Drug Use During Pregnancy and Lactation

Ma. Stephanie Fay S. Cagayan, MD,FPOGSAssociate Professor

UPCMASMPH

September 11, 2008

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

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

Increasing burden of chronic disease

Effects of increased maternal age

Obstetric complicationsHigher rates of placental abruption,

previa, preterm birth and SGA infantsOverall rates of poor outcomes low

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”

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

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

Let Us Review…

1. Normal Fetal Development and Factors Affecting Teratogenicity

2. Physiologic Changes in Pregnancy3. Maternal-Placental-Fetal Effect on Drug

Disposition

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.

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

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

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

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

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

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

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

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

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

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

Teratogenic Factors

Timing of exposure Developmental stage during exposure Maternal dose and duration Maternal pharmacokinetics Genetic factors/phenotypes Interactions between agents

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

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

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

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

Drug Transfer to the Fetus

Placental transfer may occur by: Passive diffusion Facilitated diffusion Active transport

Placental surface area Placental metabolism

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

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

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

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

Drug Concentration in Breast Milk

Lower pH than serum Varying degrees of fat concentrations

Foremilk Hindmilk

Milk/Plasma ratio

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

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

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

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

Case 1

How does the cardiovascular system change in pregnancy?

How might these changes affect a patient with cardiac disease?

What would you do?

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

Key physiologic changes: cardiovascular

Oncotic changes: Increased plasma volume by 50% Increased red cell mass by 33%Resulting dilutional anemia

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

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%

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?

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

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

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

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

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

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?

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

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

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%

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?

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

Key physiologic changes: pulmonary

Greater tendency to pulmonary edema Increased cardiac output

Decreased oncotic pressure

Leaky capillaries

Aggressive IV fluids

Meds

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

Key physiologic changes: endocrineEndocrine:

Insulin resistance, dyslipidemiaRelative TSH suppression in first trimesterOther thyroid changes

Key physiologic changes: renal

Increased glomerular filtration rate Baseline proteinuria increasesDrugs metabolized more rapidly by kidney

Creatinine fallsCollecting system dilates

Case #2

Managed with treatment dose low molecular weight heparin, converted to subcutaneous unfractionated heparin at 36 weeks

Vaginal delivery of healthy baby boy

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.

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.

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.

Anti-infectives Penicillins Cephalosporins Carbapenems Fluoroquinolones Macrolides Aminoglycosides

Sulfonamides Miscellaneous

Antibiotics Antivirals Antiretrovirals Antifungals

Penicillins

Category B in pregnancy Cross the placenta easily and rapidly Concentrations equal maternal

levels

Lactation Crosses in low concentrations Compatible with breastfeeding

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Antifungals/Polyenes

Amphotericin B Pregnancy Category B, compatible,

lipid complexes also compatible Lactation – no data available

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?

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?

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

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

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

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!

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

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

Good day!