DRUGS AND PREGNANCYAdrea R. Benkoff, M.D.

Diagnostic Ophthalmic DrugsTherapeutic Ophthalmic Drugs

Relative Benefit to MotherSide Effects in Pregnant Patients

Potential Risk to FetusStructural or Visceral AbnormalitiesAltered 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 MedicationsAbsorbed Systemically by Drainage

Through Nasopharyngeal MucosaSecreted 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 AGENTSTOPICAL ANESTHETICS

No Teratogenic Effects

MYDRIATIC/CYCLOPLEGIC AGENTSNo Animal Studies on DropsSystemic Use of Atropine, Epinephrine,

Homatropine or PhenylephrineMinor, Non-Life-Threatening Malformations

Systemic ScopalamineFetal Tachycardia and Heart Rate Variability

DIAGNOSTIC AGENTSSystemic Phenylephrine

Fetal Hypoxia and Bradycardia

Unknown if Excreted in Breast MilkLow Weight Infants are Susceptible to Systemic

Hypertension with 2.5% or 10% Phenylephrine Drops

Avoid Use in Nursing Mothers

All Mydriatic/Cycloglegic Drops – Category CRelatively Contraindicated Due to Fetal Hypoxia in

Late Pregnancy and Delivery

DIAGNOSTIC AGENTSFLUORESCEIN DYE

Crosses PlacentaEnters Fetus in Humans and Animals

No Adverse Effects Reported in HumansCategory C Rating

Avoid Angiography on Pregnant Patients Especially Those in the First Trimester

Detected in Breast MilkStop Breastfeeding for Hours or Days if Used

Topically or by IV

DIAGNOSTIC AGENTS

INDOCYANINE GREEN DYEUsed Non-Ophthalmically in Pregnant Women for

Measuring Hepatic Blood FlowNo Adverse Effects on Mother or Fetus

Does Not Cross PlacentaNot Known if Present in Breast MilkPregnancy Category C Rating

Use Only if Clearly Indicated

GLAUCOMA MEDICATIONS

INCIDENCE OF GLAUCOMALow in Women of Child-Bearing Age

DISEASE SEVERITYYoung Mothers May Tolerate Small Increases in

IOP During PregnancyDecrease or Hold Treatment to Limit Risk to Fetus

Beta-Adrenergic Antagonists

Topical Medications Include: Betagan, Betimol, Istalol, Ocupress, and Timoptic

Systemic Side Effects in GeneralRespiratory Distress, Bradycardia, Heart Failure,

Fatigue, DepressionTopical 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 PregnancyApnea Intrauterine Growth RetardationNeonatal Depression at Birth (Low APGAR)Postnatal HypoglycemiaBradycardia

Effects of Topical Use in PregnancyCase Reports of Timolol Show Both No Effects and

Adverse EffectsCase Report: Decrease Concentration From 0.5%

to 0.25% Decreased Fetal Arrythmia

Beta-Adrenergic Antagonists

Beta-Blockers and Breast FeedingSecreted and Concentrated in Breast MilkCase Report: Apnea in 18 mo/old Child Being

Breast Fed

Rating- Pregnancy Category CPotential for Serious Adverse Side EffectsDiscontinue 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

ImbalanceNational 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 SmallHepatic and Renal Effects on Infants Being Breast

Fed

Carbonic Anhydrase Inhibitors

Topical Agents (Dorzolamide/Trusopt and Brinzolamide/Azopt)Published Reports LimitedNo Adverse Effects ReportedNot Known if Excreted in Breast Milk

Rating – Pregnancy Category CDiscontinue Nursing or Discontinue Drug, Taking

into Account the Importance of the Drug to the Mother

Sympathomimetics

Epinephrine (Epifrin)Stimulates Both Alpha and Beta Adrenergic

ReceptorsHuman 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 LaborCauses Uterine Contractions of Uterine Smooth

Muscles

Animal Studies of Systemic Prostaglandins Increase Risk of Abortion or Preterm Delivery

Prostaglandin AnaloguesHuman 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

MioticsParasympathomimetic Agents

Includes Direct Acting Cholinergic Agents: Pilocarpine & Carbachol

Animal Studies:Pilocarpine--Limb AbnormalitiesCarbachol– Cervical Vertebrae Abnormalities

