On Saturday’s Around the Web I linked to a study [1] that tied low-carb dieting early in pregnancy to obesity in the child at age 9. This made Ana concerned:
I’m somewhat worried about the pregnancy diet study. Actually I am trying to conceive, 3 months ago my husbund and I changed my diet to Paleo.
Now I see this study and even though I feel great, better than before, I’m not sure, how much credibility would you give it?
I presume that perhaps there could be too little fat, and with that too low calorie intake for a pregnant woman, perhaps that could be the case, opinions please!!!
We certainly don’t want Ana to be stressed out, and it’s hard to turn down three exclamation marks, so I thought I’d interrupt the cancer discussion to address her concerns.
The Study
The study [1] claimed two things:
- Women who ate less than a thousand carb calories per day during the early part of pregnancy were more likely to give birth to babies with an overly silenced gene for the Vitamin A receptor RXR-alpha.
- Babies born with an overly silenced gene for RXR-alpha were more likely to be overweight at age 9.
Let’s look at the second point, which is more solid, first.
RXR-alpha silencing is associated with obesity
Here is the data:
It looks like it’s normal to have about 50% RXR-alpha methylation in this promoter region and if you have 80% methylation, you’re likely to become a pudgy 9-year old.
How solid is the correlation? They replicated it in a second cohort. Their first study produced two epigenetic marks that were strongly associated with childhood obesity, RXR-alpha and eNOS. A replication study confirmed the RXR-alpha but not the eNOS association.
How plausible is it that RXR-alpha silencing would contribute to obesity? Very plausible, because RXR-alpha is the hub of a network of genes regulating most aspects of metabolism and cell activity.
Vitamin A binds to two types of nuclear receptor, RAR and RXR. When it binds to RXR, a vitamin A – RXR complex is imported into the nucleus. This then looks around for a partner. Partners of RXR-alpha include:
- Vitamin A – RAR complexes.
- Vitamin D – VDR (vitamin D receptor) complexes.
- T3 thyroid hormone – TR (thyroid hormone receptor) complexes.
- LXR (liver X receptor).
- CLOCK, the circadian rhythm regulation gene.
- PPAR-gamma (peroxisome proliferator-activated receptor), a regulator of lipids whose deficiency leads to high cholesterol and hyperglycemia.
- MyoD, a factor that triggers muscle creation.
- Many others; a list can be found at Wikipedia.
The vitamin A – RXR-alpha complex “dimerizes” with these other nuclear receptors, forming a new complex that acts as a transcription factor to turn on gene expression. Most of those other partners cannot act to turn on DNA transcription unless they dimerize with RXR.
This means that the absence of RXR-alpha would be functionally equivalent to being low in vitamin A, vitamin D, T3 thyroid hormone, CLOCK, and all those other partners. It is like being born a sun-starved hypothyroid with messed up circadian rhythms who can’t form muscle and is hyperglycemic and dyslipidemic.
All of those things are associated with obesity.
RXR-alpha silencing might be a universal component of the metabolic damage in obesity:
[A]n association between increased RXRA methylation and adiposity is consistent with the observation of strongly diminished RXRA expression in visceral white adipose tissue from obese mice (35).
Personally, I think it’s very likely that silencing of RXR-alpha promotes obesity. This is the most solid part of the paper. They have data, and the mechanism makes sense.
Conclusion: some babies are getting off to a bum start in life due to epigenetic silencing of an important gene.
Does maternal diet affect RXR-alpha silencing?
This is the really weak part of the paper. Here was their data:
When I say this was their data, this was all of it. No scatter plots, no information about how other characteristics of the diet correlate with RXRA methylation, no information about health or lifestyle characteristics of the various carbohydrate intake cohorts so that we can evaluate the possibility of confounding factors.
It is unlikely that low carbohydrate intake was causing the problem. Aside from the fact that dietary carbohydrate intake is only weakly correlated to any factors seen by the baby in the womb (eg blood glucose, insulin, etc), 261 g/day is a substantial amount of carbohydrate – well above physiological needs. So the low-carb quartile included women in glucose deficiency, glucose moderation, and glucose excess; the other quartiles only women in glucose excess. If a glucose deficiency caused RXRA hypermethylation and glucose excess caused RXRA, there would have been a much larger scatter in RXRA methylation levels among the low-carb quartile compared to the 3 higher-carb quartiles. But we can see from the graph that the standard deviations are the same in every quartile.
