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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

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Drug therapy in the pregnant dental patient

Drug Therapy in the Pregnant Dental Patient

Doreen Matsui MD, FRCPC

Associate Professor, Department of Paediatrics

Children’s Hospital of Western Ontario


Objectives
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
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
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
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
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
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 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 pre-clinical medical students, 150 medical students in clinical training, 81 pregnant women and 63 non-pregnant women


General considerations
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
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
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

Methimazole

Misoprostol

Phenytoin

Thalidomide

Trimethoprim

Valproic Acid

Warfarin

Known Teratogens


Baseline risk
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
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


Associated factors
Associated Factors

  • Role of underlying maternal disease

  • Other exposures such as alcohol and cigarette smoking


General recommendations
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
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
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


Drug therapy in the pregnant dental patient
“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
FDA Classification

  • X, D, C, B, A

  • Little correlation with risk


Sources of information
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
The Pregnant Dental Patient

  • Elective vs urgent

  • 2nd trimester

  • Eliminate source of infection or pain

  • Usually short-term drug therapy


Penicillins
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
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
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
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
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
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
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
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
Local Anesthetics - Lidocaine

  • Considered relatively safe for use during pregnancy


Epinephrine
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
Acetaminophen

  • “Analgesic of choice”

  • Occasional use at therapeutic doses

  • Chronic use or overdose


Nsaids including aspirin
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

New COX-2 Inhibitors(Am J Physiol Regul Integr Comp Physiol 2000;278:R1496-505)


Narcotics codeine oxycodone etc
Narcotics(Codeine, Oxycodone, etc.)

  • Don’t appear to  risk of birth defects

  • Low dose short-term regimens acceptable

  • Respiratory depression

  • Neonatal withdrawal


Codeine
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 n 2 o with o 2
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 n 2 o
Occupational Exposure to N2O

  •  risk of spontaneous abortion?

  • Importance of scavenging equipment


Benzodiazepines bmj 1998 317 839 43
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
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 mrad
Average Fetal Exposure Dose(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
Antepartum Dental Radiography and Infant Low Birth Weight(JAMA 2004;291:1987-93)

  • Population-based case-control 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 931
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 932
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
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
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
What is Baby Drinking?Drugs and the Nursing Mother


Risk benefit ratio
Risk-Benefit Ratio

  • Benefits of continuing breastfeeding substantial

  • Convincing reason to justify cessation of breastfeeding required


Clinical implications
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 implications1
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 implications2
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
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 information1
Sources of Information

  • Peer-reviewed literature

  • Textbooks

  • Committee on Drugs (AAP)

  • Computer Databases

  • Teratogen Information Services

    • FRAME Program (London)

    • Motherisk Program (Toronto)


Metronidazole1
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
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 7041
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
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
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