drug use during pregnancy and lactation
TRANSCRIPT
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Drug Use During Pregnancy and Lactation
Ma. Stephanie Fay S. Cagayan, MD,FPOGSAssociate Professor
UPCMASMPH
September 11, 2008
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Objectives
1. Give an overview on the effects of medical illness on pregnancy and vice versa
2. Recognize factors which determine drug passage across the placenta and into breast milk.
3. Identify aspects of medications that determine safety during pregnancy and lactation.
4. Review common medications and their use in pregnancy and lactation
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Joseph, K, Obstetrics and Gynecology, 2005
Effects of increased maternal age
More preconception chronic diseaseMore women with severe illnesses of
childhood surviving to reproductive age Congenital heart disease Type I DM
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Increasing burden of chronic disease
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Effects of increased maternal age
Obstetric complicationsHigher rates of placental abruption,
previa, preterm birth and SGA infantsOverall rates of poor outcomes low
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Kaaja and Greer, JAMA 2006
Pregnancy and chronic diseasePregnancy likely to unmask occult chronic
diseaseGlucose intolerance Renal dysfunctionHypercoaguable statesValvular heart diseaseCerebral aneurysm
Pregnancy as a “stress test for life”
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Approach to Medical Illness in Pregnancy
Great need for primary providers to understand medical illness in pregnancyManagement of medical illness including
appropriate contraceptionPreconception counseling and patient
education Collaboration with subspecialists, MFM’s
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Approach to Medical Illness in Pregnancy
The tools you need:An understanding of the physiologic
changes of pregnancy and how they affect disease
A basic knowledge of pregnancy specific illnesses
A strategy for evaluating drug safety in pregnancy and lactation
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Let Us Review…
1. Normal Fetal Development and Factors Affecting Teratogenicity
2. Physiologic Changes in Pregnancy3. Maternal-Placental-Fetal Effect on Drug
Disposition
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Teratogens
A substance, organism, physical agents or deficiency state capable of inducing abnormal structure or function such as: Gross structural abnormalities Functional deficiencies Intrauterine growth restriction Behavioral aberrations Demise
Dicke, JM. Med Clin North Am 1989;73:567-81.
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Parameters determining teratogenic action -1Parameters determining teratogenic action -1Dose-response relationship
susceptibility varies with dose of agentevery teratogen has a “no-effect” level
agents are true teratogens only when they disrupt development at doses that are not toxic to the mother
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Parameters determining teratogenic action -2Parameters determining teratogenic action -2
Susceptibility depends on stage of development at time of exposurePre-implantation period= “all-or-none”
periodOrganogenesis = 2-8 weeks post
conceptionFetal period = 9 weeks- delivery
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Pre-implantation periodAlso known as the “all-or-none” periodFew malformations originate during this
time because injuries to the embryo at this stage are likely to result in death of the conceptus or in repair and recovery
Fabro 1986
Exposure of embryos to teratogens during the first two weeks usually does not cause congenital malformations
Moore 1988
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Embryonic periodPeriod of organogenesis 2-8 weeks post conceptionTime of greatest susceptibility to teratogensCritical stages for malformations of different
organ systems during this periodneural tube closes by 30 days post
conception limb buds developheart
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Fetal period
Fetus less susceptible to teratogens but still susceptible to toxicity and behavioral teratogenicity as well as to vascular and other insults
Some agents paradoxically cause more problems in 2nd trimester than in 1st trimestervaricella
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Fetal period (continued)
Birth defects may result from certain exposures causing deformations/vascular accidents in this periodOligohydramnios sequence
NSAIDSACE inhibitors
Hypotension/ cardiac arrhythmias/ hypoxia / ischaemia sequencecocainephenytoinanti-arrhythmics
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Examples of critical timingWarfarin
critical period 6-9 weeks gestationTetracyclines
safe until 16 weeksACE inhibitors
probably safe until 14-16 weeksNSAIDs
avoid from 30-32/40 until term
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Parameters determining teratogenic action-3
Genetic influenceSusceptibility to a teratogen depends
