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Gestational diabetes

Pr Jardena Puder

The phases of pregnancy

3 trimesters, between 38 et 40 weeks Phase I: anabolic = maternal phase

Up to the 20 wks gestational age Slow fetal growth Lipogenesis ↑, Increase of the maternal reserves

Phase II: catabolic = fetal phase After 20 wks gestational age Transfert of the stores to the fetus Maximal glucose transport to the fetus (most

abundant nutrient to cross placenta), release of fatty acids to the fetus (3rd T)

90% of the fetal growth

Herrera, Eu J Clin Nutr 2000

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Definition. Gestational diabetes

ADA 2018-21: GDM is a diabetes who is diagnosedfor the first time in the 2nd or third trimester whois not clearly a pre-existing diabetes.

Screening at the beginning of the pregnancy forhigh-risk women, also to exclude a pre-existingdiabetes

Prevalence in Switzerland: 10.9%

Rüetschi J, BJOG. 2016ADA, DC 2018-21

Pregnancy: «Physiological metabolic changes»

Insulin resistance IR/postprandial glucose: ↑ from the 2nd trimester

Augmentation of the hepatic and peripheral IR

Fasting glycemia: ↓ 1st trimester, after = or ↓, (evtl ↑ compared to 1st trimester)

Insulin-independent glucose uptake by fetus

HbA1c (2-3 months): 1st and 2nd trimester ↓ (↑ turnover of the red blood cells), 3rd trimester =

ADA, DC 21Murphy H, Diabetologia 12

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Insulin needs during pregnancy

Increase in insulin sensitivity

Gestational diabetes screening (HAPO)

First trimestervisit

Screening (high risk)

24-28 GAUniversal screening

Fasting glucose, (HbA1c)

75 g oGTT

Diabetes (« GDM ») normal (« Diabetes ») GDM normal

Before 24 weeks of GA, the diagnosis of GDM is not clear. HAPO up to 32 weeks GA

The thresholds for diabetes diagnosis, especially in the 1st trimester, are the same as outside of pregnancy

GDM: ≥5.1/10/8.5 mmol/l IADPS Consensus, DC 10ADA, DC 2021

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Fasting

1h

2h

HAPO: link between glycemia and risk

Legardeur H, Gynéc Obstet & Ferti 11Metzger, HAPO, NEJM 08

∆ 0.3 mmol/l per fasting category, 50% of women in cat 1 & 2. Cat 1: < 4.2; Cat 7: > 5.5 mmol/l

cat. 1: FG < 4.2 mmol/l

cat. 2: FG : 4.2 - 4.4 mmol/l

cat. 3: FG: 4.5 - 4.7 mmol/l

cat. 4: FGJ : 4.8 - 4.9 mmol/l

cat. 5: FG : 5.0 - 5.2 mmol/l

cat. 6: FG : 5.3 - 5.5 mmol/l

cat. 7: FG : > 5.5 mmol/l

Fasting

1h

2h

HAPO: Predictive glucose threshold in GDM

Legardeur H, Gynéc Obstet & Ferti 11Metzger, HAPO, NEJM 08Coustan D, American Journal of Obstetrics & Gynecology 10Cosson E Journal Gynécol Obstet Reprod 10

∆ 0.3 mmol/l per fasting category, 50% of women in cat 1 & 2. Cat 1: < 4.2; Cat 7: > 5.5 mmol/l

cat. 1: FG < 4.2 mmol/l

cat. 2: FG : 4.2 - 4.4 mmol/l

cat. 3: FG: 4.5 - 4.7 mmol/l

cat. 4: FGJ : 4.8 - 4.9 mmol/l

cat. 5: FG : 5.0 - 5.2 mmol/l

cat. 6: FG : 5.3 - 5.5 mmol/l

cat. 7: FG : > 5.5 mmol/l

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Other options for GDM diagnosis ?

