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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.

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Presentation on theme: "Drug Therapy in the Pregnant Dental Patient Doreen Matsui MD, FRCPC Associate Professor, Department of Paediatrics Children’s Hospital of Western Ontario."— Presentation transcript:

1 Drug Therapy in the Pregnant Dental Patient Doreen Matsui MD, FRCPC Associate Professor, Department of Paediatrics Children’s Hospital of Western Ontario

2 Objectives To review general principles regarding drugs in pregnancyTo review general principles regarding drugs in pregnancy To describe effects of drugs commonly used in dentistryTo describe effects of drugs commonly used in dentistry To briefly overview use of drugs during breastfeedingTo briefly overview use of drugs during breastfeeding

3 Drug Use in Pregnancy (Larimore WL et al. Prim Care 2000;27:35-53) 1991 WHO International Survey of Drug Utilization in Pregnancy1991 WHO International Survey of Drug Utilization in Pregnancy 86% of women took medication during pregnancy86% of women took medication during pregnancy Average of 2.9 prescriptionsAverage of 2.9 prescriptions Despite this high rate of medication intake, most drugs are not labeled for use during pregnancyDespite this high rate of medication intake, most drugs are not labeled for use during pregnancy

4 Inadvertent Exposure 1/2 of pregnancies unplanned1/2 of pregnancies unplanned Teratogenic potential should be considered and explained to women of childbearing age at time drug is prescribedTeratogenic potential should be considered and explained to women of childbearing age at time drug is prescribed –<50% of women know they are pregnant by 4 th week and ~20% still don’t know by 8 th week

5 Drug Use in Pregnancy (Van Trigt AM et al. Pharm World Sci 1994;16:254-9) Women interviewed within 2 weeks after deliveryWomen interviewed within 2 weeks after delivery  40% had had one or more questions about drugs during their pregnancy  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 medicationSimilar proportion said that during pregnancy important to consult a health professional before using any medication Safety was issue that raised the most questionsSafety was issue that raised the most questions

6 Compliance Pregnant women tend to comply less than optimally with drug therapyPregnant women tend to comply less than optimally with drug therapy MisinformationMisinformation 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)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)

7 Perception of Teratogenic Risk (Am J Obstet Gynecol 1989;160;1190-4) Women exposed to nonteratogens assigned a risk of 24% for major malformationsWomen exposed to nonteratogens assigned a risk of 24% for major malformations Risk in general population 5.6%Risk in general population 5.6% May be important factor in decision to terminate pregnancyMay be important factor in decision to terminate pregnancy

8 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 womenPerception 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 extentAlmost all drugs cross the placenta to some extent Majority of drugs have not been associated with adverse effects when taken during pregnancyMajority 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 fetusWeigh therapeutic benefits of drug to mother against its risk potential to developing fetus

10 Adverse Effects Spontaneous abortionSpontaneous abortion Fetal growth retardationFetal growth retardation TeratogenicityTeratogenicity Direct drug toxicityDirect drug toxicity Neonatal drug withdrawalNeonatal drug withdrawal Long term effects on neurobehavioral developmentLong term effects on neurobehavioral development CarcinogenesisCarcinogenesis

11 Teratogenic Risk (Lo et al. Obstet Gynecol 2002;100:465-73) Standard clinical teratology databasesStandard clinical teratology databases 485 drugs approved by FDA drugs approved by FDA Treatment with only small fraction (2.4%) has been associated with substantial teratogenic riskTreatment 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 riskTook on average 6.0 ± 4.1 years after approval to determine risk

12 Known Teratogens Alcohol (Ethanol)Alcohol (Ethanol) CarbamazepineCarbamazepine Cytotoxic chemotherapyCytotoxic chemotherapy DESDES Isotretinoin and EtretinateIsotretinoin and Etretinate LithiumLithium Methimazole Misoprostol Phenytoin Thalidomide Trimethoprim Valproic Acid Warfarin

13 Baseline Risk Risk of major malformation (cosmetic or functional significance) = 3% at birthRisk of major malformation (cosmetic or functional significance) = 3% at birth Assessment of magnitude of increase in risk above baseline is importantAssessment of magnitude of increase in risk above baseline is important Need to put risk in perspectiveNeed to put risk in perspective

