Gestational diabetes

Dr. Garamvölgyi ZoltánI. Sz. Szülészeti és Nőgyógyászati Klinika,

Budapest

Definition

„At first during the pregnancy identified or developed the glucose-intolerance.”

(Diabetes Care Volume 30 Supplement 1, January 2007, p S42–S47)

Unnoted to the definition:

The method of the therapy (diet or insulin)

Existed IGT before or after the pregnancy

Prevalence•

Prevalence 6-8% (USA: 3-10%) 2000-3000 cases/year

Ethnics:

caucasian: 1,5-2 %

asian: 5-8 %

afroamerican: 5-8 %

hispan: 5-8 %

Higher prevalence :

Obesitas

Typ. 2. diabetes mellitus

Ogden CL et al. (2006) Prevalence of overweight and obesity in the United States, 1999-2004.

JAMA 295: 1549-1555

Mokdad AH et al. (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors,

2001. JAMA 289: 76-79

Rosenberg TJ et al. (2005) Maternal obesity and diabetes as risk factors for adverse pregnancy

outcomes: differences among 4 racial/ethnic groups. Am J Public Health 95: 1545-1551

diabetes and pregnancy:

90 % GDM

8 % Typ. 2. DM

2 % Typ. 1. DM

Pathomechanism. of GDM

Pregnancy has got „diabetogen” effect

Insulinresistance (developing and increasing) (Progesteron, Östrogen, hPL, GH, TSH, kortizol, prolactin)

glucosetolerance and insulinsensitivity

insulinsecretion

bodyweight (fatty tissue)

GDM: β-cell dysfunction

• Autoimmunity(<10 %)

• Β-cell apoptosis(oxidative stress?)

IR

• Insulin signal pathway

Cause:- PCOS/obesity- GLUT4

- PPAR-γ expression ↓- Membrán glikoprotein-1

overexpression

+

Pregnancy

I. trimester Lipogenesis

LPL-activity

TG-level

II-III. trimester Lipolysis

HSL activity

Insulin-effect

FFA

Visceral obesity

Pregnancy

CRH

Sympathetic nervous system activity

Catecholemines Β-adrenoreceptors

II-III. trimester

I. trimester: extended anabolism fat tissue insulin sensitivity

II. trimester: katabolism, insulin sensitivity (30-60%) IR, insulin level (2-3x)Aminoacids lipids (lipolysis, keton, FFA, TG, cholesterol level incr.) Fasting bl.gl. pprandial bl.glucose

HbA1C and frustosamin: lower level in normal pregnancies than in non pregnants(hemodilution)

GDM: early ins.answ.delayed pprandial hyperglycaemia

hepatic gl.production reduced fasting pl. gl.level incr.

Pregnancy

IR o Diabetogen hormones

o Citokines

o Insulin signal cascade damaged

Chr. Β-cell damage/dysfunction Relative abscence of the insulin

(hormonal effect) >

PregnancyPlacental hormones

Insulin sensitivity of the mother

Fetal Source of Energy

GDM:

Accelerated macrophage infiltration

o musculoskeletal tissue

o fatty tissue

Citokines

o lipidperoxidation of the placenta

o oxidised LDL

Cytotoxical damage of the trophoblast

VEGF,eNOS

Placental angiogenesis and vascularisation

Fetal

Glucose

o uptake

o conversation to FFA

Abortus

spontaneusMaternal Chr. Subclinical inflammation

Embryo/fetus?

Habitualis ab.: 40-80 % of PCOS!

LH: effect on to the implantation (non PCOS vs PCOS= 12-15% vs 30-50%)

Uterinal factor: perifollicular bloodcirculation worse

Folliculus gene expression (androgen effect)

IGF-1: Y IGF-1 rec. downregulation

(morula’s gl.uptake decreases before the implantation)

GLUT-4 (cc. decr.)

IGFBP-1(cc.decr.) implantation/adhesion get worse

PCOS: else metab./endocrin. disorders

CRH-ACTH-kortizol axis activated

Hyperreninaemia/hyperaldosteronismus

PRL 2-3X

PAI-1/fibrinogen incr.

