sdls 2008 drugs and immunization during pregnancy

8/2/2019 SDLS 2008 Drugs and Immunization During Pregnancy

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DE LA SALLE HEALTH SCIENCES CAMPUS COLLEGE OF MEDICINE

Detoxicol

SDLS 2008

Subject: Obstetrics and Gynecology Lecture Date: December 07, 2005Topic: Drugs and Immunization During Pregnancy Transcriber(s): Jaime AherreraLecturer: Dr. Enrique V. Labios No. of pages: 19

DRUGS & IMMUNIZATION DURING PREGNANCY

INTRODUCTION

I. ABSORPTION

Absorption of Drugs in Pregnancy is affected

This is due to the following:

A. Gastrointestinal Disturbances

o Vomiting (Drugs are vomited out)o Reduced Gastric Secretions

o Reduced Motility

B. Pulmonary Effectso Increase in the Volume of Inspired Air / Minute

o Increase Alveolar Ventilation

**NOTE: We should Decrease the doses of Inhaled Drugs during Pregnancy (Dose Adjustment)

These Factors Increase the Absorption and Elimination of Drugs

C. Enhanced Percutaneous Drug Absorptiono Blood Flow Increases Six-Fold in pregnancy

**NOTE: We should also Decrease Dose (due to the increased blood flow)

II. DISTRIBUTION

Decrease Plasma Albumin by 50% during the Last Trimester (Increases Bioavailability of the drug)

Decrease Binding Affinity (Increases Biovailability of the Drug)

Competition for Binding Proteins (Variable)

Increased Intravascular Volume in the Last Two Trimesters of Pregnancy (Increased Drug Distribution)

**NOTE: When Drugs are NOT bound to proteins, they become more Bioavailable

III. DRUG ELIMINATION

Drugs are eliminated via Renal / Hepatic Excretion, Sweat Glands, Respiration

Most of the Time = Kidney and Liver

A. Drug Elimination is Increased due to:o Decrease Protein Binding Affinity

o Increase Renal Plasma Flow

o Increase Glomerular Filtration Rate

o Increase Rate and Minute Volume

B. Drug Elimination may be Impaired:

o Impaired Metabolism is required prior to eliminationo Hepatobiliary Excretion

o Decrease Gastrointestinal Motility

PHARMACOLOGY & PREGNANCY

I. FETAL EXPOSURE

Important = TIMING of Intake of the Drugs

There are three periods of Pregnancy:


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A. Ovumo From Fertilization to Implantation

B. Embryo

o Period of Organogenesis (2nd to 8th week of Pregnancy)

o This is the MOST Vulnerable Period

o Potential for causing Limb Malformation may last until the end of the first trimester (14th week)o Muscle Malformation is also possible at this time

C. Fetal

o Beyond the 8th Week until Term

o Histogenesis and Functional Maturation

o Diethystilbestrol (DES) = Mullerian Abnormalities include Uterine Agenesis and Vaginal Duplication

o Tetracyclein = Brownish Discoloration of the Teeth in Newborns

II. TERATOGENETICS OF DRUGS

Some Drugs have Potential for causing Limb Malformation may last to the end of the First Trimester (14 Weeks)

Beyond the Period of Organogenesis, the Fetus is STILL Susceptible since Histogenesis and Functional Maturationcontinue (ex. Tetracycline, Diethylsolbestrol / DES)

There is NO information about Long-Term Effect, like learning / behavioral problems (Functional Teratogenesis)

III. PRINCIPLES OF COUNSELING

Counseling about Teratogenic Exposure should be done in a Sympathetic, Supportive and Informative Manner

Ultrasound Examination (we can check for possible Fetal Anomalies)

Neural Tube Defects & Midline Ventral Fusion defects may be Detected by Ultrasound or Maternal Serum Screening

**NOTE: These Tests are NOT used for Assessing Drug Exposure:o Serologic Testing, Chronic Villus Sampling, Aminocentesis, Fetal Blood Sampling

**IMPORTANT Notes:o The Physicians Desk Reference (PDR) Reference

o Organization of Teratogen Information Service

o TO Avoid Liabililty, Drug Manufacturers DO NOT encourage use of their Drugs during Pregnancy

**Standard Series of Statements:o Reproductive Studies, performed in rats and mice at Maternally Toxic Dose Levels, revealed NO evidence of

Impaired Fertility or Harm to the Fetus (no human studies yet)o There are, however, NO adequate and well-controlled studies in Pregnant Women

o As animal reproduction studies are not always predictive of Human Response, ____ should be used during

pregnancy only if clearly indicated

IV. FOOD AND DRUG ADMINISTRATION (FDA) CATEGORY OF DRUGS (1979)

Based on the Available Information assessing the Risk to the Fetus balanced against the Drugs Potential Benefit tothe Mother

Most Drugs belong to Class B and C

A. Class-A Drugo Well-Controlled Studies show NO Risk

o Ex) Supplemental Drugs (Vitamin Preparations, Perisulfate, etc)

