4. Pregnancy Outcomes in 125 Women with PCOS Previously without metformin 301 pregnancies With metformin 148 pregnancies, 155 fetuses McNemar S=148.4, p<0.0001 SAB 68% Livebirths 32% SAB 14% Livebirths 86%

5. Pregnancy Outcomes in 178 Women with PCOS Previously without metformin 197 pregnancies With metformin 88 pregnancies, 91 fetuses McNemar S=64.1, p<0.0001 SAB 24% Livebirths 76% SAB 60% Livebirths 35% Other 5%

6. Metformin reduces miscarriage in PCOS by reducing hypofibrinolytic plasminogen activator inhibitor activity, an independent determinant of miscarriage, which is closely correlated with insulin, insulin resistance, and triglycerides. This is particularly important in PCOS where 4G4G PAI-1 homozygosity is much more common than in normal women

7. Pregnancy Outcomes on Metformin in 144 Women with PCOS SAB 13% Livebirths 87%

8. Pregnancy Outcomes on Metformin in 300 Women with PCOS SAB 15% Livebirths 85%

11. Recognized risk factors for GD include body mass index >25 kg/m 2 , first degree family history of type 2 DM, age  25 years, multiparity, previous GD, and previous macrosomic infants (>9 lbs. or 4000 grams). Additional risk factors for GD include pre-conception impaired fasting glucose levels (110-125 mg/dL), pre-conception impaired glucose tolerance (2 hour post oral glucose load glucose levels 140-199 mg/dL), polycystic ovary syndrome (PCOS), and ethnic group (American Indian or Alaska Native; African American; Asian; Hispanic; Pacific Islander).

12. Gestational Diabetes in 40 Women with PCOS Previously without metformin In 52 livebirth pregnancies With metformin In 40 livebirth pregnancies GD 13% GD 31% X 2 =4.3, p=0.039 McNemar S=8.3, p=0.039

13. GD IN PCOS ON METFORMIN VS COMMUNITY CONTROLS GD in 121 Women with PCOS 140 Livebirth Pregnancies on Metformin GD in 251 Livebirth Pregnancies From Community Controls GD 7% GD 16% X2 =6.2, p=0.013

14. GD IN WOMEN WITH PCOS ON METFORMIN VS COMMUNITY CONTROLS GD in 251 Livebirth Pregnancies From Community Controls GD 16% GD 17% GD in 203 Women with PCOS 211 Livebirth Pregnancies on Metformin X 2 =0.11, p=0.75

15. Pregnancy increases requirements for insulin secretion, increasing insulin resistance and demands on pancreatic β-cells, promoting development of gestational diabetes (GD), particularly in women with pre-existing insulin resistance, commonly in women with polycystic ovary syndrome (PCOS). Preliminary studies suggest that metformin may have unique potential to prevent development of GD. We postulate that interventions which reduce insulin resistance and lower requirements for endogenous insulin secretion can preserve beta cell function and prevent development of type 2 DM.

17. Pre-conception Insulin Resistance Physical inactivity  PCOS  Obesity  Race  Increased demand on beta cells for insulin secretion Hyperinsulinemia  Maternal weight gain  Neonatal macrosomia  1st trimester miscarriage  Pregnancy induced HTN  Pre-eclampsia  High PAI-Fx  Insulin resistance of pregnancy  Pregnancy increases requirements for insulin secretion Reduction in beta cell reserve  Glucose intolerance  Gestational diabetes  Type 2 diabetes

18. Insulin sensitizing drugs (Metformin) Reduces demand on beta cells for insulin secretion Protects beta cell reserve Overcomes insulin resistance Euglycemia maintained • Decreases gestational diabetes • Primary prevention of type 2 diabetes

25. Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics PCOS (123 women,142 pregnancies, 148 babies) Community (252 women, 252pregnancies 262 babies ) p N 123 252 Age 30±5 29±6 . 021 Race 94% Caucasian (116 W, 7 other) 90% Caucasian (227 W, 25 B) NS Pre-conception weight (kg) 93 ±23 72 ±18 <. 0001 Pre-conception BMI (kg/m 2 ) 33.7 ±7.9 25.6 ±5.9 <. 0001 Pre-conception Type 2 diabetes mellitus 2/123(1.6%) 1/252 (0.4%) NS Conception at age > 35 years 22/142(19%) 33/252 (13%) NS

26. Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics Pre-eclampsia 7/142(4.9%) 9/252 (3.6%) .NS Pre-eclampsia in primigravidas 5/101(5.0%) 4/92 (4.4%) NS Gestational diabetes 10/140(7.1%) 40/251 (15.9%) .013

27. Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics Percent of pregnancies as twins 3/97 (3.1%) 10/252 (4.0%) 1.0 Birth at gestational week ≥37 Birth at gestational week <37 120/148(81%) 28/148 (19%) 222/249 (89%) 27/249 (11%) .024

28. Pre-eclampsia and pregnancy outcome in 123 women with polycystic ovary syndrome (PCOS) and in 252 healthy controls from a community practice of obstetrics Birth weight for births at ≥37 weeks gestation (gram) 3363 ± 500 3481 ± 555 NS Birth weight ≥4000g for neonates ≥37 weeks gestation 10.8% (13/120) 17.5% (36/206) NS Birth weight ≥4500g for neonates ≥37 weeks gestation 0.8% (1/120) 2.9% (6/206) NS

29. Major and minor birth defects, 142 live births to 125 women with PCOS: 1 tethered spinal cord, 1 hamstring tendon contracture. Birth defects in 1.4%, national average ~4.5%