Hyperuricaemia/homociszteinaemia

Ferritin cc. Incr. (storage of iron incr.)

NAD(P)H-oxidase aktiv.Szuperoxid freeradical incr.

obesity

Musculature: gl.uptake decr.

Liver: inz.metab.decr.IR

GI tr.:Iron uptake incr.

Pedersen- hypothesis

Maternal plasma glucose:

Facilitied transplacental transmission

Obesity

GDM risk 20%

Hyperglycaemia

Hyperlipidaemia

Peripherial ins.sensitivity

Postprandial TG-level

Fuel mediated teratogenesis

I.trimester

Birth weight

Obesity

Glucose uptake of the muscle

Glycogen synthesis

LPL-activity hyperlipidaemia

Fatty tissue accumulates

-the musculoskeletal

-the live

Macrophag-infiltration

Of the fatty tissue

Proinflammatoric citokines

Obesity

LDL oxidised

Fibrinogen

PAI-1 (endothelium/liver)

enhance its production:

o bacterial lipopolisacharid

o IL-1, IL-6

o TNF-α

o TG

o thrombin

o lipoprotein-A

Thr.-aggregation:

-macrophages

-monocytes

-thrombocytes

Maternal morbidity

Urogenital infection

Hypertension

(in GDM 10%,

preeclampsia [12% vs. 8%])

Maternal morbidity

Detect GDM Hypertension Insulintherapy

I. Trimester 18,46 % 33,85 %

24-28. weeks 5,88 % 7,06 %

Diabetes mellitus diagnosed during early pregnancyJose L. Bartha, AJOG

Volume 182, Issue 2, Pages 346-350 (February 2000)

Maternal morbidity

Preeclampsia Fasting bl.glucose< 5,9 mmol/l

7,8 %

Fasting bl.glucose> 5,9 mmol/l

13,8 %

Yogev Y, Xenakis EM, Langer O. The association between preeclampsia and the

severity of gestational diabetes: the impact of glycemic control. Am J Obstet

Gynecol. Nov 2004;191(5):1655-60.

Fetal morbidity

Miscarrieges (1-2 % vs. 4-8 %, cardiovascular, malformation of the neurological system (neurol tube defect), Caudal Regression Syndrom, HbA1C-level before the conception. HbA1C <6,5%-min. 3 month, HBA1C<8,5%:3,4%, >8,5%: 22,4%!!!)

IUGR (Growth restiction: Typ.1. diabetes, hypertonia)

Growth acceleration (90th percentile, fetal insulin, central deposition of subcut. fat, 15-40 %, excessive rate of neonatal morbidity, offsprings and IGT)

Antero-posterior radiographic view showing:

omissing ribs,

oabsent lumbosacral vertebrae,

ohypoplastic pelvis

o"frog-like" position of the lower extremities

Caudal regression syndrome

Sacral agenesia

Frequency: 1:60.000 diabetical females

Diabetes mellitus!

Non GDM

Macrosomy

Postprandial average

glucose value

Macrosomy (prevalence)

> 120 mg/dl (6,5 mmol/l) 20 %

> 160 mg/dl (8,9 mmol/l) 35 %

Birth weight> 4000g: 23 % (GDM) vs. 8 % (non diabetic) p < 0.001

Casey B, Lucas M, McIntire D et al. Pregnancy outcomes in women with gestational diabetes

compared with the general obstetric population. Obstet. Gynecol. 90, 869-873 (1997).

Abdominal circumference of the abdomen (AC) > 95 percentile:

macrosomy 90 %

In case of macrosomy increases AC und TG-levels after the 24th gest.week

(statistician significancy).

Shoulder distocia (0.3-0.5 % vs. 1-2 %)

Neonatal complications

Polycythemia

(Htc>65 %, 5-10 %, fetal erythropoietin Oxygen tension

ischemia, Infarction)

Hypoglycemia (Insulintherapy, Labour)

Hypocalcemia (< 7 mg/100 ml,

Hypoparathyreoidismus?)

Hyperbilirubinemia (prematurity, polycythaemia)

IRDS (Typ. 1. IDDM, prevalence decreased sice 1970.)

