DRUGS AND PREGNANCY

1. DRUGS AND PREGNANCY Adrea R. Benkoff, M.D.

2. Diagnostic Ophthalmic DrugsTherapeutic Ophthalmic Drugs • Relative Benefit to Mother • Side Effects in Pregnant Patients • Potential Risk to Fetus • Structural or Visceral Abnormalities • Altered Physiologic Function of Nursing Baby

3. TERATOGEN • An Agent That By Acting During the Embryonic or Fetal Period Produces Morphologic or Functional Malformations That Become Apparent Postnatal

4. SOURCES • Case Reports • Individual Experience • Animal Studies

5. SYSTEMIC EFFECTS • Oral Medications • Topical Medications • Absorbed Systemically by Drainage Through Nasopharyngeal Mucosa • Secreted in Breast Milk

6. FDA CATEGORIES FOR DRUG USE IN PREGNANCY • Category A--- Adequate and well controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). • Category B--- Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. • Category C--- Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. • Category D--- There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. • Category X--- Studies in animals or humans have demonstrated fetal abnormalities and /or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

7. DIAGNOSTIC AGENTS • TOPICAL ANESTHETICS • No Teratogenic Effects • MYDRIATIC/CYCLOPLEGIC AGENTS • No Animal Studies on Drops • Systemic Use of Atropine, Epinephrine, Homatropine or Phenylephrine • Minor, Non-Life-Threatening Malformations • Systemic Scopalamine • Fetal Tachycardia and Heart Rate Variability

8. DIAGNOSTIC AGENTS • Systemic Phenylephrine • Fetal Hypoxia and Bradycardia • Unknown if Excreted in Breast Milk • Low Weight Infants are Susceptible to Systemic Hypertension with 2.5% or 10% Phenylephrine Drops • Avoid Use in Nursing Mothers • All Mydriatic/Cycloglegic Drops – Category C • Relatively Contraindicated Due to Fetal Hypoxia in Late Pregnancy and Delivery

9. DIAGNOSTIC AGENTS • FLUORESCEIN DYE • Crosses Placenta • Enters Fetus in Humans and Animals • No Adverse Effects Reported in Humans • Category C Rating • Avoid Angiography on Pregnant Patients Especially Those in the First Trimester • Detected in Breast Milk • Stop Breastfeeding for Hours or Days if Used Topically or by IV

10. DIAGNOSTIC AGENTS • INDOCYANINE GREEN DYE • Used Non-Ophthalmically in Pregnant Women for Measuring Hepatic Blood Flow • No Adverse Effects on Mother or Fetus • Does Not Cross Placenta • Not Known if Present in Breast Milk • Pregnancy Category C Rating • Use Only if Clearly Indicated

11. GLAUCOMA MEDICATIONS • INCIDENCE OF GLAUCOMA • Low in Women of Child-Bearing Age • DISEASE SEVERITY • Young Mothers May Tolerate Small Increases in IOP During Pregnancy • Decrease or Hold Treatment to Limit Risk to Fetus

12. Beta-Adrenergic Antagonists • Topical Medications Include: Betagan, Betimol, Istalol, Ocupress, and Timoptic • Systemic Side Effects in General • Respiratory Distress, Bradycardia, Heart Failure, Fatigue, Depression • Topical Medications Bypass Hepatic Metabolism and Are Not Inactivated (unlike oral beta-blockers) • Despite Low Dosage • In Children: Bradycardia & Apnea

13. Beta-Adrenergic Antagonists • Systemic Therapy Effects in Pregnancy • Apnea • Intrauterine Growth Retardation • Neonatal Depression at Birth (Low APGAR) • Postnatal Hypoglycemia • Bradycardia • Effects of Topical Use in Pregnancy • Case Reports of Timolol Show Both No Effects and Adverse Effects • Case Report: Decrease Concentration From 0.5% to 0.25% Decreased Fetal Arrythmia

14. Beta-Adrenergic Antagonists • Beta-Blockers and Breast Feeding • Secreted and Concentrated in Breast Milk • Case Report: Apnea in 18 mo/old Child Being Breast Fed • Rating- Pregnancy Category C • Potential for Serious Adverse Side Effects • Discontinue Nursing or Discontinue Drug, Taking Into Account the Importance of the Drug to the Mother

15. Carbonic Anhydrase Inhibitors • Oral Agents (Acetazolamide/Diamox) • Animal Studies: Malformations, Electrolyte Imbalance • National Collaborative Perinatal Project • No Incidence in Major or Minor Fetal Abnormalities in Infants Where Mothers Took Medication at Different Stages of Pregnancy • Study Size Considered Too Small • Hepatic and Renal Effects on Infants Being Breast Fed

