should be done in parallel with implementation of the current interventions.

Data gaps, controversies

I'll talk just a little bit about balanced energy and protein supplementation in pregnancy. One thing I find a bit interesting here, that there have been a number of different kinds of trials. I'm gonna group them all together and call them nutritious food supplements. So there's high protein supplementation. There's one trial. It's not recommended by WHO. That's actually a 1970s study from Alabama. Fascinating to me. There's only been one study on it. So I'll leave that for people to think about if there should be more. There's balanced energy protein supplements, which we talked about is recommended based on those few trials.

There's also something called lipid nutrient supplements. This is the idea of these is that there is a small number of calories that are mostly from fat bundled with the micronutrients and the thinking behind that was adding fats to the micronutrients would help absorption and improve outcomes. This actually hasn't been reviewed or a review hasn't been released by WHO.

Lastly, there's what I'm going to call a new genre of BEP products, which are micronutrient fortified and more standardized in their formulation. What do we know about LNS? So there have been three trials that look at the lipid nutrients versus IFA and in general they find kind of 6% reduction in SGA and maybe some benefit in the other outcomes, but fairly small.

We look at the lipid nutrients versus the multivitamins, which to me actually is the better study design because it's looking at the same micronutrients plus the addition of the fats. There's only three studies here as well, and in these studies we actually find no difference between the multivitamins and the lipids for these birth outcomes.

There's also just published an LNS trial in Niger. The primary outcome for that was actually rotavirus, post-rotavirus vaccine seroconversion. It hasn't been published yet. But there was one secondary paper published already that shows some neurodevelopmental benefits for kids on the LMS. Anyways, interesting area, no WHO guidance. The other topic here then is those BEP foods.

Here you're looking at all of these previous trials, and they're really different is what I'll say. The BEP foods and products range in calories from 118 to over a thousand calories. Protein range from 3 to 50 grams. Fat from 6 to 57 grams. And the micronutrient content very different. For example, one of these trials gave you a token to get cheese. So these are older studies, but more or less the problem became, these are really different from each other, and how could you implement it?

I know here in Pakistan, that as part of the Benazir Income Social Protection Program, that there's been this effort to roll out BEP as part of that program. But governments need a product to do that. That's what some of these new studies have focused on. But looking at the old trials, what did they find? 12 trials, 6,000 women, a 40% reduction in stillbirth, 41 grand increase in birth weight, about 21% reduction in small for gestational age. So that's pretty good, and this is what got the WHO recommendation.

But again, we're kind of left with what are these products. So there are five recent or ongoing BEP trials, including one in Ethiopia called E-NAT, one in Nepal called MINT, one in Burkina Faso called MASAMI. The trial you all have completed here called MUMTA or using BAMSA, and then in India, outside Delhi, the WINGS trial. And so all of these are just finished or almost finished, and all of these use a product that, one, can be commercially available, and two, is part of what I'll call this micronutrient-fortified BEP.

And so this will be really interesting to see the findings of these and see how this can be worked into programs. But when we get to programs, one of the big questions is who benefits and who should get these foods? So right now, what WHO says is that you should give these foods to all women if in that area, low BMI is more than 20% prevalent, which is actually how this kind of BISOP recommendation got into place. Because when they looked among everyone in BISOP, I think it was about 28% of women had low BMI. And so the idea was this meets the guidelines. So we estimated, we did some modeling on this a few years ago and said about 30 million women would be eligible. But most countries actually don't know, like, we don't have national BMI data or subnational BMI data, so kind of figuring out who should get the BEP is a little challenging. The other idea is to just give these foods on an individual basis. So someone comes in for their A&C, you find out they have a BMI less than 25, you give them the food. So a lot more people probably would be eligible for the intervention then.