Screening and diagnosis

OGTT and different methods

Diagnostic

methods

Carpenter-

Coustan

(100g)

ADA

(100g)

WHO

(75g)

WHO

(75g)

IGT

Fasting

Plasma glucose

5,3 mmol/l 5,8 mmol/l 5,3 mmol/l 5,6-6,9

mmol/l

(IFG)

1 hour 10 mmol/l 10 mmol/l

2 hours 8,6 mmol/l 9,1 mmol/l 7,8 mmol/l 7,8 mmol/l

3 hours 7,8 mmol/l 8 mmol/l

Two steps pregnant pregnant One step

pregnant non pregnant

7,8 mmol/l (80%) vs. 7,2 mmol/l (90%) O’Sullivan és Mahan

(1964.)

Screening and diagnosis

Selective Screening (ADA)

82 % sensitivity

35% less screennig

procedure

At high risk patients

Universal Screening (WHO)

More diagnosis (35-47%)

Prompt diagnosis

Decreased morbidity

Increased sensitivity

Low risk

24-28. week

High risk

(I.Trimester)

OGTT

(ADA)

>7,8 mmol/l

OGTT

(ADA)

Low risk (no

Screening)

Middle risk

24-28. week

High risk

(I.Trimester)

OGTT

(WHO)

50g.GCT

O’Sullivan,

1973.

Screening and diagnosis

high risk patients:

Relatives suffered by diabetes mellitus

In the history

-IGT, GDM

-Eclampsia, premature labour, intrauterine death,

macrosomy, miscarrieges, malformations, hypertonia

BMI > 30 kg/m2

Age > 35 years

twins

Glucosuria

American Diabetes Association: Gestational diabetes mellitus

Diabetes Care 2004; 27 Suppl1.: S88-S90.

ADA, 1999. 2steps (selective) screening and diagnosis

50 g, 1 hour bl.sugar

≥7,8 mmol/l >11 mmol/l

GDM: No OGTT!3 hours GTT (100g)

National Diabetes Data Group (NDDG)

hour Bl.sugar (mmol/l)

0 5,8

1 10,6

2 9,2

3 8,1

≥2 values=GDM

3 hours OGTT

(100g)

IV.GDM Workshop

2 hours

OGTT (75g)

hour Bl.sugar (mmol/l) Bl.sugar (mmol/l)

0 5,3 5,3

1 10,0 10,0

2 8,6 8,6

3 7,8

Prospective, multicentrical study 2000-2006. 23316 females, 9 countries

Fasting bl.sug.+ 75 g OGTT, 24-32.weeks: 1hr, 2hrs + random pl.glucose

(34-37.weeks)

Til the postpartum 6th weeks followed up

Inhomogen ethnicitiy:

48% white, non hispan

12% black, non hispan

29% asian

8% hispan

3% others

Hyperglycemia and adverse pregnancy outcome (HAPO),

Pasadena, California

ADA: 75 gr. OGTT: 2 path.values = diagnosis

IADSG: 1 path.value = diagnosis

16,1 % GDM!!!

ADA, 2007: 57 million americans, 19% of the adult population has got prediabetes

1., pl. sugar level is a predictive value

2., multinational study

3., international consensus

4., I.trimester: fasting pl.sugar: <4,4 mmol/l (80 mg/dl) OGTT not recommended

5., universal screening (75 gr.OGTT)

HbA1C?

n= 21064 terhes

mean±SD: 4,79±0,4

Pregnancy outcome:

pl. sugar. vs.HbA1C:

pl. sugar has got sign. correlation (exepted: PE, prenatal labour)

IADSG

International Association of Diabetes and Pregnancy Study Groups (IADPSG)

2008. 75 g OGTT

Pl.glucose mmol/l

fasting 5,1

1 hr 10,0

2 hrs 8,5

fasting plasma bl.sugar ≥7 mmol/l

HbA1C ≥6.5%

Random plasma bl.sugar ≥11,1 mmol/l

GDM=≥1 value

Manifest diabetes

International Association of Diabetes and Pregnancy Study Groups (IADPSG)

2008.

