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
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