Diabetes and Pregnancy-Saptarshi Bhattacharya.pdf

Ppt on Diabetes and Pregnancy

1. Dr. Saptarshi Bhattacharya, MD, DM
Senior Consultant, Endocrinology
Indraprastha Apollo Hospitals, Sarita Vihar, Delhi

2. Diabetes in Pregnancy

3. Pre-conceptional Management

Glycemic
Control

Obstetric
assessment

Screen for
complications

American

Diabetes
Association.

Alc < 6.5%

Attention to use of
ARB, ACEi, Statin

Comprehensive eye
examination

S. Creatinine, ACR

‘American Diabetes Association Professional Practice Committee; 15.
Management of Diabetes in Pregnancy: Standards of Care in
Diabetes—2024. Diabetes Care 1 January 2024

4. American
Diabetes

Preconception Counseling Association.

Recommendations

15.1 Starting at puberty and continuing in all people with diabetes and childbearing
potential, preconception counseling should be incorporated into routine diabetes care. A

15.2 Family planning should be discussed, and effective contraception (with consideration
of long-acting, reversible contraception) should be prescribed and used until an individual’s
treatment plan and A1C are optimized for pregnancy. A

15.3 Preconception counseling should address the importance of achieving glucose levels as
close to normal as is safely possible} ideally A1C <6.5% (<48 mmol/mol), to reduce the risk
of congenital anomalies, preeclampsta, Macrosomla, preterm birth, and other
complications. A

5. Table 15.1—Checklist for preconception care for people with diabetes American
AES...

Preconception education should include:
O Comprehensive nutrition assessment and recommendations for:
+ Overweight/obesity or underweight
Meal planni ñ
+ Meal planning Pre-conceptional Care

e Correction of dietary nutritional deficiencies
Caffeine intake ADA 2024
e Safe food preparation technique

D Lifestyle recommendations for:

e Regular moderate exercise Created using information from American
e Avoidance of hyperthermia (hot tubs) College of Obstetricians and Gynecologists and
e Adequate sleep Ramos

O Comprehensive diabetes self-management education

O Counseling on diabetes in pregnancy per current standards, including: natural history of
insulin resistance in pregnancy and postpartum; preconception glycemic goals; avoidance of
DKA/severe hyperglycemia; avoidance of severe hypoglycemia; progression of retinopathy;
PCOS (if applicable); fertility in people with diabetes; genetics of diabetes; risks to
pregnancy including miscarriage, still birth, congenital malformations, macrosomia, preterm
labor and delivery, hypertensive disorders in pregnancy, etc.

O Supplementation
e Folic acid supplement (400 ug routine)
e Appropriate use of over-the-counter medications and supplements

6. American
Diabetes
Association

Pre-conceptional Care ADA 2024
Created using information from American College of Obstetricians and Gynecologists
and Ramos

Health assessment and plan should include:

O General evaluation of overall health

O Evaluation of diabetes and its comorbidities and complications, including DKA/severe
hyperglycemia; severe hypoglycemia/hypoglycemia unawareness; barriers to care;
comorbidities such as hyperlipidemia, hypertension, NAFLD, PCOS, and thyroid
dysfunction; complications such as macrovascular disease, nephropathy, neuropathy
(including autonomic bowel and bladder dysfunction), and retinopathy

O Evaluation of obstetric/gynecologic history, including a history of cesarean section,
congenital malformations or fetal loss, current methods of contraception, hypertensive
disorders of pregnancy, postpartum hemorrhage, preterm delivery, previous
macrosomia, Rh incompatibility, and thrombotic events (DVT/PE)

O Review of current medications and appropriateness during pregnancy

7. Pre-conceptional Care ADA 2024 N American
Created using information from American College of Obstetricians and Gynecologists Association.
and Ramos

Screening should include:
O Diabetes complications and comorbidities, including comprehensive foot exam;
comprehensive ophthalmologic exam; ECG in individuals starting at age 35 years who
have cardiac signs/symptoms or risk factors and, if abnormal, further evaluation; lipid
panel; serum creatinine; TSH; and urine albumin-to-creatinine ratio
O Anemia
O Genetic carrier status (based on history):
Cystic fibrosis
e Sickle cell anemia
e Tay-Sachs disease
e Thalassemia
Others if indicated
O Infectious disease
Neisseria gonorrhoeae/Chlamydia trachomatis
e Hepatitis B and hepatitis C
“HIV
e Pap smear
e Syphilis

8. American
Diabetes
Association

Pre-conceptional Care ADA 2024
Created using information from American College of Obstetricians and Gynecologists
and Ramos

Immunizations should include:
D Inactivated influenza
O Tdap (tetanus, diphtheria, and pertussis)
E COVID-19 (certain populations)
O Hepatitis A and hepatitis B (certain populations)
a Others if indicated

Preconception plan should include:
O Nutrition and medication plan to achieve glycemic goals prior to conception, including appropriate
implementation of monitoring, continuous glucose monitoring, and pump technology
O Contraceptive plan to prevent pregnancy until glycemic goals are achieved
O Management plan for general health, gynecologic concerns, comorbid conditions, or
complications, if present, including hypertension, nephropathy, retinopathy; Rh
incompatibility; and thyroid dysfunction

9. Multicenter Study > Diabetes Care. 2

Peri-conceptional A1C and risk of serious adverse
pregnancy outcome in 933 women with type 1
diabetes

RR (95% CI) RR (95% CI) Serious RR (95% CI)
zscore Number Congenital vs. Perinatal vs. adverse vs.
(SD> of malformations background mortality background outcome background
mean) patients (%) population (%) population (%) population
>10 55 3.9 (1.8-7.8) 4 5.5 73(2.5- 3 4702581)
19.8)"
14 (0.6-3.1) . 8.3 (42- 2.2 (1.2-3.9)'
15.9)
50-69 182 3 1.8 (0.9-3.3) 33 4.4 (20-94) 2.2 (1.3-3.6)1
30-49 284 x 1.8 (1.0-2.9) : 3.8 (1.9-7.3)" 2.2 (1.5-3.3)

