Pharmacotherapy in Pregnancy: Balancing Risks and Benefits

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Pharmacotherapy in PregnancyBalancing Risks and
Benefits

• Myla Moretti
• The Hospital for Sick Children
• September 9, 2004

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Outline

• Definitions and History
• Possible effects of drugs on the fetus
• Assessing risk methods and challenges
• Current known or suspected teratogens
• Common questions/problems
• Resources

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Drug Use in Pregnancy

• the effects of a drug on human pregnancies is
  rarely evaluated before market release
• CPS typically states use in pregnancy is not
  recommended unless the potential benefits justify
  the potential risks to the fetus
• disclaimers such as this, while important
  medico-legally, can be misleading and
  particularly worrisome for the 50 of women who
  have not planned their pregnancies

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Definitions

• Teratology the science addressing inborn defects
  due to different factors
• Teratogenesis dysgenesis of fetal organ(s)
  manifested either structurally or functionally
• Teratogen an agent that may have harmful effects
  on the developing fetus

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Types of Malformation

• Major Malformation structural or functional
  defects for which medical or surgical
  intervention is necessary, or a defect that can
  impair the childs lifestyle or social
  acceptability
• Minor malformations unusual morphologic traits
  of no serious medical or cosmetic consequence to
  the child, but might signify a major malformation
  complex

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A Brief History

• 50 of women will take at least 1 drug in
  pregnancy
• 1941 - the discovery of Rubella as a human
  teratogen was an important milestone in the field
  of teratology
• 1961 - Thalidomide taught us that the placenta
  was not a barrier to drugs as once thought

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Effects on the Fetus/Infant

• malformation (anatomical), disruption,
  deformation
• IUGR
• fetal loss/neonatal loss
• fetal/neonatal toxicity or withdrawal
• neurodevelopmental (cognitive or behavioural)
• other long term effects (carcinogenesis)

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The Challenge

• How to treat the mother without adversely
  effecting the fetus?
• in many cases not treating will increase maternal
  and fetal risk (HIV, asthma, hypertension,
  diabetes, morning sickness)

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Karnofskys Law

• Everything is teratogenic if given at the right
  dose, to the right species, at the right time
• Producing positive results in teratology studies
  is only a matter of finding a sensitive stage in
  a sensitive species and of using an appropriately
  high dose of the toxicant

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Physiologic Changes in Pregnancy

• pregnancy is a time where there can be
  significant changes in maternal physiology
• these changes may be associated with altered
  responses to drugs
• this includes ? albumin concentration ?
  plasma volume ? cardiac output ? renal
  blood flow ? renal elimination ? uterine
  blood flow changes in enzymatic activity

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Risk-Benefit Analysis
Risks

• not treating mom
• teratogenesis
• poor pregnancy outcome

Benefits

• good control of maternal disease
• improved pregnancy outcome

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• most drugs cross the placenta easily
• dictated by molecular size
• but, even drugs which do not cross may cause
  physiologic changes in the mother or placenta
  which can lead to unknown fetal effects

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Methods of Assessing Risk

• IN VIVO
• animal studies
• case reports/case series
• observational cohort studies
• prospective or retrospective
• workplace assessments
• registries
• case-control studies
• meta-analytical reviews

• IN VITRO
• placental perfusion studies

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Establishing Risk

• temporal relationship
• exposure at critical times of development
• exposure precedes event
• consistent findings across studies (of good
  quality)
• specific defect, pattern or adverse outcome noted
• rare exposure associated with a rare event
• secular trends
• biological plausibility?
• dose response
• animal or experimental proof

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Obtaining and Interpreting the Data

• is it ethical?
• is it doable?
• statistics and power
• How much is enough?

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Obtaining and Interpreting the Data

• is it ethical? is it doable?
• statistics and power
• How much is enough?
• figuring out confounders (underlying maternal
  illnesses)
• bias from
• the patient
• the physician
• the researcher
• role of the media

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• less than 1 of all major malformations are known
  to be caused by drugs
• 1-2 mechanical deformation
• 3 maternal infection (CMV, rubella)
• 4 maternal illness (diabetes)
• 25 of genetic origin
• 65 multifactorial/unknown

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Known/Suspected Teratogens

• ACE inhibitors
• anticonvulsants
• benzodiazepines
• carbon monoxide
• DES
• ethanol
• hyperthermia
• lead
• lithium

• misoprostol
• organic solvents
• retinoids
• rubella
• systemic corticosteroids
• tetracyclines
• varicella
• warfarin

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Case

• Your 27 y.o. patient has been successfully
  treated with fluoxetine (Prozac) and lorazepam
  (Ativan) for depression and anxiety. Within the
  last six months she was hospitalized following a
  suicide attempt and is currently well controlled.
  She is planning to start a family in the next
  year. When approaching you for her next refill
  she asks how long it will take for these drugs to
  get out of her system. She tells you that she
  knows one should never take medications while
  pregnant.

