1. Pregnancy Outcomes of Anti-obesity Drug Exposure 대전 미즈 여성병원 홍 달 수 원장

2. Definition of Obesity Definition of Obesity  Defined as a disorder in which excess body fat has accumulated to an extent that health may be adversely affected.  The most commonly used measure of body fatness is Body Mass Index (BMI) Weight (kg) Height (m) 2 BMI The Royal Collage of Physician of London, 1998

3. Definition of Obesity Definition of Obesity  WHO Classification of Obesity BMI(kg/m 2 )DescriptionRisk of co-morbidity < 18.5UnderweightLow 18.5 – 24.9Healthy weightAverage 25.0 – 29.9Pre-obese (overweight)Mildly increased 30.0 – 34.9Obese class I (moderately obese)Moderate 35.0 – 39.9Obese class II (severely obese)Severe > 40Obese class III(morbidly obese)Very severe NHLBI and NIDDK, 1998; WHO, 2000

4. Obesity in Reproductive Women Obesity in Reproductive Women  Obesity rates are reaching epidemic proportions in the United States and other industrialized nations.  In United States (CDC, 2002),  26.5% (overweight) vs 30.2% (obese)  Proportion of Women Overweight or Obese (females aged 20 to 74 years by race, 1999-2002) Race/EthnicityOverweightObese White (non-Hispanic)25.7%31.3% African American/Black (non-Hispanic) 27.9%49.6% Mexican american32.6%38.8% Age adjusted to the U.S. year 2002 standard population. Source: CDC, National health and Nutrition Examination Survey (NHANES), 2002 NHANES in CDC, 2002

5.  Associated with increased morbidity  Type 2 diabetes, hypertension, infertility (PCOS), heart disease, gallbladder disease and osteoarthritis  Variety of cancers, including breast, uterine, and colon cancers  Endometrial cancer  Most common gynecologic malignancy in U.S.  Obese women are almost five times more likely than nonobese women (BMI 20–22.9) to develop endometrial cancer  Heart disease  Associated with Obesity and overweight  Leading cause of death of American women and an estimated 112,000 individuals die annually of obesity associated causes Azziz R et al, 1989; NIH,1998; WHO, 2000 Schouten LJ et al, 2004 NIH,1998; WHO, 2000; Mosca L et al, 2004; Flegal KM et al, 2005 Obesity in Reproductive Women Obesity in Reproductive Women

6. Obesity in Pregnancy  Increased risk for several pregnancy complications  Independent risk factor for spontaneous abortion  Among women who undergo infertility treatment and women after natural conception  Increased risk of congenital anomalies  Neural tube defects (OR 1.8) especially spina bifida (OR 2.6), heart defects (OR 1.18) and omphalocele (OR 3.3)  Due to pregestational DM and folic acid deficiencies Fedorcsak et al, 2000; Wang JX et al, 2002; Bellver J et al, 2004 Waller DK et al, 1994; Cedergren MI et al, 2003; Watkins ML et al, 2003

7. Obesity in Pregnancy  In a prospective multicenter study of more than 16,000 patients (BMI less than 30 vs Class I and Class II obesity)  Gestational hypertension (odds ratio [OR] = 2.5 and 3.2, respectively)  Preeclampsia (OR = 1.6 and 3.3)  Gestational diabetes (OR = 2.6 and 4.0)  Fetal macrosomia (OR = 1.7 and 1.9)  Cesarean delivery rate  20.7% (BMI of 29.9 or less), 33.8%(30–34.9) and 47.4%(35–39.9)  Increased preterm delivery and stillbirth  Operative and postoperative complications  Increased rates of excessive blood loss, operative time greater than 2 hours, wound infection, and endometritis  Anesthetic complications Baeten et al, 2001;Cedergren MI et al, 2004; Weiss JL et al, 2004 Schieve LA et al, 1999, 2000; Huang DY et al, 2000 Perlow JH et al, 1994; Myls TD, et al, 2002; Kabiru W et al, 2004

