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
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)
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
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) Methimazole
Carbamazepine Misoprostol
Cytotoxic chemotherapy Phenytoin
DES Thalidomide
Isotretinoin and Trimethoprim
Etretinate Valproic Acid
Lithium Warfarin
 Important Factors
Timing of exposure (sensitive period)
“All-or-none” period (first 2 weeks)
*Organogenesis*
 “Avoid drug administration, if at all possible during 1st
trimester”
Brain development
Dose of drug (threshold, dose-response)
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 (Child Protective Services)”
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
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;58:298-302 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 (1980-1996)
OR (95% CI) for clindamycin 1.2 (0.4-3.8) 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 0.73-1.18)
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”
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
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
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