Title: -based Ketone Testing in Pregnancy Complicated by

Date: 20 July 2007

Context and policy issues:

Approximately 2% to 5% of all pregnancies are complicated by diabetes mellitus,1,2 an estimated 10% to 35% of which are due to pre-existing type 1 or type 2 diabetes mellitus, termed pregestational diabetes mellitus (PDM).1-3 The remaining 65% to 90% of cases are due to gestational diabetes mellitus (GDM),1-3 defined as intolerance that initially occurs or is first recognized during pregnancy.4 A disproportionate number of Canada’s GDM cases occur in the aboriginal population, with GDM affecting 8.0% to 18.0% of pregnancies, compared to 3.5% to 3.8% of pregnancies in the non-aboriginal population.4

Both PDM and GDM are associated with numerous maternal and fetal complications, two of which include maternal diabetic ketoacidosis (DKA) and .1,3 A number of metabolic changes occur with pregnancy, the purpose of which are to supply energy to the fetus. Levels of counter-regulatory hormones (e.g. cortisol) increase, creating a state of relative resistance.5 As well, lipolysis is enhanced, levels of free fatty acids increase, and ketogenesis may occur.5 Ketosis is relatively common in pregnancy with about 30% of all pregnant women having detectable amounts of ketones in their first morning urine.6

DKA can occur in individuals with PDM (generally those with pre-existing ) when exogenous insulin requirements increase with advancing gestation, but insulin dosage adjustments do not keep pace.5 This insulin deficiency prevents glucose utilization at the cellular level, leading to the release of counter-regulatory hormones that facilitate the use of alternate energy sources including adipose tissue.5 are then broken down in large quantities and oxidized in the to , which accumulate in the blood and pass into the urine.5 DKA is a potentially life threatening condition because it lowers blood pH, affecting the function of a number of metabolic enzymes. Further, hyperglycemia associated with DKA leads to dehydration, hypovolemia, electrolyte abnormalities, and hyperosmolality. Multiple organ

Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

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systems can be affected, leading to shock, coma and even death.5 Fortunately, maternal death is relatively rare, but fetal mortality occurs in about 10% of cases.3 For those who survive, ketosis can have significant adverse effects on the baby’s brain development and can affect future intellectual and learning capacity.7,8

Starvation ketosis can occur in individuals with PDM or GDM when caloric intake is insufficient.4 The body’s glucose supply becomes depleted and is used as an alternate energy source.9 As with DKA, the broken down fats are oxidized in the liver to ketone bodies, which accumulate in the blood and pass into the urine.5 Starvation ketosis can be distinguished from DKA in that blood glucose tends to be low or only slightly elevated, whereas DKA is characterized by hyperglycemia.10 GDM is primarily managed with medical nutritional therapy, but caloric intake must remain sufficient to avoid starvation ketosis and its sequelae.4

To monitor for DKA and starvation ketosis during pregnancy, ketones can be detected in the urine using a dipstick test, or measured in the blood through home-based and lab testing.9 Generally, urine-based tests detect ketones via a colorimetric reaction between acetoacetate and a nitroprusside reagent, although some tests may also detect acetone.11 The most common blood-based tests for ketones usually quantify β-hydroxybutyrate, the predominant ketone body, via an enzymatic method.11

Research questions:

1. What is the clinical and cost effectiveness of urine ketone testing in pregnant women with pre-existing diabetes and in gestational diabetes?

2. What are the current guidelines for urine ketone testing in pregnant women with pre- existing diabetes and in gestational diabetes?

Methods:

A literature search was conducted on key health technology assessment resources, including PubMed, Embase in OVID, The Cochrane Library (Issue 2, 2007), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI’s HTAIS, EuroScan, international HTA agencies, and a focused Internet search. Results include English language publications from 2002 to date. Links to online full-text are provided when available.

Summary of findings:

1. What is the clinical and cost effectiveness of urine ketone testing in pregnant women with pre-existing diabetes and in gestational diabetes?

The literature search did not identify any health technology assessments, meta-analyses or controlled studies of the clinical effectiveness of urine ketone testing in PDM or GDM. Further, the literature search did not identify any economic evaluations of urine ketone testing in PDM and GDM.

The American Diabetes Association’s position statement on tests of glycemia does, however, state that urine ketone testing is not considered reliable for diagnosing and monitoring of ketoacidosis.6 Since urine-based testing detects acetoacetate rather than β-hydroxybutyrate, it may underestimate the total ketone body concentration.11 Further, urine-based testing can produce false positive results with highly coloured urine or in the presence of drugs that contain

Urine-based Ketone Testing in Pregnancy Complicated by Diabetes 2

sulfhydryl groups, such as captopril.6 False negative results may be produced with highly acidic urine and when test strips are exposed to air for extended periods of time.6 Finally, urine-based testing for ketones may not provide timely information if the urine that is tested has sat in bladder for a significant duration of time prior to testing.9

2. What are the current guidelines for urine ketone testing in pregnant women with pre- existing diabetes and in gestational diabetes?

