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Free Patient educational Materials (brochures, food guides,  weight gain grids, etc.) available at:
 California Diabetes and Pregnancy Program CDAPP Sweet Success Resource & Training Center


Definition of Diabetes

An abnormally high amount of sugar (glucose) in the blood . Overt diabetes may be diagnosed if any of the following criteria are present

  • Fasting plasma glucose (FPG) greater than or equal to 7 mmol/L (126 mg/dl )
  • Hemoglobin A1 C (A1C) is 6.5% or higher,
  • Random plasma glucose greater than or equal to 11.1 mmol/L ( 200 mg/dl ) . Should be confirmed by FPG or A1C.

Classification of Diabetes

  • Type 1 diabetes mellitus (T1DM):  Inability to produce insulin caused by autoimmune destruction of pancreatic β-cells. T1DM patients have a propensity to develop ketoacidosis. Previously termed insulin-dependent diabetes or juvenile diabetes.
  • Type 2 diabetes mellitus (T2DM)   Insulin resistance in muscle and liver with  β-cell failure leading to inadequate insulin secretion . Previously termed noninsulin-dependent diabetes .
  • Other: Diabetes due to other specific causes such as cystic fibrosis or drug induced (glucocorticoids).
  • Gestational diabetes mellitus (GDM) : Carbohydrate intolerance with onset or recognition during pregnancy that is not overt diabetes.

Diagnosis of Hyperglycemia in Pregnancy


Diagnosis of Gestational Diabetes Mellitus (GDM) [1-4]

The American College of Obstetricians and Gynecologists supports NIH recommendations and recommends that before the testing approach and diagnostic criteria for GDM are changed, implications of such changes should be studied.

1 Hour (50 g) Oral Glucose Tolerance Test
2 Hour (75 g) Oral Glucose Tolerance Test
3 Hour (100 g) Oral Glucose Tolerance Test


Self-Monitoring of Blood Glucose [7]

The target capillary blood glucose levels recommended by the California Sweet Success Program   during pregnancy are:

Time Glucose Value
Fasting 6 0 to 89 mg/dl ( 3.3 to 4.9 mmol/L )
Premeal /bedtime/ overnight 60 to 90 mg/dl ( 3.3 to 5 mmol/L )
Postprandial 1 hour from start of meals 100 to 129 mg/dl ( 5.6 to 7.2 mmol/L )

The California Diabetes and Pregnancy Program recommends:

 women with type 1 diabetes or type 2 diabetes on multiple daily Insulin Injections  (MDI) test their fasting, premeal, one hour after start of
meals, bedtime, and occasional 3 AM blood sugars

Women with ype 2 diabetes on oral medications should test their fasting, one hour after start of meals,
and bedtime blood sugars [1,7]
 

Example of a prescription for glucose test strips :

Name of Blood Glucose Strip
Use (4 to 10) of strips per day
# 200 strips
Refills: 6 months
Patient is pregnant
 


Diet

Key components in the management of diabetes are diet and exercise.
Click here for diabetic exchange list.
 


Anti-Diabetic Agents

Patients with diabetes prior to pregnancy, a history of diabetic ketoacidosis, liver disease, or a fasting blood sugar greater than or equal to 140 mg/dL at diagnosis are treated appropriately with insulin [8-12 ].

The ACOG recommends when pharmacologic treatment of GDM is indicated either insulin or oral medications (metformin or glyburide)   can be an appropriate first-line therapy [1]. However, meta-analysis found when compared to insulin, glyburide was associated with higher neonatal birth weight and increased incidence of neonatal hypoglycemia [14,15],


Oral hypoglycemic agents (OHA)

Glyburide (Micronase® )  [13].
Oral blood-glucose-lowering drug of the sulfonyl- urea class . Glyburide stimulates release of of insulin from the pancreas .Glyburide crosses the placenta [26,27]

  • Used as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus [1,7].

      Starting dose 1.25 mg to 2.5 mg PO daily 60 minutes before meals to control postprandial sugar. Use lower dose for women with weight less than 200 pounds..
      May give at 10 to 11 PM  to control fasting blood sugar.
      May increase by 1.25 to 2.5 mg every 3 to 7days until blood sugar controlled or a maximum daily dose of of 20 mg.