upon the genotype of the conceptus and the way in which it interacts with environmental factors
Species differencesStrain differences Inter-individual variability
pharmacogenetics
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Degree of Ionization
Weak acids (barbiturates) – cross placenta rapidly in nondissociated lipid form at lower pH and less readily in ionized form at higher pH
Weak bases (local anesthetics and meperidine)- diffuse rapidly in non-ionic form at higher pH, and at lower pH become cations and are relatively nondiffusible
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Parameters determining teratogenic action - 4
Access to the embryoFor chemicals, placental transfer depends
on certain characteristicslipid solubilitydegree of ionisationprotein bindingsurface available for diffusionpHmolecular weight
MW >1000 do not readily cross placentaMW >600 usually cross the placenta
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Teratogenic Factors
Timing of exposure Developmental stage during exposure Maternal dose and duration Maternal pharmacokinetics Genetic factors/phenotypes Interactions between agents
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FDA Pregnancy Categories
Category not required if: Drug not absorbed systemically
AND No potential for indirect fetal harm
Otherwise, in addition to the pregnancy category, information on teratogenicity, effects on reproduction, and when available, effects on later growth, development and functional maturation of the child should be included
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FDA Pregnancy Categories
Major problems exist
Established in 1979 Lack of data in humans What does a “C” drug really mean Difficult to assign an “A” to any
drug Does not address lactation safety
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FDA Labeling Changes
3 categories – fertility, pregnancy, and lactation
Clinical considerations provides risks and possible alternatives
Summary risk assessment evaluates human and animal data
Discussion of underlying data used to formulate risk
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Maternal Adaptations in Pregnancy
Expanded intravascular volume
Increased renal blood flow and GFR
Increased progesterone activated hepatic metabolism
Decreased gastrointestinal motility
Increased thinning of fetomaternal barrier with advancing gestation
Increased minute ventilation
Decreased albumin
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Drug Transfer to the Fetus
Placental transfer may occur by: Passive diffusion Facilitated diffusion Active transport
Placental surface area Placental metabolism
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Drug Passage into Breast Milk
Diffusion from maternal plasma into milk
Higher maternal plasma levels mean higher breast milk concentrations
Equilibrium will be established with most drugs between milk and plasma
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Drug Transfer
Across Placenta Molecular weight Lipid solubility Ionization Protein binding Chemical Structure
Into Breast Milk Molecular weight Lipid solubility Ionization Protein binding Drug
concentration Drug equilibrium
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Other Factors
Across Placenta Size < 400
daltons High blood
concentration Similar
configuration
Into Breast Milk Size < 200
daltons Drug pKa Equilibration
speed High blood
concentration
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Fetal Drug Disposition
60 – 80% passes through liver, the rest travels through ductus venosus to heart and brain
Hepatic drug metabolism Adrenal gland metabolism Recirculation through amniotic fluid
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Drug Concentration in Breast Milk
Lower pH than serum Varying degrees of fat concentrations
Foremilk Hindmilk
Milk/Plasma ratio
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Calculating Drug Exposure
Milk consumption – 150 ml/kg/d Milk concentration – either Cpmax or
random sample Maximum exposure will be at Cpmax Relative infant dose - < 10% better
Infant dose/maternal dose using mg/kg/d
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Neonatal Factors
Volume of milk consumed Higher gastric pH Differences in GI flora GI transit time Higher concentrations of free drug Higher percentage of body water Lower rates of metabolism and excretion
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Infant Adverse Effects
GI – diarrhea, constipation, vomiting, feeding intolerance, hypoglycemia
CNS – lethargy, sedation, poor suckling, muscle hypotonia, tremors, restlessness, withdrawal upon discontinuation
Other – possible sensitization or allergic reaction, culture results if needed may be difficult to interpret
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Case 1
23 yo G1 at 9 weeks Feeling well with the exception of mild
nauseaOn exam
BP 105/60, HR 904/6 systolic murmur at apexaxilla
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Case 1
How does the cardiovascular system change in pregnancy?