Pregestational Diabetes Mellitus

A number of diabetes management guidelines or position statements include general recommendations for ketone testing in PDM.6,12-14 While the practice of ketone testing is recommended during pregnancy, guidelines tend to be vague with respect to either the method (i.e., urine or blood), frequency or timing of testing,6,12,13 with the exception of the British Columbia Reproductive Care guidelines14 (Table 1). These guidelines specify twice daily urine ketone testing in individuals with type 1 or type 2 PDM as outlined in Table 1.

Table 1: Recommendations for urine-based ketone monitoring in pregestational diabetes mellitus

Practice Guideline or Organization, Year of Recommendation Position Statement Publication

Pre-existing Diabetes and Canadian Diabetes ‘Since starvation ketosis is common in pregnancy Pregnancy13 Association, 2003 and may have detrimental effects on the fetus, urine and/or blood monitoring of ketones is warranted to confirm that the diet is adequate.’

‘Ketosis should be avoided during pregnancy [Grade C, Level 3].’ Obstetric Guideline 10B: British Columbia Urine ketone testing is recommended daily before Diabetes Mellitus and Reproductive Care breakfast and supper, if glucose values are high, Pregnancy Type 1 & 214 Program, 2001 and when sick. If ketonuria is detected, it is recommended that all voiding is tested until the urine is clear of ketones. Tests of Glycemia6 American Diabetes ‘Ketone testing is an important part of Association, 2003 monitoring in type 1 diabetic patients, in pregnancy with pre-existing diabetes, and in gestational diabetes.’

‘Patients with type 1 diabetes should test for ketones during acute illness or stress or when blood glucose levels are consistently elevated (e.g., >300 mg/dl [>16.7 mmol/l]), during pregnancy, or when any symptoms of ketoacidosis, such as nausea, , or abdominal pain, are present.’ Section 8: Pregnancy and Indiana State Health ‘Urine ketone testing is recommended daily Diabetes12 Department, 2004 during pregnancy, in addition to blood glucose monitoring.’

Urine-based Ketone Testing in Pregnancy Complicated by Diabetes 3

Gestational Diabetes Mellitus

A number of practice guidelines for GDM recommend urine or blood-based monitoring of ketones to ensure that the maternal diet is sufficient to prevent starvation ketosis (Table 2).4,12,15- 19 Generally, urine-based testing for ketones is recommended, but the Canadian Diabetes Association guidelines state that urine and/or blood-based testing can be used.4 The British Columbia Reproductive Care Program guidelines,15 South Dakota Gestational Diabetes Care Guidelines,16 and the Wyoming Clinical Practice Recommendations for Diabetes Mellitus17 provide more detail with respect to timing, frequency and duration of testing.

Table 2: Recommendations for urine-based ketone monitoring in gestational diabetes mellitus

Practice Guideline or Organization, Year of Recommendation Position Statement Publication

Gestational Diabetes Canadian Diabetes ‘Since starvation ketosis is common in pregnancy Mellitus4 Association, 2003 and may have detrimental effects on the fetus, urine and/or blood monitoring of ketones is warranted to confirm that the diet is adequate.’ Obstetric Guideline British Columbia Daily urine ketone testing is recommended before 10A: Gestational Reproductive Care breakfast and supper. Diabetes15 Program, 2001 Recommendations for Canadian Diabetes ‘Ketones should be monitored to verify that Nutrition Best Practice Association, Dietitians of adequate calories are provided to prevent ketone in the Management of Canada, Diabete Quebec, formation, as recommended in the CDA Clinical Gestational Diabetes and the Ordre Professionnel Practice Guidelines.’ Mellitus19 de dietetistes du Quebec, 2006 Gestational Diabetes American Diabetes ‘Urine ketone monitoring may be useful in detecting Mellitus18 Association, 2004 insufficient calorie or intake in women treated with calorie restriction.’* South Dakota South Dakota Department of ‘Consider urine ketone testing if: Gestational Diabetes Health, 2003 ƒ Patient is obese (≥ 26 BMI) Care Guidelines16 ƒ Patient experiences weight loss ƒ Insulin is initiated ƒ Patient has other illnesses

Discontinue ketone testing if all results are trace or less.

If results are frequently positive then a referral to an RD† for MNT‡ should be considered even if increased calories require initiation of insulin to achieve euglycemia.’

Section 8: pregnancy Indiana State Health ‘Urine ketone testing during pregnancy is and diabetes.12 Department, 2004 recommended, in addition to blood glucose monitoring.’

Urine-based Ketone Testing in Pregnancy Complicated by Diabetes 4

Practice Guideline or Organization, Year of Recommendation Position Statement Publication

Wyoming Clinical The Wyoming Diabetes It is recommended that the first morning urine is Practice Prevention and Control tested for ketones. If urine ketones are positive, Recommendations Program. urine should be checked again later in day. If the For Diabetes urine tests positive for ketones then carbohydrate Mellitus17 may need to be increased.

