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[00:00:02] From the Jana Network, this is the JAMA Pediatrics editor summary. A discussion of the most important articles published in the latest issue of JAMA Pediatrics. Here are your hosts. Frederick Rivera and Dimitri Christakis.

[00:00:19]DC;  Hi podcast listeners, this is Dimitri Christakis, editor in chief of JAMA Pediatrics. The Premiere Pediatric Journal in the World. With me today, as always, is my friend, mentor, colleague, sidekick, Dr. Fred Rivera, editor of the new, still new, I guess, JAMA Network, Open Journal. Hello. It’s a little bit unusual. Those of you that listen to us regularly, we usually review two papers. And today we’re going to focus on just one mostly, because I think there’s gonna be, I think, some fairly brisk discussion about the paper. It certainly took us quite a bit of time to take it from submission to acceptance. So, Fred, you want to set up the paper for discussion today?

[00:00:58]FD; The paper is about fluoride and maternal fluoride exposure during pregnancy and its effects upon IQ scores of children at age 3 and 4, which in itself is like a shocking title because I had never known that there’s even any concern that maternal fluoride use might affect children’s IQ.

[00:01:19]DC; Right. In fact, for me, before they were anti vaccines, there were sort of anti fluoriders. Right. And like the traditional teaching, when I was going through residency and early in my early professional career was that there was fluoride is completely safe. All these people that are trying to take it out of the water are nuts. It’s the best thing that’s ever happened for children’s dental health. And we just need to push back and get it into every water system.

[00:01:40]FD; Right. One of our neutral mentors is Abe Bergman. And one of the first things he had worked on in terms of public health was getting the fluoridation law passed in Washington state.

[00:01:50]DC; Right. So, when I first saw this title, my initial inclination was, what the hell? Yes. So, go ahead, Fred. Set up to pay.

[00:01:58]FD; So, this was a prospective study where these researchers collected two measures of maternal exposure to fluoride, there were actually three. So they collected maternal urinary fluoride levels across three trimesters. And they averaged those. They also did a questionnaire to ask them about maternal fluoride consumption, both in drinking water and other sources, and, I didn’t realize, that actually drinking tea, which I drink a lot, has a high level of fluoride. [DC; Now, that is interesting.] And then they also looked at whether there was fluoride in the community water supply, and they were able to follow these women and their children, five hundred and twelve pairs through pregnancy and to age three to four. And at age three and four they then did IQ testing on these children. So, first of all, they found out that there were really quite a large number of mothers living in nonfluoridated areas. 369 mother child pairs and 228 were living in nonfluoridated areas. I’d say that this was from Canada and they picked some large cities in Canada. These were Montreal, Vancouver, Kingston, Toronto, Hamilton, Halifax. So I’m a little surprised that those places did not have fluoridated water supplies.

[00:03:18]DC;You wonder whether it’s the entire municipal water system or sub areas of it. I mean, it wasn’t clear and obviously it’s a separate issue. But yeah.

[00:03:25]FD; And the other interesting thing that came out like in the editorial in this paper was that in Europe, only 3 percent of municipal water supplies are fluoridated.

[00:03:34]DC Right. So, again, this was to me sort of eye opening that, you know, I sort of thought like this area. Right. Everyone did it all. Certainly all developing countries, everyone that was at any level of sophistication was putting fluoride in the water. And because they weren’t falling victim to these concerns, that it was a bad thing.

[00:03:49]FD Indeed. And they were not. So what they found these kids and what they found was, I think, fairly surprising. Now I have a little concerns about the paper.

[00:3:59]DC; Well, we’ll get to that. But tell us the finding.] Right.

[00:04:01]FD; The overall finding was that, as you would expect, the mothers who lived in fluoridated areas had higher fluoride concentration in their urine. And they had a higher fluoride concentration intake during pregnancy than mothers who lived in the non fluoridating areas. And there seemed to be an effect upon their kids IQ. Now, this effect was only seen in boys, where a 1 milligram per litre increase in the maternal urine fluoride concentration was associated with a five point lower score on the boys IQ.

[00:04:34]DC; An effect size which is a  on a par with lead.

[00:04:38]FD; Right. It is. And in the girls, they found actually a non-significant increase in their IQ. The effect size is really quite large because I think we, you know, you think about it really in terms of not the individual child so much as the shift in the curve. Right. In the shift the curve now being shifted to the left for boys. That’s a real concern, because then you look at the tails and the tails may be quite low.

[00:05:09]DC; Right.

[00:05:10]FD; My questions are a little bit about, well, first of all, the IQ testing found a range of 50 to 143. that’s humongous range.

[00:05:18]DC; Well, but that’s the range.]

[00:05:19]FD; Well, I guess that means Severely Delayed to genius. I guess I probably would have made it do a sensitivity analysis where they excluded some of these outliers and look more at the central group of kids. And then it’s also they don’t have a lot of data. They have some data about comparing the two groups in terms of maternal education, employment, income, etc..

[00:05:38]DC; Right.

[00:05:39]FD; But are there other unmeasured confounders here which are coming into play?

[00:05:40]DC; Right.

[00:05:40]FD;  then a third issue is why just in boys?

[00:05:53]CD; Yeah. So let’s take those one at a time. Those are all really good. They did do a fair amount of sensitivity analysis. I don’t recall if they did it around particularly on the IQ. It did. We had any sensors or other things. You know, one of the things that we always talk about, a JAMA Pediatrics is we try not to accept observational studies where an experimental design could be done and that clearly could not be done here, ever. So we’re stuck with observational studies, which there are. So then you always wonder in these situations what the residual confounders can be and how well could they possibly adjust for them. To me, the most obvious one here would be this issue of, as you alluded to, what areas don’t have fluoride in the water? What could the residual confound be? here, but I would normally think of those areas as being less educated, more rural.