How might these changes affect a patient with cardiac disease?
What would you do?
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Key physiologic changes: cardiovascular
Hemodynamic changes Blood volume/cardiac output increase
50% increase, with half of this by 8 weeksMaximum blood volume expansion at 28 weeksLabor may increase cardiac output another 50%
10-20% increase in HR 25% decrease in systemic vascular resistance
Systolic BP decreases by 5-10mmHg, diastolic by 10-15mmHg
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Key physiologic changes: cardiovascular
Oncotic changes: Increased plasma volume by 50% Increased red cell mass by 33%Resulting dilutional anemia
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Effects on valvular heart diseaseRegurgitant lesions improve with lower SBPStenotic lesions worsen
Increased HR and CO increase cardiac work Gradient across stenotic valve increases 25% of women with mitral stenosis present in
pregnancy Risk factors for decompensation
Mitral stenosis: increased heart rateAortic stenosis: sudden blood lossRegurgitant lesions: increased preload
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Siu, SC, Circulation 2001
Predictors of poor outcome in women with heart disease
New York Heart Association Class III or IV Symptoms with less than ordinary physical
activity or at rest
History of prior cardiac event or arrhythmiaLeft sided obstruction in mitral or aortic
valveEjection fraction less than 40%
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Case 1
Echo shows rheumatic mitral stenosisThe cardiologist recommends meds to
control her heart rateHow would you decide which
medicines are safe to give her in pregnancy?
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Lee R, 2000
Prescribing in pregnancy
Do not start any medication unless clearly indicated
Do not discontinue medicines that successfully maintain the maternal condition unless there are clear indications to do so
Ask about and document non-prescription meds
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Powrie, R SGIM 2000
Prescribing in pregnancyHave a pregnancy medication reference
availableFavor older medicines with longer record of
useCheck blood levels and consider increased
and/or more frequent dosing Increased volume of distribution, hepatic and
renal clearance Increased production of binding proteins—free
drug levels are better
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Prescribing in pregnancyEducate and negotiate with your patient
Pregnant women more likely to stop needed meds
Report adverse outcomes Add webs
Always consider the effect of not treatingRemember that few drugs are absolutely
contraindicated
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Lee, R 2000
Drugs to avoid in pregnancy
ACE inhibitors: renal dysgenesis Tetracycline: abnormalities of bone and teeth Fluoroquinolones: abnl cartilage development Systemic retinoids: CNS, craniofacial, CV defects Warfarin: skeletal and CNS defects Valproic acid: neural tube defects NSAIDS: bleeding, premature closure of the ductus
arteriosis Live vaccines (MMR, oral polio, varicella,
yellow fever): may cross placenta
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Sciali, 2004 accessed from www.reprotox.org
Limits of the FDA classification
Hard to remember May be misleading
Up to 60% of category X drugs have no human data
No information on degree of riskA drug may end up in category X simply if
it has no utility in pregnancyRarely updated
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Case #1
Your patient does well and presents to L&D at 37 weeks in early labor
How do you expect labor to affect her heart disease?
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Labor physiology
Uterine contractions increase preload (equivalent to 1-2 units of blood) and cardiac output up to 80%
Fluid shifts in a C-section can be even more abrupt—>vaginal delivery usually safer
Labor and the period immediately after delivery represent the period of maximal risk for cardiopulmonary decompensation
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Case #1
Patient developed pulmonary edema in labor
Successfully managed with metoprolol and low dose furosemide
C-section for fetal distressMom and baby boy left hospital doing
well
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Case #2
39 yo G4P2 for new primary care appointment
ObeseHistory of pulmonary embolus in prior
pregnancyUpreg positive today, 9 weeks by LMPComplaining of mild shortness of
breath, O2 sat is 93%
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Case #2
What are some changes in the respiratory and hematologic systems in pregnancy?
