Drug Use During Pregnancy and Lactation

Drug Use During Pregnancy and Lactation

Ma. Stephanie Fay S. Cagayan, MD,FPOGS Associate Professor UPCM ASMPH 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

Effects of increased maternal age  More

preconception chronic disease  More women with severe illnesses of  childhood surviving to reproductive age 

Congenital heart disease  Type I DM

Joseph, K, Obstetrics and

Increasing burden of chronic disease

Effects of increased maternal age Obstetric  Higher

complications

rates of placental abruption, previa, preterm birth and SGA infants  Overall rates of poor outcomes low

Pregnancy and chronic disease  Pregnancy

likely to unmask occult chronic

disease Glucose

intolerance Renal dysfunction Hypercoaguable states Valvular heart disease Cerebral aneurysm  Pregnancy

as a “stress test for life” 

Kaaja and Greer, JAMA 2006

Approach to Medical Illness in Pregnancy Great

need for primary providers to understand medical illness in pregnancy  Management

of medical illness including appropriate contraception  Preconception counseling and patient education  Collaboration with subspecialists, MFM’s

Approach to Medical Illness in Pregnancy The  An

tools you need:

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 Pregnancy 3. 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 -1  Dose-response

relationship  susceptibility varies with dose of  agent every

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 -2  Susceptibility

depends on stage of  development at time of exposure  Pre-implantation period= “all-or-none”  period  Organogenesis = 2-8 weeks post conception  Fetal period = 9 weeks- delivery

Pre-implantation period  Also

known as the “all-or-none” period  Few 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 period  Period

of organogenesis  2-8 weeks post conception  Time of greatest susceptibility to teratogens  Critical stages for malformations of different organ systems during this period  neural tube closes by 30 days post conception  limb buds develop  heart

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 trimester  varicella

Fetal period (continued)  Birth

defects may result from certain exposures causing deformations/vascular accidents in this period  Oligohydramnios sequence NSAIDS ACE

inhibitors

 Hypotension/

cardiac arrhythmias/ hypoxia  / ischaemia sequence cocaine phenytoin anti-arrhythmics

Examples of critical timing  Warfarin  critical

period 6-9 weeks gestation  Tetracyclines  safe until 16 weeks  ACE inhibitors  probably safe until 14-16 weeks  NSAIDs  avoid

from 30-32/40 until term

Parameters determining teratogenic action-3 Genetic

influence

 Susceptibility

to a teratogen depends upon the genotype of the conceptus and the way in which it interacts with environmental factors  Species differences  Strain 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 embryo

 For

chemicals, placental transfer depends on certain characteristics lipid solubility degree of ionisation protein binding surface available for diffusion pH molecular weight  MW

>1000 do not readily cross placenta  MW >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 Increased minute ventilation

Decreased gastrointestinal motility Increased thinning of  fetomaternal barrier with advancing gestation Decreased albumin

Drug Transfer to the Fetus 

Placental transfer may occur by:  Passive

diffusion  Facilitated 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

nausea  On exam BP

105/60, HR 90 4/6 systolic murmur at apexaxilla

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 weeks Maximum blood volume expansion at 28 weeks Labor 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 disease  Regurgitant

lesions improve with lower SBP  Stenotic 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 rate Aortic stenosis: sudden blood loss Regurgitant lesions: increased preload

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 arrhythmia  Left sided obstruction in mitral or aortic valve  Ejection fraction less than 40%

Siu, SC, Circulation 2001

Case 1 Echo

shows rheumatic mitral stenosis The cardiologist recommends meds to control her heart rate How would you decide which medicines are safe to give her in pregnancy?

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 nonprescription meds Lee R, 2000

Prescribing in pregnancy  Have

a pregnancy medication reference available  Favor older medicines with longer record of  use  Check 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 Powrie, R SGIM 2000

Prescribing in pregnancy  Educate 

Pregnant women more likely to stop needed meds

 Report 

and negotiate with your patient

adverse outcomes

Add webs

 Always

consider the effect of not treating  Remember that few drugs are absolutely contraindicated

Drugs to avoid in pregnancy        

ACE inhibitors: inhibitors: renal dysgenesis Tetracycline: Tetracycline: abnormalities of bone and teeth Fluoroquinolones:: abnl cartilage development Fluoroquinolones Systemic retinoids: retinoids: CNS, craniofacial, CV defects Warfarin: Warfarin: skeletal and CNS defects Valproic acid: acid: neural tube defects NSAIDS: NSAIDS: bleeding, premature closure of the ductus arteriosis Live vaccines (MMR, oral polio, varicella, yellow fever): fever): may cross placenta

Lee, R 2000

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 risk  A drug may end up in category X simply if  it has no utility in pregnancy  Rarely updated Sciali, 2004 accessed from

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 distress Mom and baby boy left hospital doing well

Case #2 39

yo G4P2 for new primary care appointment Obese History of pulmonary embolus in prior pregnancy Upreg positive today, 9 weeks by LMP Complaining 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 ventilation

 Mediated

by progesterone  Increased tidal volume>>respiratory rate  Compensated respiratory alkalosis  Normal ABG in pregnancy: 7.43/29/100 PaCO2

of 40mmHg is very abnormal in pregnancy Fetus relies on high maternal PaO 2

Key physiologic changes: pulmonary Greater

tendency to pulmonary

edema  Increased

cardiac output

 Decreased  Leaky

capillaries

 Aggressive  Meds

oncotic pressure

IV fluids

Key physiologic changes in pregnancy: Hematologic  Hematologic/Immunologic:  Procoagulant

factors increase: factor VIII, vWF, fibrinogen  Protein S levels markedly reduced  Increased risk of venous clots Greatest

risk in post-partum period

Key physiologic changes: endocrine  Endocrine:  Insulin

resistance, dyslipidemia  Relative TSH suppression in first trimester  Other thyroid changes

Key physiologic changes: renal Increased

glomerular filtration rate

 Baseline

proteinuria increases  Drugs metabolized more rapidly by kidney Creatinine

falls Collecting 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 Med 2003 Jul

Common cardiac drugs and pregnancy Drug

Suitability for use in pregnancy

Beta blockers

Relatively safe. No evidence of teratogenicity. 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 Als o contains infor-mation from Reimold SC,

Anticoagulation therapy and outcomes during pregnancy Anticoagulation regime

Embryopathy (%)

Spontaneous abortion (%)

Thromboembolic complications (%)

Maternal death (%)

Warfarin throughout pregnancy

6.4

25

3.9

1.8

UFH throughout pregnancy

0

24

33

15

Low

0

20

60

40

Adjusted

0

25

25

6.7

UFH during first trimester, then warfarin

3.4

25

9.2

4.2

dose

dose

Tornos P. European Society of Cardiology Conference 2003; August

Anti-infectives 

Penicillins



Sulfonamides



Cephalosporins





Carbapenems

Miscellaneous Antibiotics



Fluoroquinolones



Antivirals



Macrolides



Antiretrovirals



Aminoglycosides



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-6PD 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 t he 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 pregnant Have fun!

References 

   

 

Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 6 th 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. 10 th 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 AOG B. aspirin at 28th week AOG C. loratidine at 36th week AOG D. tetracycline at 28th week AOG E. isotretinoin at 10th week AOG F. clotrimazole at 28 th week AOG G. Ofloxacn at 30th week AOG H. Methergine at 37th week AOG

Good day!