Drugs in Pregnancy

Question 1

What is the impact of pregnancy on a woman’s GI absorption?

Answer 1

Increased progesterone = reduced motility and prolonged gastric emptying

Reduced gastric sections = higher pH (less acidic)

Increased mucous secretions which reduces membrane permeability

Question 2

What is the impact of pregnancy on a woman’s pulmonary absorption?

Answer 2

Increased tidal volume = increased pulmonary blood flow and alveolar uptake

Question 3

What is the impact of pregnancy on a woman’s drug distribution?

Answer 3

Increased body water (plasma volume) = potential decrease in Cmax (due to dilutional effect)

Question 4

What is the impact of pregnancy on protein binding?

Answer 4

Dilutional hypoalbuminemia (due to extra fluid)

Steroid/placental hormones may displace protein binding sites (increase unbound drug)

Question 5

How does pregnancy affect hepatic metabolism in pregnant women?

Answer 5

Increased estrogen and progesterone:
- Increased CYP 3A4 & 2D6 = lower nifidipine, methadone, paroxetine, fluoxetine
- Reduced CYP 1A2 = higher caffeine, theophylline, clozapine, olanzapine)
- Increased UGT = lower lamotrigine, acetaminophen

Question 6

What is the impact of pregnancy on renal elimination?

Answer 6

Increased GFR, but other mechanisms counterbalance increased GFR (less clinically relevant)

Question 7

How does the fetus/placenta absorb drugs from the mother?

Answer 7

Mostly passive diffusion → solubility, molecular size, ionization

Question 8

How does a fetus/placenta distribute drugs within itself?

Answer 8

• Fetal protein binding affinity different from maternal protein binding
• Fetal albumin concentration progressively increases while maternal decreases

Question 9

What does metabolism look like for the fetus/placenta?

Answer 9

• Placenta and fetus capable of metabolism
• More polar metabolites may accumulate

Question 10

What does elimination look like for fetus/placenta?

Answer 10

• Mainly diffusion to maternal compartment, efflux transporters present

Question 11

What is the impact of untreated epilepsy/seizures on the outcome of the pregnancy?

Answer 11

Fetal hypoxia, injury to fetus, placental abruption, miscarriage

Question 12

What is the impact of untreated hypothyroidism on the outcome of the pregnancy?

Answer 12

Gestational HTN, placental abruption, fetal neurologic deficits, fetal death

Question 13

What is the impact of untreated asthma on the outcome of pregnancy?

Answer 13

• Reduced respiratory function, reduced oxygen to fetus =
  intrauterine growth restriction
• Fetal asphyxia
• Intrauterine fetal death

Question 14

Review slide 12 for impact of drugs on congenital defects

Question 15

What is a teratogen?

Answer 15

Agents that are capable of producing structural or functional abnormalities in the embryo or fetus

Question 16

What are some negative consequences of teratogen exposure to fetus?

Answer 16

• Spontaneous abortion
• Congenital malformations
• Intrauterine growth restriction
• Cognitive / behavioural effects
• Carcinogenesis
• Mutations

Question 17

What are some considerations when it is necessary to potentially teratogenic drugs in pregnancy?

Answer 17

• Timing of exposure (when during pregnancy)
• Dose and frequency of exposure (threshold unknonw for most drugs, dose low for shortest time possible)
• Amount and quality of reproductive data

Question 18

What are the consequences of peri-conception teratogen exposure?

Answer 18

No evidence for paternal exposure having influence on birth defect risk

All or none effect (exposure in first 15 days postconception = spontaneous abortion)

Question 19

What are the potential consequences of teratogen exposure in the first trimester?

Answer 19

Most critical time for organogenesis and physical formation

Teratogen exposure during this stage more likely to cause physical malformations

Question 20

What are some potential consequences of teratogen exposure in the 2nd and 3rd trimesters?

Answer 20

• Functional and behavioral effects if exposure later in gestation
• Growth & intrauterine growth
• CNS development – IQ, language development, behaviour

Question 21

What are some potential consequences of teratogen exposure at term (~40 week)?

Answer 21

Premature labour (cigarette and illicit drug use)

Neonatal withdrawal (opioids and SSRIs)

Constriction of ductus arteriosis (NSAIDs)

Question 22

What are some considerations when deciding to go with medication use in pregnant women?

Answer 22

• Non-pharm options?
• Gestational age
• Benefit vs. risk

Question 23

What are some safe drug choice tips for pregnant women?

Answer 23

Use single entity products

Use most effective and most reassuring safety data (new gen. vs old gen drugs)

Lowest effective dose, shortest duration

Shorter half-life if possible

Question 24

How can pharmacists assist with preconception planning?

Answer 24

Up to six months before conception

Can help with drug management to improve fertility and
reduce exposure to potential teratogens

Help weigh risks vs. benefits

Question 25

What are some non-drug factors that can influence pregnancy outcome?

Answer 25

- Age - Underlying medical conditions - Genetic conditions - Obstetrical history (screening consultation) - Other exposures (including ethanol and smoking) - Socioeconomic status (affects nutrition and health care received)

Question 26

Review slides 31 to 34 for drugs in pregnancy resources

Question 27

Are drugs considered to be unsafe in pregnancy also considered to be unsafe in lactation?

Answer 27

Not necessarily Therefore, review drug list after giving birth and consider d/c or readding therapies

Question 28

What are some advantages of breastfeeding?

Answer 28

- Bonding (physical and emotional) - Nutritional (benefits growth and development) - Protective (GI infections, respiratory tract infections, SIDS) - Enhanced cognitive development Exclusive breastfeeding is recommended for the first 6 months

Question 29

Which drugs enter human milk?