How might they affect this patient?What would you do next?
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Key physiologic changes: pulmonary
Increased minute ventilationMediated by progesterone Increased tidal volume>>respiratory rateCompensated respiratory alkalosis Normal ABG in pregnancy: 7.43/29/100
PaCO2 of 40mmHg is very abnormal in pregnancy
Fetus relies on high maternal PaO2
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Key physiologic changes: pulmonary
Greater tendency to pulmonary edema Increased cardiac output
Decreased oncotic pressure
Leaky capillaries
Aggressive IV fluids
Meds
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Key physiologic changes in pregnancy: Hematologic
Hematologic/Immunologic:Procoagulant factors increase: factor VIII,
vWF, fibrinogenProtein S levels markedly reduced Increased risk of venous clots
Greatest risk in post-partum period
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Key physiologic changes: endocrineEndocrine:
Insulin resistance, dyslipidemiaRelative TSH suppression in first trimesterOther thyroid changes
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Key physiologic changes: renal
Increased glomerular filtration rate Baseline proteinuria increasesDrugs metabolized more rapidly by kidney
Creatinine fallsCollecting system dilates
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Case #2
Managed with treatment dose low molecular weight heparin, converted to subcutaneous unfractionated heparin at 36 weeks
Vaginal delivery of healthy baby boy
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Common cardiac drugs and pregnancy
Drug Suitability for use in pregnancy Digoxin Relatively safe
Methyldopa Safe. Recommended for first-line use in hypertension.
Diuretics Use controversial as concern that they might promote preeclampsia. Use only if volume excess; reduces placental blood flow; hyponatremia.
ACE inhibitors Contraindicated. High risk of fetal defects, spontaneous abortion.
Hydralazine Safe. Useful in heart failure during pregnancy.
*Adapted from Grubb NR and Newby DE. Churchill's Pocketbook of Cardiology. London, UK: Churchill Livingstone; 2000. Also contains infor-mation from Reimold SC, Rutherford JD. N Engl J Med 2003 Jul 3; 349:52-9.
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Common cardiac drugs and pregnancy
Drug Suitability for use in pregnancy Beta blockers Relatively safe. No evidence of terato-
genicity. Can cause growth retardation, fetal bradycardia, hypoglycemia at birth.
Ca2+ channel blockers
IV or short-acting versions can cause maternal hypotension. Fetal abnormalities rare. High levels excreted in breast milk.
Amiodarone Avoid if possible. Causes growth retardation, neonatal hypothyroidism, premature birth.
Adenosine Safe. For immediate conversion of SVTs.
Procainamide Safe. Occasionally used for conversion of atrial or ventricular arrhythmias.
*Adapted from Grubb NR and Newby DE. Churchill's Pocketbook of Cardiology. London, UK: Churchill Livingstone; 2000. Also contains infor-mation from Reimold SC, Rutherford JD. N Engl J Med 2003 Jul 3; 349:52-9.
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Anticoagulation therapy and
outcomes during pregnancy
Anti-coagulation regime
Embryo-pathy (%)
Spontaneous abortion (%)
Thromboembolic complications (%)
Maternal death (%)
Warfarin throughout pregnancy
6.4 25 3.9 1.8
UFH throughout pregnancy
0 24 33 15
Low dose 0 20 60 40 Adjusted dose
0 25 25 6.7
UFH during first trimester, then warfarin
3.4 25 9.2 4.2
Tornos P. European Society of Cardiology Conference 2003; August 30 - September 3, 2003; Vienna, Austria.