    Should not be used in patients who report a sulfa allergy [1]. Potential clinical adverse effects associated with the use of glyburide are hypoglycemia and allergic reaction.

(1.25, 2.5, and 5 mg tablets)

Use in Breastfeeding: Limited data indicate that the levels of glyburide in milk are negligible .  Appears to be compatible with breast-feeding. However, the  the baby  should be monitored for signs of hypoglycemia [16,17].
 


Metformin (Glucophage® ) [21].
Oral blood-glucose-lowering drug of the biguanide class  Metformin decreases glucose production by the liver, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization . Metformin crosses the placenta[ 28]

  • Used as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus [14,15]

    500 mg once or twice daily given with meals. Usually given with breakfast and dinner. May increase in increments of 500 mg every 3 to 7 days  up to a total of 2500 mg per day.

If a woman is taking metformin prior to her pregnancy or at the first prenatal visit, it is recommended she continues to take metformin [1,7]. Women taking metformin for polycystic ovarian syndrome (PCOS) may benefit from continuing  to take metformin throughout the pregnancy [19,20]

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment.  Metformin is contraindicated in renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia  Discontinued prior to major surgery, or radiological studies involving contrast materials.

(500, 850, and 1000 mg tablets)

Use in Breastfeeding:  Metformin levels in milk are low and infants would receive less than 0.5% of their mother's weight-adjusted dosage. Use with caution in premature infants and infants with renal disease [22-25].
 


 

 Insulin

Insulin is an anabolic  hormone with a  molecular weight of 5808 Da. Maternal insulin does not cross the placenta unless it is bound to IgG antibody [29].  Insulin is produced in the pancreas and is secreted in response to increased blood glucose and amino acids following ingestion of a meal. Insulin signals the cells (primarily skeletal muscle) to increase their uptake of glucose, suppresses lipolysis, acts on the liver to store glucose as glycogen, and inhibits glucagon secretion thereby  preventing glucagon from releasing glucose from the liver.

Synthetic "human" insulin is  manufactured using recombinant DNA technology.  Doses of insulin are measured in units. U-100 insulin contains 100 units/mL. The most commonly used types of insulin during pregnancy are regular insulin and NPH.  Neutral Protamine Hagedorn , NPH, is named after one of its developers the physician Hans Christian Hagedorn who discovered that combining a suspension of crystalline zinc insulin with protamine could prolong the duration of action of the insulin.  Insulin aspart , insulin lispro, insulin detemir, and insulin glargine are human insulin that have had their chemical composition slightly altered to influence their onset and duration of action. Allergy to recombinant human insulin preparations is uncommon , and more likely due to components including zinc, protamine, and meta-cresol [32].

The graph below illustrates the differences in the onset and duration of action for various types of insulin.

 

When compared to treatment with regular insulin, rapid-acting insulin analogs, lispro and aspart show better postprandial control, less hypoglycemia and a trend towards reduction of preterm delivery. The California Diabetes and Pregnancy Program recommends  the rapid acting insulin analogs lispro and aspart, and NPH as the preferred insulins for pregnancy.  In addition, women on glargine and detemir should consider switching to intermediate acting NPH or to a continuous subcutaneous insulin pump before becoming pregnant  [7].

Administration

In general, when a longer-acting insulin (e.g. NPH insulin isophane suspensions) is mixed with short-acting or rapid acting-soluble insulin (e.g., regular), the short-acting or rapid acting insulin should be drawn into the syringe first. Insulin glargine must NOT be diluted or mixed with any other insulin or solution The subcutaneous tissue of the abdomen is preferred site for injection because absorption of the insulin is more consistent from this location than subcutaneous tissues in other locations. [30]

See Initial Insulin Calculator and Intensive Multiple Daily Injections (MDI)

Among the potential clinical adverse effects associated with the use of all insulins are hypoglycemia and hypokalemia.