[00:06:34]FD;  Here they found that the reverse, if anything, they were slightly better educated and slightly higher income. And the other thing about defending JAMA Pediatrics and taking this as you think of an observational study, well, sort of one level would be an ecological study. We’re looking at kids in one area compared to kids in another area. This is actually individual level data. We actually have fluoride levels on the mother’s. Right. So it’s a very good cohort study. Exposure clearly happened before the outcome.

[00:07:00]DC; Right. No. Exactly. It is a pretty large undertaking. Took a fair amount of money to do this. The last thing you asked about and I think there are other issues to discuss as well, is this issue of boys versus girls, which I also struggled with. And yet we do see that the brain development of boys and girls is different. Much as we like to think of us as being kind of one species, we know autism is higher in boys than girls. The ADHD is higher in boys.

[00:07:25]FD;  So pregnancy mortality is higher in boys than girls.

[00:07:27]CD; Right. And in fact, even in the animal models, weirdly enough, as the article talked about, the effect is seen more in male rats than female rats. I don’t know what to make of that, but we didn’t talk about the biological plausibility, which there have been other observational studies that have shown this and there have been animal models as well that have shown this idea that fluoride could be a neurotoxin, which again, was totally news to me. I thought it was junk science. Right. Anyone would ever say, yeah.

[00:07:52]FD; They’d be like the anti vax with the same fluoride is bad for your brains. So let’s not do it. You know, that same kind of thing.

[00:07:58]DC; In one of the things we struggled with as an editorial staff was, as you alluded to, when we don’t we certainly would not want to be the publishers of the Wakefield study. The article that pulled fluoride out of water and led to decreased dentition. But, you know, the epiname of JAMA Pediatrics is the science of child and adolescent health. And science is an iterative process. It’s not perfect. We were very cognizant. And that’s why I want to have this conversation for this podcast that this may very well get a lot of attention. I expect that in the in the press might lead to a lot of conversations with parents or pregnant women about what they should do. And therein, I think, lies kind of one of the trade-offs here. Right, because it is possible from a public health standpoint that fluoride in the water is beneficial to children after they’re born with no known harms.

[00:08:49]FD; Or it could be that it’s also harmful after they’re born, just as it has in utero.You know, I mean, the brain of the infant we all know is still developing.

[00:09:00]DC; Very good point. Although we’d talk about trying to minimize fluoride exposure in the very young infants, but certainly not when they start drinking after age one.

[00:09:08]FD; I think there’s been maybe correct me if I’m wrong too much, but I think there’s been some work looking at topical fluoride versus systemic fluoride for dentition. Topical fluoride seems to be quite effective.

[00:09:20]DC; Right. But it has to be applied as a whole, as opposed to being in the water, which is sort of the usual. Right. You would argue the other

[00:09:25]FD; where is sort of what we call a passive approach versus the active approach. Everyone gets automatically versus parents having to brush their kids teeth every night or going through a dentist four times a year in getting fluoride varnish.

[00:09:37]CD; Exactly. So that was the approach we took in the US and it could be   to me is sort of where the science is right now, at least from my understanding. And I’m no expert on fluoride, that post-natal foreign exposure in the water may be harmless, may have benefits, has to be traded off against prenatal potential risks, which are avoidable because mothers could certainly drink bottled water during pregnancy if they wanted to. But it’s a complicated conversation and I don’t know where we stand on it now. What is your take?

[00:10:05]FD; Well, I hope that this will result in NIH funding some good research on this topic. I mean, I think that this is a really concerning study to me. I don’t think that people should stop using fluoridated water, overall. Pregnant women, maybe. NIH hopefully will read this and will say, huh? This is an important problem. And we need to really look at this in a careful way. Both, I think, with some more animal experiments, but also with some further cohort studies, you know, and NIH has that big ECHO program, which is looking at, after the demise of the National Children’s Study, as a way of looking at the effect of environmental toxins on kids. Well, this probably ought to be part of it.

[00:10:50]DC; Maybe it is. Actually, that’s a good, very good point. Because absent that, you are looking at, even if they started an RFA now, it will be five, six, seven years before we have a replication or an attempt to replicate this study. Right. Given that it’s a prospective longitudinal study over five years. So in the meantime, we are left with the challenge of how to advise pregnant women. This was their only paper as long as I’ve been editor that I wrote an editor’s note on. And I basically said that we decided to publish the paper after a fairly tendentious discussion.

[00:11:22]FD; I’m sure you had a very rigorous stats review.

[00:11:24]DC; We had a very rigorous stats review, several of them. We had a very tendentious discussion amongst the editors because there was concern about what the public health issue would be. But I’m certain if we didn’t take the paper, somebody else will. And I didn’t want to shy away from decision to publish it just because of the potential. But I did say in my editor’s note that science is iterative and this is not the first nor the last paper to look at the potential ill effects of fluoride.

[00:11:48]FD; So if mothers now come into their doctor’s offices and ask the pediatrician what to do, what are you gonna say?

[00:11:56]DC; I think I would advise them to drink bottled water or filtered water because it’s not a particularly odious thing to do and potentially does reduce the risk.

[00:12:05]FD; You know, the other thing is that some people may not be able to afford bottled water. It could be a financial burden to some low income families. And we need to think about that as well. Yeah, well, it’s going to get a lot of attention. And I’m very proud that you published it.

[00:12:20]DC; Well, I hope I don’t regret it. Thank you all for listening. Good luck helping your families make decisions about prenatal exposure to Fluoride. And we’ll talk to you next month.