We estimated about 120 million. And these are both about prevention. The other option could be to use it for treatment. So we could look at monthly weight gain monitoring and find out who is not gaining enough weight and give them the intervention. To do that, though, we have to have weight gain monitoring, which is actually not one of the current WHO recommendations. It makes sense, I think, but in fact, most women don't get monthly weight gain monitoring around the world, and it's not currently recommended. And there's no evidence, really, on both of these. So, this idea of targeting, it makes sense. This is an extensive intervention, but kind of from a practical perspective, how to do this is an ongoing area of work.

Calcium supplements

Calcium supplements are recommended by WHO. It says in a context where there's high risk of low calcium intake. How do we decide where that is is a bit of a challenge. The other challenge here is how many supplements to take. This recommends 1,500 to 2,000 milligrams of calcium. It tells us don't take it at the same time as your iron supplement and don't take more than 500 milligrams at a time.

So what does this mean? Maybe some of you have done this in your own pregnancies. It means take calcium three times a day and at a different time take your iron. So that means four pills in a day. So this is kind of challenging. Also from a logistics perspective, I think we did this calculation once for Tanzania for one district, the amount of containers we would have needed to store all the calcium tablets for the pregnancies in one year was crazy because they're big pills. So just logistically, I think it's a lot of challenge.

So despite this WHO recommendation, there are actually very few countries that are implementing it in a standardized way because it's costly, it takes the size is big, and people are concerned about the regimen complexity. Some colleagues at the Africa Academy of Public Health, at Harvard, Ifakara Health Institute, and St. John's Research Institute in Bangalore have just finished this parallel, individually randomized non-inferiority trial looking at single dose of calcium versus 1500 milligrams.

Two may have seen this just came out in the New England Journal of Medicine looking at these 22,000 women. This study finds that low dose calcium is non-inferior to the standard dose of 1500 milligrams. This is always challenging, a non-inferiority trial. You have to pick what makes it better or worse?

I think there's still a lot of debate about this trial or controversy. But nonetheless, as designed, this study finds that the low dose is non-inferior for both preeclampsia and preterm birth. That said, it's like you can see the low dose actually looks a little better in India, but not by the margins. We want to talk non-inferiority trials over tea. It's a big discussion, but as designed, this says no difference. But interestingly, I've already been part of some of these discussions. WHO doesn't find this too compelling. So it's going to be really interesting. Like, this was a study that was designed to try and reduce complexity and cost for country programs. But will the recommendations change?

I don't feel too optimistic at this point, but I think there's a lot of discussion and guidelines groups yet to happen for this topic. But some countries may decide to reduce the dose anyway.

MMS, or the multi-micronutrient supplementation

So far there have been 20 trials with 140,000 participants, and as a person who has done a lot of meta-analysis, this is a ton of information. There's a lot of data here. What did these trials test? An important thing to keep in mind, these studies compared MMS, which has the standard formulation that UNICEF, like a working group from UNICEF in the 90s, that is called the Unimat formulation. It has 15 vitamins and minerals, including iron and folic acid. So it's MMS compared to IFA. I say this is important because it's not MMS versus placebo. What we're going to look at this data is what's the effect of the multivitamins over and above IFA.

Here you see the summary of findings from maternal health outcomes. You can see a few trials looked at maternal mortality and find no difference for the multivitamin versus IFA. And nine trials looked at maternal anemia versus IFA and find no difference. We'll look a little sad when I look at the WHO guidelines and even these trials, most of them didn't measure any maternal outcomes, only babies' outcomes. And even the studies that measured anemia, it was mostly a subset. So although it's nine trials, it's actually not too many participants.

My interpretation of the anemia finding is that there's not much evidence there. Now if we look at the summary of findings for MMS versus IFA for infant outcomes, what you're looking at here, if you're used to looking at Cochrane reviews, it's the number of participants, number of trials, the certainty of evidence, meaning how confident are we, and then what's the relative risk. So here you can see in this latest update about 5% reduction in preterm birth, 8% reduction in SGA, 12% reduction in low birth weight, no effect on mortality, maybe a small effect or no effect on stillbirth, and no effect on neonatal mortality.