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Evidence

• several studies have not shown increased risk for
  malformations following the use of SSRIs in
  pregnancy
• fluoxetine (Prozac) and citalopram (Celexa)
  reported in the greatest numbers
• tricyclic antidepressants also not shown to pose
  risk for birth defects
• there is some concern for neonatal
  toxicity/withdrawal, although incidence is not
  known
• neurodevelopment in children (up to 5 yrs) did
  not show any impairments
• benzodiazepine studies have been conflicting

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Answer

• assure patient that many medications can be taken
  safely
• remind her of the risks of poorly controlled
  disease (suicide attempt, hospitalization, poor
  eating habits)
• available data does not indicate that the fetus
  will be at significant risk if drug therapy
  continues throughout pregnancy
• depending on clinical presentation, consider
  tapering and discontinuing benzodiazepine if
  possible
• if not, Level II ultrasound to rule out visible
  forms of cleft (risk remains very small)

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Case

• A 32 y.o. patient comes to you, frantic. A home
  pregnancy test is positive and last week her
  allergies were acting up. She was taking
  over-the-counter, Benadryl (diphenhydramine)
  daily and Claritin (loratadine) occasionally.
  She also took several tablets of acetaminophen
  because of accompanying headaches. She is not
  sure if she should terminate this pregnancy and
  is very concerned about the effects of these
  drugs on her unborn child. She can not get an
  appointment to see her doctor right away.

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Allergic Rhinitis in Pregnancy

• affects 20-30 of women of childbearing age
• rhinitis probably has no direct adverse effect on
  pregnancy
• indirectly may interfere with sleep and eating
  habits
• in uncontrolled may exacerbate coexisting asthma
• pregnancy related hormonal changes may lead to
  nasal mucosal swelling, and increase in secretion
  by the nasal mucosal glands
• symptoms worsen in 1/3 of women

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Pharmacological Therapy

• first generation antihistamines are well studied
  and considered first-line (chlorpheniramine,
  diphenhydramine, triprolidine)
• second generation antihistamines have preferred
  side-effect profile although less pregnancy data
  exists
• nasal sprays (sodium cromoglycate,
  corticosteroids) will relieve nasal congestion
  and have not been linked with birth defects
• decongestants (nasal sprays, oral
  pseudoephedrine) also effective and small
  studies do not seem to indicate significant
  riskgastroschisis risk not yet ruled out

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Answer

• reassure patient that acetaminophen at
  therapeutic doses is not harmful to the pregnancy
  or fetus and studies have not shown any link with
  birth defects
• first generation antihistamine (Benadryl) is well
  studied and not a concern
• second generation antihistamine (Claritin) is
  less well studied but the available data also did
  not show a risk for malformations
• confirm pregnancy by blood test and check
  dates(ie. pre-implantation?)
• none of these exposures is an indication for
  termination

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Resources

• The Motherisk Program at Sick Kids 416-813-6780
• recorded message service (for most common calls)
• WW W.MOTHERISK.ORG
• Canadian Family Physician
• Motherisk Newsletter (published online only)
• specialized information lines
• Nausea and Vomiting of Pregnancy
  Line 1-800-436-8477
• HIV Healthline and Network 1-888-246-5840
• Alcohol and Substance Use Line 1-877-FAS-INFO

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Texts
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Texts

• Briggs, Freeman Yaffe. Drugs in Pregnancy and
  Lactationa Reference Guide to Fetal and Neonatal
  Risk. 6th ed. Baltimore, MD Lippincott, Wiliams
  Wilkins, 2001.
• Friedman JM, Polifka JE Teratogenic Effects of
  Drugs a Resource for Clinicians (TERIS), 2nd ed.
  Baltimore, MD Johns Hopkins University Press,
  2000.
• Koren G. Maternal-Fetal Toxicology. A Clinicians
  Guide, 3rd ed. New York, NY Marcel Dekker, 2001.
• Scialli AR, Lione A, Boyle Padgett GK
  Reproductive Effects of Chemical, Physical, and
  Biologic Agents. Baltimore, MDJohns Hopkins
  University Press, 1995.
• Shepard TH Catalog of Teratogenic Agents, 10th
  ed. Baltimore, MDJohns Hopkins University
  Press,2001

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Web Sites

• The Organization of Teratology Information
  Services http//www.otispregnancy.org
• DART/ETIC A literature search engine for
  developmental and reproductive toxicology from
  the National Library of Medicine
  http//toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?DART
  ETIC.htm
• Reprotox An Information System on Environmental
  Hazards to Human Reproduction and Development
  (Subscription required) http//www.reprotox.org/
• TERIS Teratogen Information System and the
  on-line version of Shepard's Catalog of
  Teratogenic Agents (Subscription required)
  http//depts.washington.edu/terisweb/teris/index.
  html

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Articles

• Moretti ME. Pharmacy Practice, May
  200218(5)38-44
• simple review of common OTC agents
• Brent RL. Pediatrics in Review,
  200122(5)153-165.
• Rubin P. Br Med J, 19983171503-1506.

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