So there is likely to be some other factor besides carbohydrate intake that was responsible for the RXRA hypermethylation. What are the possibilities?
One possibility alluded to in the paper is that the women had low carbohydrate intake because they were starving. The paper notes that “famine during pregnancy is associated with obesity in the adult offspring (5).” However, I am unaware of recent famines in Southampton UK.
Another possibility is an excess of some other macronutrient. Those mothers who ate fewer carbs were eating more fat and possibly more protein. Given the ubiquity of vegetable oils in modern fats, the increased fat was probably largely omega-6. This raises two possibilities:
- High maternal omega-6 intake causes RXRA methylation.
- High maternal protein intake causes RXRA methylation.
Both possibilities have support from studies in rodents: maternal high protein intake and maternal omega-6 fat intake are both associated with obesity in offspring. For more on the risks of high protein, see The Danger of Protein During Pregnancy, Jul 12, 2010.
Another possibility is that the low-carb high-fat diet produced a vitamin A excess. As we discuss in the book, this is a common problem, especially among people taking a multivitamin; probably due to widespread vitamin D and vitamin K2 deficiencies, large numbers of people exhibit evidence of impaired health with vitamin A intake above 10,000 IU/day. As a fat-soluble vitamin, vitamin A intake is more or less proportional to fat intake.
If a balance between vitamin D and vitamin A is needed because the vitamin D-VDR complexes and vitamin A-RXR complexes have to be in proper proportion, then the body may respond to an excess of vitamin A and a deficit of vitamin D by upregulating VDR expression and downregulating RXR expression. Such downregulation may be achieved by RXR-alpha methylation.
Another possibility is some confounding factor that happens to be correlated with carbohydrate intake. In the US Nurses Health Study, nurses with the lowest carbohydrate intake were “rebels” who rejected not only the health advice to eat vegetable-rich and whole-grain rich diets, but also every other standard bit of health advice. The low-carb nurses smoked more, exercised less, and drank more alcohol and more coffee.
So it could be maternal smoking, lack of exercise, or drinking too much alcohol or caffeine that causes RXRA hypermethylation and childhood obesity.
Another possibility, raised in the comments by Amber, is that mothers of the obese children were obese themselves, ate low-carb diets for weight control reasons, and passed on their obesity to their children. It is indeed the case that obese mothers tend to have children who are obesity-prone, and it is suspected that epigenetics may be responsible for this “inherited” obesity. If low-carb diets have indeed become popular among the obese mothers of Southampton UK, then this is a possibility that must be considered.
Low-Carb Paleo Pitfalls?
Should Ana modify her diet because of this study?
I think it’s important to avoid a glucose deficiency. But I don’t think it’s necessary to eat 1,000 calories per day of carbs to achieve that.
I think it’s important to eat a moderate amount of protein, neither too much nor too little; and to limit the amount of omega-6 fats eaten.
I think it’s a good idea to avoid alcohol or excessive consumption of bioactive beverages like coffee during pregnancy. Also to avoid smoking, and to get some exercise and sun exposure.
If you’re doing all these things, I don’t think you need to be concerned. Ana says, “I feel great, better than before”; that’s good evidence that she’s well prepared for a healthy pregnancy.
Conclusion
The paper presents solid evidence that hypermethylation of RXR-alpha in the womb predisposes children to become obese at age 9.
The paper gives us essentially no evidence at all as to what causes hypermethylation of RXR-alpha in the womb, except that it correlates with low carbohydrate consumption in the women of Southampton UK.
I hate it when journals do this. If you’re going to link carb intake to RXRA methylation, give some real data and analysis. Probably the authors are saving their dietary analysis for a future paper. The carb graph was included as a “teaser” to make the work seem more interesting.
There are many known health dangers which are known risk factors for obesity and which correlate with low carbohydrate consumption in the general population. So until more evidence emerges, I think there’s little here for low-carb Paleo dieters to be concerned about.
References
[1] Godfrey KM et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes. 2011 May;60(5):1528-34. http://pmid.us/21471513.
via this link:
Great post.
“261 g/day is a substantial amount of carbohydrate”
Hm… I wonder why it writes -261 on the graph ?