**NOTE: It DOES NOT Include Pure and High Dose Vitamin-A and/or D Capsules

B. Class-B Drugo No Evidence of Risk in Humans BUT, there are no studies yet

o Ex) B-Lactams, Paracetamol

C. Class-C Drugso Risk cannot be ruled out

o There are studies in animals that show possible risk

D. Class-D Drugso Positive Evidence of Risk

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o Ex) Fluoroquinolones

E. Class-X Drugso There are PROVEN cases that Humans are affected by drugs

o Contraindicated in Pregnancy Teratogens with High Risk

V. FETAL EFFETS FROM SPECIFIC DRUGS

Many Dilemmas exist when Studying a Drug

The finding are NOT always conclusive

Most Human Data involve small series or case reports, biased or merely reflect the patients background risk for BirthDefects

A lack of comparability of the Dose and Route of Administration can limit interpretation

Randomized Controlled Trial are UNCOMMON

Side Effects may mimic Symptoms of Pregnancy (Nausea, Vomiting, Bloatedness)

Many agents contain Multiple Ingredients, Active and Inactive

VI. DRUGS OR SUBSTANCES SUSPECTED OR PROVEN TO BE HUMAN TERATOGENS

ACE-Inhibitor

Alcohol

Aminopterin Androgens

Busulfan

Caramazepine

Chlorbiphenyls

Coumadins

Cyclophosphamide

Danazol

DES

Etretinate

Isotretinoin

Lithium

Methimazole

Methotrexate

Penicillamine

Phenytoin

Radioactive Iodine

Tetracycline

Trimethadione

Valproic Acid

VII. PRINCIPLES OF PRESCRIBING IN HUMAN PREGNANCY

Evaluate every Drug to be Prescribed

Use Drugs with proven Tract Records of Safety

Inform the mother of any Potential Risk to the Fetus VS the Benefit to the Mother & Fetus

DRUGS AND PREGNANCY

DRUG CRITICAL PERIOD MAGNITUDE OF RISK

Androgen 8th to 13th Week = Labial Fusion2nd and 3rd Trimester = Clitoral Hypertrophy

Unknown

ACE Inhibitors 2nd and 3rd Trimester UnknownDependent on Dose and Duration

Anticoagulants(Warfarin)

6th 9th week Age of Gestation = Fetal WarfarinSyndrome (Facial Anomalies and Epiphyseal Stippling)Throughout Gestation = CNS Defects

5-10% for FWS4-5% for CNS and other Defects

Anticonvulsants 1ST Trimester (Malformation)3rd Trimester (Early HDN)

2-3-Fold Increase Risk from Epilepsy Alone12-15% for Anticonvulsant Drug Therapy1-2% NTD (Valproic Acid)1% NTD (Carbamazapine)

Antidepressant(Lithium)

1st Trimester = Cardiac Defects3rd Trimester = New Born Toxicity


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Aminoglycosides(Kanamycin, Streptomycin)

Throughout Pregnancy Low (probably


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D. Defects & Toxicityo Fetus-Anuria-Oligohydramnios, Growth Restriction (IUGR), Hypocalvaria, Persistent PDA, Stillbirths, Renal

Failure in the Newborn

o Congenital Hypocalvaria (underdevelopment of the Skull)

o Renal Anomaly (anuria)

E. Commentso Monitoring of AF-Levels is RECOMMENDED, but Renal Impairment may be IRREVERISBLE

III. ANTICOAGULANTS (WARFARIN)

A. Critical Period:

o 6th 9th week Age of Gestation = Fetal Warfarin Syndrome (Facial Anomalies & Epiphyseal Stippling)

o Throughout Gestation = CNS Defects

B. Magnitude of Risko 5-10% for FWS

o 4-5% for CNS and other Defects

C. Mechanismo Vitamin-K Deficiency in Embryo

o Microhemorrhage and Scarring (CNS Effects)

D. Defects & Toxicityo FWS-Nasal Hypoplasia, Stippled Hypophysis, IUGR, Eye Defects, Hypoplasia of Extremities, CHD

o CNS Damage (MR, Spasticity, Seizures, Scoliosis, Deafness and Hearing Loss, Death)

IV. ANTICONVULSANTS

A. Critical Period:

o 1ST Trimester (Malformation)

o 3rd Trimester (Early HDN)

B. Magnitude of Risko 2-3-Fold Increase over Risk from Epilepsy Alone

o 12-15% for Anticonvulsant Drug Therapy

o 1-2% NTD (Valproic Acid)

o 1% NTD (Carbamazapine)

C. Mechanism

o Multifactorial (Polygene-Drug Interaction)

o Folic Acid Deficiency

o Carbamazepine, Phenytoin, and Valproic Acid produce Toxic Epoxide Metabolites

o If Fetus is Homozygous for Low Epoxide Hydroxylase Activity, then High Risk for Embryopathy

o Early HDN may result from Depletion of Vitamin-K Stores in Fetus

D. Defects & Toxicity

ANTICONVULSTANT DEFECT

Carbamazepine NTD, Craniofacial Defects, Fingernail Hypoplasia, Developmental Delay

Phenobarpital / Primidone Cardiac Defects, Cleft Lip / Palate, Hypoplasia of Midface and Fingers, Microcephaly,IUGR, Impaired Cognitive Development, and HDN

Phenytoin Craniofacial and Limb Defects, HDN

Trimethadione Cardiac Septal, Craniofacial and Genitourinary Defects, IUGR, Postnatal GrowthDeficiency, and MR

Valproic Acid NTD, Craniofacial, Digit & Urogenital Defects, IUGR, Retarded PsychomotorDevelopment