At the time of the recognition of the

pregnancy at every pregnant womens

fasting pl.sugar

HbA1C

random pl.sugar

diabetes Fasting pl.sugar:

5,1-7,0 mmol/l

<5,1mmol/l

GDM

OGTT,75g:

24-28. weeks

Bl.sugar mmol/l

fasting 5,1

1 hr 10,0

2 hrs 8,5

GDM=≥1 value

Flow diagram of the screening and diagnosing of the GDM:

Clinical care of diabetic pregnancies

HbA1C (every 3 months) + fructosamin (oedema, proteins!, thyreoid

disorders)

Blood sugar levels from a capillary device 6-8 times/day

Ophthalmologic evaluation

Kidney –and liverfunction

24-h urine collection for protein and creatinin

NST

Ultrasonogram (AFI, Doppler-examination)

Fetal echocardiography (fasting plasma glucose >6,9 mmol/l, insulin dependent)

Attention at the preconceptional care:

preprand. vérc.: 3.5-5.5 mmol/lpostprand.vérc: 5-8 mmol/l + no acetonurie/glucosurie

NB: fasting bl.sugar >5.8 mmol/L: Danger of the IU death: til the 32th weeks(between the 32-36th weeks the most common)

Pregestational diabetes

Pregnancy is contraindicated:

proliferative retinopathy Advanced nephropathy severe ischaemic heartdisease HbA1C> 10%ketoacidosis during early pregnancy >40 yrs old + 2 childrenteenager girl + not planed pregnancy

Therapy

Goal: achieving euglycemia without glucosuria and

ketonuria

Metabolic control before and during pregnancy

Self-monitoring

Therapy

Dietary therapy

(total of 6 feedings, distribution, dietitian)

Insulin therapy

(increasing insulin resistance and fetal demand for

glucose, risk for hypoglycemia, timing)

Oral hypoglycemic agents

(risk of teratogenesis and hypoglycemia)

Self-monitoring :

(blood sugar measurement with capillary blood)

Fasting: 3,3-4,4 mmol/l Prepr: 3,3-5,5 mmol/l postp. 4-7 mmol/l (1ó)

3,5-6 mmol/l (2ó)

(Total weight gain < 8 kg/pregnancy)

mean. bl.sugar/day: 3,5-5 mmol/l

fructosamin: 170-220 umol/L HbA1C: 4,5-5,6 % (HbA1C <6%)

No glucosurie

Insulin therapy

When should begin?(nedded in 20-25 % of all cases)

Bloodsugar level ACOG

(American College of Obstetricians

and Gynecologists)

ADA

(American

Diabetes

Association)

WHO

(World Health

Organization)

Fasting >5,3 mmol/l > 5,9 mmol/l > 5,3 mmol/l

1. hour 7,2-7,8 mmol/l > 8,6 mmol/l

2. hours > 6,5 mmol/l > 7,2 mmol/l > 6,7 mmol/l

>7,0 mmol/l

Insulin demand

ITDM:

0-12. weeks: reduced (10%) 12-36. weeks: continually increasing(50%)>36. week: slow decreasing of the demand of the insulin.

IITDM:

Major rate the insulin resistance: III. trimester: 1,5-2 E/tskg

(90% need insulin therapy!)

7 mmol/l pp bl.sugar values:16-20 E Insulin (8-4-6 E)

>10 mmol/l pp. bl. sugar.:

(Fasting hyperglycaemia! Enhanced demand of insulin)

12-8-10 E + bedtime: 6-8 E basis (NPH-typ) insulin +

min 6 x meats/day

In case of major rate of insulin resistance:

5x or more times shortact (rapid) insulin:

6-12-17-22-3 hour(dose ratio: 5-3-4-2-1)

Time of the meats:

6:15-9:00-12:15-14:45-17:15-19:45-22:15

30-20-50-20-40-20-15 gr.

Before the mean meats: Actrapid H or Humulin R

Ultrarapid effect-insulin (Lispro, Aspart):

Need meats with great amount of the CH (not propriate in pregnancy)

Ultrarapid insulin analogs only in cases of insulin-pump (Not started at first during

pregnancy!)

