Transcript Drugs in Pregnancy

Drug Therapy in the Pregnant
Dental Patient
Doreen Matsui MD, FRCPC
Associate Professor, Department of Paediatrics
Children’s Hospital of Western Ontario
Objectives
• To review general principles
regarding drugs in pregnancy
• To describe effects of drugs
commonly used in dentistry
• To briefly overview use of drugs
during breastfeeding
Drug Use in Pregnancy
(Larimore WL et al. Prim Care 2000;27:35-53)
• 1991 WHO International Survey of Drug
Utilization in Pregnancy
• 86% of women took medication during
pregnancy
• Average of 2.9 prescriptions
• Despite this high rate of medication intake,
most drugs are not labeled for use during
pregnancy
Inadvertent Exposure
• 1/2 of pregnancies unplanned
• Teratogenic potential should be
considered and explained to women of
childbearing age at time drug is
prescribed
– <50% of women know they are pregnant by 4th
week and ~20% still don’t know by 8th week
Drug Use in Pregnancy
(Van Trigt AM et al. Pharm World Sci 1994;16:254-9)
• Women interviewed within 2 weeks after
delivery
•  40% had had one or more questions about
drugs during their pregnancy
• Similar proportion said that during pregnancy
important to consult a health professional
before using any medication
• Safety was issue that raised the most questions
Compliance
• Pregnant women tend to comply
less than optimally with drug
therapy
• Misinformation
• 39% of women reported
noncompliance predominantly due
to hesitation to use drugs during
pregnancy (Van Trigt AM et al.
Pharm World Sci1994;16:254-9)
Perception of Teratogenic Risk
(Am J Obstet Gynecol 1989;160;1190-4)
• Women exposed to nonteratogens
assigned a risk of 24% for major
malformations
• Risk in general population 5.6%
• May be important factor in
decision to terminate pregnancy
Perception of Teratogenic Risk
(Sanz E et al. Eur J Obstet Gynecol Reprod Biol
2001;95:127-31)
• Perception of risk related to medication used in
pregnancy higher than the recognized risk in a
group of 15 GPs, 10 gynaecologists, 106 preclinical medical students, 150 medical students
in clinical training, 81 pregnant women and 63
non-pregnant women
General Considerations
• Almost all drugs cross the
placenta to some extent
• Majority of drugs have not
been associated with
adverse effects when taken
during pregnancy
• Weigh therapeutic benefits
of drug to mother against
its risk potential to
developing fetus
Adverse Effects
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Spontaneous abortion
Fetal growth retardation
Teratogenicity
Direct drug toxicity
Neonatal drug withdrawal
Long term effects on neurobehavioral
development
• Carcinogenesis
Teratogenic Risk
(Lo et al. Obstet Gynecol 2002;100:465-73)
• Standard clinical teratology databases
• 485 drugs approved by FDA 1980 - 2000
• Treatment with only small fraction (2.4%)
has been associated with substantial
teratogenic risk
• Took on average 6.0 ± 4.1 years after
approval to determine risk
Known Teratogens
• Alcohol (Ethanol)
• Carbamazepine
• Cytotoxic
chemotherapy
• DES
• Isotretinoin and
Etretinate
• Lithium
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Methimazole
Misoprostol
Phenytoin
Thalidomide
Trimethoprim
Valproic Acid
Warfarin
Baseline Risk
• Risk of major malformation (cosmetic or
functional significance) = 3% at birth
• Assessment of magnitude of increase in
risk above baseline is important
• Need to put risk in perspective
Important Factors
• Timing of exposure (sensitive period)
– “All-or-none” period
– *Organogenesis*
• “Avoid drug administration, if at all possible
during 1st trimester”
– Brain development
• Dose of drug (threshold, doseresponse)
• Genetic susceptibility
Associated Factors
• Role of underlying maternal
disease
• Other exposures such as
alcohol and cigarette
smoking
General Recommendations
• Minimize use of medications to those
which are necessary and for shortest
duration possible
• Effective drugs that have been in use
for long periods preferable to newer
alternatives
Evaluating Risk - Drug Studies
• Manufacturer almost never tests
product in pregnant women prior to
marketing
• Evidence from large clinical trials does
not exist
• Reproductive toxicology studies in
animals - extrapolation?
Animals vs Humans
• 40-50 chemical and physical agents probably
human developmental toxicants
• >1200 produce developmental defects in
experimental animals
• >80% of agents known to produce defects in
humans also cause defects in at least one
test animal
“CPS”
• Majority of drugs not labeled for use
during pregnancy
• “Safety of Drug X in pregnancy has not
been established. Drug X should not be
used during pregnancy unless the
potential benefit to the patient outweighs
the possible risk to the fetus.”