<6.9 <3.0 284 3 1.4 (0.8-2.4) 2.8 (1.3-6.1)* 1.6 (1.0-2.6)

Background population (n = à 10 1.0 10
70,089)

10. Pregnancy: Glucose Monitoring & Targets
+ Alc< 6% (relaxed to <7% if necessary to prevent

hypos)

+ CGMS may be used in addition to but not as a
substitute for blood glucose monitoring

ADA: Pre-existing diabetes Low-dose
*Premeal glucose - 70-95 mg/dL Aspirin at 12-16
+1-hour PP - 110-140 mg/dL weeks decreases
-2-hour PP - 100-120 mg/dL risk of

preeclampsia

11. Continuous glucose monitoring in pregnant women with
ype 1 diabetes (CONCEPTT): a multicentre international

randomised controlled trial Lancet 2017

Denice S Feig, Lois E Donovan, Rosa Corcoy, Kellie E Murphy, Stephanie A Amiel, Katharine F Hunt, Elizabeth Asztalos, Jon F R Barrett,

Mild improvement in A1C without
an increase in hypoglycemia

«Target range 63-140 mg/dL: TIR, goal
Reductions in LGA births >70%

«Time below range (<63 mg/dL), goal
<4%

« Decreased neonatal stay

MNAE AE ° Time below range (<54 mg/dL), goal

12. American
Diabetes

CGM in Pre-existing Diabetes Association

+ 15.10 CGM is recommended in pregnancies associated with type 1
diabetes. A When used in addition to blood glucose monitoring, achieving
traditional pre- and postprandial goals, real-time CGM can reduce the risk for
large-for-gestational age infants and neonatal hypoglycemia in pregnancy
complicated by type 1 diabetes. A

+ 15.11 CGM metrics may be used in addition to but should not be used as a
substitute for blood glucose monitoring to achieve optimal pre- and
postprandial glycemic goals. E

« 15.12 Commonly used estimated A1C and glucose management indicator
calculations should not be used in pregnancy as estimates of A1C, C

13. American
Diabetes
Association.

+ 15.18 Insulin should be used to manage type 1 diabetes in
pregnancy. A Insulin is the preferred agent for the management of
type 2 diabetes in pregnancy. B

+ 15.19 Either multiple daily injections or insulin pump technology
can be used in pregnancy complicated by type 1 diabetes. C

While many health care professionals prefer insulin pumps in pregnancy, it is not clear
that they are superior to multiple daily injections.
None of the current automated insulin delivery (AID) systems approved by the FDA have

algorithms set to achieve pregnancy goals.
May be appropriate to continue or initiate AID in carefully selected pregnant individuals
with type 1 diabetes in the setting of using assistive techniques with expert guidance

14. American
Diabetes
Association

Insulin Usage in Pregnancy

None of the currently available human insulin preparations
have been demonstrated to cross the placenta.

Preferred

E Regular insulin, NPH, aspart, lispro,
1. Insulin in RCTs > detemir, degludec, fast-acting aspart
2. Insulin in cohort studies > Glargine
3. Insulin in case reports only > URLI, glargine 300, glulisine

15. Insulin degludec versus insulin detemir, both in combination with insulin
aspart, in the treatment of pregnant women with type 1 diabetes

(EXPECT): an open-label, multinational, randomised, controlled, non-
inferiority trial

Prof Elisabeth R Mathiesen, MD 2, (S] Amra Ciric Alibegovic, MD + Prof Rosa Corcoy, PhD +
Findings

Between Nov 22, 2017, and Nov 8, 2019, from 296 women screened, 225 women were randomly assigned to degludec (n=111) or
detemir (n=114). Mean HbA,, at pregnancy baseline was 6:6% (SD 0-6%; approximately 49 mmol/mol; SD 7 mmol/mol) in the
degludec group and 6:5% (08%; approximately 48 mmol/mol; 9 mmol/mol) in the detemir group. Mean last planned HbAi
measurement before delivery was 6:2% (SE 0-07%; approximately 45 mmol/mol; SE 0-8 mmol/mol) in the degludec group and 63%
ad treatment difference -0:11% [95% CI
compared with detemir, no

(SE 0-07%; approximately 46 mmol/mol;SE--8-mmot/mrotrtrtiretetemirgroup-te.
-0-31 to 0-08]; -1-2 mmol/m6H@5% Cl: -3-4 to 0-9]; Pnon-inferiority<0-0001), confirming non-inferiority

additional safety issues were observed with degludec.

Interpretation

In pregnant women with type 1 diabetes, degludec was found to be non-inferior to detemir.

16. Randomized Controlled Trial > Lancet Diabetes Endocrinol. 2023 Nov;11(11):811-821
doi: 10.1016/S2213-8587(23)00236-X. Epub 2023 Oct 4.

Faster-acting insulin aspart versus insulin aspart in
the treatment of type 1 or type 2 diabetes during
pregnancy and post-delivery (CopenFast): an open-
label, single-centre, randomised controlled trial

Sidse K Nergaard *, Julie C Saholm *, Elisabeth R Mathiesen *, Kirsten Norgaard 2

Findings: Between Nov 11, 2019 and May 10, 2022, 109 participants were included in the faster
aspart group and 107 in the insulin aspart group. Primary outcome data were available in 203 (94%)
of 216 participants, and no participants discontinued treatment during the trial. Mean birthweight
SD score was 1-0 (SD 1-4) in the faster aspart group versus 1-2 (1-3) in the insulin aspart group;
estimated treatment difference -0-22 [-0-58 to 0-14]; p=0-23. At 33 weeks of gestation, mean
HbAïe was 42 mmol/mol (SD 6 mmol/mol; 6-0% [SD 0-9%]) versus 43 mmol/mol (SD 7 mmol/mol;
6-1% [SD 1:2%]); estimated treatment difference -1-01 (-2-86 to 0-83), p=0-28. No additional safety
issues were observed with faster aspart compared with insulin aspart.

