Medications in Pregnancy: Dispelling Myths and Ensuring Safety - - PowerPoint PPT Presentation

Canadian Society of Internal Medicine

Annual Meeting 2017

Toronto, ON

Medications in Pregnancy: Dispelling Myths and Ensuring Safety

Geena Joseph, MD, FRCPC

Nephrology and Obstetrical Medicine

Renfrew Victoria Hospital The University of Ottawa

CSIM Annual Meeting 2017

The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources

• f information or your medical judgment.

Learning Objectives:

• Describe the general principles of teratogenicity
• Recite the new FDA Pregnancy and Lactation Labeling Rule

(PLLR)

• Describe an approach to counseling on the use of medications in

pregnancy and lactation

• Describe the particularities of using common medications in

pregnant and lactating patients

CSIM Annual Meeting 2017

Conflict Disclosures

Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence

• ver their judgment and actions.

“I have no conflicts to declare”

Company/Organization Details Advisory Board or equivalent

NONE

Speakers bureau member

NONE

Payment from a commercial

• rganization. (including gifts or other

consideration or ‘in kind’ compensation)

NONE

Grant(s) or an honorarium

NONE

Patent for a product referred to or marketed by a commercial

• rganization.

NONE

Investments in a pharmaceutical

• rganization, medical devices

company or communications firm.

NONE

Participating or participated in a clinical trial

NONE

Some of the drugs, devices, or treatment modalities mentioned in this presentation are: Off-label use I intend to make therapeutic recommendations for medications that have not received regulatory approval for use in pregnancy.

CSIM Annual Meeting 2017

Polling during Presentation

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can be used to respond.

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Case 1: Nellie

 33 yo G0P0 woman with Lupus Nephritis  Referred for pre-pregnancy consultation  PMH: 1.

SLE x 10 years

 Presentation: Rash, Arthritis, nephritis

 Dx/ Class IV - Diffuse proliferative glomerulonephritis  Rx/ Prednisone, MMF  azathioprine

2.

Hypertension x 10 years

Case 1: (Cont’d)

 HPI:

 Last flare 2 years ago, treated with high dose prednisone

& mycophenolate. Switched to azathioprine 8 months

• ago. Titrating dose of prednisone.

 Generally well, asymptomatic

 Meds: Prednisone 10mg OD, Azathioprine 75mg OD,

hydroxychloroquine 200mg BID, Nifedipine XL 60mg OD.

 Exam: BP 125/75, HR 80bpm

 CVS, Resp, Abdo: Normal  No rash or active joints

Case 1: (cont’d)

 Investigations:

 Hb 130  Cr 91, K=5.2  ANA 1/320, anti-DNA 186 (<50)  ESR, C3, C4, CH50 Normal  Anti-Ro positive, APLA negative  U/A: neg blood, 1+ protein

 24hr Urine Collection :

 Proteinuria 0.49g/d, Cr 9.2mmol/d  CrCl 1.09ml/s/1.73m2 (65ml/min/1.73m2)  MALB/Cr = 34.8mg/mmol Cr

Would you give her the Green light to get pregnant?

• A. No, her disease is uncontrolled, unsafe pregnancy

medications and the risk of pregnancy is too high

• B. Not yet, her disease and medications need to
• ptimized
• C. Not yet, her disease is in remission, blood pressure

stable, but we need to change some medications first

• D. Yes, her disease is in remission, blood pressure

stable, pregnancy safe medications

Background

 The use of medications in pregnancy and lactation

presents a challenge to all health care providers.

 In the US, there are 6 million pregnancies every year  50% of pregnant women report taking at least one

medication

 Pregnant women take an average of 2.6 medications

during pregnancy

 First trimester use of prescription medications has

increased by more than 60%

Mitchell AA, et al., Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol. 2011; 205(1):51

Medications in Pregnancy General Principles

 Goal is to support the mother-to-be (medically &

psychologically) while ensuring the lowest possible risk to fetus

 Optimal use of medications to treat diseases during

pregnancy can improve the mother’s quality of life, reduce maternal complications and any subsequent risk to fetus

 Fundamental principle: Risk vs. Benefit of treatment

General Principles of Teratogencity

 Teratology: the scientific study of congenital

abnormalities and abnormal formations due to different factors (eg/genetics, maternal disease, maternal exposures)