16. Carbonic Anhydrase Inhibitors • Topical Agents (Dorzolamide/Trusopt and Brinzolamide/Azopt) • Published Reports Limited • No Adverse Effects Reported • Not Known if Excreted in Breast Milk • Rating – Pregnancy Category C • Discontinue Nursing or Discontinue Drug, Taking into Account the Importance of the Drug to the Mother

17. Sympathomimetics • Epinephrine (Epifrin) • Stimulates Both Alpha and Beta Adrenergic Receptors • Human Studies: Systemic Use in First Trimester Associated with Minor and Major Anomalies-- Inguinal Hernias • Rating-- Pregnancy Category C

18. Sympathomimetics • Dipivefrin Hydrochloride (Propine) • Prodrug of Epinephrine Converted by Corneal Enzymes • Animal Studies: Negative for Side Effects • Not Known if Excreted in Breast Milk • Rating-- Pregnancy Category B • Brimonidine (Alphagan P)—Apraclonidine Hydrochloride (Iopidine) • Selective Alpha-2 Adrenergic Agonists • Case Reports: No Adverse Side Effects During Pregnancy • Not Known if Excreted in Breast Milk • Alphagan P Caused CNS Depression, Somnolence, Apnea in Neonates and Infants • Rating– • Alphagan P– Pregnancy Category B • Iopidine– Pregnancy Category C

19. Prostaglandin Analogues • Latanaprost (Xalatan), Bimatoprost (Lumigan), Travoprost (Travatan) • Prostaglandins Action in Labor • Causes Uterine Contractions of Uterine Smooth Muscles • Animal Studies of Systemic Prostaglandins • Increase Risk of Abortion or Preterm Delivery

20. Prostaglandin Analogues • Human Studies of Topical Prostaglandins • Case Studies: No Adverse Effect on Pregnancy or Neonatal Outcome • Excretion in Breast Milk • Positive in Animal Studies • Unknown in Humans • Rating—Pregnancy Category C • Because of Potential Effects on Uterine Muscle Contractibility • Prostaglandin Should Be Avoided in Women Who Are Pregnant or Desire to Become Pregnant

21. Miotics • Parasympathomimetic Agents • Includes Direct Acting Cholinergic Agents: Pilocarpine & Carbachol • Animal Studies: • Pilocarpine--Limb Abnormalities • Carbachol– Cervical Vertebrae Abnormalities • Human Study: Systemic Pilocarpine • No Side Effects in First 4 Months of Gestation • Near Term: Neonatal Hyperthermia, Seizures, Restlessness • Rating—Pregnancy Category C

22. CORTICOSTEROIDS • Systemic Corticosteroids • Increase Risk of Stillbirth • Intrauterine Growth Retardation and Adrenal Insufficiency • Topical Corticosteroids • Animal Studies: • Developmental and Teratogenic Effects Including Cleft Lip, Cleft Palate & Sex Organ Abnormalities in Mice

23. CORTICOSTEROIDS • Excreted in Breast Milk • Present if Administered Systemically • Suppressed Growth or Interferes with Endogenous Production • Unknown if Present as a Topical Medication • Rating—Pregnancy Category C • Avoid Use During Nursing Given Potential Serious Adverse Reactions.

24. ANTIBIOTICS • Erythromycin & Polymyxin B • No Known Congenital Defects • Aminoglycosides • Gentamycin, Streptomycin, Tobramycin, Neomycin • Case Studies in Humans: Used IV with No Teratogenic Abnormalities • Animal Studies: Hearing Loss, Nephrotoxicity

25. ANTIBIOTICS • Sulfonamides • Animal Studies: Increase Cleft Palate and Other Bony Abnormalities • Human Case Reports: Hyperbilirubinemia in Infant if Used During Third Trimester of Pregnancy • Fluoroquinolones • Animal Studies of Topical Ciloxan, Ocuflox, Quixin, Vigamox & Zymar: • No Teratogenic Effects • Animal Studies with High Doses • Decrease Body Weights, Delayed Skeletal Development

