Preg lactate IL fall 2016rev080516.ppt...• In a recent published systemic review, the risk of...

Prescribing in Pregnancy and LactationMonica Tombasco, MS, MSNA, FNP-BC, CRNA

Senior Lecturer, Fitzgerald Health Education Associates, LLCNorth Andover, MA

Emergency Medicine Nurse Practitioner Huggins Hospital, Wolfeboro, NH

Certified Registered Nurse AnesthetistCatholic Medical Center, Manchester, NH

Developed by: Margaret A. Fitzgerald,

DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC, FNAP President, Fitzgerald Health Education Associates, LLC,

North Andover, MA

Objectives

• Having completed the learning activities, the participant will be able to:– Recognize the most appropriate

therapeutic choices in health problems for the woman during pregnancy and lactation.

Fitzgerald Health Education Associates, LLC 2

Objectives(continued)

• Having completed the learning activities, the participant will be able to: (cont.)– Identify potentially problematic

medications during pregnancy and lactation that are commonly prescribed for chronic or recurrent health problems.


Pregnancy and Lactation

• Not diseases– Pregnancy is a

symptom-producing condition.

– Pregnant and breastfeeding women get sick.

4Fitzgerald Health Education Associates, LLC

References and Resources

• Drugs in Pregnancy and Lactation (10h ed.): A reference for fetal and neonatal risk; Briggs, Freeman, Yaffe (2014) Philadelphia: Lippincott, Williams and Wilkins.

• Medication and Mother’s Milk (2016); Thomas Hale, PhD; Amarillo, Tx: Hale Publishing; http://www.medsmilk.com/

• www.safefetus.com/index.htm; Professionally maintained site in the UK


Great Resources• www.breastfeedingbasics.org

– At Case Western Reserve University

• www.perinatology.com/exposures/druglist.htm– Menu with the basics, opportunity to link with

more detailed information

• www.OTISpregnancy.org– Organization of Teratology Information Services

• Technical and patient information on everything from medications to herbs to hair treatments


Great Resources (continued)

• Use of psychiatric medications during pregnancy and lactation– http://www.guideline.gov/content.aspx?id

=12490, referenced used in this program for comments on psychotropic medications


What is the teratogenic risk?

• For a teratogen to exert its effect, it must be taken at the point in the pregnancy when the affected organ system is developing.


Stages Of Human Development

Orange bars=Highly sensitive periods of development when major defects may be produced;Blue bars=Stages less sensitive to teratogens when minor defects may be induced.

Reproduced with permission from Moore and Persaud. The Developing Human: Clinically Oriented Embryology. 1999.

age of embryo in weeks fetal period (in weeks)

1 2 3 4 5 6 7 8 9 16 20-36 38Period of dividingzygote, implantation& bilaminar embryo Indicates common site of action of teratogenC.N.S.

heart eye eyeearearheart palate

brain

external genitalialimbs

Notsusceptible to

teratogens

major congenital anomaliesprenatal deathfunctional defects &

minor congenital anomalies

ear

external genitalia

teeth

lower limbs

eyes

upper limbs

heart

palate

Central nervous system

full term

teeth

Teratogenic Effect

• Teratogenic effect in lower species may not be seen in higher species. – Example‒ Corticosteroids– Example‒ Ciprofloxacin

• Teratogenic effect in higher species may not be seen in lower species. – Example‒ Thalidomide


Thalidomide exposure en uteroThroughout the world, about 10,000

cases of infants with phocomelia due to thalidomide; only 50% survived.

Available in many European countries in the 1960s, used for morning sickness.


Drug Properties in Pregnancy and Lactation

• Higher MW=More difficult passage– Greater than 1000 d‒ Virtually no passage

• Insulin, UF heparin, LMWH

• 500‒1000 d‒ Difficult• 250‒500 d‒ Easily passed

– The bulk of clinically useful drugs– The lower, the easier

• Alcohol, nicotine, cocaine<100


Drug Properties in Pregnancy and Lactation

(continued)

• Lipophilic easier than hydrophilic– Mammary alveolar

tissue– Placenta– Blood-brain barrier

• Drugs that are potentially sedating or exciting


What about this FDA Pregnancy Risk Categories, A, B, C, D, X?

Newer FDA RulingPregnancy and Lactation

Labeling Rule (PLLR)

Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess

/DevelopmentResources/Labeling/ucm093311.htm

• “FDA has decided to eliminate the pregnancy categories because they are often viewed as confusing and overly simplistic and don’t effectively communicate the risk a drug may have during pregnancy and lactation and in females and males of reproductive potential.”


Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources

/Labeling/ucm093307.htm


Pregnancy Subsection

• Pregnancy exposure registry– Collect and maintain data on the effects of

approved drugs that are prescribed to and used by pregnant women• Pregnancy registries in drug labeling has been

recommended but not required until now


List of Pregnancy Exposure Registries

http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm1

34848.htm

Lactation Subsection

• The nursing mothers subsection– Was renamed, the lactation

subsection, and provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed infant


Females and Males of Reproductive Potential

• New to the labeling– Includes information, when necessary

• Need for pregnancy testing, contraception recommendations, and information about infertility as this relates to the use of the drug


When does thePLLR go into effect?

• Prescription drugs, biologic products– Submitted after June 30, 2015, will use

the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001, will be phased in gradually.


Does the FDA recommendations affect all drugs?

• For labeling of products approved prior to June 30, 2001, manufacturers are required to remove the pregnancy category within 3 years of the effective date of the final rule


Does the FDA recommendationsaffect all drugs?

• OTCs– Labeling for over-

the-counter (OTC) medicines will not change.


Example of New Labeling: https://www.byetta.com/home/search?term=pregnancy

• Pregnant and nursing women:– Based on animal data, BYETTA may cause

fetal harm and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To report drug exposure during pregnancy call 1-800-633-9081. When administered to a nursing woman, a decision should be made whether to discontinue nursing or discontinue BYETTA.


FDA Pregnancy Risk Categories

• Assigned to all drugs– New drug=Animal study and perhaps

small number of inadvertent exposures during clinical trials

• Based on risk of drug exposure to human fetus– Ranked A, B, C, D, X

– Source: Briggs, Freeman & Jaffe, 2011


Category A

• Well-controlled human study fails to demonstrate fetal risk in 1st trimester

• No evidence of risk in 2d, 3d trimesters• Risk to fetus appears remote

– <1% of all medications• Needed for health• Produced by the body


Category A (continued)

• Vitamins in recommended doses– Vitamin A caution

• Risk factor X in doses>8000 units• One Airborne®=Vitamin A 5000 units

• Levothyroxine (Synthroid®) – A bioidentical hormone

• In urgent care with “unexpected” pregnancy dx, what should you advise?


Timing and Magnitude of Increases in Levothyroxine Requirements During Pregnancy in Women with

HypothyroidismAlexander, E. et al. (2004)

NEJM, Volume 351:241‒249. Vol. 3. July 15, 2004

• “An increase in the levothyroxine dose was necessary during 17 of 20 pregnancies. The mean levothyroxine requirement increased 47 percent during the first half of pregnancy (median onset of increase, eight weeks of gestation) and plateaued by week 16. This increased dose was required until delivery.”


Timing and Magnitude of Increases in Levothyroxine Requirements During Pregnancy in Women with

Hypothyroidism (continued) Alexander, E. et al. (2004)

NEJM, Volume 351:241‒249. Vol. 3. July 15, 2004

• Conclusions:– “Levothyroxine requirements increase as early as

the fifth week of gestation. Given the importance of maternal euthyroidism for normal fetal cognitive development, we propose that women with hypothyroidism increase their levothyroxine dose by approximately 30 percent as soon as pregnancy is confirmed.”


When advising a pregnant woman with hypothyroidism…

• On taking her levothyroxine dose, which of the following is the best approach?A. Take with water on an empty stomach. B. Take with food to minimize GI upset. C. Take with her prenatal vitamin to enhance adherence.


When advising a pregnant woman with hypothyroidism…

• On taking her levothyroxine dose, which of the following is the best approach?A. Take with water on an empty stomach. B. Take with food to minimize GI upset. C. Take with her prenatal vitamin to enhance adherence.


Category BB=Best because nothing in A

• Animal studies have not demonstrated fetal risk but no controlled study in humans‒ Or‒

• Animal studies have show adverse effect but not demonstrated in human study


Category B (continued)

• Beta-lactam antibiotics– Penicillins– Cephalosporins

• Macrolides– Azithromycin, erythromycin, but not

clarithromycin



• Acetaminophen• Ibuprofen

– Caution at end of pregnancy at high dose

• Diphendydramine– Often cited as safest

sleep aid during pregnancy



• Nitrofurantoin (Macrodantin®, Macrobid®)– Avoid at term due to

unlikely risk of hemolysis

• Select inhaled corticosteroids– Budesonide (Pulmicort®)

but not fluticasone (Flovent®)


Category CC=Caution

• No controlled study in humans available

• Studies in animals have revealed adverse effects on the fetus.– Embryocidal– Teratogenic– Other


Category C (continued)

• Approximately 2/3 of all medications• Select antibiotics

– Clarithromycin (C=C)– Fluoroquinolones (ciprofloxacin=C)

• -floxacin suffix

• Many drugs used to treat serious mental and physical health problems– Most SSRIs, atypical antidepressants


Emerging Treatment of Choice in Bipolar Disorder in Pregnancy

• “Lamotrigine (category C) is a potential maintenance therapy option for pregnant women with bipolar disorder because of its protective effects against bipolar depression, general tolerability, and a growing reproductive safety profile relative to alternative mood stabilizers.”

