Ketones, ketosis and ketoacidosis

Ketones are a common topic on our Facebook support group. We frequently see posts like “I have come back from my appointment and my notes say I have ketones, should I be worried?”

Ketones are not always explained to pregnant mothers and to make matters worse, it can be quite confusing reading posts in our support group where you may see some mothers saying they have been admitted to the hospital for IV fluids due to ketones, whereas in another area mothers have been sent home with the same level of ketones and yet the ketones have not been mentioned at all.

What are ketones and how do they occur?

Ketones are a by-product produced by the liver during fatty acid metabolism. Everyone produces ketones, but they are usually completely metabolised.

However, if the body cannot process glucose from the blood into the body’s cells to use as energy, it will begin to burn fat stores instead and this process causes an increase in ketone production, a state called ‘ketosis’. It is at this point that ketones may become present in urine and blood samples.

Have you been drinking enough?

Urine samples may show positive for ketones when the body is dehydrated^​1​ and increasing fluids can resolve this. Therefore, the first thing to do is to increase fluids by drinking plenty of water

Testing for ketones

There are two simple ways that ketones can be tested; via a urine sample, or a capillary blood sample: –

Testing urine samples for ketones (ketonuria)

A ketonuria test is usually completed during diabetes clinic appointments and by community midwives during antenatal check-ups. A fresh sample of urine is dipped with a reagent strip to test for the presence of acetoacetate ketones (a type of ketone which is excreted in urine). The reagent strips used are usually multipurpose urinalysis strips which can check for multiple things in one test, such as protein, infection and glucose^​2​.

Urinary ketones are usually measured on a scale, with 0 or ‘neg’ being the lowest and 4++ being the highest.

It’s important to note that urinary ketones reflect ketone levels from the past few hours.^​3​

These measurements, however, do not correspond to the current ketone concentration in the blood; yet, they allow to assess the acetoacetate level from two to four hours prior to the assay

Pregnancy Ketonemia and Development of the Fetal Central Nervous System, Bronisz A et al.

Ketone urinary test strips can be purchased from a pharmacy or online and in some cases, women may be prescribed test strips for home testing if it is felt necessary to monitor their ketone levels. These ketone test strips change colour in the presence of urinary ketones.

It is not necessary to purchase urine dip sticks for home use unless you’re advised to by a medical professional

Testing blood for ketones (ketonaemia)

If there is a concern of high levels of ketones, then a sample of capillary blood can be tested using a blood ketone monitor to test for β-hydroxybutyrate ketone levels.

The ketone monitor is similar to a blood glucose monitor, with test strips which fit into the end and a simple finger prick sample of blood is placed onto the test strip to produce a blood ketone level reading.

Pregnant women who have Type 1 or advanced Type 2 diabetes may be given ketone blood testing monitors to use, but they are rarely given to women diagnosed with gestational diabetes.

The blood β-OHB [β-hydroxybutyrate ketone] levels below 0.6 mmol/L are regarded as normal, while levels over 1 mmol/L represent hyperketonemia, and levels in excess of 3 mmol/L indicate ketoacidosis.^​4​

Evaluation of the Accuracy of Capillary Hydroxybutyrate Measurement Compared with Other Measurements in the Diagnosis of Diabetic Ketoacidosis: A Systematic Review, Brooke J et al.

The difference between the two tests

Whilst urinary ketone tests are a good and cost-effective way to monitor for ketosis, they are not accurate at showing true levels of ketosis.

A study published in Diabetes Journals by Coetzee E J et al.^​5​ showed that urinary ketones may increase 50-100-fold while blood ketones will only rise 2-fold and remain below ketonemic levels (at or above 1mmol/L).

Neonates born to diabetic mothers with ketonuria had no fetal distress or asphyxia neonatorum. The lowest Apgar score at 5 min was 8; 80% of neonates had a score of 10. Hence positive Ketostix tests in urine samples do not indicate toxic levels in the blood.

Ketonuria in pregnancy, American Diabetes Association, Coetzee E J et al.

This means that whilst urinary ketones are showing high, ketones in the blood may not be present or may be at very low/negligible levels

Causes of ketones

There are 3 types of ketosis;

• nutritional ketosis
• starvation ketosis
• diabetic ketoacidosis (DKA)

Nutritional ketosis

This type of ketosis may become present when following a low-carb diet. The body is burning fat for fuel but is still gaining sufficient calories from fat and protein in the diet (therefore is not starving).