• HbA1c ? – Problem for sensitivity & specificity

• Fructosamine?– Not useful

• Fasting glucose for triage ?– Possible, also sensibility problem except in high-risk

population

Study in Geneva and Basel: 22% of women not diagnosedwhen using the threshold of 4.4. mmol/l in a generalpopulation (but also « lower-risk »)

Agarwal M, DC 10Agarwal M, Gynec & Obstet Invest 11Rüetschi J, BJOG. 2016

Early….? FIGO: International Federation of Gynecology and Obstetrics

EARLY

EARLY

EARLY

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Early screening

Other countries

CHUV

Suspicion of early GDM Ou Glucose intolerance=prediabetes

See also abstract Cosson, EASD 2020FPG 5.5 mmol/l or Benhalima DPSG: 5.1-5.5 earlymore NICU, even if nl oGTT after

Screening 5 University HospitalsUniversitätsspital Basel Bern Genf Lausanne Zürich

Screening im I. Trimenon

auf präexistentenDiabetes mellitus (risikobasiert)

auf Gestationsdiabetes(bzw. Prediabetes)

ja

Nüchtern-BZ >7.0 mmol/Lund/oderzufälligem/2Stunden-BZ >11.1 mmol/L(zu bestätigendurch HbA1c >6.5%)

ja

1 Stunden-BZ >10.0 mmol/Lund 2 Stunden-BZ > 8.5mmol/L

ja

HbA1c > 6.5%

nein

ja

Nüchtern-BZ >7.0 mmol/Lund/oderzufälligem/2Stunden-BZ >11.1 mmol/L

nein

ja

Nüchtern-BZ >7.0 mmol/Lund/oderzufälligem/2Stunden-BZ >11.1 mmol/Loder HbA1c >6.5%

ja

HbA1c > 5.7%oder Nüchtern-BZ > 5.6mmol/L

ja

Nüchtern-BZ >7.0 mmol/Lund/oderzufälligem/2Stunden-BZ >11.1 mmol/Loder HbA1c >6.5%

ja

Nüchtern-BZ >5.1 mmol/L

Screening beiMakrosomie und/oderPolyhydramnion

ja

oGTT 75g

Ja

oGTT 75g

ja

2 Stunden- oder zufälliger BZ (random) > 11.1 mmol/L

ja

oGTT 75g < 32. SSW und/oder 4 P-BZ-Messungen über 1 Woche >32. SSW

ja

eine Woche 6 P-BZ-Messungen oder oGTT 75g

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«Classical GDM RF»

• Overweight (BMI >25 kg/m2 or >23 kg/m2 in Asian women) with at least 1 other RF or obesity (BMI > 30 kg/m2)

• History of GDM or prediabetes

• 1st degree family history

• Non-caucasian ethnicity

• PCOS, CV disease or RF

• Physical inactivity

Other «non-classical» RF have been observed in pregnancy such as:

• Excessive gestational weight gain

• Excessif intake of lipids, saccharose or animal protein or an insufficientfiber intake

• Age….

• Hypothyroidism with pos antithyroid antibodies + (3x)

• And newer: Life event, psychological stress, depressionADA, DC 2020& other studiesJia M, 2019

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«Classical GDM RF»

• Overweight (BMI >25 kg/m2 or >23 kg/m2 in Asian women) with at least 1 other RF or obesity (BMI > 30 kg/m2)

• History of GDM or prediabetes

• 1st degree family history

• Non-caucasian ethnicity

• PCOS, CV disease or RF

• Physical inactivity

• Other «non-classical» RF have been observed in pregnancy such as:

• Excessive gestational weight gain

• Excessif intake of lipids, saccharose or animal protein or an insufficientfiber intake

• Age….

• Hypothyroidism with pos antithyroid antibodies + (3x)

• And newer: Life event, psychological stress, depressionADA, DC 2021& other studiesJia M, 2019

2 types of GDM ?

