This talk was delivered for postgraduates and faculty of Dr. TMA Pai Hospital, Udupi on 07 March, 2017. This talk covered pathophysiology, screening, diagnosis, complications and management of diabetes mellitus in pregnancy.

1. Diabetes Mellitus & Pregnancy
gestational diabetes | type 2 diabetes | type 1 diabetes mellitus
Dr. Shashikiran Umakanth
Professor & Head, Medicine
Dr. TMA Pai Hospital, Udupi
Manipal University

2. Why is diabetes important in
pregnancy?
 Women with gestational diabetes are an ideal group for
primary prevention of diabetes
 Women with GDM are at an increased risk of type 2 DM in
future
 Their children are at high risk
 Even subsequent generations!

3. Pathophysiology
Screening&Diagnosis
Management
Complications

4. Patho
Diabetes Mellitus & Pregnancy

5. Glucose Metabolism in Pregnancy
Normal pregnancy is characterized by
Hyper-
insulinemia
Insulin
Resistance

6. Insulin Resistance in Pregnancy
 Insulin resistance (IR) increases due to
 Hormones by placenta
 Human placental lactogen (hPL)
 Human placental growth hormone (hPGH)
 Growth hormone, Progesterone, etc.
 Increased calorie intake, reduced exercise etc.
 Insulin resistance increases as pregnancy progresses…

7. Hormonal Changes in Pregnancy

8. Adipokines: Role in GDM
 Adipokines: leptin, adiponectin, TNF-α, interleukin-6,
resistin
 TNF-α impairs insulin signaling by
 increasing serine phosphorylation of insulin receptor substrate
(IRS)-1
 diminishing insulin receptor (IR) tyrosine kinase activity
 Low adiponectin levels correlate highly with insulin
resistance in obesity, type 2 diabetes, and GDM
Barbour LA, et al. Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes. Diabetes Care 2007 Jul;
30(Supplement 2): S112-S119

9. Why is there IR in pregnancy?
 To ensure adequate glucose and nutrients to the foetus
 especially in 3rd trimester (70% fetal growth)
 However, in about 4-14% pregnant women
 Maternal hyperglycemia occurs when pancreatic function is
not sufficient to overcome this insulin resistance

10. Glucose Homeostasis
 Balance between
 insulin resistance &
 insulin secretion
 In normal pregnancy,
hepatic glucose production
increases by 30% in 3rd
trimester
 Even more in the obese
Catalano PM, Tyzbir ED, Wolfe RR, et al: Longitudinal changes in basal hepatic glucose production and suppression during insulin
infusion in normal pregnant women. Am J Obstet Gynecol 167:913-919, 1992.

11. Mother Foetus Neonate Child
insulin
glucose
glucose
insulin
Macrosomia Hypoglycemia
RDS
Obesity
IGT
Diabetes
Pedersen Hypothesis
Effect on Mother & Child

12. Pedersen Hypothesis
 Formulated >50 years ago
 Increased transplacental transfer of glucose, stimulating the release
of insulin by the fetal beta cell, beta cell hyperplasia, and subsequent
macrosomia
 Recent developments
 Role of lipids - especially triglycerides, free fatty acids –
transplacental transfer – increased fat mass
 Explains macrosomia in spite of good glycemic control in few cases
 Role of insulin (in preventing macrosomia)
Catalano PM, Hauguel-De Mouzon S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet
Gynecol. 2011 Jun;204(6):479-87.

13. Screening&Diagnosis
Diabetes Mellitus & Pregnancy

14. Whom to screen for diabetes?
 Two modes of screening
 Selective
 Universal
 Universal screening for GDM detects more cases and
improves maternal and offspring prognosis
E. Cosson et al: Screening and insulin sensitivity in gestational
diabetes. Abstract volume of the 40th Annual Meeting of the EASD,
September 2004, A 350.

