Download prescribing in pregnancy

Medical Illness
in Pregnancy 2015
Raymond Powrie MD FRCP(C) FACP
Professor of Medicine, Obstetrics & Gynecology
Alpert School of Medicine at Brown University
Interim Chief of Medicine
Women & Infants Hospital of Rhode Island
Chief Medical Quality Officer
Care New England
24 year old asthmatic on
albuterol (Ventolin®),
fluticasone (Flovent®)
inhaler and zafirlukast
(Accolate®) thinking about
getting pregnant.
“I would never take a
medication while I was
pregnant”
Cultural Aversion
• There is a tendency for both
patients and clinicians to
withhold medications in
pregnancy because of insecurity
about fetal effects.
• but...
...Widespread use
• Pregnant women ingest an average of 3 different
prescription medications during pregnancy
(ranging from 0 to 15).
– antimicrobial, antiemetics, tranquillizers and analgesics
most common
• 86% of the women studied had taken at least one
prescription medication during their pregnancy.
• This does not include the use of over the counter
medications.
“If I did take a medication in
pregnancy it would have to
be one that I knew would
never get across the
placenta”
Despite beliefs to the
contrary, no “placental
barrier” exists.
• The fetus will be exposed to
any medication that can be
taken orally
• Drug levels in the fetus may
be the same, lower or higher
than in the mother
“If that is true, then I would
only take a medication that
solid research in humans has
shown would be safe for my
baby”
Problems with Research on
Drug Safety in Pregnancy
• Rigorous studies on humans
about medication use in
pregnancy are rarely done
because they are difficult and
expensive.
1. Pregnancy drug safety research
needs to look at many variables
• Malformation
– Most precautionary information about
medication use in pregnancy relates only to
anatomic defects noted in newborns.
•
•
•
•
Intrauterine death
Growth impairment
Neonatal toxicity
Behavioral toxicity
2. Pregnancy drug safety
research needs to be long-term
• Some toxicities may not be
apparent for years
– e.g. clonidine, DES
3. Pregnancy drug safety research
needs to involve large numbers
• Even the most teratogenic agents
are safe for the majority of
pregnancies
• Individuals probably have specific
genetic propensities for fetal
drug effects and these effects
may be missed (or over-rated) if
too small population is studied
4. Pregnancy drug safety research
is expensive and lacks funding
• Pharmaceutical industry rarely
supports research into the use of
non-obstetrical agents in
pregnancy
– Not interested in this line of
business!
“If there is little solid
human research into drugs
in pregnancy how do we
know anything about
medication safety in
pregnancy?”
Sources of pregnancy safety
data
– Animal studies
– Case reports
– Case registries
– Population studies
– Clinical trials
Problems with Animal Studies
• Animal data cannot be confidently
extrapolated to humans.
– There is a considerable variability
between species and even between
strains of a species as to the effects of
a medication on a developing fetus.
• Behavioral and intellectual effects of
medications are difficult to recognize in
animals
Problems with Case Reports
and Case Registries
• Suffer from a substantial recall
bias in that
– women who have a difficult
pregnancy outcome are more likely
to recall medication use in
pregnancy and
– clinicians are more likely to report
a difficult outcome.
Problems with Case Reports
and Case Registries
• Can raise false concerns about
medication effects
– 2-4% of infants born with some ‘defect’
•
•
•
•
20% due to chromosomal abnormalities
5% due to gene mutations
65% unexplained
Only 10% due to teratogenic agents
Population Studies
• Studies are usually done by
retrospectively comparing the
infants of mothers exposed to
the medication to those who
were not
– Do not examine WHY the
medication was given
Population Studies
• “Medication effects” observed in this
manner may reflect the reason the
mother was on the medication more
than the medication itself
– Phenytoin doubles the risk of congenital
anomalies
– However, congenital anomalies are
increased in infants of mothers and
fathers with epilepsy regardless of
treatment
“This all sounds do scary
and dangerous. How could
any woman take anything
while pregnant?”
Known teratogens
• Only about 30 known human teratogens
– coumadin
– cyclophosphamide
– diethyl stilboestrol (DES)
– phenytoin, carbamazepine, phenobarbital,
valproic acid
– lithium
– methimazole
– penicillamine
– thalidomide
– isotretinoin
– methotrexate
“I’ve heard that drugs in
pregnancy are really only
dangerous in the first trimester.