Interpretation: Treatment with faster aspart resulted in similar fetal growth and HbA\,, relative to
inzufin-aspart, in women with type 1 or type 2 diabetes. Faster aspart can be used in women with
type 1 or type 2 diabetes during pregnancy and post-delivery with no additional safety issues.

17. Basal Bolus Regimen of Insulin: If FBG and PP values
are high: Rapid Acting Insulin + Detemir/NPH/Degludec

LA RA RA RA LA

II | J |

Serum insulin (mU/L)

Time of Day

18. Serum insulin (mU/L)

Pre-mixed Insulin: Though commonly used
but usually not advocated

Mix 70/30 (Aspart/Reg) Mix 70/30 (Aspart/Reg)
| 75/25 (Lispro) | 75/25 (Lispro)

Hours

19. Early pregnancy - enhanced
sensitivity - lower insulin need -
increased risk for hypoglycemia
16 weeks - insulin resistance
increase, TDD increase linearly
~5%/week through week 36
Doubling of TDD compared with
prepregnancy

Increase in both basal and bolus,
bolus take up a larger proportion
Levels off end of third trimester
Placental insufficiency - rapid
lowering of TDD

20. Diabetes in Pregnancy

21. How prevalent is
GDM?

22. Meta-Analysis > Di in Pract. 2022 Jan;183:109050.
doi: 10.1016/j.diabres.2021.109050. Epub 2021 Dec 6.

IDF Diabetes Atlas: Estimation of Global and

Regional Gestational Diabetes Mellitus Prevalence
for 2021 by International Association of Diabetes in
Pregnancy Study Group's Criteria

ng 7, Ninghua Li *, Te

+ North America and Caribbean - 7.1%

+ Europe - 7.8%

+ South America and Central America - 10.4%
+ Africa — 14.2%.

« Western Pacific - 14.7%

+_ South-East Asia - 20.8%

+ Middle East and North Africa — 27.6%

23. Screening
strategies

24. Universal vs. Selective Screening

If women not screened prior to
pregnancy, universal early screening at
<15 weeks of gestation for undiagnosed
diabetes may be considered over
selective screening particularly in
populations with high prevalence of risk
factors and undiagnosed diabetes in
women of childbearing age.

Strong racial and ethnic disparities exist
in the prevalence of undiagnosed
diabetes.

[ DIPSI Guidelines - Kolkata Declaration |

Fifth National Conference of Diabetes in
Pregnancy Study Group, India

V Seshiah

«Indian women have 11 fold higher risk of
glucose intolerance in pregnancy compared
to Caucasian

«Universal screening for GDM detects more
cases and improves maternal and neonatal
prognosis

«Due to high prevalence, screening is
essential for all Indian pregnant women,

25. Yearproposed Approach Glucose load (g) Glucose threshold mg/l (mol)
Fasting th 2h 3h
Sulvan & Mahan 90(50) 165(92) 145 (81) 125,69)

National Diabetes Data Group (NDDG) 15158) 10106) 165192) 145181)

Carpenter & Coustan 95153) 10/00) 155/88) 140(78)

Word Health Organization (WHO) IS 1008) -

The O’Sullivan and Mahan criteria were derived mathematically and were validated for
future diabetes in the mother rather than the outcomes of pregnancy

26. Th NEW ENGLAND
JOURNAL of MEDICINE

Hyperglycemia and Adverse Pregnancy Outcomes

METHODS

A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g
oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded

CONCLUSIONS
Our results indicate strong, continuous associations of maternal glucose levels below

those diagnostic of diabetes with increased birth weight and increased cord-blood se-
rum C-peptide levels.

27. + ing glucose L-Hr glucose 2Hr glucose

A Birth Weight >90th Percentile B Primary Cesarean Section
305 35
254 30.
20

15

Frequency (%)
Frequency (%)

10

r o
4 8 3 4 à

Glucose Category Glucose Category

© Clinical Neonatal Hypoglycemia D Cord-Blood Serum € Peptide >90th Percentile

E z
ES ES

se 5 5

Glucose Category

of Primary Outcomes across the Glucose Cate;

28. IADPSG Protocol for Evaluation of Diabetes in Pregnancy

OGTT: perform after overnight fast on all women not prev found to have overt
betes or GDM durin arlier in thi ancy
0 mmol (126 mg/dl)
GDM if one ortmore values equals orexceeds thresholds indicated in fabled

No al if all va OGTT less than thresholds indicated in Table 1

International Association of Diabetes and Pregnancy Study Groups (IADPSG) and
American Diabetes Association (ADA)

292 mg/dL (5.1 mmol/L)

[2180 mg/dL (10.0 mmol/L)

|2153 mg/dl (8.5 mmol/L)
Plasma glucose (mg/dl)
Fasting 23,316 (100) 80.926.9 78.2-83.7
Ihr 23,316 [phone].9 119.5-148.2
2 hr 23,316 (100) 111.0+23.5 99.6-120.9
Length of gestation at time of OGTT (wk) 23,316 (100) 27.8+1.8 25.9-29.5

29. Recommendation
(year)
lADPSG (2010)

WHO (201372

ACOG (2018)"*

‘ADA (2020)'

Test

75 g0GIT
(one-step)

75 gOGIT
(one-step)

50 g GLI followed
by 100 g OGTT
(two-step
preferred or
one-step)

One-step or
Two-step

Glucose thresholds

Fasting 292 mg/dL
1 hour 2180 mg/dL
2 hours 2153 mg/dL.

Fasting 292-125 mg/dL

1 hour 2180 mg/dL.

2 hours 2153-199 mg/dL
Diabetes:

Fasting 2126 mg/dl

2 hours 2200 mg/dL.