15. Selective Screening- Risk factors for GDM
 Previous history of GDM or
glucose intolerance
 Family history of diabetes
 Previous macrosomia (>4000 g)
 Previous unexplained stillbirth
 Previous neonatal
hypoglycemia, hypocalcemia, or
hyperbilirubinemia
 Advanced maternal age
 Obesity
 Polyhydramnios
 Suspected macrosomia
 Bad obstetric history
 PCOD
 Ethnic group - Indians

16. Screening in India…
 Screening is essential in all pregnant women
 Indian women have a 11-fold increased risk of developing
glucose intolerance during pregnancy as compared to
Caucasian women
Dornhost A, Paterson CM, Nicholls JS, Wadsworth J, Chiu DC, Elkeles RS, Johnston DG, Beard RW: High prevalence of GDM in women
from ethnic minority groups. Diabetic Med 1992: 9 (9): 820-2.

17. When to screen?
 Universal screening is done at 24-28 weeks
 However, it is preferable to screen in the first antenatal
visit itself to detect undiagnosed type 2 DM (overt DM)
 Recent trend is to check HbA1c in the first trimester itself to
diagnose overt DM
 If HbA1c ≥ 5.9% – high risk of GDM, screen repeatedly
 If HbA1c ≥ 6.5% – T2DM

18. History of GDM Screening
 1960s: O’Sullivan et al. 3-hour 100g OGTT
 1980: International panels. 2-hour 75g OGTT
 1999: WHO 2-hour 75g OGTT
 ADA and US NDDG continued with O’Sullivan method
 2008: IADPSG. 2-hour 75-g OGTT

19. Most common guidelines (GDM)
Organization Year FBS
Glucose
Challenge
1-h
Glucose
2-h
glucose
3-h
glucose
WHO 1999 ≥ 126 75g NR ≥ 140 NR
ACOG 2011 ≥ 95 100g ≥ 180 ≥ 155 ≥ 140
IADPSG 2010 ≥ 92 75g ≥ 180 ≥ 153 NR
WHO 2013 92 - 125 75g ≥ 180 153 - 200 NR

20. Indian Guidelines (DIPSI)
 Random test
 75g glucose, orally
 Test after 2-hr
 If ≥ 140 mg/dL, diagnostic of GDM
Gestational Diabetes mellitus – Indian Guidelines, Journal of Indian medical Association Nov 2009; 107 (11): 799 – 806
Organization Year FBS
Glucose
Challenge
1-h
Glucose
2-h
glucose
3-h
glucose
WHO 1999 ≥ 126 75g NR ≥ 140 NR
DIPSI Guidelines
Kolkata Declaration
2010

21. How to Screen? 2-step approach
1
2
75g glucose
Oral Glucose Tolerance Test
(OGTT)
if 1-hr blood glucose
>140mg/dL
50g glucose
Glucose challenge test
(GCT), Spot test

22. Classification: DM in pregnancy
 Overt Diabetes
(T2DM unmasked by pregnancy)
 FBS ≥ 126mg/dL (first
antenatal visit)
 RBS ≥ 200mg/dL
 HbA1c ≥ 6.5%
 Gestational Diabetes
(pregnancy-related)
 FBS ≥ 92mg/dL (at any
gestational age)
 75gm GTT (24-28wk)
 1-hr ≥ 180mg/dL
 2-hr ≥ 153mg/dL
 any one abnormal value

23. Complications
Diabetes Mellitus & Pregnancy

24. Adverse Outcomes with Diabetes
 Preeclampsia
 Infections, recurrent
 Hydramnios
 Fetal macrosomia
 Fetal organomegaly (hepatomegaly,
cardiomegaly)
 Birth trauma
 Perinatal mortality
 Neonate: respiratory problems and
metabolic complications –
hypoglycemia, hyperbilirubinemia
etc.
 Long-term: obesity and diabetes
during childhood, impaired fine and
gross motor functions, and higher
rates of inattention & hyperactivity
 Mother: Up to 40% likelihood of
developing diabetes later in life

