Very true!



Well, experiments have been conducted in animals where calorie intake is such that they're not energy deficient but ketosis is present, other studies have infused beta-hydroxybutyrate to raise levels and others have adjusted macronutrients in diet to induce ketosis.

From human studies - we have both a starvation model (anorexia/bulemia and/or purposeful calorie restriction diet) related to ketosis in pregnancy -and- also studies where ketosis as part of gestational and/or type 1 or 2 diabetes.

I've yet to find a study inducing ketosis or infusing beta-hydroxybutyrate in healthy pregnant women to see what happens - I think that's because ethically we shouldn't - the findings from animal models and the anorexic/bulemic/dieting groups and the diabetic groups serves to provide understanding of the potential danger of hyperketonemia in pregnancy.

Let's set aside the energy deficient models - they're too confounded with other variables like nutrient-deficiency...the literature is still rich with data from studies in humans and animals where calories weren't at issue....I'll start with the human data and add the last one is energy restricted...

In a comparison study - the children of 'true' diabetics, gestational diabetics, and normoglycemic women were given mental development and intelligence tests at ages 2, 3, 4, and 5. Even after correcting for possible confounding factors like socioeconomic status, etc. their scores correlated inversely with third-trimester levels of ketones:

NEJM - Correlations between antepartum maternal metabolism and child intelligence
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

After correction for socioeconomic status, race or ethnic origin, and patient group, the children's mental-development-index scores at the age of two years correlated inversely with the mothers' third-trimester plasma beta-hydroxybutyrate levels (r = -0.21, P less than 0.01); the average Stanford-Binet scores correlated inversely with third-trimester plasma beta-hydroxybutyrate (r = -0.20, P less than 0.02) and free fatty acid (r = -0.27, P less than 0.002) levels. No other correlations were significant.

American Journal of Obestrics & Gynecology - Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Children's average score on the Bruininks-Oseretsky test at ages 6 to 9 years correlated significantly with maternal second (p < 0.02) and third trimester (p < 0.001) beta-hydroxybutyrate. There was also a borderline association between the children's scores on the psychomotor development index at age 2 years and maternal third-trimester beta-hydroxybutyrate levels (p = 0.06). No other correlations approached significance.

Diabetes - Long-term prospective evaluation of offspring of diabetic mothers
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

We found an inverse correlation between childhood IQ and second- and third-trimester maternal lipid metabolism (serum free fatty acids and beta-hydroxybutyrate). This correlation is not explained by adverse perinatal events, socioeconomic status, maternal IQ, ethnicity, or diabetes type. These long-range associations between altered maternal metabolism and childhood growth and development continue to support Freinkel's hypothesis of fuel-mediated teratogenesis.

Israel Journal of Medical Science - Embryotoxic effects of diabetes on pre-implantation embryos
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

A high correlation was found between the number of undeveloped embryos and the blood concentrations of metabolic diabetic factors: glucose (in type I diabetes), beta-hydroxybutyrate (in type II diabetes untreated or treated with Daonil), acetoacetate (in insulin-treated type II diabetes), and HbA1c (in both insulin-treated and in Daonil-treated type II diabetes).

Hormone & Metabolic Research - Maternal, amniotic fluid and cord blood metabolic profile in normal pregnant and gestational diabetics during recurrent withholding of food
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum


Positive correlation was found between the levels of BOHB in the mother and venous cord plasma on the one hand and their levels in the arterial cord plasma and liquor amnii on the other hand implying that this substrate passes unutilized through the fetus to the liquor amnii.

