Treat the Patient, not the Pregnancy:

Susan McLellan, BSc. Pharm

Safe and Effective Medication use in Pregnancy and Lactation

April 25, 2015

Objectives:

• Appropriate medication therapy during pregnancy and lactation for the treatment of depression, diabetes, and thyroid disorders

• Recommend safe non-prescription options for select conditions.

• How to assess a drug for potential safety and toxicity during pregnancy and lactation, including key references.

Outline:

1. Classification Systems for drugs in pregnancy and lactation

2. Resources – professional and patient friendly

3. Therapeutics of selected conditions: Rx and OTC

1) Drug Classification systems and how to assess drugs for safety

Old FDA classifications:• Category A Controlled studies in women

fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of risk in later trimesters), and the possibility of fetal harm appears remote.

• Category B Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of risk in later trimesters).

Old FDA Classifications:

• Category C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

• Category D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease in which safer drugs cannot be used or are ineffective).

• Category X Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

New FDA Labeling:

http://www.fda.gov/ucm/groups/fdagov-public/documents/image/ucm425205.png

New FDA Labeling:• Pregnancy and Lactation Labeling

Rule « PLLR »• In both Pregnancy and Lactation:

– Risk summary– Clinical considerations– Data (human and animal, pregnancy drug

registries)

• In Reproductive Potential:– Contraception– Infertility– Pregnancy testing

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425317.htm

What will Health Canada Do?

• Not yet decided!

RxFiles Classification:

RxFiles Drug Comparison Charts - 10th Edition. Editors Brent Jensen, Loren Regier. Saskatoon, SK: Saskatoon Health Region; 2014. Available from www.RxFiles.ca.  

Maternal-Fetal Transfer

Drug Transport across Placenta:

• Drugs more likely to cross have:• Lower molecular weight• Higher maternal blood concentration• High lipid solubility• Decreased protein binding• Decreased ionization at physiological

pH• Maternal Factors:

• Placental blood flow• Placental surface area (related to

gestational age)

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Briggs, et al. Lippincott Williams. 2011.

Factors affecting drug levels in lactation:

• Drugs more likely to enter breast milk have: – Increased half life– Decreased protein binding– Decreased molecular weight– High bioavailability– High CMax (maximum concentration)– High volume of distribution (Vd)– High milk : plasma ratio

http://www.medsmilk.com/pages/how_to_read_drug_entries (Hale’s Medications and Mothers’ Milk)

Resources:

www.motherisk.org

Mothertobaby.org

http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

Print and e-Resources:

• RxFiles• Hale’s Medications and

Mother’s Milk• Briggs Drugs in Pregnancy and

Lactation• Lexicomp application • Micromedex application

Contra-indications to breastfeeding:

• Active HIV or anti-retroviral therapy• Amiodarone• Antineoplastic agents• Lithium • Radiopharmaceuticals (temporary)• Retinoids

Medications and Mother’s Milk. Hale, Thomas, PhD. 13th Edition. 2008.

Depression in Pregnancy:

• 25% (1 in 4) Women will suffer from depression while pregnant!

• Risks of not treating depression during pregnancy:– miscarriage, perinatal complications, increased

risk of preeclampsia, low neonatal Apgar scores, and increased admissions to neonatal intensive care units

• Risks to Mom of stopping medication abruptly:– withdrawal symptoms, including nausea and

vomiting, diarrhea, sweating, anxiety and panic attacks, mood swings, and suicidal thoughts, return of depression

http://www.motherisk.org/prof/updatesDetail.jsp?content_id=1075#1

Antidepressants:

Risks of some antidepressants to baby after birth:– jitteriness; grasping muscle weakness; and respiratory difficulties that

sometimes require use of a ventilator

• The adverse effects on mothers and babies of untreated depression during pregnancy … outweigh the risk of transient poor neonatal adaptation in only a very few neonates exposed to antidepressants during the third trimester – August 2005

• “The risks of untreated moderate to severe depression far outweigh the theoretical risks of taking selective serotonin reuptake inhibitors.” – Dec 2014

• http://www.motherisk.org/prof/updatesDetail.jsp?content_id=1094

Antidepressants:• All SSRIs considered safe• Also SNRIs (Venlafaxine, Duloxetine)• Buproprion, Mirtazapine

• Dosage requirements may increase in third trimester, and return to baseline post-partum. Monitored by symptom control.

• If discontinuing – go SLOWLY, under doctor’s supervision - (decrease dose by 25% every 1-2 weeks)

Antidepressants:

• Risks of congenital malformations with paroxetine: conflicting data – recommend continuing if already stable.

• May be dose dependent (less than 25 mg/day has no increased risk).

• Possible risk of persistent pulmonary hypertension in newborn:

• Linked to SSRIs, but causality not proven. No cases of PPHN have caused death.

Antidepressants:• TCAs are safe:

• Desipramine • Amitriptyline • Nortiptyline

• Benzodiazepines: – 1st trimester: risk of oral cleft

malformation– 3rd trimester: lethargy, withdrawal

syndrome – Not generally a good treatment for

depression/anxiety

Antidepressants:

• In Lactation:• Same agents safe as during

pregnancy (SSRIs, SNRIs, TCAs)• Lowest amount of drug found in

breastmilk: – Sertraline– Paroxetine

http://www.motherisk.org/women/updatesDetail.jsp?content_id=1000

Antidepressants:• If treating for depression during pregnancy, should NOT discontinue postpartum.

–Treat at full dose for at least 6 – 12 months after remission

•Benzodiazepines: Generally safe in breastfeeding.