FDA Classification
• X, D, C, B, A
• Little correlation with risk
Sources of Information
• Reference Textbooks
– Drugs in Pregnancy and Lactation (Briggs)
– Maternal-Fetal Toxicology (Koren)
• Computer Databases
– Reprotox
– TERIS
• Teratogen Information Services
– Motherisk Program
– FRAME Program
The Pregnant Dental Patient
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Elective vs urgent
2nd trimester
Eliminate source of infection or pain
Usually short-term drug therapy
Penicillins
• Collaborative Perinatal Project
• Frequency of congenital anomalies no
greater than expected among children
of 4,356 women treated with penicillin
(or one of its derivatives) during 1st 4
lunar months of pregnancy
Penicillins and Cephalosporins
• Amoxicillin and cephalosporins also
considered safe to use during pregnancy
• No increased risk of malformations with
amoxicillin/clavulanic acid (Clavulin) in 2
studies (Br J Clin Pharmacol 2004;58:298302 and Eur J Obstet Gynecol Reprod Biol
2001;97:188-92)
Erythromycin
• Surveillance study of Michigan Medicaid
recipients (1985-1992)
• No association between drug and
congenital malformations in 6,972
newborns exposed during 1st trimester
• Avoid estolate form (cholestatic hepatitis)
• Less but reassuring data with
clarithromycin and azithromycin
Clindamycin
(Scand J Infect Dis 2000;32:579-80)
• Hungarian Case-Control Surveillance
of Congenital Abnormalities (19801996)
• OR (95% CI) for clindamycin 1.2 (0.43.8) and for lincomycin 1.3 (0.3-5.1)
• Limited numbers
Metronidazole
• Mutagenic in bacteria and
carcinogenic in animals
• Small number of reports raised
suspicion of teratogenic effect
Metronidazole
(Am J Obstet Gynecol 1995;172:525-9)
• Outcome of interest = occurrence of
birth defects in live-born infants
• Overall weighted OR during the 1st
trimester calculated by meta-analysis
of 7 studies was 0.93 (95% CI 0.731.18)
Fluoroquinolones
(Antimicrob Agents Chemother 1998;42:1336-9)
• Arthropathy in weight-bearing joints of animals
• 200 women exposed to fluoroquinolones during
pregnancy
• Rates of major malformations did not differ
between groups exposed to quinolones during
1st trimester (2.2%) and control group (2.6%)
• Gross motor milestones did not differ between
children in 2 groups
Tetracycline
• Main risk is yellow-brown discoloration
of teeth
• Risk only later than 4-5 months
gestation when deciduous teeth begin
to calcify
• No staining from doxycycline
documented
• Effects on bone minimal
Local Anesthetics - Lidocaine
• Considered relatively safe for
use during pregnancy
Epinephrine
• Potential to compromise
uterine blood flow
• Studies have failed to
demonstrate adverse fetal
effects
• Low doses used in dentistry
• Avoid inadvertent
intravascular injection
Acetaminophen
• “Analgesic of choice”
• Occasional use at
therapeutic doses
• Chronic use or overdose
NSAIDS (including Aspirin)
• Increased risk of miscarriage? (BMJ
2001;322:266-70)
• Gastroschisis (abdominal wall defect) ???
• Avoid use during late pregnancy (3rd
trimester)
–  Bleeding
– Inhibition of prostaglandin synthesis
• Prolonged labour
• Constriction of ductus arteriosus
New COX-2 Inhibitors
(Am J Physiol Regul Integr Comp Physiol 2000;278:R1496-505)
• Studies in fetal lambs demonstrated
– Celecoxib constricted isolated ductus in
vitro
– Celecoxib produced both an increase in
pressure gradient and resistance across
the ductus in vivo
Narcotics
(Codeine, Oxycodone, etc.)
• Don’t appear to  risk of birth defects
• Low dose short-term regimens
acceptable
• Respiratory depression
• Neonatal withdrawal
Codeine
• Unlikely to pose substantial teratogenic risk but
data insufficient to state no risk (TERIS, 2002)
• Associations between 1st trimester use and
congenital anomalies in case-control studies
although others have not confirmed
• Absence of consistent pattern and criticisms of
possible bias in data make it unjustified to
consider codeine as causative of these
malformations
Nitrous Oxide (N2O) with O2
• Use during pregnancy somewhat controversial
• Inhibits methionine synthetase which can affect
DNA synthesis
• Teratogenic in animals
• Single brief maternal exposure during
pregnancy unlikely to pose a substantial
teratogenic risk
• Minimize prolonged use (< 30 minutes, at least
50% O2)
Occupational Exposure to N2O
•  risk of spontaneous
abortion?
