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Anesthesia and the progress of labour

From the Department of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Address correspondence to: Dr. Scott Segal, Department of Anesthesia, CWN L1 Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115 USA. Phone: 617-732-8217; Fax: 617-732-6798; E-mail: bssegal{at}zeus.bwh.harvard.edu

IN 1847, only months after the first demonstration of anesthesia, James Simpson, an obstetrician, administered ether to a woman in labour for childbirth. He was quite impressed with the analgesia the new drug induced, as was his patient. However, his journal notes on the case indicated his concern over the possible adverse effects of anesthesia on labour and delivery:

"It will be necessary to ascertain anesthesia's precise effect, both upon the action of the uterus and on the assistant abdominal muscles; its influence, if any, upon the child; whether it has a tendency to hemorrhage or other complications" (Simpson 1871).

Thus began, more than a century and a half ago, one of the longest-lived controversies in the history of our specialty, one that continues to this day in both academic and lay circles: What is the effect of analgesia on the progress of labour and the mode of delivery? Since the introduction of regional analgesic techniques over a half-century ago, the rancor has if anything intensified. The debate unfortunately has often taken on a vituperative tone, in which obstetric anesthesiologists are blamed for self-servingly promoting a dangerous technique. Literally hundreds of papers have been published on this subject, including a handful of randomized trials in the last several years. Why, then, is the issue unsettled?

Methodological difficulties

1. The ideal clinical study is prospective, randomized, double-blind, and placebo controlled. No such study exists on the subject.
   
2. Retrospective studies are severely limited because of selection bias: women who self-select epidural analgesia are already more likely to develop dysto- cia and undergo cesarean delivery. These women are:
   • more frequently nulliparous
     
   • Come to the hospital earlier in labour, with higher fetal station
     
   • Have slower cervical dilation prior to analgesia
     
   • More frequently receive oxytocin, even before the block
     
   • Have larger babies
     
   • More frequently have other obstetrical and medical factors for operative delivery (poor fetal status, maternal systemic disease, obesity)
     
   • Have smaller pelvic outlets (Floberg 1987)
     
   • Have more pain, especially in the latent phase (Wuitchik 1997, Hess 2000)
     
   
   
3. Randomized trials have not completely answered these problems:
   • Placebo controls are practically impossible and probably unethical
     
   • Parenteral opioids are consistently inferior to epidural analgesia, so blinding is impossible
     
   • Mode of delivery is a subjective obstetrical decision, so blinding is important
     
   • Crossover between opioid and epidural groups may be problematic
     
   • If crossover does not occur, external validity (applicability to general labour and delivery popu- lation) may be minimal
     
   
   

Effects on the progress of labour

Initiation of the block: is it ever "too early"?

• Early case series implied early epidurals lengthened labour, but were uncontrolled (Siever 1944, Friedman 1959).
  
• More modern evidence differs: randomized trial (Philipsen 1989) found no difference between epidurals (placed as early as when cervical dilatation is 1 cm) and parenteral opioids. Two trials by Chestnut (1994) found no difference between early and later epidurals.
  
• ACOG and the ASA have jointly endorsed, and recently reiterated their belief that "maternal request is a sufficient medical indication for pain relief during labour. Pain management should be provided whenever medically indicated." They have also specifically condemned the practice of some 3^rd party payers of denying epidural analgesia to moth- ers without "medical indications" for pain relief (ACOG 2000).
  

Cervical dilation

• Early retrospective reports found longer, slower progress with epidurals, but with the bias noted above.
  
• Meta-analysis of ten randomized trials (Halpern 1998) found 42 min prolongation (about 8% of total first stage labour time) in epidural vs opioid patients
  

Mechanism

• Elusive and candidate hypotheses weak.
  
• Fluid loading prior to the block could cause reflex decrease in ADH, which in turn causes decreased oxytocin release (Cheek 1996)
  

Effects on second stage of labour

Mechanisms

• Inhibition of urge to push.
  
• Inhibition of ability to push (unlikely, since mater- nal expulsive efforts are Valsalva manoeuvres and are not impaired until high dense blocks are achieved [Johnson 1972])
  
• Ferguson reflex: distending the lower vagina causes oxytocin release in animals; epidurals could theo- retically block the afferent limb of this reflex. But oxytocin levels vary dramatically in labouring women, and the relationship between oxytocin lev- els and spontaneous delivery is weak (Amico 1984).
  
• However, routine oxytocin levels in the second stage do shorten it and reduce the need for forceps (Saunders 1989)
  
• Direct relaxation of the pelvic musculature. Unclear how important this is when modern dilute local anesthetic solutions are employed. However, evi- dence is clear that the pattern of fetal descent is altered in patients with epidural analgesia, and delaying maternal expulsive efforts for some time after full dilation does reduce the incidence of instrumental delivery (Goodfellow 1979, Maresh 1983).
  

