IMM 19, 25, and 26: Pregnancy and Lactation Flashcards
What is developmental toxicity?
- growth alteration
- strutural anomalies
- functional neuro-behavioural deficits
- death
What is parturition?
functional neuro-behavioural deficits or death
Developmental Toxicity
What are the 4 causes of structural anomalies?
- genetic
- chromosmal
- multifactorial
- unknown
Developmental Toxicity
What are the only preventable causes? (2)
- drug-induced
- drug deficient – untreated disease or folic acid deficiency
What are the 4 determinants of drug toxicity?
- exposure in the critical period – if exposure occurs after structures is formed, it cannot cause the anomaly
- specific anomaly or syndrome
- consistent findings in 2 or more epidemiologic studies
- rare exposure associated with a rare anomaly
Describe the drug dose relationship.
- threshold dose or no-observed-effect-level (NOEL) often unknown
- rarely quantified in terms of weight, body surface area, concentration
- unable to determine incremental exposure vs. death – as dose increases, will severity of anomaly and/or frequency increase until lethal dose is reached
How should a medication be assessed?
- is there human pregnancy data available
- what about information for medications in the same class
- does the drug cross the placenta and reach the embryo or fetus
- what toxicity does it cause in animals
What factors should be considered when determining if a drug can cross the placenta? (7)
- plasma concentration (systemic bioavailability)
- molecular weight (< 600 Daltons)
- plasma elimination half-life (↑ with time at maternal-fetal interface)
- lipid solubility (cross membrane easier)
- ionization at physiologic pH
- plasma protein binding
- placental metabolizing enzymes
What clinical factors should be considered with pregnant patients?
- assessment of need for medication – what would happen if pregnant person did not take medication (ie. sepsis, seizure, exacerbation of disease, hospitalization, etc.)
- is the pregnant person near term – does it affect labour process or neonate at birth
What are the FDA letter risk categories?
A, B, C, D, X
- letters started being removed June 2015
- do NOT account for changes to fetus
- A & B were not absolutely safe
- not all drugs labeled C were the same risk
- no progression – lowest (A) to highest (X) risk
- some products were labeled X because of no benefit
What don’t the FDA letter risk categories consider?
- categories do not consider exposure timing, dose, route, duration, frequency
- does not consider incidence, severity, reversibility
Labetalol
Pregnancy Risk
low risk
Nifedipine
Pregnancy Risk
low risk
What are the possible feeding options? (5)
- parent milk
- colactation
- donor milk
- formula
- mixed feeding (combination of all)
What does lactation care consist of?
- answer questions regarding feeding preferences/plan
- breast/chestfeeding support
- milk production
- medication reviews
What are the benefits of human milk for a postpartum person? (4)
decreases risk of:
- breast cancer
- ovarian cancer
- type II diabetes
- heart disease
What are the benefits of human milk for an infant? (3)
decreases risk of:
- infections – gastroenteritis, LRTI, acute otitis media
- necrotizing enterocolitis in pre-term infants
- sudden infant death syndrome
What is lactogenesis I?
secretory differentiation
- mid-to-late pregnancy
- differentiation of mammary epithelial cells into lactocytes in alveoli
- can produce and secrete components of milk – ie. lactose, casein
What is lactogenesis II?
secretory activation
- onset of copious milk production after delivery
- continuum of changes in composition & volume
- historically called colostrum or transitional milk
- initially lactocytes are small with large intercellular spaces
- medications, immunoglobulins, proteins, etc. easily transfer into milk from blood
- progestin levels fall, lactocytes grow, intercellular gaps narrow
- once closed, transfer of medications in plasma is greatly reduced
What is lactogenesis III?
galactopoiesis
- production and maintenance of mature milk
Drug Entry Into Human Milk
What affects entry? (7)
- plasma concentration (systemic bioavailability)
- molecular weight
- plasma elimination half-life
- lipid solubility
- ionization at physiologic pH
- plasma protein binding
- Vd
Drug Entry Into Human Milk
How does plasma concentration (systemic bioavailability) affect entry?
if higher, more drug enters milk
Drug Entry Into Human Milk
How does molecular weight affect entry?
- drugs > 800 Daltons enter milk poorly
- drugs < 300 Daltons enter milk easily
Drug Entry Into Human Milk
How does ionization at physiologic pH affect entry?