* Urine ketone monitoring is not recommended by the American Diabetes Association for diagnosing or monitoring of ketoacidosis6 † RD=Registered Dietician ‡ MNT=Medical Nutritional Therapy

Conclusions and implications for decision or policy making:

In summary, diabetic ketoacidosis and starvation ketosis can have serious consequences for both the mother and unborn child. Urine-based ketone testing can be used to detect established or impending ketoacidosis, but is not recommended for diagnostic or monitoring purposes. A search of the recent literature failed to locate information regarding the clinical and cost-effectiveness of urine ketone testing in PDM or GDM. Despite the lack of evidence, a number of clinical practice guidelines for PDM and GDM recommend the practice of urine and, in some cases, blood-based testing for ketones. Thus, these recommendations appeared to be based upon the potential for serious harm to the mother and baby should diabetic ketoacidosis or starvation ketosis develop.

Prepared by:

Sheri Pohar, BScPharm, PhD, Research Officer Monika Mierzwinski-Urban, MLIS, Information Specialist Health Technology Inquiry Service (HTIS) E-mail: [email protected] Toll free phone: 1-866-898-8439

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2. Diabetes in pregnancy. London: National Institute for Health and Clinical Excellence; 2005. Available: http://guidance.nice.org.uk/page.aspx?o=284822 (accessed 2007 Jun 19).

3. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 2005;105(3):675-85.

4. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Gestational diabetes mellitus. Can J Diabetes 2003;27 Suppl 2:S99-S105. Available: http://www.diabetes.ca/cpg2003/downloads/gdm.pdf (accessed 2007 Jun 11).

5. Carroll MA, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med 2005;33(10 Suppl):S347-S353.

6. Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan DM, Peterson CM. Tests of glycemia in diabetes. Diabetes Care 2003;26 Suppl 1:S106-S108.

7. Meltzer S. Management of diabetes in pregnancy: challenges and trends. Can J Diabetes 2005;29(3):246-56.

8. Setji TL, Brown AJ, Feinglos MN. Gestational diabetes mellitus. Clin Diabetes 2005;23:17- 24. Available: http://clinical.diabetesjournals.org/cgi/reprint/23/1/17 (accessed 2007 Jun 19).

9. The importance of blood ketone testing in diabetes management. Manag Care 2004;13 Suppl(4):2-23. Available: http://www.managedcaremag.com/supplements/0404_ketonetesting/MC0404_ketonetesti ng.pdf (accessed 2007 Jun 11).

10. Charfen MA, Fernandez-Frackelton M. Diabetic ketoacidosis. Emerg Med Clin North Am 2005;23(3):609-28, vii.

11. Sacks DB, Bruns DE, Goldstein DE, Mclaren NK, McDonald JM, Parrott M. Ketone testing. In: Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus [NACB: Laboratory Medicine Practice Guidelines (LMPG)]. Washington: American Association for Clinical Chemistry; 2002. p.24-6. Available: http://www.nacb.org/lmpg/diabetes/5_diabetes_keytone.pdf (accessed 2007 Jun 19).

12. Section 8: pregnancy and diabetes. In: Indiana consensus guidelines for diabetes care. Indianapolis (IN): Indiana State Department of Health; 2004. Available: http://www.in.gov/isdh/programs/diabetes/guidlines/section_8.htm (accessed 2007 Jun 11).

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13. Clinical Practice Guidelines Expert Committee, Canadian Diabetes Association. Pre- existing diabetes and pregnancy. Can J Diabetes 2003;27 Suppl 2:S94-S98. Available: http://www.diabetes.ca/cpg2003/downloads/pregnancy.pdf (accessed 2007 Jun 19).

14. Obstetric guideline 10B: diabetes mellitus and pregnancy type 1&2. Victoria (BC): British Columbia Reproductive Care Program; 2001. Available: http://www.rcp.gov.bc.ca/guidelines/Master.DibetesMellitus.October.pdf (accessed 2007 Jun 20).

15. Obstetric guideline 10A: gestational diabetes. Victoria (BC): British Columbia Reproductive Care Program; 2001. Available: http://www.rcp.gov.bc.ca/guidelines/Master.GestationalDiabetes.October.pdf (accessed 2007 Jun 11).

16. South Dakota gestational diabetes care guidelines. Pierre (SD): Diabetes Prevention and Control Program. South Dakota Department of Health.; 2003. Available: http://www.cdc.gov/diabetes/pubs/pdf/gest.pdf (accessed 2007 Jun 11).

17. Wyoming clinical practice recommendations for diabetes mellitus. Cheyenne ( WY): The Wyoming Diabetes Prevention and Control Program. Wyoming Department of Health; 2004. Available: http://wdh.state.wy.us/DIABETES/pdf/dmcpr.pdf (accessed 2007 Jun 11).

18. Gestational diabetes mellitus. Diabetes Care 2004;27 Suppl 1:S88-S90.

19. Recommendations for nutrition best practice in the management of gestational diabetes mellitus. Executive summary (1). Can J Diet Pract Res 2006;67(4):206-8.

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