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DRUGS IN PREGNANCY- Treating The Mother-Protecting the Unborn

DRUGS IN PREGNANCY- Treating The Mother-Protecting the Unborn. Gideon Koren MD Motherisk Program and Ivey Chair in Molecular Toxicology. Drugs in Pregnancy-The issues. Only half of all pregnancies are planned

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DRUGS IN PREGNANCY- Treating The Mother-Protecting the Unborn

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  1. DRUGS IN PREGNANCY-Treating The Mother-Protecting the Unborn Gideon Koren MD Motherisk Program and Ivey Chair in Molecular Toxicology

  2. Drugs in Pregnancy-The issues • Only half of all pregnancies are planned • Many women need medications for pregnancy induced conditions (e.g. Morning Sickness), chronic conditions (e.g. Epilepsy), intercurrent conditions (Allergies) • Women work with chemicals, exposed to radiation and use illicit drugs • During embryogenesis-drugs &chemicals may adversely affect development

  3. Situational Analysis • A) Anxiety of birth defects: • Leads women not to take medications during pregnancy& lactation. • Leads pharmaceutical companies not to develop drugs for pregnant &lactating women. • B) Women are not treated appropriately even after first trimester, or for life threatening conditions

  4. Perception of Teratogenic Risk(1) • Even when exposed to non teratogenic drugs-women assign 25% teratogenic risk (Am J Obstet Gynecol 1989) • Evidence-based counseling can prevent unnecessary pregnancy terminations (Teratology 1990)

  5. Perception of Teratogenic Risk(2) • Following the Chernobyl disaster-half of all pregnancies in Athens were terminated (Trichopolous, BMJ, 1985) • Women exposed to diagnostic radiation assign major teratogenic risk (Bentur, Teratology, 1991)

  6. Misperception and Pregnancy Terminations • Loebstein et al(Antimicrob Agent Chemother 1998): 9/200 women on quinolones terminated pregnancy vs.2/200 controls[RR 4.5(95%CI .98-20.6)] • Bar Oz et al(In Press): First trimester MMR vaccine 7/94 vs 0/95 terminations(p=.007) Cohen Kerem et al(2004): 7/198 diagnostic radiation terminated vs. 0/198 controls (p<.04)

  7. Nausea and Vomiting of Pregnancy (NVP) * NVP affects 80% of pregnant women *Bendectin (doxylamine-pyridoxine) was used by 40% pregnant American women in 1978 *Due to litigations-drug removed in 1983 despite scientific/FDA support *2-3 fold increase in hospitalization rates for NVP in USA In Canada: Diclectin use is increasing-Temporal decrease in hospitalizations

  8. U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Sales, and Hospitalizations for NVP

  9. Rate of Hospitalization in Canada

  10. Depression in Pregnancy *Affects up to 20% of pregnant women * SSRI appear safe(both dyspmorphology &neurobehavior) (Nulman et al 1996, 2002) • Neonatal Discontinuation Syndrome • Women commonly D/C therapy; high morbidity (Einarson et al 2001) * Those treated-very low average doses (Nulman 2003)

  11. Late Pregnancy; Pharmacokinetic Changes • Dempsy & Benowitz(2002):Increased nicotine clearence rate • Heikkinen(2003): Increased fluoxetine apparent clearance rate • Increased clearance rate of digoxin, lithium • Increased hepatic blood flow, GFR, lower protein binding, lower compliance rate • NEED FOR HIGHER DOSES

  12. Glyburide • Fear:oral hypoglycemics cross placenta-neonatal hypoglycemia • Elliott (Am J Obstet Gynecol 1994):Glyburide does not cross the placenta in perfusion studies. • Langer et al (NEJM 2001): Glyburide as effective and safe as insulin Undetectable umbilical cord levels with therapeutic maternal levels(50-150ng/ml) • Mechanisms: high protein binding(99.8%), short T1/2(2-6 hr), ABC transporter substrate.

  13. Fetal Safety of Oral Hypoglycemics • Motherisk Meta analysis (Can J Clin Pharmacol 2003;10:179-83) • 10 studies • 471 exposed;1,344 controls • Major malformations: OR 1.05 (.65-1.7) • Neonatal death: OR1.16(.67-2)

  14. Fetal Safety of Glyburide • Meta analysis( Motherisk 2006)-glyburide vs insulin • Macrosomia- OR1.04(.74-1.45) • Birth weight: WMD 17g(-44-80) • Gestational age: WMD 0(-.28-.27) • Neonatal hypoglycemia OR 1.33(.99-1.79) • In Langer’s study:18/201 vs. 12/203 • (OR 1.57(.73-3.34)

  15. Fetal Safety of Metformin • Motherisk meta analysis • 1% malformation rate in metformin • 7% among disease matched controls (p<0.01) Potential protective effect Possibly because of improvement in insulin resistance and in androgen status

  16. Major Medicinal Teratogens(1) • Antiepileptics • Carbamazepine-NTD(1%) • Valproate-NTD(2%);other malformations (Holmes 2003) • Phenytoin: Fetal Hydantoin Syndrome(10-15%?) • ACE inhibitors: renal insuffuciency, hypocalvaria • Lithium-Ebstein’s anomaly(1/5000) • Coumadin-Fetal Warfarin Sundrome

  17. Major Human Teratogens • Isotretinoin; 50% malformation rate • SMART program to prevent fetal exposure-fetuses still exposed • Leflunamide-Human levels teratogenic in animals; prospective study (n=40) still negative • Thalidomide-for leprosy, HIV, Drug vs Host • Misoprostol- Moebius sequence; high attributable risk, very low overall risk.

  18. Labeling(1) • Prozac product monograph(2004): “Safe use in pregnancy has not been established. Therefore, it should not be administered to women od childbearing age unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweight the possible hazards to the child or fetus”.

  19. Labeling(2) Scientific reality: Till Dec. 2003: • 6 dysmorphology studies • 3 neurodevelopmental studies • One meta analysis • All showing apparent safety

  20. Conclusions • Pregnant and lactating women are commonly orphaned from the benefits of drug therapy, even when solid data on safety/effectiveness exist. • Change labeling system • Allow evidence-based counseling • Always consider the risk of untreated maternal condition

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