I think what I’ll do then is stop my
medications when I find out I am
pregnant and then only restart
them if I absolutely need them
later in the pregnancy”
Drug effects by gestational age
• Embryonic development occurs in first 60 days
– Exposures between 0-14 days can cause miscarriage (the
“all or nothing period”)
– Some toxicities will have already occurred before the
woman gets to a doctor to confirm her pregnancy
• Valproic acid causes neural tube defects but the neural
tube has completely closed by day 27
– Exposures from day 14-60 probably have specific “window
periods” of susceptibility to toxicities
• Thalidomide effects were seen only if taken between
days 21-36
Drug effects by gestational age
• After the first trimester
medications can still have effects
on:
– Behavior and neurological
development
– Growth
– Fetal survival
– Specific organ toxicities
“This is so confusing! How
does all this play itself out in
the real world?”
examples from the real world
ACE inhibitors
• Captopril released as FDA category B drug on the
basis of animal studies
• Post marketing surveillance showed an association
with oligohydramnios, fetal calvaria hypoplasia,
fetal pulmonary hypoplasia, IUGR, IUFD and
neonatal anuria
• Probably does not effect organogenesis but is
definitely fetotoxic –
– high levels of angiotensin II may be
physiologically necessary to maintain
glomerular filtration at low perfusion
pressures.
examples from the real world
Fluoroquinolones
• Irreversible arthropathy if given
to immature dogs
• No effects in mice, rats or rabbits
• 4 cases of arthropathy in
adolescents treated for CF
• 38 human first trimester
exposures without effect at mean
of 27 months
examples from the real world
Metronidazole
• Long considered a human
teratogen
– mutagenic in bacteria
– carcinogenic in mice
– 3 case reports of facial defects
in infants exposed between 5-7
weeks gestation
Metronidazole
• Review of literature in 1992
suggested that there was no
human risk
•combined 7 articles describing
253 prospective exposures
•found an odds ratio of 1.02 ( 95% CI
0.48-2.18)
“How in the world then do
you go about deciding which
medications I can take and
which ones I can’t?”
No drug is “safe” in
pregnancy, but at the same
time no drug is absolutely
contraindicated
No “safe” period
Use the “four questions
approach”
Prescribing in Pregnancy
Approach Question 1
• Is the medication necessary
or is the symptom to be
treated self limited and/or
amenable to
nonpharmacologic
management?
In this case the woman has mild
persistent asthma that used to land her
on prednisone and in the hospital twice
a year before she got on her albuterol
and fluticasone.
She has enacted preventive measures
in her life but had to go on zafirlukast
when her family got a dog two years
ago.
Prescribing in Pregnancy
Approach Question 2
• If the medication is NOT
administered, what are the
possible outcomes for mother
and fetus?
Fetal well being is dependant on maternal well
being
Studies repeatedly suggest
that poorly controlled
asthmatics are at increased
risk of IUGR, miscarriage and
preterm delivery while well
controlled asthmatics are
not!
Prescribing in Pregnancy
Approach Question 3
• What data is available on the
safety of this medication in
pregnancy and is there a
similar drug with better
safety data available that
could be used instead?
FDA classification
FOOD AND DRUG ADMINISTRATION PREGNANCY RISK CLASSIFICATION
Category A “Controlled studies show no risk”
Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester, there is no
evidence of a risk in later trimester, and therefore the possibility of fetal harm appears remote.
Category B “No evidence of risk in humans”
Either animal reproduction studies have not demonstrated a fetal risk but there
are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse
effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the
first trimester (and there is no evidence of a risk in later trimester).
Category C “Risk cannot be ruled out “
Either studies in animals have revealed adverse effect on the fetus (teratogenic) or appropriate animal
data is not available. Drugs should be given only if the potential benefit justifies the potential risk to the
fetus.
Category D “Positive evidence of risk “
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be
acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious
disease for which safer drugs cannot be used or are ineffective). There will be an appropriate statement
in the “warnings” section of the labeling.
Category X “Contraindicated in pregnancy”
Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal
risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is contraindicated in women who are or may be pregnant.
FOOD AND DRUG ADMINISTRATION
PREGNANCY RISK CLASSIFICATION
A Flawed system
• Officially abandoned by the
FDA
– Most drugs are class C
– Neglects indications
– Oversimplifies a complicated
issue
Resources to Assess Data on
Individual Drugs
Publication
Medications in Pregnancy and
Lactation
Shepard’s catalog of Teratogenic
Agents
Handbook for Prescribing
medications in Pregnancy
Effects of Medications on the
Fetus and Nursing Infant: A
Handbook for Health Care
Professional
Authors
Briggs GS, Freeman R, Yaffe S.