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Anti-infectives Penicillins Cephalosporins Carbapenems Fluoroquinolones Macrolides Aminoglycosides
Sulfonamides Miscellaneous
Antibiotics Antivirals Antiretrovirals Antifungals
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Penicillins
Category B in pregnancy Cross the placenta easily and rapidly Concentrations equal maternal
levels
Lactation Crosses in low concentrations Compatible with breastfeeding
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Cephalosporins Category B in pregnancy
Cross the placenta during pregnancy Some reports of increased anomalies
with specific cephalosporins (cefaclor, cephalexin, cephradrine)
Primarily cardiac and oral cleft defects
Lactation Excreted into breastmilk in low
concentrations Considered compatible with
breastfeeding
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Fluoroquinolones(floxins)
Pregnancy Category C Not recommended in pregnancy Cartilage damage in animals Safer alternatives usually exist
Lactation Excreted into breastmilk Limited human data AAP says compatible with breastfeeding
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Macrolides(azithromycin, clarithromycin, erythromycin)
Pregnancy Categories B/C/B Cross the placenta in low amounts Limited data with azithromycin and
clarithromycin
Lactation Erythromycin compatible Others probably compatible
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Aminoglycosides(amikacin, gentamicin, tobramycin)
Pregnancy Category C Rapidly cross placenta Enter amniotic fluid through fetal
circulation
Lactation Compatible with breastfeeding Not absorbed through GI tract
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Sulfonamides
Pregnancy Category C Readily cross the placenta Concerns of use at term
Lactation Excreted into breastmilk in low levels Use should be avoided in premature
infants
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Tetracyclines (doxycycline, minocycline, tetracycline)
Pregnancy Category D Can cause problems with teeth and bone
and other defects/effects Have been linked to maternal liver
toxicity
Lactation Compatible with breastfeeding Serum levels in infants undetectable
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Miscellaneous Antibiotics
Aztreonam Pregnancy Category B, likely safe in
pregnancy, little human data Lactation – Compatible per AAP
Clindamycin Pregnancy Category B, commonly used Lactation – Compatible per AAP
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Miscellaneous Antibiotics Linezolid
Pregnancy Category C, no human data available
Lactation – unknown, myelosuppression in animals
Metronidazole Pregnancy Category B, carcinogenic in
animals, avoid in 1st trimester if possible Lactation – hold feeds for 12-24hrs
afterward
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Miscellaneous Antibiotics Nitrofurantoin
Pregnancy Category B, possible hemolytic anemia with use at term
Lactation – Compatible, avoid with G-6-PD deficiency
Trimethoprim Pregnancy Category C, potentially
problematic early in pregnancy Lactation – Compatible as combination
drug
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Antivirals(acyclovir, famciclovir, valacyclovir)
Pregnancy Category B Acyclovir and valacyclovir readily cross
the placenta Can be used for HSV treatment and
suppression Lactation
Acyclovir and valacyclovir are compatible Famciclovir should be avoided
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Antiretrovirals/NRTI(abacavir, didanosine (ddI), emtricitabine (FTC))
Pregnancy Categories C/B/B Maternal benefit usually outweighs fetal
risk Cross the placenta Limited data with each do not show
increased risk of anomalies Didanosine has been associated with
severe lactic acidosis w/ or w/o pancreatitis
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Antiretrovirals/NRTI(lamuvidine (3TC), stavudine (d4T))
Pregnancy Category C Maternal benefit usually outweighs fetal risk Cross the placenta by simple diffusion Data with lamivudine show no increased risk of
anomalies Stavudine has been associated with severe lactic
acidosis w/ or w/o pancreatitis All NRTIs have been possibly linked to
mitochondrial dysfunction postnatally
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Antiretrovirals/NRTI(tenofivir, zalcitabine (ddC), zidovudine (AZT))
Pregnancy Category B/C/C Maternal benefit usually outweighs fetal risk Cross the placenta by simple diffusion Limited data with zalcitabine do not show
increased risk of anomalies Zidovudine is commonly used, but may cause
neonatal anemia Limited data with tenofivir show low risk of
teratogenicity