The data from animal studies digs a bit deeper since animal experiments often give us data we can't get with humans due to ethical considerations in designing studies:

Development of rat embryos in culture media containing different concentrations of normal and diabetic rat serum

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

When the embryonic growth and development were compared at 50% and 80% serum concentrations, increased D-glucose or beta-hydroxybutyrate concentrations caused similar degrees of embryonic dysmorphogenesis. Also, the uptake of each compound by the embryos exposed to elevated levels of the two agents were similar in 50% and 80% serum cultures. There was, therefore, no protection against the teratogenic and growth-retarding effects of increased D-glucose or beta-hydroxybutyrate offered by high serum concentrations in the culture medium (i.e., 80% vs. 50%). Embryos cultured in 50% or 80% diabetic rat serum at 30 mmol/L or 50 mmol/L D-glucose concentration showed similar rates of somatic malformations as did embryos exposed to the same proportion of normal rat serum at similar glucose concentrations.

Morphological and physiological effects of beta-hydroxybutyrate on rat embryos grown in vitro at different stages

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

The results of experiments in which embryos were cultured with beta-hydroxybutyrate from 9.5 days of gestation for 24 h (equivalent to 9.5 to 10.5 days of gestation) showed that some effects of beta-hydroxybutyrate are already apparent after 24 hours in culture. Many of the abnormalities produced by beta-hydroxybutyrate can be classified as embryonic retardations rather than malformations--that is, embryos show features characteristic of normal, but younger, embryos. Embryos exposed to beta-hydroxybutyrate for the complete 48 h culture period consume less glucose and produce less lactate than control embryos on a per embryo basis, but not on a per microgram protein basis, suggesting that the reduced metabolism is an effect of beta-hydroxybutyrate-induced developmental delay rather than a cause of it.

Evidence for multifactorial origin of diabetes-induced embryopathies

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

The results demonstrate that glucose and D-beta-hydroxybutyrate can act synergistically to produce growth retardation and additively to induce malformations. The addition of the somatomedin inhibitor exacerbates the induction of malformations produced by the ketone body and glucose.

Effect of maternal hyperketonemia in hyperglycemic pregnant ewes and their fetuses

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

The fetus of the pregnant diabetic woman is exposed to hyperglycemia frequently accompanied by ketoacidosis. Previous studies have demonstrated that beta-hydroxybutyrate, a major ketone body, crosses the ovine placenta in significant amounts, leading to significant reductions in fetal PaO2 and increased fetal heart rate. In the present study the pregnant ewe was used to evaluate the maternal and fetal cardiovascular and metabolic responses to hyperketonemia in the presence of hyperglycemia and to determine if the combined diabetic insults were more detrimental to the fetus than hyperketonemia alone. A glucose priming dose of 25 gm was administered in the maternal femoral vein followed by a continuous glucose infusion of 200 mg/min to achieve steady maternal plasma glucose levels of 180 mg/dl. Once glucose levels were stable, beta-hydroxybutyrate was infused for 2 hours at a rate of 0.39 mmol/100 ml of uterine blood flow into both left and right uterine arteries. Infusion of glucose alone did not significantly alter fetal cardiovascular and blood gas parameters but did increase the fetal glucose level from 17 +/- 4 to 58 +/- 8 mg/dl. The simultaneous infusion of beta-hydroxybutyrate and glucose produced significant decreases in fetal PaO2 and oxygen content as were reported for hyperketonemia alone and significant time-related increases in fetal lactate levels and fetal heart rate. These data suggest that hyperketonemia in the pregnant ewe leads to quantitatively similar changes in oxygenation in both normoglycemic and hyperglycemic fetuses.

Effects of beta-hydroxybutyrate on rat embryos grown in culture

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

the presence of beta-hydroxybutyrate, one of the ketone bodies produced by diabetics. At 10 mM, beta-hydroxybutyrate produced minor abnormalities and at 20 mM it produced major abnormalities in rat embryos.


Effects of hyperglycemia and ketone bodies on the in vitro development of early somite rate embryos

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Ketone bodies (acetoacetate and beta-hydroxybutyrate, B-HOB) were individually added to normal or to hyperglycemic sera (total glucose concentrations of 3 mg/ml) in the following concentrations: acetoacetate--5, 10, 20, and 40 micrograms/ml; B-HOB--2, 5, and 8 mg/ml. The higher concentrations of each of the substances induced growth retardation and abnormalities.