 Baseline Risk:

 Risk in the general population for major birth

defects is 2-4%and for miscarriage is 15-20%

 Critical Time period:

 Teratogens produce specific abnormalities at

specific, susceptible periods during gestation

General Principles of Teratogencity

 Types of Teratogencity

1.Pregnancy loss (miscarriage, stillbirth) 2.Congenital malformations



Major –Structural or functional defect that requires intervention or can impair future lifestyle



Minor –Unusual morphologic traits of no serious consequence to the child

3.Neurobehavioral abnormalities (eg/ impaired IQ) 4.Growth Restriction (IUGR) 5.Carcinogenicity

Critical Time Period

Moore KL et al. The developing human: clinically oriented embryology. 2003:520

Different Periods of Teratogenicity

 First 2 weeks (conception to implantation)

 “All or nothing” period

 First Trimester (Embryogenesis)

 Structural malformations

 Second & third Trimester (Fetal period)

 Growth Restriction & neurodevelopment

abnormalities

Causes for Congenital Malformations

 65% Unknown

 Multifactorial, spontaneous errors of development

 25% Genetic

 Inherited genetic disorders, new mutations,

chromosomal abnormalities

 10% Environmental

 4% Maternal Disease (eg/ DM, Obesity)  3% Maternal Infection (eg/rubella, CMV)  1-2% Mechanical deformities  < 1% Drugs, radiation, chemical, hyperthermia Brent RL. Addressing environmentally caused human birth defects. Pediatr Rev 2001; 22:153-165

Original FDA Pregnancy Categories

Problems with the Original FDA Classification

 The letter classification was overly simplistic and did not

provide meaningful clinical information about drug exposure

 The category system allowed drugs with evidence of risk

and those without evidence of risk to be assigned the same category

 Majority of medications classified as Category C

 Misinterpreted as a grading system  Drug category could not be changed or updated unless

better evidence such as controlled studies were completed which is very challenging to do in pregnancy

History of Pregnancy and Lactation Labeling Rule (PLLR)

www.fda.gov

Phased Implementation

 After June 2015, all

new drugs approved by the FDA will have the new labels

 By June 2018, all

drugs approved after June 2001 will have the new labels.

Pernia, S & DeMaagd G. The New Pregnancy and Lactation Labeling

• Rule. P&T November 2016;

41(11):713.

Labeling Changes

www.fda.gov

8.1 Pregnancy

 Pregnancy Exposure Registry

 Included if a registry exists for the product and will

include information about how to enroll in the registry

 Risk Summary

 Presented as a narrative and summarizes any human,

animal, and pharmacological risk data available

 Clinical Considerations

 Details disease associated maternal and fetal risk,

relevant dose adjustments, maternal and fetal adverse reactions, and labor and delivery information

 Data

 Describes the information used for the “Risk Summary”

and “Clinical Considerations”

Examples:

8.1 Pregnancy

 Pregnancy Exposure Registry

 Included if a registry exists for the product and will

include information about how to enroll in the registry

 Risk Summary

 Presented as a narrative and summarizes any human,

animal, and pharmacological risk data available

 Clinical Considerations

 Details disease associated maternal and fetal risk,

relevant dose adjustments, maternal and fetal adverse reactions, and labor and delivery information

 Data

 Describes the information used for the “Risk Summary”

and “Clinical Considerations”

Zepatier (elbasvir and grazoprevir) Product Monograph

8.2 Lactation

• Risk Summary
• Describes the presence of the drug in human milk and

the effects on milk production and the breastfed child, and contains a statement on the risk–benefit ratio related to use

• Clinical Considerations
• Includes information on minimizing exposure and

monitoring for adverse reactions

• Data
• Describes the information used for the “Risk Summary”

and “Clinical Considerations”

8.3 Female and Males of Reproductive Potential

 Recommendations or requirements for pregnancy

testing and/or contraception before, during, or after drug therapy OR

 Human and/or animal data suggesting drug-

associated effects on fertility and/or preimplantation loss effects

 Subheadings:

 Pregnancy Testing  Contraception  Infertility

Goal of the PLLR

• To provide Prescribers with relevant information

for critical decision-making when treating pregnant or lactating women

• Considerations of medical/disease factors
• Animal data put in context of human exposure
• Human data added when available
• More complete statement of the known risks based
• n the available data
• Explicitly states when no data are available

Limitations

 Drugs approved before June 2001 will have neither a

pregnancy category nor narrative

 Updates dependent on collaboration between the FDA and

manufacturers

 Consumers need to cooperate with the pregnancy registry

process and share their health information in order to accumulate a meaningful quantity of data.