Storage

Unopened insulin should be stored in a refrigerator between 2 and 8°C (36 and 46°F); it should not be placed in a freezer. After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight.  Unused insulin should be thrown away after the expiration date. Insulin in a pump reservoir should be discarded after at least every 48 hours of use or after exposure to temperatures that exceed 37°C (98.6°F).

Syringes

Insulin syringes are available in three barrel sizes 1mL (100 units), ˝ mL (50 units) and 3/10 mL (30 units). Needles also come in different sizes

BD Micro-Fine™ IV Needle is a 28-gauge, 12.7mm (1/2") thin
BD Ultra-Fine™ Needle is a 30-gauge, 12.7mm (1/2") Thinner
BD Ultra-Fine™ Short Needle  31-gauge, 8mm (5/16") Thinnest needle

Insulin Pen Needle sizes
29 gauge, 31 gauge, or 32 gauge.
Insulin Pen Needle lengths
 4, 5, 6, 8, or 12.7 mm

Example of a prescription for syringes :

Syringe Size: 1 cc, ˝ cc, 1/3 cc, or 1/3 cc with half-unit scale
Ultra-Fine™ Short Needle  31-gauge, 8mm (5/16")
Sig: 4 of syringes used per day
#  100:
Refills: 6 months

For information on safe disposal of needles, syringes, and other sharps in the community contact:

California
http://www.cdph.ca.gov/certlic/medicalwaste/Pages/HomeGeneratedMedWaste.aspx
http://oclandfills.com/hazardous/
http://www.sbcity.org/cityhall/publicworks/integrated_waste_management_division/
http://www.calrecycle.ca.gov/HomeHazWaste/Sharps/


Rapid-acting Insulins- Onset 15 minutes

Insulin aspart [rDNA origin] injection (NovoLog® )
Insulin lispro, [rDNA origin] injection (Humalog®)
Insulin analogs. Onset 1 to 15 minutes , peak of action 1 to 2 hours, duration 4 to 5 hours [32]

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia.

    Give calculated dose subcutaneously 15 minutes before a meal.
    The algorithm below may used, but may need to be modified according to the patient population. [31]
     
    Preprandial or Bedtime Blood Glucose average for at least 3 consecutive days (mg/dl) Adjust dose of aspart (Novolog) units
    >180 +3
    160-180 +2
    140-159 +2
    120-139 +1
    100-119 maintain dose
    80-99 -1
    60-79 -2
    <60 -4

(100 Units per mL in 10 mL vials, 3 mL cartridges, or 3 mL Pens)
 


Short-acting Insulins- Onset 30 to 60 minutes

Regular insulin human injection, USP (rDNA origin)
(Humulin®  -R,
Novolin® -R)
Insulin. Onset 30 to 60 minutes , peak of action 2 to 3 hours, duration of action 5 to 8 hours [33].

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia.

    Give calculated dose subcutaneously 30 minutes before a meal.
     

(100 Units per mL in 10 mL vials)


Regular insulin human injection, USP (rDNA origin)
(
Humulin R (U-500) ® ,Concentrated)

Insulin. Onset 30 to 60 minutes , peak of action 2 to 4 hours, duration of action 6 to 8 hours

  • Indicated in the treatment of diabetic patients with marked insulin resistance (daily requirments more than 200 units)

    Give calculated dose subcutaneously 30 minutes before a meal.

(500 Units per mL in 20 mL vials)


Intermediate-acting, Basal Insulin- Onset 2 to 4 hours

Neutral Protamine Hagedorn (NPH) Human Insulin (rDNA origin) Isophane Suspension 
(Humulin
®  -N , Novolin® N)
Zinc insulin combined with the polypeptide protamine. Onset  2 to 4 hours, peak of action 4  to 10  hours, duration of action 10 to 16 hours

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia.

Give calculated dose alone or mixed with short or rapid acting insulin subcutaneously.

(100 Units per mL in 10 mL vials)


Long-acting, Basal Insulin- Onset

Insulin detemir [rDNA origin] injection
(Levemir® )[35]
Onset 1 to 3  hours, peak of action 4  to 14  hours (no true peak), duration of action 6 to 24 hours (dose dependent)

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Not recommended for treating diabetic ketoacidosis.