• Importance of scavenging
equipment
Benzodiazepines
(BMJ 1998;317:839-43)
• Meta-analysis
• Cohort studies showed no association
between fetal exposure to BZDs and risk for
major malformations or oral cleft
• Case-control studies showed that risk for
major malformations or oral cleft alone was
increased
• Use around delivery - “floppy infant”
Radiation
• In most cases of diagnostic x-rays
the fetal radiation exposure is
much below the threshold dose of
5 to 10 rad
Average Fetal Exposure Dose
CXR
<5
Abdomen
200-289
UGI
48-360
IVP
358-880
Dental
0.01
(mrad)
• Fetal exposure dose from a full mouth series (18 films) or
panoramic radiograph is <1/1000 value of concern
• 40-fold < naturally occurring background radiation
Antepartum Dental Radiography and Infant
Low Birth Weight
(JAMA 2004;291:1987-93)
• Population-based casecontrol study
• Dental utilization data from
Washington Dental Service
• Vital record birth
certificates from
Washington state
Antepartum Dental Radiography and Infant
Low Birth Weight
(JAMA 2004;291:1987-93)
• When thyroid radiation dose was >0.4
mGy (40 mrad), adjusted OR for a term
low birth weight infant was 3.61 (95% CI
1.46-8.92) when compared with women
with no known dental radiograph
Dose to thyroid of dental radiograph 0.08 mGy
Antepartum Dental Radiography and Infant
Low Birth Weight
(JAMA 2004;291:1987-93)
• Weaknesses of study including chance finding
and missing data
• Criticisms (JAMA 2004;292:1019-21)
– Confounding factors
– Dental pathology
– Radiation dose was related to maternal smoking and
late prenatal care
– Large # of statistical tests (Type 1 error)
– Overestimation of radiation doses
American Dental Association
• Abdominal exposure during dental
radiography is negligible
• Recommend that pregnant women
postpone elective dental x-rays until after
delivery; however, there are times when
an x-ray may be required during
pregnancy to help diagnose and treat oral
disease (thyroid collar and apron)
Drugs and Pregnancy - Summary
• List of drugs which have been associated
with adverse effects when taken during
pregnancy is relatively short
• Teratogenic potential should be explained
to women of childbearing age at time drug
is prescribed
• Lack of information but important to avoid
misinformation
• Importance of baseline risk
What is Baby Drinking?
Drugs and the Nursing Mother
Risk-Benefit Ratio
• Benefits of continuing breastfeeding
substantial
• Convincing reason to justify cessation
of breastfeeding required
Clinical Implications
• Majority of drugs cross from maternal
plasma into breast milk
• Most medications found in very small
amounts in breast milk (<1% of maternal
dose)
• Risk of adverse effects in nursing infants
is negligible for most drugs
Clinical Implications
• Reluctance to encourage
continuation of breastfeeding
– Pharmacological action of drug
suggests that a toxic effect may occur
– Adverse effects have previously been
noted in nursing infants
Clinical Implications
• Experience with direct use of drug in
infants for therapy may provide
reassurance
• Infant’s age (< 6 months), clinical status
and frequency of feeding may be
important
Clinical Implications
- Risk Assessment
• Arbitrarily define as safe a value of
<10% of the therapeutic dose for
infants (or the adult dose standardized
by weight)
Sources of Information
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Peer-reviewed literature
Textbooks
Committee on Drugs (AAP)
Computer Databases
Teratogen Information Services
– FRAME Program (London)
– Motherisk Program (Toronto)
Metronidazole
• Use during lactation controversial
• Excreted into breast milk in relatively large amounts
• Concern expressed with respect to possible
mutagenic effects
• No reports of adverse effects in nursing infants
• In conventional doses compatible with
breastfeeding
• If taken in single large dose breastfeeding may be
temporarily withheld for 12 to 24 hours
Codeine
(Lancet 2006;368:704)
• Full term healthy male infant
• Intermittent difficulty
breastfeeding and lethargy starting
Day 7 and died Day 13
• Blood morphine concentration
very high
Codeine
(Lancet 2006;368:704)
• Mother
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Taking acetaminophen/codeine preparation
 dose due to somnolence and constipation
Morphine [ ] of stored milk was very high
Ultra-rapid metabolizer
• Picture consistent with opioid toxicity
• Careful follow-up of breastfeeding mothers
using codeine and their infants (somnolence,
poor feeding, etc.)
Benzodiazepines
• Milk levels of benzodiazepines not
excessive but rarely sedation has been
reported in breastfed infants
• If sedative required, shorter half-life drugs
such as lorazepam and midazolam
preferred
• Long term exposure not recommended
Drugs and Breastfeeding Summary
• Most medications found in very small
amounts in breast milk
• Risk of adverse effects in nursing infants is
negligible for most drugs
• Consequences of misinformation
(medication noncompliance, breastfeeding
cessation)  NB to consult appropriate
available sources