25. Additional Complications in
Overt Diabetes
 Hyperglycemia is present during organogenesis too
 increased miscarriages
 congenital abnormalities
 Diabetic complications - slight increase in progression
 Retinopathy
 Nephropathy
 Ketoacidosis (T1DM) - increased risk

26. Management
Diabetes Mellitus & Pregnancy

27. Management of “Overt” Diabetes
 At diagnosis: Detailed assessment for DM complications
 especially complications which can affect pregnancy or be
aggravated by it
 retinopathy
 renal impairment
 During pregnancy: More intensive monitoring and treatment
 After delivery: Closer follow-up and ongoing monitoring and
treatment

28. Metabolic Management of
Diabetes in Pregnancy
 Diet Advice (MNT)
 Glucose Monitoring
 Pharmacological Therapy
 Peripartum management
 Goals of therapy:
 Achieve normoglycemia
 Prevent ketosis
 Provide adequate weight gain
 Contribute to fetal well-being

29. Diet Advice
 A typical meal plan: 3 small-to-moderate sized meals and 2-4
snacks
 Carbohydrates: about 40% of calories (20% protein, 40% fats, less
saturated fats)
 Calorie requirement for the present pregnant weight
 ideal body weight: 30 kcal/kg/day
 overweight: 22-25 kcal/kg/day
 morbidly obese: 12-14 kcal/kg/day
 underweight: 40 kcal/kg/day

30. Glucose Monitoring
 Ideally 4 times in a day,
everyday, at home (SMBG)
 once fasting
 once each, 2-hr after major
meals
 Practically?
 Targets
 FBS < 95mg/dL
 1-hr < 140mg/dL
 2-hr < 120mg/dL

31. Glucose Monitoring - HbA1c
 Glycated hemoglobin (HbA1c)
 Useful to detect overt diabetes in early pregnancy
 Generally lower in pregnant than non-pregnant
 reduced RBC lifespan, increased RBC mass
 relative iron deficiency
 A general idea of control, but too crude to guide insulin
adjustment

32. Pharmacological Therapy
 When diet management is inadequate
 INSULIN
 Sometimes, selected oral anti-diabetic drugs

33. Insulin
 Human Insulin
 Regular insulin
 Premixed insulin
 Usual requirement:
 0.5 - 2.0 units/kg
 Short-acting analogues
 Insulin Lispro (Class B)
 Insulin Aspart (Class B)
 Long-acting analogues
 Insulin Detemir (Class B)
 Insulin Glargine? (Class C)

34. Insulin analogues are viable therapeutic options for diabetes in
pregnancy, specifically lispro, aspart and detemir.

36. Insulin in GDM
 Clinical inertia!
 Reasonable time on dietary interventions alone: 1-2 wk
(waiting longer does not improve control further)
 Most effective period to reduce macrosomia incidence is
from 24 to 33 weeks - insulin is essential
Crowther CA, Hiller JE, Moss JR, et al: Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
N Engl J Med 2005; 352:2477-2486. (ACHOIS trial)

37. Insulin initiation
 One principle:
 Start with the simplest regimen
 Increase the complexity as needed
 Hospitalization is not mandatory, but is sometimes
necessary

38. Insulin in Pregnancy
 In overt (pregestational) diabetes, insulin requirement
reduces in first trimester (10-25%)
 Gradually rises to reach an increase of 30%-150% of pre-
pregnant requirement by end of third trimester
 Usual requirement: 0.7 u/kg/day in first trimester
 Additional bedtime snack to avoid nocturnal
hypoglycemia

40. Hypoglycemia management
 Severe hypoglycemia is uncommon in women with GDM
 If mild, treated by administering 10 to 20 g of a mixed protein
and carbohydrate snack immediately.
 Pure simple sugar use leads to
 rapid elevation of glucose
 followed by rapid decline
 Frequent or severe hypoglycemia needs insulin dose reduction

41. Oral anti-diabetics
 Metformin: Established safety in PCOS pregnancies, can
also be used in others
 Crosses placenta, levels may be higher in foetus than mother
 No long term follow-up studies

42. Oral anti-diabetics
 Glibenclamide (glyburide): Recently increasing use. Some
groups advice caution.
 Generally well tolerated, no fetal hypoglycemia
 But long-term follow-up studies are not available
Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes
mellitus. N Engl J Med. 2000;343(16):1134
Moore TR: Glyburide for the treatment of gestational diabetes: A critical appraisal. Diabetes Care 2007; 30:S209-S213.