GLI: >130, 135 or 140 mg/dL

OGTT: Carpenter-Coustan criteria
Fasting 295 mg/dL

1 hour 2180 mg/dL

2 hours 2155 mg/dL

3 hours 2140 mg/dL

or

\ADPSG criteria

\ADPSG criteria or
Carpenter-Coustan criteria

31. + Assessment of blood glucose can be performed either
1 or 2 hours post-prandially

+ No evidence to suggest superiority of either approach

*Fasting < 95 mg/dL
«1 hr PP < 140 mg/dL
«2 hr PP < 120 mg/dL

32. Medical Nutrition Therapy & Physical Activity

Achieve normal blood glucose levels
Prevent ketosis

Provide adequate weight gain - IOM 2009
Appropriate fetal growth & development

Carbohydrate intake be limited to 33-
40% of calories, with the remaining
calories divided between protein (20%)
and fat (40%)

The food plan based on nutrition assessment
with guidance from the Dietary Reference
Intakes (DRI)

The DRI recommends

Min of 175 g of carbohydrate (~35% of a
2,000-calorie diet)

Minimum of 71 g of protein

Min 28 g of fiber

Emphasize monounsaturated and
polyunsaturated fats

Limit saturated fats & avoid trans fats

33. Weight gain during pregnancy

Weight Gain During Pregnancy: Reexamining the
Guidelines
Institute of Medicine (US) and National Research Council (US) Committee to Reexamine IOM
Pregnancy Weight Guidelines
Total Weight Gain Rites of Weigh Gain* 2nd and 3rd Trimester
Prepregnancy BMI Range inkg Range in lbs f Mean (range) in KA/week Mean (range) in Ibs/week
Underweight (< 18.5 kg/m’) 125-18 28-40 0.51 (0.44-0,58) 1 (1-13)
Normal weight (18.5-24.9 kg/m?) 115-16 25-35 0.42 (0.35-0.50) 1(0.8-1)
Overweight (25.0-29.9 kg, /m?) 15-25 0.28 (0.23-0.33) 0.6 (0.5-0.7)
Obese (2 30.0 kg/m?) 5-9 11-20 0.22 (0.7-0.27) 05 (04-06)

*Calculations assume a 0.5-2 kg (11-44 lbs) weight gain in the first trimester (bas SigggeMiz et al, 1994; Abrams et al, 1995; Carmichael et al., 1997)

34. Timing of Delivery ACOG 2018

« GDM controlled with diet and exercise- not before 39 wk, unless
otherwise indicated. Expectant management - 40 6/7 wk in setting
of indicated antepartum testing

+ GDMwell controlled by medications). delivery from 39 0/7 weeks

to 39 6/7 weeks of gestation.

o Poorly controlled GDM - Expert opinion - earlier delivery. Trade

offs between risks of prematurity and stillbirth.
« Delivery between 37 0/7 and 38 6/7 wk may be justified.

+ Late preterm period from 34 0/7 to 36 6/7 wk reserved for failed
in-hospital attempts of glycemic control or with abnormal
antepartum fetal testing

35. Postpartum Evaluation : Fifth International
Workshop-conference

Time Test Purpose.

Post-delivery (1-3d) Fasting or random PG Detect persistent, overt
diabetes

Early postpartum (4-12wk) 75 g 2-h OGTT Postpartum classification of
glucose metabolism

1 yr postpartum 75 g 2-h OGTT Assess glucose metabolism

Annually FPG Assess glucose metabolism

Tri-annually 75 g 2-h OGTT Assess glucose metabolism
Prepregnancy 75 g 2-h OGTT Classify glucose metabolism

36. ALL POSSIBLE KNOWLEDGE

what you

7 know

what you
don’tknow — what you
you don’t —- know you
know don’t know

39. Clinical scenario: When Metformin can be
used?

AF R * GDM

, , * PCOS

» Pre-existing type 2
DM

40. Sequence of Metformin use

+ Metformin alone
+ Metformin > Metformin + Insulin

* Insulin > Insulin + Metformin

41. Guide Country Year Requirements
The American Diabetes American 2020 Insulin is the first line of treatment for GDM in the United States. Although
Association (ADA) several randomized controlled trials ha
metformin and glyburide in reducing glucose levels in the treatment of GDM,
these drugs are not recommended as first-line agents for GDM because they
Metformin, when used to treat polycystic ovary syndrome and induce ovulation,
should be discontinued by the end of the first trimester
American Congress American 2018
of Obstetricians and women cannot safely use insulin, patient with metformi
Gynecologists (ACOG) second-line choice, but it is necessary to inform patients the risk of adverse
events, such as increasing prematurity, drugs through the placenta, and lack of
International Federation of - 2015 | Insulin, glyburide and metformin are safe and effective treatment options during
Gynecology and Obstetrics the second and second trimester of pregnancy if blood glucose cannot be
(FIGO)
The National Institutes of UK 2015 | Metformin is used if the blood sugar target is not achieved through lifestyle
Health Care Excellence (NICE) changes within 1-2 weeks. If the patient is intolerant or cannot accept
- 2009 if blood sugar targets are not met within 1-2 weeks of lifestyle changes, blood
Federation (IDF) sugar levels should be lowered. Insulin is a treatment of choice, but there is
now sufficient evidence to consider metformin and glyburide in women who are
known to be at risk. Combination therapy has not been studied specifically
The Australasian Diabetes in Australian 2005 it is recommended to change treatment to insulin and to use metformin only in

Pregnancy Society (ADIPS)
and the Australian Electronic
Treatment Guidelines (eTG)

the following cases: patients are opposed to injections

Ann Palliat Med 2021 :10(3):3423-3437

43. The NEW ENGLAND JOURNAL of MEDICINE

Metformin versus Insulin for the Treatment
of Gestational Diabetes

Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D., Wanzhen Gao, Ph.D.,

MiG Trial
Women with GDM requiring medication
751 women recruited

Supplemental insulin
was required in 168
women (46.3%) in
the metformin group }

363 completed study 370 completed study

44. Metformin versus Insulin for the Treatment
of Gestational Diabetes

Metformin
Group Relative Risk
(N=363) (95% Ci)

