Pregnancy & Lactation Flashcards
How does GI absorption change in pregnancy? (5)
- Increased plasma progesterone –> decreased intestinal motility, prolonged gastric emptying
- Decreased gastric acid secretions –> increased pH (weak acids are ionized, less diffusion; weak bases primarily unionized, more diffusion)
- Increased mucous secretions which reduces membrane permeability
- Nausea and vomiting
- ?clinically significant as increased cardiac output and intestinal blood flow allow for overall increased absorption
How does pulmonary absorption change in pregnancy?
Increased tidal volume –> increased pulmonary blood flow, increased alveolar uptake
How does Vd change in pregnancy?
Increased body water (plasma volume) –> may see decreased Cmax
How does protein binding change in pregnancy? (2)
- Dilutional hypoalbuminemia
- Steroid/placental hormones binding to proteins may decrease drug binding
How does hepatic metabolism/excretion change in pregnancy? (3)
Increased estrogen and progesterone –>
- CYP 3A4, 2D6 ↑ (nifedipine, methadone, paroxetine, fluoxetine)
- CYP 1A2 ↓ (caffeine, theophylline, clozapine, olanzapine)
- UGT ↑ (lamotrigine, acetaminophen)
How does renal metabolism/excretion change in pregnancy?
Increased GFR –> increased elimination but generally not clinically significant
Describe absorption in fetoplacental kinetics
Mostly passive diffusion –>
- Solubility
- Molecular size
- Ionization
How does distribution change in fetoplacental kinetics? (2)
- Fetal protein binding affinity different from maternal protein binding
- Fetal albumin concentration progressively increases while maternal decreases
How does metabolism change in fetoplacental kinetics? (2)
- Placenta and fetus capable of metabolism
- More polar metabolites may accumulate
How does elimination change in fetoplacental kinetics?
Mainly diffusion to maternal compartment, efflux transporters present
- Over time, concentrations in both compartments are similar.
What are the triad of effects to be concerned with in drugs and pregnancy?
- Effect of condition on pregnancy
- Effect of drug therapy on pregnancy
- Effect of pregnancy on condition
How could the mom having uncontrolled seizures affect the outcome of the pregnancy? (4)
- Fetal hypoxia
- Injury to fetus
- Placental abruption
- Miscarriage
How could the mom having uncontrolled hypothyroidism affect the outcome of the pregnancy? (4)
- Gestational HTN
- Placental abruption
- Fetal neurologic deficits
- Fetal death
How could the mom having uncontrolled asthma affect the outcome of the pregnancy? (4)
- Reduced respiratory function
- Reduced oxygen to fetus –> intrauterine growth restriction
- Fetal asphyxia
- Intrauterine fetal death
How might pregnancy affect seizure frequency?
- 45% increase
- 5% decrease
- 50% unchanged
Define teratogen
Agents that are capable of producing structural or functional abnormalities in the embryo or fetus
Teratogens may cause… (6)
- Spontaneous abortion
- Congenital malformations
- Intrauterine growth restriction
- Cognitive / behavioural effects
- Carcinogenesis
- Mutations
What are some considerations to…consider about teratogens? (3)
- Timing of exposure
- Dose, frequency of exposure
- Amount and quality of reproductive data
Teratogens - what to know about using drugs near time of conception? (2)
- Preconception drug use
- Maternal
- Paternal – uncertain; no evidence that paternal exposure increases risk of birth defects - All or none effect: exposure in first ~15 days postconception = spontaneous abortion
Teratogens - what to know about using drugs in first trimester? (2)
- Most critical time for organogenesis and physical formation
- Teratogen exposure during this stage more likely to cause physical malformations
Teratogens - what to know about using drugs in 2nd and 3rd trimester? (3)
- Functional and behavioral effects if exposure later in gestation
- Growth
- CNS development – IQ, language development, behaviour
NSAID use during term may cause?
Constriction of ductus arteriosus
Neonatal withdrawal may be associated with these drugs: (2)
- Opioids
- SSRIs
What to know about dose-dependent relationship between pregnancy and drug use? (2)
- Threshold dose is not known for many teratogens
- As a general rule, use the lowest dose for the shortest amount of time
What sort of studies/data do we have in pregnant folks? (4)
- Case reports
- Case-control studies = people with a certain outcome (case) compared to without outcome (control)
- Cohort studies = people who took a drug
- Registries
What are 4 problems with epidemiological studies?
- Recall bias – participants don’t recall accurately, omit details
- Selection bias – proper randomization not achieved
- i.e., only case reports with negative consequences, only publish studies that show relationship - No control of confounding factors
- i.e., a cohort study in which some women potentially had more severe disease - Sample size
What are 3 considerations for medication use in pregnancy?
- Non-pharmacological
- Gestational age
- Benefit vs. risk
What are we thinking when it comes to drug selection in pregnancy? (5)
- Single entity
- Published data
- Most effective and most reassuring safety data
- Older vs. newer drug - Local application if possible
- Lowest effective dose, shortest duration
- Shorter t1/2 when possible?