 Long Narrative to review. Instead of a quick letter

classification

 Concern that people will not have a easy way to check

medication safety & may not be used.

Approach to Medications in pregnancy and Lactation

1.

What is the condition being treated?

2.

Impact of pregnancy on the condition

3.

Impact of the condition on pregnancy

4.

Pharmacological treatment options

5.

Criteria to choose treatment:

 Safety for the fetus  Efficacy of the drug  Potential adverse effects

Case 1: Nellie

 33 yo G0P0 woman  Referred for pre-pregnancy consultation  PMH: Class IV Lupus Nephritis & HTN x 10 years  Meds: Prednisone 10mg OD, Azathioprine 75mg OD,

hydroxychloroquine 200mg BID, Nifedipine XL 60mg OD.

 HPI: Last flare 2 years ago. Feels well.  Exam: BP 125/75, HR 80bpm

 Labs: Hb 130, Cr 91, ANA 1/320. Urine ACR = 34.8mg/mmol

Approach to Medication Counseling

1.

What is the condition being treated?



Lupus Nephritis

2.

Impact of pregnancy on the condition



Risk of lupus flare



Risk of disease progression

3.

Impact of the condition on pregnancy



Increased risk pregnancy complications - IUGR, Prematurity, preeclampsia



Risk of maternal mortality with uncontrolled disease

Approach to Medication Counseling

4.

Pharmacological treatment options



Azathioprine, Mycophenolate, Prednisone

5.

Criteria to choose treatment:

 Safety for the fetus  Efficacy of the drug  Potential adverse effects

Drug (Old FDA risk) Comments Glucocorticosteroids (B) 1st Trimester risk of cleft palate (< 9weeks GA) 1/1000 (gen pop), 3/1000 (steroids) Rare cases fetal adrenal suppression & thymic hypoplasia if dose >prednisolone 15mg/day closer to term Azathioprine (D) Safe based on large cohorts of transplant, SLE, crohn patients. Not converted by fetal liver to active form Rare neonatal leukopenia reported if dose >2mg/kg Cyclosporine ( C) Increased risk of miscarriage Increased risk of IUGR, perterm delivery, hypertension Tacrolimus (C) Increased risk of IUGR, perterm delivery, and diabetes Mycophenolate (D) Highly teratogenic 22-27% with exposure 4-9weeks GA Risk of facial deformities (cleft palate, micrognathia, microtia, absent auditory canals) and limb anomalies in humans. Miscarriage risk 30-40%

Medications in Lupus & Pregnancy

Medications in Lupus & Lactation

Pregnancy Lactation Lactation Comment NSAIDs Yes/No (avoid after 32 weeks) Yes Antimalarials Yes Yes Very small amount excreted in breast milk Corticosteroids Yes Yes Excreted in breast milk. No issues Cyclosporine Yes Yes/No Excreted in breast milk. Monitor baby Azathioprine Yes Yes Excreted in breast milk. Mycophenolate No No Methotrexate No No

Stop 3 month before conception & restart after BF

Cyclophosphamide No No Warfarin Yes/No Yes Safe after 1st trimester Heparin Yes Yes Aspirin (low dose) Yes Yes/No Potential bleeding risk in infant

Rubin, Peter & Ramsay, Margaret. Prescribing in Pregnancy, 4th edition 2008 Organization of Teratology Information Specialists (OTIS) www.MotherToBaby.org

Would you give her the Green light to get pregnant?

• A. No, her disease is uncontrolled, unsafe pregnancy

medications and the risk of pregnancy is too high

• B. Not yet, her disease and medications need to
• ptimized
• C. Not yet, her disease is in remission, blood pressure

stable, but we need to change some medications first

• D. Yes, her disease is in remission, blood pressure

stable, pregnancy safe medications

Case 2: Rachel

 38yo G0P0 woman with type 1 DM since age 5  Referred for pre-pregnancy consultation  PMH: 1.