There is more info in paper “Early Nutrition, Epigenetic Changes at Transposons and Imprinted Genes, and Enhanced Susceptibility to Adult Chronic Diseases” for those interested.
I remember that starved mothers and fathers produced offsprings with genetic predisposition to diabetes, but that was AFAIK reversible by introducing lots of Vitamin B very early in the baby diet.
Interesting!
My though is that lower carbohydrate consumption is probably confounded by low, and imbalanced, methyl donor intake.
Healthy cultures that sourced their food primarily from animal sources likely ate more liver, brains, skin, bones, and glands than the modern low-carber who probably eats too much muscle meat and not enough liver and connective tissue (which together provide folate, choline, and glycine. As you pointed out, modern low carbers also probably over-consume omega 6.
Weird things happen when methyl donors are out of whack… I suspect that one modern health-woe (probably not the one shared by the low carbers in your study) is caused by people consuming excessive amounts of folate while being choline deficient. Higher RBC folate is associated with more promoter methylation while higher intakes of choline seems to cause less promoter methylation.
See
http://cancerpreventionresearch.aacrjournals.org/content/3/12/1552.abstract
and
http://www.jbc.org/content/284/4/1982.full.
Ah, logic. Indeed, I didn’t think that we could have really said anything definitive about that given the data.
In the context of the American junk diet, whole grains are probably a lot better than potato chips and ice cream. How much of the population is replacing their carbs with non-toxic fats? I’m thinking about Stephan’s post about multi-generational obesity and seed oils. Also can’t we find one culture that gets a lot of their calories from fat but their children aren’t obese? Probably.
This was a very interesting paper that definitely raises eyebrows. I am glad it was addressed in this post as it stuck out like a sore thumb in the ATW post! I wish I knew more about epigenetic gene expression than I do at this point. The human body is proving to be gloriously complex. Carbohydrate intake and it’s relation to a vitamin-A receptor didn’t make any sense to me as ‘carbs’ would seemingly have nothing to do with a fat soluble vitamin. On the other hand I would expect the receptor to be upregulated in low-fat eaters, but we don’t know if these diets were high-carb/high-fat either. I tend to view the body as an adaptive organism. So, in my view it would seem that the body would do this to avoid toxicity due to overabundance of a certain vitamin or as was mentioned, perhaps other vitamins/hormones were not replete. I’m curious to see more pertaining to epigenetics and involved nutritional consequences. Lastly, is there a good primer available on the subject at the moment?
When I saw n=5 in the abstract I imediately thought this is not worth considering even.
If you think about with 5 participants, how many are represented by one bar of the graph? 1 or maximum 2!
And yes, personally I believe Omega-6 as a cause makes much more sense.
This article raises a question that is not directly related but which I ask myself every time when it comes to macronutrient-ratio: Should we focus on total numbers or percentages? for example, 100 g of starch = 400 kcal correlates with 20% of 2000 diet. I am a 105 pound female which means (at least in my case)I do not need 2000 kcal/day. Should I still aim at 400 kcal from starch or should I focus on 20% of my usual intake of about 1600-1700 kcal?
Thanks for asking the question, Janina. I’ll be interesting in the answer, too.
Hi maj, thanks for the idea. Haven’t heard of B vitamins (presumably B6/B12/folate) reversing epigenetic changes.
Hi Daniel, thanks much, another idea to add to the list. Definitely choline is better than folate, that’s especially true in pregnancy when choline needs are higher. Those are cool links.
Hi Janina,
Neither one is perfect as a guideline. Glucose needs are more proportional to brain size than body size; total calorie needs are more proportional to body size; brain size scales roughly as body size to the 3/4 power (http://www.beyondveg.com/billings-t/comp-anat/comp-anat-4a.shtml). So women may need less starch in terms of grams, but more starch in terms of percentage of calories, than men.
So let’s say a woman needs 1600 calories per day. The equivalent of 400 calories for her would be about 340 calories, which is about 21% of calories.
It looks like the percentage-of-calories approach would give the best results.
Thank you very much for making this clear! I think it would be appreciated very, very much if you might consider to dedicate one whole post to the “women`s needs”. When it comes to nutritional advice, even among Paleo dieters, it is always “a men`s world” and woman are always left with wondering what to make of it. Numbers always base on a 2000 kcal diet which isn´t appropriate for most women and I feel other aspects often lack as well…
Your thoughts on the issue would be most interesting!