- pH of milk is lower than plasma
- ion trap for basic drugs with a pKa >7.2
Drug Entry Into Human Milk
How does plasma protein binding affect entry?
- plasma proteins bind better than milk proteins
- highly protein bound drugs do not concentrate in milk
Drug Entry Into Human Milk
How does Vd affect entry?
if higher Vd (> 1 L/kg), lower levels in milk
What other factors must be considered? (2)
- oral bioavailability – drug exposure via milk depends on bioavailability of drug in infant (large molecular weight = poorly absorbed orally)
- stability in GI tract of infant
What is the milk/plasma (M/P) ratio?
ratio of concentration of drug in milk divided by concentration in plasma
- unless plasma level is known, ratio is meaningless
- M/P ratio between 1-5 may indicate drug accumulates in milk
How do you calculate average milk concentration (mg/mL)?
average plasma concentration (mg/mL) x M/P
How do you calculate average infant dose (mg/kg/day)?
average milk concentration (mg/mL) x 150 mL/kg/day
What is relative infant dose (RID)?
daily infant dose via milk divided by lactating parent dose
(daily infant dose/daily lactating parent dose) x 100
- calculated using parent weight commonly adjusted to a 70 kg female
- calculated using daily infant milk intake – usually 150 mL/kg/day
- < 10% of lactating parent daily dose is acceptable
- do not use M/P ratio unless it is really low (less than 1)
What risk does exposure from milk have on the infant?
exposure from milk is often less than in utero
- fetal exposure can be > 10x that of milk
- organogenesis is complete at birth
What does the risk to the infant from exposure to milk depend on? (3)
- choice of drug
- volume of milk
- infant’s current medical status
How do we evaluate the infant? (7)
- age
- prematurity – glomerular filtration and tubular secretion are underdeveloped in neonates
- weight/growth
- infants pre-existing medical condition
- infants current medications
- infants exposure in utero
- timing postpartum
What age is risk the lowest in infants?
risk is lowest after 2 months, as renal excretion matures and as other nutrition is introduced
What are some medications with potential for adverse effects? (5)
- water soluble beta blockers – atenolol, acebutolol
- lithium
- narcotics and sedatives (ie. codeine, diazepam)
- alcohol, substances, or medications used other than prescribed
- hemolytic agents (ie. nitrofurantoin, SMX/TMP)
How can lithium plasma levels change?
depending on hydration and renal function
- infants at greater risk of toxicity are premature, become unwell, or dehydrated
How should lithium be monitored throughout lactation?
- lactating person’s lithium levels
- clinical assessment of infant for adverse effects
- routine infant lab monitoring
- more commonly close clinical assessment and labs only if clinical concerns arise with medication exposure in milk
What are the potential adverse effects of hemolytic agents?
increased susceptibility of neonatal red cell membrane increases risk of drug-induced hemolysis
- not recommended < 1 month
What drugs decrease milk supply? (6)
- alcohol
- estrogens
- progesterone
- cigarette smoking
- pseudoephedrine
- ergot alkaloids
What drugs increase milk supply? (4)
- dopamine antagonists – metoclopramide, domperidone
- milk thistle (poor evidence)
- fenugreek (poor evidence)
Key Points
- choose effective therapy
- assess medications’ typical side effects in adults and pediatrics – try to limit number pf medications with CNS effects
- always evaluate stage of lactation – milk volume and infant age
- use relative infant dose (RID) – < 10% typically suitable
- monitor infant – changes in growth, feeding, or sleep patterns, inform health care providers of medication(s) infant is exposed to via milk
Vancomycin
- suitable for use in lactation
- may want to monitor infant for diarrhea – but easier to look for signs of dehydration such as lethargic/not waking to feed, sunken fontanel, pale skin, or diaper rash (hard to quantify loose stool in neonate)
What is the lactation risk for loratadine?
L1
What is fenugreek?
most commonly used herbal for increasing milk supply
- conflicting data: most reports of benefit are anecdotal or in a population not reported to have concerns with milk supply – benefits may be due to chance, natural increase in maternal milk supply, other support provided etc.
- not recommended to increase milk production
What are the concerns about herbal medications?
- quality and consistency of product purchased will vary
- may put pregnant person and/or infant at risk of unknown adverse effects
