Download Pharmacotherapy in Pregnancy

Pharmacotherapy in Pregnancy:
Balancing Risks and Benefits
Myla Moretti
The Hospital for Sick Children
September 9, 2004
Outline
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Definitions and History
Possible effects of drugs on the fetus
Assessing risk: methods and challenges
Current known or suspected teratogens
Common questions/problems
Resources
Drug Use in Pregnancy
• the effects of a drug on human pregnancies is rarely
evaluated before market release
• CPS typically states “use in pregnancy is not
recommended unless the potential benefits justify the
potential risks to the fetus”
• disclaimers such as this, while important medico-legally,
can be misleading and particularly worrisome for the
50% of women who have not planned their pregnancies
Definitions
• Teratology: the science addressing inborn defects due to
different factors
• Teratogenesis: dysgenesis of fetal organ(s) manifested
either structurally or functionally
• Teratogen: an agent that may have harmful effects on
the developing fetus
Types of Malformation
• Major Malformation: structural or functional defects
for which medical or surgical intervention is necessary,
or a defect that can impair the child’s lifestyle or social
acceptability
• Minor malformations: unusual morphologic traits of
no serious medical or cosmetic consequence to the child,
but might signify a major malformation complex
A Brief History
• 50% of women will take at least 1 drug in pregnancy
• 1941 - the discovery of Rubella as a human teratogen
was an important milestone in the field of teratology
• 1961 - Thalidomide taught us that the placenta was not a
barrier to drugs as once thought
Effects on the Fetus/Infant
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malformation (anatomical), disruption, deformation
IUGR
fetal loss/neonatal loss
fetal/neonatal toxicity or withdrawal
neurodevelopmental (cognitive or behavioural)
other long term effects (carcinogenesis)
The Challenge
• How to treat the mother without adversely effecting the
fetus?
• in many cases not treating will increase maternal and
fetal risk (HIV, asthma, hypertension, diabetes, morning
sickness)
Karnofsky’s Law
• Everything is teratogenic if given at the right dose,
to the right species, at the right time
• Producing positive results in teratology studies is
only a matter of finding a sensitive stage in a
sensitive species and of using an appropriately high
dose of the toxicant
Physiologic Changes in Pregnancy
• pregnancy is a time where there can be significant
changes in maternal physiology
• these changes may be associated with altered responses
to drugs
• this includes:  albumin concentration
 plasma volume
 cardiac output
 renal blood flow
 renal elimination
 uterine blood flow
changes in enzymatic activity
Risk-Benefit Analysis
Risks
Benefits
• good control of maternal
disease
• improved pregnancy
outcome
• not treating mom
• teratogenesis
• poor pregnancy
outcome
• most drugs cross the placenta easily
• dictated by molecular size
• but, even drugs which do not cross may cause
physiologic changes in the mother or placenta which can
lead to unknown fetal effects
Methods of Assessing Risk
IN VIVO
• animal studies
• case reports/case series
• observational cohort studies
– prospective or retrospective
– workplace assessments
– registries
• case-control studies
• meta-analytical reviews
IN VITRO
• placental perfusion studies
Establishing Risk
• temporal relationship
– exposure at critical times of development
– exposure precedes event
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consistent findings across studies (of good quality)
specific defect, pattern or adverse outcome noted
rare exposure associated with a rare event
secular trends
biological plausibility?
dose response
animal or experimental proof
Obtaining and Interpreting the Data
• is it ethical?
• is it doable?
• statistics and power
– How much is enough?
Obtaining and Interpreting the Data
• is it ethical?
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• statistics and power
is it doable?
– How much is enough?
• figuring out confounders (underlying maternal illnesses)
• bias from
– the patient
– the physician
– the researcher
• role of the media
• less than 1% of all major malformations are known to be
caused by drugs
• 1-2% mechanical deformation
• 3% maternal infection (CMV, rubella)
• 4% maternal illness (diabetes)
• 25% of genetic origin
• 65% multifactorial/unknown
Known/Suspected Teratogens
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ACE inhibitors
anticonvulsants
benzodiazepines
carbon monoxide
DES
ethanol
hyperthermia
lead
lithium
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misoprostol
organic solvents
retinoids
rubella
systemic corticosteroids
tetracyclines
varicella
warfarin
Case
• Your 27 y.o. patient has been successfully treated with
fluoxetine (Prozac) and lorazepam (Ativan) for
depression and anxiety. Within the last six months she
was hospitalized following a suicide attempt and is
currently well controlled. She is planning to start a
family in the next year. When approaching you for her
next refill she asks how long it will take for these drugs
to “get out of her system.” She tells you that she knows
one should never take medications while pregnant.