Metabolic alteration in neural tissue of rat embryos exposed to beta-hydroxybutyrate during organogenesis

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Hyperketonemia has been identified as an important factor in diabetic pregnancy affecting growth and development of the offspring. In order to assess the immediate metabolic alterations in embryos caused by excess ketone bodies, we studied rat embryonic neural tissue exposed to a high concentration of beta-hydroxybutyrate in vitro. Beta-hydroxybutyrate inhibited oxygen uptake of the neural tissue of day 9 and day 10 embryos by 12.8% and 1 1.2%, but did not affect that of day 11 and day 12 tissue. In contrast, glucose utilization of the neural tissue of day 9 and day 10 embryos was not altered. However, a 30% decrease in glucose utilization was observed in the neural tissue of day 11 and day 12 embryos exposed to beta-hydroxybutyrate. Thus, beta-hydroxybutyrate induced different metabolic alterations in the embryonic neural tissue during early and late organogenesis, which suggests different modes of teratogenic action of ketone bodies in different parts of gestation.

Altered mitochondrial morphology of rat embryos in diabetic pregnancy

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Ultrastructural analysis of day-9 embryos cultured for 48 hours in the presence of high concentrations of D-glucose, pyruvate, beta-hydroxybutyrate, and alpha-ketoisocaproate also showed high-amplitude mitochondrial swelling in the neuroepithelium. The mitochondrial swelling was, however, not found in embryos cultured in a high concentration of L-glucose, excluding simple osmotic effects of the diabetes-related substrates and metabolites. CONCLUSIONS: The mitochondrial morphological changes appeared in embryos subjected to a diabetic environment during a time period when the congenital malformations in diabetic pregnancy are induced. The results support the notion that embryonic mitochondria are involved in the teratological process of diabetic pregnancy.

Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Ultrastructurally, these "vacuoles" proved to be mitochondria that had undergone high-amplitude swelling with a loss of matrix density and few identifiable cristae. No other consistent ultrastructural changes were noted, and the mitochondria of control tissues displayed a typical orthodox configuration. While this study does not conclusively limit the effects to the D-form of B-OHB, possible relationships exist between the ultrastructural alterations, ketone body metabolism, and abnormal morphogenesis.


Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

during both types of infusion, the brain arterio-venous difference for glucose decreased 30% (P less than 0.05). Since the brain arterio-venous difference for oxygen was unchanged, and blood flow to the cerebral hemispheres (measured in 11 studies) was also unchanged, the infusions appeared to cause a true decrease in brain glucose uptake. This decrease paralleled the rise in lactate concentration during lactate infusions, and the rise in lactate and butyrate concentrations during the butyrate infusions. Both substrates have metabolic actions that may inhibit brain glucose uptake. We speculate that the deleterious effects of high lactate and ketone states in the perinatal period may in part be due to inhibition of brain glucose uptake.

Effects of hyperketonemia on mouse embryonic and fetal glucose metabolism in vitro

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

The ketone body beta-hydroxybutyrate (B-OHB) has been shown to be teratogenic to early-somite mouse embryos, although the mechanism responsible for these defects has not been determined. In an attempt to define this mechanism, the present study investigated the normal pattern of both glucose and B-OHB utilization in the developing embryo and fetus. Furthermore, the metabolic interaction of these two substrates, i.e., the potential for B-OHB to inhibit glycolysis, was studied. All studies compared early and late embryonic periods of development as well as fetal stages. The results show that the early embryo relies almost exclusively on glycolysis for energy metabolism and suggests that there is an increasing importance of the Krebs cycle with increasing gestational age. Similarly, the early embryo has a low capacity to metabolize B-OHB, whereas later gestational stages display a greater rate of utilization. Finally, there appears to be no inhibition of glycolysis by B-OHB (via so-called "substrate interactions") during early embryonic stages. However, the compound significantly inhibits glycolysis during later embryonic and fetal stages. These studies suggest that the teratogenicity of B-OHB in the early embryo is not due to its effects on modulating glycolysis, although this mechanism may be operating at later periods of gestation.

