2004 NJ ACP2004 NJ ACPObstetric Medicine Obstetric Medicine

WorkshopWorkshop

Michael P. Carson, MDMichael P. Carson, MD

Asst. Clin. Prof of Medicine and ObstetricsAsst. Clin. Prof of Medicine and Obstetrics

UMDNJ - RWJMSUMDNJ - RWJMS

Chief, Division of General Internal MedicineChief, Division of General Internal Medicine

Saint Peter’s University HospitalSaint Peter’s University Hospital

Common DisordersCommon Disorders

• Asthma – No changes to managementAsthma – No changes to management

• HypothyroidismHypothyroidism– Check TSH each trimester.Check TSH each trimester.

– Check it 4 weeks after any dosing changeCheck it 4 weeks after any dosing change

• SLE – Be very careful. SLE – Be very careful. – Increased risk of flareIncreased risk of flare

• RA RA – flares postpartumflares postpartum

• Multiple Sclerosis – Multiple Sclerosis – – increased flare risk, follow-up period may not be adequate.increased flare risk, follow-up period may not be adequate.

Background: Pregnancy & Background: Pregnancy & DKADKA

• Respiratory alkalosis leads to Bicarb loss by kidneys. Respiratory alkalosis leads to Bicarb loss by kidneys. – HCOHCO33

-- is ~ 20 is ~ 20– Less buffering capacityLess buffering capacity

• Ketogenesis is accelerated 2-4 times during pregnancyKetogenesis is accelerated 2-4 times during pregnancy• Less hyperglycemia is required to cause DKA during Less hyperglycemia is required to cause DKA during

pregnancypregnancy• Mortality: Mortality:

– Maternal 5-15%Maternal 5-15%– Fetal 50-90%Fetal 50-90%

Diabetic KetoacidosisDiabetic Ketoacidosis

Metabolic Effects of DKAMetabolic Effects of DKA

• Abnormal Insulin:Glucagon ratio favors Abnormal Insulin:Glucagon ratio favors triglyceride release from adipose tissue. Then, triglyceride release from adipose tissue. Then, they’re metabolized to ketones rather than they’re metabolized to ketones rather than being stored or metabolized to carbon dioxide. being stored or metabolized to carbon dioxide. – Notice a theme here?Notice a theme here?

• Ketones:Ketones:– Primary is beta-hydroxybutyric acidPrimary is beta-hydroxybutyric acid– Aceto acetic acidAceto acetic acid

• Reacts with the nitroprusside test. Reacts with the nitroprusside test. • Responsible for fruity odor on the breath.Responsible for fruity odor on the breath.

Diabetic KetoacidosisDiabetic Ketoacidosis

GlyburideGlyburide

• Increases Pancreatic Insulin OutputIncreases Pancreatic Insulin Output

Langer et al. N Engl J Med 2000;343:1134-8Langer et al. N Engl J Med 2000;343:1134-8

A comparison of glyburide and insulin in women A comparison of glyburide and insulin in women with gestational diabetes mellituswith gestational diabetes mellitus

• 404 women with GDM requiring treatment404 women with GDM requiring treatment– Insulin or glyburide between 11-33 weeksInsulin or glyburide between 11-33 weeks

– Insulin 0.7 U/kg (admission) tid & Insulin 0.7 U/kg (admission) tid & weekly prn weekly prn

– Glyburide 2.5 mg/d; Glyburide 2.5 mg/d; weekly up to 20 mg/d max. weekly up to 20 mg/d max.

GlyburideGlyburide

Metabolic Outcomes During Treatment

Variable Glyburide Insulin P Value (N=201) (N=203)

Gestational Age (wks) 286 278 0.22

Duration of Testing (wks) 106 117 0.12

Blood Glucose (mg/dl) Fasting 9813 9616 0.17 Preprandial 9515 9714 0.17 Postprandial 11322 11215 0.60 Mean 10516 10518 0.99

Glycosylated Hgb (%) 5.50.7 5.40.6 0.12

GlyburideGlyburide

Neonatal Outcomes

Outcome Glyburide Insulin P Value

LGA (%) 24(12) 26(13) 0.76 Birth weight - g 3256543 3194598 0.28 Macrosomia (%) 14(7) 9(4) 0.26 Cord serum insulin - U/ml 1513 1521 0.84 Hypoglycemia (%) 18(9) 12(6) 0.25 Congenital Anomaly (%) 5(2) 4(2) 0.74 Stillbirth (%) 1(0.5) 1(0.5) 0.99 Neonatal death (%) 1(0.5) 1(0.5) 0.99

GlyburideGlyburide

• Metabolic control similar in both groupsMetabolic control similar in both groups• MaternalMaternal hypoglycemia hypoglycemia in insulin in insulin

groupgroup• Glyburide not detected in cord bloodGlyburide not detected in cord blood

– Despite being present in maternal serumDespite being present in maternal serum– Corroborates their in vitro dataCorroborates their in vitro data

• Only given after 11 weeks gestationOnly given after 11 weeks gestation– No first trimester dataNo first trimester data

Glyburide: WhenGlyburide: When

• Started for the same indications as insulinStarted for the same indications as insulin• ComplianceCompliance• TrendTrend• 2.5mg once a day2.5mg once a day

– Timing depends on the patternTiming depends on the pattern

– May give doses BIDMay give doses BID

– Max is 20mgMax is 20mg

• Test as an A2 GDM.Test as an A2 GDM.

