IMM: L22/25 Medication in Pregnancy & Lactation

What are the 4 things that can happen in developmental toxicity?

Growth alteration, structural anomalies, functional neuro-behavioural deficits, and death

What are the 4 causes of structural anomalies?

Genetic, chromosomal, multifactorial, and unknown

What are the 2 only preventable causes in developmental toxicity?

Drug-induced, and drug deficient

Determinants of Drug Toxicity:

• Four Essential Criteria

  • Exposure in the "… Period"

  • For an exposure to affect a pregnancy, it must happen during the “critical period” when a body part is forming

  • If exposure occurs … structure is formed it cannot cause an anomaly

• Specific … or …

• Consistent findings in > … epidemiologic studies

• Rare … associated with a rare anomaly

Critical, after, anomaly, syndrome, 2, exposure

When is the critical period?

5-12 weeks gestation

Can it cross the placenta?

• Plasma … (systemic bioavailability)

• Molecular weight (<… Daltons)

• Plasma elimination … (increases with time at maternal-fetal interface)

• Lipid … (cross membrane easier)

• Ionization at physiological …

• Plasma protein …

• Placental … enzymes

concentration, 600, half-life, solubility, pH, binding, metabolizing

FDA letter risk categories (A, B, C, D, X) started being removed June 2015

• They do not account for changes to …

• A & B were not … safe

• Not all drugs labeled C were the .. risk

• No … — lowest (A) to highest (X) risk

• Some products were labeled X because of no …

• Categories do no consider

  • Exposure timing, dose, route, duration, frequency, incidence, severity, reversibility

fetus, absolutely, same, progression, benefit

Benefits of human milk for a postpartum person:

• Decreases risk of:

  • … cancer

  • … cancer

  • … diabetes

  • … disease

Breast, Ovarian, Type II, Heart

Benefits of human milk in infants:

• Decreases risk of:

  • …

    • Gastroenteritis

    • LRTI

    • Acute otitis media

  • … enterocolitis in preterm infants

  • …. syndrome

Infections, Necrotizing, Sudden infant death

Lactation Physiology

• Secretory … (Lactogenesis I)

  • … to late pregnancy

  • Differentiation of mammary epithelial cells into … in alveoli

  • Can produce & secrete components of milk

    • e.g. lactose, casein

• Secretory … (Lactogenesis II)

  • Onset of … milk production after delivery

  • Continuum of changes in composition & volume

  • Historically called colostrum or transitional milk

• … (Lactogenesis III)

  • Production & maintenance of … milk

differentiation, Mid, lactocytes, activation, copious, Galactopoiesis, mature

Lactogenesis II

• Initially lactocytes are … with large … spaces

• Medications, immunoglobulins, proteins, etc. easily transfer into milk from …

• … levels fall, lactocytes grow, intercellular gaps …

• Once closed, transfer of medications in plasma is greatly …

small, intercellular, blood, Progestin, narrow, reduced

Drug Entry Into Human Milk

• Plasma … (systemic bioavailability)

  • … = more drug enters milk

• Molecular weight

  • Drugs > … Daltons enter milk poorly

  • Drugs < … Daltons enter milk easily

• Plasma elimination …

• Lipid …

• Ionization at … pH

  • pH of milk is … than plasma

  • Ion trap for basic drugs with a pKa >…

• Plasma protein binding

  • Plasma proteins bind … than milk proteins

  • Highly protein bound drugs … concentrate in milk

• Vd

  • Higher Vd > … L/kg - lower levels in milk

concentration, Higher, 800, 300, half-life, solubility, physiologic, lower, 7.2, better, do not, 1

Other factors of drug entry into human milk:

• … bioavailability (F)

• Drug exposure via milk depends on bioavailability of drug in …

• Large molecular weight = … absorbed orally (e.g. heparin)

• Stability in … tract of infant is important

Oral, infant, poorly, GI

Extent of Drug in Milk:

• … (M/P) Ratio

• Ratio of concentration of drug in milk divided by concentration in plasma

• Unless plasma level is …, ratio is meaningless

• M/P ratio between … to … may indicate drug accumulates in milk

Milk/Plasma, known, 1, 5

Relative Infant Dose (RID):

• Daily … dose via milk divided by lactating … dose

• Calculated using

  • Parent weight — commonly adjusted to a … kg female

  • Daily infant milk intake — usually … mL/kg/day

• < …% of lactating parent daily dose is acceptable

infant, parent, 70, 150, 10

Risk to Infant

• Exposure from milk is often … than in utero

• Fetal exposure can be > …x that of milk

• … is complete at birth

• Risk depends on 3 major factors

  • Choice of …

  • … of milk

  • Infants current … status

less, 10, Organogenesis, drug, Volume, medical

… filtration and … secretion are underdeveloped in neonates

Glomerular, tubular

Risk is lowest after .. months, as …excretion matures & as other nutrition is introduced

2, renal

What 6 things that decrease milk supply?

Alcohol, estrogen, progesterone, cigarette smoking, pseudoephedrine, and ergot alkaloids

What 3 things that increase milk supply?

Dopamine antagonists, milk thistle, and fenugreek