Gestational Diabetes is the most common as well as the very prevalent medical disorder in females of reproductive age group. It has got significant impact on future development of T2D as well as CVD in women.
3. GOALS AND OBJECTIVES
1. TO DISCUSS GDM, THE MOST COMMON
LIFE STYLE DISORDER IN FEMALES OF
REPRODUCTIVE AGE .
2. STRATEGIES AND SOLUTIONS FOR
TAMING THE PREGNANCY OUT COME
3. THE LONG TERM SEQUELAE AND THE
IMPACT OF GDM FOR THE FUTURE RISK
OF T2D, & CVD
4. GESTATIONAL DIABETES
A 37 YO G2 P1 FEMALE AT 26 WEEKS
GESTATION PRESENTS TO DISCUSS THE
RESULTS OF HER 3 HOUR GTT.
HER RESULTS ARE LISTED BELOW
FBS= 110mg/dL
1h BLOOD SUGAR =200mg/dL
2h BLOOD SUGAR= 112mg/dL
3h BLOOD SUGAR=110mg/dL
5. WHAT DO YOU THINK ?
WHAT IS THE NEXT BEST STEP IN THE
MANAGEMENT ?
A.PLACE PATIENT ON INSULIN
B. START ORAL HYPOGLYCAEMIC
MEDICATION
C.BEGIN ANTENATAL TESTING
D.RECOMMEND DIET MODIFICATION
6. WHAT DO YOU THINK ?
WHAT IS THE NEXT BEST STEP IN THE
MANAGEMENT?
A.PLACE PATIENT ON INSULIN
B. START ORAL HYPOGLYCAEMIC
MEDICATION
C. BEGIN ANTENATAL TESTING
D. RECOMMEND DIET MODIFICATION
7. VIGNETTE 2
A 38 YO. G5 P4 WOMAN PERFORMS A 3H.
GLUCOLA TEST, AFTER SCREENING
POSITIVE FOR GDM DURING HER FIRST
TRIMESTER.
HER FBS 100mg/Dl,
1h. BLOOD SUGAR IS 200mg/dL
2h.BLOOD SUGAR IS 155mg/dL
3h.BLOOD SUGAR IS 145mg/dL
WHAT IS THE NEXT BEST STEP IN HER
TREATMENT PLAN ?
8. CONT…
A. RESULTS ARE BORDERLINE, SO PERFORM
CONFIRMATION TEST AGAIN AFTER
1WEEK
B. START DIETARY MANAGEMENT FOR
GDM AND FOLLOW UP IN 2WEEKS
C. START INSULIN AND FU IN 1WEEK
D. START ORAL HYPOGLYCAEMIC
MANAGEMENT AND FU IN 2WEEKS
E. RESULTS ARE NORMAL AND ,SO PROCEED
WITH ROUTINE FU
9. CONT….
A. RESULTS ARE BORDERLINE, SO PERFORM
CONFIRMATION TEST AGAIN AFTER
1WEEK
B. START DIETARY MANAGEMENT FOR
GDM AND FOLLOW UP IN 2WEEKS
C. START INSULIN AND FU IN 1WEEK
D. START ORAL HYPOGLYCAEMIC
MANAGEMENT AND FU IN 2WEEKS
E. RESULTS ARE NORMAL AND ,SO PROCEED
WITH ROUTINE FU
10. VIGNETTE: 3
A34 YO. G2P1 AT 25 WKS. HAD A BLOOD
GLUCOSE LEVEL OF 150mg/dL,1hr.AFTER
CONSUMING 50g.ORAL GLUCOSE.
WHAT IS THE NEXT BEST STEP IN HER
MANAGEMENT?
A.PROCEED WITH ROUTINE ANTENATAL CARE
B.PERFORM A 3HR. CONFIRMATION TEST
C.START DIETARY MANAGEMENT OF GDM
D. START OHA
E. START INSULIN MANAGEMENT OF GDM
11. WHAT IS GDM ?
GDM IS A TYPE OF DIABETES OR HIGH
BLOOD SUGAR THAT OCCURS IN
PREGNANT WOMAN ,WHO HAVE NEVER
HAD IT.
A CONDITION OF GLUCOSE
INTOLERANCE WITH ONSET OR FIRST
RECOGNITION IN PREGNANCY
12.