With nutritional ketosis, blood sugar levels remain ‘normal‘

If ketones are not caused by dehydration, it is usually this type of ketosis that is seen in many pregnant mothers following a lower-carb GD diet.

Ketogenic or ‘keto‘ diets, aim to achieve this level of ketosis. Keto diets are very low in carbohydrates (around 30g carbs or less per day) and are popular diets for people wanting to lose weight.

The keto diet is also used to help some other medical conditions; epilepsy^​6–8​, Type 2 diabetes^​9,10​, Type 1 diabetes^​11​, Attention-Deficit/Hyperactivity Disorder (ADHD)^​12​, Alzheimer’s disease^​13​, Parkinson’s disease^​14​, PCOS (polycystic ovarian syndrome)^​15​, to name but a few.

Starvation ketosis

Just as the name suggests, starvation ketosis may become present because the body is burning fat stores because this is the only source of fuel due to starvation.

Starvation ketosis is rare in the otherwise healthy non-pregnant population, taking 14 days to reach maximum severity. Whereas starvation ketosis can be apparent much earlier in pregnant women following a short duration of vomiting (less than 24 hours).^​16​

This type of ketosis is often seen in pregnant women suffering hyperemesis gravidarum (severe sickness in pregnancy) or if the mother has a sickness bug.

Diabetic Ketoacidosis (DKA)

DKA is a condition that may become present in insulin-dependent diabetics and can be fatal if not treated. It is caused by a severe lack of insulin, where the body cannot process glucose at all. Without the ability to process glucose for energy, the body then starts to break down fat to create an alternative source of energy. Ketones are the by-product of this process. Ketones are poisonous acidic chemicals which build up, hence the name ‘acidosis’. As a result of this acidic build-up, many of the enzymes that control the body’s metabolic processes aren’t able to function as well.

Unlike the two other types of ketosis, in DKA, blood sugar levels are also high, or ‘hyperglycaemic’ (>11.0mmol/litre), often extremely high!

β-OHB [β-hydroxybutyrate ketone] levels are the most abundant in the blood in DKA, representing 75% of total ketones formed^​4​

Abnormally high levels of β-hydroxybutyrate ketones alongside extremely high blood sugar levels cause a teratogenic environment (can cause birth defects) for the baby

DKA is a life-threatening medical emergency and anyone who is dependent on insulin can develop DKA. Although extremely rare in those diagnosed with gestational diabetes, it is still something that all should be wary of in case a gestational diabetes diagnosis has been made when the mother has pre-existing diabetes (such as Type 1 diabetes).

Symptoms of DKA:

• High blood glucose levels (over 11mmol/L)
• Ketones in the blood
• Frequently passing urine
• Thirst
• Feeling tired and lethargic
• Blurry vision
• Abdominal pain, nausea, vomiting
• Struggling to catch breath
• Smell of pear drops, or a fruity smell on the breath
• Collapse/unconsciousness
• Coma

For insulin-dependent diabetics, missed doses of insulin, excessive exercise and illness can all be causes of DKA.

If you have any concerns over DKA or are worried as you are experiencing any of the above symptoms, then please seek medical advice by calling your hospital, or 111 out of hours for advice.  If situations arise where you collapse or there is the smell of pear drops on your breath, then 999 should be called immediately for emergency medical assistance.

NICE Guidelines for ketone testing and DKA^​17​

Ketone testing and diabetic ketoacidosis
1.3.20 Offer pregnant women with type 1 diabetes blood ketone testing strips and a meter, and advise them to test for ketonaemia and to seek urgent medical advice if they become hyperglycaemic or unwell. [new 2015]
1.3.21 Advise pregnant women with type 2 diabetes or gestational diabetes to seek urgent medical advice if they become hyperglycaemic or unwell. [new 2015]
1.3.22 Test urgently for ketonaemia if a pregnant woman with any form of diabetes presents with hyperglycaemia or is unwell, to exclude diabetic ketoacidosis. [new 2015]
1.3.23 During pregnancy, admit immediately women who are suspected of having diabetic ketoacidosis for level 2 critical care^[8], where they can receive both medical and obstetric care. [2008]

NICE guideline [NG3] Diabetes in pregnancy: management from preconception to the postnatal period

DKA treatment is given in the hospital, replacing fluids and electrolytes and by the administration of insulin by using an insulin infusion (sliding scale) until the blood-ketone concentration is below 0.3 mmol/litre

Ketones in pregnancy

Studies have shown all women have increased ketone levels during pregnancy^​18,19​ and so mild levels of ketosis should be expected and should be considered ‘normal’, especially when taken from early morning urine samples after fasting through the night.