Thomas H. Shepard
Coustan DR and Mochizuli TK
Friedman JM and Polifka JE
Resources to Assess Data on
Individual Drugs
Publication
Authors
Medications & Mothers’ Milk: A
Manual of Lactational Pharmacology
Thomas Hale
Reprotox®
TERIS ®
• Reprotox® www.REPROTOX.org also distributed
by Micromedix, Inc.’s TOMES Reprorisk module
• TERIS www.weber.u.washington.edu also
distributed by Micromedix, Inc.’s TOMES Reprorisk
module
• FDA pregnancy categories found in most
prescription medication package inserts/labeling
and in Physician’s Desk Reference published
annually by Medical Economics Press
• Be particularly cautious about
newer agents - many fetal
toxicities have been
identified years after release.
For this patient
Use generally
justifiable
Inhaled steroids
Inhaled bronchodilators
Cromolyn
Ipatropium [Atrovent®]
Theophyllines
Systemic steroids
Use sometimes
justifiable
Leukotriene inhibitors
Use rarely if ever
justifiable
(montelukast [Singulair®] and
Zafirlukast [Accolate®] better
than zileuton [Zyflo®])
Prescribing in Pregnancy
Approach Question 4
• How is the patient’s (and the
provider’s) understanding
and value system affecting
decisions about the use of
this medication in pregnancy?
• Women believe that ‘teratogens’
lead to abnormalities in 25% of
infants
• 55% of articles in women’s
magazines about drugs in
pregnancy contain major
inaccuracies
How to talk to patients
about this issue
• Work with the patient to make a
judgement based on both the
available data and the indication of
a particular agent as to whether the
available information justifies or
warrants the risk inherent in the use
of the medication in pregnancy.
-Our patient has a friend who took cold
medicines during pregnancy whose
baby has a VSD that needed surgery
and is very worried about this
outcome.
-She’s crazy about her dog!
-You have a sister with asthma who has
ended up twice in the ICU due to
severe exacerbations.
-You gave your cat to the SPCA when
your son started having trouble with
allergies last year.
•
Working with you she
decides to:
• Come off the zafirlukast
• Switch from fluticasone
inhaler to beclomethasone
• Continue the albuterol
• Have her dog stay at a friends
until the second trimester
She switches her regimen and
conceives. However, her
asthma gets worse.
Are there any other specific
issues related to medication
use in pregnancy that need to
be considered?
Four issues to always
consider when medications
aren’t working
• Wrong regimen
• ‘Environmental’ issues
• Pharmacokinetic changes
• Compliance, compliance,
compliance!
Changes in pharmacokinetics in
pregnancy
• Volume of distribution changes: Plasma
volume increases to 150% of normal by 2428 weeks gestation so that the volume of
distribution is increased and therefore drugs
may require dosage adjustments.
• Protein binding alterations: physiological
delusional hypoalbuminemia may lead to an
increase in free drug levels for a particular
total serum level.
Changes in pharmacokinetics
in pregnancy
• Absorption changes: slowed gastrointestinal motility
may delay absorption of oral agents
• Renal clearance: glomerular filtration rates increase
in pregnancy to 150% of normal range and many
medications that are renally cleared require dosage
alterations in pregnancy
• Hepatic clearance: Hepatic clearance of
pharmacologic agents is often increased in
pregnancy
Labetalol
Pharmacokinetics in Pregnancy
Elimination
half life
(minutes)
Clearance
(mL/minute)
Pregnant 102
1704
Control
1430
160-480
What should the clinician do
about this?
• Consideration of monitoring of medication
levels and adjustments of medication
dosing is advisable in pregnancy.
– Free drug levels will be better guides than total
serum levels.
• Dosing intervals may need to be shortened
in pregnancy
– inadequate dosing frequency always needs
consideration in pregnancy as a possible cause
for treatment failure of agents during
pregnancy
Compliance
• Drug compliance can be a great
challenge in pregnancy
– drug labeling warnings,
pharmacists, and an unrealistically
high perception of teratogenic risk
all contribute
In this case, the woman admits to
not having taken only half her
recommended dose of her inhaled
steroids to minimize the impact on
her fetus.
After further discussions she
decides to start taking the
prescribed dose and does much
better.
Summary
• Think about drugs as indicated or not
indicated in pregnancy rather than
safe or not safe.
• Decide if a medication is necessary
and if so choose the best one
available for that indication balancing
benefits and risk data
• Collaborate with your patients