Hi Janina, That’s a great idea. I’ll have to gather thoughts on it.
@ Stabby re: higher fat culture/obesity of offspring – Amish in US (Pennsylvania Dutch cooking – direct farm to plate local agriculture – local butchering, etc.) Joel Pomerene Hospital in Millersburg, Holmes County, OH has a large, Amish dedicated family practice – maybe stats available.
Thank you so much, my apologies if I was too fussy with my exclamation marks.
Actually, last friday I knew I am pregnant, and I am about to be 42. There was no problem on me, though I am overweight even though I ate mostly salads all the time with a little bit of fatless protein, and some olive oil as the only source of fat. When the gyneo suggested that I should go inmediately onto IVF at my age, I decided to try it, as we had been trying to conceive for more than a year, with no stress on our part. So I investigated and what I discovered about paleo, resonated.
I was on the pill, resting after an IVF cycle, and before beginning another, when I got pregnant, actually I am only one week pregnant.
It’s been 3 months since my husband and I changed to Paleo,not strict, I mean I eat one to two pieces of fruit every day. We had taken the supplements that are supposed to be good for this, and I did an auto-coaching treatment about conceiving (I’m a coach).
And the “miracle” happen. Now I see that I was on a very low fat diet, and I kept gaining weight. No I feel so much better every day, while I am losing weight and celullitis. My husbands whole life’s migraines have dissapeared as well. I’m losing fat and my muscles are there more obvious every day.
Thank you so much again for this amazing articles, and for this one too, it says more or less what I thought, usually this studies misunderstood fat for every fat, and not all fat are made equal. Sorry for my really long post, but just wanted to give some hope to all the women, and their partners, who are out there being told it is imposible to be pregnant at 42.
Hi Ana,
Congratulations!!! That’s great news. I do hope many older women take hope from your story. Who knows, maybe it’s bad diet that makes so many women infertile in their late 30s.
Be sure to eat some safe starches during your pregnancy, and let us know how you do!
Best, Paul
Thank you so much.
Yes, my plan is to have quinoa,bulgur and buckwheat, and from time to time some pasta, but just a little bit.
Paul, about B vitamins more is available here
http://advances.nutrition.org/content/1/1/8.full
“It appears that folate is essential for DNA methylation reprogramming during the early embryonic period.
Vitamin B-12, a water-soluble B vitamin and essential cofactor of methionine synthase in 1-carbon metabolism, has been known to affect genomic DNA methylation
Biotin, an essential water-soluble B vitamin, has been known to modify tails of histone H2A, H3, and H4 through a covalent attachment of biotin to specific lysine residues catalyzed by the enzymes biotinidase and holocarboxylase synthase.
”
I can’t find paper right now about reversible diabetes epigenotype after pre-pregnancy overfeeding with B vitamins.
An now a pro-paleo argument 🙂
In rats moderate maternal dietary protein restriction is known to alter phenotypes in the offspring, which manifests as hypertension, dyslipidemia, and impaired glucose metabolism. However, these abnormalities can be reversed by folate supplementation. It has been shown that the induction of an altered phenotype by a maternal protein restriction diet during pregnancy involves changes in DNA methylation and histone modifications in specific genes, including the glucocorticoid receptor (GR) (33% lower; P < 0.001) and PPAR? (26% lower; P < 0.05) in the liver of juvenile and adult offspring (19,20).
This post eased my worries about that study. I ate low carb all through out my last pregnancy. It was my 6th pregnancy and I usually have miserable pregnancies with morning sickness as bad as the whole 9 mo and very tired and fatigued. My last pregnancy I ate meat, eggs, low carb vegetables, berries, and raw dairy in the form of cheese, cream and kefir and some nuts as well. I would often drink two glasses of raw cream a day with egg yolks in it. I also exercised daily and slept well. I’ve never felt better in my life. It was the best pregnancy ever. I had no morning sickness at all which I at least partially attribute to taking milk thistle throughout it. I wish I’d felt so well with my other children. But I’ll admit this study made me second guess myself. Thanks for making me feel better!
It seems like you didn’t point out what seems the most obvious mistake in the study to me – lack of data on caloric intake. It’s very likely that all the control groups who ate less carbohydrates just ate less calories altogether.
