NICHD Perspective on Needs NICHD Perspective on Needs for the Study of Therapeutic for the Study of Therapeutic

Drug Drug Use in PregnancyUse in Pregnancy

NICHD Perspective on Needs NICHD Perspective on Needs for the Study of Therapeutic for the Study of Therapeutic

Drug Drug Use in PregnancyUse in Pregnancy

Catherine Y Spong, MD Catherine Y Spong, MD

PPB, CRMC, NICHD, NIHPPB, CRMC, NICHD, NIH

IssuesIssuesIssuesIssues Therapeutic drug use in pregnancy: Therapeutic drug use in pregnancy:

common and necessarycommon and necessary Maternal physiologic changes affect drug Maternal physiologic changes affect drug

levelslevels Maternal-fetal transferMaternal-fetal transfer Fetal drug levelsFetal drug levels Ethical considerations & study designEthical considerations & study design

Therapeutic drug use is common Therapeutic drug use is common and required in pregnancy for:and required in pregnancy for:Therapeutic drug use is common Therapeutic drug use is common and required in pregnancy for:and required in pregnancy for:

Maternal conditionsMaternal conditions Pregnancy-related conditionsPregnancy-related conditions Fetal conditionsFetal conditions

Maternal conditions commonly Maternal conditions commonly requiring therapy in pregnancyrequiring therapy in pregnancyMaternal conditions commonly Maternal conditions commonly requiring therapy in pregnancyrequiring therapy in pregnancy

AsthmaAsthma HypertensionHypertension Psychiatric conditionsPsychiatric conditions DiabetesDiabetes Thyroid dysfunctionThyroid dysfunction Autoimmune disordersAutoimmune disorders

Pregnancy-related conditions Pregnancy-related conditions commonly requiring therapycommonly requiring therapyPregnancy-related conditions Pregnancy-related conditions commonly requiring therapycommonly requiring therapy

Gestational diabetesGestational diabetes Gestational hypertensionGestational hypertension Preterm laborPreterm labor PreeclampsiaPreeclampsia Hyperemesis / morning sicknessHyperemesis / morning sickness

Fetal conditions commonly Fetal conditions commonly requiring drug therapy requiring drug therapy Fetal conditions commonly Fetal conditions commonly requiring drug therapy requiring drug therapy

Cardiac conditions Cardiac conditions Supraventricular tachycardiaSupraventricular tachycardia Complete heart blockComplete heart block

Impending preterm deliveryImpending preterm delivery

Drug therapy in pregnancyDrug therapy in pregnancyDrug therapy in pregnancyDrug therapy in pregnancy

Balancing actBalancing act

maternalmaternal treatmenttreatment

fetal fetal effectseffects

Little scientific evidenceLittle scientific evidence

Pregnancy:Pregnancy:Maternal physiologic changes Maternal physiologic changes affect therapeutic drug affect therapeutic drug administrationadministration

Pregnancy:Pregnancy:Maternal physiologic changes Maternal physiologic changes affect therapeutic drug affect therapeutic drug administrationadministration

CardiovascularCardiovascular GastrointestinalGastrointestinal RenalRenal Enzymatic activityEnzymatic activity

Pregnancy: Cardiovascular Pregnancy: Cardiovascular changeschangesPregnancy: Cardiovascular Pregnancy: Cardiovascular changeschanges Gestational age dependentGestational age dependent Plasma volume expansionPlasma volume expansion

Decrease in serum albumin concentrationDecrease in serum albumin concentration Increase in cardiac outputIncrease in cardiac output Alterations in regional blood flowAlterations in regional blood flow

All affect pharmacokinetics of drugsAll affect pharmacokinetics of drugs

Pregnancy: Cardiovascular Pregnancy: Cardiovascular changeschangesPregnancy: Cardiovascular Pregnancy: Cardiovascular changeschanges

Plasma volume expansion Plasma volume expansion Begins at 6-8 and peaks at 32 weeks’ Begins at 6-8 and peaks at 32 weeks’ Additional ~ 1.5 liters Additional ~ 1.5 liters

Cardiac outputCardiac output Increases 30-50%Increases 30-50% stroke volume (early) heart rate (late)stroke volume (early) heart rate (late)

