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Acute Pain | Chronic Pain | General

Intrathecal opioids and foetal bradycardia in labour

Clinical bottom line

Higher doses of intrathecal opioids are associated with increased rates of foetal bradycardia. About one foetus in 26 is affected by these changes who would not have been without intrathecal opioid..

Written September 2007


Background

Large numbers of women receive anaesthetic during labour each year, and intrathecal opioid analgesia involving direct injection of opioid into the cerebrospinal fluid is becoming more popular. The technique has advantages over injection of opioid into the epidural space, because uptake from the epidural space into fat and blood is rapid, and can lead to systemic as well as local opioid effects.

A problem with intrathecal opioids may be increased incidence of foetal bradycardia - slowing of the foetal heart rate, sometimes spontaneously, and sometimes after a contraction, which can lead to concerns about the foetus. Two forms are of particular concern, namely heart rate slowing to less than 100 bpm after a contraction (late decelerations), or frank bradycardia of less than 100 bpm.

A systematic review [1] and two large randomised trials [2,3] indicate that higher doses of intrathecal opioids do appear to be causally related to foetal bradycardia.

Systematic review

The systematic review prepared a comprehensive search to January 2001 for randomised trials reporting on the use of intrathecal opioids during labour and foetal bradycardia. The comparison was between any intrathecal opioid with or without local anaesthetic with any analgesic regimen that excluded intrathecal opioids.

The primary endpoint was the incidence of one or more episodes of foetal bradycardia occurring within one hour after the injection of study drugs and not related to maternal hypotension. Data on other endpoints were also collected.

The review found 24 trials with 3,500 women. The median trial size was 73 women, with a range from 24 to 1,008. The intrathecal opioids tested were sufenatnil, fentanyl, and morphine. The main results are in Table 1. The only significant difference was that foetal bradycardia was more frequent with intrathecal opioids (7.3%) than with control (4.8%) - with a relative risk of 1.8 (1.04 to 3.1). The absolute risk difference was 2.5%, and the number needed to harm was calculated as 28 (11 to 590).

Table 1: Main outcomes from systematic review of intrathecal opioids

Number of
Percent with
Outcome
Studies
Patients
IT opioid
Control
All foetal heart rate abnormalities
17
2081
7.7
6.7
Foetal bradycardia within 1 hour
9
927
7.3
4.8
C section for heart rate abnormality
8
1560
6.0
7.8
Apgar <7 at 5 min
11
1623
1.0
0.9

Randomised trials

The first randomised trial [2] set out specifically to test the effect of intrathecal opioid on nonreassuring foetal heart rate abnormalities. The trial was properly randomised, and properly blind, using both a double dummy technique of both epidural and intrathecal injections, and blind assessment of foetal heart rate by an experienced paediatrician. It tested three anaesthetic regimens:

The primary outcome was the occurrence of late foetal heart rate decelerations with foetal heart rate less than 100 bpm after a contraction, of bradycardia with a foetal heart rate less than 100 bpm for more than 90 seconds. Three hundred women were randomised.

The main result was that there was a significantly raised rate of nonreassuring foetal heart rate and uterine hyperactivity in women receiving 7.5 g intrathecal sufenatnil, but not those receiving a lower 1.5 g dose intrathecally, or epidural sufenatnil (Figure 1).

Figure 1: Main outcomes for three anaesthetic regimens

A second randomised trial [3] randomised 750 women to receive either 25 g intrathecal fentanyl or intravenous and intramuscular hydromorphone. The main outcome sought was cesarian section rate, but also reported was the rate of nonreassuring change of late decelerations in foetal heart rate (patterns that would lead to an obstetric intervention. These occurred significantly more frequently (15/362; 4.1%) after intrathecal opioid than after control (4/358; 1.1%).

Comment

Figure 2 pulls together all of the trials from the systematic review and subsequently. There is a consistent increase in the rate of foetal bradycardia with intrathecal opioids (7.8%; 78/995) compared with controls with other anaesthetic and analgesic regimens (4.0%; 34/850). In 1,1845 women the relative risk was 2.0 (1.4 to 3.0) and the number needed to harm was 26 (17 to 58). About one foetus in 26 is affected by these changes who would not have been without intrathecal opioid.

Figure 2: Individual RCTs reporting on intrathecal opioids and foetal bradycardia

There may well be issues of dose here, and the one trial that was designed specifically to test the hypothesis that intrathecal opioid is associated with foetal bradycardia had a low dose intrathecal opioid arm that did not show increased bradycardia (BES, Figure 1). There are many other issues not addressed here, not least whether intrathecal opioids is a sensible regimen for labour in the first place. Many anaesthetists consider it to be anathema: others think it the best thing since sliced bread. Partly it surrounds the importance given to foetal bradycardia.

What is interesting here is two things. First, a meta-analysis of randomised trials with only 945 women indicated that there may be an issue, though with bare statistical significance and a lower confidence interval of just 1.04. Two large trials doubled the numbers, but hardly changed the size of the effect. Second, a larger systematic review [4] also examined observational studies, which came to much the same conclusion.

What we have here is an object lesson in tracking down a reasonably uncommon adverse event, and causally linking it with a treatment. The absolute event rate was about 4%. It is easy to see just how difficult it would be if the absolute rate was 1%, or 0.1%.

References

  1. C Mardirosoff et al. Fetal bradycardia due to intrathecal opioids for labour analgesia: a systematic review. British Journal of Obstetrics and Gynaecology 2002 109: 274-281.
  2. M Van de Velde et al. Intrathecal sufenatnil and fetal heart rate abnormalities: a double-blind, double placebo-controlled trial comparing two forms of combined spinal epidural analgesia with epidural analgesia in labor. Anesthesia and Analgesia 2004 98: 1153-1159.
  3. CA Wong et al. The risk of Cesarian delivery with neuraxial analgesia given early versus late in labor. New England Journal of Medicine 2005 352:655-665.
  4. C Mardirosoff, MR Tramr. Intrathecal opioids in labour - do they increase the risk offetal bradycardia? In Evidence-based obstetric anesthesia. Eds SH Halpern & MJ Douglas; BMJ Books and Blackwell, 2005.