13. GDM MANAGEMENT…
WE HAVE DATA THAT WHEN GDM IS
TREATED IT DECREASES
LARGE FOR GESTATIONAL AGE INFANTS
SHOULDER DYSTOCIA
C SECTIONS
PRE ECLAMPSIA
14. MEDICAL MANAGEMENT GDM
MANY PATIENTS WITH GDM CAN BE
MANAGED BY DIET ALONE
THE ASSISTANCE OF A NUTRITIONIST
ESPECIALLY ONE WITH EXPERTISE IN
GDM IS A HUGE ASSET FOR WOMEN
WITH GDM
15. MEDICAL MANAGEMENT GDM
GOAL : GOOD GLYCAEMIC CONTROL WITH DIET /
EXERCISE ALONE
MEDICATION OF CHOICE : INSULIN
NPH : CATEGORY B, GENERALLY FIRST LINE
DATA ON LONG ACTING INSULIN LACKING
IF PERSISTENT HYPERGLYCEMIA AFTER 1WEEK
OF DIET CONTROL PROCEED TO INSULIN
6-14 WEEKS 0.5 U/KG/D
14-26 WEEKS 0.7 U/KG/D
26-36 WEEKS 0.9 U/KG/D
36-40WEEKS 1.0 U /KG/D
16. IF FASTING HYPERGLYCEMIA, START
WITH NPH @ HS
INITIAL DOSE : 6-8 UNITS
IF ONLY POST MEAL HYPERGLYCEMIA
USE : HUMALOG
2-4 UNITS AC THE SPECIFIC MEAL
ADJUST 2U/ TIME ; 1 FORMULA /TIME
BLOOD SUGAR TARGET:
FASTING <5.3 (90MG.)
2 H. PPBS <6.7 ( 120 MG)
MANAGEMENT…….
17. ORAL HYPOGLYCEMIC AGENTS
ORAL AGENTS
TRADITIONALLY NOT RECOMMENDED IN
PREGNANCY
GLYBURIDE & METFORMIN ARE OPTIONS.
GENERALLY ONLY OPT FOR IN WOMEN WHO
DECLINE OR CANNOT COMPLY WITH INSULIN
RCT OF ORAL GLYBURIDE VS. INSULIN FOR GDM:
440 PATIENTS
BLOOD GLUCOSE MEASURED 7X DAILY
TREATMENT STARTED AFTER 11 WEEKS
GESTATION
19. THE BLOOD SUGAR LEVEL UNDER
CONTROL
TIME OF BLOOD SUGAR TEST HEALTHY TARGET LEVEL IN
mg/dL
FASTING LESS THAN 95
1 HOUR POST MEAL LESS THAN 140
2 HOUR POST MEAL LESS THAN 120
20. SOME OF THE RISK FACTORS
GDM IN PREVIOUS PREGNANCY (13.2 x)
PRE PREGNANCY BMI >30 (3.2x)
ASIANS (2.3x)
PREVIOUS BABY >9 lbs
MATERNAL BIRTH WT >9 lbs
PCOS
HTN
FAMILY HISTORY OF DM
LOW RISK WOMEN MUST NOT HAVE ANY RISK
FACTORS
21. VIT.D DEFICIENCY AND GDM
VITAMIN D DEFICIENCY IS COMMON IN
PREGNANCY.
EMERGING EVIDENCE SUGGESTS
THAT VITAMIN D ADMINISTRATION
CAN IMPROVE INSULIN SENSITIVITY
AND GLUCOSE TOLERANCE,
WHETHER VITAMIN
D SUPPLEMENTATION CAN
PREVENT GDM IS UNKNOWN.
22. PHYSIOLOGY
1. PLACENTA SECRETES HPL(HUMAN
PLACENTAL LACTOGEN) WHICH REDUCES
INSULIN SENSITIVITY
2. MATERNAL PANCREATIC BETA CELL
HYPERPLASIA IN RESPONSE TO HPL
INCREASES MATERNAL INSULIN LEVELS
3. GDM IS THOUGHT TO RESULT FROM AN
IMBALANCE OF THESE TWO PROCESSES
23. GLUCOSE METABOLISM IN
PREGNANCY
PREGNANCY IS A RELATIVE INSULIN –
RESISTANT STATE
RELATIVE INSULIN RESISTANCE IN
PREGNANCY FAVORS GLUCOSE DELIVERY TO
FETUS
GLUCOSE INTOLERANCE OCCURS WHEN BETA
CELL SECRETION IS NO LONGER SUFFICIENT
TO COMPENSATE FOR INSULIN RESISTANCE
HBA1C LEVELS IS LOWER IN PREGNANT Vs.