Primary composite outcome 116 32.0) 119(32.2) 0.99 (0.80-1.23) 0.95

Recurrent blood glucose level =46.8 me/AT 557152) 557186) 0.81 (055-112)
Any blood glucose level =28.8 mg/dl 12 3.3) 30 (8.1) 0.41 (0.21-0.78)
Respiratory distress. 1263) T6 (43) 0.76 (0371.59)
Transient tachypnea 7 (19) 8 (2.2)
Respiratory distress syndrome aan) 5 (1.4)
Sepsis 1 (0.3) 5 (1.4)
Pulmonary hypertension o 2 (0.5)
Phototherapy 29 (8.0) 31 (8.4) 0.95 (0.59-1.55)

Birth trauma§, 16 (4.4) 17 (4.6) 0.96 (0.49-1.87)
Mild 16 (4.4) 15 (4.1)
Moderate or severe o 2 (0.5)

5-Min Apgar score <74] 3 (0.8) 1 (0.3) 3.06 (0.32-29.26)

Preterm birth (<37 wk of gestation) 44 (12.1) 28 (7.6) 1.60 (1.02-2.52)
latrogenic (indicated

‘Spontaneous 1.77 (0.95-3.28)

Additional neonatal complications

Admission to level 2 or 3 neonatal intensive care unit 68 (18.7) 78 (21.1) 0.89 (0.66-1.19)

>24-Hr stay in neonatal intensive care unit 46 (12.7) 45 (12.2) 1.04 (0.71-1.53)
mean +SD

PH ofumbilical-cord or scalp blood] 7272007 7.26:0.07

45. urwnp

. Neonatal anthropometric measurements
. Maternal glycemic control

. Maternal hypertensive complications

. Postpartum glucose tolerance

a Cl Oi treatment There were no serious adverse events associated with
¡e use of metfor:

Results: Favoured Metformin
More women stated they would choose to receive

metformin again(76.6% vs. 27.2%)
The rates of other secondary outcomes did not differ
significantly between the groups

* Preterm births were more in metformin.
* Spontaneous>iatrogenic preterm

Metformin alone Supplemental insulin P
N: 8 alu

chi tel
Maternal family history of diabetes — no (%) 74 (38.0) 88 (52.4)
75 g OGTT: fasting glucose (mg/dl) + 9544 144 109.8 + 19.8
Enrollment fasting glucose (mg/dl) $ 90.0 + 10.8 10444 19.8
Enrollment HbAlc (%)|| 5.6+0.6 5.9£0.7 <0.001

46. REVIEW ARTICLE OB WILEY

The efficacy and safety of metformin alone or as an add-on
therapy to insulin in pregnancy with GDM or T2DM:A
systematic review and meta-analysis of 21 randomized
controlled trials 4,545 patients

Favours metformin over insulin

Maternal weight gain [MD -1.51 kg, 95%CI (-1.90 kg, -1.12 kg), P < 0.00001]

Gestational age at birth [MD -0.12 week, 95%CI (-0.21 week, -0.02 week), P = 5e difference
0.02] Caesarean section
Gestational hypertension [RR 0.63, 95%CI (0.48, 0.82), P = 0.0006] Preterm birth

Maternal hypoglycaemia [RR 0.33, 95%CI (0.15, 0.73), P = 0.006] Maternal glycaemic
Birthweight [MD -0.13 kg, 95%CI (-0.20 kg, -0.07 kg), P < 0.0001] control
Neonatal hypoglycaemia [RR 0.56, 95%CI (0.49, 0.64), P < 0.00001] ne
Neonatal ICU admission [RR 0.73, 95%CI (0.64, 0.83), P < 0.00001] aa a
Birthweight 24000 g [RR 0.70, 95%CI (0.59, 0.83), P < 0.0001]

Perinatal mortality
Large for gestational age [RR 0.83, 95%CI (0.72, 0.97), P = 0.02] 5-min Apgar score

Apgar score <7 at 5 min
Favours insulin over metformin Congenital anomaly
* Small for gestational age [RR 1.43, 95%CI (1.08, 1.89), P = 0.01] Birth injury

47. Summary: Metformin perinatal outcome in
GDM

Lesser macrosomia and birth weight
+ More small for gestational age
Lesser CS

Lesser neonatal hypoglycemia and ICU + Trend towards preterm delivery
admission

Lesser maternal hypoglycemia [x]

Lesser maternal weight gain and
hypertension

48. CARDIOVASCULAR AND METABOLIC RISK | SEPTEMBER 152011
Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG
TOFU): Body composition at 2 years of age 3

‘tam a MO

ect toutes

Camping amor ne A Ronan pronom
nat Caw 201194102279 284
Papa an 102201011000 Any ©

Women with Gi

751 women recruited

MiG Trial
¡DM requiring medication

y

t

363 completed study

370 completed study

4

y

2 year old follow-up planned at three sites
577 eligible for follow-up
323 women and children seen (56%)

|

I

Metformin arm
Body composition measures
on offspring
Anthropometry n = 154
Bioimpedance n = 103
DEXA n= 57

Insulin arm
Body composition measures
on offspring
‘Anthropometry n = 164
Bioimpedance n= 118
DEXA n= 57

49. MIG-TOFU Study

Insulin p value
Weight (kg) 14.342.1 14.0+2.2
Waist (cms) 50.5+3.5 50.1+4.0

Upper arm circ (cms) 17.2+1.5 16.7+1.5 0.002
Triceps skinfold (cms) 10.1+2.0 9.9+2.4

Subscapular skinfold (cms) 6.341.9 6.01.7 0.02
Biceps skinfold (cms) 6.01.9 5.6+1.7 0.04
DEXA total fat (g) 242141002 22744711 0.37
Abdominal fat (g) 132473 131460 0.92

Offspring had higher s.c. fat, no difference in central fat
Rowan, Diabetes Care 2011

50. Metformin in gestational diabetes: the

offspring follow-up (MiG TOFU): body
composition and metabolic outcomes at
7-9 years of age

Children were assessed at
« 7 years in Adelaide (n=109/181)
« 9 years in Auckland (n=99/396)
* anthropometry
« bioimpedance analysis
« dual-energy X-ray absorptiometry (DXA)
* magnetic resonance imaging (MRI) (n=92/99)
« fasting bloods (n=82/99)