The Cochrane Review interprets this evidence saying they find a positive impact of the MMS on birth outcomes. It reduced the risk of low birth weight. And SGA probably reduces preterm birth.

No benefits are harmed for mortality outcomes. And they say, may provide some basis to guide replacement of IFA with MMS for pregnant women. So that's the Cochrane conclusion. We also, I'll say there's been a lot of concern about this intervention, about whether potentially it's harmful. So let's say you have a great diet. You eat really healthy.

Should you take a multivitamin?

That's a big question, and some people really have felt concerned that maybe it would be harmful in this case. There was also this idea commonly that if we have women who have experience undernutrition who are very small, maybe they take the multivitamin, the baby's big, we increase the risk of stillbirth or increase the risk of cephalopelvic disproportion or obstructed labor. And so this is a hypothesis that's, as far as I can tell, been floating around since before my time.

But it came out as a big concern when WHO released the 2016 guidelines about this. So we came together with all of the clinical trial investigators and said, well, we can answer this question for WHO. We can see if everyone benefits or if maybe there are some groups of people that might be harmed by taking a multivitamin.

We have a global collaboration to address these concerns. We had 35 investigators who contributed data from 17 different trials. Here you see where all the trials took place. So in Africa, one study in Mexico, and several studies in Asia, including one from your colleagues here at AKU.

We looked at 14 different outcomes, all in the same way, and we looked at 10 different subgroups. So we said, well, what if mom is young or old? What if mom is short to begin with? What if mom has anemia or a low BMI or a high BMI? Is it still safe? Is it still effective? And so we did this in a consistent way.

This ends up being 280 different meta-analyses to look at this question in a lot of different ways. You actually don't have to look at every dot, but each one of these dots is a different meta-analysis. And what you're seeing here are the different subgroups. So for example, what if you start taking the supplements less than 20 weeks or more than 20 weeks?

What if mom's BMI is less than 18.5 or more than 18.5? What if her height is less than 150 centimeters or greater? What if she's anemic or not? Down here is the pool of relative risk. So a relative risk less than 1 means MMS is protective. A relative risk of greater than 1 would mean MMS is harmful. So what I'm just showing you here is you don't have to look at every single dot, but first of all you see that every one of these dots is less than one on the left side here, meaning that in all of these cases we actually find that MMS is beneficial on these outcomes for low birth weight, preterm birth, and SGA. We don't find anywhere it's harmful.

If anyone's worried about multiple testing, you'll learn this is part of stats that everyone gets worried about. By chance we should have had at least five of these that were harmful if in fact there was no effect. So it is important that we find no harm. And the other thing when we kind of get into all of these is that we do find some larger effect sizes for undernourished women, but even for healthy or kind of adequate nutritional status, we still find a benefit of the MMS. So I think it's pretty clear here on birth outcomes that its apparent benefits are apparent and there's no harms. Then there's just the question of what's the effect of the multivitamin when it comes to stillbirth and neonatal death. So here I'm showing there's kind of two different meta-analyses.

The IPD that I just showed you that we did in the Cochrane review. Both of these we find a 5 to 8 percent reduction in stillbirth, and then both of them they find no effect on neonatal death. So this has been another important part of the discussion where people say, well, if you reduce preterm birth, you reduce slow birth weight, why don't you see a benefit on survival? Good question. So one of the things we find in the IPD meta-analysis is we found that there seems to be effect modification by infant sex. And so if you look at this neonatal and infant mortality here, you see for male neonates

there seems to be no effect on a neonatal mortality, but for female 13 to 15% reduction in mortality. You see the p-values for heterogeneity are significant here. What to make of this?

I actually don't know.

I don't think anyone knows the reason for this. One of the reasons it's hard to say is because we don't have good accounting of the causes and timing of death by infant sex globally. So maybe we have it in a few of our studies, but in almost none of these studies did they conduct verbal autopsies or cause of death. So we can't well say, although we do know that in general, male and female humans have different causes and timing of death. We've done some work in the Tanzania trials that also suggests that reducing SGA and preterm birth primarily benefits female neonates.