NON PREGNANT WOMEN
24. WHY LOWER HBA1C LEVELS ?
THERE IS RAPID CELL TURN OVER DUE TO
INCREASED RED CELL MASS IN THE
SETTING OF PREGNANCY
THIS MAY INTERFERE WITH RED CELL
GLYCOSYLATION LEADING TO LOWER
HBA1C LEVELS
25. GDM PREVALENCE 1
THE MOST COMMON MEDICAL
COMPLICATION OF PREGNANCY.
THE GDM PREVALENCE IS INCREASING
1998: AVERAGE OF 3-8% OF PREGNANCIES
2010: AVG.OF 18% OF PREGNANCIES
• BACK GROUND RISK DM ~11%
• BACKGROUND RISK IGT ~35%
http://diabetes.niddk.nih.gov/dm/pubs/statistics
26. PREVALENCE…….
THE PREVALENCE OF GDM IS INCREASED
COMPARED TO PREVIOUS DECADES LIKELY
PRIMARILY DUE TO THE RISING
PREVALENCE OF BOTH
-OBESITY AND
-IMPAIRED FASTING GLUCOSE
IN THE GENERAL POPULATION OF WOMEN
OF REPRODUCTIVE AGE
29. WHO SHOULD BE SCREENED FOR
GDM ?
A. ALL PREGNANT WOMEN
B. OBESE PREGNANT WOMEN
C. PREGNANT WOMEN WITH A FAMILY H/O
DIABETES
D. PREGNANT WOMEN WITH A H/O GDM
E. PREGNANT WOMEN WHO HAVE
GLUCOSURIA
30.
31. WHO IS EXEMPT FROM SCREENING FOR
GDM BETWEEN 24-28WKS GESTATION ?
A. CAUCASIAN WOMEN
B. WOMEN WHO HAVE A BMI LESS THAN 20
C. WOMEN WHO ARE LESS THAN 35 YEARS
D. HIGH RISK PREGNANT WOMEN WHO ALREADY
HAVE GDM DIAGNOSED FROM THEIR FIRST
TRIMESTER SCREENING
E. WOMEN WHO HAVE A HISTORY OF AT LEAST
2 NORMAL PREGNANCIES AND NO DIAGNOSIS
OF GDM IN THE PAST
32. SCREENING DONE @24-28WKS2
SOONER IF PRIOR GDM
2-STEP (ACOG) VS.1 STEP(ADA) APPROACH
50GM.OGTT FOR SCREENING,
IF +VE : 100GM. 3 HR. OGTT WITH 2
ELEVATED VALUES FOR DIAGNOSIS.
1 STEP: 75 GM. 2 HR. OGTT
WITH 1 ELEVATED VALUE FOR DIAGNOSIS
Hiller TA, et al. Screening for GDM[Internet]