8. Obesity in Pregnancy  For obese women who are pregnant or planning a pregnancy  Preconception assessment and counseling  Provision of specific information concerning the maternal and fetal risks of obesity in pregnancy  Consideration of screening for GDM upon presentation or in the first trimester, and repeated screening later in pregnancy if results are initially negative  Assessment and possible supplementation of vitamin B12, folate, iron, and calcium for women who have undergone bariatric surgery  Possible use of graduated compression stockings, hydration, and early mobilization during and after cesarean delivery  Continuation of nutrition counseling and exercise program after delivery, and consultation with weight loss specialists before attempting another pregnancy ACOG Recommendation ACOG, 2005

9. Weight loss in pregnancy  A variety of reports have associated excess body weight with reproductive complications  Control of pre-pregnancy weight has been suggested as a major area of preventable morbidity and mortality However, Once pregnant, overweight or obese are encouraged to gain less weight but should not attempt weight loss Hall LF et al, 2005

10. Weight loss in pregnancy  Weight loss during early pregnancy has been hypothesized as a contributor to neural tube defect risk  Robert et al. 1994,1995  9 of 150 women who had children with open spina bifida reported weight loss in early pregnancy  Only one was on an anorectant drug  Case-control study from California  Spina bifida associated with 15 kg loss in early pregnancy (OR 3.07)  Swedish discharge registry report  incidence of neural tube defects among offspring of women with anorexia nervosa to be 1:313, compared to the general Swedish incidence of 1:2000  Also consistent with the production of neural tube defects in the embryos of fasted pregnant mice Miller JR et al, 1962 Robert et al. 1994,1995

11. Weight loss in pregnancy  Ketosis, such as may be seen in fasted animals and humans, is a cause of neural tube defects  ketoacids may exert an effect similar to valproic acid  Supported by the association between these defects and diabetes mellitus  Ketosis is associated with poor controlled DM  May reflect the propensity to ketosis of obese women Rosa FW et al, 1989 Watkins MA et al, 1994; Werler MM et al, 1995; Shaw GM et al, 1995 ; Waller DK et al, 1994, 1996

12. Treatment for Obesity Treatment for Obesity  It is clear that significant health benefits result from a modest weight reduction of 5-10%.  Benefits of a 10% weight loss with co-morbidities Jung RT et al, 1997; The Royal Collage of Physician of London, 1998 Goldstein D et al, 1992

13.  Lifestyle therapy and physical therapy should be considered before drug therapy.  Weight loss drugs approved by the FDA may be used as part of a comprehensive weight loss program  BMI ≥30 with no accompanying obesity-related risk factors or diseases  BMI ≥27 with accompanying obesity-related risk factors or diseases.  Discontinue use if the drug is ineffective in weight loss or weight maintenance, or if there are serious adverse effects. Recommendations : Pharmacotherapy Adapted from National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults-the evidence report. Obes Res 1998;6(suppl 2):51S-209S. Retrieved September 2000 from: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm. Treatment for Obesity Treatment for Obesity

14. Anti-obesity Drug 종류작용기전성분명 ( 제품명 ) 참고 Appetite Suppres- ant 중추성 아드레날린 수용체를 흥분 Phendimetrazine(Adipost, Anorex, Bontril, Parzine, Phendiet, Plegine, Wehless) 1961 년 미국 FDA 승인 잘 쓰지 않음. Dietylpropion(Amfepramone,Tenuate, Tenuate Dospan) Primary pulmonay hypertension 가능성 있음. Mazindol(Maznor, Sanorex) 1973 년 미국 FDA 승인. 남용가능성으로 상용되지 않음. Phenylpropanolamine(Acutrim, Dexatrim, Phenozine, Phenyldrine,Propagest, Rhindecon, 로즈카캅셀 ) Over the counter drug(OTC) 로 미국 FDA 승인 phentermine(Adipex-P, Fastin, Ionamin, Oby-Cap, Phentamine, T-Diet, Zantryl) Resin complex 로 1959 년 미국 FDA 승인 세로토닌 재흡수를 억제 Fenfluramine(Pondimin, ponderal) 심장판막 손상가능성으로 97 년 9 월 15 일 자진 FDA 승인 취소 Dexfenfluramine(Redux) 96 년 4 월 미국 FDA 승인, 97 년 9 월 15 일 심 장판막 손상가능성 때문에 자진 승인 취소 Fluoxetine(Prozac, 푸로작, 푸록틴 캅셀 ) 비만 치료제로 미국 FDA 승인 받지 못함 아드레날린 / 세로토닌 재흡수를 억 제 Sibutramine(Meridia) 97 년 11 월 미국 FDA 승인을 받음