Answer 29

Almost all drugs which reach systemic circulation will enter human milk to some degree Fortunately in most cases, drug levels in human milk are not likely to be at a level that is harmful to an infant and rarely produces a clinical dose in the infant

Question 30

What is required to maintain milk supply?

Answer 30

Sufficient production and effective extraction is maintained by regularly emptying of milk supply

Question 31

What are some causes of insufficient milk production?

Answer 31

- Previous breast surgery (augmentation or reduction) - Poor initial feeding routines early post-partum (infrequent feeding, inadequate latch-on, parent-infant separation) - Drugs (estrogen containing oral contraceptives, oral decongestants, antihistamines, nicotine, diuretics)

Question 32

What are some causes of ineffective milk extraction?

Answer 32

- Poor technique - Poor initial feeding routines early postpartum (infrequent feeding, inadequate latching, parent-infant separation) - Abnormalities of nipple or infant's mouth - Blocked ducts (can cause infection, make sure breast is drained regularly and fully)

Question 33

What are main considerations of drug use in lactation?

Answer 33

Effect of drug exposure on infant via milk (dose exposure) Effect of drug on milk production (limit nutritional access)

Question 34

What are some drug factors that enhance drug exposure to breastfeeding infant?

Answer 34

1. Drug molecular weight over 500 daltons 2. Low protein binding (more unbound) 3. Small Vd 4. Lipid solubility (Highly lipid soluble drugs) 5. Unionized 6. Drug pKa (basic drugs are more likely to be unionized in plasma, but then become ionized in acidic milk and then become trapped) 7. High bioavailability 8. Longer half-life

Question 35

What are some parent variables that may enhance drug exposure to a breastfeeding infant?

Answer 35

- Milk composition (last amount of milk has higher fat content, so fat soluble drugs will be concentrated - Concentration of drug (dose, ADME, renal/hepatic impairment) - Drug interactions

Question 36

What are some infant variables that may enhance drug exposure to a breastfeeding infant?

Answer 36

Milk consumption (correlates with exposure to drugs) - Frequency of feeding decreases with age - Volume consumed increases with age Age (GFR and hepatic metabolism increases with age, robust by 6-12 months) For pre-term infants (immature, permeable gut, lower capacity to metabolize and excrete drugs)

Question 37

What are some potential drug effects on infant via milk?

Answer 37

- Drowsiness - Irritability - GI upset - Diarrhea - Constipation - Non-dose-related toxicities (allergic sensitization, hemolysis, blood dyscrasias)

Question 38

What are some methods by which infant exposure to drugs can be estimated?

Answer 38

1. Milk to Plasma Ratio 2. Relative Infant Dose 3. Infant Plasma Concentrations

Question 39

What is Milk to Plasma Ratio (M/P)?

Answer 39

Concentration of the drug in the milk compared to concentration of the drug in the plasma A M/P ratio over 1 is considered to be concentrated

Question 40

What is the significance of a Milk to Plasma Ratio (M/P) over 1?

Answer 40

Does not necessarily indicate safety of medication, as does not consider absolute amount of drug entering milk

Question 41

What is a relative infant dose (RID)?

Answer 41

A means of estimating infant exposure to drugs used in lactation Infant dose(calculated by determining drug concentration and milk volume)/maternal dose x 100%

Question 42

What are safe relative infant doses for term and premature infants?

Answer 42

Under 10% for term infants Under 1% for premature infants Most medications have low penetration into milk, so RID is less than 1%

Question 43

What are some characteristics of measuring infant plasma concnetrations directly to determine exposure to drug via milk?

Answer 43

More accurate Accounts for absorption and elimination effects, and final exposure to drug

Question 44

What are some strategies to limit infant exposure to drugs while breastfeeding?

Answer 44

Use drugs only if necessary Switch to formulations with lower parental systemic exposure Avoid feeding when drug concentrations are highest in mother (relevant for PRN drugs)

Question 45

What is the utility of the "pump & dump" with respect to drugs in lactation?

Answer 45

Substitute with previously expressed milk or formula; current milk pumped and discarded (contains too much drug and unnecessary exposure to baby)

Question 46

What are some drugs that may reduce milk production?

Answer 46

- Antihistamines - Decongestants - Stimulants - Diuretics - Estrogen - Nicotine - Ergot alkaloids - bromocriptine

Question 47

What are some drugs that may increase milk production?

Answer 47

- Metoclopramide - Domperidone - Antipsychotics

Question 48

What should pharmacists do if a mother believes she has low milk production?

Answer 48

Refer to primary care provider

Question 49

What are the most commonly prescribed medications used to increase mlk production?

Answer 49

Known as galactagogues Metoclopramide and domperidone (both are dopamine receptor antagonists, stimulate prolactin release)

Question 50

Can galactagoges like metoclopramide and domperidone be used regularly?

Answer 50

Routine use is not recomended Limited evidence to show efficacy and potential safety concerns Try non-pharm options first

Question 51

When selecting drug therapy for breastfeeding mothers, what are some considerations?

Answer 51

- RIsks of not breastfeeding vs not treating condition - Necessity of pharmacotherapy - Published safety data - RID if available - Infant variables - Drug properties

Question 52

What is the role of pharmacists in drug management for lactating mothers?

Answer 52

Help support breastfeeding where possible Advise use of meds with widely known efficacy & safety data Educate parents about strategies of limiting infant exposure to drug Communicate advantages and disadvantages of galactagogues