V. ANTIDEPRESSANT (LITHIUM)

A. Critical Period

o 1st Trimester = Cardiac Defects

o 3rd Trimester = New Born Toxicity

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B. Magnitude of Risko


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IX. TETRACYCLINE

A. Critical Period

o Beyond 4th Month

B. Magnitude of Risko Unknown

o Duration-Dependent

C. Mechanism

o Chelation: Drug forms a complex with Calcium Orthophosphate and is Incorporated into Bones an Teeth

undergoing Calcificationo Complex is permanent in TEETH because remodeling and Calcium exchange DO NOT occur after

Calcification is Completed

D. Defects & Toxicityo Intense Yellow Gold Fluorescence of Mineralized Skeletal Structure and Teeth

o Impairment of Bone Growth may occur but it is NOT clinically significant

X. CORTICOSTEROIDS (SYSTEMIC) ALL MEMBERS OF CLASS

A. Critical Periodo Before 10 weeks = Oral Clefts

o Throughout Gestation = IUGR

B. Magnitude of Risko 0.1-0.2% = Cleft Lip (+ / - ) Cleft Palate

o May increase to seven fold

C. Mechanismo Unknown

D. Defects & Toxicityo NONSYNDROMIC CLEFT LIP (with or without Cleft Palate)

o IUGR (Intrauterine Growth Retardation)

XI. PEINICILLAMINE

A. Critical Periodo Unknown

B. Magnitude of Risk

o Unknowno Probably Less than 5%

C. Mechanismo Chelation of Metals (ex. Copper)


o Cutis Laxa (Limiting Dose to 1g/d or less during Gestation may reduce the Risk)

o If Cesarean Section is planned, limit the dose to 250md/day for 6 weeks before delivery and after surgery

until Wound Healing is Complete

XII. SYNTHETIC ESTROGEN (DES)

A. Critical Period

o 10-13 Weeks of Gestation = Highest Risk of Vaginal Adenocarcinoma, but some risk up to 18 weeks

o Up to 20 weeks = Genital Malformation

B. Magnitude of Risko


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C. Mechanismo Possible Inhibition of Upward Growth of Vaginal Plate of Stimulation of Mullerian Epithelium so that it persists

in the Developing Vagina

D. Defects & Toxicity (Infertility)1. Females

Lower Mullerian Tract = Vaginal Adenosis, Vaginal & Cervical Clear Cell Adenocarcinoma (morethan 90% occur after 14years of age), Cervical and Vaginal Fornix Defect

Vaginal Defects = Incomplete Transverse and/or Longitudinal Septum

Upper Mullerian = Uterine and Fallopian Structural Defects

2. Males

Epididymal Cyst, Hypotrophic Testis, Microphalus, Varicocele, Capsular Induration, Altered Semen

XIII. MISOPROSTOL

A. Critical Periodo Highest Risk = 6-8weeks

o Any time during the 1st Trimester

B. Magnitude of Risko Up to 7-times Background Risk for Mobius Syndrome

o Almost all Adverse Outcomes have been related to Unsuccessful Abortion Attempts with large,

sometimes massive doses (same with Quinine)

C. Mechanism

o Vascular Disruption caused by Uterine Contractions

o Deformation

o With Uterine Contractions it Expells the Fetus

**Problem: DEFORMATION (because of the compression of the Fetus)

D. Defects & Toxicityo Vaginal Bleeding

o Abortion

o If Abortion does not occur, reported defects include the following: Mobius Syndrome (6th and 7th Nerve

Palsies), Defect of Cranium and Scalp, Cleft Lip/Palate, Ocular Hypertelorism, Arthrogryposis (MultipleNonprogressive Congenital Joint Contractures), Hydrocephalus

XIV. IMMUNODULATORS (THALIDOMIDE)

Defects will NOT be seen when baby is born

These defects will be seen when he is about 40-50y/o

A. Critical Periodo Days 34-50 days after LMP (20-36days after Conception)

o Critical Maternal Dose is at least 100mg

**NOTE: 34 14 = 20 days

B. Magnitude of Risko 20-50%

C. Mechanism

o Intercalates into DNA of Specific Promoter Genes that code for Proteins involved in Normal Limb

Development, thereby inhibiting Transcription of these Genes and Disrupting Development of New BloodVessels, resulting in Truncation of Limbs


o Limb Defects =Amelia or Phocomelia of Upper & Lower Limbs, Osteochondritis of Femoral Head, Laxity of

Cruciate Ligamens in Knee Joints

o Craniofacial Defects = Defects of Eye, Ears, Face, Skull, Tongue, Nose (including Choanal Atresia)

o CNS Defects = Facial Nerve Palsy, Hydrocephalus, NTD, Epilepsy, Autism, Marcus Gunn Phenomenon (Jaw

Winking Syndrome)o Multiple Organ Malformation

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XV. ANTITHYROID DRUGS

PTU has No known Cases of Defects (even if used in First Trimester)

A. Iodine1. Critical Period

2nd and 3rd Trimesters

2. Magnitude of Risk

Dose and Duration Dependent

3. Mechanism

Inhibition of Fetal Thyroid Gland with Compensatory Hypertrophy

4. Defects & Toxicity

Hypothyroidism, Goiter

May cause Tracheal Compression in the New Born

B. Methimazole / Carbumazole

1. Critical Period Up to 9weeks after LMP


Unknown but probably LOW

3. Mechanism

Possible Phenotype (Polygene Interaction)