Type 1 DM since age 5

 DM retinopathy  DM Nephropathy, Cr 60, Urine ACR 30

2.

Hypertension x 10 years

 Meds: Aspirin 81mg daily, Perindopril 8mg daily,

HCTZ 25mg daily, Atorvastatin 40mg daily, Insulin pump

Case 2: (Cont’d)

 HPI:

 Poorly controlled DM for many years. Excellent control

with insulin pump for the last 2 years.

 Home BP readings 100-120/70s  Generally well, asymptomatic

 Exam: BP 128/75, HR 85 bpm

 CVS, Resp, Abdo: Normal

 Investigations:

 Hb 125  K=4.5, Cr 60, eGFR >120, HBA1C 6.5%  U/A: neg blood, 1+ protein  Urine ACR 30

Would you give her the Green light to get pregnant?

• A. No, her disease is uncontrolled, unsafe pregnancy

medications and the risk of pregnancy is too high

• B. Not yet, her disease and medications need to
• ptimized
• C. Not yet, her disease is in remission, blood pressure

stable, but we need to change some medications first

• D. Yes, her disease is in remission, blood pressure

stable, pregnancy safe medications

1.

What is the condition being treated?



Diabetes & Hypertension

2.

Impact of pregnancy on the condition



Risk of worsening Diabetic Retinopathy



Risk of worsening Proteinuria, hypertension

3.

Impact of the condition on pregnancy



Increased risk pregnancy complications – congenital abnormalities, macrosomia, prematurity, preeclampsia

4.

Pharmacological treatment options



DM - Insulin only option



HTN – ACE inhibitor or not?

5.

Criteria to choose treatment:

 Safety for the fetus  Efficacy of the drug  Potential adverse effects

Approach to Medication Counseling

What about ACE Inhibitors in pregnancy? (Select all that apply)

1.

ACE Inhibitors are safe

2.

ACE Inhibitors are teratogenic

3.

ACE Inhibitors are fetotoxic

4.

ACE Inhibitors should be stopped 3months before pregnancy

5.

ACE Inhibitors can be stopped at conception

6.

ACE Inhibitors can be continued throughout pregnancy

Anti-Hypertensive Medications

Drug (Previous FDA risk) Dose Comments Methyldopa (B) 125mg-500mg PO BID-QID (Max 2500mg/day) 40year in use, safe SE: Elevated LFTs Labetalol (C) 100mg-400mg PO BID-QID (Max 1600mg/day) Lots of experience, safe Atenolol/metoprolol – IUGR Adalat XL (C) 20-120mg PO OD-BID (Max 120mg/day) Hydralazine (C) 10-50mg PO TID-QID (Max 300mg/day) Lots of experience as adjunctive Thiazide (C) 12.5-25mg PO OD Theoretical risk of volume

• depletion. Safe otherwise

ACE-inhibitors (C/D) Fetotoxic in 2nd & 3rd trimester. 1st trimester – Risk vs Benefit Angiotensin Receptor Blockers (ARB) (C/D) Fetotoxic in 2nd & 3rd Trimester Teratogenicity in 1st trimester has been reported. Retrospective review of RCT – no harm. Overall, 1st trimester – Risk vs Benefit Direct Renin Inhibitors (DRI) No data. Do not use.

Angiotensin Converting Enzyme Inhibitors

 Second and Third Trimester Exposure

 Fetal (before birth)

 Hypoplastic Skull  Oligohydramnios  limb contractures  IUGR  Renal failure  Hypoplastic lung

u Neonatal (after birth)

u Patent ductus arteriosus u Renal failure u RDS u Prolonged hypotension u Neonatal death

Cooper, W et al. NEJM 2006

 18 congenital malformations in 209 patients (ACE group)  834 congenital malformations in 29,096

(no ACE group)

Motherisk Meta-analysis & Qualitative analysis

Walfisch A, et al. J Obs Gyne. 2011

5 Studies in the Meta-analysis

 786 exposed to ACE  1800 exposed to other anti-hypertensives  > 1 Million Controls

Walfisch A, et al. J Obs Gyne. 2011

Walfisch A, et al. J Obs Gyne. 2011

Summary of Motherisk Study

 Qualitative review: 20 malformations/424 exposed

 NO pattern of malformations

 First trimester exposure to ACE inhibitors is not

associated with an elevated risk of major malformations compared with other antihypertensives

 First trimester exposure to antihypertensives in

general MAY be associated with an elevated risk of malformations

 Drug effect VS characteristics of this population?

