Drug%20Therapy%20in%20the%20Pregnant%20Dental%20Patient

1
Drug Therapy in the Pregnant Dental Patient

• Doreen Matsui MD, FRCPC
• Associate Professor, Department of Paediatrics
• Childrens Hospital of Western Ontario

2
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

3
Drug Use in Pregnancy(Larimore WL et al. Prim
Care 20002735-53)

• 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

4
Inadvertent Exposure

• 1/2 of pregnancies unplanned
• Teratogenic potential should be considered and
  explained to women of childbearing age at time
  drug is prescribed
• lt50 of women know they are pregnant by 4th week
  and 20 still dont know by 8th week

5
Drug Use in Pregnancy(Van Trigt AM et al. Pharm
World Sci 199416254-9)

• 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

6
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
  Sci199416254-9)

7
Perception of Teratogenic Risk(Am J Obstet
Gynecol 19891601190-4)

• 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

8
Perception of Teratogenic Risk(Sanz E et al.
Eur J Obstet Gynecol Reprod Biol 200195127-31)

• Perception of risk related to medication used in
  pregnancy higher than the recognized risk in a
  group of 15 GPs, 10 gynaecologists, 106
  pre-clinical medical students, 150 medical
  students in clinical training, 81 pregnant women
  and 63 non-pregnant women

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

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Adverse Effects

• Spontaneous abortion
• Fetal growth retardation
• Teratogenicity
• Direct drug toxicity
• Neonatal drug withdrawal
• Long term effects on neurobehavioral development
• Carcinogenesis

11
Teratogenic Risk(Lo et al. Obstet Gynecol
2002100465-73)

• 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

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Known Teratogens

• Alcohol (Ethanol)
• Carbamazepine
• Cytotoxic chemotherapy
• DES
• Isotretinoin and Etretinate
• Lithium

• Methimazole
• Misoprostol
• Phenytoin
• Thalidomide
• Trimethoprim
• Valproic Acid
• Warfarin

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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

14
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, dose-response)
• Genetic susceptibility

15
Associated Factors

• Role of underlying maternal disease
• Other exposures such as alcohol and cigarette
  smoking

16
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

17
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?

18
Animals vs Humans

• 40-50 chemical and physical agents probably human
  developmental toxicants
• gt1200 produce developmental defects in
  experimental animals
• gt80 of agents known to produce defects in humans
  also cause defects in at least one test animal

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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.

20
FDA Classification

• X, D, C, B, A
• Little correlation with risk

21
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

22
The Pregnant Dental Patient

• Elective vs urgent
• 2nd trimester
• Eliminate source of infection or pain
• Usually short-term drug therapy

23
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

24
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 200458298-302 and
  Eur J Obstet Gynecol Reprod Biol 200197188-92)

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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

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Clindamycin(Scand J Infect Dis 200032579-80)

• 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

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Metronidazole

• Mutagenic in bacteria and carcinogenic in animals
• Small number of reports raised suspicion of
  teratogenic effect

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Metronidazole(Am J Obstet Gynecol 1995172525-9)

• 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)

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Fluoroquinolones(Antimicrob Agents Chemother
1998421336-9)

• 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

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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

31
Local Anesthetics - Lidocaine

• Considered relatively safe for use during
  pregnancy

32
Epinephrine

• Potential to compromise uterine blood flow
• Studies have failed to demonstrate adverse fetal
  effects
• Low doses used in dentistry
• Avoid inadvertent intravascular injection

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Acetaminophen

• Analgesic of choice
• Occasional use at therapeutic doses
• Chronic use or overdose

34
NSAIDS (including Aspirin)

• Increased risk of miscarriage? (BMJ
  2001322266-70)
• Gastroschisis (abdominal wall defect) ???
• Avoid use during late pregnancy (3rd trimester)
• ? Bleeding
• Inhibition of prostaglandin synthesis
• Prolonged labour
• Constriction of ductus arteriosus

35
New COX-2 Inhibitors(Am J Physiol Regul Integr
Comp Physiol 2000278R1496-505)

• 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

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Narcotics(Codeine, Oxycodone, etc.)

• Dont appear to ? risk of birth defects
• Low dose short-term regimens acceptable
• Respiratory depression
• Neonatal withdrawal

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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

38
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 (lt 30 minutes, at least
  50 O2)

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Occupational Exposure to N2O

• ? risk of spontaneous abortion?
• Importance of scavenging equipment

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Benzodiazepines(BMJ 1998317839-43)

• 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

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Radiation

• In most cases of diagnostic x-rays the fetal
  radiation exposure is much below the threshold
  dose of 5 to 10 rad

42
Average Fetal Exposure Dose (mrad)

• Fetal exposure dose from a full mouth series (18
  films) or panoramic radiograph is lt1/1000 value
  of concern
• 40-fold lt naturally occurring background
  radiation

43
Antepartum Dental Radiography and Infant Low
Birth Weight(JAMA 20042911987-93)

• Population-based case-control study
• Dental utilization data from Washington Dental
  Service
• Vital record birth certificates from Washington
  state

44
Antepartum Dental Radiography and Infant Low
Birth Weight(JAMA 20042911987-93)

• When thyroid radiation dose was gt0.4 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
45
Antepartum Dental Radiography and Infant Low
Birth Weight(JAMA 20042911987-93)

• Weaknesses of study including chance finding and
  missing data
• Criticisms (JAMA 20042921019-21)
• 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

46
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)

47
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

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What is Baby Drinking?Drugs and the Nursing
Mother
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Risk-Benefit Ratio

• Benefits of continuing breastfeeding substantial
• Convincing reason to justify cessation of
  breastfeeding required

50
Clinical Implications

• Majority of drugs cross from maternal plasma into
  breast milk
• Most medications found in very small amounts in
  breast milk (lt1 of maternal dose)
• Risk of adverse effects in nursing infants is
  negligible for most drugs

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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

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Clinical Implications

• Experience with direct use of drug in infants for
  therapy may provide reassurance
• Infants age (lt 6 months), clinical status and
  frequency of feeding may be important

53
Clinical Implications- Risk Assessment

• Arbitrarily define as safe a value of lt10 of the
  therapeutic dose for infants (or the adult dose
  standardized by weight)

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Sources of Information

• Peer-reviewed literature
• Textbooks
• Committee on Drugs (AAP)
• Computer Databases
• Teratogen Information Services
• FRAME Program (London)
• Motherisk Program (Toronto)

55
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

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Codeine(Lancet 2006368704)

• Full term healthy male infant
• Intermittent difficulty breastfeeding and
  lethargy starting Day 7 and died Day 13
• Blood morphine concentration very high

57
Codeine(Lancet 2006368704)

• 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.)

58
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

59
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