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Antiretrovirals/NNRTI(delavirdine, efavirenz, nevirapine)
Pregnancy Category C Maternal risk usually outweighs fetal risk Likely cross into fetus (nevirapine readily) Delavirdine has possible VSD risk, but limited
human data Efavirenz is associated with anomalies in
monkeys, limited human data, possible NTD Nevirapine can cause hepatotoxicity and rash Nevirapine can be used as a single dose in labor
to prevent HIV transmission
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Antiretrovirals/PI
Pregnancy Category B/C Maternal benefit usually outweighs fetal
risk Likely cross the placenta All PIs can cause hyperglycemia (
GDM?) Atazanavir can cause hyperbilirubinemia Indinavir can cause nephrolithiasis
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Antiretrovirals/Fusion Inhibitor(enfuvirtide)
Pregnancy Category B Maternal benefit usually outweighs fetal
risk Very large molecule (4492 daltons),
likely does not cross placenta Animal data does not show risk No human data available Hold during first trimester if possible
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Antifungals/Azoles (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)
Pregnancy Categories C/C/C/D Likely cross placenta Fluconazole > 400mg/day seems to be
associated with cranio-facial abnormalities Itraconazole appears to have low risk Ketoconazole can impair testosterone and
cortisol synthesis No data in humans is available for voriconazole,
increased risk in animals
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Antifungals/Azoles(fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)
Lactation Fluconazole is compatible per AAP Itraconazole could concentrate in milk
and body tissues, not recommended Ketoconazole is compatible per AAP No data with voriconazole, not
recommended
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Antifungals/Polyenes
Amphotericin B Pregnancy Category B, compatible,
lipid complexes also compatible Lactation – no data available
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Questions to Ask
Are there alternative therapies? Can treatment wait until postpartum? Is the disease worse than the therapy? What does the available literature say?
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Questions to Ask
Is this drug used in neonates? How old is the infant? What is the duration of therapy? What are the pharmacokinetics of the
agent? What is the risk/benefit for the mother? Does this medicine cause problems in
G6PD deficiency?
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Considerations in Breastfeeding
Withhold or delay therapy if possible Use a drug with poor penetration into milk Use an alternate route of administration Avoid nursing at peak drug concentrations Give drug before infants longest sleep Pump and dump milk Discontinue breastfeeding
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References for Pregnancy Briggs – Drugs in
Pregnancy and Lactation
Shepard – Catalog of Teratogenic Agents
Primary literature Registries for specific
drugs or drug classes Databases such as
ReproTox or Teris
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References for Lactation
Briggs – Drugs in Pregnancy and Lactation Hale – Medications and Mothers’ Milk American Academy of Pediatrics Micromedex Primary literature Infant’s pediatrician Pediatric dosing handbooks
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Medical illness and Pregnancy
Remember the key physiologic changes
Have prescribing references available Think about what you would do if she
weren’t pregnantHave fun!
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References Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy
and Lactation. 6th ed. Philadelphia, PA: Lippencott, Williams & Wilkins. 2002
Boothby LA, Doering PL. FDA labeling system for drugs in pregnancy. Ann Pharmacother 2001;35:1485-9.
Hale TW. Medications and Mothers’ Milk. 10th ed. Amarillo, TX: Pharmasoft Publishing 2002.
Anderson, PO. Drug use during breastfeeding. Clin Pharm 1991;10:594-624
Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
Micromedex, 2007 update, Thomson Healthcare, Inc Medline searches for each agent
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Write Yes or No
The following drugs can be given to a pregnant woman
A. cefuroxime during 5 weeks AOGB. aspirin at 28th week AOGC. loratidine at 36th week AOGD. tetracycline at 28th week AOGE. isotretinoin at 10th week AOGF. clotrimazole at 28th week AOGG. Ofloxacn at 30th week AOGH. Methergine at 37th week AOG
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Good day!