– Source: http://www.guideline.gov/content.aspx?id=12490


SSRI Use in Pregnancy

• Most category C• Paroxetine category D

– Teratogenic concern generally less that most common neonatal abstinence findings of restlessness, feeding problems, irritability, and hypothermia

– Usually evident by day 3 of life– Supportive care


True or false?

• In a recent published systemic review, the risk of persistent pulmonary hypertension of the newborn (PPHN) associated with use of an SSRI during pregnancy is estimated to be less than 1%.

– Source: Reprod Toxicol. 2012 Nov;34(3):293‒7. doi: 10.1016/j.reprotox.2012.04.015. Epub 2012 May 5.

Fitzgerald Health Education Associates, LLC

TRUE

40

Category DD=Danger

• Positive evidence of human fetal risk• Benefit from use in pregnancy might

be acceptable despite the risk – Is the condition potentially life-

threatening disease vs. life-altering?


Category D(continued)

• ACEI (-pril suffix) – 2d, 3d trimester

• ARB (-sartan) – 2d, 3d trimester

• Risk of fetal hypotension, IUFD, renal atrophy

• The tetracyclines– Doxycycline=D

• Carbamazepine– Tegretol®

– Benefit might outweigh risk in seizure disorder

• Lithium– 1:400‒1:4000 risk of

Ebstein anomaly with tricuspid valve and other cardiac problems


After years of use…• “The U.S. Food and Drug Administration

(FDA) is advising health care professionals and women that the anti-seizure medication valproate sodium and related products, valproic acid and divalproex sodium, are contraindicated and should not be taken by pregnant women for the prevention of migraine headaches.



After years of use… (continued)

• Based on information from a recent study, there is evidence that these medications can cause decreased IQ scores in children whose mothers took them while pregnant.”



• Paroxetine category D– 50‒100% increase in cardiac defects

• From 1% to 2% in one study• From 1% to 1.5% in another study

– Most commonly observed=ASD, VSD– Source: FDA MedWatch 12.05 report

Fitzgerald Health Education Associates, LLC 45.

After years of use… (continued) Paroxetine Withdrawal

• Known to produce a particularly severe withdrawal syndrome in user

• Why? – CYP2D6 substrate– CYP2D6 inhibitor– T½=~26 h


SSRI T½

Paroxetine (Paxil®) 26 hSertraline (Zoloft®) 25‒65 h

Citalopram (Celexa®)24‒48 hMetabolites=2 d & 4 d

Fluoxetine (Prozac®)24‒72 hMetabolite=4‒16 d

When will SSRI withdrawal become evident? 3‒5 T½


SSRI, TCA Withdrawal Syndrome

• Dizziness • Paresthesia • Anxiety • Nausea • Insomnia• Nightmares

• Life-threatening or bothersome?

• How long does this last?


Bothersome

Lasts 3‒7 days, related to the T½ of the drug.

Category X

• Animal or human studies have demonstrated fetal abnormalities

• Evidence of fetal risk based on human study

• No therapeutic indication in pregnancy


Category X (continued)

• Isotretinoin (Accutane®)– ~33% increase

• Thalidomide– ~25% increase

• The statins– 3- to 4-fold increase in

congenital anomalies, “congenital statin syndrome” not yet identified


Myths About MedicationUse in Lactation

• Drugs get into milk and stay there.– Diffusion from area of higher concentration

to lower concentration• Two-way diffusion

– Serum to breast– Breast to serum

– This area can be to the breast or from the breast.• Basic drugs such as macrolides trapped in breast

milkFitzgerald Health Education Associates, LLC 51

Myths About Maternal Medication Use in Lactation

• “Pump and dump” is helpful in reducing drug levels in mother’s milk.– Creates area of lower drug concentration

in empty breast– Drug diffuses from area of high

concentration (maternal serum) to area of low concentration


When is “pump and dump” helpful?

What happens in 3‒5 drug-free T½?

When is “Pump and Dump” helpful? (continued)

• Maternal ingestion of contraindicated drug – Need to continue for drug’s 3‒5 T½

• Cocaine (T½=0.8 hours) – 3‒5 T½=~2.5‒4 h

• PCP (T½=24‒51 hours)– Stored in fat– 3‒5 T½=~3‒7 days


Infant Influence on Dose Ingested

• Most models of drug ingestion via lactation based on 1 liter/day milk intake– Can under or overestimate infant drug

exposure

• Hale’s rule: Infant receives ≤1% of maternal drug dose.