14 Important Factors Timing of exposure (sensitive period)Timing of exposure (sensitive period) –“All-or-none” period –*Organogenesis* “Avoid drug administration, if at all possible during 1st trimester”“Avoid drug administration, if at all possible during 1st trimester” –Brain development Dose of drug (threshold, dose- response)Dose of drug (threshold, dose- response) Genetic susceptibilityGenetic susceptibility

15 Associated Factors Role of underlying maternal diseaseRole of underlying maternal disease Other exposures such as alcohol and cigarette smokingOther exposures such as alcohol and cigarette smoking

16 General Recommendations Minimize use of medications to those which are necessary and for shortest duration possibleMinimize 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 alternativesEffective 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 marketingManufacturer almost never tests product in pregnant women prior to marketing Evidence from large clinical trials does not existEvidence from large clinical trials does not exist Reproductive toxicology studies in animals - extrapolation?Reproductive toxicology studies in animals - extrapolation?

18 Animals vs Humans chemical and physical agents probably human developmental toxicants40-50 chemical and physical agents probably human developmental toxicants >1200 produce developmental defects in experimental animals>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>80% of agents known to produce defects in humans also cause defects in at least one test animal

19 “CPS” Majority of drugs not labeled for use during pregnancyMajority 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.”“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, AX, D, C, B, A Little correlation with riskLittle correlation with risk

21 Sources of Information Reference TextbooksReference Textbooks –Drugs in Pregnancy and Lactation (Briggs) –Maternal-Fetal Toxicology (Koren) Computer DatabasesComputer Databases –Reprotox –TERIS Teratogen Information ServicesTeratogen Information Services –Motherisk Program –FRAME Program

22 The Pregnant Dental Patient Elective vs urgentElective vs urgent 2nd trimester2nd trimester Eliminate source of infection or painEliminate source of infection or pain Usually short-term drug therapyUsually short-term drug therapy

23 Penicillins Collaborative Perinatal ProjectCollaborative 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 1 st 4 lunar months of pregnancyFrequency of congenital anomalies no greater than expected among children of 4,356 women treated with penicillin (or one of its derivatives) during 1 st 4 lunar months of pregnancy

24 Penicillins and Cephalosporins Amoxicillin and cephalosporins also considered safe to use during pregnancyAmoxicillin 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: and Eur J Obstet Gynecol Reprod Biol 2001;97:188-92)No increased risk of malformations with amoxicillin/clavulanic acid (Clavulin) in 2 studies (Br J Clin Pharmacol 2004;58: and Eur J Obstet Gynecol Reprod Biol 2001;97:188-92)

25 Erythromycin Surveillance study of Michigan Medicaid recipients ( )Surveillance study of Michigan Medicaid recipients ( ) No association between drug and congenital malformations in 6,972 newborns exposed during 1 st trimesterNo association between drug and congenital malformations in 6,972 newborns exposed during 1 st trimester Avoid estolate form (cholestatic hepatitis)Avoid estolate form (cholestatic hepatitis) Less but reassuring data with clarithromycin and azithromycinLess but reassuring data with clarithromycin and azithromycin

26 Clindamycin (Scand J Infect Dis 2000;32:579-80) Hungarian Case-Control Surveillance of Congenital Abnormalities ( )Hungarian Case-Control Surveillance of Congenital Abnormalities ( ) OR (95% CI) for clindamycin 1.2 ( ) and for lincomycin 1.3 ( )OR (95% CI) for clindamycin 1.2 ( ) and for lincomycin 1.3 ( ) Limited numbersLimited numbers

27 Metronidazole Mutagenic in bacteria and carcinogenic in animalsMutagenic in bacteria and carcinogenic in animals Small number of reports raised suspicion of teratogenic effectSmall number of reports raised suspicion of teratogenic effect

28 Metronidazole (Am J Obstet Gynecol 1995;172:525-9) Outcome of interest = occurrence of birth defects in live-born infantsOutcome 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 )Overall weighted OR during the 1st trimester calculated by meta-analysis of 7 studies was 0.93 (95% CI )

