DRUGS%20AND%20PREGNANCY

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DRUGS AND PREGNANCY

• Adrea R. Benkoff, M.D.

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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

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TERATOGEN

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

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SOURCES

• Case Reports
• Individual Experience
• Animal Studies

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SYSTEMIC EFFECTS

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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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
• RatingPregnancy Category C
• Because of Potential Effects on Uterine Muscle
  Contractibility
• Prostaglandin Should Be Avoided in Women Who Are
  Pregnant or Desire to Become Pregnant

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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
• RatingPregnancy Category C

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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

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CORTICOSTEROIDS

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

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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

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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

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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

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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

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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

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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

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ANTI-INFLAMMATORY DRUGS

• Cyclosporine (Restasis)
• Immunomodulator
• Animal Studies No Abnormalities
• Breast Milk Excreted When Used Systemically
• RatingPregnancy Category C
• NSAIDS
• Flurbiprofen (Ocufen)
• Animal Studies Embryocidal, Prolonged
  Gestation, Retarded Growth

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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

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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

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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

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DOSAGE

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

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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

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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

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THERAPEUTIC AGENTS

• Corticosteroids
• Use Topically with Caution
• Antibiotics
• ErythromycinRelatively Safe
• TetracyclineAvoid
• FluoroqinolonesEffects Unknown

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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

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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

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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

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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

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• GUIDELINES
• FOR
• MANAGEMENT

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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

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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

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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

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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

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GLAUCOMA DURING PREGNANCY AND LACTATION

• Several Glaucoma Medications Have Potential
  Adverse Effects in the Fetus or Breastfeeding
  Infant
• Beta-BlockersClass 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

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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