51. (Adelaide) n=109

Pr e ee,

(Auckland) n=99

Metformin Insulin Metformin Insulin
n=58 n=51 P values n=45 n=54
Age (years) 70x10 7.411 0.02 8.020.5 8.020.4
Male/temale (n) 35/23 23/28 0.16 28/17 28/26
Weight (ka) 26.945.2 26.324.9 0.59 37.0212.6 32.77.7
Height (em) 124.545.2 124.545.0 0.99 197.527.4 135.446.6
BMI (kg/m°) 17.222. 16.922.5 0.48 19.324.6 17.73.0
Leg length (em) 55.827.7 87.543.1 0.13 63.624.2 63.944.1
Head circumference (em) 52.2#1.2 51.921.5 0.24 53.622.2 53.121.8

Chest circumference (cm)

Mid-upper arm
circumference (em)

Waist:height ratio
Triceps skinfold thickné

Subscapular skinfold
thickness (mm)

Biceps skinfold thickness
(mm)

Fat-free mass (0)
Total fat (9)
Abdominal fat
Thigh fat (9)
Arm fat (9)

Abdominal fat:thigh fat
ratio

Total fat %

Abdominal fat % of
abdominal mass

Bioimpedance
Fat-free mass (kg)
Total fat %

63.5+6.0
197224

67.62.6.4
0.480.085
11.424.3

1970222564
765143006
4234384
12522618
10792492
0.300.141

26.847.6
21.3211.8

n=56
21.522.8
18.847.0

63.125.0

67.725.7
0.48+0.04
11.424.0

1927122532
798723339
4304315
13232618
11034422
0.3020.10

28.546.8
22.4410.5

n=51
20.723.0
20.825.4

0.66

0.63
0.84
0.99

0.37
0.71

0.94
0.18

70.4210.2

77.6211.
0.5120.08
19.529.0

13.129.6

13.97.5

2438525804
1255047214
7742681
198321122
15682801
0.342013

32.0x8.5
29.7214.4

27.727.7
23.648.1

67.7+8.0
21.2229

7a.727.1
0.470.085
16.226.7

10.526.8

11.825.0

2251123680
102814550
5481413
16552710
12854534
0.3020.09

30.346.6

26.6:10.5

25.145.2
22.348.9

0.10
0.047
0.15

0.28
0.24

0.065
0.43

52. PLoS Med. 2019 Aug; 16(8): e1002848. PMCID: PMC6684046
Published online 2019 Aug 6. doi: 10.1371/journal.pmed.1002848 PMII 1386659

Neonatal, infant, and childhood growth following metformin versus insulin treatment for

gestational diabetes: A systematic review and meta-analysis

Metformin: Insulin Mean Difference Mean Difference
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI
Rowan JA - Adelaide 7yrs, 2018 17.2 25 58 169 25 51 339% 0,30(-0.64, 1.24) +
Rowan JA - Auckland 9yrs, 2018 193 46 45 177 3 54 123% 1.60(0.04,3.16] ae
TerttiK Syr, 2016 164 21 45 15515 48 539% 0,90(0.15, 1.65] +
Total (95% CI) 148 153 100.0% 0.78 (0.23, 1.33] +
Hanna Ci 216 a= ta ATK + + i + 4
CL ZEZBONESI0.000) Decreases with metformin Increases with metformin

Childhood BMI.
Expressed as mean differences (fixed effects model) and 95% Cl. IV, mean

difference

53. Lo ed. 2019 Aug; 16(8): e1002848. PMCID: PMC6684046
Published online 2019 Aug 6. doi: 1( ) PMD:

Neonatal, infant, and childhood growth following metformin versus insulin treatment for
gestational diabetes: A systematic review and meta-analysis

+ Following intrauterine exposure to metformin for GDM, neonates are
significantly smaller than insulin treated group

+ Metformin-exposed children have accelerated postnatal growth,
resulting in heavier infants and higher BMI by mid-childhood

+ Such patterns of low birth weight and postnatal catch-up associated with
adverse long-term cardio-metabolic outcomes

+ Suggests need for further studies examining longitudinal perinatal and
childhood outcomes following intrauterine metformin exposure

54. Metformin: Hero or Villain?

55. Endocrine
Practice™

www.endocrinepractice.org

Review Article

Long-Term Impact on Offspring (5 to 11 Years of Age) of Metformin
Use in Pregnancy in Mothers With Diabetes: A Systematic Review and
Meta-Analysis

Dutta, MD, DM, FRCP !”, Meha Sharma, MD. DM ?, Lakshmi Nagendra, MD, DM °,
Bhattacharya,] MD, DM *, Ritin Mohindra, MD
ERCP ©

ittaranjan S. Yajnil

56. Results: Children at the age of 9 years born to mothers wo were treated with metformin during
pregnancy had isiinilar BMI (mean difference [MD], 1.09 kg/ Im? [95% confidence interval {CI}, —0.44 to
2.62]; P=.16; 1? = 16%), waist circumference-to-) -height ratio (MD, 0.13 [95% CI, —0.05 to 0.30]; 16;
P = 94%), dual-energy X-ray absorptiometry (DXA) total fat mass (MD, 0.68 kg [95% Cl, —2.39 to
3.79]; P =.66; I? = 70%), DXA total fat percent (MD, 0.04% [95% CI, —3.44 to 3.51]; P =.98; I? = 56%),
DXA total fat-free mass (MD, 0.81 kg [95% Cl, —0.96 to 2.58]; P =.37; 1? = 55%), magnetic resonance

the ages of Y and 11 years, the occurrence ot obesity, diabetes, or challenges in motor and social
development were comparable between the 2 groups. After 9 years of childbirth, BMI and the risk of
developing diabetes were similar between the 2 groups of women.
Conclusion: Metformin use in pregnancy did not show any adverse effects compared with insulin on
long-term outcomes in children and their mothers.