Give calculated dose alone . Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump, intramuscularly, or intravenously.

If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis. If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients with type 2 diabetes may require more LEVEMIR than NPH

(100 Units per mL in 10 mL vials,3 mL LEVEMIR FlexTouch ® )


Continuous subcutaneous insulin infusion (CSII) therapy- Insulin pump[34]

The American Association of Clinical Endocrinologists (AACE) considers suitabe insulin pump candidates to have  the following characteristics .

Women with type 1 Diabetes who do not reach glycemic goals despite adherence to maximum multiple daily injections of insulin especially if they have very labile diabetes , frequent severe hypoglycemia and/or hypoglycemia unawareness, significant “dawn phenomenon,” extreme insulin sensitivity , and in special populations (e.g. pregnant women , competitive athletes) or other patients who, after investigation and careful consideration, feel that CSII would be helpful in achieving and maintaining treatment targets

Women with insulin requiring type 2 Diabetes who satisfy any or all of the following: are C-peptide positive, but with suboptimal control on a maximal program of basal/bolus injections, have substantial “dawn phenomenon”, erratic lifestyle (e.g., unpredictable schedules), OR severe insulin resistance.

AACE also recommends "After delivery, the insulin pump infusion should be stopped temporarily to avoid hypoglycemia; once the blood glucose is >100 mg/dL, infusion should be resumed at the prepregnancy settings".

See Calculation of Initial Insulin Pump settings (AACE)
See Calculation of Initial Insulin Pump settings (Sweet Success)


REFERENCES

1. Gestational diabetes mellitus. Practice Bulletin No. 137. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013; 122:406–16.  PMID:23748438
2. Vandorsten JP, NIH consensus development conference: diagnosing gestational diabetes mellitus.NIH Consens State Sci Statements. 2013 Mar 6;29(1):1-31.PMID:23748438
3. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. Diabetes Care 2010;33:676–82. PMID:20587717
4. Guidelines for Diagnosis of Hyperglycemia in Pregnancy – 2011
http://www.cdph.ca.gov/programs/cdapp/Documents/MO-CDAPP-Hyperglycemia Algorithm-7-18-11.pdf Accessed 4/4/2014
5. American Diabetes Association. Standards of medical care in diabetes2012. Diabetes Care 2012;35(suppl 1):S11–63.http://care.diabetesjournals.org/content/35/Supplement_1/S11.full.pdf+html