AutoimmuneGDM

Non-autoimmuneGDM

The presence and quantity of anti-islets antibodies is associatedwith an increased risk of DM1 in high-risk populations/regions

such as Finnland and Sardinia

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All GDM? Antibodies in women with GDM

9.9% pos for 1 antibody during pregnancyOther studies: 6% (or even 44%..., AC anti-islets)

Antibodies % of women withGDM who are +

Zn T8 4.8%

GAD 2.3%

IA-2 2%

Insuline 1.3%

Rudland, Diabetic Medicine 15Cossu E, JEI 18Amer H, 18

Antibodies in women with GDM with pp testing

Rudland, Diabetic Medicine 15

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Association depression scores (EPDS) and laterdiagnosis of GDM

Hinkle, Diabetologia 2016

Hyperglycemia Fetalhyperglycemia

Chronic hypoxia

Cardiomyopathy

Beta cellhyperplasia

Hyperinsulinemia

Fetal EPO

Macrosomia

Surfactant

HKR

Asphyxia

Pulmonaryhypertension

Cesareansections

Hyperbilirubinemia

Thromboemboliccomplications

TransientTachypnoa

Neonate

Birth trauma

Prematurity

Neonatalhypoglycemia

RDS

Fetal magnesium

Glucosuria

Short-term risks of GDM

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Long-term risks of GDM : Offspring

• GDM and pediatric obesity– Present at birth

– Present (obesity and central obesity) at 6-14 years and at adolescence (including IR, independent of maternaland offspring BMI)

• Type 2 Diabetes (10-22 years): (breastfeeding: protective effect)– OR 6 for maternal DM during pregnancy (>90% GDM)

– OR 3 for maternal obesity during pregnancy (mediatedby offspring BMI)

HAPO, unpublished. DIP 2019Crume TL-EPOCH, 6-13 ans, Diabetologia 11, Mayer-Davis E, DC 07Pettitt D- HAPO, 2 ans, Diabetes Care 10, Silverman BL, 7-8 ans, Diabetes 91Dabelea D, DC 08, Pettitt DJ, 5-24 ans- Pima, Diabetes 91, Grunnet L, DC 2017

Dabelea, Diabetes 2000

Intrauterine exposure to GDM

Exposed sibling:Risk for DM: O.R. 3.7 (p=0.02)Higher mean BMI: 2.6 (p=0.03)

Mean BMI of exposed and non-exposed sibilings to a diabetic intrauterine environment (> 90% GDM)

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Long-term risks of GDM:Mother

GDM recurrence:

30-70% of pregnancies

Depending on the ethnicity and changes of BMI between pregnancies

Diabetes :

Up to 7-10 x increased risk compared to women without GDM

Metabolic syndrome:

2x increased risk

Cardiovascular disease:

2x increased risk (even if no diabetes)

Bellamy L, Lancet 09Reece EA, J Maternal Fetal Med 10Vohr BR, J Maternal Fetal Med 08Carr DB, Diabetes Care 06Kramer C, Diabetologia 19

Ehrlich SF, Obstet Gynecol 11Kim C, Diabetes Care 07Retnakaran R, CMAJ 09Shah BR, DC 08

Risk of a CV event

2.3 x in the 10 yearsafter diagnosis

Also increased in patients whodo not develop diabetes

Kramer C, Diabetologia 19

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Glycemic control At what moment? What cut-offs?

Glycemic control What are the cut-offs?