Evidence
• several studies have not shown increased risk for
malformations following the use of SSRI’s in pregnancy
• fluoxetine (Prozac) and citalopram (Celexa) reported in the
greatest numbers
• tricyclic antidepressants also not shown to pose risk for birth
defects
• there is some concern for neonatal toxicity/withdrawal,
although incidence is not known
• neurodevelopment in children (up to 5 yrs) did not show any
impairments
• benzodiazepine studies have been conflicting
Answer
• assure patient that many medications can be taken safely
• remind her of the risks of poorly controlled disease (suicide
attempt, hospitalization, poor eating habits)
• available data does not indicate that the fetus will be at
significant risk if drug therapy continues throughout
pregnancy
• depending on clinical presentation, consider tapering and
discontinuing benzodiazepine if possible
• if not, Level II ultrasound to rule out visible forms of cleft
(risk remains very small)
Case
• A 32 y.o. patient comes to you, frantic. A home
pregnancy test is positive and last week her allergies
were acting up. She was taking over-the-counter,
Benadryl (diphenhydramine) daily and Claritin
(loratadine) occasionally. She also took several tablets
of acetaminophen because of accompanying headaches.
She is not sure if she should terminate this pregnancy
and is very concerned about the effects of these drugs on
her unborn child. She can not get an appointment to see
her doctor right away.
Allergic Rhinitis in Pregnancy
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affects 20-30% of women of childbearing age
rhinitis probably has no direct adverse effect on pregnancy
indirectly: may interfere with sleep and eating habits
in uncontrolled may exacerbate coexisting asthma
pregnancy related hormonal changes may lead to nasal
mucosal swelling, and increase in secretion by the nasal
mucosal glands
• symptoms worsen in 1/3 of women
Pharmacological Therapy
• first generation antihistamines are well studied and
considered first-line (chlorpheniramine, diphenhydramine,
triprolidine)
• second generation antihistamines have preferred side-effect
profile although less pregnancy data exists
• nasal sprays (sodium cromoglycate, corticosteroids) will
relieve nasal congestion and have not been linked with birth
defects
• decongestants (nasal sprays, oral pseudoephedrine*) also
effective and small studies do not seem to indicate
significant risk
*gastroschisis risk not yet ruled out
Answer
• reassure patient that acetaminophen at therapeutic doses is
not harmful to the pregnancy or fetus and studies have not
shown any link with birth defects
• first generation antihistamine (Benadryl) is well studied and
not a concern
• second generation antihistamine (Claritin) is less well
studied but the available data also did not show a risk for
malformations
• confirm pregnancy by blood test and check dates
(ie. pre-implantation?)
• none of these exposures is an indication for termination
Resources
• The Motherisk Program at Sick Kids 416-813-6780
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recorded message service (for most common calls)
WW W.MOTHERISK.ORG
Canadian Family Physician
Motherisk Newsletter (published online only)
– specialized information lines
• Nausea and Vomiting of Pregnancy Line
• HIV Healthline and Network
• Alcohol and Substance Use Line
1-800-436-8477
1-888-246-5840
1-877-FAS-INFO
Texts
Texts
• Briggs, Freeman & Yaffe. Drugs in Pregnancy and Lactation:a
Reference Guide to Fetal and Neonatal Risk. 6th ed. Baltimore, MD:
Lippincott, Wiliams & Wilkins, 2001.
• Friedman JM, Polifka JE: Teratogenic Effects of Drugs: a Resource for
Clinicians (TERIS), 2nd ed. Baltimore, MD: Johns Hopkins University
Press, 2000.
• Koren G. Maternal-Fetal Toxicology. A Clinician’s Guide, 3rd ed. New
York, NY: Marcel Dekker, 2001.
• Scialli AR, Lione A, Boyle Padgett GK: Reproductive Effects of
Chemical, Physical, and Biologic Agents. Baltimore, MD:Johns
Hopkins University Press, 1995.
• Shepard TH: Catalog of Teratogenic Agents, 10th ed. Baltimore,
MD:Johns Hopkins University Press,2001
Web Sites
• The Organization of Teratology Information Services
http://www.otispregnancy.org
• DART/ETIC: A literature search engine for developmental and
reproductive toxicology from the National Library of Medicine
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?DARTETIC.htm
• Reprotox: An Information System on Environmental Hazards to
Human Reproduction and Development (Subscription required)
http://www.reprotox.org/
• TERIS – Teratogen Information System and the on-line version of
Shepard's Catalog of Teratogenic Agents (Subscription required)
http://depts.washington.edu/~terisweb/teris/index.html
Articles
• Moretti ME. Pharmacy Practice, May 2002;18(5):38-44
– simple review of common OTC agents
• Brent RL. Pediatrics in Review, 2001;22(5):153-165.
• Rubin P. Br Med J, 1998;317:1503-1506.