–Lorazepam: short half life, low levels in milk

Diabetes:

– Risks to mother: • retinopathy, nephropathy, hypertension, pre-

eclampsia, caesarean section– Risks to infant:

• still birth, hypoglycemia, macrosomia, infant/childhood obesity

– Glycemic targets for pre-existing and GDM:

Diabetes:

• Insulin in pregnancy:– Regular and NPH insulin have most safety

evidence– may use glargine and detemir

• Oral agents in pregnancy: – metformin and glyburide are safe.

• Folic acid 5mg daily recommended.

RxFiles Diabetes and Pregnancy Q and A. March 2012.

Diabetes:•Lactation:•If GDM:

– no treatment needed post-partum– But risk of developing DM

•Should screen with OGT between 6 weeks and 6 months postpartum.•Same insulins and oral treatments are safe in lactation.

– Others have unknown safety.

Hypothyroidism:• Levothyroxine is safe in pregnancy and lactation:

• Need for thyroid hormone goes up by 25- 50% during pregnancy

• Can take 2 extra pills per week (ex. 2 tabs on Monday and Friday)

•Postpartum: return to pre-pregnancy dose

•Monitor TSH regularly

•Liothyronine also safe, but not preferred

Hyperthyroidism:•1st trimester: Propylthiouracil (PTU) preferred

•2nd and 3rd trimesters: Methimazole (MMI) preferred

• Dose requirements often increase in 1st trimester, and decrease in 2nd – 3rd trimester

•Lactation: MMI and PTU safe

•MMI is 10 times more potent than PTU

Antibiotics:

• Many are safe during pregnancy!– Amoxicillin (penicillin) – Keflex (cephalexin) – Erythromycin non-estolate

• Caution! – Avoid these:– Cipro (ciprofloxacin) - 1st trimester– Bactrim (sulfamethoxazole/trimethoprim) - 1st and

3rd trimester– Tetracyclines – all 3 trimesters– Macrobid (nitrofurantoin) – 3rd trimester – Erythromycin estolate – all 3 trimesters– Clarithromycin – all 3 trimesters (no definite link)

Antibiotics:

RxFiles Peri-Pregnancy Drug Treatment Considerations. Jan 2015.

Headache and Pain:

• Acetaminophen:– Safe for all three trimesters and

lactation– Maximum dose: 4000 mg per day

• Aspirin (Acetylsalicylic acid):– avoid unless prescribed

Headache and Pain:• NSAIDs:

– 1st trimester: increased miscarriage risk

– 3rd trimester: premature PDA closure, renal toxicity.

– Generally avoid in pregnancy!

• Lactation: – Ibuprofen preferred– Naproxen often used post-partum

Cough and Cold:

Cough: • Honey, hot drinks, humidifier, raise

head of bed • DM syrup safe, but no more effective

than honey

Sore throat: • pain medication (Tylenol), hot drinks,

lozenges

Cough and Cold:• Codeine: Risk of neonatal withdrawal if used

close to term• May cause premature labour if stopped

abruptly• Lactation: Risk of toxicity to baby in rapid

metabolizers. • Monitor baby for breathing, feeding, limpness

• Simpler to avoid OTC codeine products!

Allergies/Sinus:

Rhinitis in pregnancy is commonAll antihistamines safe in pregnancy and lactation

• Diphenhydramine, Loratadine, Cetirizine– 1st generation drugs may decrease milk production

http://www.motherisk.org/prof/updatesDetail.jsp?content_id=927

Allergies/Sinus:• Saline sprays and rinses are safe

• Intranasal conticosteroids are safe

• Topical decongestant sprays:– watch for rebound congestion

• Pseudoephedrine: – 1st trimester: may increase malformations– Caution if hypertension– Safe for short term use in later pregnancy and

lactation

Nausea:• Hard candies• Frequent small meals, • Split prenatal vitamin, or take one without

iron• Lots of fluids• Popsicles, smoothies, Boost/Ensure • Ginger – may be effective, not harmful

Nausea:

• Vitamin B6 – lollipops (B-Natal), tablets– Watch maximum daily dose. (up to 150mg of Vitamin B6 per day is

safe)

• Diclectin – Rx– Contains Vitamin B6 (10mg) and Doxylamine (10mg) – Good first step for nausea and vomiting– Side effects – drowsy, dry mouth

• Gravol – is safe, but should try Diclectin first

Heartburn:• Elevate head of bed• Avoid late night snacks• Quit smoking• Antacids (TUMS) – perfectly safe!

– May be constipating

• Anti-gas (Simethicone) – – good for bloating, is safe

Heartburn:

• Ranitidine: safe in pregnancy and lactation• PPIs safe – Omeprazole has most data• Can take PRN, or regularly

Constipation:• Fluids, fibre, and exercise• May reduce/eliminate iron from prenatal if

early in pregnancy• Metamucil• Docusate• Sennokot• Lax-a-Day

Diarrhea:

• Lots of water• Bananas – Rice – Applesauce - Toast• Kaopectate – not absorbed into body,

therefore perfectly safe• Loperamide – safe• Pepto Bismol – not recommended

– Contains salicylate

Smoking cessation:

• Nicotine Replacement– Good alternative if you can’t quit completely –

avoid the 4000 other chemicals from cigarettes

• Available as: gum, inhaler, lozenges, patches • Either use the patch OR the gum/lozenges

Summary of Resources:• RxFiles and Brigg’s Drugs in Pregnancy and

Lactation: online through SHIRP!

• Motherisk: http://www.motherisk.org/

• Lact Med: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

• Mother to Baby: http://mothertobaby.org

Questions?