Pharmacotherapy in Pregnancy: Balancing Risks and Benefits

1. Pharmacotherapy in Pregnancy:Balancing Risks and Benefits Myla Moretti The Hospital for Sick Children September 9, 2004

2. 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

3. 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

4. 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

5. Types of Malformation • Major Malformation: structural or functional defects for which medical or surgical intervention is necessary, or a defect that can impair the child’s 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

6. 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

8. 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)

9. 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)

10. Karnofsky’s 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

11. 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

12. Risk-Benefit Analysis Risks • not treating mom • teratogenesis • poor pregnancy outcome Benefits • good control of maternal disease • improved pregnancy outcome

13. 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

14. 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 Methods of Assessing Risk

16. 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

17. Obtaining and Interpreting the Data • is it ethical? • is it doable? • statistics and power • How much is enough?

19. 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

20. 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

21. ACE inhibitors anticonvulsants benzodiazepines carbon monoxide DES ethanol hyperthermia lead lithium misoprostol organic solvents retinoids rubella systemic corticosteroids tetracyclines varicella warfarin Known/Suspected Teratogens

22. 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.

24. Evidence • several studies have not shown increased risk for malformations following the use of SSRI’s 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

25. 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)

26. 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.

27. 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

28. 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 risk*gastroschisis risk not yet ruled out

29. 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

31. 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

32. Texts

33. Texts • Briggs, Freeman & Yaffe. Drugs in Pregnancy and Lactation:a 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 Clinician’s 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, MD:Johns Hopkins University Press, 1995. • Shepard TH: Catalog of Teratogenic Agents, 10th ed. Baltimore, MD:Johns Hopkins University Press,2001

34. 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?DARTETIC.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

35. Articles • Moretti ME. Pharmacy Practice, May 2002;18(5):38-44 • simple review of common OTC agents • Brent RL. Pediatrics in Review, 2001;22(5):153-165. • Rubin P. Br Med J, 1998;317:1503-1506.