What are a few counselling points to touch on for pregnant/pre-pregnant patients? (4)
- Preconception planning
- Share information to help weigh risk vs. benefit
- Resources
- How information is presented - Risk
- Baseline risk
- Risk versus benefit – eg: Malarone
- Minimizing risk – eg: folic acid supplementation with gabapentin - Other factors affecting pregnancy outcome
- Age
- Underlying medical conditions
- Genetic conditions
- Obstetrical history
- Other exposures (including ethanol and smoking)
- Socioeconomic status (affects nutrition and health care received)
How does pregnancy and lactation differ when it comes to drug kinetics? (2)
- Kinetics of transfer through placenta are different from the transfer of drugs into human milk
- A drug deemed unsafe in pregnancy is not necessarily unsafe for breast/chestfeeding
What are some advantages of breastfeeding/chestfeeding (4)?
- Bonding → physical / emotional
- Nutritional → benefits growth and development
- Protective → GI infections, AOM, respiratory tract infections, SIDS
- Enhanced cognitive development
Exclusive breastfeeding/chestfeeding is recommended for the first _ months
6
What is the goal regarding breastfeeding/chestfeeding and drug use?
Continue breastfeeding/chestfeeding, shared decision making
Almost all drugs which reach systemic circulation will enter human milk to some degree. What to be aware of with that? (3)
- Not likely at a level that is harmful to a breast/chest fed infant
- Rarely produce clinical doses in the infant
- However, there is a chance that breastfeeding/chestfeeding can lead to toxicity in the infant if the drug enters the milk in pharmacologic quantities
- e.g., ultra-rapid 2D6 metabolizer + codeine
Maintenance of milk supply requires: (2)
- Sufficient production
- Effective extraction
Inefficient milk production may be due to what potential factors? (4)
- Previous breast surgery
- Augmentation or reduction - Poor initial feeding routines early postpartum:
- Infrequent feeding
- Inadequate latch-on
- Parent-infant separation
- Use of supplemental formulation - Incomplete drainage
- Medications: bromocriptine, combination oral contraceptives (estrogen dose-related), oral decongestants, antihistamines, nicotine, diuretics
Ineffective milk extraction may be due to what potential factors? (4)
- Poor technique
- Poor initial feeding routines early postpartum:
- Infrequent feeding
- Inadequate latch-on
- Parent-infant separation - Abnormalities of nipple or infant’s mouth
- Blocked ducts
What are the 2 main considerations of drug use in lactation?
- Effect of drug exposure on infant via milk
- Effect of drug on milk production
List the potential drug properties that have an effect on the likelihood of entering milk (8)
- Molecular weight
- Protein binding
- Vd
- Lipid solubility
- Ionization
- Drug pKa
- Bioavailability
- Half-life
What property of molecular weight increases the likelihood of a drug entering the milk?
<500-800 daltons
What property of protein binding increases the likelihood of a drug entering the milk?
Low protein binding
What property of Vd increases the likelihood of a drug entering the milk?
Small Vd
What property of lipid solubility increases the likelihood of a drug entering the milk?
Highly lipid soluble (drugs active in the CNS)
What property of ionization increases the likelihood of a drug entering the milk?
Unionized
What property of drug pKa increases the likelihood of a drug entering the milk?
Basic drugs (milk more acidic, basic drugs more likely to be unionized in plasma, cross and become ionized)
What property of bioavailability increases the likelihood of a drug entering the milk?
High bioavailability
What property of half-life increases the likelihood of a drug entering the milk?
Longer half-life
Factors that determine exposure of drug through milk - what are the parent variables? (2)
- Milk composition
- Concentration of drug
- Dose
- ADME (renal/hepatic impairment)
- Drug interactions
Factors that determine exposure of drug through milk - what are the infant variables? (2)
- Milk consumption
- Frequency of feeding
- Volume consumed - Age
- Glomerular filtration, hepatic metabolism (less robust until 6-12 months)
- Preterm –> immature, permeable gut, lower capacity to metabolize and excrete drugs
Dose of medication transferred to infant via milk is generally ___________ with ___ ____________
subclinical; few exceptions
True or False? If infant is on medication, is breastfed, and mother is on a medication, drug interactions don’t need to be considered?
False - caution with interactions between medications being given to parent and medications being given to infant
What are some potential ADEs the infant may experience via drugs through the milk? (5)
- Drowsiness
- Irritability
- GI upset
- Diarrhea
- Constipation
What are some non-dose-related toxicities that may be seen in infants via drugs through the milk? (3)
- Allergic sensitization
- Hemolysis (i.e. azathioprine + G6PD deficiency)
- Blood dyscrasias (i.e. chloramphenicol)
Lactation safety data has similar limitations to drugs in pregnancy. That being? (2)
- Lactation an exclusion criterion for RCTs
- Same defaults –> animal and observational data
What are 2 potential safety advantages to getting safety data in lactation?
- Direct observation
- Generally lower exposure via milk than placenta
What are 3 ways to estimate (and limit) infant drug exposure?