I would say non-overweight women who consume a high amount of carbohydrates expose their child to a hyperglycemic environment. The child adapts quickly, develops hypoglycemic tendencies as a coping strategy – among one of them methylation of the RXR-Alpha gene. Whether it’s fat, protein or carbohydrates – any food eaten in large quantity will produce a sizable or consistent elevation of blood glucose levels. There’s been studies on the Maasai people, a tribe that engages in fattening their pregnant and pre-marriage women with well up to a gallon of milk a day, and when comparing urban Maasai and traditional Maasai, the traditional Maasai had way better biomarkers (cholesterol, LBM, musculature, height, etc). You don’t need to be starving to rob your child of epigenetic advantages, not eating in excess probably accomplishes just that.
“Well how come obese people have obese children, despite the fetus being an a hyperglycemic environment?” It’s obvious, isn’t it? Those obese people are also passing on methylation sites that encode inflammatory obesity-inducing genetic expression, among other things. The poor mitochondrial behavior, poor insulin sensitivity, cytokinetic inflammation – the list goes on. They probably pass on a whole host of other obesity inducing traits.
It’s no surprise that it’s traditional in a lot of cultures for healthy pregnant women to eat a massive amount of food. Nobody looks at a pregnant woman scarfing down on a massive plate food and shakes their head in disgust. Most people intuitively applaud that behavior – and for good reason. It probably leads to healthier offspring. Doctors always recommend that pregnant mothers just eat a lot – it’s common sense.
I don’t know, it just seems like caloric intake would have been the most obvious thing to track. It’s pretty lame that the researchers didn’t even think of this – they didn’t even mention the word calorie in the entire paper.
Well, it is obvious that the last comment here is from a man who never was pregnant and who doesn´t know how miserable it is when you are obese after giving birth and have to lose 30 excessive pounds to come close to what is a healthy weight for you. I did just what he recommended with my first – ate a lot, fattended up, had bad, bad blood markers, elavated blood sugar (borderline for pregnancy diabetes) and high blood pressure. By the way, only 6,5 pounds of my 50 punds gained where baby. With my second I ate like a normal person and gained 21 pounds and felt so much better. My child was exactly 7 pounds. Fattening up your wife is such a sick idea, please reconsider the motives that drive you to give such an advice!
I also would like to add that it is not true that “doctors recommend to just eat a lot” as Matthew suggests (which might be due to the fact that he doesn´t spend much time at Obs/gyns). The common (and common sense!) advice is to increase calorie intake gradually and moderately when the pregnancy progresses…It is a priority to produce a healthy child but not at the cost of severe compromises in the mother´s health! Also, none of the mothers I know who followed a Paleo diet gained excessive body fat. Force-feeding is such a disgusting idea!
Would the recommendations for pregnancy be the same for a woman who was diagnosed with PCOS, but conceived the very first month she switched to a low carb diet? That is what happened to my daughter, after more than a year of trying to conceive, she switched to low carb (totally cut out sugar and any grains) after getting a PCOS diagnosis and she is now pregnant. Now, how to eat while pregnant is the question of the moment. With PCOS is insulin resistance, so I am wondering if the recommendations would be the same or not. I am sure her protein was higher than your recommendations this last month, but her fat intake was pretty high, using coconut oil a lot. We could sure use some advice because she is unlikely to get any from her OB when it comes to nutrition that isn’t the standard, low fat, high carb.
Hi Deb,
I would recommend something like our diet for both PCOS and pregnancy.
A very low carb diet is likely to become problematic as the pregnancy progresses. Also, both high protein and high omega-6 fat (which requires a lot of care to avoid on a high-fat diet; coconut oil is a good start) have problems of their own. Moderate carb intake (20-30% of calories as safe starches) is likely to do her and the baby good. Keeping sugar and wheat out of the diet, along with vegetable oils, are very helpful.
Best, Paul
Thank you Paul! I guess the next question would be, in order to get the percentages, my daughter would need to know how many calories she would need to be consuming. She probably has 30+ pounds to lose, and I’m sure she would like to keep her pregnancy gain to whatever is a safe minimum. She is only 5′ tall, if that helps to know.
Thanks again, your advice is so helpful.
