DRUGS AND PREGNANCY Adrea R Benkoff M D

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

Diagnostic Ophthalmic Drugs Therapeutic 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

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

SOURCES Case Reports Individual Experience Animal Studies

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

Tetracycline ANTIBIOTICS 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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”

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

GUIDELINES FOR MANAGEMENT

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

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

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

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

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

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