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NICHD Perspective on Needs for the Study of Therapeutic Drug Use in Pregnancy

Catherine Y Spong, MD PPB, CRMC, NICHD, NIH. NICHD Perspective on Needs for the Study of Therapeutic Drug Use in Pregnancy. Issues. Therapeutic drug use in pregnancy: common and necessary Maternal physiologic changes affect drug levels Maternal-fetal transfer Fetal drug levels

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NICHD Perspective on Needs for the Study of Therapeutic Drug Use in Pregnancy

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

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

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

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

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

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

  7. Drug therapy in pregnancy Balancing act maternal treatment fetal effects Little scientific evidence

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

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

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

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

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

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

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

  15. Timing: Effect of gestational age embryogenesis 1st 3rd 2nd fetal development

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

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

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

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

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

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