Impact

• Duration of second stage is largely irrelevant in the era of electronic fetal monitoring. Halpern's (1998) meta-analysis of randomized trials found the second stage to be prolonged by 14 min in the epidural groups.
  
• Instrumental (forceps) delivery may very well be increased in patients with epidural analgesia, by up to two-fold (Halpern 1998). But there is tremen- dous variability between institutions and among obstetricians in these rates (from 0–80% in various studies), implying obstetrical practice style is prob- ably the dominant factor. Moreover, the presence of a comfortable patient with relaxed pelvic muscu- lature may lead to elective or semi-elective forceps deliveries in epidural patients, perhaps for teaching purposes (Bofill 1997).
  

Effect on the mode of delivery

This has become the issue in the debate in recent years, as epidural analgesia has become part of a larger discussion of the causes of the cesarean "epidemic" in the United States. Some insurers have even officially discouraged epidural analgesia as part of an initiative to reduce the rate of operative delivery. The evidence as of 2001 does not support this move.

Randomized trials of epidural analgesia vs parenteral opioids
Since the early 1990's several North American trials have appeared in which women were randomly assigned to receive epidural analgesia or iv or im opioids. Some have been deeply flawed.

Thorp et al. 1993. 93 nulliparous women in spontaneous labour were randomized to epidural bupivacaine or im meperidine. There was a 12-fold increase in cesarean section, as well as slower cervical dilation, longer 1st and 2nd stages, greater need for oxytocin, and more frequent malposition. The report generated a firestorm of controversy, including 11 letters to the editor and a response from Thorp exceeding the original article in length. Many criticisms have been levelled at the paper, including: lack of blinding, very low crossover from the meperidine group despite very poor pain scores, premature data analysis ("peeking" at the data before study completion), low doses of oxytocin, low use of forceps, and the 0% section rate in patients receiving epidural analgesia after 4 cm cervical dilation (not mentioned in the abstract or cited elsewhere).

Ramin et al. 1995. This group from Dallas' Parkland Hospital published another randomized trial of epidural analgesia vs iv meperidine. In the largest study performed to date, they randomized 1330 women of mixed parity to epidural bupivacaine and fentanyl or iv meperidine. These investigators, too, found higher rates of cesarean section (9% vs 4%) in the epidural group. A fatal methodological shortcoming of this paper, however, was the tremendous crossover between epidural and narcotic groups (about 1/3 of each group). The authors analysed their data for the protocol-compliant women only (by the treatment actually received, rather than on an intent-to-treat basis). Therefore patients essentially selected their own group, and the study becomes functionally a retrospective analysis with all the problems associated with such a design. Moreover, the patients excluded from the epidural group were often those who delivered too rapidly to receive an epidural (low risk patients); those excluded from the narcotic group were often those who demanded epidural analgesia because of slow painful labours (high risk patients). When analysed on an intent-to-treat basis, only total operative delivery (forceps and cesarean section combined) was increased in the epidural group.

Remarkably, the Parkland group has now acknowledged this shortcoming in print, and has published the rates of cesarean section, analysed on an intent-to-treat basis. The rates in both groups was 6% (Sharma and Leveno, 2000).

In 1997 the same group published a second report (Sharma et al. 1997) markedly better than their first effort. 715 patients were randomized to epidural bupivacaine/fentanyl or iv patient-controlled analgesia (PCA) with meperidine. When analysed on an intent-to-treat basis, there was no difference in the rate of cesarean section. There were fewer patients who demanded epidural analgesia in the PCA group, so that while almost 30% of each group did not receive their randomized treatment, it was generally due to rapid delivery with no analgesia. Even when analysed on a protocol-compliant basis, there was no difference in the incidence of cesarean section.

Recently, Bofill et al. (1997) published another randomized trial, of epidural bupivacaine and fentanyl vs iv butorphanol. When analysed on an intent-to-treat basis, there was no difference between the groups with regard to incidence of cesarean delivery (though the study is underpowered, given the low rates of cesarean section observed and the sample size of only 100). An apparent increase in the risk of forceps delivery was in fact due to an increase in forceps preformed for resident teaching (clearly more likely in the epidural group); the difference vanished when considering forceps performed for obstetrical indications.

Clark et al. (1998) reported a trial of 318 nulliparous women randomized to epidural bupivacaine/fentanyl vs iv meperidine. They found no difference in the risk of cesarean section, when analysed by either intent-to-treat or protocol-compliant methods.

Taken together, these five prospective, randomized trials and two others (one preliminary report (Muir 1996) and an older European trial (Philipsen 1989) represent the experience of nearly 2400 patients. Meta-analysis of these studies has found no difference in the risk of cesarean section between epidural or opioid analgesia groups.(Halpern 1998) Moreover, the results are unchanged when analysing only cesarean section for dystocia, or when analysing only nulliparous patients. A second meta-analysis, which included a quality rating for inclusion of the various studies, found virtually identically the same (Zhang et al., 1999). This latter study, from the NIH, also analysed the retrospective studies (which collectively found an increase in the rate of cesarean in patients with epidural analgesia) and concluded the difference was in fact due to selection bias.