- Milk to plasma ratio (very rarely used)
- Relative infant dose
- Infant plasma concentrations
What is milk to plasma ratio (M/P)?
Concentration of the drug in the milk compared to concentration of the drug in the plasma.
- >1 indicates that the drug concentrates in the milk
- Doesn’t indicate safety though, just a ratio.
What is relative infant dose (RID)?
A means of estimating infant exposure to drugs used in lactation
What 2 numbers are we looking for in relative infant dose that indicates that the drug is likely safe for short-term use?
- <10% (term infants)
- <1% (premature infants)
Generally, selecting medications with _____ RID may help maximize safety.
Most medications have an RID __%
lower; <1
Infant plasma concentrations is the most accurate form of measuring drug intake via milk. What does it account for? (4)
- Bioavailability
- pH effects - infant’s GI tract is more acidic
- Gut permeability
- Underdeveloped liver/kidneys
(Limited availability)
What are some strats to limit infant exposure to drugs via milk? (3)
- Use only if necessary
- Decrease parental systemic exposure
- e.g. local application - Avoid feeding at times of peak drug concentration if possible
- Once Css reached, timing not really possible
- If taking infrequently, preferentially choose short-acting drug; take immediately after feeding before infant’s longest sleep (if possible)
Another strat to help limit infant risk from drugs via milk is called “Pump and Dump” what is that?
Substitute with previously expressed milk or formula; current milk pumped and discarded
- Duration determined by the elimination half-life of the medication (~4-5 t1/2)
- No true standard guidelines beyond this measure
True or False? Donated milk can be used to help limit infant exposure to drug via milk
True
- Milk bank collects milk from healthy parents with excess milk. Expensive though
What are 2 potential drug effects on milk production (don’t overthink it)?
- Decrease production (insufficient to meet infant’s needs)
- Before breastfeeding is established
- Cues to monitor in infant = urination/BMs, alertness, skin color, consistent weight gain - Increased production
- Exploited therapeutically
Name some drugs that may reduce milk production (7)
- Antihistamines
- Decongestants
- Stimulants
- Diuretics
- Estrogen
- Nicotine
- Ergot alkaloids - bromocriptine
Name some drugs that may increase milk production (4)
- Metoclopramide
- Domperidone
- Antipsychotics
- Fenugreek
What class of medications may help augment (increase) maternal milk production?
Galactogogues
The most commonly used prescription galactogogue agents are?
- Metoclopramide
- Domperidone
What is the MOA of metoclopramide and domperidone as galactogogues?
Dopamine receptor antagonists, stimulate prolactin release
Why is metoclopramide and domperidone not routinely used as galactogogues? (3)
- Limited evidence to support their efficacy
- Potential safety concerns
- Use with caution - parents need to be aware of potential side effects and the lack of data supporting use
True or False? If parent has low milk production, it is not necessary to meet with an HCP to have it checked out
False - obviously, dumbass, go to the doc.
What are some parent ADEs of domperidone? (4)
- Poor distribution to BBB and breastmilk
- Dry mouth, headache, nausea, diarrhea, dizziness, abdominal cramping, palpitations, malaise, shortness of breath
- QT
- Withdrawal
What are some infant ADEs associated with domperidone? (4)
- Few reports
Non-serious: - Diaper rash
- Hematuria
- Constipation
RID of domperidone and metoclopramide is how much, respectively?
~0.1% and ~4%
What are some parental ADEs associated with metoclopramide? (4)
BBB distribution
- Depression
- Tardive dyskinesia with long term use
- HA, N, D, dry mouth, tiredness, breast discomfort, vertigo, restless legs, intestinal gas, hair loss, anxiety
What are some infant ADEs associated with metoclopramide? (3)
- Few reports
- Intestinal gas (1 report)
- Intestinal discomfort (1 report)
What are some potential herbal galactogogues? (6)
- Fenugreek
- Asparagus
- Milk thistle
- Fennel
- Caraway
- Goat’s rue
Are herbal galactogogues recommended?
Nah
What is the bottom line when it comes to selecting galactogogues?(4)
- Most parents who receive instruction on BF technique and frequency are unlikely to derive much benefit from galactagogues
- Galactagogues should not be considered before support, education, assessment of BF technique - Optimal dose unknown
- Studies low and short term
- 10 mg TID (both), possibly 20 mg TID (domperidone) - Taper on d/c (regimen?)
- Monitor adverse effects
What to consider when selecting drug therapy for breastfeeding mother? (4)
- Risks of not breastfeeding or not treating condition
- Necessity of pharmacotherapy
- Published data, especially:
- Effect on infant
- Effect on milk supply - RID if available
What are infant variables to think about when it comes to drug therapy selection in breastfeeding mother? (3)
- Gestational age at birth
- Current age/health
- Feeding pattern
What are some (ideal) drug properties to think about when selecting drug therapy in breastfeeding mother? (3)
- Low oral bioavailability
- Shorter acting
- Less likely to pass into milk
