DRUGS IN PREGNANCY- Treating The Mother-Protecting the Unborn

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DRUGS IN PREGNANCY-Treating The
Mother-Protecting the Unborn

• Gideon Koren MD
• Motherisk Program
• and Ivey Chair in Molecular Toxicology

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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

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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

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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)

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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)

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Misperception and Pregnancy Terminations

• Loebstein et al(Antimicrob Agent Chemother 1998)
• 9/200 women on quinolones terminated pregnancy
  vs.2/200 controlsRR 4.5(95CI .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 (plt.04)

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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

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U.S.A. Temporal Trends for Limb Reduction
Deformities, Bendectin Sales, and
Hospitalizations for NVP
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Rate of Hospitalization in Canada
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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)

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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

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Glyburide

• Fearoral 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.

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Fetal Safety of Oral Hypoglycemics

• Motherisk Meta analysis (Can J Clin Pharmacol
  200310179-83)
• 10 studies
• 471 exposed1,344 controls
• Major malformations OR 1.05 (.65-1.7)
• Neonatal death OR1.16(.67-2)

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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 Langers study18/201 vs. 12/203
• (OR 1.57(.73-3.34)

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Fetal Safety of Metformin

• Motherisk meta analysis
• 1 malformation rate in metformin
• 7 among disease matched controls
• (plt0.01)
• Potential protective effect
• Possibly because of improvement in insulin
  resistance and in androgen status

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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-Ebsteins anomaly(1/5000)
• Coumadin-Fetal Warfarin Sundrome

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Major Human Teratogens

• Isotretinoin 50 malformation rate
• SMART program to prevent fetal exposure-fetuses
  still exposed
• Leflunamide-Human levels teratogenic in animals
  prospective study (n40) still negative
• Thalidomide-for leprosy, HIV, Drug vs Host
• Misoprostol- Moebius sequence high attributable
  risk, very low overall risk.

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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.

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Labeling(2)

• Scientific reality
• Till Dec. 2003
• 6 dysmorphology studies
• 3 neurodevelopmental studies
• One meta analysis
• All showing apparent safety

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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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