Guideline Fasting/ Preprandial

Post Prandial 1h Post prandial 2h

NICE (UK)1 ≤5.3 mmol/l ≤ 7.8 mmol/l ≤6.4 mmol/l

ADA2 ≤5.3 mmol/l ≤7.8 mmol/l ≤ 6.7 mmol/l

Endocrine Society3

≤ 5.3 mmol/l (≤ 5.0 mmol/l)

≤7.8 mmol/l ≤ 6.7 mmol/l

SGED4 ≤ 5.3 mmol/l ≤ 8.0 mmol/l ≤ 7.0 mmol/l

1 - Clinical Guideline - 2018

2 – Standards of medical care in diabetes 2019, Diabetes Care 2020

3 - Guideline on Diabetes and Pregnancy J Clin Endocrinol Metab, 2013;98:4227–4249

4 - Neue Erkenntnisse zur Diagnostik und Management des Gestations diabetes.Therapeutische Umschau 2009; DOI 10.1024/0040-5930.66.10.695 –

Crowther C, NEJM 2005; Landon M, NJEM 2009

Discussion about lower cut-offs, especially in the obese population

Similar since 4th international workshop 1997. Russians are lower…(5.1)Used in large RCT’s such as ACHOIS (Crowther) - but FPG 5.5, and Landon et al – FPG 5.3

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Utility of lower glycemic targets?Especially if complication such a LGA, Polyhydramnion?

Little data: A retrospective Study

FG < 5.3

2h pp < 6.7 mmol/l

FG < 4.7 mmol/l

2h pp < 6.1 mmol/lHagen G, 2019

Or adapted/higher targets ?Special situations (IUGR) or if US normal ?

Standard: FPG 5, 2h 6.7: 30% Insulin

US: abdominal circumference > p75 (Hadlock, not consistenly reproduced in

other groups) or if FPG > 6.7 or any > 11. But titrated to <4.4 & 2h 6.1. 40% InsulinUS all 4 weeks with complete biometry (3 AC measures)

Schaefer-Graf, DC 04

Start study: 29 GA

Start insulin up to 36 GA

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Or adapted/higher targets ?Special situations (IUGR) or if US normal ?

Schaefer-Graf, DC 04

Additional discussion:- Decreasing thresholds last 2 weeks ?

- FPG/Glycemia & Stillbirth

And what about a sensor for the peaks?

Glucosensor x 3 days: 1x; then every 2-4 weeks AND7x/d capillary measures

7x/d capillary measures

Visit each week. Looking at capillary values, sensor curves, nutrition etc.

«Strict» study done in China. 2 groups:

Less glycemic variability on «blind» sensor Less peaks hypo et hyper Less pré-éclampsia, less first-time C-section Less prematurity Babies 200 g less heavy and less macrosomia (> 4kg) Less neonatal hypoglycemia and less respiratory problems

Yu F, JCEM 2014

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Insufficient evidence… more research is required…

2016

2019

AND…. IT IS NOT ALL SUGAR …. !

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Maternal predictors of adverse outcomes

Antoniou M and Puder, 2019 Multiple regression analyses

Multifactorial, also placental insufficiency

Other risk factors for macrosomia/neonataladiposity

Maternal BMI fasting glycemia TriglyceridesGestational weight gain

cord blood leptin & cord bloodtriglycerides Benhalima K, 2019

Huvinen, 2020 DPSG

Independent predictors

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Physical activity

Impact of prenatal exercise on neonatal and childhood outcomes

Meta-AnalysisDavenport, Br J Sports Med 18Pastorino, BJOG 18

Impact on macrosomia (RCT)

Protective effects also in late, but not early pregnancyLarger effects with higher intensity

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Physical activity and glycemia I

Davenport, App Physiol Nutr Metab 2008Am J Obstet Gynecol 2010

Walking in whiteControls in black

Reductions in insulin needs also observed in resistance/strenghtactivity

Aerobic physical activity (walking): reduction in insulin needs

Physical activity and glycemia II

Bgeginski R, Journal of Diabetes 17

PA and fasting glycemia (0-0.4 mmol/l)

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Nutrition

Recommendations

Medical nutrition therapy for GDM :

• Individualized nutrition plan developed between the woman and the dietician

• Adequate calories intake to promote fetal/neonatal and maternal health, achieve glycemic goals, and promote optimal gestational weight gain

