Placental Transfer of Drugs

🔷 INTRODUCTION

Understanding placental transfer of drugs is crucial in obstetric anesthesia, as maternal administration of drugs can affect the fetus directly via the placenta. Anesthesiologists must select agents that are effective for the mother while minimizing fetal risks. This is especially relevant during labor analgesia, cesarean section, and non-obstetric surgeries during pregnancy.


🔷 ANATOMY OF PLACENTA

  • Feto-maternal interface: Allows exchange of gases, nutrients, and drugs
  • Placental barrier:
    • Consists of syncytiotrophoblast, cytotrophoblast, fetal capillary endothelium
    • Acts as a semi-permeable membrane for substances between mother and fetus


🔷 MECHANISMS OF DRUG TRANSFER

Mechanism

Examples

Passive diffusion (most common)

Most anesthetic drugs

Facilitated diffusion

Glucose

Active transport

Amino acids, ions

Pinocytosis

Immunoglobulins

Breaks in placental barrier

Trauma, infections (TORCH)


🔷 FACTORS AFFECTING PLACENTAL DRUG TRANSFER

Factor

Effect

Molecular weight

Drugs <500 Da cross easily (e.g., fentanyl); >1000 Da (e.g., heparin, insulin) do not cross

Lipid solubility

Lipophilic drugs (thiopentone, fentanyl) cross rapidly

Ionization

Non-ionized drugs cross more easily

Protein binding

Only free (unbound) drug can cross

Placental blood flow

Affects rate of transfer

Maternal-fetal concentration gradient

Drives passive diffusion

pKa of drug

Ion trapping may occur if fetal pH is more acidic


🔷 CLINICAL IMPLICATION: ION TRAPPING

  • Fetal acidosis causes ionization of weakly basic drugs (e.g., local anesthetics, opioids)
  • These drugs become trapped in fetal circulation
  • ↑ risk of fetal drug accumulation and toxicity


🔷 DRUG CLASSES & PLACENTAL TRANSFER

Drug Category

Crosses Placenta?

Remarks

Inhalational agents

Yes

Minimal fetal depression at MAC <1

IV anesthetics

Yes

Thiopentone crosses rapidly; propofol crosses, but short-acting

Opioids

Yes

Fentanyl, morphine cross; risk of neonatal respiratory depression

Benzodiazepines

Yes

Diazepam crosses readily; potential for neonatal sedation

Muscle relaxants

No

Quaternary structure prevents crossing

Local anesthetics

Yes

Bupivacaine, lignocaine cross placenta

Anticholinergics

Glycopyrrolate – No (does not cross) 

Atropine – Yes (crosses)


Antibiotics

Varies

Penicillin crosses; gentamicin crosses poorly

Vasopressors

Ephedrine – crosses (can cause fetal acidosis) 

Phenylephrine – minimal crossing


Antihypertensives

Labetalol – crosses 

Hydralazine – crosses 

Methyldopa – safe


Antiemetics

Metoclopramide, ondansetron – cross placenta but considered safe


Magnesium sulfate

Yes

Fetal exposure monitored; causes muscle weakness

Heparin

No

Does not cross; safe anticoagulant in pregnancy

Warfarin

Yes

Teratogenic (Category X)


🔷 SAFETY CLASSIFICATION OF DRUGS (FDA Pregnancy Categories – phased out but still used in older literature)

Category

Meaning

A

Controlled human studies show no risk

B

Animal studies show no risk; no human data

C

Animal studies show adverse effect; no adequate human studies

D

Evidence of human fetal risk, but benefit may outweigh risk

X

Contraindicated in pregnancy

⚠️ Now replaced by the FDA “Pregnancy and Lactation Labeling Rule (PLLR)” which includes risk summary, clinical considerations, and data.


🔷 EXAMPLES OF COMMONLY USED DRUGS & THEIR EFFECT ON FETUS

Drug

Effect

Thiopentone

Rapid fetal depression if high dose given during induction

Fentanyl

Neonatal respiratory depression (esp. in labor analgesia)

Bupivacaine

Crosses placenta; ion trapping in fetal acidosis may occur

Ketamine

Crosses; high doses may cause uterine tone increase and neonatal depression

Volatile agents

Uterine relaxation → can increase blood loss

Lidocaine

Crosses; seizures in fetus in maternal toxicity

Magnesium sulfate

Neonatal hypotonia, respiratory depression if toxic levels


🔷 ANESTHETIC IMPLICATIONS

✅ Preferred agents

  • Glycopyrrolate over atropine
  • Phenylephrine over ephedrine
  • Use low-dose, short-acting opioids
  • Avoid excessive benzodiazepines
  • Be cautious with local anesthetics – avoid toxicity

🛑 Avoid / Use with Caution

  • Long-acting opioids (morphine) before delivery
  • Diazepam (risk of hypotonia, sedation)
  • Ephedrine (risk of fetal acidosis)
  • High-dose ketamine (↑ uterine tone)


🔷 VIVA QUESTIONS

  1. Why doesn’t glycopyrrolate cross placenta?
  2. Which opioid causes least neonatal respiratory depression?


🔷 MCQ PEARLS

Question

Answer

Drug that does NOT cross placenta

Glycopyrrolate, heparin

Drug causing neonatal respiratory depression

Fentanyl, morphine

Best vasopressor in pregnancy (least fetal acidosis)

Phenylephrine

Example of ion trapping

Local anesthetics in fetal acidosis

Risk of benzodiazepines

Neonatal sedation, hypotonia


🔷 SUMMARY

The placenta is not an absolute barrier, and most anesthetic drugs do cross to some extent. The anesthesiologist must balance maternal benefit vs fetal safety, choose drugs with favorable pharmacokinetics, and understand conditions like ion trapping and placental blood flow alterations. Tailoring anesthetic techniques to minimize fetal exposure and optimize uteroplacental perfusion is key in obstetric practice.