 General population Risk 2-4%  Obesity Risk 4-5%  Hyperglycemia Risk 3-4%

ACE-inhibitor or Not??

 Potential risk of teratogenicity vs. known risk of

increased complications with poorly controlled disease

 ACE-inhibitors preserve renal function & improves

proteinuria, cardiac protection

Fetal Teratogenicity?? Fetal & Maternal Complications

What about ACE Inhibitors in pregnancy? (Select all that apply)

1.

ACE Inhibitors are safe

2.

ACE Inhibitors are teratogenic

3.

ACE Inhibitors are fetotoxic

4.

ACE Inhibitors should be stopped 3months before pregnancy

5.

ACE Inhibitors can be stopped at conception

6.

ACE Inhibitors can be continued throughout pregnancy

Back to Case 2: Rachel

 38yo G0P0 woman with type 1 DM & Hypertension  Well controlled Disease, Lowest possible risk for

complications

 Meds: Aspirin 81mg daily, Perindopril 8mg daily,

HCTZ 25mg daily, Atorvastatin 40mg daily, Insulin pump

 Adjustments:

 D/C Aspirin, Perindopril, HCTZ, Atorvastatin  Started Labetalol 200mg TID, Nifedipine XL 60mg BID  Given the go ahead for pregnancy when BP controlled  Following urine ACR

Case 3: Diane

 25yo G2P1 woman at 9weeks GA who has a fever, SOB

and cough x 8 days.

 Exam: Right lower lung crackles & wheezes  CXR – Right lower lobe infiltrate.  Labs: Hb 120, WBC 15.0  Allergies: NKDA  Impression: Pneumonia  What are the antibiotic options in pregnancy?

What Antibiotics are safe in all the trimesters of Pregnancy? (Select all that apply)

1.

Amoxicillin

2.

Levofloxacin

3.

Amoxicillin/Clavulanate

4.

Tetracycline

5.

Cephalexin

6.

Trimethoprim-sulfamethoxazole

7.

Erythromycin

Common Antibiotics in pregnancy:

Drug (FDA risk) Comments Penicillins (B)

• Safe. Lots of data. Amox-Clavulanate also safe

Cephalosporins (B)

• Safe. Lots of data

Nitrofurantoin (B)

• Safe. Lots of data

3rd trimestter – theoretical risk in G6PD deficient pts of neonatal hemolysis Macrolides (B/C) Erythromycin, Azithromycin. Safe.

• Clarithromycin. Animals adverse fetal effects. No human

reports. Aminoglycosides (C) Safe. One report of fetal ototoxicity after use of Streptomycin. Quinolones (C) No known congenital defects. Animal & humans – quinolones known to accumulate in joints. Animal study – “arthropathy” Not seen in humans. Tetracyclines (D) 5-6months GA – abnormal teeth & bone development (contraindicated after 4-5months GA) Trimethoprim- sulfamethoxazole (C/D) Safe in 1st and 2nd trimester with folic acid supplement (4mg) 3rd trimester – theoretical risk of neonatal kernicterus (esp preterm)

What Antibiotics are safe in all the trimesters of Pregnancy? (Select all that apply)

1.

Amoxicillin

2.

Levofloxacin

3.

Amoxicillin/Clavulanate

4.

Tetracycline

5.

Cephalexin

6.

Trimethoprim-sulfamethoxazole

7.

Erythromycin

Summary

 The use of medications in pregnancy and lactation

presents a challenge to all health care providers.

 Pregnancy and Lactation Labeling Rule (PLLR)

will improve the quality of the information to assist with counseling about medications in pregnancy and lactation

 Approach to counseling in regards to medication

in pregnancy is a risk vs benefit discussion

Thank You

Practical Resources:

 MotheRisk: MotheRisk.org or toll-free

1-877-439-2744 or Fax: 416-813-7562

 Organization of Teratology

Information Specialists (OTIS): MotherToBaby.org or toll-free 1-866- 626-6847