Cephalosporins in Pregnancy

Cephalosporins in Pregnancy

• Cefazolin clearance increases by 74% in pregnancy, making it difficult to maintain free cefazolin concentrations above 8 mg/L (MIC for susceptible Gram-positive bacteria) when 1 hour prior to surgery.
• Recommendation: Cefazolin 2 gm at 1 hour prior to surgery.

Digoxin in Pregnancy

• Fetal tachyarrythmias occur in approximately 0.5% of all pregnancies.
• If untreated, it can lead to fetal cardiac failure.
• Digoxin is the primary initial therapy, but it is difficult to achieve therapeutic levels in the fetus (fetal levels are very low/sub-therapeutic) due to P-glycoprotein (Pgp) expression in the placenta, which inhibits its penetration into the fetus.
• Direct injection of digoxin intramuscularly into the fetal thigh (increased fetal risk) or addition of a second anti-arrhythmic drug (flecainide, sotalol, amiodarone) can help overcome the problem.

Plasma Proteins in Pregnancy

• Mean albumin concentrations:
  • 2nd trimester: 3.6 gm/dl
  • Nonpregnant: 4.2 gm/dl
• Drugs with narrow therapeutic index that are highly protein bound: monitor free fraction, not total drug.

Pregnancy and Drug Metabolism

• Lamotrigine (LTG) levels decrease as pregnancy progresses, suggesting enhanced clearance of LTG during pregnancy.
• Clearance (CL) increases by 240% and returns to pre-pregnancy level by 3 weeks postpartum with a mean increase in dose of 250% to maintain plasma LTG levels.
• Lamotrigine levels are similarly affected by birth control pills (COC).

Changes in LMWH PK

• Normally, the Vd of LMWHs is approximately plasma volume.
• Normally, LMWHs are cleared by hepatic desulfation and depolymerization + renal clearance.
• In pregnancy:
  • There is an increase in plasma volume during pregnancy (~ 1200 - 1300 mL above the non-pregnant state, 40%).
  • Renal blood flow and GFR increase in pregnancy.
• Based on the increase in Vd and increase in renal clearance, LMWH blood concentrations and their anticoagulant effects are expected to decrease.
• Normal dose is 100 IU/Kg bid, but doses up to 140 IU/Kg may be needed during pregnancy.

Intrapartum Management

• In anticipation of labor (≥36 weeks), change to UFH.
• LMWHs have longer half-lives than UFH, increasing the risk of bleeding with epidural and caesarean section.
• Anticoagulant effects of UFH are more easily reversed with protamine sulfate.
• UFH can be stopped 3-6 hours prior to caesarean or epidural.
• Restart LMWHs 12-24 hours after delivery.
• Anticipate the need to decrease dose as renal clearance normalizes.

Renal Clearance of Amoxicillin

• The increase in amoxicillin renal clearance is due to:
  • Increased GFR
  • Decreased reabsorption caused by inhibition of PEPT1 transcription by progesterone