Anyways, this hypothesis, more work to be done here. I'm sure we have some data here that we could try and answer that question. But I think, at least for me, this clears up a little bit that this kind of null finding on infant mortality. All right, so where are we now when it comes to MMS guidelines? There was a 2020 update that came to the ANC guidelines based on some of this work we did saying here's new evidence, we did these additional analyses, you did, and they did update the guideline from not recommended to recommended in context.

These are kind of goofy categories that WHO has, but it says context-specific recommendation. It's recommended in the context of rigorous research. One of the big points that they made here is they had questions about the iron dose in the multivitamin. And then there was also this question of, well, the SGA effects are kind of small, the low birth weight effects are kind of small, and why is that? And are they important effect sizes?

So colleagues at WHO wrote this kind of editorial in BMJ Global Health to try and better explain what were the research questions that they or the guidelines development group still had about MMS. So one of the first one is basically, oh, I'm going to say misguided. I have to secure this idea that, oh, we didn't actually have enough evidence in trials where they used ultrasound. And I will tell you why. A lot of this evidence is old.

The first trial my colleagues did in Tanzania was in 1990. There were no ultrasounds for gestational age available at the time. But that said, there was surveillance, urine testing, like regular documentation of the last menstrual period. There was really good work done to improve gestational age dating in a lot of these trials, even without ultrasound. Anyways, nonetheless, WHO said it was a question.

The second question that was highlighted was needing to understand the iron dose. Why is this? So I think in Pakistan you use a standard of care iron and folic acid with 60 milligrams of iron. Most countries in the world use that dosage. But the UNIMAP or the UNICEF recommended multivitamin has only 30 milligrams of iron. And so the Guidelines Development Group said, what to make of this? And it is an interesting question.

Work since 2020

First, we tried to answer this question of, does it matter that some of the trials didn't use an ultrasound. So here you see a meta-analysis that we did looking at the effect size by gestational age assessment. So there's three different groups here, trials that used an ultrasound, trials that use prospective date of LNP, and confirmation of the pregnancy by urine test, so meaning household surveillance every month or every two months, collecting LNP and getting the urine test strip.

And then some trials, five trials, just asked when you showed up to ANC, asked what your LNP is. So this is probably the least reliable method, right? I will summarize and say that there is no significant difference between the three methods. Although you might see, if you're reading the tea leaves, if you want, that you'll see kind of a slightly stronger effect size in the better methods.

And if you group them in a different way, you see that is true. And this is really consistent. I kept joking, I could tell you this just as an epidemiologist that when we have misclassification, we'll have this bias towards the null. So if anything, we kind of have an underestimate when the method of gestational age dating is worse than in fact this meta-analysis is consistent with that. So I think this more or less answers that question is maybe we've convinced W.H.L. you don't need to do a new trial with an ultrasound, there's already 20 trials. So I think that question may be sufficiently answered by this updated analysis last year. But the question on the iron dose remains. So currently, IFA guidelines recommend 60 milligrams where anemia is more than 40% prevalent. So here's the latest WHO estimates and you see all of these blue colors. So West Africa, Central Africa, East Africa, a lot of South Asia. Most of the world's population is living in a place where they use iron and folic acid with 60 milligrams of iron.

We ask the question, what do we actually know about the optimal iron dose. So this is a slight aside, but we did a review a few years ago that looked at the nutrient reference values. So when we say you should get 27 milligrams of iron or 1500 milligrams of calcium, why do we say that? It comes from nutrient reference values. So what we did in this study was looked at all of the studies that fed into those nutrient reference values and asked, did they include women and did they include pregnant women in those studies? And actually what you find, all of these pink and red colors, they're different sections of reference values, like the indicator section tells you which biomarker to use, which health outcome to use. The life stages section is what tells you it's 1500 milligrams of calcium. And the upper limits section is the section that tells you how much is too much or toxic. Anyways, most of these, there actually were zero studies that included pregnant or lactating women. It's mostly a model of exercise. So again, it's not to say that we have no idea what an optimal dose is. doses. They're educated guesses, but I will argue they could be better informed by empirical evidence.