57. 1:19(12): 143, Published online 2019 Nov 21. doi: 10,1007/511892-019-1267-6

PMCID: PMG7008468 | NIHMSID: NIHMS1552660 | PMID: 31754898

Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes

ca E. Biar 1d Jami L. Josefson'2

HAPOFUS: Summary of GDM associations with childhood
anthropometric outcomes under full model adjustment including
maternal BMI during pregnancy.

Overweight/obesity 1.21 (1.00-1.46); p=0.052|

Obesity o———_158 (1.24-2.01); p<0.001

BOD POD % body fat eye: 1.35 (1.08-1.68); p=0.007
> 85% percentile

Waist circumference iliac 1.34 (1.08-1.67); p=0.009
> 85% percentile

Sum of skinfolds

1.57 (1.27-1.95); p<0.001
> 85% percentile t ho

10 15 2.0
OR (95% Cl)

58. Meta-Analysis > Diabetes Care. 2022 Mar 1;45(3):614-623. doi: 10.2337/dc21-1701.

Maternal Glycemic Dysregulation During Pregnancy
and Neonatal Blood DNA Methylation: Meta-analyses
of Epigenome-Wide Association Studies

Transgenerational
epigenetic inheritance

Terz

T2DM

Macrosomia
Obesity
Hypoglycemia —
_Hypérinsulinemia || Metabolic syndrome |

com | Pregnancy complications
Obesity Large for gestational age

59. Standard GDM vs “we GDM

Tay GDM
Before 20 weeks

Possibly in 15 trimester
m ee ?OGTT

€

60. If Glycemic Status Intermediate ???

ha há

61. American
Diabetes
Association.

Screen for early abnormal glucose
metabolism with dysglycemia

using FPG of 110-125 mg/dL (6.1-
6.9 mmol/L) or A1C 5.9-6.4% (41-

47 mmol/mol). (B)

62. 2.26e Screen for early abnormal glucose metabolism using fasting glucose
of 110-125 mg/dL (6.1 mmol/L) or A1C 5.9-6.4% (41-47 mmol/mol). B

Early abnormal glucose metabolism,

63. 4 medical Med. Sci. 2021, 9(4), 59;
sciences MDPI

Review
Early Gestational Diabetes Mellitus: Diagnostic Strategies
and Clinical Implications

Sp a = Kapoor 50,
Bha

64. 12. Summary and Recommendations
12.1. Fasting Plasma Glucose

Intermediate elevations in FPG in early pregnancy correlate with an increased risk
for cGDM and adverse feto-maternal events. There is inadequate evidence, however, to
suggesta specific cut-off value for early pregnancy FPG that could predict future GDM.
FPG > 92 mg/dL (5.1 mmol/L) in early pregnancy is associated with worsened perinatal
outcome, including a higher chance of LGA infants and macrosomia, even in the absence
of the later development of cGDM. Pre-pregnancy BMI in the overweight range or above,
in conjunction with FPG > 92 mg/dL (5.1 mmol/L), may represent pregnancies at higher
risk of complications and should be considered for close monitoring.

Considering the limitations of the currently available literature, and the possible

association between fasting hyperglycemia and worsened perinatal outcome, the earlier
proposed criteria of FPG > 92 mg/dL (5.1 mmol/L) can be reconsidered as a plausible
threshold for the diagnosis of GDM. The same cut-off will help to maintain consistency
and uniformity but needs to be validated in large multicenter studies.

12.2. OGTT and HbAlc

A deranged one-step (with IADPSG cut-off) or two-step (Carpenter- Corn criteria)
OGTT in early pregnancy does not predict CGDM consistently and does not haya
data to support its usage as a screening test for eGDM. Early pregnanc
is associated with an increased risk of CGDM and might correlate with
outcomes. However, there is insufficient data to recommend it as a screening test for eGDM.

Bhattacharya et al.
Med. Sci. 2021, 9(4),
59;

65. Meta-Analysis > Diabetes Metab Syndr. 2024 Jun;18(6):103051
doi: 10.1016/j.dsx.2024.103051. Epub 2024 Jun 1.

First-trimester fasting plasma glucose as a predictor
of subsequent gestational diabetes mellitus and
adverse fetomaternal outcomes: A systematic review
and meta-analysis

Saptarshi Bhattacharya *, Lakshmi Nagendra ?, Deep Dutta 3, Sunetra Mondal 4
Sowrabha Bhat 5, John Michael Raj €, Hiya Boro 7, ABM Kamrul-Hasan ®, Sanjay Kalra 9

0.006], gestational hypertension [RR1.47 (95%C1:1.20-1.79); P = 0.0001], large-for-gestational-age
(LGA) [RR 1.32 (95%C1:1.13-1.54); P = 0.0004], and macrosomia [RR1.29 (95%CI:1.15-1.44); P <
0.001]. However, at the above threshold, the rates of preterm delivery, lower-segment cesarean
section (LSCS), small-for gestational age (SGA), and neonatal hypoglycemia were not significantly
higher. First-trimester FPG 25.6 mmol/L (100 mg/dL) correlated with occurrence of macrosomia
[RR1.47 (95 % Cl:1.22-1.79); P < 0.0001], LGA [RR 1.43 (95%C1:1.24-1.65); P < 0.00001], and
preterm delivery [RR1.51 (95%CI:1.15-1.98); P = 0.003], but not SGA and LSCS.

Limitations: Only one study reported outcomes at first-trimester FPG of 6.1 mmol/L (110 mg/dL),
and hence was not analyzed.

Conclusion: The risk of development of GDM at 24-28 weeks increased linearly with higher first-
trimester FPG. First trimester FPG cut-offs of 5.1 mmol/L (92 mg/dL) and 5.6 mmol/L (100 mg/dL)
predicted several adverse pregnancy outcomes.

