DIABETES DAN KEHAMILAN Lab FarmakologiFKUBMALANG

1. Preexisting DM and pregnancy

2. Gestational diabetes

Preexisting diabetes in pregnancyType 1 DM ( IDDM)Type 2 DM (NIDDM)

Preexisting DM in pregnancyEffect of pregnancy on pre-existing DMIncrease requirement for insulin dosesNephropathy , autonomic neuropathy may deteriorateProgress in diabetic retinopathy (2X)HypoglycemiaDiabetic ketoacidosis

Preexisting DM In PregnancyEffect of preexisting DM on pregnancyMaternal 1. increase risk of miscarriage 2. increase risk of preclampsia 3. increase risk of infection eg vaginal candidiasis, UTI, endometrial or wound infection

Preexisting DM in Pregnancy(2) Fetal 1. increase risk of congenital abnormalities sacral agenesis, congenital heart disease, neural tube defects Hba1c level Risk normal not increased 10% 25 %

Preexisting DM in Pregnancy2. Perinatal mortality (excluding congenital abnormality ) 2 fold increased3. Increase risk of sudden unexplained intrauterine fetal death.

Complications of pregnancy in pre-existing DMMaternal:Increase insulin requirmentHypoglycemiaInfectionKetoacidosisDeterioration in retinopathyIncreased proteinuria+edemaMiscarriagePolyhydramnioShoulder dystociaPreeclampsiaIncreased caesarean rate

Fetal: Congenital abnormalitiesIncreased neonatal and perinatal mortalityMacrosomiaLate stillbirthNeonatal hypoglycemiaPolycythemiajaundice

Maternal hyperglycemia|Fetal hyperglycemia|Fetal pancreatic beta-cell hyperplasia|Fetal hyperinsulinaemia|Macrosomia,organomegaly, polycythaemia, hypoglycemia, RDS

Management Aim

Achieve maternal near normoglycemic level to prevent adverse perinatal outcomes

DietLow-carbohydrate diet , high fibre with caloric restrictionFrequent small snacks may be needed between mealsAvoid starvation

Insulin3 pre-meal short acting insulin (actrapid) +/- intermediate-acting insulin (protophane) as it allows maximum flexibility Target blood glucose: fasting < 5mmol/L 2 hr

Oral Hypoglycemic agents Implicated as teratogeneic in animal studies esp first generation sulfonyureasIn humans, scattered case reports of congenital abnormalityRisk of congenital abnormality related to maternal glycemic control rather than mode of the anti-DM agents

Oral hypoglycemic agentsFor Type 2 DM patients, to stop oral hypoglycemic agents and change to insulin

Reassure that the risk of congenital abnormality due to drug is small

Oral hypoglycemic agentsBiguanides ( metformin)Cat B drugCommonly used in Polycystic Ovarian Disease (PCOD) to treat insulin resistance and normalize reproductive functionNot teratogeneicReduce first trimester miscarriage10X reduce gestational diabetesGlueck, Fertil Steril 2002Reece, Curr Opin Endocrinol Diabetes, 2006Hague, BMJ, 2003Glueck, Human Reprod, 2004

Oral hypoglycemic agentsSulfonylureas1st generation drug increase risk of neonatal hypoglycemia2nd generation drug (Glyburide) no such effect and other morbidities . Cat C drug4%-20% patients failed to achieve glucose control with maximum dose of drugIncrease risk of preeclampsia and need for phototherapy Langer, N Eng Med J , 2000Kremer, Am J Obst Gynaecol, 2004Chmait, J Perinatol ,2004Langer, Am J Obst Gynaecol, 2005

Management Aim

Achieve maternal near normoglycemic level to prevent adverse perinatal outcomes

Insulin3 pre-meal short acting insulin (actrapid) +/- intermediate-acting insulin (protophane) as it allows maximum flexibility Target blood glucose: fasting < 5mmol/L 2 hr

Oral Hypoglycemic agents Implicated as teratogeneic in animal studies esp first generation sulfonyureasIn humans, scattered case reports of congenital abnormalityRisk of congenital abnormality related to maternal glycemic control rather than mode of the anti-DM agents

Oral hypoglycemic agentsFor Type 2 DM patients, to stop oral hypoglycemic agents and change to insulin

Reassure that the risk of congenital abnormality due to drug is small

Oral hypoglycemic agentsBiguanides ( metformin)Cat B drugCommonly used in Polycystic Ovarian Disease (PCOD) to treat insulin resistance and normalize reproductive functionNot teratogeneicReduce first trimester miscarriage10X reduce gestational diabetesGlueck, Fertil Steril 2002Reece, Curr Opin Endocrinol Diabetes, 2006Hague, BMJ, 2003Glueck, Human Reprod, 2004

Oral hypoglycemic agentsSulfonylureas1st generation drug increase risk of neonatal hypoglycemia2nd generation drug (Glyburide) no such effect and other morbidities . Cat C drug4%-20% patients failed to achieve glucose control with maximum dose of drugIncrease risk of preeclampsia and need for phototherapy Langer, N Eng Med J , 2000Kremer, Am J Obst Gynaecol, 2004Chmait, J Perinatol ,2004Langer, Am J Obst Gynaecol, 2005