A Pattern of Rare Congenital Malformation, possible indicating a Phenotype, that consists of some orall of the Following: Scalp (Aplasia Cutis) or Patchy Hair Defects, Choanal Atresia, Esophageal

Atresia with TEF, Minor Facial Anomalies, Hypoplastic or Absent Nipples, Psychomotor Delay, Goiter

XVI. VITAMIN-A DERIVATIVES

A. Etretinate & Acitretin1. Critical Period

Day 15 after Conception to the End of 1st Trimester


Unknown

May be same as Isotretinoin

3. Mechanism

Unknown

May be same as Isotretinoin


Upper / Lower Limb Reduction Defects

Neural Tube Defects and CNS Defects = Meningomyelocele, Meningoencephalocele, PeripheralFacial Nerve Paresis

Head Defects = Microcephaly, Small Mandible

Facial Dysmorphia = Asymmetric Nares, Microtia or Low Set, Protruding Ears with malformedantihelices, and enlarged keyhole-shaped entrances to External Ear Canal

Strabusmus, Cardiac Malformation (TOF), Syndactylies, Poor Head Control

5. Comment

Because of Prolonged Elimination Times of Etretinate and Acitretin, Effective Contraception shouldbe used for at least 3years after stopping therapy

B. Isotretinoin1. Critical Period

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Day 15 After Conception to End of 1st Trimester


30-50%

TERATOGENIC DOSE RANGE is LESS THAN 0.2 to 1.5mg/kg/day

3. Mechanism

Disruption of Initial Differentiation and Migration of Cephalic Neural Crest Cells


Spontaneous Abortion (Most Common)

CNS-Hydrocephalus, 7th Nerve Palsy, Posterior Fossa structure defects, Cortical and CerebellarDefects, Cortical Blindness, Optic Nerve Hypoplasia, Retinal Defects, Microphthalmia,

Craniofacial, Cardiovascular, Thymic Gland Defects

DRUGS USED FOR TREATMENT

I. HYPERTENSION THERAPY DURING PREGNANCY

Most Common = METHYLDOPA Belong to Classification B and C

DRUG USUAL NONACUTE DOSINGMethyldopa 250-1,500mg bid to max 3,000mg/d

Hydralazine 10, 25, 50, 100 tid-qid to max 400mg/d

Labetalol 100, 200, 300mg to max 2,400 mg/d

Nifedipine Long Acting: 30-60mg max 120mg/d

Felodipine 5-10mg/d to max 10mg bid

Thiazide 12.5mg increasing to 25mg daily

Furosemide 20-40mg/d to 160mg bid

Nitroprusside Not usually used in Non-Acute Hypertension

A. Strategies for Control of Chronic Hypertension in Pregnancy / Postpartum

o Antepartum = Before Delivery

o Postpartum = After Delivery

REGIMEN PRIMARY SECONDARY THIRD DRUG

Antepartum (Before Delivery)I Methyldopa Labetalol Hydralazine

II Felodipine Diuretic Labetalol

III Felodipine Labetalol Hydralazine

IV Hydralazine Labetalol Diuretic

Postpartum (After Delivery)I Hydralazine Ca2+ Blocker Labetalol

II Ca2+ Blocker Labetalol Diuretic

III ACE Inhibitors Ca2+ Blocker Beta Blocker

o ACE-Inhibitors are NOT used Ante-Natally (before Delivery)

o Diuretics are NOT very popular because if we give Diuretics (even in early pregnancy), there could be a

Decrease in Intravascular Volume Possibility of Decreasing Blood flowing to the Uterine ArteryDecreased Blood Flow to the Fetus

**IMPORTANT note:

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There are NO Effects on Blood Flow during the THIRD Trimester

NO known studies in the First Trimester

B. Acute Severe Hypertensiono Most Commonly Used for Acute Hypertension = Hydralazine, Labetalol, Nifedipine, Sodium Nitroprusside

o Hydralazine = when there is NO response to Hydralazine (Non-Responders), we may add Labetalol &

Nifedipine

o Nifedipine = NOT Approved by FDA

o Sodium Nitroprusside = LAST Choice (Arterial and Venous Dilator) because Fetal Cyanide Poisoning mayoccur if used for > 4hours

DRUG RECOMMENDATION

Hydralazine 5-10mg IV or IM; Repeat at 20-minute interval

Labetalol 20mg IV-Bolus; If suboptimal Effect, give 40mg q 10min later x3 and 80mg for 20 doses20, 40, 40, 40, 80, 80 for a total of 300mgContinuous Infusion at 0.5 to 3mg/min

Nifedipine 10mg po. Repeat in 30 minutes if necessaryNOT Approved by FDA

Sodium Nitropruside 0.25mg/kg/min max of 5mg/kg/minFor Nonresponder or with EncephalopathyNOTE: Fetal Cyanide Poisoning may occur if used for > 4hours

**NOTE: DISADVANTAGE of BETA-BLOCKERS:

Manifested by GROWTH RESTRICTION among Fetuses

We should monitor the Growth Pattern of the Fetus

C. Discussion of the Individual Antihypertensive Agents1. Methylopa

Central Acting Alpha Agonist MOA: Weak, Short-Acting, Central Acting

Stimulate A2-Receptors decreases Sympathetic Tone and Arterial BP

Use: Chronic Hypertension, Hypertensive Crisis

**Maternal Side Effects:

Lethargy, Dry Mouth, Sedation, Depression, Postural Hypotension, Hemolytic Anemia, DrugInduced Hepatitis