43. Both metformin and glyburide (glibenclamide) are suitable for use in
the management of GDM because of good glycemic control.
However, glyburide (glibenclamide) treatment is associated with
increased risk of
• neonatal hypoglycemia
• high maternal weight gain
• high neonatal birth weight, and
• macrosomia.

44. At short term, in women with gestational diabetes requiring drug
treatment, glibenclamide is clearly inferior to both insulin and
metformin, while metformin (plus insulin when required) performs
slightly better than insulin. According to these results, glibenclamide
should not be used for the treatment of women with gestational
diabetes if insulin or metformin is available.
For metformin, results were better for maternal outcomes in terms
of weight gain and pregnancy induced hypertension but uneven for
fetal outcomes: more preterm birth and less severe neonatal
hypoglycaemia. It is important to bear in mind, however, that
metformin is associated with a higher rate of treatment failure and
that its long term safety remains unknown.

46. Other oral
drugs
Kelley KW, Carroll DG, Meyer A. A review of
current treatment strategies for gestational
diabetes mellitus. Drugs in Context.
2015;4:212282. doi:10.7573/dic.212282.

47. AMPK activators
 AMP-activated protein kinase
 central regulator of energy homeostasis
 coordinates metabolic pathways
 balances nutrient supply with energy demand
 Activation results in favourable metabolic outcomes
AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016 Apr; 48(4): e224.

48. AMPK

49.  Metformin, thiazolidinediones
 Ginsenosides, alpha-lipoic acid (ALA)
 Polyphenols
 Direct activators like
 Salicylates
 5-aminoimidazole-4-carboxamide riboside (AICAR)
 Thienopyridone (A-769662)
 benzimidazole (Compound 911)
AMPK activators

50. Peripartum management
 Avoid maternal hyperglycemia during labour, to reduce
 fetal acidosis
 neonatal asphyxia
 neonatal hypoglycemia

51. Intrapartum glycemic management
 Withhold morning dose of insulin
 Plan induction or Caesarean delivery early in the day
 Start 5% dextrose infusion - 100 mL/hr
 Start a separate regular insulin infusion - 0.5 U/hr
 Hourly blood glucose measurement
 Adjust insulin as per blood glucose
 Maintain between 80-110 mg/dL

52. Insulin infusion titration
 Intrapartum period: titrate
insulin dose
 hourly blood glucose
 when rate has to increase,
give 2-5 U bolus IV
 Glucose and insulin
separately
Blood glucose
(mg/dL)
Insulin
(U/hr)
Dextrose
(mL/hr)
<80 -
100
80-100 0.5
101-140 1
141-180 1.5
181-220 2
>220 2.5

53. Intrapartum glucose control
Goal: 80-110 mg/dL
Blood glucose
(mg/dL)
IV insulin
(units/hr)
IV fluid solution
Start of labour HOLD start NS infusion
<70 HOLD
5%D @ 100-150 mL/hr
until glucose 100mg/dL
>100
regular insulin @
1.25 u/hr
5%D @ 100 mL/hr
until glucose 100mg/dL
ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational
diabetes mellitus. Obstet Gynecol 2005; 105:675.

54. Postpartum period
 GDM: insulin requirement reduces drastically and can be
stopped
 T2DM: insulin can be continued as per need with frequent
monitoring
 oral drugs may be started before discharge
 However, insulin is safer as it does not enter breast milk
 T1DM: honeymoon period common and insulin requirement
will reduce temporarily

55. Long term management
 As GDM poses a 40% risk of T2DM later, life style changes
are strongly recommended

56. Thank you