33. DIAGNOSTIC TEST
THE DIAGNOSTIC TEST (100gm.3 HOUR
OGTT) IS RESERVED FOR WOMEN
FAILING THE SCREENING TEST
THE DIAGNOSTIC TEST SHOULD BE
ADMINISTERED AFTER 8-14 HOURS FAST
AND WOMEN MUST BE SEATED FOR THE
DURATION
35. 75gm - 2HOUR OGTT
THE DIAGNOSIS OF GESTATIONAL DIABETES IS
MADE WHEN ANY OF THE FOLLOWING PLASMA
GLUCOSE VALUES ARE EXCEEDED
FASTING 92 mg/dL
1 HOUR 180mg/dL
2 HOUR 153 mg/dL
36. VIGNETTE . 4
Ms. JESSICA 34 YO G1P1,WHOM YOU MEET
AFTER 9 MO.POST DELIVERY OF HER FIRST
CHILD
-DIAGNOSED WITH GDM WHICH WAS
CONTROLLED WITH DIET DURING PREGNANCY
-HAS BEEN NORMOGLYCAEMIC SINCE DELIVERY
SOCIAL HISTORY : WORKS AS A TEACHER
NO TOBACCO OR DRUGS
SEXUALLY ACTIVE WITH HUSBAND
F H/O- PARENTS HTNve
FATHER :OBESE DIABETIC
PATERNAL GRAND FATHER: CAD
38. HOW WOULD YOU COUNSEL JESSICA?
A. IN WOMEN WHOSE BLOOD SUGARS RETURN TO
NORMAL IMMEDIATELY POST PARTUM THERE IS MINIMAL
RISK FOR T2D
B. STARTING IMMEDIATELY AND LASTING INDEFINITELY
HER RISK OF T2D IS SIGNIFICANTLY HIGHER THAN
WOMEN WITHOUT PRIOR GDM
C. HER RISK OF T2D IS SLIGHTLY HIGHER THAN WOMEN
WITHOUT GDM FOR THE FIRST 5 YEARS ONLY; IF SHE IS
NORMOGLYCAEMIC AT 5 YEARS, HER RISK RETURNS TO
AVERAGE
D. SHE IS AT AVERAGE RISK FOR T2D FOR THE NEXT FEW
YEARS, BUT AT SIGNIFICANTLY INCREASED RISK
STARTING AT THE AGE 40
39. STARTING IMMEDIATELY
AND LASTING INDEFINITELY
HER RISK OF T2D IS
SIGNIFICANTLY HIGHER THAN
WOMEN WITHOUT PRIOR GDM
40. WHICH OF THE FOLLOWING IS TRUE
OF GDM?
A. THERE IS EVIDENCE OF BOTH LARGE AND
SMALL VESSEL ENDOTHELIAL DAMAGE IN
WOMEN WITH GDM AT THE TIME OF
DELIVERY
B. THERE IS EVIDENCE OF ENDOTHELIAL
DAMAGE IN WOMEN WITH GDM,BUT NOT
UNTIL AFTER THE AGE OF 50
C. WOMEN WITH GDM ARE AT INCREASED RISK
FOR HYPERLIPIDAEMIA BUT NOT FOR HTN
41.
42. IS DELIVERY A CURE ?
AFTER DELIVERY INSULIN RESISTANT
STATE RAPIDLY RESOLVES
HYPERGLYCAEMIA DRIVEN IN LARGE PART
BY PLACENTAL HORMONES
MOST WOMEN CAN STOP MEDS
ESSENTIALLY IMMMEDIATELY
MOST DO NOT REQUIRE GLUCOSE
MONITORING AFTER HOSPITAL
DISCHARGE
43. POST PARTUM FOLLOW UP
6 WKS. AFTER THE DELIVERY MAY HAVE A
BLOOD TEST TO FIND OUT WHETHER THE
BLOOD SUGAR LEVEL IS BACK TO
NORMAL.
RISK FOR T2D PRECIPITOUSLY
INCREASES FIRST 9 MONTHS.
NO CLEAR EVIDENCE /GUIDELINES ON
RESCREENING WITHIN THAT TIME
FRAME
44. POST PARTUM FOLLOW UP
• 75 GM 2 HR. OGTT 6-12 WEEKS AFTER
DELIVERY (Level E)
BASED ON THE RESULTS MAY FALL INTO
ONE OF THE THREE CATEGORIES.
45. CATEGORY STRATEGY
1.NORMAL Get checked for diabetes every 3 years
2.IMPAIRED GLUCOSE
TOLERANCE
Get checked for diabetes every year and plan
strategies to lower the risk for developing
diabetes.
3.DIABETIC
Work with the health care provider in setting
up a treatment plan for diabetes.
46. POSTPARTUM STRATEGIES :
IF THERE IS PERSISTENT FASTING
HYPERGLYCEMIA – MORE LIKELY TO
DEVELOP PERSISTENT DIABETES
SUGGESTS 6 WEEKS POST PARTUM 75gm.
OGTT (LEVEL E)
– THEN YEARLY FASTING BLOOD GLUCOSE
AND HBA1C
– EMPHASISE THE IMPORTANCE OF
MAINTAINING NORMAL WEIGHT,AND
HAVING REGULAR EXERCISE
AFTER GDM………..
47. POST PARTUM SCREENING….
ADA : SCREEN AT LEAST Q3YEARS
INDEFINITELY
AN A1C AND FBS IS ADEQUATE
IT IS ACTUALLY A DOMAIN OF PCP
A1C DIFFICULT TO INTERPRET FOR AT
LEAST 3 MONTHS POST PARTUM
PROBABLY IT IS COST EFFECTIVE
48. GDM:RISK OF PROGRESSION TO
T2D3
LARGEST COHORT STUDY ,
> 600,000 POST PARTUM WOMEN
WOMEN WITH LIVE BIRTHS IN ONTARIO,
1995-2002 ;EXCLUDED PRE EXISTING T2D
OBJECTIVE: QUANTIFY T2D INCIDENCE IN
YEARS FOLLOWING PREGNANCY COMPLICATED
BY GDM.