2. Clonidine

Alternative Drug to Methyldopa

Central Acting Alpha Agonist

MOA: Central Acting, Stimulate A2-Receptors Decreases Sympathetic Tone & Arterial BP

Use: Chronic Hypertension

Dosage: 0.1 to 0.3mg orally two or three times a day, max 2.4mg/d

3. Hydralazine

Long Acting, Peripheral Acting

MOA: Directly acts on Arterial Smooth Muscle to cause Vasodilation

Rapidly absorbed (Peak Plasma in 30minutes)

Duration of Effect = 6-8hours

Use: Chronic Hypertension, Hypertensive Crisis

**Maternal Side Effects: Fluid Retention, Tachycardia, Headache, Depression, Postural Hypotension, Hemolytic

Anemia, Drug-Induced Hepatitis

4. Propranolol

Beta-Adrenergic Receptor Blocker (Non-Selective)

MOA: Short-Acting, (-) Chronotropic Rapidly

Use: Use in patients with Cardiac and Thyroid Abnormalities, Chronic Hypertenstion


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IUGR, Bradycardia, Fatigue, Depression, Dizziness, Nausea, Vomiting

5. Labetalol

Beta Adrenergic Receptor Blockade

Short Acting

MOA: Has Beta Blockade Actions

Onset in 5minutes

Rapidly Absorbed (Peak Plasma in 10-20minutes) Half Life: 6 hours

Use: Acute Severe Hypertension; Combined with other drugs for Chronic Essential Hyperension


IUGR, Bradycardia, Fatigue, Depression, Dizziness, Nausea, Vomiting

6. Nifedipine / Felodipine (Calcium Antagonists)

MOA: Short or Long Acting

Use: Chronic Hypertension


Peripheral Edema, Headache Potential Concern is its Synergism with Magnesium Sulfate, with Variable Degree of

Hypotension, Neuromuscular Blockade, or BOTH

7. Diuretics (Thiazide / Furosemide)

MOA: Inhibits Na+ and Corpus Luteum Reabsorption in the Distal Renal Tubules and CollectingSystem

Use: Secondary or Associated Therapy with other Primary Drug

Concerns: Blood Volume, Uric Acid


Hypokalemia, Hypomagnesemia, Hyperuricemia, and Hyponatremia

**Neonatal Side Effects:

Electrolyte Imbalance, Hyperlycemia, Thrombocytopenia

8. Sodium Nitroprusside

MOA: Short-Acting Vasodilator of BOTH Arterial and Venous Smooth Muscle

Onset of Action = < 1minute

Duration = 1-3 minutes

Dose = 0.25 to 1.0ug/kg/min IV

Caution when used for > 4 hours Cyanide Poisoning of Fetus may occur

Use: Hypertensive Crisis, other agents are NOT effective

II. CORTICOSTEROIDS & FETAL LUNG MATURITY

Steroids are used for Lung Maturity in the New Born

Benefits of Steroids were first reported in 1972

A. Main Benefits:o Decrease Respiratory Distress Syndrome

o Decrease IVH

o Decrease Neonatal Mortality

**IMPORTANT Notes:

No Adverse on Long-Term follow up of Children

Affect Biochemical Systems within Type-II Pneumocytes:

Increased Surfactant Production

Increased Compliance & Maximal Lung Volume

More Mature Parenchymal Structure

Enhanced Response to Surfactant Treatment

B. Drugs used:o Betamethasone (12mg q 24hours x 2 doses)

o Dexamethasone (6mg q 12 hours x 4 doses)

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**IMPORTANT Note:

Since Steroids Action involves mRNA and Protein Synthesis takes time, it is NOT useful to DecreaseDosing Intervals

C. NIH Consensus Statement Recommends:o All Fetuses at risk for Preterm Delivery between 24 and 34 weeks

o Betamethasone and Dexamethasoneo In Preterm PROM, at less than 30 to 32-week gestation in the Absence of Chorioamnionitis

III. DRUGS FOR SPECIFIC CONDITIONS

ANTIBACTERIALS ANTI-FUNGALS ANTIVIRALS ANTI-PARASITIC

Penicillins (B)Macrolide (B)CephalosporinsTetracyclinesAminoglycosidesClindamycin (B)

ChloramphenicolSulfonamidesNitrofurantoin (B)VancomycinFluoroquinolones

Anti-TB

CotrimazoleMiconazoleNystatinFluconazoleItraconazoleButoconazole

Amphotericin-BGriseofulvin

ZidovudineZalcitabineDidanosineStavudineLamuvudine

Acyclovir

GanciclovirAmantadine (C)Ribavirin

Alpha-InterferonIdoxuridineTrifuridineVidarabine

Metronidazole (B)LindaneCrotamitonChloroquineQuinine (D)Pyrimethamine

Spiramycin (B)MebendazoleThiabendazolePyrantel Pamoate

**NOTE: Those with (B) are part of Drug Category-B

**Antibacterials:

o Tetracyclines = Causes Discoloration of the Teeth

o Aminoglycosides = Streptomycin causes Cranial 8th Nerve Palsy

o Chloramphenicol = Gray Baby Syndromeo Nitofurantoin = Safe in Pregnancy

o Fluoroquinolones = Embryonic Arthropathy

o Anti-TB Drugs = Safe to Use

IV. OVER-THE-COUNTER PRODUCTS

Nonprescription Medication, Nutraceuticals, and Herbal Agents

Over the Counter Drugs are taken 1.5 times more often than prescribed medication during Pregnancy

