1. NICHD Perspective on Needs for the Study of Therapeutic Drug Use in Pregnancy Catherine Y Spong, MD PPB, CRMC, NICHD, NIH

2. IssuesIssues l Therapeutic drug use in pregnancy: common and necessary l Maternal physiologic changes affect drug levels l Maternal-fetal transfer l Fetal drug levels l Ethical considerations & study design

3. Therapeutic drug use is common and required in pregnancy for: l Maternal conditions l Pregnancy-related conditions l Fetal conditions

4. Maternal conditions commonly requiring therapy in pregnancy l Asthma l Hypertension l Psychiatric conditions l Diabetes l Thyroid dysfunction l Autoimmune disorders

5. Pregnancy-related conditions commonly requiring therapy l Gestational diabetes l Gestational hypertension l Preterm labor l Preeclampsia l Hyperemesis / morning sickness

6. Fetal conditions commonly requiring drug therapy l Cardiac conditions l Supraventricular tachycardia l Complete heart block l Impending preterm delivery

7. Drug therapy in pregnancy Balancing act maternaltreatment fetaleffects Little scientific evidence

8. Pregnancy: Maternal physiologic changes affect therapeutic drug administration l Cardiovascular l Gastrointestinal l Renal l Enzymatic activity

9. Pregnancy: Cardiovascular changes l Gestational age dependent l Plasma volume expansion l Decrease in serum albumin concentration l Increase in cardiac output l Alterations in regional blood flow All affect pharmacokinetics of drugs

10. Pregnancy: Cardiovascular changes l Plasma volume expansion l Begins at 6-8 and peaks at 32 weeks’ l Additional ~ 1.5 liters l Cardiac output l Increases 30-50% l stroke volume (early) heart rate (late) Gestational age dependent

11. Pregnancy: Cardiovascular changes l Alterations in regional blood flow l flow to uterus l renal blood flow l skin blood flow l mammary blood flow l skeletal muscle blood flow

12. Gastrointestinal changes l Gastric emptying delayed l Transit time increased (progesterone) l Gastric acidity decreased Renal changes l Increase in glomerular filtration rate Enzymatic activity changes l ~ related to pregnancy hormonal changes

13. Consequences of physiologic changes: l Volume expansion l Increase in free fraction of drug l Due to decreased albumin l Clearance changes l Renal and enzymatic l Gastrointestinal changes in oral drugs Result: Dosing changes

14. l Increased cardiac output l Increased GFR l Diuresis l Breastfeeding l Significant variability between individuals Consequences of physiologic changes: Postpartum

15. Timing: Effect of gestational age 1st3rd 2nd embryogenesis fetal development

16. Maternal fetal transfer l Placental transfer l Drugs & metabolites in fetus l Fetal GI absorption l Transfer via breastmilk

17. Monitoring fetal drug levels l Difficult l Often rely on clinical exam, response l Aim for lowest effective dose l Fetal condition: ultrasound cordocentesis: limited role

18. Ethical considerations & study design l Drug labeling inadequate for guidance in pregnancy l Research available on drugs in pregnancy is sparse l Pharmacokinetic studies in pregnancy inadequate l IRB difficulties l Pharmaceutical companies NOT INTERESTED

19. NICHD & FDA Initiatives: l Workshop: fall 2000, Bethesda MD l Future Meeting Research on pharmacokinetics and pharmacodynamics of therapeutic drugs used in 2nd and 3rd ∆ of pregnancy Discuss issues Generate interest Stimulate research initiatives Generate mechanisms for study

20. Bottom line l Therapeutic drugs required in pregnancy l Research needed to evaluate l Efficacy l Safety l Required alterations in dosing, timing, etc l Pharmaceutical companies will never provide