Gestational age dependentGestational age dependent

Pregnancy: Cardiovascular Pregnancy: Cardiovascular changeschangesPregnancy: Cardiovascular Pregnancy: Cardiovascular changeschanges

Alterations in regional blood flowAlterations in regional blood flow flow to uterusflow to uterus renal blood flowrenal blood flow skin blood flowskin blood flow mammary blood flowmammary blood flow skeletal muscle blood flowskeletal muscle blood flow

Gastrointestinal changesGastrointestinal changesGastrointestinal changesGastrointestinal changes Gastric emptying delayedGastric emptying delayed Transit time increased (progesterone)Transit time increased (progesterone) Gastric acidity decreasedGastric acidity decreased

Renal changesRenal changesRenal changesRenal changes Increase in glomerular filtration rate Increase in glomerular filtration rate

Enzymatic activity changesEnzymatic activity changesEnzymatic activity changesEnzymatic activity changes ~ related to pregnancy hormonal changes~ related to pregnancy hormonal changes

Consequences of physiologic Consequences of physiologic changes: changes: Consequences of physiologic Consequences of physiologic changes: changes: Volume expansionVolume expansion Increase in free fraction of drug Increase in free fraction of drug

Due to decreased albuminDue to decreased albumin Clearance changes Clearance changes

Renal and enzymaticRenal and enzymatic Gastrointestinal changes in oral drugsGastrointestinal changes in oral drugs

Result: Dosing changesResult: Dosing changes

Increased cardiac outputIncreased cardiac output Increased GFRIncreased GFR DiuresisDiuresis BreastfeedingBreastfeeding Significant variability between individualsSignificant variability between individuals

Consequences of physiologic Consequences of physiologic changes: changes: Consequences of physiologic Consequences of physiologic changes: changes:

PostpartumPostpartum

Timing: Effect of gestational ageTiming: Effect of gestational ageTiming: Effect of gestational ageTiming: Effect of gestational age

1st 3rd2nd

embryogenesis

fetal development

Maternal fetal transferMaternal fetal transferMaternal fetal transferMaternal fetal transfer

Placental transferPlacental transfer Drugs & metabolites in fetusDrugs & metabolites in fetus Fetal GI absorptionFetal GI absorption Transfer via breastmilkTransfer via breastmilk

Monitoring fetal drug levelsMonitoring fetal drug levelsMonitoring fetal drug levelsMonitoring fetal drug levels

DifficultDifficult Often rely on clinical exam, responseOften rely on clinical exam, response Aim for Aim for lowest effectivelowest effective dose dose Fetal condition: ultrasoundFetal condition: ultrasound

cordocentesis: limited cordocentesis: limited rolerole

Ethical considerations & study Ethical considerations & study designdesignEthical considerations & study Ethical considerations & study designdesign

Drug labeling inadequate for guidance in Drug labeling inadequate for guidance in pregnancypregnancy

Research available on drugs in pregnancy is Research available on drugs in pregnancy is sparsesparse

Pharmacokinetic studies in pregnancy inadequatePharmacokinetic studies in pregnancy inadequate IRB difficultiesIRB difficulties Pharmaceutical companies Pharmaceutical companies NOT INTERESTEDNOT INTERESTED

NICHD & FDA Initiatives:NICHD & FDA Initiatives:NICHD & FDA Initiatives:NICHD & FDA Initiatives:

Workshop: fall 2000, Bethesda MDWorkshop: fall 2000, Bethesda MD

Future Meeting Future Meeting

Research on pharmacokinetics and pharmacodynamics Research on pharmacokinetics and pharmacodynamics of therapeutic drugs used in 2nd and 3rd ∆ of pregnancyof therapeutic drugs used in 2nd and 3rd ∆ of pregnancy

• Discuss issues• Generate interest• Stimulate research initiatives• Generate mechanisms for study

Bottom lineBottom lineBottom lineBottom line Therapeutic drugs required in pregnancyTherapeutic drugs required in pregnancy Research needed to evaluateResearch needed to evaluate

EfficacyEfficacy SafetySafety Required alterations in dosing, timing, etcRequired alterations in dosing, timing, etc

Pharmaceutical companies will never providePharmaceutical companies will never provide