What do we know about iron dose from the iron and folic acid trials? There's a Cochrane review, 44 trials, 43,000 infants included. What did they find? They find that, again, this is iron versus placebo, so iron versus nothing. We've got a 70% reduction in anemia. Great news. That's what we expect to see. We have about a 57% reduction in iron deficiency. Again, good news. Almost 80% reduction in severe anemia.

It's actually no significant effect on maternal death and infection during pregnancy. No, no effect. For the iron versus placebo trials at infant outcomes, we see about a 16% reduction in low birth weight, 23 grand difference in birth weight, 7% reduction in preterm birth, no effect on neonatal death, no effect on congenital anomalies.

Okay, so that's what the IRN1 is based on, and the Cochrane Review concludes, very similarly to NMS, if you will, that this has benefits.

Just for fun, I compared against what are the effect sizes we're saying. IFA reduces low birth weight by 16%. MMS gives you another 12% reduction in low birth weight. Calcium, no effect. BEP and counseling, no data. When we look at preterm birth, it's about a 7% reduction for IFA placebo. And then you get another 5% for MMS.

It's actually no significant effect for calcium, no significant effect for BEP. And then for small for gestational age, it actually was never measured in these IFA trials. We've got, we have this 21% reduction for BEP, no effect in counseling. It's an interesting question: what is the bar for saying something is effective? It partly depends on who shows up to your guidelines development group in reality, but it's also an important question for us as researchers to think, what is an effect size that we care about and that we think policymakers will care about? And that informs a lot how we design our studies.

Iron doses
What do we know about the iron dose? Here is a bit of data. So we said 44 trials for the iron trials, iron versus placebo, but unfortunately only a few of them actually measured this anemia at term. There were three trials that had a moderate dose, I think it's 45 milligrams, and 10 trials that had this higher dose of 60 milligrams or more. And so we see, I don't know, you want read the tea leaves here or not, to say that there's maybe a dose response relationship with a lower relative risk, meaning a bigger benefit at the high dose than the low dose. But there's not enough data here, is what I will say. Maybe we'll say there's a dose-response relationship. But tool hider, maybe some of you know, did a meta-regression and included observational data as well. Here this is looking at iron dose increases, the relative risk goes down.

Meaning every 10 mg per day increase in iron supplementation reduced the risk of anemia by 12%. So higher iron dose, lower relative risk, bigger benefit. This includes observational data though, so maybe not as good evidence, but giving us some suggestion. Again, it also makes sense biologically. What about when it comes to babies' outcomes? So you can see again we have the low, moderate, and high doses of iron versus placebo, and I will simplify all these numbers and say there's no pattern. I don't see any pattern here, but again, really not much data in the medium doses and even these high doses. Only 4,000 infants, that's really probably not enough for an outcome that happens 10%

of the time. Again, from this high-dermeta regression where they included observational data, this suggests as iron dose increases, birth weight seems to increase until about 45 milligrams. And then after 45 milligrams, birth weight seems to decrease. So this is surprising maybe that potentially there is some, and I think it's true, right? Iron is not water soluble. It can be, it can have harms as well. So you know, this is, this is, this is a model though.

The one other outcome here to look at is neonatal mortality. So iron versus placebo, you can see there were only four trials that measured mortality. Again, not enough data really to look at mortality. Maybe some people will say high dose had the lowest mortality. Low dose had the highest mortality.

I still say there's not enough data, but some people read it like higher dose better for survival. But all of this to say is from the IM versus placebo, to me, suggests that there might actually be different outcomes or different doses that are better for mom's outcomes or better for baby's outcomes. And overall, there's not too much data in there. We have a little other data to look at, which is from the MMS trials.