Worrisome because its use are WITHOUT Physicians Knowledge and may not be recognized by the patient aspotentially harmful

Many agents contain Multiple Ingredients

A. Mild Analgesics

o Drugs MOST COMMONLY taken during Pregnancy

1. Acetaminophen

(+) Pregnancy DOC for Fever and Pain (B)

Analgesic and Antipyretic DOC during Pregnancy

Side Effects = Hepatotoxicity and Nephrotoxicity among mothers and infants

2. NSAID (Aspirin, Ibuprofen, Mefenamic)

Generally DISCOURAGED (particularly in 3rd Trimester)

Possibility of Premature Closure of Ductus Arteriosus and Subsequent persistent PulmonaryHypertention in the Newborn

Oligohydramnios, Delayed Labor

B. Cold Medications

o Agents used are mostly Sympathomimetics= Stimulate Adrenergic Receptor may induce Maternal

Hypertension or Reduce Uterine Blood Flow

1. Pseudoephedrine

DOC (Drug of Choice)

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Use with Caution during the 1st Trimester and choose a LOW-Dose, Short Acting preparation

2. Oxymethazoline

Incorporated in Long-Acting Nasal Sprays

3. Guiafenesin, Dextromethorpan

Used as Expectorant

Reserved for cases of Significant Maternal Need

C. Anti-Histamines

o Sedating (LOW RISK) = Brompheniramine, Chlorpheniramine, Diphenhydramine

o Less Sedating (Considered Over the Counter) =Loratadine, Fexofenadine, Cetrizine

o Nasal Spray = Cromolyn

D. Antacidso Moderate use would appear to present MINIMAL Risk to the Fetus

o Patients on Low-Sodium Diet should use a Low-Sodium Antacid

o Several Large Studies have NOT found an association with Malformations in Infants exposed during the 1st

Trimester or Adverse Outcomes in Infants exposed later in pregnancy

1. Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone

Limited Studies

Limited Intestinal Absorption

2. Sodium Bicarbonate

Can produce Metabolic Alkalosis and Fluid Overload in BOTH mother and offspring

3. H2-Receptor Antagonists

Cimetidine, Ranitidine, and Famotidine = available as Over-the-Counter Preparation

4. Cimetidine

Has Antiandrogenic Effects

E. Anti-Diarrheals and Laxatives1. Bismuth Subsalicylate

2. Aluminum Hydroxide, Magnesium

Use for Relief of Indigestion, Nausea, and Vomiting, and Diarrhea

Used in SMALL quantities or AVOIDED during Pregnancy

3. Loperamide

Antidiarrheal

Shares some Opioid-Binding Properties of Meperidine in the Intestine Poorly Absorbed in the Gut

MINIMUM Risk for Malformation

4. Docusate

Emulsifying Agent used as Stool Softener

No Association with Malformation

5. Psyllium

Dietary Fiber used as Laxative

6. Phenolphthalein

A Laxative / Catharic

F. Motion Sickness Preparation1. Dimenhydrinate

Can Increase Level of Uterine Activity & Anecdotally Implicated as a cause of Preterm Labor in thelatter part of Pregnancy

Avoid using in the First Trimester because it contains MECLIZINE

2. Meclizine

Cause Cleft Palate & Other Malformations

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HOWEVER, Studies involving BOTH agents have found the frequency of Congenital Anomalies to beNO Greater than Expected among Children exposed to these agents in the 1st Trimester

G. Topical Preparations:o Many Topical Agents result in Minimal Systemic Levels

o Studies are NOT frequent with regard to Reproductive Toxicity:

**Topical Preparations Included: Benzoyl Peroxide

Zinc Pyrithione

Bacitracin

Benzocaine

Hydrocortisone 1% Cream

Terbinafine

Miconazole

Pytethrin + Piperonyl Butoxide = Pediculicide

V. PHARMACOLOGIC INHIBITION OF LABOR

Prematurity = Maternal / fetal risk of prolonging Gestations

A. Goals of Preterm Labor Inhibition1. Immediate Goals:

Achieve a 24- to 48- hour delay to administer Glucocorticoids

Transfer Antepartum Patient to a Tertiary Care Facility for a Higher Level of Neonatal Intensive Care

2. Long Term Goals

Maintain labor suppression for a sufficient time to enable the fetus to mature in utero

Reduce duration of hospital stay and number of Hospital Admissions for Recurrent Preterm Labor

B. Criteria for Labor Inhibitiono A Diagnosis of Preterm Labor

o A Gestational age greater than 15 weeks and less than 34 weeks

o An Absence of medical or Obstetrical Contraindication to Labor Inhibition (FDU, fetal Anomaly, Fetal Distress,

Severe IUGR, Chorioamnionitis, Severe Maternal Hemorrhage, Eclampsia or Severe Preeclampasia)o An Absence of Contraindication To specific labor inhibiting agents