• The food plan should be based with guidance of a min. of 175 g of carbohydrate, a min. of 71 g of protein, 28 g of fiber and not high in saturated fat

Nutrition therapy for women with GDM:

• To help achieve and maintain desired glycemic control while providing essential nutrient requirements

• Optimal weight gain• 35-45% carbohydrates• 3 small- to moderate-sized meals and 2

to 4 snacks

For obese women• Caloric restriction by approximately

one-third, min. intake of 1600-1800 kcal/d

2020 2013

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Low-Carbohydrate Diet

Example: No difference in insulin needs (both around 55%) between “low CHO (40%)” vs “normal CHO diet (55%)”. No differences in obstetric or fetal outcomes

Meta-analysis: Total restriction and low carbohydrate diets did not change either maternal or newborn outcomesAttention: Compensation with (low quality) fat intake and increase of insulin resistance !

Moreno-Castilla C, Diabetes Care 2013Viana, Diabetes Care 2014Wei J, Medicine 2016Hernandez T, Diabetes Research and Clinical Practice 2018

Nutrition: Low glycemic index (GI)

2-h pp values : 0.1-0.8 mmol/l lower

Low GI: 31 9 (29%) required insulin. High GI: 32 19 (59%) required insulin. No differences in obstetric or fetal outcomesOther studies with reduced birth weight

But:

Difficult and complicated to put in place (especially long-term) Moses R, Diabetes Care 2009

Xu J, JMFNM 2018Viana, Diabetes Care 2014Wei J, Medicine 2016

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Nutrition: Summary

Low glycemic index nutrition, sometimes in combination with high-fiber intake

Favorable for: Insulin needs ( by ¼) Birth weight (mean diff : -162 g).

Macrosomia (RR for combination 0.17 !)

Cochrane 2017: It remains unclear what type of advice is best. Need for more evidence about type of nutritional advice. Louie JCY, Journal of nutrition and metabolism 2011

Viana, Diabetes Care 2014Wei J, Medicine 2016Han S, The Cochrane database of systematic reviews 2017

Sweetener and body composition

44

Maternal consumption of edulcorants and sweet beverages and offspring body composition at 1 year

Azad M, JAMA Pediatr. 2016

Size: 1 can (12 oz=350 ml)

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Which medical therapeutic options?

Metformine….

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Take home…., upfront

The good: Advantages gestationalhypertension, weight gain, neonatal hypo, NICU, LGA

The bad: treatment failures, limitation, malformations?/pregnancy losses? (confounders)

The ugly: long term: body composition children, «intelligence».

Verunreinigungen

Effects of metformin vs insuline in pregnancy

gestationalhypertension

weight gain neonatal hypoglycemia Neonat Hospitalisation LGA No changes premat, SGA,

perinatal mortality, cesarian section

gestationalhypertension

weight gain severe neonatal

hypoglycemia HbA1c end of pregnancy

Butalia: GDM and DM2 Feng: GDM

Diabetic Medicine 2017 J Matern Fetal Neonatal Med. 2017

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Metformine Insuline

BMI < 35 Kg/m2 > 35 Kg/m2

Fasting glycemia <5.6 mmol/l >6.1 mmol/l

GA at diagnosis Advanced Early

Medical history No GDM GDM

Hypoglycemia risk Absent Present

Patient wish Fear of injections

Metformin: treatment failures

• Treatment failures: 33.8% (between 18% and 46% depending on the studies)

Treatment choice to reduce failures

Adapté de: Review of metformin and glyburide in the management of gestational diabetes. Pharm Prac 2014;12:528

Combination with insuline possible (↓insuline doses)

Long-term metformin offspring

9 years after (largest) RCT in GDM:

Metformin offspring : larger, weight, arm and waist circumferences, BMI, triceps skinfold; DXA fat mass and lean mass (p=0.07); MRI abdominal fat volume (p=0.051). No difference between groups: Body fat percent (DXA and BIA) abdominal fat % (visceral adipose tissue, sc adipose tissue and liver; all MRI) Fasting glucose, triglyceride, insulin, insulin resistance, HbA1c, cholesterol, liver transaminases, leptin and adiponectin