26. ANTIBIOTICS • Tetracycline • Human Case Reports– Systemic Use: • Permanent Discoloration of Teeth in Offspring • Excreted in Breast Milk • Positive with Systemic Erythromycin, Tetracycline & Ciprofloxacin • Maternal Medications Usually Compatible with Breast Feeding By American Academy of Pediatrics • Rating: • Pregnancy Category B--Erythromycin • Pregnancy Category C--Gentamycin, Neomycin, Polymyxin B, Sulfonamides, Fluoroquinolones • Pregnancy Category D-- Tetracycline

27. ANTIVIRALS • Topical: Trifluridine (Viroptic) & Vidarabine ( Vira-A) • For Treatment of HSV Keratitis • Rating– Pregnancy Category C • Avoid in Pregnancy Due to Teratogenic and Tumorgenicity Effect • Oral: Acyclovir (Zovirax) & Valacyclovir (Valtrex) • For Treatment of Epithelial Corneal Disease • Rating--Pregnancy Category B

28. THERAPY FOR CHOROIDAL NEOVASCULARIZATION • Verteporfin (Visudyne) • Human Studies: None • Animal Studies: Increase Anophthalmia and Microphthalmia in Rat Fetuses • Rating– Pregnancy Category C • Pegaptanib (Macugen) • Human Studies: None • Animal Studies: No Maternal or Fetal Abnormalities • Rating– Pregnancy Category B

29. THERAPY FOR CHOROIDAL NEOVASCULARIZATION • Bevacizumab (Avastin) • Human Studies: None • Animal Studies: Teratogenic in Rabbits, Disrupts Angiogenesis • Rating – Pregnancy Category C • Ranibizumab (Lucentis) • Human Studies: None • Animal Studies : None • Rating-- Pregnancy Category C

30. ANTI-INFLAMMATORY DRUGS • Cyclosporine (Restasis) • Immunomodulator • Animal Studies: No Abnormalities • Breast Milk: Excreted When Used Systemically • Rating—Pregnancy Category C • NSAIDS • Flurbiprofen (Ocufen) • Animal Studies: Embryocidal, Prolonged Gestation, Retarded Growth

31. ANTI-INFLAMMATORY DRUGS • Diclofenac (Voltaren) • Animal Studies: Crosses Placenta • Nepafenac (Nevanac) • Animal Studies: Crosses Placenta • Found in Breast Milk • Bromfenac (Xibrom) • Ketorolac (Acular) • All NSAIDS Rating- Pregnancy Category C • Affects Fetal Cardiovascular System

32. MEDICAL MARIJUANA • Crosses Placenta • Contains Toxins-- Decrease Oxygen to Fetus • Increases Miscarriage, Low Birth Weight, Premature Birth, Developmental Delays, Behavioral and Learning Problems, Increase Childhood Leukemia • Excreted in Breast Milk • Active Ingredient THC-- Impairs Infant Motor Development

33. COMMUNICATION • Clear Indication for Use • Relative Benefits vs. Potential Risks • Birth Defects Occur in 2% or More of All Neonates. Drugs Used Coincidently Might Be Wrongly Implicated as Contributing to a Birth Defect • Discussion with Patient and Obstetrician

34. DOSAGE • Minimal Effective Dose • Shortest Duration • Limit Systemic Absorption of Drops • Nasolacrimal Duct Occlusion • Eyelid Closure • Removal of Excess Medication with Absorbent Material

35. OPHTHALMIC OINTMENTS • Safety Profile Different from Drops • Ointment Creates Reservoir of Active Drug • Prolonged Absorption Time • Reduced Serum Level of Medication • May Create Lower Therapeutic Level Within Eye

36. DIAGNOSTIC AGENTS • Routine Use of Anesthetic Drops or Dilating Drops Should be Avoided • UNLESS: • New Symptoms Occur • Monitoring of Specific Disease (i.e. Diabetic Retinopathy) • Lowest Concentration and Duration • Tropicamide 0.5% • Fluorescein Dye and ICG Dye • Vitreoretinal Specialists Avoid Use During Pregnancy • Use OCT instead

37. THERAPEUTIC AGENTS • Corticosteroids • Use Topically with Caution • Antibiotics • Erythromycin—Relatively Safe • Tetracycline—Avoid • Fluoroqinolones—Effects Unknown

38. THERAPEUTIC AGENTS • Antivirals • Topical Viroptic & Vira-A – Avoid Because of Tumor Formation and Teratogenic Effect • Oral Zovirax & Valtrex – Relatively Safe For Treatment of Epithelial Keratitis • Anti-Inflammatory Drugs • Restasis – Use Only if Clearly Needed • NSAIDS – Avoid Use in Late Pregnancy Because of Fetal Cardiovascular System Complications