C. Labor Inhibiting Agentso Beta Adrenergic Receptor Agonist

o Magnesium Sulfate

o Prostaglandin Synthetase Inhibitors

o Calcium Channel Antagonist

o Oxytocin Receptor Antagonist

o Nitric Oxide Donor

1. Beta Adrenergic Receptor Agonist (Ritodrine, Terbutalline, Sabutamol, Fenoterol, Isoxsuprine)

MOA: Binds to receptor and this complex acts via the Guanyl Nucleotide Regulatory Protein toActivate Adenyl Cyclase

The resultant Increase in Cytoplasmic cAMP Decreases Intracellular Calcium and Inhibits MLCK

Decreased Activity of MLCK Decreases Phosphorylation of Myosin = Decrease Myocyte Contractility


hypotension, Tachycardia, Arrhythmia, Pulmonary Edema, Hyperglycemia, Hypokalemia

**Fetal / Neonatal Effects:

Tachycardia, Hyperinsulinemia with Hypoglycemia

2. Magnesium Sulfate MOA: Competitive Inhibition of Calcium at the Voltage Operated Calcium Channels at the Plasma

Membrane leading to Hyperpolarization of the Membrane

May directly compete with intracellular calcium by decreasing the Calcium-Calmodulin Binding Affinityto MLCK


Flushing, Warmth Sensation, Nausea, Emesis, Dizziness, Nystagmus, Lethargy, PulmonaryEdema

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Nonreactive Heart Rate, Fetal Breathing, Hypotonia, Lethargy

3. Prostaglandin Synthetase Inhibitor (Indomethacin)

MOA: Reversible Competitive Inhibitor of Cyclooxygenase, thereby Reducing Level of Prostaglandinand Diminishing Myometrial Contractility

NOTE: Prostaglandin stimulates Myometrial Gap Junction Formation and raise Intracellular Ca

Levels = by Increasing Ca2+ Flux across the cell membrane and stimulating release fromSarcoplasmic Reticulum


Nausea, Dyspepsia, Vomiting


Fetal Constriction of Ductus Arteriosus - AVOID giving after 32-week gestation

Oligohydramnios by Decreasing Urinary Output

4. Calcium Channel Antagonist (Nifedipine)

MOA: blocks the Voltage-Dependent Calcium Channels in the Plasma Membrane

It may also Inhibit Release of Intracellular Calcium from Sarcolemmal Stores and Increase CalciumEfflux from the cell

The resultant Decrease in Intracellular Calcium inhibits MLCK

Decreased Activity of MLCK Decreases Phosphorylation of Myosin = Decrease MyocyteContractility**Maternal Side Effect:

Flushing, Nausea, Headache, Dizziness, Palpitations Hypotension, Tachycardia


Possible decrease in Uterine Blood Flow

5. Oxytocin Receptor Antagonist (Atosiban)

MOA: Competitive Inhibition of Oxytocin Receptors in the Myometrium and Decidua

This results to Decrease in Intracellular Free-Calcium


Injection-Site Reaction


Not yet approved by FDA; Used only in Europe.

6. Nitric Oxide Donors (Nitroglycerin)

MOA: Activate the cGMP pathway involved in Muscle Relaxation, leading to Decrease in IntracellularCalcium and Inhibits MLCK.

Decreased activity of MLCK Decreases Phosphorylation of Myosin = Decreased Contractility

**Maternal Side Effect:

Headache, Light-Headedness, Nausea, Emesis, Hypotension


No Reported Adverse Effects

VI. DRUGS FOR SPECIFIC CONDITIONS

A. Bronchial Asthma (No Change in Management during Pregnancy)o Epinephrine

o

Terbutallineo Metaproterenol

o Albuterol

o Aminophylline

o Cromolyn

o Corticosteroids (Beclometasone, Betamethasone, Prednisone)

B. Anticonvulsant:o Phenytoin

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o Carbamazepine

o Trimethadione

o Valproic acid

o Phenobarbital

**Side Effects:

Impedes Folic Metabolism, causes Cleft Lip, Cardiac and Limb Defects

C. Psychiatric:o Benzodiazepines

o Antidepressant

o Lithium

o MAO Inhibitors = Isocarboxid, Phenelzine

o SSRI (B) = Fluoxetine, Sertraline

o Antipsychotic = Chorpromazine, Halperidol

**Side Effects:

Causes Cardiac Defects

NOTE: SSRI is the only group of Psychiatric Drugs SAFE in Pregnancy (prenotes)

D. Anesthetics (Non-Teratogenic):o Thiopental

o Ketamine

o Succinylcholine, curare

o Nitrous oxide

o Halothane

o Isoflurane

o Lidocaine, tetracaine, procaine, bupivacaine

VII. CHEMOTHERAPY AND PREGNANCY

Cancer complicates 1 in 1,000 pregnancies Most common = Cervical, Breast, Melanoma, Ovarian, Thyroid, Leukemia, Lymphoma, and Colorectal

Chemotherapeutic agents are usually given in combination because it provides the maximum tumor cell kill rate

Chemotherapy treats the mother but may damage the fetus. This dilemma requires compromises and makes themanagement of pregnant women one of the most challenging areas in all of medine

Chemotherapeutic agents generally fall into the C or D Categories

X is NOT assigned to these drugs because their use may be Life Preserving to Mother

A. Alkylating Agents:o Cyclophosphamide (D)

o Thiotepa (D)

o Chlorambucil (D)

o

Melphalan (D)o Busulfan (D)

o Cisplatin (D)

o Carboplatin (D)

o Dacarbazine (C)

o

B. Antibiotics:o Dactinomycin (C)

o Bleomycin (D)