MetforminMetformin• Used since the 1950’sUsed since the 1950’s• Several mechanisms of action have been proposed: Several mechanisms of action have been proposed:

– Enhanced peripheral glucose uptake and utilization. Enhanced peripheral glucose uptake and utilization.

– Increased insulin receptor affinity (reduced insulin Increased insulin receptor affinity (reduced insulin resistance).resistance).

– Inhibition of hepatic gluconeogenesis (glucose Inhibition of hepatic gluconeogenesis (glucose production). production).

• Most SignificantMost Significant

• Will improve fertility in PCOSWill improve fertility in PCOS

Metformin: PCOS and GDMMetformin: PCOS and GDM

• Gluek 2002Gluek 2002– Retrospective 39 Women with PCOS and NO h/o DMRetrospective 39 Women with PCOS and NO h/o DM

• GDM in 14/60 pregnancies (23%)GDM in 14/60 pregnancies (23%)

– Prospective 33 Women with PCOSProspective 33 Women with PCOS• 8/12 (67%) developed GDM during historical pregnancies8/12 (67%) developed GDM during historical pregnancies

• GDM 1/33 (3%) when treated GDM 1/33 (3%) when treated

• Metformin may decrease GDM, but Fetal effects?Metformin may decrease GDM, but Fetal effects?

Metformin: PCOS and IVFMetformin: PCOS and IVF

• Clomiphene Resistant PCOSClomiphene Resistant PCOS• IVF cycles: 46 Women 60 CyclesIVF cycles: 46 Women 60 Cycles

– ½ cycles given Metformin 1000-1500 mg½ cycles given Metformin 1000-1500 mgMetMet ControlControl

– Oocytes Retrieved Oocytes Retrieved 22 +/- 1.9 22 +/- 1.9 20.3 +/- 1.520.3 +/- 1.5 – Mature Oocytes Mature Oocytes 18.4 +/- 1.5 18.4 +/- 1.5 13 +/- 1.513 +/- 1.5– Embryos Cleaved Embryos Cleaved 12.5 +/- 1.5 12.5 +/- 1.5 5.9 +/- 0.9 5.9 +/- 0.9 – Fertilization rates Fertilization rates 64% 64% 43%43%– Clinical Pregnancy Rates Clinical Pregnancy Rates 70% 70% 30% 30%

Stadtmauer. Fertil Steril. 2001 Mar;75(3):505-9. Stadtmauer. Fertil Steril. 2001 Mar;75(3):505-9.

Metformin: PCOS and SABMetformin: PCOS and SAB

• Gluek 2001 and 2002Gluek 2001 and 2002– 72 Women with PCOS treated with Metformin72 Women with PCOS treated with Metformin– 84 Pregnancies84 Pregnancies– First Trimester MiscarriagesFirst Trimester Miscarriages

• Historically: 40 women had 100 pregnanciesHistorically: 40 women had 100 pregnancies– 62% First Trimester Loss62% First Trimester Loss

• With Metformin 14 of 84 Pregnancies With Metformin 14 of 84 Pregnancies – 17% First Trimester Loss17% First Trimester Loss

– Congenital DefectsCongenital Defects• None in the 63 completed pregnanciesNone in the 63 completed pregnancies• 9 ongoing pregnancies >13 weeks have normal U/S9 ongoing pregnancies >13 weeks have normal U/S

Metformin and...oopsMetformin and...oops

• Hellmuth 2000Hellmuth 2000– Known diabetics in Pregnancy (160 Pregnancies)Known diabetics in Pregnancy (160 Pregnancies)

MetforminMetformin GlyburideGlyburide InsulinInsulin

nn 5050 6868 4242

PIH (%)PIH (%) 3232 77 1010

Mortality (%)Mortality (%) 11.611.6 1.3 1.3 (combined)(combined)

Summary: Oral AgentsSummary: Oral Agents

• Glyburide appears effectiveGlyburide appears effective– Accepted by patientsAccepted by patients

– Has dataHas data

• MetforminMetformin– Improves fertility in PCOSImproves fertility in PCOS

– May decrease first trimester loss in PCOSMay decrease first trimester loss in PCOS

– Appears to improve IVF resultsAppears to improve IVF results

– May increase risk of PIH and MortalityMay increase risk of PIH and Mortality

– Duration?Duration?

SLE, APLAb, SLE, APLAb, Anti-beta-2 Glycoprotein-1Anti-beta-2 Glycoprotein-1

nn ClincialClincial SerologySerology b2GP1b2GP1

TotalTotal 9494

Group 1Group 1 2121 ++ ++

Group 2Group 2 1818 ++ --

Group 3Group 3 3333 -- --

Group 4Group 4 2222 -- ++

[Cabiedes J Rheumatol 1995;22:1899][Cabiedes J Rheumatol 1995;22:1899]

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