Insulin therapy

Insulin therapy

Insulinanalogs and GDM

Changed structure of insulin:

Teratogenic effect?

High GF1 rec. affinity

Lispro + Aspart : not contraindicated

Glargin: cc.+malformatio 5-6x

Levemir: no datas+ „off label use”

Ultrarapid To hinder

Pp.bloodsugar

increasing

Humalog

Novorapid

Long effect Maternal

Hypoglycemia

Lantus (glargin)

Levemir

(detemir)

mixed Novomix 30

Humalog Mix 25

Insulin therapy:

Insulin analogs are differed to each other in structure of the aminoacids(better absorption, less risk of hypoglycaemia)

Human insulinLess immunogen activity, the insulin-antibodies do not cross the placenta

Before bedtime blood sugar measure obligated!Every 1-2 weeks diabetological controll.

HbA1C:In the I. trimester usableII. and III. trimester: routine-like usage not recommended(rather the pp. bl.sugar! (NICE))

Risk of the hypoglycaemia: vomiting make it severe (exp. between 10-15th weeks) I.TDM>II.TDM (NICE): <3,5 mmol/l.

Oral medicaments

name Medicament

-group

Effect Crossable to

placenta

I.

Trimester

Hypoglycemia +Insulin Lact.

Glyburide Szulfanilurea

II.Generation

Insulin

secretion

(Pancreas)

slightly (T1/2 ,

binding to

proteins)

no yes yes yes

Metformin Biguanoid Glucose

secretion

(Liver)

Glucose

uptake

(tissues)

highly yes

(PCOS!)

no yes

(30%)

no

Sulfanilurea, Glibenclamide (Glyburide)Enhanced insulin secretion. Risk of hypoglycaemia and weight gain!

Chlorpropamide and tolbutamide: no malformations, But neonatal icterus and hypoglycaemia. Minimum transmission through the placenta

Randomised controlled study(Langet et al, A comparison of glyburide and insulin in women with gestational diabetes mellitus. N. Engl. J. Med. 2000, 343: 1134-8.): NS: neonatal outcomes.

Metformin

Hepatic glucose production reducedEnhanced glucose uptake of the peripherial tissuesFFA cc. decreased, IR reduced.Entirely transmitted through the placentaMIG study: metformin vs insulin: after 20th weeks prefered the metformin (?)NICE ajánlás:NICE. Diabetes and pregnancy. Management of diabetes and its complications from pre-

conception to the postnatal period. London, 2008.

Management of the labour

GDM normal p

Induced labour 38,6 % 10,8 % <0,001

Cesarian section 34 % 20 % <0,001

Peled Y, Perri T, Cen R et al. Gestational diabetes mellitus - implications of

different treatment protocols. J. Pediatr. Endocrinol. Metab. 17(6), 847-852 (2004).

Intrapartum management of diabetic deliveries

Goal: maternal euglycemia during labour (4-7 mmol/l)

Insulin- glucose- potassium combinated infusion

Capillary glucose levels monitoring

Fetal heart rate monitoring

(intrauterine asphyxia)

Postpartum

Insulin?

Diet

Reclassification

contraception

Lactation

Postpartum

reclassification

170 g Diatery th.

6 weeks after the delivery

OGTT (WHO)

Normal OGTT Pathological OGTT

Repeat of OGTT after ½-1 year IFG IGT DM

World Health Organization (1999)

Definition, diagnosis and classification of diabetes mellitus and its complications.

Baranyi Éva

Late effect of the GDM

GDM + LGA Child

10-16 years:

overweight

Hypertension

Dyslipidemia

IGT (19,3 %)

Mother

IGT/DM (15 %)

recurrency of GDM (30-69 %)

Evans E, Patry R. Management of gestational diabetes mellitus and pharmacists'role in patient

education. Am. J. Health Syst. Pharm. 61, 1460-1465 (2004).

McKinney PA, Parslow R, Gurney KA, Law GR, Bodansky HJ, Williams R. Perinatal and neonatal

determinants of childhood type 1 diabetes. A case-control study in Yorkshire, U.K.

Diabetes Care. Jun 1999;22(6):928-32.