6. Sacks DA, Metzger BE. Classification of diabetes in pregnancy: time to reassess the alphabet. Obstet Gynecol. 2013 Feb;121(2 Pt 1):345-8. doi: http://10.1097/AOG.0b013e31827f09b5.PMID: 23344285
7. Shields, L and Tsay, GS. Editors, California Diabetes and Pregnancy Program Sweet Success Guidelines for Care. Developed with California Department of Public Health; Maternal, Child and Adolescent Health Division; revised edition, July, 2012. Guidelines for Care, California Diabetes and Pregnancy Program,2012.
8. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001.Gestational diabetes. Obstet Gynecol. 2001;98:525-38. PMID:1
9.Langer O, Conway DL, Berkus MD, Xenakis EM-J, Gonzalez O.A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000 ;343:1134-8.PMID: 11036118
10. Jacobson GF, et al. Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol. 2005 Jul;193(1):118-24. PMID: 16021069
11. Langer O, et al. Insulin and glyburide therapy: dosage, severity level of gestational diabetes, and pregnancy outcome. Am J Obstet Gynecol.2005;192:134-9. PMID: 15672015
12. Kahn BF, et al., Predictors of glyburide failure in the treatment of gestational diabetes. Obstet Gynecol.2006;107:1303-9. PMID: 16738156
13. Glyburide pakage insert . http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d367e16-fc74-4a63-ac6d-85e038164de5. Accessed 6/6/2015
14. Jiang YF, Chen XY, Ding T, Wang XF, Zhu ZN, Su SW.Comparative Efficacy and Safety of OADs in Management of GDM: Network Meta-analysis of Randomized Controlled Trials.
J Clin Endocrinol Metab. 2015 May;100(5):2071-80. doi: 10.1210/jc.2014-4403. Epub 2015 Mar 24.
PMID: 25803270
15. Poolsup N, Suksomboon N, Amin M.Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: a meta-analysis.
PLoS One. 2014 Oct 10;9(10):e109985. doi: 10.1371/journal.pone.0109985. eCollection 2014.
PMID: 25302493
16. Feig DS, Briggs GG, Kraemer JM et al. Transfer of glyburide and glipizide into breast milk. Diabetes Care. 2005;28:1851-5. PMID: 16043722
17. Glatstein MM, et. al., Transfer of glyburide and glipizide into breast milk.
Can Fam Physician. 2009 Apr;55(4):371-3. PMID: 19366943
18. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators.Metformin versus insulin for the treatment of gestational diabetes.
N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193. Erratum in: N Engl J Med. 2008 Jul 3;359(1):106. PMID: 18463376
19. Nawaz FH, Khalid R, Naru T, Rizvi J.Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome?
J Obstet Gynaecol Res. 2008 Oct;34(5):832-7. doi: 10.1111/j.1447-0756.2008.00856.x.PMID: 18834342
20 . Lautatzis ME, Goulis DG, Vrontakis M.Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.
Metabolism. 2013 Nov;62(11):1522-34. doi: 10.1016/j.metabol.2013.06.006. Epub 2013 Jul 23. PMID: 23886298
21. Metformin package insert. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=56d13a1c-b289-4528-b23c-60f5427b4552. Accessed 6/6/2015
22. Gardiner SJ,et. al., Transfer of metformin into human milk. Clin Pharmacol Ther. 2003 Jan;73(1):71-7.PMID: 12545145
23. Hale TW, et., al., Transfer of metformin into human milk. Diabetologia. 2002 Nov;45(11):1509-14. Epub 2002 Sep 25.PMID: 12436333
24. Briggs GG, et. al., Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol. 2005 Jun;105(6):1437-41. PMID: 15932841
25. Glueck CJ, Salehi M, Sieve L, Wang P. Growth, motor, and social development in breast- and formula-fed infants of metformin-treated women with polycystic ovary syndrome. J Pediatr. 2006;148:628-32.e2. PMID: 16737874
26Kraemer J, Klein J, Lubetsky A, Koren G. Perfusion studies of glyburide transfer across the human placenta: implications for fetal safety. Am J Obstet Gynecol. 2006;195(1):270-274.PMID: 16579925
27. Nanovskaya TN, Nekhayeva I, Hankins GD, Ahmed MS. Effect of human serum albumin on transplacental transfer of glyburide. Biochem Pharmacol. 2006;72(5):632-639.PMID: 16828060
28. Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 2005;83:1575–1578PMID: 15866611
29. Menon RK, et. al. Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus. Its role in fetal macrosomia. N Engl J Med. 1990 Aug 2;323(5):309-15. Erratum in: N Engl J Med 1992 Jan 23;326(4):280.
PMID: 2195347
30.  ter Braak, EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996;19(2):1437–1440
31. Ambulatory Insulin Titration Form: Toolkit for Implementing the Chronic Care Model in an Academic Environment. October 2014. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/professionals/education/curriculum-tools/chroniccaremodel/chronic3a11b.html accessed 6/7/2015
32. Ghazavi MK, Johnston GA Insulin allergy. Clin Dermatol. 2011 May-Jun;29(3):300-5. doi: 10.1016/j.clindermatol.2010.11.009. PMID: 21496738
33. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus.
ACOG Committee on Practice Bulletins.Obstet Gynecol. 2005 Mar;105(3):675-85. PMID: 15738045
34.
Grunberger G, et. al. Consensus statement by the american association of clinical endocrinologists/american college of endocrinology insulin pump management task force.
Endocr Pract. 2014 May;20(5):463-89. doi: 10.4158/EP14145.PS. PMID: 24816754
https://www.aace.com/files/insulin-pump-management-cs.pdf ACCESSED 6/7/2015
35. Levemir package insert
 http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d38d65c1-25bf-401d-9c7e-a2c3222da8af

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