Following an overnight fast, 10-20% of all pregnant women have ketones in their blood. This fasting ketonemia or “starvation ketonemia” has not been associated to fetal detriment.^​20​

Textbook of Diabetes and Pregnancy, Medical nutritional therapy for GDM, Jovanovic L

Under fasting conditions, fatty acids are converted into ketone bodies throughout the b-oxidation pathway, and these compounds easily cross the placental barrier and are metabolized by the fetus.^​21​

Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus, Herrera E

It becomes even more likely that a mother will test positive for mild ketosis during the 3rd trimester when maternal metabolism changes.

Maternal ketone body levels are elevated by 33% higher during the third trimester of pregnancy than in the post partum period^​22​

Textbook of Diabetes in Pregnancy, ’56. Diabetic Ketoacidosis‘ Lapolla A, Dalfrà M

Ketones in gestational diabetes

Ketones can be detected when the mother has not eaten for a long period of time and may be found in urine samples taken in the morning due to fasting overnight, or if meals or snacks have been missed.

It is common for mothers with gestational diabetes to develop ketones due to limiting carbohydrates from the diet, causing nutritional ketosis

Once diagnosed with gestational diabetes, many ladies worry about what foods to eat and may avoid eating, or knowing that carbs cause rises in blood glucose levels, they cut them out of the diet or limit them severely as a way of controlling blood glucose levels.

Why test for ketones?

Studies on ketones, pregnancy and their effect on the baby are typically based on the effects of DKA, or severe non-diabetic ketoacidosis which can be caused by starvation and has been shown to cause a teratogenic environment for the baby. Therefore, the detection of ketones during pregnancy is very important for this reason alone.

DKA can result in intrauterine death, with mortality rates estimated at 9–35% [20]. Fetal death has also been reported in severe non-diabetic ketoacidosis [2]. Ketoacids readily cross the placenta and may contribute directly to fetal demise, although it is likely that other maternal influences such as volume depletion or electrolyte imbalance are important.^​16​

Starvation ketoacidosis in pregnancy, Frise C et al.

But why are ketones a cause of concern in some hospitals, but of little or less concern in others?

We should not presume that all types of ketosis are equal, however, this is what some medical professionals may do. You cannot compare DKA or starvation ketosis with mild nutritional ketosis, as the levels of ketosis and ketoacidosis are completely different.

Clinical studies on the effect of mild ketosis such as that caused by nutritional ketosis are lacking in pregnant human subjects. This is due to ethical reasons (it is extremely difficult to complete medical research on human pregnant women or fetuses) and so many medical professionals are not concerned over low levels of ketones when no other symptoms are present.

Some studies on mice suggest nutritional ketosis may be harmful to the fetus, resulting in alterations in embryonic organ growth^​23​ and differences in brain anatomy as well as behavioural alterations.^​24​

But, we are not mice and mothers following a lower carb or ketogenic diet will be eating plenty of nutrient-dense real foods rich in a multitude of micronutrients, vitamins and minerals, as opposed to synthetically prepared compositions such as what was fed to the mice in these studies.

Many professionals such as Lily Nicols RDN (author of Real Food for Gestational Diabetes) and Dr. Michael Fox, (fertility specialist at the Jacksonville Center for Reproductive Medicine) point out in their articles, many ancient cultures have lived on ketogenic diets for centuries without adverse effects on their offspring.^​25,26​

It should also be noted that babies are naturally in a state of ketosis during growth in the womb which is actually essential for the development of the brain and nerve cells. Also, following birth, ketones account for 25% of the newborn’s energy needs.^​27​

One study suggests that ketonuria may cause problems in pregnancy and it is this study that has led to the recommendation to avoid ketosis in pregnancy.