Rowan J, 2018van Weelden W; 2018

Meta: 10 RCT studies, 778 kids of GDM/PCOS: Metformin offspring: heavier compared to controls (SMD 0.26), but not taller. No difference between groups: BMI z-scores Individual small studies : greater mid-upper arm, waist circumferences,

biceps skinfolds, more arm fat Higher fasting glucose, ferritin and lower LDL cholesterol

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Metformin: Metaanalysis: Children

Tarry-Adkins JL, PLOS Medicine 2019

Reduction in birth weight, macrosomia (OR 0.59) and LGA (OR 0.78) without difference in SGA.Same abdominal circumference, reduction in neonatal head and chest circumference.

Higher abdominal & visceral fat volume (MRI)No differences in DXA indices or skinfolds (Aidelaide & Auckland)

Das Swissmedic Labor (OMCL) hat – wie die nationale Zulassungsbehörde HSA in

Singapur – bei eigenen Untersuchungen in einzelnen Metformin-Präparaten

Verunreinigungen mit NDMA festgestellt, die über der international tolerierten

Unbedenklichkeitsgrenze für Arzneimittel liegen.

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Insulin analogues

Insulin and pregnancy

« Rapid » insulin analoguesMetaboliccontrol

Malformations Outcome Complications

Lispro(Humalog)

Comp: PrudenceRetro &prosp studies, no RCT

HbA1c =or ↓

Hypos=or ↓Insulin needs=or ↓Flexibility ↑

= Maternal ou neonatal =Ev anthro-pometric effect

Retinopathie↑? no!

Aspart RCT(Novorapid)

Comp: Can beused2 RCT

(Fiasp) ultra-fast acting

pp= or ↓HbA1c =

Hypo =

Flexibility ↑

= Maternel ou neonatal =Satisfaction ↑

F: No specific data, but probably ok

=

F: Niacinamide & L-Arginine (inactifs ingredients)

GlulisineNo studies, contr.

- - - -

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Basal insulin analogues

Metaboliccontrol

Malformations Outcome Complications

Glargine(Lantus, Abasaglar)

ToujeoComp: Can beused

HbA1c =or ↓(only 1st trimester)

Hypos=or↓Insulin needs=

= (over 300 DM1)

Maternal or neonatal =2 retromacrosomie ↓ (c/w NPH & DET), hypo & hyperbili ↓

Does not cross placenta at therapeuticdoses. Ev proteffect retino & nephro

Detemir RCT(Levemir)

Comp: Can beused

Efficacitycomparable toNPH (DM1), evtlfasting glucose↓

= Maternal or neonatal = (but a lot

of fetal complic in a high-

risk cohort), weightgain =

=No progression retino & nephro

Lantus: Most studies retro/case-control. 1 prospective, but no controlled studies, no study Toujeo. Detemir: 1 large RCT (n=310 DM1), several non-controlled studies

Torlone E, Acta Diabet 09Shenoy V, DM 12Durnwald CP, Curr Diab Rep 11Mathiesen ER, Diab/Metab Res Rev 11Leperc J, Obstet & Gynecol Int 12Mathiesen ER, Diabetes Care 13Callesen N, J Mat-Feta Neonat Med 13

Tresiba (only case reports, ongoing RCT)….

What to do in the postpartum period?

ADA 2021: oGTT 75 g 4-12 wks pp, HbA1c not ideal

NICE 2015: HbA1c @3mo and/or fasting glucose (no routine oGTT) & timing not clearCH: 6-8 wks ppet puis tous les 1-3 ans (si nl) !

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Diabetes risk after GDM according to breastfeeding (1/3 reduction)

Feng L, Journal of Diabetes Investigation 18

Merci pour votre

attention !