ORIGINAL ARTICLE
Estimation of infant dose and exposure to pethidine and norpethidine via breast milk following patient-controlled epidural pethidine for analgesia post caesarean delivery

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Abstract

Background

There is no information about the distribution of pethidine into breast milk and/or exposure of the breastfed infant during pethidine patient-controlled epidural analgesia after caesarean delivery.

Methods

We conducted an observational study among 20 women. The mean (95% confidence interval) pethidine dose administered was 670 (346–818) mg over 41 (35–46) h. Maternal plasma and milk and neonatal plasma were collected near the time of pethidine cessation and 6 h later. Absolute and relative infant doses via milk and infant exposure were calculated. Infant behaviour was assessed using the Neurologic and Adaptive Capacity Score.

Results

At first and second sampling times, mean absolute infant doses for pethidine were 20 (14–27) μg/kg/day and 10 (7–13) μg/kg/day, while mean relative infant doses were 0.7 (0.1–1.4)% and 0.3 (0.1–0.5)% respectively. Similar values for norpethidine (expressed as pethidine equivalents) were 21 (16–26) μg/kg/day and 22 (12–32) μg/kg/day; and 0.7 (0.3–1)% and 0.6 (0.2–1)% respectively. Mean pethidine and norpethidine concentrations in neonatal plasma were 3 (0–6.1) μg/L and 0.6 (0.2–1) μg/L. Compared with a time-matched maternal sample, the infant’s exposure was 1.4 (0.2–2.8)% for pethidine and 0.4 (0.2–0.6)% for norpethidine. The mean (95% confidence interval) neurologic and adaptive capacity score was 33.6 (32.2–34.9).

Conclusion

The combined absolute infant dose of pethidine and norpethidine received via milk was 1.8% of the neonatal therapeutic dose and the combined relative infant dose was below the 10% recommended safety level. Breastfed infants are at low risk of drug exposure when mothers self-administer epidural pethidine after caesarean delivery.

Introduction

Pethidine is a μ-opioid receptor agonist with potent spinal and supraspinal effects.1 Its moderate lipophilicity makes it attractive for epidural administration, after which it provides rapid onset of analgesia and a very low risk of respiratory depression. In adults, pethidine has a short elimination half-life (mean 3.2 h).2 It is metabolised in the liver to pharmacologically active norpethidine, with a much longer half-life (15–40 h), which is then excreted via the kidneys.3 Norpethidine may accumulate after prolonged or high-dose pethidine administration or in renal failure and cause adverse central nervous system effects such as agitation, tremulousness, hallucinations and convulsions.3, 4, 5 Metabolism of pethidine is impaired in neonates and infants,6 and in two separate studies, its half-life was longer than in adults, with mean values of 10.7 h and 22.7 h.7, 8

Pethidine continues to be widely used in birth suites in Australasia and the United Kingdom for labour analgesia via the intramuscular (i.m.) route. The potentially harmful effects of parenteral pethidine in neonates were demonstrated approximately three decades ago.9, 10, 11, 12, 13, 14, 15 Breastfed infants of mothers who receive repeated post-caesarean doses of intravenous (i.v.) pethidine show diminished alertness on day 3–4 of life.16, 17 Pethidine excretion in breast milk following i.m. or i.v. administration postpartum has been investigated previously,18, 19, 20 and infant exposure to pethidine (relative infant dose) ranged from 0.6 to 6% of the weight-adjusted maternal dose. Only one study measured norpethidine in milk, with the metabolite contributing an additional estimated infant dose of 6%.20

Administration of pethidine early after caesarean delivery using patient-controlled epidural analgesia (PCEA) is efficacious, but significant maternal plasma concentrations of pethidine and norpethidine can be measured at the time therapy is ceased.21 Given that lactation commences around the same time, the primary aim of our study was to estimate the transfer of pethidine and norpethidine via breast milk following PCEA administration of pethidine to women post-caesarean delivery. We also measured pethidine and norpethidine in the exposed infant’s plasma (expressed as a percentage of the corresponding concentrations in the mother’s plasma), as a novel additional measure of drug exposure via milk.

Section snippets

Methods

This prospective observational study was approved by the Human Research and Ethics Committee of King Edward Memorial Hospital for Women and registered with the Australian and New Zealand Clinical Trials Registry. Twenty healthy women undergoing elective caesarean section were recruited at antenatal clinics and gave written informed consent to their own and their infants’ participation. The sample size was chosen based on our previous experience of sparse-sampling study design for drug studies

Results

The first woman in the study was transferred to another hospital for ongoing care and therefore only contributed the first samples of plasma and milk and neonatal plasma. Maternal and infant demographics are shown in Table 1. There were 9 male and 11 female neonates. Characteristics of the maternal pethidine dose, its relation to infant blood sampling and NACS administration, as well as NACS, are shown in Table 2. The median [IQR] pethidine dose of 670 [346–818] mg was delivered at a mean (95%

Discussion

The combined pethidine plus norpethidine milk RID estimates of 1.4% and 0.9% at our two separate sampling times compare favourably with the notional 10% cut-off value of acceptability that has been applied to a wide range of drugs,26 provided the drug effects on the infant are also acceptable.29 Our RID values are similar to the 1.3% that can be calculated using the highest pethidine concentration occurring after a 50-mg i.v. dose18 and lower than the 1.2–3.5% after 25–75-mg single i.v.

Acknowledgements

This study was funded by a grant from the Women and Infants Research Foundation of Western Australia. The corresponding author of this article has no affiliation with the funding body. The design and implementation of this original work were completely independent of the funding source.

References (36)

  • H.H. Szeto et al.

    Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer

    Ann Intern Med

    (1977)
  • R. Kaiko et al.

    Central nervous system excitatory effects of meperidine in cancer patients

    Ann Neurol

    (1983)
  • M.L. Pokela et al.

    Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants

    Clin Pharmacol Ther

    (1992)
  • P. Belfrage et al.

    Neonatal depression after obstetrical analgesia with pethidine: the role of the injection–delivery time interval and of the plasma concentrations of pethidine and norpethidine

    Acta Obstet Gynecol Scand

    (1981)
  • R. Hodgkinson et al.

    Double-blind comparison of the neurobehaviour of neonates following the administration of different doses of meperidine to the mother

    Can Anaesth Soc J

    (1978)
  • E.M. Belsey et al.

    The influence of maternal analgesia on neonatal behaviour. I. Pethidine

    BJOG

    (1981)
  • B.R. Kuhnert et al.

    Effects of low doses of meperidine on neonatal behavior

    Anesth Analg

    (1985)
  • E. Nissen et al.

    Effects of routinely given pethidine during labour on infants’ developing breastfeeding behaviour: effects of dose–delivery time interval and various concentrations of pethidine/norpethidine in cord plasma

    Acta Paediatr

    (1997)
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