A randomized trial of combined spinal-epidural analgesia with intrathecal sufentanil followed by epidural bupivacaine/fentanyl vs iv meperidine recently appeared (and was not included in the meta-analysis). This study, also by the Parkland Hospital group, found no difference in the rate of cesarean section between the groups, which persisted in the subgroup of nulliparous patients as well (Gambling 1998).

Several other randomized trials have recently appeared, and all confirm the growing body of evidence against an increased risk of cesarean section:

Loughnan (2000) reported a trial of 614 nulliparous women randomized to epidural bupivacaine (10 ml .25% + .125% 10–15/hr) or 100 mg IM meperidine prn, to a maximum of 300 mg. They utilized a standardized, active management of labour protocol for labour management and analysed their data on a intention-to-treat basis. The rates of cesarean section (epidural 12% vs opioid 13%) and instrumental vaginal delivery (epidural 29% vs opioid 26%) did not differ between the groups.

Howell (2001) randomized 369 primigravid women to epidural analgesia (intermittent doses of 0.25% bupivacaine) or im meperidine 50–100 mg PRN. As in many other past studies, approximately 1/3 of each group failed to receive the assigned treatment. When analysed on an intention-to-treat basis, however, there was no difference in the rate of cervical dilation or cesarean section (epidural 7%, opioid 9%). The authors did find a longer second stage (80.7 vs 62 min, P=.003) increased use of instrumental vaginal delivery (30% vs 19%, P=.03).

It is notable that the above-mentioned meta-analysis confirms some important differences between epidural analgesia and opioid analgesia. First, there were adverse effects on labour: fever > 38°C was five times more common in patients with epidural analgesia, hypotension occurred in nearly 40% of the epidural group but almost 0% in the opioid group, and oxytocin was required after analgesia nearly twice as frequently in the epidural group. Conversely, pain was much worse and dissatisfaction much more common in the opioid groups, and low one and five-minute Apgar scores, low umbilical cord pH, and need for naloxone treatment were all much more common among neonates born to mothers receiving opioid analgesia.

Other evidence
Some will still argue that the randomized trials only study women who are ambivalent about labour analgesia, and therefore not representative of the general labour and delivery population. Other approaches to this question have appeared, and also support the lack of an effect of epidural analgesia on cesarean section:

Several authors have reported the cesarean section rate in various institutions at the time of initiation of an on- demand epidural analgesia service (Gribble 1991, Lyon 1997, Fogel 1998, Yancey 1999, Impey 2000). Nearly all have reported stable or declining cesarean section rates despite sharply rising epidural analgesia utilization. The assumption of these "catastrophe theory" studies is that the patient population and obstetrical practice styles are likely to change little, or at least slowly, when compared to the sudden availability of epidural analgesia. Meta-analysis of 9 such studies of over 37,000 patients found no increase in cesarean rates with increased availability of epidural analgesia (Segal 2000).

Other investigators have reported variation in cesarean section rates between indigent patients and those with private health insurance, despite similar rates of epidural analgesia use (Neuhoff 1989, Cary 1990)

Still others have focussed on the variation in rates of cesarean section among obstetricians. Two studies have reported 50% decreases in hospital-wide cesarean rates by peer-review, physician education, and publishing individual obstetricians' rates of operation, while simultaneously doubling the rate of epidural analgesia usage (Iglesias 1992, Socol 1993). Another found no correlation between individual obstetricians' rates of cesarean section and the rates of epidural analgesia utilization among their patients (Segal 1999).

Conclusions

The last decade has seen a remarkable advance in our understanding of the effects of regional analgesia on the progress and outcome of labour. In particular, the appearance of several well conducted prospective, randomized trials have helped confirm the opinion of most anesthesiologists and a growing number of obstetricians, that epidural analgesia only minimally lengthens labour and does not increase the risk of cesarean section. But the extraordinary methodological complexities of studying this unblindable treatment in patients who are anything but ambivalent about whether or not they receive it ensures the debate will continue. It is perhaps time to move away from outcome studies and on to investigations of the putative mechanisms of any effects epidural analgesia may have on the labour and delivery process. It is also vital to place greater emphasis on the interaction between obstetrical practice, analgesic technique, and the patient. There may be important differences between subsets of patients with regard to their risk of cesarean section and the effect epidural analgesia may have on this risk. This is almost certainly true for certain obstetrical practices. Only by an appreciation of the actual physiology of epidural analgesia in the context of obstetrical care and the labour process itself will one of the longest running debates in anesthesiology come to an end.

Further reading

American College of Obstetricians and Gynecologists, Committee. Opinion #231, February 2000 (replaces #118, January 1993).

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