Fetal fuels. VII. Ketone bodies inhibit synthesis of purines in fetal rat brain

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_DocSum

Unlike the de novo pathway, the salvage pathway measured by incorporation of [8-14C]adenine into labeled nucleotides was not significantly inhibited even by supraphysiological levels of 3OHB (21.6 mM). Serial measurements of the de novo and salvage pathways in neonatal brain slices showed a maintenance of salvage activity during the first 2 wk but a progressive fall in activity of the de novo pathway. Thus ketone bodies could act to restrain the synthesis of purine nucleotide building blocks for new cell formation in fetal but not in neonatal rat brain.

Fetal fuels. V. Ketone bodies inhibit pyrimidine biosynthesis in fetal rat brain

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Ketonemic states complicating late pregnancy are accompanied by lower brain weights in the newborn. Potential mechanisms whereby ketone bodies might inhibit cell proliferation were therefore examined in the fetal rat brain slice by measuring their impact on the de novo pathway for pyrimidine biosynthesis. DL-beta-hydroxybutyrate (10.8 mM) and acetoacetate (5.4 mM) were both found to diminish the incorporation of NaH14CO3 into [14C]UMP by 30%. This effect was similar in fetal tissues from fed and 48-h starved mothers. Graded concentrations of DL-beta-hydroxybutyrate (1.4-43.2 mM) resulted in a progressive inhibition that could not be explained either by isotope dilution consequent to ketone body oxidation or by a generalized inhibition of protein synthesis. The inhibition was not reversed with 10 mM glutamine, the principal nitrogen substrate for de novo biosynthesis of pyrimidines. When the conversion of orotic acid into UMP was blocked with 6-azauridine, DL-beta-hydroxybutyrate (10.8 mM) inhibited the incorporation of NaH14CO3 into orotic acid by 28%. By contrast, maximally inhibitory concentrations of this ketone body (43.2 mM) had no effect on the incorporation of [6-14C]orotic acid into [14C]UMP. Is is concluded that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal brain slices and that they do so at a site proximal to orotic acid formation.



To date, I've probably evaluated over 5,000 low-carb menus - can you achieve a high nutrient intake with a low-carb menu? Absolutely! But - if you're not paying attention to critical essential nutrients specifically when planning a menu, I've found that menus are often deficient in one or more essential nutrients unless care is taken to specifically meet or exceed some nutrients. Problematic nutrients in low-carb diets often include: calcium, resolved with careful attention to leafy green; vitamin D, resolved with careful attention with eggs, butter, cream, fish or addition of cod liver oil - the last has its own problems though of overdose with vitamin A in pregnancy; omega-3's, resolved with careful attention to fish, alpine cheese, nuts, nut oils, seeds; potassium, resolved with careful attention with vegetables, mushrooms and lentils; selenium, resolved with careful attention to select vegetables, lamb, beef, fish and mushrooms.

I can continue, but basically I'm saying that when you're pregnant, if you're not paying attention, it's easy to miss some really critical nutrients if you're eaitng low-carb (less than 60g net) - it's just easier and requires less forethought to meet nutrient requirements with moderate carb levels.



I posted some of the findings from a broad selection of the literature - it's certainly not an exhaustive list, but I think it speaks to the necessity of prudence about dietary extremes in pregnancy. To be clear - I think most know I am a strong advocate for low-carb and controlled-carb diets - I cannot, however, in good conscience say well, low-carb that induces continuous ketosis might be ok when you're pregnant...I'm much more comfortable with a more conservative perspective - that the data simply is not suggestive that ketosis is harmless and until it is shown, convincingly to be harmless, you're better off avoiding continuous ketosis - and doing that is relatively simply - just eat some more carbohydrate...not excessively high amounts, just enough to give more glucose availability from sources other than hepatic-GNG.

