There are concerns that drugs administered to the mother may affect the new-born through placental transfer. In order to avoid the potential for neonatal depression, general anaesthesia is usually induced with thiopental and succinylcholine with maintenance of anaesthesia using nitrous oxide (N₂O) and low concentrations of inhalation agents. A single induction dose of thiopental rapidly redistributes and quickly appears in the umbilical venous blood after injection with a mean foeto/maternal (F/M) ratio of 0.4–1.1, which requires the introduction of volatile anaesthetic to prevent awareness. The latter may be associated with neonatal depression and uterine atony in a dose-dependent manner particularly when the induction-delivery (I-D) time interval exceeds 8 min. High lipid solubility and low molecular weight of volatile anaesthetics facilitate their rapid transfer across the placenta. When administered for caesarean section, N₂O results in F/M ratio of 0.83, isoflurane of 0.71 and sevoflurane of 0.31.¹ When placental transfer of different anaesthetic drugs were compared between different foetal perfusion states, lower placental transfer of drugs were observed during foetal hypoperfusion suggesting that the maintenance of volatile anaesthetics at a marginally low concentration may not be necessary when foetal distress is observed during emergency caesarean delivery because their placental transfer decreases with decreasing placental perfusion.² Propofol with a dose of 2–2.5 mg/kg allows rapid and smooth induction of anaesthesia when used for caesarean section. It readily crosses the placenta after both bolus induction and intravenous maintenance anaesthesia with F/M ratio between 0.65–0.85. Propofol plasma level in the neonate depends on the maternal dose and I-D interval. Higher bolus dosages >2.5 mg/kg were associated with depressed newborns, while lower doses 2 mg/kg did not induce neonatal depression as measured by Apgar scores and neurobehavioral scores.³ Although opioids are not drugs of choice in induction of general anaesthesia during caesarean section, fentanyl is administered in special cases potentially resulting in low Apgar scores and respiratory depression necessitating tracheal intubation of the newborn, as well as low neurobehavioral scores due to a potential accumulation in the breast milk. Muscle relaxants are fully ionised, quaternary ammonium salts, which do not rapidly cross the placenta; however, single doses of muscle relaxants can result in detectable foetal blood concentrations. After a standard induction dose, succinyholine is not detected in umbilical venous blood at deliver; doses larger than 300 mg are required before the drug can be detected. The administration of nondepolarizing muscle relaxants results in low F/M ratio, for instance, 0.16 for rocuronium.⁴

Meperidine injection used for labour analgesia results in rapid placental transfer of 90 sec. F/M ratio may exceed 1 after 2–3 hours. Maternal levels fall more rapidly than foetal levels because of the mother’s greater capacity to metabolise the drug. The same time interval is associated with the greatest likelihood of neonatal depression, in part because of the active metabolite normeperidine. As maternal levels fall, the meperidine and normeperidine will transfer from the foetus back to the mother, correlating well with the clinically observed decrease in neonatal sedation 4 hours after maternal administration.⁴

Remifentanil is an ultra-short acting systemic opioid with a fast onset of action (30–60 sec), peak analgesic effect of 2.5 min and a high metabolic rate (context-sensitive half-time 3–4 min) with no accumulation with a repeated or long-term use. Although it crosses the placenta, it is metabolised and redistributed quickly by the foetus. When remifentanil was used for patient controlled intravenous labour analgesia no adverse neonatal outcome was observed in a wide range of the doses.⁵ However, when remifentanil was used for induction of general anaesthesia for caesarean section, thoracic rigidity, negative effect on Apgar scores and neonatal ventilation were encountered pointing to the importance of providing enough time between remifentanil infusion stopping and cord clamping (at least 5–10 minutes) to allow the drug clearance from the foetal blood.⁶

Opioids used for epidural analgesia reach peak concentration in maternal plasma within 10–15 min. The highly lipofilic drugs such as fentanyl diffuse readily across the placental membrane in non-ionised and nonprotein bound forms approaching transplacental equilibrium in a single circulation. Despite that, the combined spinal epidural analgesia for labour using 0.1% bupivacaine with 2 µg fentanyl/ml epidurally for periods up to 15 h is unlikely to result in significant drug accumulation in either the mother or the neonate. On the contrary, after an epidural bolus of 150–200 µg fentanyl, respiratory depression needed resuscitation was observed in some neonates. Relative short acting local anaesthetic such as lignocaine, when given at a rate necessary to maintain epidural analgesia, can achieve plasma concentrations approaching the toxic range. Such drugs may therefore depress newborn neurobehavioural scores. This is not the case with bupivacaine which, in normal dose for caesarean section or labour, is not associated with maternal toxicity or adverse neonatal effects.⁷

In conclusion, the rate of the drug placental transfer is governed by the concentration gradient of the free nonionised drug and by the maternal and foetal placental blood flows, and it is influenced by pH gradient and the protein binding on either side of the placenta. However, additional caution should be taken with a repeated or long time use of the drugs.

References

1. Pournajafiana A, Rokhtabnak F, Kholdbarin A, Ghodrati M, Ghavam S. Comparison of remifentanil and fentanyl regarding hemodynamic changes due to endotracheal intubation in preeclamptic parturient candidate for cesarean delivery. Anesth Pain Med 2012;2:90–93.

2. Satoh D, Iwatsuki N, Naito M, Sato M, Hashimoto Y. Compariosn of the placental transfer of halothane, emflurane, sevoflurane, and isoflurane during caesarean section. J Anesth 1995;9:220–223.

3. Taiwan J. Obstet Gynecol 2017;56:521–526.

4. Chestnut DH, Wong CA, Tsen L, Ngan Kee W, Beilin Y, Mhyre JM. Chestnut’s obstetric anesthesia principles and practice 5th ed. Elsevier, Saunders, 2014.

5. Anesthesiology 1998;88(6):1467–1474.

6. Anesth Analg 2017;124(4):1029–1031.

7. Fernando R, Bonello E, Gill P, et al. Neonatal walfare and placental transfer of fentanyl and bupivacaine during ambulatory combined spinal epidural analgesia for labour. Anaesthesia 1997;52:517–524.