OVERALL RR 12.6 (95% CI 12.1-13.1)
REALLY DRAMATICALLY INCREASED RISK !
Feig DS, et al. Canadian Medical Association Journal,2008;179(3),229-234
49. …RISK OF T2D HIGHER IN GDM4
IN 9-Yr PROJECTIONS , RISK OF T2D IS
HIGHER IN WOMEN WITH PRIOR GDM
RAPID INCREASE IN T2D PREVALENCE IN
FIRST 15 MONTHS (5% PREVALENCE)
BY 9 YEAR FOLLOW UP:
-19% PREVALENCE IN GDM GROUP
- 1.3% RISK IN CONTROLS
50. META ANALYSIS: GDM &T2D RISK 5
675000 WOMEN, 1960-2009 (MAJORITY
FROM Feig)
FOLLOW UP PERIOD SPANNED 50 YEARS!
OVERALL RR 7.3 (96% CI 5-12)
51. GDM AND CVD RISK
NO DATA ESTABLISHING DIRECT
ASSOCIATION
MULTIPLE RISK FACTORS FOUND TO BE
PERTURBED AFTER PREGNANCY COMPLICATED
BY GDM
-WOMEN WITH H/O GDM, NO SUBSEQUENT T2D
EVALUATED UPTO 5 YEARS AFTER DELIVERY
-Vs CONTROLS, SIGNIFICANTLY HIGHER
TOTAL CHOLESTEROL,LDL
FASTING GLUCOSE
SYSTOLIC BP
52. GDM AND CVD
WOMEN WITH GDM ARE AT A HIGHER
RISK OF DEVELOPING CVD AT A YOUNGER
AGE
MUCH OF THIS EXCESS RISK IS RELATED
TO DEVELOPMENT OF T2D LATER IN LIFE
EVEN MILD GLUCOSE IMPAIRMENT
APPEARS TO IDENTIFY WOMEN AT
INCREASED RISK OF FUTURE
DEVELOPMENT OF CVD, USUALLY HEART
ATTACK OR STROKE
53. ADDITIONAL RISK7
HYPERTENSION
THERE HAS BEEN CLEAR DATA FROM
NURSE’S HEALTH STUDY, 16 YR.FOLLOW UP:
WOMEN WITH GDM HAVE HIGHER RISK OF HTN
-RR 1.26(95%CI 1.11-1.43)
INDEPENDENT OF PIH, PRE ECLAMPSIA, SUBSEQ.
T2D
-MECHANISM UNCLEAR ( PRE EXISTING COMMON
RISK FACTORS)
54. RISK OF METABOLIC SYNDROME
METSYNDROME: NURSES’ HEALTH STUDY
487 WOMEN, 137 WITH GDM ; 3 MONTHS
POST PARTUM
*20% IF GDM HISTORY
THERE IS A HIGH PREVALAENCE OF MBS IN
GENERAL POPULATION
*10% PREVALENCE IF NO GDM
* GDM AND METSY.WITH COMMON
ETIOLOGIES/ MANIFESTATIONS
Tobias DK,etal.Diabetes Care.2011;34(1):223-9
55. GDM & IMPAIRED ENDOTHELIUM
WOMEN WITH H/O GDM, 2-4 YEARS POST
PARTUM FOLLOW UP:
LARGE VS:
US MEASUREMENTS OF ABDOMINAL AORTA
AND CAROTID ARTERY: INCREASED WALL
STIFFNESS IN WOMEN WITH GDM
SMALL VS:
MICROVASCULAR PERFUSION SKIN OF HAND
AND FOOT.
US MEASUREMENT OF VASODILATORY
RESPONSE TO ACh. -VS. CONTROLS,
DECREASED VASODILATION IN GDM GROUPS
56. IMPAIRED ENDOTHELIAL…8
CONCLUSION:
BOTH LARGE AND SMALL VESSEL
ENDOTHELIUM SHOWS EVIDENCE OF
IMPAIRED FUNCTION ONLY 2-4 YEARS
POST PARTUM IN WOMEN WITH HISTORY
OF GDM
Hu J,et al. British J Obstet Gynecol.1988;105(12)1279-87
57. ENDOTHELIAL DYSFUNCTION
POINT TO PONDER:
THERE IS CERTAINLY A BIOLOGIC
PLAUSIBILITY THAT STARTING A STATIN
POST PARTUM IN WOMEN WHO ARE NOT
BREAST FEEDING MAY REDUCE THE RISK OF
FUTURE ENDOTHELIAL DYSFUNCTION BUT
WE CURRENTLY HAVE NO EVIDENCE TO
SUPPORT THIS PRACTICE
58.