15. Anti-obesity Drug 종류작용기전성분명 ( 제품명 ) 참고 Thermogenic agent 아드레날린성 베타 3 효능제 Ephedrine/caffein Combination Anticonvulsant Topiramate( 토팜 정, 토파맥스 ) 비만 치료제로 미국 FDA 승인 받지 못함 Digestive inhibitor Lipase 억제제 Orlistat(Xenical) 97 년 5 월 17 일 미국 FDA 승인추천 97 년 8 월 유방암 때문에 FDA 승인 자진 취 소 99 년에 FDA 재승인을 받음 Hormone manipulation Leptine 유사체, Neuropeptide Y 억제제

16. Counseling on Korean Motherisk Program at Cheil General Hospital between Jan. 2003 and Oct. 2006 Anti-obesity drug exposed cases (n=68) ∙ Phendimetrazine ∙ Phentermine ∙ Fluoxetine ∙ Sibutramine ∙ Topiramate ∙ Orlistat ∙ Ephedrine/caffein Combination Age and Gravidity matched controls (n=136) A case-control study Pregnancy Outcomes  Major and minor anomaly  Fetal macrosomia  Preterm delivery Primary outcome

17. 약물별 임신 노출수수 및 노출된 임신부 숫 자를 표로 삽입할 예정입니다.

18. characteristics for sample recruitment Counseling due to Anti-obesity drug exposure N=91 Counseling due to Anti-obesity drug exposure N=91 Exposure to anti-obesity drug N= 79 Exposure to anti-obesity drug N= 79 Follow-up loss N=12 (13.2%) Follow-up loss N=12 (13.2%) Delivery N=68 (74.7%) Delivery N=68 (74.7%) Artificial abortion N=8 (8.8%) Artificial abortion N=8 (8.8%) Anomaly N=2 Anomaly N=2 Normal N=66 Normal N=66 Spontaneous abortion N=3 (3.3%) Spontaneous abortion N=3 (3.3%) Case 1 : Liver mass ( 자세히 기입할 예정입니다 ) Case 2 : Choledochal cyst Pregnancy Outcomes

19. Sample charateristics Case (n= 68) Control (n=136) P-value Age (yr) 31.6  3.531.6  3.4 0.95 Gestational age (wks) 38.8  1.639.2  1.4 0.08 Birth weight (g) 3372.4  466.73248.9  442.0 0.07 Parity (n) 2.5  1.62.5  1.3 0.94 Significance : p < 0.05 Pregnancy Outcomes

20. Exposure to teatogen Case (%)Control (%)P-value Alcohol26 (40.6%)67 (49.3%)0.29 Smoking9 (13.2%)12 (8.8%)0.34 Radiation5 (7.4%)30 (22.1%)0.01 Significance : p < 0.05 Pregnancy Outcomes

21. Primary outcome Case (%)Control (%)P-value Anomaly2 (2.9%)3 (2.2%)1.00 Fetal macrosomia6 (8.8%)3 (2.2%)0.06 Preterm delivery4 (5.9%)7 (5.2%)1.00 Significance : p < 0.05 Pregnancy Outcomes

22. Conclusions Conclusions  Exposure to anti-obesity drugs during the 1 st trimester of pregnancy not associated with increased adverse pregnancy outcome including major malformations.  Accordingly, pregnant women inadvertently exposed to anti-obesity drugs should be reassured and not to choose unnecessary artificial abortion.  However, topiramate as an used anti-epileptic drug is necessary more cases of study and further evaluation.

23. Review of Anti-obesity Drug  Amphetamine analogue that acts as a sympathomimetics with anorectic properties  No adequate epidemiological studies of congenital anomalies in infants who exposure to phendimetrazine in utero  No experimental animal teratology studies of phendimetrazine  Phenmetrazine  Structurally similar compound, a metabolite of phendimetrazine, is also marketed as an anorectic drug  Four clinical reports of malformations  Between the third and 12th weeks of gestation  Congenital defects involved abnormalities of the viscera  Other investigations for more than 600 women  Not found an increased incidence of congenital abnormalities in exposed offspring Phendimetrazine Powell PD et al, 1962; Moss PD et al, 1962; Lenz W et al, 1962; Fogh-Anderson P, 1962 Notter A et al, 1962; Milkovich L et al, 1972; Heinonen OP et al, 1977