C. Antimetabolites:

o Methotrexate (D)o 5-Fluouracil (D)

D. Ducleoside Analogues:o Cytarabine (D)

o Gemcitabine (D)

E. Topoisomerase-I Inhibitors

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o Topotecan (D)

o Irinotecan (D)

F. Topoisomerase-II Inhibitors:o Etoposide (D)

o Doxorubicin (D)

o Daunorubicin (D)

G. Vinca Alkaloids:o Vincristine (D)

o Vinblastine (D)

o Vinorelbine (D)

H. Taxanes:o Paclitaxel (D)

VIII. THERAPY OF DIABETES IN PREGNANCY

Diet = 30 kcal/kg (40-50 % CHO; 20%CHON; 30-40% Fat)

Insulin

A. Target Plasma Glucose Concentration:o Fasting - under 95 mg/dL

o Postprandial - under 120 mg/dL

B. Insulin Formulations:

ONSET PEAK DURATIONLispro 15-20min 1-2 4

Regular 30-60min 2-4 4-6

NPH 1-2 5-7 10-12

Lente 1-2 10-12 14-18

Ultralente 1-2 None 20-24

Lantus 1-2 None 20

IMMUNIZATIONS DURING PREGNANCY

Prevention of Disease

Eradication of the Disease

I. ACTIVE VS PASSIVE IMMUNIZATION

A. Active Immunization (Vaccination)o Elicits an Immununologic Response

o Duration of effect could be life-long or partial

o Agent: Live Virus Vaccine, Killed or Inactivated Bacterial or Viral Vaccine

B. Passive Immunizationo Administration of Preformed Antibody

o Immediate protection is possible

o Duration is brief because the half-life of IgG is 20 to 30 days

**Indication:

Defective immune system

Exposure to the disease

Therapeutic purpose/amelioration of disease

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II. CURRENTLY AVAILABLE ACTIVE IMMUNIZING AGENT

BACTERIA VIRUSES

Live:

Bacille Calmette-Guerin

Tularemia

Typhoid

Killed

Cholera

Meningococcus

Pertussis

Yersinia

Pneumococcus

Typhoid

H-Influenza Type-B

Lyme Disease

Toxoid

Anthrax

Diphtheria

MeaslesMumpsPoliomyelitis, OralRubella

VacciniaVaricella-ZosterYellow FeverHepatitis-AHepatitis-BInfluenzaJapanese EncephalitisPoliomyelitisRabies

III. ADVERSE REACTION TO VACCINE/ IMMUNOGLOBULIN

Discomfort and pain at the injection site

Local irritation/abscess

Arthralgias or frank arthritis (eg, rubella)

Headache

Chills, Fever, Encephalopathy (eg, pertusis)

Nausea

Chest pain

Bronchoconstriction

Anaphylaxis Flushing

Convulsion

IV. ADMINISTRATION OF VACCINES

Storage

Appropriate solvent

Use of plastic syringe for live vaccine

Avoidance of light exposure

Aseptic administration

Appropriate measures to counteract side effect

V. IMMUNIZATIONS DURING PREGNANCY

A. Tetanuso Recommended for Routine Use During Pregnancy

o 2 Vaccine Preparation:

**Tetanus Vaccine (Adsorbed)

0.5 ml IM, at lease 2 doses, preferably 3 doses at 3-8 weeks interval for primary immunization

1st injection = at least 60 days, preferably 90 days or more before delivery

2nd injection = 20 days or more before delivery

B. Rubellao Accidental vaccination up to 3 months before conception places the pregnant women at high risk

o Appropriate counseling is warranted

o Abortion is not warranted

o First Trimester Maternal Infection = 20 -35% risk

o By 4th month = 4-5% risk

**Rubella Contact

Confirm the diagnosis

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If close contact and there is desire to continue pregnancy - give 750 mg Ig IM, then repeat the dosewithin 3 -4 days

If no desire to continue = DONT give Ig

Take a 2nd Blood Sample after 3-4 weeks to Check Seroconversion - (Rubella IgM)

**Rubella Positive

Confirm the diagnosis

Appropriate counseling is warranted for proven case First Trimester Maternal Infection = 20 -35% risk

By 4th month - 4-5% risk

2 IM injections, 750 mg within 4 days

**Rubella vaccine

Contraindicated During Pregnancy

Given to Seronegative Women Postpartum

After vaccination, prevent pregnancy for the next 3 months

Other C/I: after blood transfusion, within 3 months of Ig injections, high fever, allergic diathesis,steroid and immunosuppresive therapy

C. Varicella (Chicken Pox)o No reported birth defects after vaccine exposure during pregnancy

o May cause maternal pneumonia and preterm labor

o 1st trimester = 10% fetal risk

o Within 2 weeks before delivery = neonatal varicella may be seen

**Varicella Vaccine

Vaccine is given to non-pregnant women

2 doses, 4 to 8 weeks apart

**Varicella Contact

Anti-Varicella-Zoster Ig, 1000 mg within 3 days of exposure

**Varicella Infected

Admit

Acyclovir 0.5 mg/kg IV/1 hour, repeated every 8 hours for 5 days

Neonate should receive Ig

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sdls 2008 drugs and immunization during pregnancy

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