Indeed, clinically, it's hard to know. The only thing we can say for certain is that the bodies of human mothers and babies EXPECT ketosis.

Intermittent? Absolutely!

As a favorable influence in energy for labor and delivery? Absolutely!

As a favorable metabolic asset in short periods of food inavailability or while sleeping fast? Absolutely!

Continuous ketosis induced by dietary restriction of carbohydrate on purpose? Highly debatable with, IMHO, the evidence tipping toward prudence to avoid continuous ketosis and high levels of circulating ketones. I think you'd be hard-pressed to find an OB/GYN or RE who'd give a green-light to a ketosis inducing diet while TTC or while pregnant because there isn't any evidence to support that it's harmless, while on the other hand, there are reams of data to suggest potential negative effects, especially from high levels of circulating ketones.

And to be clear - I'm NOT advocating a high-carb diet as the remedy - just an increase of carbohydrate to a moderate level to reduce the risk of persistent ketosis and high levels of circulating ketones.

I'm not going to get into the baby thing. I almost didn't even read this thread 'cause of the predominating ignorance about ketosis vs. DKA. I get stuck having to listen to this from time to time. I've been a Type 1 diabetic for 25 years. I do not produce insulin. I have been in DKA two times. Horrible experience. I was NOT doing low carb at that time. The first time I had a stomach virus and the vomiting and dehydration threw me into it. It didn't help that I had spent the day before in the south Alabama sun helping my kids with Field Day. The second time was due to an insulin pump malfunction. I am on a very fast acting insulin and did not realize that I was getting no true delivery while I slept.

My symptoms of DKA were rapid-- irratic heartbeat. Shallow, difficult breathing, horrific nausea, projectile vomiting, debilitating dehydration. It can be fatal. Sound graphic enough for ya?

Ketosis is not like that. I have no similar symptoms. I don't even get nausea. My endocrinologist is fully aware and supportive of my low-carb plan. In fact, he agrees with me that this is probably the only way I could get the weight off--and reap the health benefits of this loss.

There is a lot of confusion about diabetes....especially Type 1. Most people do not understand that it is an autoimmune casued disease....and that it is presently incurable. Now that I've lost weight, people constantly want to know when I will get off of insulin. I always say, "When I die." As for the ADA....please! I respect the money and efforts spent in research, but that is it. Following ADA guidelines gave me poor control of my diabetes. That is why I appreciate Dr. Bernstein. He got as pissed with them as I did!!! His plan makes sense and works. And, you can't follow his plan without moving into ketosis.

Thanks for fretting about all of us; I'm sure you mean well. But, I'm taking better care of my diabetes and my body with this way of life.
I'm happily peeing purple,
Sara<><

No, not what I'm talking about.



No, continuous ketosis induced by dietary restriction of carbohydrate by season, as botany commanded until a few thousand years ago.



Actually, we have millions of years of evidence that it's required.

What we should really be talking about are the dangers to mothers and babies who aren't in ketosis for most or all of pregnancy.

Intermittent or continuous?

I met a native american last night, Chippawa. He is from N. Minnesota and I guess they still eat very much like they always have. He was a skinny fellow. I, of course, had to ask about their diet which is:

Game meat, duck, fish and wild rice, berries in season

They have no agriculture at all. I wish I had had the presence of mind to ask him what the diet of preggers consist of.

MCG is TERRIBLY misinformed..at BEST.
The MEDICAL facts are that ANYONE and EVERYONE who burns fat EVER is in ketosis.
So to call it unhealthy is 100 percent false.
Below im listing TWO independent medical studies that give the truth about ketosis. The first a medical DEFINITION of it.
The second is a long term medical study of locarb, ketosis, etc.
http://en.wikipedia.org/wiki/Ketosis http://www.lowcarb.org/ketosis.htm
The facts speak for themselves. EVERYONE who burns fat is in ketosis, even if its short term.