So remember, it's MMS versus IFA. And the interesting thing that happened is that 10 trials used the same dose in the MMS and the IFA arms, meaning MMS with 30 milligrams versus IFA with 30 milligrams, or MMS with 60 versus IFA with 60.

But 9 trials actually used MMS with a low dose versus IFA with a high dose. I don't love this design, and I'll say why. You know, these trials that use the same dose of iron in IFA and MMS are telling us what's the benefit of adding 13 other micronutrients. The studies like this where they have IFA with 60 milligrams and MMS with 30milligrams are answering two questions.

What's the benefit of added micronutrients and less iron? And we can't disentangle the two things. So you might even hypothesize like less iron is bad for you but more micronutrients is good for you and you end up kind of ahead. What can we what can we do for this? This is how the Cochran Review tried to answer this question is they looked at these each of versus IFA-60, MMS low versus IFA high, and then these two same dose ones. They get split up like this and suggest the outcomes, there's no trend by iron dose. We did this meta-analysis as part of a technical advisory group, kind of using the same groupings here. Again, this is not a significantly different effect. We also have analysis out, two years ago now looking at the iron dose by maternal hemoglobin. Again, there's only these 11 trials and find no significant difference, I guess, by these three groups on MMS by iron dose with maternal anemia. That said, there's very little data here.

This is a big debate among the author group. Some people said they're the same. I would say there's no evidence that they're different, but there's insufficient evidence. So nuance to difference. The one other thing I'll say about this data is that here is how we did the analysis looking at same dose iron versus lower dose iron.

And to me, that answers the question I wanna know, which is, you know, is there any potential harm from the low-dose iron? And this is what I'll say. In the, for example, the stillbirth outcome, the low-dose trials show a 10% reduction. The, sorry, same dose, 10% reduction of stillbirth. Low-dose iron, 8% increase in stillbirths with kind of a significant P value for heterogeneity. And same for early neonatal mortality.

You again see this trend that looks like potential increased risk of neonatal mortality with this lower iron dose. I am again reading tea leaves here. These are secondary sensitivity analysis of a meta-analysis. But nonetheless, at least for me, it says I want to look at this question more.

MMS vs 60mg of Iron
How are we going to look at the question? We have, hopefully starting any day now, a new trial in Tanzania that is a three-arm superiority trial comparing MMS with 60 milligrams of iron or MMS with 45 milligrams of iron to the UNIMAP standard formula, which is MMS with 30 milligrams of iron.

Our original design was a non-inferiority trial, because in Tanzania, we're kind of thinking, the government's thinking, this is the standard dose because they currently give 60 milligrams of iron. But in discussions with WHO, they say, no, the standard dose, the one we are considering in the guidelines is this one. So you need to design your trial to show it's superior to kind of facilitate the discussion on the policy level. So it's an interesting example of, as a scientist, I thought there was a better design, but from a policy perspective, this seems to be the better design. So this is where we landed.

This will be individually randomized, daily supplementation, three arms, about 6,000 pregnant women, and the primary endpoint is moderate or severe anemia, partially informed by our remap study evidence that we have going on in collaboration with you. So this will start soon. And then we'll also do what is a crossover trial. And the idea of a crossover trial, you may have seen, they're used some, I would say more in kind of food trials, but the idea is the same person gets randomized to the order at which they receive the different doses. So each person serves as their own control. So you might get 30 milligrams month one, 45 month two, 60 month three, or you might get 60, 30, 45. You get randomized to one of these patterns. And then the primary outcome here is how much acceptability.

Can you tell the difference between the three doses? And then looking also at the side effects. And so this is a really efficient design, only 200 people here. And so we'll also do this in parallel. And then we've just added another one that's the MMS-60 versus IFA-60. Because sometimes you hear people say, the multivitamin people like it better. Women tolerate it better. I don't know if that's true. There's no evidence about this, but anecdotally people will say this. So we added a second crossover trial.

So something to look forward to: MMS, there's a couple of different studies, including some I know you all are planning. So I think stay tuned. In three years, we'll have more updates.