29 Fluoroquinolones (Antimicrob Agents Chemother 1998;42:1336-9) Arthropathy in weight-bearing joints of animalsArthropathy in weight-bearing joints of animals 200 women exposed to fluoroquinolones during pregnancy200 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%)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 groupsGross motor milestones did not differ between children in 2 groups

30 Tetracycline Main risk is yellow-brown discoloration of teethMain risk is yellow-brown discoloration of teeth Risk only later than 4-5 months gestation when deciduous teeth begin to calcifyRisk only later than 4-5 months gestation when deciduous teeth begin to calcify No staining from doxycycline documentedNo staining from doxycycline documented Effects on bone minimalEffects on bone minimal

31 Local Anesthetics - Lidocaine Considered relatively safe for use during pregnancyConsidered relatively safe for use during pregnancy

32 Epinephrine Potential to compromise uterine blood flowPotential to compromise uterine blood flow Studies have failed to demonstrate adverse fetal effectsStudies have failed to demonstrate adverse fetal effects Low doses used in dentistryLow doses used in dentistry Avoid inadvertent intravascular injectionAvoid inadvertent intravascular injection

33 Acetaminophen “Analgesic of choice”“Analgesic of choice” Occasional use at therapeutic dosesOccasional use at therapeutic doses Chronic use or overdoseChronic use or overdose

34 NSAIDS (including Aspirin) Increased risk of miscarriage? (BMJ 2001;322:266-70)Increased risk of miscarriage? (BMJ 2001;322:266-70) Gastroschisis (abdominal wall defect) ???Gastroschisis (abdominal wall defect) ??? Avoid use during late pregnancy (3 rd trimester)Avoid use during late pregnancy (3 rd trimester) –  Bleeding –Inhibition of prostaglandin synthesis Prolonged labourProlonged labour Constriction of ductus arteriosusConstriction of ductus arteriosus

35 New COX-2 Inhibitors (Am J Physiol Regul Integr Comp Physiol 2000;278:R ) Studies in fetal lambs demonstrated 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

36 Narcotics (Codeine, Oxycodone, etc.) Don’t appear to  risk of birth defectsDon’t appear to  risk of birth defects Low dose short-term regimens acceptableLow dose short-term regimens acceptable Respiratory depressionRespiratory depression Neonatal withdrawalNeonatal withdrawal

37 Codeine Unlikely to pose substantial teratogenic risk but data insufficient to state no risk (TERIS, 2002) Unlikely to pose substantial teratogenic risk but data insufficient to state no risk (TERIS, 2002) Associations between 1 st trimester use and congenital anomalies in case-control studies although others have not confirmed Associations between 1 st 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 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 (N 2 O) with O 2 Use during pregnancy somewhat controversialUse during pregnancy somewhat controversial Inhibits methionine synthetase which can affect DNA synthesisInhibits methionine synthetase which can affect DNA synthesis Teratogenic in animalsTeratogenic in animals Single brief maternal exposure during pregnancy unlikely to pose a substantial teratogenic riskSingle brief maternal exposure during pregnancy unlikely to pose a substantial teratogenic risk Minimize prolonged use (< 30 minutes, at least 50% O 2 )Minimize prolonged use (< 30 minutes, at least 50% O 2 )

39 Occupational Exposure to N 2 O  risk of spontaneous abortion?  risk of spontaneous abortion? Importance of scavenging equipmentImportance of scavenging equipment

40 Benzodiazepines (BMJ 1998;317:839-43) Meta-analysisMeta-analysis Cohort studies showed no association between fetal exposure to BZDs and risk for major malformations or oral cleftCohort 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 increasedCase-control studies showed that risk for major malformations or oral cleft alone was increased Use around delivery - “floppy infant”Use around delivery - “floppy infant”

41 Radiation In most cases of diagnostic x-rays the fetal radiation exposure is much below the threshold dose of 5 to 10 radIn 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 <1/1000 value of concern 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 40-fold < naturally occurring background radiation

43 Antepartum Dental Radiography and Infant Low Birth Weight (JAMA 2004;291: ) Population-based case- control studyPopulation-based case- control study Dental utilization data from Washington Dental ServiceDental utilization data from Washington Dental Service Vital record birth certificates from Washington stateVital record birth certificates from Washington state