The 1969 study published in the American Journal of Obstetrics and Gynaecology​28​ found that excess urinary ketones in pregnancy may affect the developing brain cells of the baby, leading to a lower IQ and future learning disabilities. However, this study was not reliable as blood ketones were not tested in this study, which we know is the best way to ascertain true ketone levels and only one single sample of urinary ketones was tested on the day of birth.

Other studies since have not been able to confirm these findings.^​5,28​

Some Trusts and Doctors feel safer testing for ketones and if any are found in urine, they prefer to treat them by flushing them through with fluids (this may mean encouraging drinking and/or being given IV fluids) and encouraging the mother to eat.

To avoid the recurrence of ketones, they may advise ongoing dietary changes to increase carbohydrates, which in turn may require medication or insulin to help lower blood sugar levels that may rise in line with eating more carbohydrates.

What can I do if I have ketones in my urine sample?

Firstly, think about reasons why ketones may be present in your urine sample:

• Is your sample following a period of fasting e.g. first thing in the morning, or after skipping a meal or snack?
• Are you possibly dehydrated? How much have you had to drink and has anything else impacted you becoming more dehydrated than usual e.g. have you had more exercise than normal, or is it a much warmer day?

If you can answer yes to either or both situations above then it is to be expected that you will have ketones in your urine sample. You simply need to have something to eat and to increase your fluids.

What is the level of ketosis and do you have any other symptoms?

Your medical professional should advise if there is any concern over the level of ketones present. Often trace or small amounts may be shown as mentioned above. But if you have any worries, discuss any concerns with your healthcare professional.

If the urinary ketone level is low and you have no other symptoms of feeling unwell, then it suggests that this is just mild ketosis and most probably caused by one of the 2 reasons suggested above.

If you have higher levels of urinary ketones, then your medical professional may suggest drinking, eating and/or increasing the number of carbohydrates in your diet.

Having a bedtime snack has been associated with lower ketone levels.^​29​ This does not mean that you MUST eat a bowl of cereal or a slice of toast before bed, or for breakfast (which has previously been suggested by some medical professionals to mothers in our support group). You can increase carb amounts with safer carb choices which tend to be tolerated better and give lower blood sugar levels.

Cereals are never going to be a type of food we recommend eating, due to our own surveys on the matter showing it is very rare for women with GD to tolerate it. Therefore, we advise trying better alternatives, which will release glucose at slower rates e.g. Scottish oatcakes, Ryvita, wholewheat crackers, a slice of Hi-Lo or Burgen soya & linseed bread, paired well with plenty of protein and natural fats.

Admitted to hospital due to ketones, have they tested blood ketones?

In more severe cases, you may be admitted to the hospital for intravenous fluids and a sliding scale.

In some cases we see mothers admitted for long periods of time and the medical professionals have only tested for urinary ketones.

If capillary blood ketones have not been tested and urinary ketones are still showing (therefore meaning the hospital is advising that you should not leave due to the presence of urinary ketones), yet you feel fine, ask them to test the levels of ketones in your blood.

They may find that blood ketones are actually at very low/trace levels.

As mentioned at the start of this article^​5​

urinary ketones may increase 50-100-fold while blood ketones will only rise 2-fold and remain below ketonemic levels (at or above 1mmol/L)… Hence positive Ketostix tests in urine samples do not indicate toxic levels in the blood.

Increasing carbs v’s higher blood sugar levels – “Should I go keto?”

Only you can decide if you would feel comfortable following a lower-carb or keto diet during pregnancy and no one can force you to eat anything you do not wish to.

The diet we [Gestational Diabetes UK] advocate is low carb and high fat, similar to the keto style diet, but incorporating small servings of starchy unrefined complex carbs with each meal. Therefore it incorporates higher amounts of carbs than a ketogenic diet.

We have found this is a good balance between achieving good blood glucose management and prevention of moderate urinary ketosis.

If you are used to following a keto diet previous to pregnancy, then you may find it better for you to continue. However, if you have concerns over ketosis and the effect it may have on your baby, then increasing carbs may be a more suitable option for you.

If you would like to read more on ketosis in pregnancy, then I highly recommend reading Chapter 11 of Lily Nichol’s book, Real Food For Gestational Diabetes^​26​. Lily’s book chapter is the most in-depth review of literature on ketosis in pregnancy that I have found and goes into so much detail.

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