Human Study: Systemic PilocarpineNo Side Effects in First 4 Months of GestationNear Term: Neonatal Hyperthermia, Seizures,

RestlessnessRating—Pregnancy Category C

CORTICOSTEROIDSSystemic Corticosteroids

Increase Risk of Stillbirth Intrauterine Growth Retardation and Adrenal

Insufficiency

Topical CorticosteroidsAnimal Studies:

Developmental and Teratogenic Effects Including Cleft Lip, Cleft Palate & Sex Organ Abnormalities in Mice

CORTICOSTEROIDS

Excreted in Breast MilkPresent if Administered Systemically

Suppressed Growth or Interferes with Endogenous Production

Unknown if Present as a Topical Medication

Rating—Pregnancy Category CAvoid Use During Nursing Given Potential Serious

Adverse Reactions.

ANTIBIOTICS

Erythromycin & Polymyxin BNo Known Congenital Defects

AminoglycosidesGentamycin, Streptomycin, Tobramycin, NeomycinCase Studies in Humans: Used IV with No

Teratogenic AbnormalitiesAnimal Studies: Hearing Loss, Nephrotoxicity

ANTIBIOTICSSulfonamides

Animal Studies: Increase Cleft Palate and Other Bony Abnormalities

Human Case Reports: Hyperbilirubinemia in Infant if Used During Third Trimester of Pregnancy

FluoroquinolonesAnimal Studies of Topical Ciloxan, Ocuflox, Quixin,

Vigamox & Zymar:No Teratogenic Effects

Animal Studies with High DosesDecrease Body Weights, Delayed Skeletal Development

ANTIBIOTICSTetracycline

Human Case Reports– Systemic Use: Permanent Discoloration of Teeth in Offspring

Excreted in Breast MilkPositive with Systemic Erythromycin, Tetracycline &

CiprofloxacinMaternal Medications Usually Compatible with Breast

Feeding By American Academy of Pediatrics

Rating:Pregnancy Category B--ErythromycinPregnancy Category C--Gentamycin, Neomycin, Polymyxin

B, Sulfonamides, FluoroquinolonesPregnancy Category D-- Tetracycline

ANTIVIRALSTopical: Trifluridine (Viroptic) & Vidarabine

( Vira-A)For Treatment of HSV KeratitisRating– Pregnancy Category C

Avoid in Pregnancy Due to Teratogenic and Tumorgenicity Effect

Oral: Acyclovir (Zovirax) & Valacyclovir (Valtrex)For Treatment of Epithelial Corneal DiseaseRating--Pregnancy Category B

THERAPY FOR CHOROIDAL NEOVASCULARIZATION

Verteporfin (Visudyne)Human Studies: NoneAnimal Studies: Increase Anophthalmia and

Microphthalmia in Rat FetusesRating– Pregnancy Category C

Pegaptanib (Macugen)Human Studies: NoneAnimal Studies: No Maternal or Fetal AbnormalitiesRating– Pregnancy Category B

THERAPY FOR CHOROIDAL NEOVASCULARIZATION

Bevacizumab (Avastin)Human Studies: NoneAnimal Studies: Teratogenic in Rabbits, Disrupts

AngiogenesisRating – Pregnancy Category C

Ranibizumab (Lucentis)Human Studies: NoneAnimal Studies : NoneRating-- Pregnancy Category C

ANTI-INFLAMMATORY DRUGS

Cyclosporine (Restasis) ImmunomodulatorAnimal Studies: No AbnormalitiesBreast Milk: Excreted When Used SystemicallyRating—Pregnancy Category C

NSAIDSFlurbiprofen (Ocufen)

Animal Studies: Embryocidal, Prolonged Gestation, Retarded Growth

ANTI-INFLAMMATORY DRUGS

Diclofenac (Voltaren)Animal Studies: Crosses Placenta

Nepafenac (Nevanac)Animal Studies: Crosses PlacentaFound in Breast Milk

Bromfenac (Xibrom)

Ketorolac (Acular)

All NSAIDS Rating- Pregnancy Category CAffects Fetal Cardiovascular System

MEDICAL MARIJUANA

Crosses PlacentaContains Toxins-- Decrease Oxygen to Fetus Increases Miscarriage, Low Birth Weight,