44 Antepartum Dental Radiography and Infant Low Birth Weight (JAMA 2004;291: ) When thyroid radiation dose was >0.4 mGy (40 mrad), adjusted OR for a term low birth weight infant was 3.61 (95% CI ) when compared with women with no known dental radiographWhen thyroid radiation dose was >0.4 mGy (40 mrad), adjusted OR for a term low birth weight infant was 3.61 (95% CI ) 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 2004;291: ) Weaknesses of study including chance finding and missing dataWeaknesses of study including chance finding and missing data Criticisms (JAMA 2004;292: )Criticisms (JAMA 2004;292: ) –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 negligibleAbdominal 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)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 shortList 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 prescribedTeratogenic potential should be explained to women of childbearing age at time drug is prescribed Lack of information but important to avoid misinformationLack of information but important to avoid misinformation Importance of baseline riskImportance of baseline risk

48 What is Baby Drinking? Drugs and the Nursing Mother

49 Risk-Benefit Ratio Benefits of continuing breastfeeding substantialBenefits of continuing breastfeeding substantial Convincing reason to justify cessation of breastfeeding requiredConvincing reason to justify cessation of breastfeeding required

50 Clinical Implications Majority of drugs cross from maternal plasma into breast milkMajority of drugs cross from maternal plasma into breast milk Most medications found in very small amounts in breast milk (<1% of maternal dose)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 drugsRisk of adverse effects in nursing infants is negligible for most drugs

51 Clinical Implications Reluctance to encourage continuation of breastfeedingReluctance 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

52 Clinical Implications Experience with direct use of drug in infants for therapy may provide reassuranceExperience 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 importantInfant’s age (< 6 months), clinical status and frequency of feeding may be important

53 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)Arbitrarily define as safe a value of <10% of the therapeutic dose for infants (or the adult dose standardized by weight)

54 Sources of Information Peer-reviewed literaturePeer-reviewed literature TextbooksTextbooks Committee on Drugs (AAP)Committee on Drugs (AAP) Computer DatabasesComputer Databases Teratogen Information ServicesTeratogen Information Services –FRAME Program (London) –Motherisk Program (Toronto)

55 Metronidazole Use during lactation controversialUse during lactation controversial Excreted into breast milk in relatively large amountsExcreted into breast milk in relatively large amounts Concern expressed with respect to possible mutagenic effectsConcern expressed with respect to possible mutagenic effects No reports of adverse effects in nursing infantsNo reports of adverse effects in nursing infants In conventional doses compatible with breastfeedingIn conventional doses compatible with breastfeeding If taken in single large dose breastfeeding may be temporarily withheld for 12 to 24 hoursIf taken in single large dose breastfeeding may be temporarily withheld for 12 to 24 hours

56 Codeine (Lancet 2006;368:704) Full term healthy male infantFull term healthy male infant Intermittent difficulty breastfeeding and lethargy starting Day 7 and died Day 13Intermittent difficulty breastfeeding and lethargy starting Day 7 and died Day 13 Blood morphine concentration very highBlood morphine concentration very high

57 Codeine (Lancet 2006;368:704) MotherMother –Taking acetaminophen/codeine preparation –  dose due to somnolence and constipation –Morphine [ ] of stored milk was very high –Ultra-rapid metabolizer Picture consistent with opioid toxicityPicture consistent with opioid toxicity Careful follow-up of breastfeeding mothers using codeine and their infants (somnolence, poor feeding, etc.)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 infantsMilk 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 preferredIf sedative required, shorter half-life drugs such as lorazepam and midazolam preferred Long term exposure not recommendedLong term exposure not recommended

59 Drugs and Breastfeeding - Summary Most medications found in very small amounts in breast milkMost medications found in very small amounts in breast milk Risk of adverse effects in nursing infants is negligible for most drugsRisk of adverse effects in nursing infants is negligible for most drugs Consequences of misinformation (medication noncompliance, breastfeeding cessation)  NB to consult appropriate available sourcesConsequences of misinformation (medication noncompliance, breastfeeding cessation)  NB to consult appropriate available sources


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