Deb
Hi Deb,
The best thing to do is to eat nourishing foods, and supplement micronutrients intelligently, so that there is a high ratio of nutrients to calories, and then listen to her body/appetite. The brain will set her appetite appropriately if she is well nourished. If she is hungry, she should eat.
My wife and I have been together for 7 years and for most of that we have been trying to conceive. For awhile we had no idea what was wrong until a GYN and a endocrinologist diagnosed my wife with PCOS. A few months before this both of us went on a diet that is more Atkins/Keto than anything else. My wife’s hormones were all over the place and she was borderline diabetic. The endocrinologist advised her to take Metformin for her symptoms. She was on the Metformin for maybe a week at the most, but stopped due to extreme fatigue. We assume that the low carb diet was lowering her blood sugar levels and the Metformin was lowering it even more. We could be wrong, but we stopped it and that is the important part. She continued with the diet and 6 months later, at a followup visit with her endocrinologist, the doctor was proud to say that all her hormone and blood glucose levels were completely normal. He said that this had nothing to do with the brief time she was taking the Metformin. He said these levels going back to normal can be 100% contributed to the low carb diet.
It has been several months since that last visit, my wife has lost over 70lbs, and we found out that she is finally pregnant (she even took 6 pregnancy tests across 3 different brands). Shortly before she knew she was pregnant, we both thought about switching to paleo. Of course, I know the OB-GYN is going to likely go on about how a low fat diet is the way to go and that paleo is the devil, but I don’t take nutrition advice from doctors. We both feel that paleo is what we want to stay on for long term.
Now while we were on the keto diet, we strictly stayed away from all fruits. We understand that some fruits are lower sugar (raspberries, strawberries, grapefruit, etc) than others, but I am afraid to have my wife eat fruit because I would hate to change the very thing that allowed her to be pregnant in the first place – which included staying away from anything with sugar. However, I have read that women should increase their carbs while pregnant. Can anyone give us advice on what my wife should/should not be eating while pregnant? Women with PCOS have a very high miscarriage rate, so we are nervous about doing anything that will cause any problems.
Hi Damien,
Congratulations on your baby! And your wife’s recovery from PCOS, prediabetes, and obesity. You must be very, very happy.
I do think some carbs are important during pregnancy. She doesn’t need a lot, but 400 calories per day would be good. That’s equivalent to about a fist-sized amount of cooked white rice or baked potato taken twice a day, plus incidental carbs (eg banana at breakfast, etc).
However, fruit is OK as an option if she prefers that. I think “safe starches” are better, but your wife should favor what she likes.
I don’t think a small amount of carbs, eg 400 calories a day, would bring back any health problems. If they do cause problems, it will indicate a gut infection/dysbiosis. If that happens then I would recommend diagnostic steps for that, eg a stool test, possibly other tests, and then conferring with a doctor about what to do.
Best, Paul
I have to purchasea birthday gift for an obese co-worker that does not want to tell me his shirt size. It’s odd to me because I am almost as big as him. So I started asking myself whyisn’t therea wish-list website where somebody can buy you something but theywil not know what size you wear. Does anyone know of a website who offers that service.
A thought I have on this is that a mother on a paleo diet could be programming the child to that diet, but when the child comes into the world and doesn’t eat the paleo diet, that is where the problem would be.
Anecdotally though my own experience has not shown this. I ate very low carb for the 1st 6 weeks of my pregnancies because I am a diabetic and wanted to protect my children from blood sugar spikes during the period that their organs were forming. I then switched to a moderate carb diet, the zone diet, for the remainder of my pregnancies. None of my children are overweight, and 2 of them are 9 or older now. They even had the obesity deck stacked against them since I was an obese kid.
I believe thoroughly that famine during pregnancy will bring on obesity in the offspring since that is what happened to me kinda. I had an umbilical chord defect, which starved me at the end of the pregnancy, and according to my mom I was obese by 8 years old. I am the only person in my extended family to have childhood obesity.
During my early pregnancies I had an aversion to meat though, so I didn’t eat too much of it. I ate more nuts, cheeses, eggs, lots of low carb veggies, high fat meat like bacon, cream, and plenty of vegetable oil I am sure in my salad dressing. Meat aversion is pretty common in pregnancy. Pay heed to your aversions in pregnancy.