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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


Gynecology, 2005
Increasing burden of chronic
disease
Effects of increased maternal age

Obstetric complications
 Higher 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 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 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 Decreased
renal blood gastrointestinal motility
flow and GFR

Increased Increased thinning of


progesterone fetomaternal barrier with
activated hepatic advancing gestation
metabolism
Increased minute Decreased albumin
ventilation
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  Into Breast Milk
 Molecular weight  Molecular weight
 Lipid solubility  Lipid solubility
 Ionization  Ionization
 Protein binding  Protein binding
 Chemical Structure  Drug
concentration
 Drug equilibrium
Other Factors

 Across Placenta  Into Breast Milk


 Size < 400  Size < 200
daltons daltons
 High blood  Drug pKa
concentration  Equilibration
 Similar speed
configuration  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 non-
prescription 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 and negotiate with your patient
 Pregnant women more likely to stop needed meds
 Report 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: 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

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


www.reprotox.org
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 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, 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 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 IV or short-acting versions can cause
blockers 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- Embryo- Spontaneous Thromboembolic Maternal


coagulation pathy abortion (%) complications death
regime (%) (%) (%)
Warfarin 6.4 25 3.9 1.8
throughout
pregnancy
UFH 0 24 33 15
throughout
pregnancy
Low dose 0 20 60 40
Adjusted 0 25 25 6.7
dose

UFH during 3.4 25 9.2 4.2


first trimester,
then warfarin
Tornos P. European Society of Cardiology Conference 2003; August
30 - September 3, 2003; Vienna, Austria.
Anti-infectives
 Penicillins  Sulfonamides
 Cephalosporins  Miscellaneous
 Carbapenems 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-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 pregnant
Have 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 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 28th week AOG
G. Ofloxacn at 30th week AOG
H. Methergine at 37th week AOG
Good day!