39. THERAPEUTIC AGENTS • Glaucoma Treatment • Prostaglandins • Avoid Due to Effects on Uterine Contractility • Topical Beta Blockers • Reported Positive and Negative for Fetal Side Effects • Topical Carbonic Anhydrase Inhibitors • Relatively Safe After First Trimester • Propine & Alphagan • Both are Pregnancy Category B • Avoid Use of Alphagan at Term of Pregnancy Due to Reports of Apnea and Somnolence in Neonates

40. NURSING MOTHER • Dilating Drops – Avoid Due to Infant Systemic Hypertension • Fluorescein Dye – If Use Necessary, Must Stop Breastfeeding for Hours or Days • Corticosteroids – Potentially Serious Side Effects • Antibiotics – American Academy of Pediatrics Classified Erythromycin, Gentamycin, Tetracycline & Ciprofloxacin as “Maternal Medications Usually Compatible with Breast Feeding”

41. NURSING MOTHER • Antivirals • Topicals – Avoid Unless Benefit Outweighs Risk • Orals – Found in Breast Milk, Use with Caution • Anti-Inflammatory Drugs • Restasis & NSAIDS – Use with Caution • Glaucoma Treatment • Propine & Alphagan P – Not Known if Excreted in Breast Milk • Beta Blockers, CA Inhibitors, Pilocarpine, Carbachol, Epifrin, Iopidine, Prostaglandins – Discontinue Nursing or Discontinue Drug

42. GUIDELINES FOR MANAGEMENT

43. HSV KERATITIS DURING PREGNANCY • Epithelial Lesions • Frequently Dendritic and Often Contain Live Virus • Dendrites May Heal Spontaneously After Debridement and Lubrication • Topical Viroptic Used in Appropriate Dosage Unlikely to Cause Fetal Damage • Stromal Keratitis • Herpetic Eye Disease Study– Topical Antiviral Therapy with Topical Steroids Reduces Progression and Duration of Disease

44. HSV KERATITIS DURING PREGNANCY • Iridocyclitis • Addition of Oral Zovirax to Topical Antiviral Therapy and Corticosteroid was Beneficial • No Fetal Abnormalities from Oral Zovirax or Valtrex Reported

45. OPTIC NEURITIS IN FIRST TRIMESTER DUE TO DEMYLENATING DISEASE • Optic Neuritis Treatment Trial • IV Methylprednisolone • Faster Resolution of the Visual Loss but Did NOT Affect Long-Term Outcome After 6 Months • Decrease Risk of Recurrence of Optic Neuritis and Development of MS in the Future • No IV Steroids • Only Observation in the First Trimester as the Risk of Fetal Abnormalities Outweighs the Benefit of Faster Visual Recovery

46. CHRONIC UVEITIS • Mainstay of Treatment • Topical Cycloplegia • No Teratogenic Effects • Topical Corticosteroids • No Teratogenic Effects • If Oral Steroids and/or Nonsteroidals (Methotrexate) Are Needed • NO Methotrexate-- Known Teratogen • NO Systemic Steroids– Risk of Cleft Lip and Palate • Consider Periocular or Intravitreal Steroids • Secondary to Reduced Systemic Levels • Weigh Risk/Benefits to Patient

47. GLAUCOMA DURING PREGNANCY AND LACTATION • Several Glaucoma Medications Have Potential Adverse Effects in the Fetus or Breastfeeding Infant • Beta-Blockers—Class C • Alpha 2 Agonists (Alphagan P)– Class B • Prostaglandin Analogues– Class C • Topical and Oral Carbonic Anhydrase Inhibitors– Class C • Alternatives Include: • Laser Trabeculoplasty • Observation OFF Treatment • Avoid Glaucoma Surgery • Because of Anesthetic Concerns, Surgical Positioning and Intra and Peri-Operative Medications

48. WORSENING OF GLAUCOMA IN DRUGS USED TO TREAT ECLAMPSIA AND PREMATURE LABOR • Management of Premature Labor and Eclampsia • Beta-Mimetics • Rarely Causes Acute Angle-Closure Glaucoma • Magnesium Sulfate • Ptosis, Accommodative and Convergence Insufficiency with Diplopia and/or Pupillary Abnormalities • Antiprostaglandins (Indocin) • Decreases IOP Lowering Effect of Epinephrine in Glaucoma Patients • After Treatment for Premature Labor, Pregnant Woman is Given Glucocorticoids for 2 Days Before Delivery • Glaucoma May Worsen After Steroid Therapy