59. BREASTFEEDING AND GDM
IN WOMEN WITH PRIOR GDM , LACTATION
IS AN INDEPENDENT PREDICTOR OF :
1. HIGHER INSULIN SENSITIVITY
2. HIGHER GLUCOSE TOLERANCE
3. LOWER INSULIN CONCENTRATIONS
60. BREASTFEEDING……..
IT IS NOT ONLY BENEFICIAL TO THE
BABY, BUT ALSO BENEFICIAL TO THE
MOTHER.
BREASTFEEDING ALLOWS THE BODY TO
USE EXTRA CALORIES STORED DURING
PREGNANCY, ALLOWING FOR WT. LOSS.
A WT. LOSS AFTER HAVING THE BABY
NOT ONLY ENHANCES OVERALL HEALTH,
BUT ALSO HELPS TO REDUCE THE RISK OF
DEVELOPING T2D LATER IN LIFE.
61. BENEFITS OF LACTATION12
GDM SHOULD BREASTFEED THEIR
BABIES, IF POSSIBLE.
LACTATION DECREASES DIABETES RISK
IT DECREASES METSY. RISK IN WOMEN
WITH GDM HISTORY
BENEFITS PERSIST AFTER CONTROLLING
FOR BMI
Chounard- Castonguay S, etal. Euro J Endo.2013
Zeigler AG,et al.Diabetes.2012
Kjos SL.Obstet Gyn.1993
Gunderson EP,et al.Diabetes.2010
62. PREVENTION OF FUTURE CVD
GIVEN INCREASING EVIDENCE OF AN
ASSOCIATION BETWEEN GDM AND FUTURE CVD
EVEN IN THE ABSENCE OF PROGRESSION TO T2D,
IT IS REASONABLE TO DISCUSS HEALTHY LIFE
STYLE BEHAVIORS LIKE
HEART HEALTHY DIET,
MAINTENANCE OF HEALTHY WEIGHT,
TOBACCO AVOIDANCE AND
PHYSICAL ACTIVITY
WITH ALL WOMEN WHO HAVE HAD GDM
63. CONCLUSIONS
SCREEN ALL PREGNANT WOMEN WITH OGTT
WOMEN WITH H/O GDM ARE AT SIGNIFICANTLY
HIGHER RISK FOR IMPAIRED ENDOTHELIAL
FUNCTION, HTN, METSY,T2D AND
DYSLIPIDAEMIA
BREAST FEEDING DECREASES T2D RISK IN ALL
WOMEN AND AT A MINIMUM DECREASES
METABOLIC SYNDROME RISK IN WOMEN WITH
PRIOR GDM
LIFE STYLE INTERVENTIONS ARE CLEARLY
BENEFICIAL FOR REDUCING THE INCIDENCE OF
T2D AND CVD
64. REFERENCES
1.http://diabetes.niddk.nih.gov/dm/pubs/statistics
2.Hiller TA,et al.Screening for GDM[Internet]
3.Feig DS,et al.Canadian Medical Association Journal,2008;179(3),229-234
4.Feig DS,et al.Canadian Medical Association Journal,2008;179(3),229-234
5.Feig DS,et al.Canadian Medical Association Journal,2008;179(3),229-234
6.Meyers-Seifer CH,et al.Diabetes Care .1996;1996(12):1351-6
7Tobias DK,etal.Diabetes Care.2011;34(1):223-9
8.Hu J,et al. British J Obstet Gynecol.1988;105(12)1279-87
9.Wyatt JW, Frias JL, Hoyme HE, Jovanovic L, et al. Congenital anomaly rate in offspring of pre-
gestational diabetic women treated with insulin lispro during pregnancy. Diabetic Medicine
21:2001-2007, 2004.
10.Bhattacharyya A et al. Q J Med. 2001;94:255-260
11.Langer NEJM 2000
12.Chounard-Castonguay S, etal. Euro J Endo.2013
Zeigler AG,et al.Diabetes.2012
Kjos SL.Obstet Gyn.1993
Gunderson EP,et al.Diabetes.2010