Premature Birth, Developmental Delays, Behavioral and Learning Problems, Increase Childhood Leukemia

Excreted in Breast MilkActive Ingredient THC-- Impairs Infant Motor

Development

COMMUNICATION

Clear Indication for Use

Relative Benefits vs. Potential RisksBirth 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 DropsNasolacrimal Duct OcclusionEyelid ClosureRemoval 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 AGENTSRoutine Use of Anesthetic Drops or Dilating Drops

Should be AvoidedUNLESS:

New Symptoms OccurMonitoring of Specific Disease (i.e. Diabetic Retinopathy)

Lowest Concentration and DurationTropicamide 0.5%

Fluorescein Dye and ICG DyeVitreoretinal Specialists Avoid Use During PregnancyUse OCT instead

THERAPEUTIC AGENTS

CorticosteroidsUse Topically with Caution

AntibioticsErythromycin—Relatively SafeTetracycline—AvoidFluoroqinolones—Effects Unknown

THERAPEUTIC AGENTSAntivirals

Topical Viroptic & Vira-A – Avoid Because of Tumor Formation and Teratogenic Effect

Oral Zovirax & Valtrex – Relatively Safe For Treatment of Epithelial Keratitis

Anti-Inflammatory DrugsRestasis – Use Only if Clearly NeededNSAIDS – Avoid Use in Late Pregnancy Because of

Fetal Cardiovascular System Complications

THERAPEUTIC AGENTSGlaucoma Treatment

ProstaglandinsAvoid Due to Effects on Uterine Contractility

Topical Beta BlockersReported Positive and Negative for Fetal Side Effects

Topical Carbonic Anhydrase InhibitorsRelatively Safe After First Trimester

Propine & AlphaganBoth are Pregnancy Category BAvoid Use of Alphagan at Term of Pregnancy Due to

Reports of Apnea and Somnolence in Neonates

NURSING MOTHERDilating 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 MOTHERAntivirals

Topicals – Avoid Unless Benefit Outweighs RiskOrals – Found in Breast Milk, Use with Caution

Anti-Inflammatory DrugsRestasis & NSAIDS – Use with Caution

Glaucoma TreatmentPropine & Alphagan P – Not Known if Excreted in

Breast MilkBeta Blockers, CA Inhibitors, Pilocarpine, Carbachol,

Epifrin, Iopidine, Prostaglandins – Discontinue Nursing or Discontinue Drug

GUIDELINES

FOR

MANAGEMENT

HSV KERATITIS DURING PREGNANCY

Epithelial LesionsFrequently Dendritic and Often Contain Live VirusDendrites May Heal Spontaneously After

Debridement and LubricationTopical Viroptic Used in Appropriate Dosage

Unlikely to Cause Fetal Damage

Stromal KeratitisHerpetic Eye Disease Study– Topical Antiviral

Therapy with Topical Steroids Reduces Progression and Duration of Disease

HSV KERATITIS DURING PREGNANCY

IridocyclitisAddition of Oral Zovirax to Topical Antiviral

Therapy and Corticosteroid was BeneficialNo 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 SteroidsOnly Observation in the First Trimester as the Risk

of Fetal Abnormalities Outweighs the Benefit of Faster Visual Recovery

CHRONIC UVEITISMainstay of Treatment

Topical CycloplegiaNo Teratogenic Effects

Topical CorticosteroidsNo Teratogenic Effects

If Oral Steroids and/or Nonsteroidals (Methotrexate) Are NeededNO Methotrexate-- Known TeratogenNO Systemic Steroids– Risk of Cleft Lip and Palate

Consider Periocular or Intravitreal SteroidsSecondary to Reduced Systemic LevelsWeigh 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 LABORManagement of Premature Labor and Eclampsia

Beta-MimeticsRarely Causes Acute Angle-Closure Glaucoma

Magnesium SulfatePtosis, Accommodative and Convergence Insufficiency with

Diplopia and/or Pupillary AbnormalitiesAntiprostaglandins (Indocin)

Decreases IOP Lowering Effect of Epinephrine in Glaucoma Patients

After Treatment for Premature Labor, Pregnant Woman is Given Glucocorticoids for 2 Days Before DeliveryGlaucoma May Worsen After Steroid Therapy