24.  Sympathomimetic amine used as an appetite suppressant  In experimental animal study  Co-administration of phentermine plus fenfluramine from days 3 through 17 of gestation in rat  Not found adverse effects on embryo development  Report for the fetotoxic effects of phentermine in human  Data from the California Teratology Information Service  Used the combination phentermine/fenfluramine during the first trimester of pregnancy (n=84)  No significant increase in the frequency of major congenital anomalies  Data from the British National Teratology Information Service  Anorectic drug during pregnancy (m.c used agent was phentermine)  6 (9.5%) diverse congenital anomalies in 63 liveborn infants  At least 1 of 7 spontaneous abortion Phentermine Bratter J et al, 1999 Jones KL et al, 2002 McElhatton PR et al, 2000 Review of Anti-obesity Drug

25.  Selective serotonin reuptake inhibitor (or SSRI)  Used as an antidepressant, for Tourette's syndrome, for obsessive compulsive disorder, and for premenstrual syndrome  Manufacturer’s report  Doses up to 11 times the maximum daily human dose did not cause adverse reproductive or neurotoxic effects in rats and rabbits  In experimental animal study  Rats used 17 times the human dose on a mg/kg basis  Increase in skin hematomas Fluoxetine Cooper GL et al, 1988; Hoyt JA et al, 1994; Byrd RA et al, 1994; Vorhees CV et al, 1994 Stanford MS et al, 1993 Review of Anti-obesity Drug

26.  No significant increase in major congenital anomalies in human  Fluoxetine exposure during the first trimester  One report suggests an increase in minor anomalies  Of 97 children exposed to fluoxetine early in pregnancy  15(15.5%) had three or more minor malformations(vs 6.5% in control)  Long-term neuro-developmental studies  Antenatal fluoxetine exposure does not adversely affect outcome Fluoxetine Pastuszak A et al., 1993; Chambers CD et al., 1996; Robert E et al., 1996 Chambers CD et al., 1996 Nulman & Koren, 1996; Loebstein & Koren, 1997; Nulman et al., 1997; Mattson et al., 1999;Nulman et al., 2002 Review of Anti-obesity Drug

27.  Appetite suppressant marketed in the treatment of obesity  In experimental animal study  Not increased structural malformation at doses that did not produce maternal toxicity  First trimester exposures in human  No congenital defects were reported in three case-report Sibutramine Kadioglu M et al., 2004; Einarson A et al., 2004; De Santis M et al., 2006 FDA, 2004 Review of Anti-obesity Drug

28.  Sympathomimetic agent  Used in cold and allergy preparations  Short term effectiveness for weight loss  In one experimental animal study and one human case report  Associated with cardiovascular anomalies  Limb reduction defect  In report included 373 exposed pregnancies  No association between ephedrine exposure in the first trimester and an increase in any kind of birth defect Ephedrine Nishikawa T et al., 1985; Gilbert-Barness E et al., 2000 Heinonen OP et al., 1977 Shekelle PG et al., 2003 Review of Anti-obesity Drug

29.  Used as an anticonvulsant and as a mood stabilizer  In experimental animal study  Developmental toxicity in mice, rats, and rabbits  Craniofacial malformations (m.c), skeletal abnormalities with a limb reduction defects, reduced fetal body weight and abortion  UK Epilepsy and Pregnancy Register (n=28)  2 of which resulted in children with major malformations  One case report  Monotherapy with topiramate (700 mg bid) throughout gestation  Prenatal onset growth deficiency, generalized hirsuitism, short nose with anteverted nares, blunt distal phalanges, and generalized blunting of the nails with 5th nail hypoplasia Topiramate Gordon A et al., 1999; Calabrese JR et al., 2001; Roy Chengappa KN et al., 2001 Morrow J et al., 2006 Hoyme HE et al., 1998 Review of Anti-obesity Drug

30.  Intestinal lipase inhibitor marketed as Xenical for the treatment of obesity  Poorly absorbed from the gastrointestinal tract  In preclinical animal studies  Not result in reproducible evidence of developmental toxicity Orlistat Review of Anti-obesity Drug

31. 경청해 주셔서 감사합니다.