Hale’s LactationRisk Category

• L1‒ Safest– Controlled study=Fail to demonstrate risk

• Cromolyn (nasal, ophthalmologic) • Acetaminophen• The penicillins• Medroxyprogesterone acetate (Depo-

Provera®) (≥1 month post birth)


Hale’s Lactation Risk Category (continued)

• L2‒ Safer– Limited number of women studied

without risk• Macrolides (azithromycin, clarithromycin,

erythromycin)• Nitrofurantoin (Macrodantin®, Macrobid®)• Cephalosporins• 2d generation antihistamines (loratadine

{Claritin®}, et al.)



• L2‒ Safer (cont.)– Limited number of women studied

without risk• Prednisone• SSRIs


Which SSRI During Lactation?

• “Results of the pooled analyses indicated that breastfed infants exposed to paroxetine and sertraline were unlikely to develop detectable serum drug levels.

– Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902256/


Which SSRI During Lactation? (continued)

• Infants exposed to fluoxetine through breast milk were more likely to develop elevated levels of the drug especially if the mothers started the treatment during pregnancy (due to prenatal loading).



Which SSRI During Lactation? (continued)

• The data on citalopram were limited compared the other SSRIs, but suggested that some infants developed quantifiable serum levels of the drug which may be associated with adverse effects.”



And might I go “off science” for a moment and offer some advice for all

women who recently gave birth?


• L3‒ Moderately safe– No controlled study or controlled study

shows minimal, non life-threatening risk• TMP-SMX (Bactrim®)• FQ antibiotics (-floxacin suffix, ciprofloxacin,

levofloxacin)• 1st generation antihistamines

(diphenhydramine {Benadryl®}, et al.) • Doxycycline



• L4‒ Hazardous– Positive evidence of risk but may be used

if maternal life-threatening situation• Lithium• Ergot preparations• HD daily corticosteroids



• L5‒ Contraindicated– Significant and

documented risk • Radioactive isotopes• Cocaine


Immunizations DuringPregnancy and Lactation

Reference: http://www.cdc.gov/vaccines/pub

s/preg-guide.htm#glines

Immunizations During Pregnancy: Priority Vaccines

• Inactivated influenza – Women in 2d, 3d trimesters at increased

risk for hospitalization from influenza– Routine influenza vaccination

recommended for all women who are or will be pregnant (in any trimester) during influenza season.


Additional Benefits from Influenza Vaccine

• Reduced risk of preterm birth and SGA in immunized moms– Limited to babies born during flu season

• Infants born to mothers who received flu vaccine while pregnant ~50% less likely to be hospitalized for flu than infants born to mothers who did not receive vaccine

– Source: http://www.sciencedaily.com/releases/2011/06/110623085955.htm


Immunizations During Pregnancy: Priority Vaccines

• Tdap dose during each pregnancy irrespective of prior Tdap history

• To maximize the maternal antibody response and passive antibody transfer to the infant, optimal timing for Tdap administration is between 27 and 36 weeks of gestation although Tdap can be given at any time during pregnancy.


All household members and caregivers of the newborn should receive the annual influenza and

updated Tdap vaccine. If mom did not receive these

vaccines during pregnancy, she should be immunized postpartum

whether breastfeeding or not.

Conclusion

• Pregnant and lactating women can and do get sick.

• By choosing the best pharmacologic intervention, you can work with her to have the healthiest mom and baby.


End of Presentation

Thank you for your time and attention.

Monica Tombasco, MS, MSNA, FNP-BC, CRNA

www.fhea.com [email protected]

• Images/Illustrations: Unless otherwise noted, all images/illustrations are from open sources, such as the CDC or Wikipedia or property of FHEA or author.

• All websites listed active at the time of publication.


Copyright Notice

Copyright by Fitzgerald Health Education Associates, LLCAll rights reserved. No part of this publication may be reproduced or transmitted

in any form or by any means, electronic or mechanical, including photocopy, recording or any information storage and retrieval system, without permission

from Fitzgerald Health Education Associates, LLC

Requests for permission to make copies of any part of the work should be mailed to:

Fitzgerald Health Education Associates, LLC85 Flagship Drive

North Andover, MA 01845-6184

Statement of Liability

• The information in this program has been thoroughly researched and checked for accuracy. However, clinical practice and techniques are a dynamic process and new information becomes available daily. Prudent practice dictates that the clinician consult further sources prior to applying information obtained from this program, whether in printed, visual or verbal form.

• Fitzgerald Health Education Associates, LLC disclaims any liability, loss, injury or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents of this presentation.

Fitzgerald Health Education Associates, LLC

85 Flagship Drive

North Andover, MA 01845-6154978.794.8366 Fax-978.794.2455

Website: fhea.com

Learning & Testing Center: fhea.com/npexpert

www.facebook.com/fitzgeraldhealth

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