drugs in pregnancy and lactation

PEBC

teratogen

• any agent that can cause Malformation or impairs the proper development of an embryo or fetus

pharmacokinetics in pregnancy

• increased water content in body = need larger doses of water soluble drugs (aminoglycosides)

• increased cardiovascular output

• increased GFR and renal blood flow

• decreased serum protein binding

• decreased intestinal motility (due to progesterone mediated smooth muscle relaxation)

• decreased gastric acidity = increased gastric pH

placental drug transfer

• placenta acts as as intravenous portal for entry of drugs into fetus

• drug properties increase the chance of placental transfer:

  • high fat solubility

  • low degree of ionization

  • low degree of protein binding

  • low molecular mass (<500 kDa rapid transit, 500-1000 kDa slower transit)

    • heparin and insulin = high weight and safe

critical periods in pre-natal development

• greatest period of sensitvity to teratogens is during organogenesis which lasts 6 weeks

  • really critical phase is when organs develop = between 6-8 weeks = 1st trimester!

• teratogens during fetal period = more likely to cause problems with organ function or stunt growth rather than causing structural damage

• 3 trimesters:

  • 1st = very critical about the medications

    • 0-12 weeks

  • 2nd = golden phase = pts have less sx and more safe bc critical period has passed

    • 13-27 weeks

  • 3rd =

    • 27/28 weeks - term (38/39 weeks)

proven teratogens

• ACEI/ARBs:

  • intrauterine renal insufficiency, neonatal hypotension, oliguria with renal failure, hyperkalemia, intrauterine growth restriction, prematurity, fetal death

• Antineoplastic agents:

  • exposure in 1st trimester → malformations and miscarraiges

• Carbamazepine and Valproic acid:

  • exposure in 1st trimester leads to neural tube defects and cardiovascular malformations

    • supplement with folic acid 5mg 3 months before conception

• Cocaine:

  • prematurity, death, limb defects, urinary tract malformations

• Corticosteroids (systemic):

  • in 1st trimester = oral cleft risk (risk <1%)

• Mycophenolate Mofetil:

  • 1st trimester: CNS, facial (ear, eye, oral cleft), cardiac, GI, skeletal and urogenital malformations

• warfarin:

  • 1st trimester: fetal warfarin syndrome, restriction in intrauterine growth, delay in CNS development, hearing and vision impairment, miscarriage etc

• ethanol

  • fetal alcohol spectrum, neuro developmental disorders

• folic acid antagonists:

  • abnormalities in CNS development and cranial ossification, intrauterine growth restriction

  • maternal dose of >10 mg/ week will induce defects with MTX

• phenytoin

  • cardiovascular, craniofacial and CNS malformations

• lithium

  • small risk of cardiac malformations if >900 mg/d

• misoprostol

  • 1st trimester: CNS abnormalities

  • induces uterine contractions = fetal malformations

• Retinoids: high doses of vitamin A

  • craniofacial, cardiac and CNS malformations, miscarriage

• Tetracyclines:

  • discolouration of teeth (after 17 weeks gestation), crowns of permanent teeth stained (close to term)

  • doxy has lower risk

• Thalidomide:

  • limbs, ears, cardiac and GI malformations

• Topiramate:

  • 1st trimester: oral clefts

• Valproic acid:

  • 1st trimester: neural tube defects

possible teratogens

weigh the risk vs benefit

• Diazepam

  • small risk between cleft lip/palate and maternal diazepam (only small studies)

• Fingolimod (used in MS)

  • small studies: possible risk of increased congenital malformations

• Fluconazole (high dose)

  • case reports: cardiac, skeletal and facial abnormalities

• Methimazole

  • case reports: scalp defects

• Penicillamine (high dose)

  • connective tissues anomalies

• SMX/TMP

  • possible risk: oral clefts, neural tube defects, cardiac anomalies

  • supplementing with folic acid can reduce risk

• Statins

  • retrospective reports = increase in limb and CNS anomalies

factors to consider (breastfeeding)

• drug characteristics

• route of administration:

  • oral = undergoes first pass metabolism before entering blood stream

  • IV = bypasses barriers of GI tract to enter bloodstream and milk

  • IM = bypasses barriers of GI tract to enter bloodstream through blood vessels surrounding the muscles

  • topical = low systemic absorption

• CYP2D6 substrates:

  • codeine = can lead to increased active metabolite levels in infants causing toxicity

• Baby’s age, maturity, weight and health status

  • GI transit time and flora, rate of metabolism and excretion

• Frequency and volume of milk feedings

• Premature/low birth weight infants or G6PD deficiency

  • infants with G6PD deficiency may develop hemolytic anemia if exposed through breastmilk

drugs that can enter breastmilk

• low plasma protein binding

• non-ionized

• low molecular weight

• lipophilic

• weakly alkaline

clinical pearls (breastfeeding)

drugs incompatible with breastfeeding