66. Preeclampsia

Gestational hypertension

A on ns mate m re armen
ES du NUS NO E aa anh ake RA

a Macrosomia

depen as pci an oo a a a
June 2022100) 39 350 il 1977 28% 1881102001 Mane 2019| 26 ms #4 61% 140 (089,221)
nt cas X= 2222 8 she
una sue ms moon mann ery ee
E A LOS AN meas, meets mata SS

eee SE a ee IA A
ed me m Eulen: SE

na GA

° Neonatal hypoglycemia"==="

—|

De mm mn. ne TA
Kun 55 ae oar ier DR Sane tie aan Fo Da a sia
Whore” ans tn ess Gm SR 2, 7 Fee 22e
ra a7 ne ax aan pertes a

PER RR ent Be Ta 04h di atom

Figure-2. Forest plot highlighting the impact of fasting plasma glucose >5.1 mmol/L. in the first trimester as compared to controls on the occurrence of (a) pre-
eclampsia, (b) gestational hypertension, (c) large for gestational age, (4) macrosomia, (e) preterm delivery, () lower-segment Caesarean section, (g) small for
gestational age, and (h) neonatal hypoglycemia. FPG - fasting plasma glucose (value in mmol/L).

67. FPG Cut-offs

FPG 2 92 mg/dL was linked FPG > 100 mg/dL predicted
to

* GDM at 24-28 weeks * Macrosomia

* Gestational hypertension *LGA

+ Preeclampsia * Preterm delivery

« Large-for-gestational-age
+ Macrosomia

First-trimester fasting plasma glucose as a predictor of subsequent gestational diabetes mellitus

Only one study assessed and adverse fetomaternal outcomes: A systematic review and meta-analy:
FPG cut off 110 mg/dL

68. FPG Summary

FPG > 92 and
100 mg/dL
predict
adverse
pregnancy
outcome

69. Hyperglycaemia
in early
pregnancy: ane
Treatment of
Booking Gestatio
nal diabetes

Treatment of Gestational Diabetes Mellitus Diagnosed
Early in Pregnancy

rational diabetes

of ges |
; er adverse neonata
5 observed for

Cc
body mass:

70. A Composite Neonatal Outcome

Subgroup

Overall

Glycemic range
Higher glycemic range
Lower glycemic range

Timing of early oral glucose tolerance test
<14 wk

4 wk

No. of Patients Difference in Percent (95% Cl)

793 re! -5.6 (-10.1 to-1.2)
429 m! -78 (-14.610-03)
319 4 2.5 (-104 to 5.5)
171 HA -8.9 (-15.1 to -2.6)
577 HA -5.0 (-11.6 to 1.6)
AA
180 -90 00 90 180

Intervention Better Control Better

B Pregnancy Hypertension

Subgroup
Overall
Glycemic range
Higher glycemic range
Lower glycemic range
Timing of early oral glucose tolerance test
<14 wk
=14 wk

No. of Patients Difference in Percent (95% Cl)

793 He 07 (-1.6 to 2.9)
430 eo -0.5 (-5.0 to 4.0)
320 Kae 2.2 (-2.7 to 7.2)
im H— > -6.9 (-17.6t0 3.7)
573 *S 26.011052)
nn
180 -90 00 90 180

Intervention Better Control Better

High FPG
> 110-125 mg/dL

Higher glycemic range
FPG - 95 - 109 mg/dL
1-hour > 191 m/dL
2-hour - 162 - 199 mg/dL

Lower glycemic range
FPG - 92 - 94 mg/dL

1-hour 180-190 mg/dL
2-hour — 153 -162 mg/

71. Key Lessons: TOBOGM

« Early intervention resulted in 1.2 -10.1 percentage-point reduction (95%CI)
in the risk of an adverse neonatal outcome event

+ The major contributor to the between-group difference with respect to the
first primary outcome was neonatal respiratory distress.

« Exploratory subgroup analyses suggested benefit of early treatment among
women with OGTT results in the higher, but not the lower, glycemic range

72. Meta-analysis of intervention trials in early
GDM: under publication

GDM treatment eGDM no treatment Odds ratio Odds ratio
Study or Subgroup Events Total Events Total Weight IV, Random, 95% CI IV, Random, 95% CI

Hughes 2018 23 21 19% 017(0.01,3.67) ¿|
Simmons 2023 376 365 981% 0.53 [0.35 , 0.82] |

Neonatal
Total (95% Cl) 399 386 100.0% 0.52 0.34, 0.80] > .
Total events: 37 64 Respi ratory
Heterogeneity: Tau? = 0.00; Ch = 0.54, df= 1 (P = 0.46); F = 0% ot 02 o's 1 à + + E
Test for overall effect: Z = 2.96 (P = 0.003) Favours eatly treatment of GM Favours no treatment of eGOM i DESMA
Test for subgroup differences: Not applicable

eGDM treatment — eGDM no treatment ‘Odds ratio Odds ratio
Study or Subgroup Events Total Events Total Weight IV, Random, 95% CI IV, Random, 95% CI

Osmundson 2015 2 x 37 64% — 0.37007, 2.02)
Roeder 2019 1 8 75 36% 0.30(003,291)
Simmons 2023 2 37 369 72% 032(006, 1.61]
Tehrani 2023 71198 2099 58.0% 064(037, 1.13]
Vinter 2018 15 36 54 240% 1041043,251]

pe {ml} t |

Macrosomia

Total (95% Cl) 1730 2634 100.0% 0,640.42, 0.99}
Total events: 36 1

Heterogeneity: Tau? = 0.00; Ch = 2.72, f = 4 (P= 0.61); = 0% ob ott do ido

Test for overall efect: = 200 (P = 0.05) Favours early treatment of ©GOM "Favours no treatment of eGOM
Test for subgroup differences: Not applicable

73. Take Home Message

Pre-conceptional optimization for diagnosed DM — utmost importance
Insulin — basal bolus regimen — approved treatment

Screen for pre-existing DM in early pregnancy

A single consistent approach for diagnosing GDM in 24 to 28 weeks (One
step vs 2 step)

Once diagnosed prescribe nutrition therapy, exercise and SMBG

Start insulin if SMBG values above target range

For metformin counsel that long-term safety data is limited

Early GDM - approach not defined may be beneficial at higher glucose
values if treated early

74. Indraprastha Apollo Hospital, Delhi

75. Thank you