Insulin Analogues1. rapid-acting insulin analogs (lispro) Cat B concerns about teratogenesis, antibodies formation, growth-promoting properties majority of evidence showed that it does not cross placenta, and has no adverse maternal or fetal effects

Insulin Analogues2. Long acting analogs glargine

Cat C drugNot well studied systemically

MonitoringRegular home glucose monitoring with hstixInsulin may be need to be adjusted as gestation advancesHba1c monitoringFetal monitoring with USGRefer ophthamologist

DeliveryTiming and mode of delivery individualisedIntrapartum insulin infusion with glucose monitoring no contraindication for Breast feeding either with insulin or oral hypoglycemic agents

Pre-conception CounsellingAllows for optimisation of diabetic control prior to conception, and assessment of the presence of complications like hypertension, nephropathy, and retinopathyShould counsel that good control and lower hba1c lower the risk of congenital abnormalities and improve outcomeIf necessary, proliferative retinopathy may be treated with photocoagulation prior to conceptionContraindications to pregnancy only :ischemic heart dx, untreated proliferative retinopathy, severe renal impairment(creatinine>250 mmol/L)

Gestational diabetesDefinition Carbohydate intolerance of variable severity first recognised during the present pregnancy. This includes women with preexisting but previously unrecognised diabetes

Gestational diabetes

No consensus for 4 decades!

Gestational diabetesShould all pregnant women be screened or only those with risk factors?Is it safe to screen all?Which screening test and which diagnostic test are the most reliable?Which cut-off values should we use?What are the risk for mothers and babies and can treatment improve outcome?What are the connection between gestational diabetes and type 2 DM?Is it physiological or pathological ?

Gestational diabetes Screening and diagnosis In general, the test is performed btn 24-28 wk because at this point in gestation the diabetogenic effect of pregnancy is manifest and there is sufficient time remaining in pregnancy for therapy to exert its effect

Gestational diabetesScreening and diagnosis In general, risk factor includes: 1. age>25y 2. BMI > 25 3. previous GDM 4. Family hx of DM in 1st degree relative 5. previous macrosomic baby (

Gestational diabetesScreening Fasting / random glucose/ glucose challenge test(50gm)

Diagnosis Glucose challenge test (75gm/100gm ?)

Gestational diabetes Diagnosis WHO criteria 1998, 75 gm glucose fasting 2 hr (mmol/L) Impaired fasting glucose 6.1-6.9 IGT or = 7 or > or=11.1

Gestational diabetesIncidence 2-9% more common in Asian and Indian women In developed countries, increasing trend because of epidemic of obesity

Gestational diabetesClinical significance of GDMHigh incidence of macrosomia, and adverse pregnancy outcomes, A significant proportion(30%) identified as GDM in fact have DM before pregnancy

Gestational diabetesWomen with glucose intolerance just above normal range are at low risk for pregnancy complications, those with more severe glucose intolerance approaching the criteria of diabetes are at risk of neonatal complications

Fetal complicationsMacrosomia (>4 kg) risk is 16-29% as compared to 10% in controlIncrease in caesarean delivery, intrumental deliveries ( forceps/vacuum), birth trauma, such as brachial plexus injuries , clavicular fracturesIncrease in neonatal hypoglycemia (24% ), hyperbilirubinemia, hypocalcemia, polycythemiaChildren are at risk of type 2 DM and obesity in life

Maternal complicationsIncrease risk of hypertensive disordersIncrease risk of caesarean and intrumental deliveriesIncreased Risk (40-60%) of developing type 2 DM within10-15 yr.

Gestational diabetesDoes treatment improves outcomes?Conflicting results 1. Cochrane datebase systemic review 2005 (3 studies only) no difference in outcomes except neonatal hypoglycemia

2. Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS study) 2005 ( 490/510 subjects) treatment of diabetes reduces serious perinatal morbility and may improve the womans health-related quality of life

Gestational diabetesLarge randomized study on going

HAPO trial in USA (Hyperglycemia and Adverse Pregnancy Outcome study)

Gestational diabetesManagementManagement similar as preexisting DMNeed for glucose monitoringStart with Diet controlCommence insulin for poor controlDelivery plan individualised

Gestational diabetesIn view of risk of developing type 2 DM the woman should be screened annually for DM on yearly basis.

Diabetes and PregnancyConclusionPreexisting DM in pregnancyGood glucose control is important for decreasing morbiditiesInsulin is still the gold standard of tx in pregnancyIncreasing evidence for clincial effectiveness for treatment with oral hypoglycemic agents

Diabetes and pregnancyconclusion(2) Gestational diabetes no consensusThe morbidities increases as glucose level approaching the diagnosis as DMPossible that treatment improves outcomesOverlap with preexisting DM, esp type2Long term implication for health of the mother and baby

Thank you very much!

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